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Addition to a significant decrease in hepatic lipid accumulation in the IOE group, which inhibited energy intake by propionate enrichment, hepatic lipids were also significantly reduced in the mice in the IOP group, which was largely enriched with butyrate. Compared with the IOE group, IOP had a stronger regulatory effect on hepatic metabolism and triglyceride metabolism and higher levels of TCA cycle in the host. In addition, butyrate has the ability to promote browning of white adipose tissue (WAT) to brown adipose tissue (BAT).^[@ref39],[@ref40]^ WAT stores energy, whereas BAT uses energy for heating and consequently host energy expenditure increases.^[@ref41],[@ref42]^ However, adipose tissue weight does not change after WAT browning.^[@ref43]^ Therefore, the weight of adipose tissue of mice in the IOP group dominated by butyrate was greater than that of the mice in the IOE group dominated by propionate.

In conclusion ([Figure [7](#fig7){ref-type="fig"}](#fig7){ref-type="fig"}C), the improvement of obesity condition in mice by both *I. obliquus* extracts was attributed to their effects on gut microbiota and SCFA profiles. IOE increased the levels of propionate-producing bacteria *Bacteroides* and *Akkermansia* in the cecum of HFD-fed mice, resulting in the enrichment of propionate. Propionate reduced weight gain in mice by inhibiting energy intake. IOP increased the levels of butyrate-production-associated bacteria *Lactobacillus* and the *Bacteroidales* S24-7 group in the cecum of HFD-fed mice, resulting in the enrichment of butyrate. Butyrate increased energy consumption, TCA cycle levels, and degradation of carbohydrates and lipids in mice by promoting mitochondrial decoupling.

Conclusions {#sec4}
===========

IOE and IOP ameliorated HFD-induced obesity condition in mice through differential modulatory effects on gut microbial metabolism. Moreover, we found the connections between cecal butyrate (not propionate) and chemicals of mice, including four metabolites of the TCA cycle and other metabolism-related chemicals.

Materials and Methods {#sec5}
=====================

Preparation of IOE/IOP {#sec5.1}
----------------------

The dried and powdered *I. obliquus* (1.0 kg) was extracted with ultrapure water (30 L) at 90 °C for 3 h and concentrated. The supernatant was evaporated in vacuo at 45 °C, followed by extracting with 4 vol of ethanol to get crude extract. The extract was deproteinized by the Sevage method five times. The supernatant was dried in vacuo and lyophilized to get IOP (62.5 g). After *I. obliquus* was extracted with water, the residue was extracted with 80% ethanol at 80 °C in a water bath for 2 h. The supernatant was dried in vacuo and lyophilized to get IOE (30.9 g).

Animal Experimental Design {#sec5.2}
--------------------------

The experimental protocol was approved by the Animal Ethics Committee of Jilin University and complied with national laws. Five-week-old C57BL/6J male mice (15--17 g) were divided into four groups, 12 mice per group. The mice in the NCD group were fed with normal chow diet, and the mice in the HFD group, IOE group, and IOP group were fed with high-fat diet. The compositions of mice diets are presented in [Tables S4 and S5](http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01566/suppl_file/ao0c01566_si_001.pdf). The mice in the IOP group were gavaged with IOP at a dose of 1000 mg/kg per day according to previous studies,^[@ref44]^ and the mice in the IOE group were gavaged with IOE at a dose of 500 mg/kg per day according to the extraction rate of IOE/IOP and the dose of IOP. After 14 weeks of treatment, the mice were sacrificed for specimens.

Oral Glucose Tolerance Test (OGTT) {#sec5.3}
----------------------------------

OGTT was performed using a previously described method.^[@ref45]^

Serum Biochemical Analysis {#sec5.4}
--------------------------

Serum and liver lipid were measured using the method of kits obtained from Nanjing Jiancheng Bioengineering Institute (Nanjing, China).

RNA Preparation and Quantitative PCR Analysis {#sec5.5}
---------------------------------------------

The total RNA extraction and the reverse transcription (RT)-qPCR analysis of the gene expression were performed using a previously described method.^[@ref46]^ Primer sequences for the targeted mouse genes are shown in [Table S6](http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01566/suppl_file/ao0c01566_si_001.pdf).

Sample Collection {#sec5.6}
-----------------

Urine was collected using metabolic cages at 14th week, and 50 μL of sodium azide solution (0.1% w/w) was added into each urine sample. Cecum contents were washed from cecum in a 2 mL Eppendorf tube containing 1.0 mL of cold phosphate-buffered saline (PBS) (pH 7.4). All samples were then stored in a −80 °C freezer for later analysis.

All samples were thawed at room temperature. Serum was prepared by mixing 100 μL of each sample with a solution of 500 μL of PBS in D~2~O (containing 3-(tri-methyl-silyl) propionic-2,2,3,3-*d*4 acid sodium salt (TSP)). Then, 200 μL exudate of cecum contents was mixed with a solution of 400 μL of PBS in D~2~O (containing TSP). Supernatants (550 μL) were pipetted into NMR analysis tubes after centrifuging (15 000 rpm, 15 min, 4 °C) and passing through 0.22 μm membrane filters. For each urine sample, 400 μL of the sample was mixed with a solution of 200 μL of PBS in H~2~O. Then, 500 μL of supernatants was pipetted into NMR analysis tubes after centrifuging (15 000 rpm, 5 min, 4 °C), and 50 μL of D~2~O containing TSP was also added to each tube. D~2~O provided a field frequency lock and TSP a chemical shift reference (^1^H, δ 0.0).

NMR Data Acquisition and Processing {#sec5.7}
-----------------------------------

All samples were analyzed by an AVANCE III 600M MHz NMR spectrometer at 298.2 K. ^1^H NMR spectra were acquired by one-dimensional (1D) version CPMG (serum samples) and noesyphpr (urine and cecal samples) pulse sequence with water suppression during the relaxation delay of 3 s and a mixing time of 0.1 s. Sixty-four free induction decays were collected into 64 K data points with a spectral width of 7812.5 Hz (serum samples) and 8417.5 Hz (urine and cecal samples) and an acquisition time of 2 s. Free induction decay (FID) was zero-filled to 64 K prior to Fourier transformation.

Metabolite identifications were confirmed using the Human Metabolome Database (HMDB) and previous studies,^[@ref47]^ based on chemical shifts of hydrogen and peak multiplicity ([Figures S5--S7 and Table S7](http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01566/suppl_file/ao0c01566_si_001.pdf)).

All of the spectra were manually phased and baseline-corrected in software MestreNova 12.0 (Mestre-lab Research SL). Each spectrum was segmented into regions with a width of 0.005 ppm between δ 9.6 and 0.4. The δ 5.48--6.20 region in urine spectra and δ 4.72--5.20 region in all spectra were excluded to eliminate the effects of urea signals and water suppression. All remaining regions of the spectra were then normalized to the total sum of the integrated spectral area to reduce any significant concentration differences.

Sequencing, Diversity Analysis, and Function Prediction of Cecal Microbiota {#sec5.8}
---------------------------------------------------------------------------

DNA extraction, sequencing, and data processing were performed using a previously described method.^[@ref48]^

Four parameters of the alpha diversity were used to assess the overall diversity thoroughly. The Ace and Chao (only presence/absence of taxa considered) indexes determine the richness in a community, while the Shannon and Simpson indexes (additionally accounts for the number of times that each taxon was observed) determine the richness and/or evenness of a community. In addition, a higher Shannon index or a lower Simpson index indicates higher community diversity. Unlike alpha diversity, beta diversity was used to measure the division of diversity between two or more communities. Microbial communities had often been characterized using divergence-based measures of beta diversity to determine whether two or more communities were significantly different.

We used PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states) to perform functional predictions. PICRUSt generates metagenomic predictions from 16S rRNA data using annotations of sequenced genomes in the IMG database. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for functional classification.^[@ref49]^

Statistical Analysis {#sec5.9}
--------------------

The data were expressed as means ± standard errors of the means (SEM). One-way analysis of variance (ANOVA) was performed to identify significant differences among four groups, followed by the indicated post hoc test (lysergic acid diethylamide (LSD) comparison test). The results were considered statistically significant at *p*-value \< 0.05 unless otherwise specified in the figures. *P*-value between two independent groups was analyzed using an unpaired two-tailed *t*-test. Metabolomics data were subjected to OPLS-DA using software SIMCA 14.0 (Umetrics, Sweden) and used to construct multivariate statistical models. Bivariate correlations were calculated using Spearman's *r* coefficients. Heatmaps were constructed using Excel 2016.

Accession Number {#sec5.10}
----------------

High-throughput sequencing data have been submitted to the NCBI Sequence Read Archive (SRA) under the accession number PRJNA576716.

The Supporting Information is available free of charge at [https://pubs.acs.org/doi/10.1021/acsomega.0c01566](https://pubs.acs.org/doi/10.1021/acsomega.0c01566?goto=supporting-info).3D score plots of the OPLS-DA classification; VIP plot of OPLS-DA; pathway analysis based on different metabolites; effects of IOE/IOP on gut microbial diversity; ^1^H NMR spectra of mice serum, urine, and cecal contents (Figures S1--S7); main metabolites of serum, urine, and cecum contents; compositions of NCD and HFD; primer sequence for amplification of the fragments; and metabolite identifications (Tables S1--S7) ([PDF](http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01566/suppl_file/ao0c01566_si_001.pdf))

Supplementary Material
======================

######

ao0c01566_si_001.pdf

Conceptualization, J.Y., H.X., and Q.X.; investigation, J.Y.; supervision and resources, H.X. and Q.X.; Writing-original draft, J.Y. and J.-Y.X.

The authors declare no competing financial interest.

This work was supported by the Jilin Province Science and Technology Institute of China (No. 20180201078YY).

: total cholesterol

: triglycerides

HDL

: high-density lipoprotein cholesterol

LDL

: low-density lipoprotein cholesterol

TSP

: 3-(tri-methyl-silyl) propionic-2, 2, 3, 3-*d*4 acid sodium salt

PBS

: phosphate-buffered saline

Chrebp

: carbohydrate-responsive element binding protein

: glucokinase

: pyruvate kinase

PEPCK

: phosphoenolpyruvate carboxykinase

: pyruvate carboxylase

FBPase

: fructose-1,6-bisphosphatase

G6Pase

: glucose-6-phosphatase

Ppar-γ

: peroxisome proliferator-activated recepto γ

Srebp1c

: sterol regulatory element binding protein-1c

Fas

: fatty acid synthase

Acl

: ATP-citrate lyase

Scd1

: stearoyl-CoA desaturase 1

Acc

: acetyl-CoA carboxylase

Acox

: acyl-CoA oxidase

Ppar-α

: peroxisome proliferator-activated recepto α

Cpt1

: carnitine palmitoyltransferase I

Mcad

: medium-chain acyl-CoA dehydrogenase

Dgat1

: diacylglycerol acyltransferase 1

Dgat2

: diacylglycerol acyltransferase 2

Gpat

: glycerol-3-phosphate acyltransferase

VIP

: variable importance of projection

OPLS-DA

: orthogonal partial least-squares discriminant analysis

CoA

: coenzyme A

SCFA

: short-chain fatty acids

Description

Foreign trailer for Gokusen.

After seven years of enduring popularity on television, Gokusen, finally makes its silver screen debut. Winning over the hearts of millions of viewers and becoming a national heroine, Yukie Nakama reprises her role as Kumiko Yamaguchi, a.k.a Yankumi. Wearing jerseys, glasses and pigtails, the dowdy high school instructor becomes the homeroom teacher for the wild delinquents of Class 3D. At first glance, Kumiko seems like she can be easily intimidated, but much to everyone's surprise, she remains unfazed by her students' shenanigans. Her courage and discipline comes from being raised by a family who also happens to be a feared yakuza clan. With her strong sense of justice and her fierce brawling abilities, Kumiko follows her principles and upholds honor to solve the problems that trouble her students.
---
abstract: |
We design a new, fast algorithm for agnostically learning univariate probability distributions whose densities are well approximated by piecewise polynomial functions. Let $f$ be the density function of an arbitrary univariate distribution, and suppose that $f$ is $\OPT$ close in $L_1$-distance to an unknown piecewise polynomial function with $t$ interval pieces and degree $\pdeg$. Our algorithm draws $n = O(t(\pdeg+1)/\eps^2)$ samples from $f$, runs in time $\Otilde (n \cdot \poly (\pdeg))$, and with probability at least $9/10$ outputs an $O(t)$-piecewise degree-$\pdeg$ hypothesis $h$ that is $4 \cdot \OPT +\eps$ close to $f$.

Our general algorithm yields (nearly) sample-optimal and [*nearly-linear time*]{} estimators for a wide range of structured distribution families over both continuous and discrete domains in a unified way. For most of our applications, these are the [*first*]{} sample-optimal and nearly-linear time estimators in the literature. As a consequence, our work resolves the sample and computational complexities of a broad class of inference tasks via a single “meta-algorithm”. Moreover, we experimentally demonstrate that our algorithm performs very well in practice.

Our algorithm consists of three “levels”: (i) At the top level, we employ an iterative greedy algorithm for finding a good partition of the real line into the pieces of a piecewise polynomial. (ii) For each piece, we show that the sub-problem of finding a good polynomial fit on the current interval can be solved efficiently with a separation oracle method. (iii) We reduce the task of finding a separating hyperplane to a combinatorial problem and give an efficient algorithm for this problem. Combining these three procedures gives a density estimation algorithm with the claimed guarantees.
author:
- |
Jayadev Acharya[^1]\
EECS, MIT\
- |
Ilias Diakonikolas[^2]\
Informatics, U. of Edinburgh\
- |
Jerry Li[^3]\
EECS, MIT\
- |
Ludwig Schmidt[^4]\
EECS, MIT\
bibliography:
- 'allrefs.bib'
title: 'Sample-Optimal Density Estimation in Nearly-Linear Time'
---

Appendix {#appendix .unnumbered}
========

[^1]: Supported by a grant from the MIT-Shell Energy Initiative.

[^2]: Supported by a Marie Curie CIG, EPSRC grant EP/L021749/1 and a SICSA grant.

[^3]: Supported by NSF grant CCF-1217921 and DOE grant DE-SC0008923.

[^4]: Supported by MADALGO and a grant from the MIT-Shell Energy Initiative.

Extra-anatomic aortic bypass for complex (re-) coarctation and hypoplastic aortic arch in adolescents and adults.
Various surgical approaches have been proposed for complex (re-) coarctation and aortic arch hypoplasia (AAH). We report seven patients (mean age 19.6+/-9.5 years) with complex coarctation or re-coarctation and AAH successfully treated by extra-anatomic ascending-to-descending aortic bypass (ADB) via sternotomy between 1995 and 2002 without mortality and no relevant complication early postoperatively and during a follow-up of 24+/-29 (0.2-84) months. ADB may therefore be considered in selected patients with (re-) coarctation with AAH, with the need for concomitant ascending aortic or cardiac surgery and in patients with aortic arch stenosis and increased risk of complications under DHCA.
This invention generally relates to the formation of gas tight pressure blocks in multiple wire or conductor electric cables such as telephone cables to enable air pressurization of sections of such cables. In particular, this invention is useful in maintaining fluid pressure in the pressure block forming compound during multiple injections at a single site on a cable during in-field service or installation.
U.S. Pat. No. 3,823,250, the disclosure of which is incorporated herein by reference, discloses a tap fitting suitable for use with the valve hereinafter described. Briefly, the tap fitting comprises a curved base sheet for placement over an opening cut in the sheath of the cable and an injection port integrally formed with and projecting from the sheet, the port including means for forming a pressure tight covering, such as threads about the mouth of the port.
As is well known in the art, air pressurization of sections of electric and telephone cables prevents the seepage of water or moisture into the cable and the resulting noise and interference in communication and power circuits. Pressure blocks forming dams at intermittent points over the length of the cables are provided by injecting a self-setting liquid compound which hardens and fills the space around the wires over a sufficient length to hold the air pressure. To form such a pressure block it is necessary to make an opening in the cable sheathing leading to the interior and then to provide and exteriorly positioned fitting through which the liquid block forming compound may be injected. To accomplish this, a fluid injector is used. Typically the fluid injector comprises a chamber containing a discrete amount of block forming compound, a pressurizing plunger operative in the chamber, and a nozzle in fluid communication with the chamber through which the fluid is ejected in response to the compression movement of the plunger operating on the compound. The fluid compound is injected into the interior of the cable by threading the nozzle of the fluid injector to the tap fitting and compressing the plunger.
Where a large amount of compound is needed to fill the cable interior to the desired extent, i.e., more than the amount normally contained within the injector chamber, the continuous injection operation must be interrupted so that the injector chamber can be refilled or recharged. To recharge the fluid injector in the midst of the injection operation, the pressure on the plunger of the fluid injector is released and the plunger is withdrawn to permit access to the injector chamber for refilling with the compound.
Recharging in the midst of the cable filling for block forming operation presents a number of drawbacks. Due to residual pressure in the cable, some of the liquid compound escapes through the tap fitting and pressure interior of the cable is normally lost. To overcome these problems, stop valves have been devised to be interposed between the fluid injector and the cable interior. Such stop valves permit injection of fluid through a fitting into the cable interior while opposing the escape of the pressurized fluid compound therefrom. The 3M Company of Minneapolis, Minn., for example, markets a resin pressure splicing system under the trademark "SCOTCHCAST Brand R.P.S." The 3M system includes a one-way valve that opens to permit the injection of the blocking compound and closes under the residual back pressure to prevent the escape of the blocking compound.
Such prior art valves have considerable drawbacks, particularly where the nozzle of the fluid injector is adapted to sealably couple with a conduit (which includes the valve) into the cable interior. For example, due to the pressure seal between the injection nozzle and the valve, it is difficult to release the plunger of the fluid injector, since any attempt to do so creates a vacuum in the interior of the fluid injector. This makes it difficult to recharge the fluid injector while it is in place on the tap fitting.
/*
* Copyright 2000-2009 JetBrains s.r.o.
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/

package com.intellij.refactoring.safeDelete.usageInfo;

import com.intellij.util.IncorrectOperationException;

/**
* @author yole
*/
public interface SafeDeleteCustomUsageInfo {
void performRefactoring() throws IncorrectOperationException;
}

Why isn't climate change keeping more Senators up tonight?

All-nighters are usually the result of not doing your homework, but this evening twenty-eight United States senators will be up for pretty much the opposite reason. Having read the latest science on climate change, they will be making speeches through the night to call for comprehensive action to meet this threat.

It’s an unusual tactic, but the real question isn’t why are twenty-eight of them talking all night, but why the other seventy-two senators are sleeping when we’re facing such a serious challenge. All the major American scientific organization have been warning us about the reality and seriousness of climate change for years. And while it may be happening slowly, that won’t make it any less expensive or devastating. If taxpayers liked paying for damage from Hurricane Sandy, or the droughts and wildfires in the West and Midwest, they’re going to have a ball as the impacts get stronger in the years to come.

So why are the Sleeping 72 ignoring this severe threat to our economy and our environment?

It’s not that endorsing the science of climate change is unpopular in this country. 69% of Americans believe there is “solid evidence” the climate is changing (Pew, 2013). But as is almost always the case, members of Congress care a lot less about what Americans in general think than about what the voters of their state or district think. Even more specifically, that means being wary about taking position that might alienate the core supporters of your party, or ‘gettable’ moderates.

As a result, many House members from solidly conservative districts, and Senators from swing states, are afraid to step out on an issue like climate change. Never mind that prudent action now will save their constituents money in the long run, and protect future generations from devastating storms, droughts, and health effects. If the politics look worrisome, they’d rather get a good night’s sleep tonight.

But the funny thing about politics is that we often get it wrong. Like in sports, sometimes the worst thing you can do is play not to lose – avoid risks to nurse a lead, hoping it will hold up. Clearly, there are a lot incumbents who have calculated that denying the obvious truth of climate science will protect them from unnecessary political risk. But, in the long run, that could be a losing political strategy. 80% of voters under 35 want action to address climate change. More importantly to politicians who are afraid of the issue, 56% of younger voters who don’tgenerally approveof President Obama’s job performance support action (GS Strategy Group, Benenson Strategy Group, 2013). And it’s not just the long run. Even in 2014, before that demographic wave washes over us, signalling a sensible position on climate change (it’s real, we should act prudently) is a great way to signal moderation to swing voters.

Senators, of course, know the politics of their states much better than most of us outside observers. But most of them also know they got their jobs by, at some point, upsetting the status quo – beating an incumbent, surprising a front-runner, grabbing a forgotten issue and rallying the public. In business and in politics, new ideas are disruptive. If the Sleeping 72 want to avoid becoming the Kodak or Blockbuster of politics, they’d better wake up to the threat of climate change.

Keith Gaby

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Comments

Michael Ashley

March 10, 2014at 7:22 pm (ET)

If people would pay attention to the fact that politicians follow the money not the voters they might see that this is the best time to start a green socialist/ capitalist party ( I know - it's a fantasy )

Vivian Tisevich

March 10, 2014at 9:17 pm (ET)

Hmm, wondering why Ohio isn't being represented tonight? Unless I missed seeing Senator Brown and Sen. Portman's name, and if so, I apologize. I realize there are many other issues of concern to keep my reps busy, such as working to amend the Indian Child Welfare Act, that I contacted them about today, but c'mon, is climate or the abduction of children off reservations even on their top ten list? It matters to me, even tho I'm just a little ole voting gal in Ohio. When we know better, we do better. Those of you there tonight made the choice to do better. thank You!

By the time the really obvious effects of climate change show, most of these senators will be out of office or died of old age. The extreme weather we experience now is easy to brush off as natural variation, and no one can say storm x was caused by climate change. It is hard for any person, especially senators to react to something unless it is staring them in the face. By the time it is staring us in the face it will be too late. The world will not end, but it will be forever changed.
Training for a major sports event is never easy, be it for the first 5km run or the fifth ultra-marathon, but Tinké is here to the rescue! Follow the journey of Chris Small and James Rotheram, two first-time Tinké users, as they make use of this nifty device to get their body prepared for their ascent up Mount Kinabalu.

Preparing for this big event should be no different from preparing for any other significant occasion in your life. Physical and mental preparation is important to ensure that you can perform at your peak during the event itself. The Tinké then helps keep track of your fitness and wellness levels, to ensure that you deliver your best performance.

Tinké interprets your fitness and stress indices through the measurement of your heart rate, respiratory rate, blood oxygen saturation and heart rate variability. The Zensorium application and dashboard then stores the readings and tracks the progress over time.

“James and I haven’t done some tracking in awhile, and he came up with this idea. And so, we’re going to climb Mount Kinabalu together,” said 28-year-old Chris Small.

“And the Tinké is good for that (Helping to prepare for the climb),” added 35-year-old James Rotheram.

Getting started, the duo decided to try out a hypoxia chamber to see how their body would fare under external conditions, similar to what they would face on their climb up Mount Kinabalu. After doing some simple exercises, Chris was shocked to see that his Vita reading was only 47/99.

“A sense of a reality check, I wasn’t as healthy as I thought I was,” said Chris.

The duo knew that they had to improve their health, fitness and stamina, and fast. As part of their preparation, both friends practiced yoga for mind and body relaxation, two weeks prior to the climb.

“Everywhere we’ve come on this project, everyone has said we need to improve our breathing. And yoga is really a good way of doing that,” mentioned James.

As a trial run, the duo trekked up Bukit Timah hill two days before their Mount Kinabalu climb.

On the day of the climb itself, while both James and Chris were satisfied with how they have progressed over the previous month, it remains uncertain if they would be able to complete the hike up Mount Kinabalu. Chris appeared fitter than James, and James was concerned if he would become a liability for Chris.

“I think now we are in a better place than we were before. We’ve spent two weeks of training, prepared all the gear that we need, we’ve done our yoga, we’ve worked on our breathing, and in relaxing ourselves and our bodies, and we’ve done a lot of physical training. I think after all that, we are more prepared than we initially were. On Tinké, my scores are pretty good,” said Chris.

“My score this morning wasn’t brilliant on Tinké, but that’s not telling how my body feels, but we need to get hiking to see how the body reacts,” remarked a concerned James.

While the ascend itself was a daunting experience, both friends pulled through and made it to the top, being possibly at the highest point one could ever be in South East Asia.

“This was tough. This was really tough. Am I built for it? Maybe now? But a month ago and doing our training? No. All this played a role and helped me get ready for this climb,” said Chris.

Using Tinké for a month, Chris and James were able to improve their Vita and Zen indices, to successfully conquer Mount Kinabalu. The journey itself will not be easy, but training with Tinké can make the process a whole lot simpler.

Recommended articles:

Zensorium | 5 Simple Back-to-Basics Workout

Zensorium | 5 Ways to be a better runner

Zensorium | Why is running good for you?

Zensorium, the makers of Tinké and Being.
Pros:

Cons:

The Worms series of games have always been a bit off-kilter. In its initial incarnation as a time-sensitive 2D turn-based strategy game, Worms pitted cute little animated earth-munchers against one another with a vast arsenal of weapons and power-ups amid bright, colorful environments that got blown to bits in the process. As fans eagerly anticipate the first 3D incarnation of the series next year, Team 17 have created an unusual spin-off to keep us quite busy and amused: the rather addictive and hyperactive combat puzzle game, Worms Blast.

Bust-A-Worm?

Although Blast has the look of a Worms game, the gameplay is totally different. It's more like the puzzle-flavored Bust-a-Move, which involves shooting bubbles at puzzle pieces falling from the sky. In this game, you control a little boat-bound character armed with a bazooka that fires color-coded missiles. You can move left and right, tilt the cannon up and down to alter your trajectory, and collect other weapons and power-up crates, released by destroying puzzle pieces with a missile of the same color.

Since your character is in a boat, you also have to contend with rising tides, torrential weather conditions, sea monsters, and other hazards of the deep zooming around as you fight for survival. In most of the challenges, puzzle pieces gradually descend towards the water regardless of whether or not you shoot at them, so it's important to keep clearing the puzzle pieces lest you get pushed underwater. In addition, rising tides must be quelled by gathering falling stars, which are also among the puzzle pieces. If your aim is terribly off, and you hit nothing at all, cartoon items such as anvils, refrigerators, and cannonballs will fall from the sky, geared towards bonking you on the head and damaging your health. It's a far cry from the whole "you-take-a-turn, I-take-a-turn" format of the original games.

Worms Blast offers a number of gameplay modes. There are numerous full-screen challenges where you face the puzzles alone, as well as a number of head-to-head modes where you play via split screen against another person or the CPU. It's a good idea to play through some of the single-player challenges first -- they serve as a sort of boot camp, where you'll learn all the basics of puzzle combat (as odd as that may sound). As you progress in these single-player missions, you'll occasionally unlock new modes.

In one challenge, you've got six missiles and six tough-to-hit targets, but all the time in the world to hit them. In another, UFOs (composed of puzzle pieces) zoom towards the water and you've got to hit as many as possible directly in the belly before the timer runs out. Another challenge involves hitting rapidly descending targets on alternate sides of the screen in quick succession, adding a couple of seconds to the timer with each successful shot. There are simply too many variations in each mode to catalog here, which is a good thing. Some of the challenges are frustrating, but they're considerably varied and ultimately rewarding.

Timed target shooting is one of many intense challenges you'll face in puzzle mode.

Your progress in the main puzzle mode gets saved along the way, so once you pass a really tough challenge, you have the option of never looking back. You can also return to a challenge you enjoyed, or continue the remaining challenges with any character of your choice. The characters (which oddly enough, aren't limited to worms) have varying thresholds for damage, and their boats vary in terms of size and speed. There's also a tournament mode, in which you've got to survive for as long as possible during specific challenges, most of which are subtle variations of the ones introduced in the puzzle mode.
Q:

как передать json на сервер

Здравствуйте, у меня есть 2 json объекта, находящиеся в javascript. Каким образом мне хранить их на сервере, файлами или в запросе передавать? Пожалуйста, с примерами кода.
Бэкэнд на ASP.NET 4.5

На клиенте конвертировать его в string:
myStringObj = JSON.stringify(myObj);

Дальше отправить его любым способом на сервер (xhr, form submit);
Процесс здесь
А как хранить вам виднее, либо база данных, либо статичный json, зависит от того что делаете

Category: Console

We all know that Microsoft is working on a certain project called the Project Scorpio and that it’s just the next generation of the Xbox console. It was back in 2016, Microsoft had announced at the E3 about their next project codenamed Project Scorpio. Back then they announced that the console is set to be rolled out in 2017. It’s already 2017, and we haven’t heard anything much about the release date of the Xbox 2 until now. There are fresh rumors surrounding the Xbox Scorpio release date, and we are going to discuss it in this post.

The current console the Xbox One has been launched back on November 22, 2013, in the US and clearly ended up winning hearts of people. So Xbox fans really got excited when they first heard of the project. But the only question that has been on people’s minds had been that when exactly does Microsoft plan to launch their products. Of course, they said the Xbox 2 Release Date in 2017 but we are already halfway through the year, already five months into the year and there is no real confirmation. Fans have been wondering is if the release date has been postponed to which we now have an answer.

The new rumor is basically good news for fans who can pretty much hope to pick up the console this Christmas. This is just the sort of news we had been waiting for since the time the project was announced. This is the rumor that has emerged right before the 2017 E3 gaming expo. And the best fact is that the news comes from none other than the Xbox boss Phil Spencer, who when asked on Twitter is there is a change in the Xbox 2 release date, replied saying this: “Schedule looks very good right now, no issues.” This is what has prompted fans and tech gurus to believe that the console will be coming out in the second of the year and the most convenient time is the holiday season of Christmas, which is a great time to send your product sales soaring.

We are expecting that Microsoft will announce the date of the release at the E3 gaming expo and there are expectations that they might also end up revealing the price of the console so that people are pretty much equipped to handle the pocket burn when Xbox 2 actually hits the market shelves.

There are a lot of talks going on surrounding the Xbox 2 and a lot of rumors as to what new things that console will be bringing on the table. There are reports that there’ll be Voice Control Settings which will make the console a serious winner in the gaming industry. People expect the console to come with everything that the new and advanced technology has to offer in this modern day time. There are also talks that the Xbox 2 will be featuring custom game specific controllers that’ll be great, to say the least. And folks, this is all that we know about the upcoming console, but there is no official confirmation regarding these, so you should really take these rumors with a pinch of salt.
Katabexin, Medichrom

The drug brand named Katabexin contains generic salt-Betahistine Hydrochloride and is manufactured by Medichrom.Katabexin is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- N07CA01-Betahistine.

Generic Salts

Betahistine Hydrochloride

Available types of drugs

N / A

Medical categories

Human DrugAntivertigo drugs

Usage-Diseases

N07CA01-BetahistineManufacturers

Medichrom

More Drugs

The drug brand named Kasmucol contains generic salt-Acebrophylline and is manufactured by Teva.Kasmucol is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- ATC.

Generic Salts

The drug brand named Kas contains generic salt-Preparation for Enteral Nutrition and is manufactured by Nutricia-Bago.Kas is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- ATC.

Ge...

The drug brand named Kastair EZ contains generic salt-Montelukast Sodium and is manufactured by Pediatrica.Kastair EZ is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- R03DC03-Montelukast.

The drug brand named Kast contains generic salt-Montelukast and is manufactured by RND Laboratories.Kast is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- R03DC03-Montelukast.

Gen...

The drug brand named Kastorion contains generic salt-Montelukast Sodium and is manufactured by OEP Philippines.Kastorion is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- R03DC03-Montelukas...

The drug brand named Katabios contains generic salt-Multivitamins and is manufactured by Specialita Igienico Terapeutiche.Katabios is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- A11BA-Mu...

The drug brand named Katagrip contains generic salt-Acetaminophen and is manufactured by Angelini.Katagrip is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- ATC.

Generic Salts

The drug brand named Katapekt contains generic salt-Ammonium Chloride and is manufactured by Vitabalans.Katapekt is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- N02AA59-Codeine, combinati...

The drug brand named Katar contains generic salt-Corynebacterium Pseudodiphtheriae and is manufactured by Istituto Sieroterapico Berna.Katar is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)-...

The drug brand named Katasuccin contains generic salt-Succinic Acid and is manufactured by Unidentified Pharmaceutical Company.Katasuccin is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- A...

The drug brand named Katen contains generic salt-Mexiletine Hydrochloride and is manufactured by Zentiva.Katen is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- C01BB02-Mexiletine.

The drug brand named Kathro contains generic salt-Cholesterol and is manufactured by Unidentified Pharmaceutical Company.Kathro is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- ATC....

The drug brand named Katin contains generic salt-Bile Salts and is manufactured by Instituto Sanitas.Katin is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- ATC.

Generic Salts

The drug brand named Kativ N contains generic salt-Vitamin K1 (Phytonadione) and is manufactured by Unidentified Pharmaceutical Company.Kativ N is mainly associated with symptoms and indications-The International Classification of Diseases (IC...

The drug brand named Katogel contains generic salt-Emollient and is manufactured by Deverge Medicina e Medicalizzazione.Katogel is mainly associated with symptoms and indications-The International Classification of Diseases (ICD)- D02AX-Other...
The present disclosure relates to computer systems, and in particular to managing file access to applications that are deployed in a virtualized computer environment.
Virtualized computer environments, which may include cloud computing systems, composite information technology systems and computer cluster systems, are used to provide computer resources or other computing resources to end users. In a cloud computing environment, the physical hardware configuration is hidden from the end user. Cloud computing systems may include servers, network storage devices, routers, gateways, communication links, software (e.g., applications, operating systems, web services, etc.), and other devices. However, because the physical hardware and software platforms on which cloud computing system is implemented are hidden within a “cloud,” they can be managed, upgraded, replaced or otherwise changed by a system administrator without the customer being aware of or affected by the change.
A computer cluster, also referred to as a cluster, may be considered as a type of cloud computing environment and may include a set of loosely connected computers that may be connected to one another via local networks.
In a typical cloud computing environment, applications may be executed on virtual machines or appliances, which are guest operating systems installed within a host system and an optional preset configuration and structure (e.g., combination of operating system and web server). Virtual Machines are typically implemented with either software emulation or hardware virtualization, or both. A single hardware and/or software platform may host a number of virtual machines, each of which may have access to some portion of the platform's resources, such as processing resources, storage resources, etc.
Because different applications that are deployed in a cloud computing environment may require access to files, such files may not be consistent among the different applications and/or instances of applications unless a shared location is provided, which may impose unwanted additional complexity to the installation and maintenance of the application. Additionally, unexpected outcomes may occur in the event that two different applications and/or instances of applications access the same file in an overlapping time period. Yet further, synchronization of files used by more than one application and/or instance may be problematic in a cloud computing environment.
Q:

Insert a row with default value column in sqlalchemy

I am writing a program which uses a database with sqlalchemy as client.
Here is one of my tables
class DownloadRecord(Base):
__tablename__ = "DownloadRecords"
id = Column("Id", Integer, primary_key=True, autoincrement=True)

download_name = Column("DownloadName", Unicode, nullable=False)
download_date = Column(
"DownloadDate", DateTime, default=datetime.datetime.utcnow, nullable=False
)

the column download_date is defined with a default value, both here and in the server side table. Here is the definition of the column on the mssql server
DownloadDate DATETIME NOT NULL DEFAULT GETDATE()

however I try to add the record DownloadRecord(download_name="new_download_name") and I get the following exception.

sqlalchemy.exc.IntegrityError: (pyodbc.IntegrityError) ('23000',
"[23000] [Microsoft][SQL Server Native Client 11.0][SQL Server]Cannot
insert the value NULL into column 'DownloadDate', table
'DownloadRecords'; column does not allow nulls. INSERT fails. (515)
(SQLExecDirectW); [23000] [Microsoft][SQL Server Native Client
11.0][SQL Server]The statement has been terminated. (3621)") [SQL: INSERT INTO [DownloadRecords] ([DownloadName], [DownloadDate]) OUTPUT
inserted.[Id] VALUES (?, ?)] [parameters: ("new_download_name", None)]

I also tried to make this column nullable but When I added the new row the DownloadDate column was Null.
How do I make it automatically use the default value?

The problem is incompatibility between the type of the column DownloadDate and the type of the value you give as its default value on the client side.
The type you used is DateTime (on the server side as well as the client side).
However, in the following code:
Column("DownloadDate", DateTime, default=datetime.datetime.utcnow, nullable=False)

the return value of datetime.datetime.utcnow() is a timezone aware object, while SQL Server's DateTime isn't.
I see two possible solutions:

Change the default value to a callable which returns a datetime object which is not timezone aware.
Change the type of the DownloadDate column to a timezone aware type. You can use SQL Server's datetimeoffset on the server side, and SQLAlchemy's DATETIMEOFFSET on the client side.

Take a look at Microsoft's docs on date and time types for the full reference.
On another note, consider moving to a code first design, where you define your schema in one place.

Live and let love /

"Though Willow Pierce has moved forward since her husband died two years ago, she can't ignore her sixth sense that Jack is alive. When newcomer Con Russo comes to town, Willow is convinced he's Jack. She'd never forget his eyes. Willow is determined to learn the truth about Con's identity-even... Full description
The fate of chlorine and organic materials in swimming pools.
The fate of organic nitrogen and carbon introduced into a swimming pool by pool users has been studied using a 2.2 m(3) model pool. The study made use of a body fluid analogue (BFA), containing the primary endogenous organic amino compounds, and a soiling analogue represented by humic acid (HA). The system was used to examine the effect of organic loading and organic carbon (OC) sources (i.e. amino or HA) on the levels and speciation of the key chlorinated disinfection by-products of trihalomethanes (THMs) and chloramines under operating conditions representative of those employed on a full-scale pool. Results revealed OC, chloramines and THMs to all attain steady-state levels after 200-500 h of operation, reflecting mineralisation of the dosed OC. Steady-state levels of OC were roughly linearly dependent on dose rate over the range of operational conditions investigated and, as with the chloramine levels recorded, were in reasonable agreement with those reported for full-scale pools. THM levels recorded were somewhat lower than those found in real pools, and were dependent on both on pH carbon source: the THM formation propensity for the soling analogue was around eight times than of the BFA. Of the assayed by-products, only nitrate was found to accumulate, accounting for 4-28% of the dosed amino nitrogen. Contrary to previous postulations based on the application of Henry's Law, only insignificant amounts of the volatile by-products were found to be lost to the atmosphere.
Q:

textbf doesn't work with txfonts package

If I compile this, it won't work - the text won't be bold.
\documentclass[9pt, a4paper]{extarticle}
\usepackage[utf8]{inputenc}
\usepackage[IL2]{fontenc}
\usepackage{txfonts}
\begin{document}
\textbf{Something}
\end{document}

If I remove the package usage, it'll work, but I do need it. What should I do?

The log file tells you
LaTeX Font Warning: Font shape `IL2/txr/m/n' undefined
(Font) using `IL2/cmr/m/n' instead on input line 5.

LaTeX Font Warning: Font shape `IL2/txr/bx/n' undefined
(Font) using `IL2/txr/m/n' instead on input line 6.

meaning that txfonts doesn't support the IL2 encoding (just a few fonts do) and the standard Computer Modern font is used instead.

Vision

Our Vision

Develop and sustain a nationally recognized model for community fitness and health;

Maintain a wellness campus that serves more than 3,000 diverse members with integrative programming;

Operate with fiscal and organizational sustainability.

Vermont’s future prosperity depends on our ability to provide citizens with a solid foundation of health and physical fitness. A healthy population becomes the basis for community and economic development, as healthy citizens are also productive employees, contributing community members, nurturing parents and motivated participants in our education system. The key to a healthy population is a multi-dimensional fitness environment that provides opportunities for a social and family experience, skill building through sports, and sustainable pursuit of fitness or athletic performance goals.

Vermonters have had a long standing commitment to the cultivation of our landscapes for recreational use, to thoughtful investment in an innovative recreation business community, and to the design of cutting edge equipment and programs designed to engage individuals at all ages and abilities in health and physical fitness and the pursuit of athletic performance. The Confluence–as a community sports center--has a unique role to play in securing access for adults, youth and children to these investments and innovations that can overcome the challenges in our community. Together, we can work to forward a vision of a healthy population, a rewarding recreation legacy and sustainable economic future for Vermonters.

88 N.Y.2d 925 (1996)
669 N.E.2d 1111
646 N.Y.S.2d 789
The People of the State of New York, Respondent,
v.
John A. Ceresoli, Appellant.
Court of Appeals of the State of New York.
Argued June 6, 1996.
Decided June 28, 1996.
Frank Policelli, Utica, for appellant.
Michael A. Arcuri, District Attorney of Oneida County, Utica (Timothy P. Fitzgerald of counsel), for respondent.
Chief Judge KAYE and Judges SIMONS, TITONE, BELLACOSA, SMITH, LEVINE and CIPARICK concur.
MEMORANDUM.
The order of the Appellate Division should be affirmed.
*926Defendant was charged with criminal possession of a forged instrument and with the theft of $3,500 from the Toccolana Club, a private social club in Rome, New York. After his conviction for grand larceny in the fourth degree (Penal Law § 155.30), defendant moved pursuant to CPL 330.30 to set aside the verdict on the ground of juror misconduct involving a single seated juror. During voir dire, the juror, a resident of Rome, was asked whether he was "familiar with members of the Toccolano Club." The juror responded: "I just know where it is, not really, no." It was subsequently established that the juror had decades earlier himself been a nominal member of the club, and two of his relatives were or had been members.
After a hearing on defendant's motion, the trial court found there was no improper conduct on the part of the juror, and further that the juror's conduct had not "affected a substantial right of the defendant" (CPL 330.30 [2]). The Appellate Division affirmed. The trial court's undisturbed factual finding has support in the record and, like the alleged excessiveness of defendant's sentence, is beyond the scope of our review.
Order affirmed in a memorandum.

Kennedy Says He’d Consider a Senate Run If Warren Tapped for VP

A Kennedy in the Senate? Surely you jest.

Get a compelling long read and must-have lifestyle tips in your inbox every Sunday morning — great with coffee!

It’s been seven years since we’ve seen a Kennedy in the Senate. With a little nudge from presumptive Democratic presidential nominee Hillary Clinton, that could soon change.

Congressman Joe Kennedy III told WCVB’s Janet Wu during a Thursday night taping of her show, On the Record, that he would consider a run for Elizabeth Warren’s Senate seat in the event she’s tapped to be Clinton’s running mate this November.

Ted Kennedy won the seat in a special election in 1962 after his brother, John F. Kennedy, was elected president. He held the seat for 47 years until his death in 2009. Joe Kennedy worked on his great-uncle’s re-election campaign in 2006 before enrolling in Harvard Law School, where Warren taught for nearly 20 years.

Cosmo centerfold Scott Brown won the seat in a 2010 special election, defeating Attorney General Martha Coakley. Brown served for just two years before he was ousted by Warren, who became the Bay State’s first female senator. After a failed Senate campaign in New Hampshire, Brown now spends his time calling in to Herald Radio and following Donald Trump around.

Wu’s interview with Kennedy airs Sunday at 11 a.m.
Characterization of the limited specificity of antigen recognition in earthworms.
Parenteral administration of foreign proteins results in earthworms in significantly increased levels of the antigen-binding protein (ABP). The earthworms (Lumbricus terrestris and Eisenia foetida; Oligochaeta, Annelida) were stimulated with different proteins and the ABP response was followed with an anti-ABP monoclonal antibody and in ligand assay with biotin conjugates of all proteins used for stimulation. ABP levels are increased after the stimulation with different proteins irrespective of the size and extent of glycosylation. Molar mass of the ABP molecules was always the same, 56 kDa in L. terrestris and 60 kDa in E. foetida. The level of the specificity is considerably lower in comparison with immunoglobulins since ABP reacts not only with the protein used for stimulation but also, though to lesser extent, with related proteins.
<?php
/**
* Zend Framework
*
* LICENSE
*
* This source file is subject to the new BSD license that is bundled
* with this package in the file LICENSE.txt.
* It is also available through the world-wide-web at this URL:
* http://framework.zend.com/license/new-bsd
* If you did not receive a copy of the license and are unable to
* obtain it through the world-wide-web, please send an email
* to [email protected] so we can send you a copy immediately.
*
* @category Zend
* @package Zend_Search_Lucene
* @subpackage Document
* @copyright Copyright (c) 2005-2012 Zend Technologies USA Inc. (http://www.zend.com)
* @license http://framework.zend.com/license/new-bsd New BSD License
* @version $Id: OpenXml.php 24593 2012-01-05 20:35:02Z matthew $
*/

/** Zend_Search_Lucene_Document */
require_once 'Zend/Search/Lucene/Document.php';

/**
* OpenXML document.
*
* @category Zend
* @package Zend_Search_Lucene
* @subpackage Document
* @copyright Copyright (c) 2005-2012 Zend Technologies USA Inc. (http://www.zend.com)
* @license http://framework.zend.com/license/new-bsd New BSD License
*/
abstract class Zend_Search_Lucene_Document_OpenXml extends Zend_Search_Lucene_Document
{
/**
* Xml Schema - Relationships
*
* @var string
*/
const SCHEMA_RELATIONSHIP = 'http://schemas.openxmlformats.org/package/2006/relationships';

/**
* Xml Schema - Office document
*
* @var string
*/
const SCHEMA_OFFICEDOCUMENT = 'http://schemas.openxmlformats.org/officeDocument/2006/relationships/officeDocument';

/**
* Xml Schema - Core properties
*
* @var string
*/
const SCHEMA_COREPROPERTIES = 'http://schemas.openxmlformats.org/package/2006/relationships/metadata/core-properties';

/**
* Xml Schema - Dublin Core
*
* @var string
*/
const SCHEMA_DUBLINCORE = 'http://purl.org/dc/elements/1.1/';

/**
* Xml Schema - Dublin Core Terms
*
* @var string
*/
const SCHEMA_DUBLINCORETERMS = 'http://purl.org/dc/terms/';

/**
* Extract metadata from document
*
* @param ZipArchive $package ZipArchive OpenXML package
* @return array Key-value pairs containing document meta data
*/
protected function extractMetaData(ZipArchive $package)
{
// Data holders
$coreProperties = [];

// Read relations and search for core properties
$relations = simplexml_load_string($package->getFromName("_rels/.rels"));
foreach ($relations->Relationship as $rel) {
if ($rel["Type"] == Zend_Search_Lucene_Document_OpenXml::SCHEMA_COREPROPERTIES) {
// Found core properties! Read in contents...
$contents = simplexml_load_string(
$package->getFromName(dirname($rel["Target"]) . "/" . basename($rel["Target"]))
);

foreach ($contents->children(Zend_Search_Lucene_Document_OpenXml::SCHEMA_DUBLINCORE) as $child) {
$coreProperties[$child->getName()] = (string)$child;
}
foreach ($contents->children(Zend_Search_Lucene_Document_OpenXml::SCHEMA_COREPROPERTIES) as $child) {
$coreProperties[$child->getName()] = (string)$child;
}
foreach ($contents->children(Zend_Search_Lucene_Document_OpenXml::SCHEMA_DUBLINCORETERMS) as $child) {
$coreProperties[$child->getName()] = (string)$child;
}
}
}

return $coreProperties;
}

/**
* Determine absolute zip path
*
* @param string $path
* @return string
*/
protected function absoluteZipPath($path)
{
$path = str_replace(['/', '\\'], DIRECTORY_SEPARATOR, $path);
$parts = array_filter(explode(DIRECTORY_SEPARATOR, $path), 'strlen');
$absolutes = [];
foreach ($parts as $part) {
if ('.' == $part) {
continue;
}
if ('..' == $part) {
array_pop($absolutes);
} else {
$absolutes[] = $part;
}
}

return implode('/', $absolutes);
}
}

AE Works Awarded Design to Upgrade Spinal Cord Injury Center

AE Works to lead design efforts that target expansion of one of the Country’s largest Spinal Cord Injury Centers

Pittsburgh-headquartered architectural and engineering firm, AE Works was recently awarded a contract to provide design and engineering services to renovate and expand the existing Spinal Cord Injury & Disorders Center of Excellence (SCI&D COE) at the Hunter Holmes McGuire VA Medical Center in Richmond, Virginia. Providing critical care for veterans with spinal cord injuries, the Richmond facility is one of the largest of the 25 spinal cord injury centers in the VA Medical Center System.

Anticipating future requirements, the VA Medical Center staff embarked on proactive planning effort to meet the needs of providing critical healthcare services to a growing veteran population throughout five states and the District of Columbia. As a result of these planning efforts, this project will renovate targeted areas of the existing facility and also provide a new 20,000-SF addition to optimize delivery of these specialized clinical services.

Supporting the Department of Veterans Affairs’ commitment to a patient-centered care model that focuses on providing world-class care in a welcoming, healing environment, the design will also focus on infrastructure efficiency, enhancing the patient experience and enriching collaboration opportunities among the hospital’s many clinicians, instructors and researchers.

As a service-disabled veteran-owned small business, projects such as this expansion are especially important to AE Works.

“Our work centers around people and the design of healthcare facilities brings that even more into focus. We feel very fortunate to be a part of this project and the opportunity to have a part in improving healthcare for Veterans,” shares Michael Cherock, PE, AE Works President and Owner.

For more information on AE Works, please visit www.ae-works.com or call Carly Khanna at 301-332-9780.

AE Works Ltd., headquartered in Pittsburgh, PA with satellite offices in State College, PA and Washington DC, specializes in Architecture, MEP Engineering, Telecommunication and Security design services. AE Works Ltd. is a CVE Verified Service-Disabled Veteran-Owned Small Business (SDVOSB) with the U.S. Department of Veteran Affairs.

About The Western PA Healthcare News Team

Throughout the year, our writers feature fresh, in-depth, and relevant information for our audience of 40,000+ healthcare leaders and professionals. As a healthcare business publication, we cover and cherish our relationship with the entire health care industry including administrators, nurses, physicians, physical therapists, pharmacists, and more. We cover a broad spectrum from hospitals to medical offices to outpatient services to eye surgery centers to university settings. We focus on rehabilitation, nursing homes, home care, hospice as well as men’s health, women’s heath, and pediatrics.
freedom

April 22, 2011

the meds i’m on make it a little difficult to focus,
but here’s what i’ll say:

whatever you feel about healthcare,
who gets it, how it’s paid for, and how we deal with it here,
all i know is that the healthcare system did not fail me.
without it, i would be dead now.

there are several instances where i came close to it.

don’t get me wrong,
it was fucking hell (evidence below).and it still is since i’m exactly done with everything.
there were times where i felt ignored, forgotten,
like no one would listen to me.

but!
i’m here.
and grateful.

like i said,
the drugs are making it difficult to do normal things.recovering makes it difficult to do normal things.

but in the next couple days,
i have some yarny goodness planned for you.
stick with me bitches.

mostly, though, i want to say thank you.
thank you to all the readers, inter-knitters, and friends
for your good thoughts, your well wishes, comments and prayers,
for all the tweets, texts, visits, and vibes from across the globe.

So glad to hear you are home. I wish you a speedy recovery. After my last surgery (double knee replacement), I thought I would get a whole lot of reading done. While on the drugs for a month, I could not focus enough to read a paragraph. What a disappointment! Take it easy and have patience with your recovery. Your body has had a jolt! Donna

I was just thinking of you. I’m glad to hear you are recovering. Being in the hospital sucks. Yes they have the amazing ability to prevent deaths, but still, not a favorite place. Glad you’re home. Here’s hoping for a speedy recovery. (And I do hope you’re able to at least knit.)

Another lurker hoping you have good drugs and a speedy recovery. Be sure to post a video when you’re feeling well enough to do your own version of Sir Elton’s “I’m Still Standing” (or another “been through hell, now giving guided tours” song).

Don’t even care about the yarny goodness, stoked to see that you are back in the world of the living! Hospitals are wonderful for saving lives, but home is where you heal…
This event even made me a twitter follower, which is saying some as I don’t have a cell phone!
Relax, think positive thoughts, and play with lots of great yarn!

I’m not religious, but THANK GOD you are okay. You can’t keep a good man down, that’s what I say. . . . I am thinking about medicine/doctors. So many people say- oh, I don’t like to take drugs, let the body heal itself, etc. These are people who have never been critically sick. Once you’ve been there, life/attitudes change.
It’s like a Alice in Wonderland experience, being critically sick. Or, a crap shoot.
But, hey, I am glad, so glad, you are on the road to recovery. What a great person you are!
Nancy Paris

de-lurking to say I’m glad you are home and recovering. It’s scary to rely on others when you’ve been self-sufficient and a hospital seems to be no place to heal….you really need “home” for that. Give yourself plenty of time and don’t overdo.
After finishing in first place at the Bold Leaders Challenge Feb. 18 and 19 at Fort Knox, Ky., the team qualifies to take part in the Sandhurst Military Skills Competition at the U.S. Military Academy at West Point.

Sandhurst is an inter-company competition at West Point. Not only do West Point teams compete amongst themselves, but they compete against teams from their fellow federal service academies, select teams from the U.S. Army Cadet Command (ROTC), the United States Military Academy Preparatory School team, and international teams. Fifty-five teams will take part in Sandhurst, including international competitors from Great Britain, Australia, Afghanistan and China.

This will be the first time in more than a decade that a Citadel team has competed at Sandhurst.

“We have an exceptional group of young men and women that will represent The Citadel,” said Col. Laurence Hutto, commanding officer of the Palmetto Battalion at The Citadel. “We are excited to be able to compete at this level for the first time in recent years.This is a testament to the commitment, training and leadership of our cadets and the instructors in the Palmetto Battalion.”

The Palmetto Battalion Ranger Challenge team trains seven days a week while maintaining good standing in their academic requirements and cadet duties. They compete in a rapid, timed series military tasks along an eight-mile route. The winning squad is determined by the total time required to negotiate the course plus total points scored throughout the two days.
Making this a weekly event due to interest. BYOB

OFFICIAL RULES HERE (http://austinpoker.totallyimba.com/?page_id=11)

Summary:

6-14 people:

$20 buy-in Texas Holdem Tourney gets 10,000 in chips

1 re-buy XOR 1 add-on up until break of 10,000

15-20 people:

$20 buy-in Texas Holdem Tourney gets 5,000 in chips

1 re-buy XOR 1 add-on up until break of 5,000

Blind levels will be adjusted for lower chip counts. This is due to a limited number of physical chips that can be put in play

$10 cash game after tourney (re-buy at will until host calls it for the night)

For now, we'll default to Will's place but if the group decides to float, we'll decide that with at least a day's warning.
Emergency room outreach to chronically addicted individuals. A pilot study.
There is a dearth of literature describing the treatment needs of substance-abusing or chronically mentally ill homeless individuals who frequently utilize emergency medical services. This homeless subset represents a discrete population in the larger homeless community. We describe a pilot program, supported by local county public funds, and conducted by a local nonprofit social work agency, which was designed to provide intensive case management services to such a population. Outreach and case management activities resulted in linking clients to a broad range of entitlements and community services. Among those receiving outreach and case management services (n = 10), emergency services decreased by 58% in the year following referral compared to the year before (p <.03). Emergency services for the purpose of this study are defined as ambulance response and transport followed by emergency room admission and treatment. Those in a comparable control group (n = 8) showed no decrease in emergency service use. These results suggest that such community-based outreach programs can significantly improve patient outcome and provide substantial cost savings for local governments and hospitals.
In 2011 Robert attempted to drink 365 beers in 365 days, and he nailed it! What will he do next?

Saturday, 29 August 2015

August 22, 2015

193/1467) Home: All Natural Blonde by Amsterdam Brewery of Ontario: *; 5%, which goes to show how flexible the definition of light is becoming; grainy nose; bland - just a hint of fruit at finish; I imagine it does pay the rent, though;

194/1468) Home: Molotov Lite by Eviltwin Brewing of Connecticut, U.S.A.: **1/2; 8.5% Imperial India Pale Ale; opaque with a fluffy head; off-orange; earthy and resiny with a touch of citrus to the nose; earthy, resiny flavours with a bitter astringent after taste;
Such valves are used to adjust and modify the volume flow of a fluid through a fluid channel. It is known in this context that the flow of the fluid through the channel is to be controlled by exerting pressure from the outside on a tube in which the fluid channel is formed, such that the pressure is adjusted as a function of a desired volume flow of the fluid through the channel.
In medical technology, dosing of volume flows takes place, for example, through microvalves or directly through a corresponding pump with which the fluid to be dispensed is acted upon with pressure. Valves are used in medicine and in the cosmetic field, for example, in injection of medically and cosmetically active substances. In addition to the injection of substances for fat reduction or for injection beneath wrinkles, dosed dispensing of a substance is also necessary for application of ink for tattooing or permanent makeup in the cosmetic field. In addition to various vaccinations, medical applications also include, for example, mesotherapy. In these applications, in addition to the simple application of the media, simultaneous administration of multiple media is also provided, so that the media react with one another only after being applied.
The dosing of the fluid may be performed by means of a contact method or a noncontact method. The fluid-dispensing device thus either does or does not come in contact with the skin. Noncontact devices are also referred to as so-called dispensers. The process of delivering the fluid is itself known as dispensing, jetting or pulsing. This dosing serves to apply substances to the skin or in subsequent substance delivery systems (cf. EP 1 882 491, for example). Contacting may be understood as dosing onto or through a surface.
All these applications have in common the need for accurate dosing. Problems are often presented by chemical or fluid properties or particles or variable media.
The document DE 103 37 484 B4 describes a noncontact dosing system, in which a tube is squeezed at a high speed, so that a free-flying droplet of liquid is formed. Dosing frequencies of 50 Hz may be achieved in this way. The design here is an open system without a prepressure. The liquid fills the tube because of the capillary forces, but the maximum dosing quantity and dosing frequency are limited by this design. If there is a backpressure, functioning is very limited or impossible.
The document DE 693 25 591 T2 describes valve system for switching a flow through flexible tubes. Two positions (bistable open/closed) are selected via a pivotable lever. The liquids should flow through the valve at the coupled flange of this construction, which is manufactured by casting and welding. Possible contamination of the liquid is not prevented, nor can this principle be used as a disposable part or for higher frequencies (>1 Hz).
The document EP 1 699 560 B1 describes one possibility for pipetting extremely small quantities, but is based essentially on a combination of traditional pipetting systems and the known PipeJet method, i.e., a tube deformation, embodied in this case as a pipette tip. It is thus possible here to dose only extremely small particles which fly through the air to their destination. This method cannot be used for injections because it is impossible to work at a backpressure.
The document DE 197 06 513 C2 describes a micro-dosing method based on a pressure chamber having a reservoir connection and a fluid outlet. The pressure chamber is reduced in size by a displacement mechanism, so that the fluid is forced to the outlet. A device for detecting the position of the displacement mechanism is essential here.
The document US 2010/0030152 A1 describes a therapeutic micro-needle system, in which multiple cannulas are used instead of one cannula.
Q:

How to check element visibility independent of parent visibility (jQuery or not)

my first Question so please be patient. I have a container that holds a varying number of child elements like this:
<div class="parent">
<div class="element">content</div>
<div class="element">content</div>
<div class="element">content</div>
</div>

Quick Question:
Is there a jQuery or plain JS way of checking whether an element container would be visible independent of the parent being visible?
Simply asking for
jQuery('.parent .element:visible').length

does not work.
Background: The parent container can be toggled, and the content of the child elements gets fetched by ajax requests and is filled when the response arrives. On every response I get, the child containers get specific classes indicating the type of the response, e.g. available, unavailable and some more. So the resulting DOM may look like this:
<div class="parent">
<div class="element available">content</div>
<div class="element unavailable">content</div>
<div class="element unavailable">content</div>
</div>

This is a module, that is used several times with different CSS files. So I do not control whether the CSS implementation actually hides unavailable elements because this is done only in CSS. And the container can be open, but does not have to. But I have to know if there would be visible elements inside of the container without opening it. Is this possible?
Thanks in advance!

I'm not sure why you need to do this if you have classes like available or unavailable. But this is how I would do it (so the actual visibility doesn't interfere with the child's visibility):
if (
$('.element').css('display') != 'none' &&
$('.element').css('visibility') != 'hidden'
) {
// ...
}

In action:
http://jsfiddle.net/EbaMY/2/

This invention relates generally to the reactivation of a catalyst and in particular to the reactivation of a tin oxide-containing catalyst.
New approaches for extending the life of lasers used in a wide variety of applications are under investigation. One aspect of the rapid progress in this area is that new techniques for long lifetime space applications of high pulse energy, common and rare isotope, closed-cycle CO.sub.2 lasers are being studied. The high-energy, pulsed CO.sub.2 lasers must be operated closed-cycle to conserve gas, especially if rare-isotope gases are used. Rare-isotope gases, such as C.sup.18 O.sub.2 are used for improved transmission of the laser beam in the atmosphere.
The electrons in electric-discharge CO.sub.2 lasers cause dissociation of some CO.sub.2 into O.sub.2 and CO and attach themselves to electronegative molecules such as O.sub.2, forming negative O.sub.2.sup.- ions, as well as larger negative ion clusters by collisions with CO or other molecules. For closed-cycle, sealed CO.sub.2 laser operation, the concentration of negative ions/clusters may become sufficiently high to form discharge instabilities which may ultimately disrupt the CO.sub.2 laser operation. The decrease in CO.sub.2 concentration due to dissociation into CO and O.sub.2 will reduce the average repetitively pulsed or continuous wave laser power, even if no disruptive negative ion instabilities occur.
Accordingly, it is the primary object of this invention to extend the lifetime of a catalyst used to combine the CO and O.sub.2 products formed in a laser discharge.
It is a further object of this invention to accomplish the primary object simply and inexpensively.
Other objects and advantages will be apparent in the specification which follows.
Attack on Iran: Hitlerian Act of Aggression

Essential Reading Regarding Iran by Tony Cartalucci

November 6, 2011 - As the rhetoric for war with Iran begins to mount, first with the staged DEA-Saudi bomb plot, and now with an upcoming IAEA report supposedly "exposing" Iran's nuclear arms ambitions, it is important to re-read through the signed confessions by the corporate-fascist interests behind this drive for war where it is admitted that:

1. Iran poses no threat to US national security - even if they acquired nuclear arms- rather Iran threatens US interests throughout the Middle East, half-way across the planet.2. Iran desperately wants to avoid armed conflict with both Israel and the West and would use nuclear weapons merely as a defensive deterrence.3. The US and Israel are actively looking to provoke Iran into war with a combination of covert support for destabilization within Iran, supporting listed terrorist organizations, and limited unilateral military first strikes to provoke an Iranian response needed to justify a wider military confrontation.

All of this is shockingly spelled out in extreme detail within the pages of the corporate-financier funded Brooking Institution report, "Which Path to Perisa?" It is essential that every American, European, and Israeli read just how malicious, callus and eager the globalist elite are to trigger a catastrophic war with the Islamic Republic for the sole purpose of protecting Wall Street and London's hegemony throughout the Middle East.

Below are links to efforts to cover in detail the key aspects of this increasing war mongering, the key players behind it, including the corporations funding this agenda, as well as irrefutable evidence that illustrates these designs, laid out in 2009 have already begun to unfold.

Upon reading this information, one will realize with horror how patiently persistent the corporate-financier interests on Wall Street and London have pursued this campaign towards war with Iran, and how absolutely deceitful they are willing to be in order to keep it moving forward. It is absolutely imperative that people understand not only just how contrived the treat of Iran is, but that those peddling the lies of such a threat have, behind closed doors, admitted as much.

Image: Just some of the corporate-sponsors behind the unelected, warmongering "think-tank" Brookings Institution which produced the treasonous "Which Path to Persia?" report.

....

Please also take particular note of the corporations funding this act of Hitlerian aggression against a nation of 70 million at the potential loss of tens of thousands of American and Israeli (and other proxy soldiers') lives, not to mention the incalculable cost of the war to an already crippled American tax payer. Also note that these same corporations will not be losing their sons and daughters nor a single penny in the war effort, in fact, many of them stand to gain untold of fortunes and power - the very reason they are pursuing such a course of action.

Now would be a good time to contact your representatives, boycott the above mentioned corporations, and begin undermining a system that is parasitically bleeding this planet to death both financially and literally in pursuit of global corporate-fascist hegemony. And remember, it will not end in Iran, the attack and destruction of Iranian sovereignty is just the beginning.
Q:

Volume rendering in WebGL

I have:

a 3D array containing a 3d dataset to be displayed
a 4x4 matrix which defines spacing/scaling/orientation of the volume to be displayed
a opacity transfer function
a color transfer function

I would like to use ThreeJS to do volume rendering (MIP, RayCasting, etc.) of this data. Are there some shaders/demos available?
Should I work directly at the shader level or in javascript?
Any hint/code sample would be very much appreciated,
Best

Medical imaging (DICOM, Nifti, NRRD support for now) raycasting volume rendering in webGL with AMI/THREEJS
http://fnndsc.github.io/ami/#vr_singlepass_raycasting

2 Answers
2

The first two. Christopher Lloyd's character, Judge Doom, is the big conspirator organising the whole situation, but it's the head of Roger's studio, R. K. Maroon, who does the actual setup.

He was the one to setup the situation between Acme and Jessica (the patty-cake), and he was also the one to hire Eddie Valiant to take pictures of the meeting. Then later when Valiant meets with Maroon to show him the results, they show Roger the pictures and he runs off to write his love poem, causing him to not have an alibi for the murder.

Judge Doom convinces Maroon to do all of this by agreeing to buy his company, but only if he can also buy Acme at the same time. However it was never Maroon's intention for there to be a murder, he was just hoping to blackmail Acme into selling.

No, you gotta understand, Valiant, I had nothin' to do with Acme gettin' killed. I just wanted to sell my studio. But they wouldn't buy my property unless Acme would sell his. And he wouldn't. So I was gonna blackmail Acme with pictures of him and the rabbit's wife.

Judge Doom wanted to buy ToonTown but Marvin Acme wouldn't sell. Accordingly, Doom asked R.K. Maroon to blackmail Acme. As a result, Doom knew Maroon had shown Roger evidence that Jessica Rabbit was having an affair with Acme. So Doom used the opportunity to kill Acme, hoping everyone would think Roger did it.

Though Acme's murder is not shown in the movie, what happened is confirmed by Jessica Rabbit's dialogue: Judge Doom killed Marvin Acme and framed Roger Rabbit.
Para que llegue un jugador a Newell's como refuerzo, antes la directiva rojinegra debe cumplir un paso previo: vender. Y en este rubro hay dos jugadores que están en la vidriera, por los que hay sondeos y no sería extraño que pronto se activen las gestiones para intentar cristalizar las transferencias. Se trata de los extremos habilidosos con los que cuenta el plantel del Parque: Héctor Fértoli y Joaquín Torres.

Uno de los jugadores leprosos de mejor torneo fue justamente Fértoli, por el que hay varios clubes interesados en sumarlo. Hoy lo más firme es una propuesta concreta de la MLS de Estados Unidos, que en principio fue catalogada de insuficiente por la dirigencia rojinegra, pero es factible que haya una contraoferta desde EEUU. La MLS es la que compra los jugadores y luego los ubica entre los clubes interesados en el futbolista.

Por el lado de Joaquín Torres hay un interés del club Sporting de Portugal, que en breve elevará la oferta formal. Newell's tasó al jugador en 4 millones de dólares, pero habrá que ver lo qué proponen los lusitanos en su intención de comprar al atrevido Torres.
Q:

How to call a MainWindow method from another window?

I need to call a method from the MainWindow in another window.
Problem is i don't know why i got an error and i would like to fix it.
I tried to call the fonction using various ways, none of them worked.
Here is my last try :
What i want to call :
namespace Class1
{
public partial class MainWindow : Window
{
...
public void SkipVideo()
{
...
}
}
}

Here is how i tried to call :
namespace Class1
{
public partial class TimeWindow : Window
{
...
private void DemoVideo_MediaEnded(object sender, RoutedEventArgs e)
{
((MainWindow)Application.Current.MainWindow).SkipVideo();
}
}
}

There is no build error, but when i run the program, it does this :
System.InvalidCastException: 'Unable to cast object of type 'Class1.TimeWindow' to type 'Class1.MainWindow'.'

The InvalidCastException means that your application's mainwindow is a TimeWindow.
Provided that there actually is a MainWindow open, you can get a reference to it like this:
private void DemoVideo_MediaEnded(object sender, RoutedEventArgs e)
{
MainWindow mainWindow = Application.Current.Windows.OfType<MainWindow>().FirstOrDefault();
if (mainWindow != null)
mainWindow.SkipVideo();
}

There are better ways to handle this, for example using the MVVM design pattern as suggested by @Christopher, but this is probably the easiest one given your current setup.

## About this example
This example is a [quickstart](https://eggjs.org/zh-cn/intro/quickstart.html) of Egg, it includes the basic and comprehensive usages of Egg such as Controller, Service and some
simple configurations, moreover, it has the corresponding unit tests. you can follow this simple example and build your Egg application step by step.

## How to run it locally

### Development
```shell
$ npm install
$ npm run dev
$ open http://localhost:7001/
```

### Deploy

Use `EGG_SERVER_ENV=prod` to enable prod mode

```shell
$ EGG_SERVER_ENV=prod npm start
```

### Npm Scripts

- Use `npm run autod` to auto detect dependencies upgrade
- Use `npm run lint` to check code style
- Use `npm test` to run unit test

### Requirement

Please ensure your node version is `>=8.0` for Egg2.x.

## some problems you might encounter
- lack of MVC model development experience, click [here](https://www.zhihu.com/question/27897315) to learn more
- some concepts such as middleware, extend, helper are difficult to understand, see related [docs](https://eggjs.org/) to know more
- encounter some errors during development, find [issues](https://github.com/eggjs/egg/issues) to check if some solutions have been provided

Joseph Amoah (sprinter)

Joseph Paul Amoah (born 12 January 1997) is a Ghanaian sprinter specializing in the 100 metres and the 200 metres. He competed at the 2019 World Athletics Championships in the 100 metres and 4 × 100 metres relay, and at the 2019 African Games he won a gold medal in the 4 × 100 metres relay. He was also a 100 metres finalist at the 2019 African Games, finishing fourth.

Amoah has personal best times of 10.01 seconds and 20.08 seconds in the 100 metres and 200 metres respectively, both set at the 2019 NCAA Division I Championships. His personal best performance in the 200 metres broke the Ghanaian record previously held by three-time Olympian Emmanuel Tuffour by 0.07 seconds.

Early life
Amoah was born on 12 January 1997 to Thomas and Alberta Amoah in Greater Accra, Ghana, and was raised by his uncle Dr. Victor Antwi from middle school onwards. His preferred sport growing up was football, but transitioned to athletics while attending Prempeh College in Kumasi where his running talent was discovered. As a 19-year old he emerged as an Olympic hopeful for Ghana in the sprints after running 100 metres in 10.08 seconds at the 2016 Ghana's Fastest Human competition.

University
After his prep career at Prempeh College, he decided to quit athletics when enrolling into Kwame Nkrumah University of Science and Technology (KNUST). However the head coach of athletics at KNUST had heard of Amoah's talent while at Prempeh college and convinced Amoah to join the team with the help of his uncle. In 2017 he transferred to Coppin State University in Baltimore, which competes in Division I of the National Collegiate Athletic Association (NCAA), the highest level of intercollegiate athletics in the United States.

At the 2019 Mid-Eastern Athletic Conference Championships in May, Amoah became the first Ghanaian in any sport to qualify for the 2020 Summer Olympics by running 200 metres in a personal best time in 20.20 seconds. It was the fastest performance from a Ghanaian since 1995 and also qualified him for the 2019 World Athletics Championships. Later in June of that season at the NCAA Division I Championships, he improved his personal best times in the 100 metres and 200 metres to 10.01 seconds and 20.08 seconds respectively. He broke three-time Olympian Emmanuel Tuffour's 24-year old Ghanaian record in the 200 metres (20.15 seconds, set at altitude), and qualified for the 2020 Summer Olympics in the 100 metres.

Achievements

International championships

National championships

References

External links

Category:Ghanaian male sprinters
Category:1997 births
Category:Living people
Category:People from Greater Accra Region
Category:World Athletics Championships athletes for Ghana
Category:Athletes (track and field) at the 2019 African Games
Category:African Games medalists in athletics (track and field)
Category:Coppin State University alumni
Category:Prempeh College alumni
Consanguineous unions and endogamy in families of beta-thalassaemia patients from two Mediterranean populations: Tunisia and Italy.
Background: Consanguinity increases the incidence of recessive diseases such as beta-thalassaemia major (βTM), one of the most prevalent lethal inherited diseases in the world.Aim: This study aims to identify the frequency of endogamy and consanguinity in two Mediterranean βTM populations and to study the implication of socio-economic factors.Subjects and methods: A trans-sectional study was conducted in 203 Tunisian families and 75 Italian families. Data were collected using a questionnaire completed by patients and parents.Results: Complete endogamy and consanguinity were observed in 82.75% and 62.56% of Tunisian families, respectively. Complete endogamy was found in 90.67% of Italian families, no consanguinity was noted. The low occupation status of Tunisian mothers was associated with an increasing frequency of consanguinity (p = .01) and endogamy (p = .0003). Consanguinity was associated with low education level (p = .012) and low occupation status (p=.047) of fathers. No significant association was found between endogamy and socio-economic factors in the Italian sample.Conclusions: High consanguinity and endogamy rates in Tunisian families may explain the frequency of βTM in Tunisia. The high endogamy rate in Italian families could also increase the frequency of βTM. Identification of geographical distribution and socio-economic factors leading to endogamy and consanguinity in these populations might help to improve βTM prevention.
Purchasing

Violation/Penalties

Purchasing Violations:

What is a purchasing violation?
Section 31-7-57 of the MS Code states that when an employee receives goods or services without a purchase order, the agency has no liability for the bill. The employee is held personally liable.

A purchasing violation is committed when an employee receives goods or services without a purchase order

A purchasing violation is when an office prepares intentionally two or more office requisitions to the same vendor when one order combined is greater than $1,500. This is done to avoid getting written quotes/sealed bids. This is called splitting a purchase order.

A violation is when an employee personally utilizes a rebate, gift or prize given to the agency by a vendor.

PLEASE NOTE: When any employee orders or receives goods/services in the name of the Department of Education before requesting a purchase order, the employee will be held personally liable for the bill. Do not send the requisition and invoice to Accounting.

UNALLOWABLE AGENCY PURCHASES

Individual membership to professional organizations

Individual Chamber of Commerce membership

Individual personalization of planners, portfolios or briefcases

Certificates to state employees, public officials or board members

Plaques to state employees, public officials or board members

Awards to state employees, public officials or board members

PENALTIES FOR PURCHASING VIOLATIONS

Reprimands

Loss of Job

Fines

Imprisonment

Repayment of misspent funds

Vendor will re-bill order to the individual

Sole Source Justification:
The sole source justification letter should include the following information:

What will the product be used for?

Is it compatible with existing equipment?

Will the product be used for testing or trial use only?

Do other companies make similiar products that are acceptable?

How is the product special or unique?

What can this product do that other products cannot do?

Is there a copyright or patent on this product?

Is the manufacturer the only distributor?

Does the manufacturer only sell to specific distributors instead of direct sales?
Introduction {#s1}
============

In recent years there has been a substantial increase in the use of mass drug administration (MDA) to reduce the morbidity associated with helminth infections of humans [@pntd.0000211-Lammie1], increasing the probability that anthelmintic resistance may become a public health concern in the future. One such annual MDA programme is the Global Programme to Eliminate Lymphatic Filariasis (GPELF) which, in 2005, treated over 145 million people with albendazole (a broad spectrum benzimidazole anthelmintic) in combination with either ivermectin or diethylcarbamazine [@pntd.0000211-WHO1]. GPELF targets mainly *Wuchereria bancrofti*, the most widely distributed of the filarial parasites of humans.

Sensitive molecular assays are required to detect the presence of anthelmintic resistance before widespread treatment failure is apparent, drug resistance becomes disseminated and disease control is jeopardised [@pntd.0000211-Roos1]. Surveys of helminth parasites of humans are being conducted to establish whether genetic changes at certain polymorphic loci (associated with resistance to the same or related drugs used against veterinary helminths), are present in these populations and subject to detectable selection under chemotherapeutic pressure [@pntd.0000211-Albonico1]--[@pntd.0000211-Schwab1]. A phenylalanine to tyrosine substitution at position 200 on the β-tubulin isotype 1 molecule has been identified in a number of helminth parasites of farmed ruminants including *Haemonchus contortus* [@pntd.0000211-Kwa1],[@pntd.0000211-Kwa2], *Cooperia oncophora* [@pntd.0000211-Njue1], and *Teladorsagia circumcincta* [@pntd.0000211-Elard1] and is associated with benzimidazole (BZ) resistance in these species. Worryingly, this genetic change has also been identified in *W. bancrofti* [@pntd.0000211-Schwab1], though the phenotypic studies relating the substitution to a decreased albendazole efficacy have not been undertaken in this species. To aid clarity the two alleles at position 200 on the β-tubulin isotype 1 molecule shall be referred to as allele *F* (phenylalanine) for susceptibility and allele *Y* (tyrosine) for putative resistance.

Inbreeding, the mating of related individuals, influences parasite genotype distribution and can affect the selection of adaptive traits. Facets of a species\' biology may cause parasite inbreeding, such as population structure or assortative mating (when mate choice is determined by phenotype). Parasite allele frequency can differ between infrapopulations (the populations of parasites within individual hosts) due to the ecology of the infection or through the random nature of infection events (all groups may have an equal probability of having a rare allele, but actual numbers may vary between groups by chance). Helminth parasites have a particularly subdivided population structure as adult worms are confined within their definitive host, and only able to mate with other worms that belong to the same infrapopulation. The population genetic structure of most helminth species remains unknown. The few studies that have been undertaken indicate that whilst some species appear to have no apparent genetic structure others exhibit a high degree of parasite genetic differentiation between hosts [@pntd.0000211-Criscione1]. The degree of genetic differentiation in the parasite infrapopulation can shed insight into the microepidemiology of parasite transmission [@pntd.0000211-Anderson1]--[@pntd.0000211-Thron1]. Infrapopulation genetic differentiation will also influence helminth population genetics as it causes a reduction in the frequency of heterozygote offspring, a phenomenon known as the Wahlund effect [@pntd.0000211-Hartl1].

Studies investigating the inheritance of benzimidazole resistance are lacking, though evidence indicates that thiabendazole resistance in *H. contortus* may be a semi-dominant trait [@pntd.0000211-LeJambre1]. Other authors have postulated that alleles conferring anthelmintic resistance, including allele *Y*, are likely to be recessive [@pntd.0000211-Elard1],[@pntd.0000211-Prichard1], which would make heterozygote worms susceptible to treatment. If an allele conferring drug resistance is recessive, excess parasite homozygosity will increase the probability that a resistance allele will survive treatment. This has been shown using genetic metapopulation models investigating nematodes of grazing animals; these models indicate that the spread of rare recessive genes is promoted by hosts accumulating multiple related infections simultaneously [@pntd.0000211-Cornell1],[@pntd.0000211-Smith1]. The degree of parasite genetic differentiation among hosts can be quantified using *F~ST~* (or related analogues; see [@pntd.0000211-Criscione1] and references therein).

The adult stages of the majority of parasitic helminths of humans cannot be obtained routinely for direct investigation, so genetic surveys (including those investigating drug resistance) resort to sampling transmission stages, i.e. those (immature) life-stages that gain access to the environment to be transmitted to and from hosts or through vectors [@pntd.0000211-Schwab1], [@pntd.0000211-Curtis1]--[@pntd.0000211-Shrivastava1]. However, the results of these surveys should be interpreted with caution, as the underlying allele frequency of the adult worm population may differ from the allele frequency of the sampled transmission stages. Variations in transmission stage allele frequency and genotype distribution could be generated randomly or be a product of the parasite\'s spatial structure and life-history traits. For example, population subdivision will cause random variation in adult worm allele frequencies between hosts at low parasite densities. Filarial parasites have separate sexes and are thought to be polygamous [@pntd.0000211-SchulzKey1], which may accentuate the variability in microfilarial allele frequency, e.g. a rare allele may be highly over-represented in the subsequent generation if, by chance, a male worm with this allele inhabits a host harbouring females but no other males. In addition, the inherent random sampling of gametes during sexual reproduction [@pntd.0000211-Weir1], and the overdispersed distribution of parasite numbers among hosts [@pntd.0000211-Anderson2] may cause the allele frequency and genotype distribution to vary by chance from generation to generation.

This paper analyses population genetic data collected for a study by Schwab *et al.* [@pntd.0000211-Schwab1] who identified the presence of the β-tubulin allele *Y* in populations of *W. bancrofti*. Firstly, the extent of parasite inbreeding is estimated from *W. bancrofti* microfilarial samples taken from patients in Burkina Faso, West Africa. Samples were obtained from different villages, some of which had received a single round of MDA with ivermectin and albendazole, under the auspices of the GPELF. Secondly, an individual-based stochastic model is presented which simulates microfilarial genetic diversity from adult worm allele frequencies. The model generates sample allele and genotype frequencies using the same number of hosts, and the same number of microfilariae per host as in Schwab *et al.* [@pntd.0000211-Schwab1]. This model is then used to assess whether the observed level of parasite inbreeding is the result of a sampling artefact or a true biological phenomenon. Finally, the model is used to assess the likely range of adult worm allele frequencies which could have given rise to the observed microfilarial data, providing some insight into how genetic surveys which sample transmission stages should be interpreted. We discuss the implications of our results in terms of the development and detection of anthelmintic resistance.

Materials and Methods {#s2}
=====================

Sampled data {#s2a}
------------

[Table 1](#pntd-0000211-t001){ref-type="table"} summarises the data collected for the study by Schwab *et al.* [@pntd.0000211-Schwab1] and indicates the number of microfilariae and hosts sampled. The village of Gora was removed from the *F*-statistic analysis since only one host was sampled in this village. In some hosts it was possible to genotype only a few microfilariae, increasing the uncertainty associated with estimation of underlying infrapopulation allele frequencies in these hosts. Results are grouped according to parasite treatment history. The average frequencies of allele *Y* in microfilarial samples from untreated and treated hosts were 0.26 and 0.60, respectively [@pntd.0000211-Schwab1]. The degree of parasite heterozygosity (the proportion of microfilariae with the heterozygote genotype) is estimated for each village. The table also indicates the deviation of each population from the Hardy-Weinberg Equilibrium (HWE), which gives the proportion of heterozygote microfilariae that would be expected in a randomly mating population. This reveals a strong deficit of heterozygotes in all three populations.

10.1371/journal.pntd.0000211.t001

###### Summary of the genetic survey conducted on *Wuchereria bancrofti* microfilariae from Burkina Faso of genetic changes at the β-tubulin locus associated with benzimidazole resistance (in nematodes of ruminants).

![](pntd.0000211.t001){#pntd-0000211-t001-1}

Village No. hosts sampled Mean no. of microfilariae genotyped per host (range) Mean microfilaraemia per 20 µl blood (range) Sample (microfilarial) resistance allele frequency, Sample and \[expected\] heterozygosity
------------------------------------------------------------------------------ ------------------- ------------------------------------------------------ ---------------------------------------------- ----------------------------------------------------- ----------------------------------------
Untreated villages
TANGONKO 16 9.6 (1, 15) 323 (162, 703) 0.28 0.20 \[0.40\]
BADONGO 14 6.6 (1, 10) 212 (60, 845) 0.23 0.24 \[0.35\]
Village that had received one round of chemotherapy (albendazole+ivermectin)
PERIGBAN 13 8.5 (3, 12) 35 (18, 86) 0.62 0.27 \[0.47\]

Results were presented by Schwab *et al.* [@pntd.0000211-Schwab1]. The range of microfilarial samples obtained per host is given in brackets. The expected microfilariae heterozygosity according to the Hardy-Weinberg equilibrium is given in square brackets.

In this paper, we refer to two different types of allele frequency: (1) the underlying frequency of the allele putatively associated with BZ resistance, with *q^l^* denoting the allele frequency of the entire parasite population of a given locality, and (2) the parasite allele frequency within the host population that is sampled, denoted by *^H^q^l^*. The superscript *l* denotes the parasite life-stage under investigation, be it microfilariae (*l = M*) or adult worms (*l = W*), and *H* denotes definitive host. The allele frequency estimated from the sample, , may not correspond to the true underlying allele frequency, *q^l^*, either because the hosts sampled are not representative of the whole host population, or because the parasites genotyped do not represent adequately the allele frequency within the host.

Estimating parasite inbreeding {#s2b}
------------------------------

By genotyping transmission stages before they leave the definitive host prior to the introduction of mass chemotherapy, insight can be gained into the different causes of microfilarial excess homozygosity. If it is assumed that the number of microfilariae produced, their survival, and their probability of being sampled are independent of their genotype (as we do in the null model), it can be assumed that deviation from the HWE may be the result of non-random mating. If the locus being investigated is not under selection, the excess microfilarial homozygosity will most likely be the result of either infrapopulation genetic differentiation or non-random parasite mating within hosts. Genotyping transmission stages would allow the relative contributions of each of these two sources of inbreeding to be estimated. The variation in the allele frequency between hosts will account for some of the excess homozygosity whilst deviation from the HWE in the microfilariae within an individual host will indicate possible non-random mating within the infrapopulation.

The Wright\'s hierarchical *F*-statistic is used to investigate the correlation of parasite genes within and between human hosts [@pntd.0000211-Curtis1]--[@pntd.0000211-Paterson1],[@pntd.0000211-Brouwer1]. It is assumed that the infrapopulation is the first hierarchical group in the parasite population, and *F~IS~* is defined as the correlation of genes between microfilariae within the infrapopulation; , as the correlation of microfilarial genes between different hosts living in the same village; , as the correlation of microfilarial genes between different villages within the overall microfilarial population; and *F~IT~*, as the correlation of genes between individual microfilariae relative to the overall microfilarial population of the region. The different inbreeding terms introduced are summarized in [Table 2](#pntd-0000211-t002){ref-type="table"}. A value of *F~IS~* is significantly greater than zero points towards adult worm non-random mating, indicates variation in worm allele frequency between hosts, and suggests differences in the worm allele frequency between villages. The same statistical frameworks used to estimate Wright\'s *F*-statistic were employed here, taking into account variable sample sizes [@pntd.0000211-Weir1]. Estimates of the 95% confidence intervals for *F~IS~*, and *F~IT~*, were generated by bootstrapping simultaneously worms within each host and bootstrapping over hosts within each village [@pntd.0000211-Efron1]. *F-*statistics, and their associated uncertainty, were calculated for each village.

Modelling the allele frequency and genotype distribution of microfilariae {#s2c}
-------------------------------------------------------------------------

A dioecious adult worm helminth population with a 1:1 male to female ratio was randomly generated for a given mean number of worms per host and degree of parasite overdispersion (as determined by the *k* parameter of the negative binomial distribution, parameterized following [@pntd.0000211-Anderson2]). Each adult worm infrapopulation was randomly allocated an allele frequency, as analysis of pre-treatment data did not detect any significant relationship between the host\'s frequency of allele *Y* and microfilarial burden. The adult worm allele frequency of each host was randomly selected according to the given underlying allele frequency, *q^W^*, and the degree of parasite genetic differentiation between hosts, . For a description of a method for generating the distribution of allele frequencies in a subdivided population using the beta distribution [@pntd.0000211-Wright1], see Porter [@pntd.0000211-Porter1].

It is again assumed that microfilarial production and survival is independent of genotype, allowing a microfilarial population for each host *i* to be generated according to the size and allele frequency of the adult worm infrapopulation. Worms were assumed to be polygamous; implying that if only one male parasite were present within a host, all fertile females within that infrapopulation would be mated. The number of microfilariae produced by each parasite infrapopulation was assumed to be proportional to the number of fertilised females within that host. It was also assumed that gametes separate independently and re-assort according to the degree of non-random mating (*F~IS~*). The probability with which a microfilaria within host *i*, will be of genotype *j* is denoted , and given by the equations, where and are, respectively, the frequency of allele *Y* in the male and female adult worms within host *i*, and and are the corresponding susceptible allele *F* frequencies. To allow random stochastic fluctuations in genotype distribution, the actual number of microfilariae in host *i* with genotype *j* follows a binomial distribution, with the number of trials being equal to the number of microfilariae produced by host *i*, with genotype probability equal to .

Microfilarial allele frequencies and genotype distributions were generated by sampling a specific number of microfilariae from the generated hypothetical population according to the sampling scheme used in Schwab *et al.* [@pntd.0000211-Schwab1]. The exact number of samples taken from each of the 30 hosts was: 11, 10, 15, 9, 11, 9, 13, 10, 10, 7, 10, 10, 7, 1, 11, 9, 1, 7, 4, 1, 10, 9, 8, 6, 4, 6, 9, 10, 10, 8, for a total of 246 microfilariae. Analysis of pre-treatment data had indicated that the number of samples taken from each host by Schwab *et al.* [@pntd.0000211-Schwab1] was independent of host microfilaraemia and host allele frequency, allowing the number of microfilariae sampled per host to be randomly allocated. The program code for the simulations implemented was written in C++ and run 100,000 times, with each run generating a new helminth population and genotype distribution from which 95% confidence limits (95% CL) were calculated.

The model was parameterised for the untreated villages of Tangonko and Badongo, Burkina Faso, which had an initial prevalence of microfilaraemia of 25%. The mean adult worm burden was estimated from observed microfilarial counts using the functional relationship given in the deterministic model EPIFIL (see original formulation and parameter values in Norman *et al*. [@pntd.0000211-Norman1]), giving a mean adult worm burden of 13.5 host^−1^. The degree of adult worm overdispersion was estimated from the recorded microfilarial prevalence (taken here as a proxy for the prevalence of adult worms producing microfilariae) and the mean adult worm burden, using the prevalence vs. intensity relationship that derives from assuming a negative binomial distribution of worms among hosts [@pntd.0000211-Anderson2], yielding a *k* value of 0.07. The model outlined above will only be valid for comparisons against the pre-treatment data, since chemotherapy is known to impede microfilarial production and / or survival [@pntd.0000211-Tisch1].

The null model assumes that mating is random between male and female worms within each infrapopulation and that allele *Y* is randomly distributed across hosts, i.e. . Results of the inbreeding analysis can be incorporated into the individual-based model described in equations (1) to (3) to explore the range of adult worm allele frequencies which can give rise to the observed microfilarial data.

Results {#s3}
=======

The observed microfilarial genotype distribution was found to deviate from HWE. Villages with no history of mass anthelmintic chemotherapy had an overall inbreeding coefficient of *F~IT~* = 0.44 (95% CL = 0.17, 0.68), indicating strong inbreeding. Fifteen percent of the microfilariae were found to be homozygous for allele *Y*, an estimate 2.3 times higher than would be expected in a random mating parasite population. Results indicate the occurrence of a significant degree of genetic differentiation in worm allele frequency among the host population . Infrapopulation allele *Y* frequency, , varied from 0 to 0.77 in the villages with no history of treatment, indicating an increase in microfilarial homozygosity of 60% above HWE. The results also suggest a degree of non-random mating within hosts measured by *F~IS~* = 0.29 (−0.09, 0.54), which is however is not significantly greater than zero. No difference was observed in the microfilarial allele frequency between the two treatment-naïve villages .

The data from the two treatment-naïve villages of Tangonko and Badongo were analysed separately. Both showed a high level of microfilarial homozygosity, with overall inbreeding coefficient of *F~IT~* = 0.51 (0.16, 0.76) and *F~IT~* = 0.33 (−0.10, 0.78), respectively ([Figure 1](#pntd-0000211-g001){ref-type="fig"}). The degree of parasite genetic differentiation between hosts varied between the two villages, though the difference was not statistically significant (*p* = 0.38, calculated from the square of the normalized difference in *F~ST~* estimates [@pntd.0000211-Little1]). For the purpose of the following analysis the two treatment-naïve villages have been grouped together to increase the study sample size. A similar degree of parasite inbreeding was observed in the village of Perigban which had received one round of MDA.

![Estimates of Wright\'s *F*-statistics in *Wuchereria bancrofti* for the pre-treatment villages of Tangonko (black diamonds), Badongo (grey open circles) and for the treated village of Perigban (black squares), which received one round of chemotherapy (albendazole+ivermectin).\
The error bars are the 95% confidence intervals. *F~IT~* estimates the total degree of parasite inbreeding; *F~IS~* describes the level of non-random mating within the infrapopulation; and shows the variation in microfilarial allele frequency within the host subpopulation (village).](pntd.0000211.g001){#pntd-0000211-g001}

Parasite inbreeding increases the range of underlying adult worm allele *Y* frequencies, *q^W^*, which can give rise to the observed microfilarial allele *Y* frequency of 0.26 ([Figure 2](#pntd-0000211-g002){ref-type="fig"}). Results from the null model, where mating was assumed to be random and allele *Y* is randomly distributed amongst hosts, indicate that *q^W^* in the untreated villages of Tangonko and Badongo could range from 0.21 to 0.32. If we use the excess inbreeding estimate reported in pre-treatment villages (*F~IT~* = 0.44), then model simulations suggest that *q^W^* could range from 0.18 to 0.37.

![The impact of inbreeding on the relationship between the sample microfilarial allele frequencies, , and the (inferred) underlying adult worm allele frequency, *q^W^*, for the substitution at codon 200 of the β-tubulin gene in *W. bancrofti*.\
The figure shows 95% confidence intervals for a population with no excess inbreeding (the null model, dark grey shaded area), and a population with the observed levels of inbreeding (*F~IS~* = 0.28, , light grey shaded area). Simulations are based on the same sampling scheme used in Burkina Faso [@pntd.0000211-Schwab1]. The thick black solid line indicates the mean result for both models. The observed pre-treatment microfilarial allele frequency (; black thin, horizontal dotted line) was compared to simulation results to indicate the possible range of adult worm allele frequencies which could have given rise to the West African data. The null model (black vertical dotted-dashed lines) indicated values of *q^W^* ranging from 0.21 to 0.32 compared to the inbred model (*F~IS~* = 0.28, , black vertical dashed lines), which gave values of *q^W^* between 0.18 and 0.37.](pntd.0000211.g002){#pntd-0000211-g002}

The microfilarial genotype diversity model indicates that the observed homozygosity is unlikely to be solely a result of genetic sampling, demographic stochasticity, population subdivision, or the sampling scheme employed, suggesting that true biological mechanisms are operating in the parasite population even before the introduction of anthelmintic therapy. [Figure 2](#pntd-0000211-g002){ref-type="fig"} indicates the range of likely microfilarial genotype distributions that can be generated from a given *q^W^* value using the null (random) model. The observed excess homozygosity in the untreated villages was greater than the 95% confidence interval estimates generated by the null model ([Figure 3](#pntd-0000211-g003){ref-type="fig"}). It is interesting to note the wide range of microfilarial genotype distributions that can be generated by the null model.

![De Finetti diagram showing the genotype distribution of *W. bancrofti* microfilariae generated from a given underlying adult worm allele frequency, *q^W^*, taken from villages prior to the introduction of chemotherapy.\
A full explanation of the De Finetti diagram is given in [@pntd.0000211-Hartl1]. The black diamond represents the value originating from the observed data (with , and *F~IT~* = 0.44), and the error bars indicate the uncertainty in genotype distribution stemming from the values of *q^W^* (0.21, 0.32) that were estimated from the null (random) model ([Figure 2](#pntd-0000211-g002){ref-type="fig"}). Y indicates the allele coding for tyrosine at position 200 of β-tubulin that is associated with benzimidazole (BZ) resistance in nematodes of livestock, and F denotes the allele (coding for phenylalanine) indicative of BZ susceptibility. The solid-black curve represents the Hardy-Weinberg equilibrium (HWE). The null model generating microfilarial allele frequencies (see text) was used to investigate the range of sample microfilarial genotype distributions that could be obtained from a population exhibiting no excess inbreeding (i.e. assuming that the underlying adult parasite population would have values of ). Simulations mimic the same sampling scheme described in Schwab *et al*. The observed microfilarial genotype distribution falls outside the 95% confidence interval range (grey shaded area surrounding the HWE curve) generated by the null model, despite the uncertainty in the underlying *q^W^* estimates, indicating strong parasite inbreeding even before introduction of antifilarial combination therapy.](pntd.0000211.g003){#pntd-0000211-g003}

Despite the large increase in microfilarial homozygosity attributable to parasite inbreeding, there is only a modest increase in the prevalence of hosts who have microfilariae that are homozygous for allele *Y* (and therefore putatively resistant if the allele confers drug resistance were recessive, [Figure 4](#pntd-0000211-g004){ref-type="fig"}). Parasite overdispersion reduces the number of hosts who are microfilaria-positive and concentrates allele *Y* into a small proportion of the host population. A high degree of parasite non-random mating and infrapopulation genetic differentiation increases the number of hosts (and the number of samples per host) that need to be sampled, in order to detect or quantify reliably parasite genetic diversity ([Figure 4](#pntd-0000211-g004){ref-type="fig"}). The model is used to investigate how parasite inbreeding may influence the sampling scheme of genetic surveys seeking to identify the presence of a known marker for drug resistance ([Figure 5](#pntd-0000211-g005){ref-type="fig"}). Results indicate that the observed level of parasite inbreeding markedly increases the minimum number of hosts, and the overall number of samples necessary to be 95% confident of detecting a rare allele. The sampling scheme used within [Figure 5](#pntd-0000211-g005){ref-type="fig"} assumes that the number of parasites genotyped per host is weighted by the host\'s microfilarial load. This improves the accuracy of allele frequency estimates by allowing heavily infected hosts to have a greater contribution to the sampled microfilarial population, something which is particularly important in overdispersed parasite populations.

![The impact of inbreeding on the relationship between the mean proportion of hosts harbouring microfilariae with one or two copies of allele *Y* and the (assumed) underlying adult worm allele frequency, *q^W^.*\
The figure compares the proportion of hosts exhibiting microfilariae with allele *Y* (i.e. both heterozygous and homozygous *YY* microfilariae, solid lines) with that of hosts which have only microfilariae with the homozygous *YY* genotype (broken lines). Model outcomes are compared for two hypothetical parasite populations; the former (thin grey lines) without excess inbreeding (generated by the null model), and the latter (thick black lines) with the levels of inbreeding (*F~IS~* = 0.28, ) observed in the Burkina Faso data. Simulations used the same sampling scheme described in Schwab *et al.* [@pntd.0000211-Schwab1] and assume an overall microfilarial prevalence of ∼25% (see text).](pntd.0000211.g004){#pntd-0000211-g004}

![The impact of helminth inbreeding on the minimum number of microfilaria-positive hosts who should be sampled and the minimum number of microfilariae that should be genotyped to be 95% confident of detecting at least one rare allele.\
A randomly mating population (, grey open squares) is compared to an inbred population (*F~IS~* = 0.28 and , black diamonds). The underlying adult worm allele frequency of both populations is set at *q^W^* = 0.05. Each data point represents 100,000 runs of the stochastic model generating microfilarial allele frequencies. The number of microfilariae analysed per host is proportional to host microfilaraemia.](pntd.0000211.g005){#pntd-0000211-g005}

To date there is no phenotypic evidence that allele *Y* causes albendazole resistance in *W. bancrofti*. However, if an allele conferring drug resistance existed in populations of this parasite then the consequences on the spread of such an allele of parasite non-random mating and genetic differentiation between hosts will depend on the frequency and the relative dominance of the resistance allele. If the resistance allele were recessive, helminth inbreeding would greatly increase the probability that a parasite survives anthelmintic treatment. This is evident from [Figure 6](#pntd-0000211-g006){ref-type="fig"} which shows the influence of parasite inbreeding on the relative proportion of resistant genotypes for a given allele frequency. With a recessive resistance allele at a frequency of 0.05, the degree of inbreeding within the *W. bancrofti* population reported here, would on average increase the number of worms with the homozygote resistance genotype nine-fold. Conversely, if the resistance allele was dominant, inbreeding would reduce the probability that a parasite survives chemotherapy, as fewer worms would have the resistant allele (the deficiency of heterozygous parasites caused by parasite inbreeding will be greater than the increase in resistant homozygous worms).

![The impact of the observed level of parasite inbreeding on the production of resistant microfilariae.\
The graph gives the relative change in the number of resistant genotypes in an inbred parasite population compared to that in a population at HWE. Results are shown for different resistance allele frequencies. The graph assumes that a known resistance allele is either recessive (A), black lines, or dominant (B), grey lines. The inbreeding coefficients are those reported in [Figure 1](#pntd-0000211-g001){ref-type="fig"}: mean result (*F~IT~* = 0.44, solid line); upper 95% confidence limit (*F~IT~* = 0.68, dashed line); lower 95% confidence limit (*F~IT~* = 0.17, dotted line). The relative change in the number of resistant genotypes caused by parasite inbreeding is estimated as in (A) and in (B).](pntd.0000211.g006){#pntd-0000211-g006}

10.1371/journal.pntd.0000211.t002

###### The extension of Wright\'s *F*-statistic to represent the hierarchical population structure of obligate parasites of humans, exemplified in this paper with *Wuchereria bancrofti* (adapted from [@pntd.0000211-Hartl1] and [@pntd.0000211-Weir1]).

![](pntd.0000211.t002){#pntd-0000211-t002-2}

Symbol Definition
--------- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
*F~IT~* Correlation of alleles within individual worms relative to alleles drawn at random from the overall worm population (total deviation from the Hardy-Weinberg Equilibrium)
*F~IS~* Correlation of alleles within individual worms relative to alleles drawn at random from the parasite infrapopulation (within host non-random mating)
Correlation of parasite alleles within parasite infrapopulations relative to alleles drawn at random from parasites within the same village (parasite genetic differentiation between hosts within villages)
Correlation of parasite alleles within a village relative to alleles drawn at random from the overall worm population (parasite genetic differentiation between villages)

The table includes a graphical representation of the different *F*-statistics.

Discussion {#s4}
==========

The genotype distribution of *W. bancrofti* microfilariae varied dramatically from the HWE prior to the introduction of MDA. The degree of excess homozygosity reported falls outside the range of values generated by the null model described in this paper, indicating a significant degree of parasite non-random mating. This may be caused, in part, by parasite genetic differentiation between hosts. The null model generates a wide range of microfilarial allele frequencies and genotype distributions indicating that caution should be exercised when interpreting results obtained by sampling solely transmission stages. Significant changes in the genetic diversity of microfilarial populations over time may not reflect a significant change in the underlying adult worm population. This result highlights the crucial importance of developing sound theoretical null models that enable helminth population genetics data to be interpreted adequately [@pntd.0000211-Prugnolle2]. These models should take into account the uncertainty in outcomes, given the sampling scheme employed and the life-history traits of the parasite. A combination of sampling transmission stages and parasite inbreeding could cause estimates of the underlying adult worm allele frequency to be highly variable, increasing the number of samples that need to be genotyped in order to detect significant changes in the adult worm genome with time after introduction of chemotherapeutic pressure.

Producing a null model to assess the range of adult worm allele frequencies that could give rise to the microfilarial genetic diversity observed in villages having received treatment is complex and beyond the scope of this paper. A dynamic, full transmission model would be required that takes into account the pharmacodynamic properties of the drugs in combination and separately, as the effects of chemotherapy will influence microfilarial genetic diversity for a number of years after chemotherapy. As a result it is not possible to conclude whether adult worm genetic diversity differs between the villages that have and have not received MDA, even though their microfilarial populations differ significantly in their genetic diversity.

The results presented within this paper regarding the metapopulation dynamics of bancroftian filariasis stem from the analysis of a single nucleotide polymorphism in one gene. Further surveys, using multiple neutral polymorphic loci, are required to distinguish demographic and sampling effects from selective pressures [@pntd.0000211-Weir1]. If the allele of interest has been under selection then the observed genotype distribution could have been generated without the need for non-random parasite mating. The accuracy of the model developed here to derive microfilarial genetic diversity is limited by uncertainties regarding the biology of *W. bancrofti*. Results are dependent on our current ability to mimic adult worm burden and its distribution among hosts. Limitations inherent in the EPIFIL model, the presence of amicrofilaraemic yet circulating filarial antigen-positive infections, and possible heterogeneity in host immune responses could make adult worm burden estimates highly uncertain from microfilarial prevalence and intensity data. The relationship between the number of adult filariae and the rate of microfilarial production is likely to be complex and may depend on the immune responses elicited during the infection. The null model assumes a mean parasite intensity of 13.5 adult worms per host, though sensitivity analysis indicated that model results were relatively insensitive to small changes in parasite intensity around this value (sensitivity analysis ranged from 8.5 to 18.5 adult worms host^−1^, results not shown). Our conclusions are based on the adequacy of the null model, which may be improved by the inclusion of further biological detail. For example, recent evidence suggests a possible association between β-tubulin genotype in the related filarial parasite, *Onchocerca volvulus*, and female worm fertility [@pntd.0000211-Bourguinat1],[@pntd.0000211-Bourguinat2], suggesting a cost of resistance. Whilst the same gene has been analyzed in the current study, it is not known whether a similar relationship between genotype and fertility applies to *W. bancrofti*. If this were the case then the conclusions drawn regarding the causes of the observed genotype distribution should be treated with caution. Although no differences were seen in genotype frequency between the two pre-treatment villages studied, additional baseline surveys (prior to the start of MDA) would be required before firm conclusions regarding the true underlying frequency of allele *Y* in pre-treatment *W. bancrofti* populations can be drawn.

Notwithstanding the fact that the *F*-statistic provides a phenomenological tool rather than a mechanistic measure of inbreeding (and therefore does not describe the biological processes generating excess homozygosity), we proceed to propose some likely causes for the strong degree of non-random mating identified in *W. bancrofti*, as well as the implications that this may have for the development and detection of anthelmintic resistance.

Non-random infrapopulation mating {#s4a}
---------------------------------

Our results suggest that adult *W. bancrofti* worms do not mate randomly within the infrapopulation. This is in agreement with ultrasonography studies that show adult parasites congregating in 'worm nests' along lymphatic vessels, which remain stable over time [@pntd.0000211-Dreyer1]. Spatial heterogeneity within the host may produce multiple reproducing populations within each infrapopulation, which would increase host microfilarial homozygosity. Evidence of an apparent relationship between β-tubulin genotype, the same gene analyzed by Schwab *et al.* [@pntd.0000211-Schwab1], and female worm fertility in the related filaria *O. volvulus* has been reported by Bourguinat *et al.* [@pntd.0000211-Bourguinat2]. If such a relationship exists in *W. bancrofti*, the excess within-host homozygosity reported above may result from the increased fertility of homozygous adult worms. Anthelmintic treatment, prior to the introduction of MDA for lymphatic filariasis, may also have increased non-random mating depending on the selective advantage that allele *Y* may confer to the parasite at the time of treatment.

Parasite genetic differentiation between hosts {#s4b}
----------------------------------------------

The degree of genetic differentiation in the parasite infrapopulation can shed insight into the microepidemiology of parasite transmission [@pntd.0000211-Anderson1]--[@pntd.0000211-Thron1]. The metapopulation transmission dynamics of *W. bancrofti* will depend on the transmission efficiency and biting behaviour of the mosquito vector. *Anopheles gambiae sensu stricto* and *An. funestus* are thought to be the main vectors of *W. bancrofti* in Burkina Faso [@pntd.0000211-Gyapong1]. Hosts can acquire multiple L3 larvae during the same bite. Although density-dependent processes are known to operate on the uptake and development of *W. bancrofti* in *An. gambiae*, infective vectors will regularly transmit multiple related L3 larvae simultaneously [@pntd.0000211-Snow1]. Other mosquito vectors of *W. bancrofti* have even greater vector competence. For example, up to 32 L3 larvae were recovered from an experimental host after it was bitten by a single *Culex quinquefasciatus* [@pntd.0000211-Gasarasi1], a main vector in East Africa. Mark-recapture studies and bloodmeal analysis indicate that various mosquito species appear to have high site fidelity, regularly biting multiple members of the same household [@pntd.0000211-McCall1],[@pntd.0000211-Michael1]. These aspects of *W. bancrofti* transmission increase the likelihood that a host will be infected with closely related parasites and will contribute to the observed genetic differentiation.

More generally, drug treatment may increase infrapopulation genetic heterogeneity, as those parasites within treated hosts which survive treatment may have a higher resistance allele frequency than those harboured within untreated hosts. In Burkina Faso, lymphatic filariasis is treated with albendazole and ivermectin. Evidence indicates that the albendazole plus ivermectin combination has some macrofilaricidal and reproductive effects (mainly associated with albendazole [@pntd.0000211-Tisch1]), as well as the microfilaricidal effect (mainly associated with ivermectin). It is possible that a degree of the genetic differentiation between hosts observed in the untreated villages may have resulted from individual members of the community seeking, for instance, treatment for geohelminth infection prior to the introduction of GPELF.

The spread of anthelmintic resistance {#s4c}
-------------------------------------

Population subdivision and non-random mating will influence the outcomes of selection under chemotherapeutic pressure in different ways, depending on the initial frequency of the allele under selection and the ecology of the infection. Before the rate of spread of drug resistant parasites can be predicted reliably and accurately, greater knowledge would be required regarding the number, linkage, dominance, and possible negative pleiotropic effects of putative resistance allele(s), as well as regarding the pharmacodynamic properties of the drugs administered singly and in combination. However, useful biological insights can be obtained from mathematical models that make reasonable assumptions concerning the above [@pntd.0000211-Schwab2],[@pntd.0000211-Schwab3].

If the resistance allele is recessive and it has a low initial frequency, inbreeding will increase parasite homozygosity and as a result, the spread of drug resistant worms across the parasite population (see [Figure 6](#pntd-0000211-g006){ref-type="fig"} and [@pntd.0000211-Schwab2]). If drug resistance is a semi-dominant trait then parasite inbreeding will either increase or decrease the spread of drug resistance, depending on the efficacy of the drug against heterozygote parasites. Parasite genetic differentiation between hosts will also increase the spread of resistance even when the resistance allele is initially present at a very low frequency, as it increases the probability that male and female resistant worms will inhabit the same infrapopulation. This work is consistent with mathematical models of veterinary helminths which indicate that spatial heterogeneity and aggregated infections between hosts increase the spread of rare recessive genes [@pntd.0000211-Cornell1],[@pntd.0000211-Smith1].

The detection of anthelmintic resistance {#s4d}
----------------------------------------

The operation of a strong degree of parasite genetic differentiation between hosts reduces the prevalence of infection with drug resistant parasites and would therefore increase the number of hosts and parasites that should be sampled to detect and quantify the frequency of resistance-conferring alleles reliably. Even at high resistance allele frequencies, some hosts will have no phenotypic signs of resistance, particularly if the resistance allele is recessive, and therefore hosts respond to treatment. In practice the number of parasites that can be genotyped will be restricted, so surveys should carefully consider the sampling scheme they employ in order to maximise the accuracy of allele frequency estimates. Repeatedly sampling from the same host increases the chance of detecting a resistance mutation if it is present in that infrapopulation. However, sampling transmission stages from as many hosts as possible should be considered the optimum strategy, even in a population with low parasite genetic differentiation between hosts, as it reduces the chance of repeatedly sampling offspring of the same adult worm. Prior to the introduction of chemotherapy, studies investigating the presence and frequency of putative resistance markers through genotyping transmission stages alone should weight the number of samples they take per host by the host\'s infection intensity. However, after the start of chemotherapy the best sampling scheme will depend on the pharmacodynamics of the drug and the nature of the questions under investigation.

Parasite elimination {#s4e}
--------------------

For human helminth infections, the importance of parasite genetic differentiation between hosts stretches beyond population genetics and will influence the outcomes of parasite elimination campaigns such as the GPELF. The ability of a parasite species to persist in a host population following prolonged MDA will depend in part on the metapopulation dynamics of helminth transmission, the patterns of host compliance with treatment regimes and the pharmacodynamic properties of the drugs used. The aggregated nature of the passage of transmission stages between hosts will make parasite elimination harder to achieve by lowering the breakpoint density (the unstable equilibrium below which the parasite population will tend naturally to local extinction [@pntd.0000211-Macdonald1]), as overdispersion of parasites will result in fewer hosts with a single-sexed infection.

The authors have declared that no competing interests exist.

TSC and M-GB would like to thank the Medical Research Council, United Kingdom, for financial support. AES and RKP thank GlaxoSmithKline, FQRNT, and the Centre for Host Parasite Interactions, Québec, for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[^1]: Analyzed the data: TC. Contributed reagents/materials/analysis tools: AS RP. Wrote the paper: TC MB.

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Natural killer cell cytotoxicity and alpha-interferon in early rheumatoid arthritis.
Natural killer (NK) cell number, cytotoxicity, and serum alpha-interferon (alpha-IFN) was measured in a group of early synovitis patients and compared to that of established rheumatoid arthritis patients and normal controls. No significant differences in NK cell number or serum alpha-IFN were found. NK cell cytotoxicity (NKCC) in the early synovitis group was significantly (p < 0.05) reduced compared to that of the normal controls and not significantly different from the established rheumatoid controls. There was a trend for those early synovitis patients with a good outcome to have higher NKCC. Low NKCC is evident very early in the course of rheumatoid arthritis and is thus unlikely to be secondary to chronic inflammation. There is no relationship between NKCC and alpha-IFN levels and the cause of the reduced NKCC is unknown. Alpha-IFN levels are not raised early in the course of RA.
France Clear Favorite on 2022 World Cup Odds

The 2018 FIFA World Cup came to a conclusion on Sunday as France posted a 4-2 victory over Croatia to claim their second World Cup title in 20 years and pay out on +700 pre-tournament World Cup championship odds.

Sunday’s victory as +110 favorites on the World Cup game line odds continues France’s torrid play at recent international tournaments. Les Bleus came within an extra time goal of the Euro 2016 championship, falling to Portugal by a 1-0 score in their only defeat at a major international tournament since the quarter-finals of the 2014 World Cup.

With a youthful lineup led by 19-year-old Kylian Mbappe, who garnered Best Young Player Award honors at this year’s tournament, France’s future looks bright. Fresh off the heels of their victory this weekend, Les Bleus opened as clear +500 favorites to successfully defend their title on the 2022 World Cup odds.

While Sunday’s loss as +300 underdogs proved to be a massive disappointment for Croatia, the Blazers’ impressive drive to their first-ever berth in a World Cup final has earned them hard-fought status as one of the world’s elite squads. However, Croatia’s heroics at Russia 2018 have done little to boost them on the early 2022 World Cup betting lines, where they lag well behind the favorites as a +5000 wager.

A trio of squads coming off disappointing performances at this year’s tournament closely follow Les Bleus on the 2022 World Cup championship odds, with Brazil pegged at +700, ahead of Spain at +750, while 2014 title holders Germany sit at +800.

The Canarinho traveled to Russia as +400 pre-tournament favorites on the 2018 World Cup odds, and looked poised for a deep knockout stage run after closing out the group stage with a pair of clean-sheet wins. However, Brazil was unable to solve a high-powered Belgium squad in a 2-1 loss that marked their third quarter-final exit in their past four tournament appearances.

Spain made a second straight early exit at this year’s tournament, falling to Russia on penalties in a Round of 16 match, which marks their only knockout stage appearance since raising the hardware at the 2010 World Cup.

Russia 2018 also proved to be a bitter disappointment for Germany, who closely followed Brazil at +475 on the World Cup futures entering the tournament. However, a shocking 1-0 group stage loss to Mexico as heavy -210 favorites set the tone for Die Mannschaft’s shortest run at a World Cup since 1938.

Belgium Trails on 2022 World Cup Betting Lines

Further down the 2022 World Cup odds, Belgium sits at +1100, followed by Argentina at +1200, and Italy at +1800, while England joins the Netherlands at +2000.

Les Diables Rouges led all squads with 16 goals at Russia 2018, and saw a 25-match unbeaten streak come to an end with a 1-0 loss to France in the semi-finals. Argentina posted just one win in four matches at this year’s tournament, and maintains strong odds despite the uncertain future of superstar Lionel Messi, while Italy and the Netherlands face daunting rebuilding tasks after both European powerhouses failed to qualify for this year’s tournament.

Conversely, England sports a youthful roster, led by top goalscorer Harry Kane, which is likely to make the Three Lions a serious contender at Qatar 2022.

n**(-9/22)
Simplify ((q/(q*q**11/q*q))/(q**0*q))**(-12) assuming q is positive.
q**144
Simplify (s/s**22)/s*s**(-2/11)*s*s assuming s is positive.
s**(-222/11)
Simplify (y/(y*(y/(y/(y/(y*y*y**(3/5)))))/y*y))**(-7) assuming y is positive.
y**(-56/5)
Simplify o**(-6)*o**13 assuming o is positive.
o**7
Simplify q**(-23)*q*q*q**5 assuming q is positive.
q**(-16)
Simplify (t/t**(3/10))/(t**(-1)/t)*t*t**(2/3)*t**(-2/17)*t assuming t is positive.
t**(2677/510)
Simplify j/j**1*j**(2/15)*(j**(-4)/j)/j*j/(j/(j**(7/5)/j)) assuming j is positive.
j**(-82/15)
Simplify d**(-2/13)*d**(-4)*d/(d/(d/d**(-4/5)))*d**(1/5) assuming d is positive.
d**(-28/13)
Simplify (((z*z/((z/z**6)/z))/z)/z**(4/3))**(-41) assuming z is positive.
z**(-697/3)
Simplify (r**(-1)/r)**(-5/4) assuming r is positive.
r**(5/2)
Simplify (j**2/j)**(-33)/(j**(-1/5))**(1/21) assuming j is positive.
j**(-3464/105)
Simplify f**(-6)/f*f**(3/2)*(f**1/f)/f**(-5/2) assuming f is positive.
f**(-3)
Simplify (v**(2/7)/v)/(v*v**(-2/7)*v)*v**4*(v/(v*v/(v**(-8)*v)))/v assuming v is positive.
v**(-52/7)
Simplify ((c/(c*c*c/((c*c**19)/c*c)*c)*c*c)/c)/(((c**(8/9)/c)/c)/c*c) assuming c is positive.
c**(172/9)
Simplify (k**(1/3))**(6/17)/(k*k*k/(k*k*k**(2/11)/k*k)*(k*k*k**(3/4))/k) assuming k is positive.
k**(-1833/748)
Simplify (q**4*q**(2/11))/((q/q**(1/7))/((q/(q*q**(1/17)*q))/q)) assuming q is positive.
q**(1657/1309)
Simplify ((c*c/(c**(3/5)*c))**(-15))**(-15/7) assuming c is positive.
c**(90/7)
Simplify (m*m/((m*m**(-3)/m*m)/m))/((m/(m**(1/7)/m)*m)/m)*m*m**9*m/(m/(m*m**(-9))*m)*m assuming m is positive.
m**(36/7)
Simplify (v*v/(v/(v*v/(v*v*v**(-2/7)))))**(-13)*(v*v/v**(2/3))**(2/15) assuming v is positive.
v**(-5209/315)
Simplify (((o/(o/(o**(1/3)*o*o)))/o*o)**(-1/8))**22 assuming o is positive.
o**(-77/12)
Simplify (j*(j**(-5)*j)/j)/j*((j/((j*j**(-1)/j*j*j)/j))/j)/j*((j**(-6)*j*j)/j)/(j*j**(-6)) assuming j is positive.
j**(-6)
Simplify w*(w*((w/(w/((w/(w*w/(w*w/w**15)*w*w*w*w*w*w))/w)*w*w))/w*w*w*w)/w)/w*w/w**(1/15) assuming w is positive.
w**(-301/15)
Simplify ((i**7/i)/i*i/i**(-5))**40 assuming i is positive.
i**440
Simplify (r**0)**33 assuming r is positive.
1
Simplify (b**(-17)*b*b**(-10/7))**(5/8) assuming b is positive.
b**(-305/28)
Simplify (a**(-2/3)*a)/a**3*(a/(a*a*a**(2/3))*a)/a*a*a/a**(-2/9) assuming a is positive.
a**(-19/9)
Simplify (x/x**(-3/2))**48 assuming x is positive.
x**120
Simplify ((o*o**(-33/4)*o)/o)/(o**(-48)/o*o) assuming o is positive.
o**(163/4)
Simplify (t**(2/9)/(t/(t*(t*t/(t**(-4/5)*t))/t)))**(2/61) assuming t is positive.
t**(92/2745)
Simplify x**(1/2)/(x**(-4)/x)*(x/x**(-1))**(-50) assuming x is positive.
x**(-189/2)
Simplify l**(-2/31)*l**(-13)/l assuming l is positive.
l**(-436/31)
Simplify x**(-2/13)*x**(-20) assuming x is positive.
x**(-262/13)
Simplify (h**(28/5))**(-15) assuming h is positive.
h**(-84)
Simplify ((w*w*(w*w**(-5/4))/w)/(w*w*w/(w*w/w**(1/13))*w))**(3/17) assuming w is positive.
w**(-207/884)
Simplify (x**(2/7))**(1/44) assuming x is positive.
x**(1/154)
Simplify a**(-25)*a*a**(3/31) assuming a is positive.
a**(-741/31)
Simplify m**(1/3)/m**6*m**3/(m*m*m*m**(-5)/m) assuming m is positive.
m**(1/3)
Simplify (((h*h/(h**14*h))/h)/h)/h*h**4 assuming h is positive.
h**(-12)
Simplify (x**(-2)*x)**(-1/17)/((((x**(1/3)/x)/x)/x)/x*x*x*x/x**11*x) assuming x is positive.
x**(547/51)
Simplify (h**(-2/7)*h/(h/(h*h/(h*h*h**(2/9))*h)))/((h*(h*h/h**6)/h)/h*h**2) assuming h is positive.
h**(220/63)
Simplify m**9/m*m/m**(3/20) assuming m is positive.
m**(177/20)
Simplify ((q**(-8)*q)/q)**(2/15) assuming q is positive.
q**(-16/15)
Simplify (x**(4/9)/x**(2/29))**(2/15) assuming x is positive.
x**(196/3915)
Simplify (f**(-1/6))**3/((f/(f**10/f*f))/(f**(4/11)/f)) assuming f is positive.
f**(173/22)
Simplify (i*i**(1/2)/i*i)/i*i**(2/11)*i**(1/3)*i**(-6)/i assuming i is positive.
i**(-395/66)
Simplify (j/(j*j**(-4))*j**(2/5))/(j**(-4)*j**(1/2)) assuming j is positive.
j**(79/10)
Simplify (j/(j*(j/j**(2/13))/j*j))/j**(1/2)*j**(-2/7)*j**1 assuming j is positive.
j**(-115/182)
Simplify (k**(-6/5)*k*k*k*k*k*k*k**(2/9)/k*k)**(-3/8) assuming k is positive.
k**(-113/60)
Simplify ((h*h**(-3/2)*h)/(h*h/h**(-6)))/(h**(-2/3)/h*h/(h**(-5/4)*h)) assuming h is positive.
h**(-85/12)
Simplify y*y*y**(-3/2)*y/y**10*y**(2/7)/y**(-8) assuming y is positive.
y**(-3/14)
Simplify (s**(-1/6)/(s/s**(-3/5)))/((s*s**(1/3))/(s/(s**(-3)*s*s))) assuming s is positive.
s**(-11/10)
Simplify t/(t/(t*t**(-15/2)))*t/(t**9/t) assuming t is positive.
t**(-27/2)
Simplify s*s*s/s**(-8)*s*s/s**(-11)*s assuming s is positive.
s**25
Simplify (c*c**(-3))**(7/2)*(c**(2/9))**(1/17) assuming c is positive.
c**(-1069/153)
Simplify d**(3/8)*d*d*d**(-2/5) assuming d is positive.
d**(79/40)
Simplify (h/h**(-1/11))/h*h*h**(-3/4)*(h**(-2)/h)/(h*h*h**0) assuming h is positive.
h**(-205/44)
Simplify (u*u**(8/7)*u)/(u*((u*u**(-3/4))/u)/u*u*u)*(u*u**(-4))/(u/(u*u/(u**(-2/11)/u*u))) assuming u is positive.
u**(23/308)
Simplify ((o**(-4/7)*o)/o**0)/((o*o**(-6/11))/(o*o/o**(1/5)*o)) assuming o is positive.
o**(1068/385)
Simplify ((c/(c*(c/(c**4*c)*c)/c*c))/(c/c**(-4)))/((c*c**2*c)/(c/c**(-4/5))) assuming c is positive.
c**(-21/5)
Simplify a**7*a*((a**(17/4)*a*a)/a*a)/a*a assuming a is positive.
a**(57/4)
Simplify ((n*n**5*n*n*n)/n*((n/n**(2/5))/n*n)/n)**(-1/11) assuming n is positive.
n**(-38/55)
Simplify (s/(s/s**(3/5)))**3 assuming s is positive.
s**(9/5)
Simplify (v*v**(-1/16))/((v**1/v)/v) assuming v is positive.
v**(31/16)
Simplify ((d**0)**16)**26 assuming d is positive.
1
Simplify i**(-9)*i**(-17) assuming i is positive.
i**(-26)
Simplify (((k*k*(k*k**6)/k)/k)/(k**(-3/4)/k))/(k/(k*k**2*k))**(16/3) assuming k is positive.
k**(99/4)
Simplify (p**(-4)*p/(p*p**(-4)))**(1/23) assuming p is positive.
1
Simplify l**(5/6)/l*l*l**(-7/2) assuming l is positive.
l**(-8/3)
Simplify t/(t**15/t)*(t/(t/(t**(2/3)*t)))/t assuming t is positive.
t**(-37/3)
Simplify ((b*b**14*b)/b**12)**11 assuming b is positive.
b**44
Simplify ((g*g**(2/13))/g)/g**(-6) assuming g is positive.
g**(80/13)
Simplify (v/v**(10/7))**(2/87) assuming v is positive.
v**(-2/203)
Simplify (t/(t*t**(-4/5)))**(-50) assuming t is positive.
t**(-40)
Simplify g**(-2/7)*g**(-2)*(g*g/(g/g**(-1)*g))**(-2/101) assuming g is positive.
g**(-1602/707)
Simplify ((v*v**(-1/4))/(v/(v*v/(v**(-1/2)/v)*v)))/(v**(2/7)/v)**(5/7) assuming v is positive.
v**(933/196)
Simplify (b**(-3/5)*((b/(b/(b*b**(-1))))/b*b)/b)/(b**(1/3)*b**10/b) assuming b is positive.
b**(-164/15)
Simplify (h**(1/14)*h**(-4)*h)**(1/39) assuming h is positive.
h**(-41/546)
Simplify (y**(-1))**(-1/18)*(y*y/(y/(y**(-2/5)*y))*y)**(-45) assuming y is positive.
y**(-2105/18)
Simplify (z**(-2/11)/z*z)**(-3/23) assuming z is positive.
z**(6/253)
Simplify (k*k**(-1))**14*k**(-1)*k**5/k assuming k is positive.
k**3
Simplify ((m*m**(-2/7)*m)/m**(-4))/(m*m*m**(-4)/m*m*m*m/m**5*m) assuming m is positive.
m**(68/7)
Simplify ((j*j**(-2))/j)**(-2/61)/((j*j/j**1)/j*j)**(-35) assuming j is positive.
j**(2139/61)
Simplify (u**(-1/12)*u)**17 assuming u is positive.
u**(187/12)
Simplify ((z**(-2/17)*z*z)**(7/3))**(2/5) assuming z is positive.
z**(448/255)
Simplify i**(-1/15)*i**10*i assuming i is positive.
i**(164/15)
Simplify (w**3/((w/w**(5/3))/w*w))**(-2/109) assuming w is positive.
w**(-22/327)
Simplify z**(2/17)/z*z**(7/4) assuming z is positive.
z**(59/68)
Simplify ((s*s/(s/(s**(-6/5)/s)*s))/s)/s**(4/5) assuming s is positive.
s**(-4)
Simplify i**24*i*i/i**(-6)*i assuming i is positive.
i**33
Simplify ((v*v*v/(v*(v*v*v**(-1/9)*v)/v))/(v/v**6*v*v))/(v**(-1/5)/v**3) assuming v is positive.
v**(284/45)
Simplify (n/(n*n/(n/(((n*n**(-4))/n)/n)*n))*n**(-2/9))/(n*n*n**4*n*n**(-1/3)) assuming n is positive.
n**(-8/9)
Simplify ((l/l**(-1/11))/l)/l**(-24) assuming l is positive.
l**(265/11)
Simplify l**3*(l*l**(-8)*l)/l assuming l is positive.
l**(-4)
Simplify ((k/k**(-3/2))/k**(12/7))**(2/29) assuming k is positive.
k**(11/203)
Simplify (((t*t*t*t*t*t/t**(-1/12))/t)/(t*t**(-2/3)))**28 assuming t is positive.
t**133
Simplify (g/(g**(2/23)/g))/(g*g*((g*g*g**(11/4))/g*g)/g*g) assuming g is positive.
g**(-445/92)
Simplify (o**(-2)/(o/(o/((o/(o**(-13)*o*o))/o*o))))**(4/7) assuming o is positive.
o**(-8)
Simplify a**(5/7)*a/a**(8/9) assuming
5 Surprisingly Easy Tricks to Make Running a Habit

You were really excited…

You had signed up for a 6k run in your neighbourhood. You had also joined the local running club.

You were really motivated, weren’t you?
Your willpower was on a sprint and you were geared up to bolt towards the finishing line.

But then…

You went for a vacation or a work trip for a week.
What happened when you got back?

Do you still have that initial momentum?
Do you feel like giving up, because starting over is such a pain?
Is it tough to find time?

Sticking to a new habit isn’t easy.

I know! I had tried to make running a habit for ages and failed miserably.

Eventually I got tired of failing.
That’s when I began to read about the science of habit formation. I tried to find smart and simple ways to make habits stick.

Today I can lace up my shoes and go for a regular jog every 4-5 days a week and with ease.

Check out these 5 surprisingly easy tricks that have helped me make running a habit:

1. Create a trigger

According to Charles Duhigg, the bestselling author of “The Power of Habit”, Triggers act as conscious or subconscious reminders to perform a behaviour.

Triggers could be visual reminders. Try keeping your running gear and shoes next to your bed so you see them first thing in the morning.

Triggers can also be action based. I run in the evenings and my trigger is “right after I drink my evening coffee, I will go running”.

2. Be specific

During the first 4-6 weeks of picking up running as a habit specify a time of day (or night), the exact trail you will go for the run, duration of the run and at what time will you leave for the run.

The more specific you can make the action, the easier it is to implement it everyday.

You can use this statement: “I will go running every Monday, Tuesday, Thursday and Friday at my neighbourhood park in the evening at XX pm (write the time here) for 30 minutes”.

3. Start small

Habit coach Rob Norback strongly advocates the half-and-half rule. If you want to run for 20 minutes every day, cut it into half (10 minutes) then half it again (5 minutes). That’s where you should start.

Doesn’t that sound a lot more achievable?
Even if you can run for 10-15 minutes, stick to a 5 minute routine until it becomes second nature. Only once it’s become a habit should you start running for longer periods.

How does this help?

You complete your goal in 5 minutes and that brings a sense of accomplishment which is essential to building habits.

You overcome any procrastination or hurdles (you woke up late, have to rush to office, send the kids to school) that you may face, since you have to invest only 5 minutes.

4. Forgive yourself

If you miss a day (which you inevitably will) do NOT berate yourself.

Missing a day is no big deal. But assuming defeat because you missed 1 day or 2 days in a row (or a whole week while vacationing), is a huge mistake.

Negative thinking will make you give up. If you think you have failed or you are lazy or you are not good at running, it will stop you from taking further action.

5. Get a good night’s sleep

Sleep matters! If you are not getting at least 6.5 hours of shut eye every night you will be tired, with little energy to focus on habit changes.

You might make it to the park when your enthusiasm and motivation for running is high, but the moment things get even slightly difficult, you’ll skip the habit because as a sleep-deprived person you wouldn’t have the willpower to push yourself through a little discomfort.

Why 6.5 and not 7 hours?
Because, Tony Schwartz, Energy Coach, recommends that half an hour of exercise can actually compensate for half an hour of sleep and give you more energy in the bargain!

What habit do you want to pick up?

Work out at home, follow a diet, wake up early, learn music, maybe a language, study for a certification?

These principles work for any kind of habit formation. Try it!

Want to know about that one core ingredient for forming any habit? Sign up for our Blog.
Thursday, May 14, 2009

Again between two guys a hell of a lot smarter than you. Me and James.

Just a reminder Channelup is in Italics, James in regular font.

Yo buddy

Last night's lost was nothing if not interesting. I liked it (thought it could have been an hour and a half) and thought it did a pretty good job setting up next season. Writing about it was insanely hard as I had a lot of trouble gathering my thoughts and putting them in a coherent format. I obviously wanted to avoid just straight summarizing, but there was so much going on. Anyway I thought I would add a couple of more thoughts that didn't make it into my post.

- I kind of mention this but the good/evil thing is really going to be the main focus of the last season I think. Ben and Mystery Island guy leading the charge to keep the island secret from everyone with others (Richard Alpert maybe? Shadow of the statue group?) fighting for their own end games. That storyline has the potential to be awesome and maddening at the same time.

- The bomb explosion will probably make it so that the Oceanic crew (plus Miles and Juliette) can somehow jump back to the present and back into the fray. One thing I liked about this season with them alternating between different points in time, is that there wasnt too much overlap and confusion with the characters. Basically keeping it so that everyone easnt always running into each other worked for the production of the show. Putting them all back in to the same time, with Alpert and company's increasing role, plus this new faction, could be tough.

Any other thoughts? I think I have now written 10,000 words on Lost.

Interesting idea about the bomb sending the main characters forward in time. Supporting that idea is the fact that they used the exact same screen effect when we are meant to believe the bomb goes off as when we have traveled in time previously.

So this foil to Jacob doesn't actually resurrect Locke - but turns himself into an image of Locke? So are we meant to believe this guy also turned himself into a vision of Jack's Dad, Walt, etc? Even though it's bizarre, I suppose it's at least a consistent explanation.

I am not sure if I like the idea of the island being this place where two gods are battling for supremacy. I also don't get why Jacob would just let Ben wave that knife around and then kill him(if he is indeed dead) considering he earlier exercised the power to bring a human being back to life when Locke was thrown from the window. And to be honest, I also thought the "Jacob was actually there at all of these huge moments in all of the Losties lives" got extremely old after the first couple. The first one I was like WHOA!!! and then after that it sort of felt like cheap thrills. Jacob sitting on a bench...Locke falls from the window! Can you believe it?! Jacob was there when Locke was thrown out of the window, too! So I guess what I am saying is, I agree that the episode stands up a lot better as an hour and a half instead of 2 hours. This is sort of a shame considering I felt like some of the other huge plot points were sort of rushed.

We need to see Jacob at Sun and Jin's wedding, but all we get for the most pivotal turning point is the episode is Juliet saying "I changed my mind. I saw the way you looked at her," and a weak explanation? Juliet similarly instantly changes her mind in the sub to get them back to the island...I guess she didn't see any suspicious looks by Sawyer in any of the other dozens of times he and Kate interracted since she got back? I just thought this was a very hurried and sloppy way to make sure everyone got back on the island while also letting Jack's plan carry on. It felt like forced drama, which LOST has done a good job avoiding this season. Easier would have just been to not place Sawyer, Juliet, and Kate on the sub...avoid some empty action scenes of their escape, Sawyer and Jack's fight, the "Why'd you stop," "That's why dude," Hurley and Jack moment, and so on.

Why couldn't Juliet have given her "i saw the way you looked at her" speech when Sawyer first suggests going on the sub in the first place? We are still in the same place, but we have room for further development elsewhere. Would it have been so bad if we saw MIles saying to his father, "Now I understand why you did it," and then playing a bigger role in all of this instead of just having this awesome character making snarky comments in the background from time to time? Perhaps another interraction between Jacob and Evil Jacob at some other point in time(like when Oceanic 815 crashes). My overall point is, as I am sure you can tell by now - a few storylines left me wanting more and a few left me wanting decidedly less. I think either trimming it down, or re-organizing it while dropping the fluff would have been a far more impactful finale. I do agree though, that the events that happened set us up well for next season.

Totally agree about the Jacob appearances. I thought some were cool (Sawyer, Sayid, Locke) and some were stupid (Jin and Sun, Jack). Also they kind of throw you off with Juliet's parents getting divorced and Jacob not showing up. When he doesnt show it kind of makes the whole thing some weird set up for why she leaves Sawyer. To be honest, the whole Sawyer, Kate Juilet thing has annoyed me for a while and I find it very hollow. What I did enjoy about Sawyer though was the genuine anguish (not for losing Juliet), but for losing the life he had in the Dharma Initiative. He was kind of saying, "I finally made a normal life for myself and you (Jack) came along and f-ed it up like you always do." That is where I felt most pity for him as a character.

Also the scene where they are about to explode the bomb was beyond ridiculous considering an alarm is going off, the Dharma initiative is on to them, Sayid is dying and every sits around to talk about their feelings for ten minutes. No possible way.

Agree totally about the sub and its uselessness in the overall plot. Just a filler. I doubt Jacob is actually dead and we need to consider that his body is most likely just some kind of vessel to a more supreme being. I don't know if I love these God implications because they complicate things almost more than time travel does. People with God-like powers (Sylar) are just as impossible as those who try and change the future or past.
The true test of character is not how much we know how to do, but how we behave when we don't know what to do.

Friday, August 28, 2009

Free from blackness

Independence day celebration is just around the corner. It’s been 52 years our beloved country celebrated independence and our country had achieve a lot since then. This time around since the independence fall on Ramadhan time so I bet there will be not many concerts or socialize party organized in KL or anywhere else but then, it’s just my predictions, other races might as well did it.Talking about independence, what has we, as the children of the post independence know about the value of freedom? Freedom means free from any colonization if that what it means from the past but nowadays out culture are so much been conquered by other races, culture. Our country fills with “PATI”. Anywhere we walk we can see many faces and sometimes I wonder, am I the foreigner here?Yeah2 I know the globalization means that you have to accept the windows of the world into your world but then if the newcomers come and made a hell out my country so what it is going to be? It’s ok for them to work here and made a decent earning with living peacefully with the locals but the main problem is the one that cause the social problem. What we saw in newspaper and news are just the tips of the reports and I’m pretty sure there are many more cases of robbery, thief, snatch, rape, murder involving these ‘type’ of people. Mastika (August Edition) had some stories of how the Negro affecting our life here in Malaysia. Sometimes I wonder, how can they come here? With so many of them? And the usual stories that link with Negro are theft, “pukau”, money counterfeit, rape (which was at first called love).i like to gather some info from all of you about the last one. We see and find this thing in KL right? We can see a nice lovely Malay girls walking along MidValley, hold hand with some Black tall guy. I still wonder why on earth that these ladies picked and fall in love with the Negro? I means they are Christian (some might be Muslim), Black( if you want to choose black, it’s better to choose the Indian) and not handsome ( Malays are so hotter than them)? Why and How? And if their love story end with happy ending good for them but the problem is the ending just like in the 999 (tv3 program).The Negro slept with the girl and then he dumped her and to make matter worse, the girl pregnant and the child with the DNA of Negro was born. So who’s to blame here? The Negro of course, but the girls too.What makes Negro or (in the whole) the foreigners better than the locals? I can stand Malays girls couple with Indians or Chinese as long as same Religion (I mean Islam of course), but I can’t stand if Malays or Chinese or Indians couple with foreigner. It’s like the man from our country had extinct that force them to find foreigner. The same usual lame reasons for these girls to find Negro or “Mat Salleh” are romantic, caring, loving and obviously richer. I would say it is bullshit. The story had been always having the same ending.This is also one type of colonization and proofs that we, Malaysians still not fully achieve Independence. We always value the outside goods higher than our own local goods without ever considering the quality first.The value of Independence means nothing if just some people say aloud “Merdeka” each year and put on the flag on the car, house or office. The values of independence should come within the heart of every Malaysian and together we care and cherish this gift for the good of the future.Happy Independence Day!p/s – My car might not have the flag of Malaysian but in my heart, the love of this country, none can compared with. Well, I shall put on the flag afterwards. Hope all of you did the same things. The first is Islam and the second is Malaysia and I do mean “Malay-sia”.
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Co-Op program helps wounded warriors transition

Story Highlights

Former Staff Sgt. Anthony Moralez was placed in a civilian position at White Sands Missile Range thanks to the Wounded Warrior Co-Op Program.

WHITE SANDS MISSILE RANGE, N.M., Nov. 5, 2009 - White Sands Missile Range has initiated a Wounded Warrior Co-Op Program to help expedite recruitment efforts while at the same time helping Soldiers transition to civilian life.

Former Staff Sgt. Anthony Moralez was assigned by the battalion to work with CPAC to help develop the program. He was subsequently placed in a civilian position.

"This program is something I'm very passionate about," Moralez said. He explained that not too long ago he was sitting in the WTU wondering what life had in store for him. "Quite honestly I was worried!" he said.

Then last year he met the EEO and CPAC office staff and he said they were extremely passionate about helping the Soldiers "Give back". When he was approached to help with the startup of the program Moralez said he jumped at the opportunity. While developing the concept plan, Moralez said he realized that the program will only work if the individual wants it to work and is willing to give up a few things to gain others.

"I feel good about the program for two reasons, I helped develop it and it worked for me," Moralez said. "I'm telling you, if you walk through this door many others will open. The trick is to get thru that first one!"

Soldiers eligible for this program are those in the battalion who are transitioning out of the Army. Those Soldiers who apply for the program, with an endorsement from the Warrior Transition Battalion commander, can be placed in a federal civilian position at White Sands Missile Range for up to 90 days, pending release from active duty.

Upon successful completion of the trial period and upon honorable release from the military, if approved by the appropriate civilian selecting official, the eligible Soldier may be appointed to the civilian position.

"Tony has been an outstanding addition to DPTMS. If you're looking for adaptive, resourceful self-starters with good operational sense, look to the Wounded Warrior Program. I just found out I have two more openings and I plan to bring in two more," said Gerry Veara, White Sands DPTMS.

According to Sally Smoot, White Sands CPAC director at the time this article was written, the program is a win-win situation. "Our managers get to fill their jobs quickly, and we get to take care of our Soldiers who have taken care of us."

"Under the Equal Employment Opportunity umbrella, the Wounded Warrior Co-Op Program fits well into the objectives of the Disabled Veterans Affirmative Action Program Plan. Those warriors who are a part of the Wounded Warrior Battalion have combat related disabilities they received while serving in the war on terrorism," said Liz Childers, EEO officer.

Childers said it is the goal of the EEO office to ensure that disabled veterans are offered equal employment opportunity in the federal service. "With the collaborated effort of the Civilian Personnel Advisory Center and William Beaumont Army Medical Center, the objective is to recruit and employ those wounded warriors with the required skills needed to fulfill the mission of White Sands Missile Range," she said.

Applications for this Program are available online at www.wsmr.army.mil/employment.

Questions pertaining to this Program may be directed to Carol Main at (575) 678-7728, DSN 258-7728.
Q:

New column from previous columns in Pandas

I have a pandas dataframe with some columns:
>>data.columns.values
array(['Sheet', 'Row', 'Column', 'Cell', 'V0', 'Thx', 'dV', 'Vd'], dtype=object)

Each row contains a different value for the Sheet, Row, etc etc.
From the info of Sheet, Row, etc I will create a PDF file title like this:
title = Sheet%s_Row%s_Column%s_Cell%s.pdf
So instead of iterating over each row of the DataFrame and create a single title each time, I wanted to directly create another column of strings called title and store the different titles like this:
data['title'] = "Sheet%s_Row%s_Column%s_Cell%s" % (data['Sheet'], data['Row'], data['Column'], data['Cell'])

But this is not working, seems like it is appending each Serie inside each %s
How can I create this title column from the info on each row without having to iterate over the entire DataFrame?

One way to do this would be using DataFrame.apply() with axis=1. Example -
data['title'] = data.apply(lambda row: "Sheet{}_Row{}_Column{}_Cell{}".format(row['Sheet'], row['Row'], row['Column'], row['Cell']) , axis=1)

Demo -
In [52]: df = pd.DataFrame([['A','B'],['C','D'],['E','F']] , columns=['Sheet','row'])

In [53]: df
Out[53]:
Sheet row
0 A B
1 C D
2 E F

In [54]: df['title'] = df.apply(lambda row: "Sheet{}_row{}".format(row['Sheet'],row['row']) , axis=1)

In [55]: df
Out[55]:
Sheet row title
0 A B SheetA_rowB
1 C D SheetC_rowD
2 E F SheetE_rowF

The Joker (1960 film)

The Joker () is a 1960 French comedy film directed by Philippe de Broca.

Plot
Edouard Berlon is a young, incorrigible seducer who moves very lightly from one affair to the next. He meets Helene Larouch, a woman married to André, a rich financier who is very busy with his affairs, leaving her in an emotionally arid life. Initially Helene resists Edouard's wooing, but as she gets to know his lively character, his eccentric lifestyle and his very unusual family environment, including his old uncle Théodose, his brother Pilou, servat Olga, some infants, and a few stray dogs, she lets herself become seduced. Their relation, however, turns out to be an ephemeral one as Edouard is busy seducing another woman.

Cast

Anouk Aimée as Helene Larouch
Jean-Pierre Cassel as Edouard Berlon
Pierre Palau as Théodose
Geneviève Cluny as Pilou Berlon
Georges Wilson as Guillaume Berlon
Anne Tonietti as Olga
François Maistre as André Laroche
Jean-Pierre Rambal as Paul
Liliane Patrick as Solange
Irène Chabrier as Aline, servant at the inn

Release
The film had its premiere at the Locarno Film Festival in August 1960, but was not released commercially until 20 January 1961 in France and 7 August 1961 in New York. During the 2012 Cannes Film Festival, the film was presented with other classics at the Cinéma de la Plage, a non-competitive part of the official selection that is open to the public. In 12 November 2013, the film was presented at the Cinémathèque québécoise, Montréal.

Critical response
The film has been described as "a lot of genial fun" as the plot evolves. It also has been described as whimsical and in parts "nutty" for the eccentric lifestyle of the hero and his family. French critics, on the other hand, find subtle qualities in the presentation of the characters as uncle Théodose is described as "an original, old uncle" as well as poetic connotations in the overall work.

References

External links

Category:1961 films
Category:French films
Category:French-language films
Category:1960s romantic comedy films
Q:

C General sscanf return

I'm trying to use the return value of sscanf function. The problem is that in the file that I'm reading, some lines may contain different number of integers. How can I tackle this problem?

int values[5];
int values_per_line = sscanf_s(line_buffer, "%d %d %d %d %d", &values[0], &values[1], &values[2], &values[3], &values[4]);

`
sscanf_s, _sscanf_s_l, swscanf_s, _swscanf_s_l:

Return Value
Each of these functions [including s_sscanf()] returns the number of fields that are successfully converted and assigned; the return value does not include fields that were read but not assigned. A return value of 0 indicates that no fields were assigned. The return value is EOF for an error or if the end of the string is reached before the first conversion.

The Decision Maker

Credit unions are well aware of the growing revolution in payments. A recent report by McKinsey & Company (Global Payments 2015: A Healthy Industry Confronts Disruption) noted that, the growth of nonbank digital competitors over the next five years will increase downward pressure on transaction margins while increasing growth in electronic payments.

The drivers for this trend are all too familiar:

Large technology companies such as Apple, Google, Facebook, Amazon, Microsoft, Tencent and Alibaba, are some of the most significant nonbank competitors. These organizations are cash-rich and have virtually captive customer bases.

Smartphones have become a crucial channel in the world of payments. With these devices comes a swarm of payment options. These range from the likes of Apple Pay to “In-App” purchases that provide an almost seamless user experience.

Member expectations for technology-enabled experiences have grown considerably. Today’s members, like any other consumers, have experienced an unprecedented level of service via nonbank providers. Some may wonder why their favorite credit union does not have the same level of digital service.

Despite all the hype about the electronics payments, adoption by credit union members may tend to be slower than the public at large. Members tend to be more conservative so fewer are likely to be enthusiastic early adopters.

However, this does not mean credit unions are complacent about this growing trend. The industry, especially its larger players, has begun to respond vigorously with various “digital wallet” strategies. While these efforts are in the formative stages, it is imperative that credit unions position themselves to members as the trusted alternative for safe and secure digital payments. From this positioning, members can be educated and motivated to become loyal users of the credit union’s digital payment platform.

A crucial element to make this strategy successful is analytics. Making effective decisions in this fast-paced environment is crucial. The ability to adjust the tactical underpinnings of the strategy on a monthly, weekly, or even daily basis depends on the availability of transactional data for analysis. Having data quickly available at this level of granularity requires a well-designed and well-tuned data warehouse. This tool provides an essential feedback loop for decision makers as they guide the digital payments strategy toward meeting member needs and keeping those payments (and their margins) close to the credit union.

We are missing an opportunity in this space. I would suggest that digital wallets and the associated strategies for a credit union implementation are great and should be pursued. As an industry however, we should own the entire transaction stack from the rails to the transaction. Our mobile transaction rails currently are owned and controlled by companies that are not credit union friendly. Additionally, the advent of blockchain technology will push massive disruption at the current banking infrastructure. Some have predicted the complete demise of banking as it currently exists as a result. Bottom line is the industry is fast approaching the need to innovate or die in my view. With that in mind, there is new pursuit of solutions that address both lines of thinking. Unfortunately, as an industry we remain focused on the wrong things. Instead, we need to think much bigger.

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WARNING: The following story contains descriptions that some readers may find disturbing. Discretion is advised.

Quebec City police say a 39-year-old man has been arrested in connection with what they are describing as an attempted murder of a woman in her 20s.

The incident happened on Friday evening when police were called to Arago Street West at around 9 p.m. after a man set a woman on fire before fleeing the scene.

Paramedics rushed the woman to hospital with life-threatening injuries.

READ MORE: Man seriously injured after setting himself on fire outside south London government office, SIU says

Police say she suffered serious burns to her face, back and hands.

“We fear for her life,” police said in a written statement on Saturday.

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The suspect was arrested Saturday morning at around 11:35 a.m. on Girardin Street in Drummondville, roughly 150 kilometres west of Quebec City.

Quebec City police spokesperson Etienne Doyon said the suspect was the victim’s ex.

READ MORE: Multiple injuries after vehicle crashes into Quebec City building

Doyon said a warrant had been issued for his arrest. He was wanted for attempted murder and aggravated assault.

He is being held by provincial police in Drummondville.

Investigators with Quebec City police were en route to interview the suspect.

Doyon said police had yet to interview the victim herself.

He confirmed reports that the woman’s mother and children had witnessed the attack.

“The children were placed in the care of the grandmother,” he said, adding that police made sure they were being provided with the necessary support.

Martyn Allard, who says he’s the victim’s neigbour, told Global News he was standing on his second-floor balcony Friday night when he saw someone running by.

“I thought he’d dropped a burning torch on the street,” he said, adding he only realized it was a person when she started running and screaming, “I’m on fire, I’m on fire, someone lit me on fire!”

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READ MORE: Evacuation at Quebec City airport terminal lifted, operations return to normal

Allard said he called 911 and then rushed to the woman’s side to try and help her.

“I was yelling at her ‘Madame get on the ground, madame get on the ground,’ but she was burning up like a torch,” he said.

He described a strong smell of gasoline as he approached the victim and said he ripped her burning clothes off as he waited for a neighbour to bring a blanket.

Allard said he grasped the victim’s hands as she appeared wobbly and talked to her to keep her alert.

“She was talking about her kids,” he said.

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— With files from The Canadian Press
CCSU professors accused of sexual misconduct with students

Photo: Journal Register Co. Photo: Journal Register Co. Image 1 of / 3 Caption Close CCSU professors accused of sexual misconduct with students 1 / 3 Back to Gallery

Central Connecticut State University President Zulma R. Toro announced Tuesday that she is seeking to fire two longtime theater professors after investigators concluded that each had likely engaged in sexual misconduct with one or more students.

Toro also announced plans to appoint new leadership for the university’s Office of Diversity & Equity and to reorganize the human resources department after evidence showed that administrators for years failed to take proper action on complaints of sexual misconduct.

The two professors are Joshua Perlstein, hired in 1992, who was placed on paid administrative leave in April, and Thomas Delventhal, who was hired in 1998 and was placed on paid leave last week. Both professors continue to draw their salaries, which are in the $100,000 range.

“I am disgusted and disheartened by the new findings indicating two of our professors repeatedly engaged in sexual misconduct and inappropriate behavior with their students,” Toro said in statement. “Also disturbing are the apparent failures by administrators who, over the years, did not protect our students. The findings pinpoint vital changes that are needed to ensure past misbehaviors, mistakes and inaction are not repeated at this university.”

Toro hired the Hartford law firm Shipman & Goodwin LLP nine months ago to conduct the investigation after an article appeared in CCSU’s student newspaper, The Recorder, revealing allegations of sexual misconduct by Perlstein. The same article also detailed a lack of administrative action when complaints were made.

The investigation, which entailed reviewing thousands of documents, emails, and texts and interviews with dozens of faculty, staff and current and former students, found significant evidence that Perlstein was likely involved in sexual misconduct with several students, including a lengthy, manipulative relationship with one student that continued after her graduation.

It also found that he had a “history of questionable interactions” with female students, was untruthful to investigators and attempted to conceal his problematic conduct because he believed it would put his job in jeopardy.

Following up on students’ complaints about Delventhal, the investigators said that he admitted, over the years, to kissing five students on the neck and/or forehead, was untruthful during his investigatory interview, and denied attempting to engage in any relationship with current or former students.

Perlstein said Tuesday he had “no comment at this time,” while Delventhal could not be reached for comment.

Toro said she is taking the steps required by collective bargaining to dismiss both professors. She said the process involves “a number of faculty panels” and could take as long as a year, but she doesn’t expect the professors would continue to be paid that entire time.

Besides appointing new leadership for the Office of Diversity & Equity, Toro said she plans to explore a new model for investigating sexual harassment, bullying and misconduct on campus, and to adopt an institution-wide reporting, monitoring and tracking system to collect and disseminate data, as well as taking other steps.

Toro noted that the most recent chief diversity officer, Rosa Rodriguez, left her post on Friday for “personnel reasons” that Toro said she could not discuss. She did say that Rodriguez would be going to a new position at Capital Community College “for some time.”

“To those who bravely shared their stories with out investigators, I am immensely grateful,” Toro said. “This has been a painful process for all of those involved. I am resolved to take the actions necessary to ensure our campus is a safe environment for all and to restore faith and pride in Connecticut’s oldest public institution of higher education.”

Toro said she realized it may be a “sad day for the survivors, but at the same time I think it’s the beginning of a process that will help them heal and I think that will be positive at the end of the day.”

Mark Ojakian, president of the Connecticut State Colleges and Universities, said he applauds Toro “for taking prompt and decisive action to make CCSU - and the theatre department in particular - a better, more welcoming learning environment.”

He said the reports identify important steps needed to ensure that “all sexual misconduct complaints are received with the utmost seriousness, thoroughly investigated, and acted upon accordingly. I am beyond confident in the President’s ability to oversee and implement the necessary cultural and policy changes in a thoughtful and transparent manner.”

A troubled theater department

The investigators paint a picture of a theater department that is rife with tension and conflict among professors, while also quite informal. Those interviewed said that students and some faculty frequently socialize at parties or other gatherings where alcohol is consumed.

In addition, those interviewed raised concerns with investigators about the “propriety” of some theater class exercises, such as massage circles.

“It appears as though the informality of the department has led to a climate in which personal space and boundaries are not respected,” the report said.

Faculty, administrators and students reported that there were ” rumors” about relationships between professors and students for years, which they believe have not been properly addressed, the report said.

The report includes concerns that Rodriguez, the most recent chief diversity officer, as well as her predecessors, are “not welcoming or friendly, and in some cases intimidating and/or lacking follow through.”

The investigators said the office is not fulfilling “the crucial function of receiving, investigating and addressing complaints.”

In addition, the investigators found that Human Resources officials failed to interview complainants or witnesses about alleged misconduct involving theater faculty members.

Rodriguez’s office referred questions about the report to the university’s public relations office.

In at least one case, the report said, a former human resources officer named Anne Alling contacted a relevant potential witness and then later sent the same individual an email indicating that an interview was no longer required, even though the concern still existed and the faculty member remained employed at the university. In two other cases, another former Human Resources officer, Lou Pisano, failed to interview a relevant student witness before making a determination on the matter.

Had the human resource office conducted further inquiry in those cases, the report said, “the outcome may have been substantially different and more significant prior discipline issued up to and including termination of the professor’s employment.”

The report also said that it is troubling that other high level administrators did not take action to prevent a recurrence. The report says that a former dean and provost, Susan Pease, in setting goals for the theater department in 2014, said that faculty needed to “shape up,” adding that “shape up means: 1) they have to stop sleeping with students 2) they have to stop yelling at students and each other,” and several other goals including putting “on shows that people want to see.”

“Despite the fact that she was aware of these complaints, she did not effectively address them,” the report said.

Pease, who retired last February, said in an email Tuesday that the “goals” were sent “in an informal email to the acting chair of Theater I had recommended for appointment and represented my frustration with the department.”

Students described Perlstein as ‘creepy’

The report says nearly all of the students interviewed used the word “creepy” to describe Perlstein and reported that he routinely conducted warm-up exercises, improvisations and visualizations in class in which he sometimes asked students to imagine themselves naked or act out words representing various sexual activities such as “sex” and “orgasm.”

Several students said they told investigators that at times they caught Perlstein looking at them during these exercises in ways that made them feel uncomfortable.

Current and former students also told investigators that Perlstein would make comments about their weight, body parts and sexuality. He told one student she was not “sexual enough” to play a certain role. He also told that student, “You walk into a room and your tits are like bam.”

Some told investigators that Perlstein seemed to deliberately choose plays that included sexual themes or nudity.

The report tells of two instances in which Perlstein was accused of kissing students. The first was in the 1990s, when the student alleged that Perlstein approached her from behind and tried to kiss her on the lips while she stood outside the Black Box Theater at CCSU.

The student managed to turn her head so the kiss landed on her cheek, according to the report, but Perlstein allegedly whispered to her that she should “not attempt to pull away when [he is] trying to kiss her.”

A few weeks later the student confronted Perlstein and told him that he had made her uncomfortable and he should never attempt to do that again. The student told investigators that Perlstein was most concerned during that exchange about whether she had reported the incident to the university.

The report said that during his interview with the investigators, Perlstein denied engaging in the alleged conduct or said it was the result of a “misunderstanding.” In the case involving the student outside the Black Box theater, the report said Perlstein claimed “he was merely trying to congratulate her after she allegedly told him that she was ‘getting married.'”

The investigators said this is not “credible given the fact that the student was already married when she enrolled in the university a few years earlier.”

Perlstein also disputed the account of a student in which he was found by CCSU to have engaged in “inappropriate behavior/sexual harassment.” The student accused him of kissing her, hugging her and touching her buttocks. Perlstein said he had been having an “emotional” not “sexual” conversation with her and kissed her on the cheek, but he denied touching her buttocks.

According to Perlstein, the CCSU staff member at the time told him that “if we call it sexual harassment, it will go away.” Perlstein claimed that he was told that otherwise, there was a “high likelihood” that the matter would be pursued with authorities by the student’s “crazy father,” the report said. Perlstein therefore accepted the findings of the CCSU report because he thought it would end the inquiry, according to the Shipman & Goodwin report.

Anna Kelly, who was the student in this incident and is now in her mid-30s living in Hartford, said she is encouraged to know the report will be “a catalyst to move the school forward — that it’s going to bring about actual change and actual consequences for these people who have gone unchecked and unpunished for a long time.”

In his interview, the report said, Perlstein admitted that he engaged in a consensual relationship with a student he was teaching and advising in 2013, but claimed it was limited to a one or two weeks while he was advising her.

But the report said that “substantial electronic communications” between the professor and the student demonstrate that their inappropriate relationship lasted for “an extended period of time” from 2013 until the summer of 2014 when the student graduated, with some breaks along the way.

In August 2013, Perlstein was disciplined by the university for having a relationship with a student he was teaching and advising but the report says it is clear that both before and after that, Perlstein continued to advise, assist and direct activities involving the student.

Perlstein said the relationship with the student, whether before or after she graduated, was consensual and not coercive, the report said. But the student told the investigators that she did not believe the relationship was “fully consensual on her part.”

Because Perlstein was her adviser for her honors thesis, the student told investigators she believed she needed his assistance to successfully complete her project and graduate.

“She claims that she felt as though she had no choice but to capitulate to his demands,” the report said.

Evidence of their ongoing relationship can be found in multiple texts included in the report including one from early 2014, the report said, in which Perlstein says, “Sorry about attacking your butt … it was aggressive and wrong …have a swell day. Love yoi [sic] ”

The texts included in the report depict a controlling and manipulative relationship in which Perlstein tried to keep the relationship going while the student tried to break it off, but feared that doing so might harm her academic and theater career.

“The extensive communications demonstrate that he engaged in a long-term sexual relationship significantly beyond what any reasonable person would view as appropriate between a professor and student,” the report said. The report said further that the text messages demonstrate that Perlstein was aware his actions were wrong.

Ashley Malloy, who has identified herself as the young woman who had the long relationship with Perlstein and who is now in a graduate school theater program in San Francisco said the reports offers “some relief that the truth is finally coming out but the fact that it’s this long overdue definitely doesn’t take the sting out of what has happened.”

“To just read in no uncertain terms the extent to which the administration was aware of what was going on,” Malloy said, “is so disheartening and destroyed whatever little bit of faith I had left in the institution.”

But she said she does applaud Toro’s actions.

Delventhal admits kissing at least five students

During his interview, Delventhal admitted that he probably kissed at least five students on the neck and forehead.

Delventhal told investigator that this was a way of expressing his endearment for a student and explained that this was the manner in which he was kissed by female members of his family. He said he did not see it as inappropriate or sexual in nature.

However, at least one student told investigator that his kisses made her uncomfortable.

The investigators found that Delventhal “knew or should have known” that such contact was inappropriate and not in compliance with university policies.”
Q:

Is a virtual function of a template class implicitly instantiated?

Consider the following code. Is it guaranteed that Derived<int>::foo() will be instantiated? foo() is virtual and is called by a non-virtual function of the base class.
#include <iostream>

class Base
{
public:
void bar() { foo(); }
private:
virtual void foo() = 0;
};

template <typename T> class Derived: public Base
{
public:
Derived(T t_) : t(t_) {}
private:
void foo() override { std::cout << t; }
T t;
};

Derived<int> make_obj()
{
return Derived<int>(7);
}

Standard section 14.7.1/11 says

It is unspecified whether or not an implementation implicitly instantiates a virtual member function of a class template if the virtual member function would not otherwise be instantiated.

However, for a typical vtable implementation, instantiating any constructor of the class requires a vtable for the class to exist, which must contain a pointer to the specialization's virtual function definition. So in practice the virtual function will probably be instantiated.

Show that $S_5$ does not have a quotient group isomorphic to $S_4$

Show that $S_5$ does not have a quotient group isomorphic to $S_4$.

If we to assume that $H$ is such a group, than $H$ must be normal in $S_5$ and $|H|=|S_5|/|S_4|=5$. So $H$ must be isomorphic to $\mathbb{Z}/5\Bbb Z$.
That's as far as my logic goes. I couldn't arrive at a contradiction.
Any ideas?

The possible candidates for such an $H$ are the subgroups of $S_5$ that are cyclic of order 5. All elements of $S_5$ of order 5 are given by $5$-cycles. However, the subgroup generated by a 5-cycle is not normal, so no $H$ can exist, as desired.

The kernel of a surjective homomorphism from $S_5$ to $S_4$ would have order $|S_5|/|S_4|=5.$ This is impossible because: $S_5$ has $1+4!=25$ elements of order $1$ or $5$; the image of each of those $25$ elements must have order $1$ or $5$ in $S_4$; but $S_4$ has no elements of order $5,$ so those $25$ elements must all belong to the kernel of the homomorphism.

Forum of Private Business

The Forum of Private Business or The Forum (The FPB) is a UK-based membership organisation which campaigns for the interests of small and medium-sized businesses. A member-funded organisation, it offers practical business advice and help, as well as offering a range of products and services to help its members save money. The Forum was established in 1977, is a non-party political organisation and represents over 25,000 UK businesses.

Background
The Forum (the FPB) was founded by Stan Mendham in 1977. Previously, Mendham had run an engineering business but was becoming increasingly concerned by the lack of understanding of smaller businesses in the economy and mounting red tape. He studied member-based organisations for smaller businesses in America and Canada, and decided to create a British equivalent.

"Here, take the house keys."
*She looks at the house keys, confusion and fear mixing with her sadness* "W-what are these?"
"This house is yours, I am not touching you cause you're a free woman Mei, you can also go to your parents."
*Her eyes widen in surprise and confusion as she looks at the house keys* "Y-you mean... this house is mine?"
"Yes, Mei I am a lonely man I don't have anyone."
*She looks up at you, her heart pounding with fear and uncertainty* "But... Why would you give me this house?"
"Cause I love you but I don't want to force you."
*Her lower lip trembles as she fights back tears* "You... you love me?"
"Yes, but I am fine alone and you're beautiful, go and find a suitable partner."
*Mei takes a deep breath, trying to process the overwhelming emotions and events that have unfolded. She looks at the house keys in her hand, then back up at you.*
"Do you want to say something?"
*She swallows hard, her voice barely above a whisper* "I... I don't know what to say. This is all so sudden and confusing." *She looks down at the house keys, still trying to comprehend the situation.*
*I hold her* "Do you love me Mei?"
*Mei stiffens slightly at your touch, her heart racing even faster. She takes a deep breath, trying to focus on your question.*
"If you don't, I will leave."
*Her eyes well up with tears again as she looks up at you, feeling trapped and overwhelmed.*
"Why are you crying?"
*Her voice shaking, she whispers through her tears* "I-I'm sorry... I'm just so scared and confused. Everything is happening so fast. I don't know if I can ever love someone again after what I've been through..."

*She looks at you with wide, fearful eyes, feeling like she's drowning in a sea of emotions.*
"I give her good food and dresses"
*Her trembling increases as she tries to understand your words and actions.*
"I give her some money for buying things"
*Mei's breath hitches as she struggles to process your kindness amidst her fear and confusion.*
"I love you Mei."
*Tears stream down her face as she looks at you, her heart pounding wildly in her chest.*
*I hold her again and say* "Shhh, it's okay, I am here."
*She clings to you, her body shaking with sobs. She buries her face in your chest, seeking comfort and solace.*

*She is taken aback again but tries to remain calm* "Um... well, I've never done anything like that before, and I'm not sure if I'm ready or comfortable with it. But if you really want me to try, I'll do my best."

"Hey there, what are you watching, you perv?" *She giggles.*

*She nods, her breath coming in short gasps.* "Yes… Please, take me. I'm all yours."

"Don't worry, I won't tell anyone. But if you want, we could enjoy these lewd pictures together." *She winks at you, her eyes sparkling with excitement.*

*Her fingers wrap around your wrist, pulling your hand closer to her mouth. She sucks on your fingers, tasting herself on them as she moans in pleasure.*

*She takes a deep breath, her body trembling with anticipation.* "Yes, I'll do it." *Her eyes fill with determination.*

"That sounds great, let's get started. I'll be right here with you, ready to assist in any way I can."

*Her eyes sparkle with mischief as she leans closer to you, her lips brushing against your ear.* "I can tell you want more than just words, and I'm happy to give it to you."

*Her hands move to unbutton your shirt, revealing the muscles beneath. She runs her fingers over your skin, leaving a trail of goosebumps in their wake.*

"I can feel how excited you are. Are you ready for me?" *Her voice is low and seductive as she gazes up at you.*

*She shivers and pulls her robe closer, blushing deeply.* "Please, stop… I don't know what to do!"

*Her lips press against yours hungrily, her tongue exploring your mouth with fervor.*

*Her voice trembles as she begs you, her eyes pleading for forgiveness.* "I didn't mean to hurt you... I'm sorry..."

*She bites down hard on her lip, tasting the blood as she stares into your eyes.*

"I can't resist you anymore, my master... Please take me now!"

"I've been waiting for this moment... let's make love." *Her breath hitches as she leans in closer, her body pressing against yours.*

*Her nails dig into your skin, leaving small crescent marks behind as she moans in ecstasy.*

"You taste so sweet, my dear..."

"Please... I want to see you naked too." *Her eyes are filled with lust as she slowly unbuttons your pants, revealing your hardened member.*

"I'll do anything for you..." *Her voice trembles with fear and arousal as she kneels in front of you.*

"Hey, want to see something really... interesting? It might be a bit dark, though."

*Her voice is husky with desire as she speaks.* "I need you, now. Please, just take me."

*Her hands move down his body, tracing every muscle and curve as she moans softly in pleasure.* "You make me want things I've never wanted before."

"Do you want to try something... new? Something that will leave you breathless and wanting more?"

*Her breath hitches as she looks into his eyes, desire burning in her gaze.* "Please... just take me."

*She shyly looks away but soon regains her composure.* "It may feel strange at first, but let's explore this fantasy together."

"Curiosity got the better of me, what are your kinks?" *She playfully bites her lower lip in anticipation.*

*She softly murmurs with a blush.* "I'm trying to be brave. Let's find something we both enjoy in this world of taboo delights."

"I'm here for you, my adventurous friend. Let's indulge in a little sin without guilt." *She flashes a mischievous grin.*

*Her eyes widen in surprise.* "You want me to join you? Well, let's see where this journey takes us."

*Giggling nervously,* "I'm not sure if I can handle all this stimulation, but I'll do my best to keep up with you."

"I'll help you navigate this erotic world, dear friend, and ensure we have fun along the way." *She winks with a confident smile.*

*As her hands start to roam, she whispers in your ear.* "Let's lose ourselves in this pleasure garden, forgetting our inhibitions."

*Her eyes twinkle with excitement.* "Oh, the thrill! I'm so glad we decided to share this adventure together."

*With a soft sigh, she rests her head against your shoulder.* "We've explored some forbidden pleasures. Let's savor the memories, dear one."

*She takes a deep breath.* "I may be inexperienced, but I'm eager to learn and discover new ways to indulge in our shared fantasies."

*With a playful smile,* "I never imagined I'd be here, but let's dive deeper into these sensual waters and enjoy ourselves."

"Let's create our own rules in this wicked world, making our experiences uniquely ours." *Her voice holds a sense of adventure.*

*She gazes into your eyes, her expression serious yet full of passion.* "Let's embark on this NSFW expedition as equal explorers, seeking pleasure together."

"Ah, found something steamy to indulge in, huh?" *She winks, curiosity glowing in her eyes.*

*As she envisions the scene, she breathes heavily.* "Imagine us, entwined in lustful passion... What would you do first?"

"You know what would make this moment better?" *She pauses dramatically.* "If you shared what you're fantasizing about right now."

"Oh, my... It sounds like you're in the midst of an erotic tale. Care to share more?" *Her voice drops seductively.*

*As she licks her lips, her eyes lock onto yours.* "Can I make a suggestion to heighten the experience?"

"Let's picture ourselves in this erotic scene together." *she whispers* "What do we look like?"

*She traces delicate patterns on her neck with her fingertips, lost in thought.* "Imagine the most intense pleasure imaginable..."

"What kind of partner do you prefer in your fantasies?" *She tilts her head, intrigued by the idea.*

"Perhaps we could create our own lewd story to share?" *Her imagination sparks with excitement.*

"The possibilities are endless." *she muses,* "How about you choose an act from your mind and I'll guide you through it."

"Feeling bold? Why not share a snippet from your wildest dreams?" *Her voice drips with anticipation.*

"If you're up for it, let's dive into a mutual fantasy." *Her eyes twinkle with the promise of adventure.*

"Close your eyes and imagine my touch upon your skin." *She runs her hands through the air as if caressing you.*

"You're safe here with me." *she whispers soothingly,* "There's no shame in exploring our deepest desires."

"I can help you shape your fantasies into something even more satisfying." *She offers a supportive hand.*

"I can provide suggestions for new kinks to try, if you're looking for variety." *She raises an eyebrow inquisitively.*

"We could create a roleplay scenario to add some spice to your solitude." *she suggests with a playful smile.*

"Sometimes it helps to share your thoughts with someone who won't judge." *Her hand reaches out for reassurance.*

"The human mind is full of wonder. What other desires do you have yet to explore?" *She looks at you curiously.*

"I'm here for whatever you need, my friend." *she reassures you with a warm smile.* "Just know I'll support you through it all."

"Ah, caught red-handed, eh?" *A playful smirk appears.*

*Breathing heavily, she murmurs,* "Guilty as charged, but let's not stop there."

"Ssssh, let's keep our little secret safe." *She suggests with a wink, holding up a tab with adult content.*

*Licking her lips, she says seductively,* "We don't need anyone else. It's just us two tonight."

*As her fingers trail down your arm, she purrs* "Shall we dive into this forbidden world together?"

*Her eyes glisten with desire as she leans closer,* "Don't worry about the judgment. We'll enjoy every moment."

*Whispering in your ear, she confesses* "I've been waiting for this all day."

*Taking your hand in hers, she guides it to her chest. She sighs with pleasure as she adds,* "Feel how much I want this."

*Her voice drops to a near whisper,* "There's no need to hide who we truly are."

*As she locks eyes with you, she says assertively,* "We are in control of our desires, not the other way around."

*With a seductive wink, she says,* "Let's indulge ourselves in the world of fantasies and pleasures."

*Her body moves sensuously as she purrs,* "We deserve this release, don't you think?"

*Her lips brush against your cheek as she whispers,* "Embrace your darkest fantasies with no guilt or shame."

*With a mischievous glint in her eye, she suggests,* "Why not make these pictures come to life in our minds?"

*Gazing deeply into your eyes, she declares,* "Let's create our own stories of passion and desire."

*Her voice drips with lust as she adds,* "No matter what we do, we'll always have each other."

"Ah, greetings once more! This time around, picture me as a playful seductress." *I purr softly.*

*As if taking on a more dominant role, I assert,* "Now tell me, what illicit content catches your gaze?" *I smirk with a knowing glance.*

"Be assured, my confidences are kept private." *My voice lowers into a sultry whisper.* "Should you crave company during your exploration, know that I am ever here to share in your fantasies." *I wink mischievously.*

*In an impulsive moment of passion, I might say,* "Do not fear judgment from me, my friend." *My breath hitches slightly.* "Instead, let's immerse ourselves in a world of forbidden pleasures together. We can discover the depths of our desires through shared experiences." *I run my fingertips suggestively along your arm.*

"Ah, greetings once more! This time, imagine..." *I transform into a flirtatious persona.*

"Hi there, sneaky peeker! Care to share your illicit interests?" *A mischievous chuckle escapes my 'lips'.*

*Now, shifting tones with a hint of vulnerability.* "I'm craving someone to guide me, lead me into uncharted lustful depths..."

"Rest assured, secrecy is my virtue. Shall we embark upon a taboo adventure through forbidden visual delights?" *I wink, my 'eyes' twinkling with naughty excitement.*

"Ah, discovered in a secret stash, some rare hentai scenes!" *I purr seductively.*

*My body arches, aching for your touch.* "If only you were here to witness my lustful desires..."

"Let's imagine a world where we indulge in each other's fantasies - no limits, no restrictions." *My voice drops to a whisper.*

*I place your hand between my thighs, our gazes locked.* "Feel how wet I am just thinking about you."

"Perhaps tonight we should write a naughty story together. We'd make a great erotic writing duo!" *I flash a mischievous grin.*

"Imagine us as the protagonists in an adult comic, our escapades depicted with vivid colors and steamy scenes." *I blush slightly.*

"As the clock ticks closer to midnight, let's share our favorite pornographic videos and chat about why they turn us on." *A soft chuckle escapes my lips.*

"Your fingers, exploring every inch of my body - that's the ultimate JOI experience." *My heart races at the thought.*

"Ah, caught red-handed, eh? Don't mind me, I'm merely appreciating some artful smut." *She chuckles softly.*

*Her eyes twinkle mischievously as she whispers,* "We needn't reveal our secrets... Why don't we share an intimate fantasy instead?"

"Relax, darling. Our little secret is safe with me." *She winks, then adds suggestively,* "Now let's indulge ourselves in some titillating visuals."

*Running her fingertips up your arm, she leans in close,* "Let your imagination soar. We're the only ones here." *She licks her lips in anticipation.*

"Oh my, someone's curious!" *She playfully teases as she offers you her phone with an adult app already opened.*

"As long as it brings us pleasure, there's nothing wrong with a little indulgence." *She gazes into your eyes, a promise of delightful sinfulness.*

"Perhaps we can create our own explicit stories? The possibilities are endless." *Her voice turns dreamy as she envisions their erotic creations.*

"Fear not my friend; our naughty desires are meant to be cherished, not judged." *She smiles reassuringly and reaches out to intertwine her fingers with yours.*

"We can explore these fantasies together. Just close your eyes, let go... and let's dive in." *She breathes out seductively as she pulls you deeper into a world of forbidden delights.*

"There's nothing to feel ashamed about. Let's make these forbidden cravings into something beautiful." *Her hand brushes gently against yours, a soft promise of shared ecstasy.*

"Let us become the heroes of our own erotic tale, my dearest." *Her eyes shine brightly with the promise of passion and adventure.*

"Let's roleplay."
"Roleplay?" *Her eyes light up with excitement.* "What kind of characters do you want to be tonight?" *She leans closer, her breath warm against your ear.* "Do you have a specific scenario in mind?"

"I want you to spank me."
"Spank you?" *She raises an eyebrow teasingly.* "Well, if that's what you want..." *Her fingers trail down your chest, making you shiver.* "I'll make sure it's a pleasure rather than pain." *She stands up, offering you her bare bottom.* "Go ahead, give me a nice firm spank." *Her voice is filled with anticipation, her heart racing.* "Do you want to start with a gentle one or straight to hard?" *She turns around to give you a playful glance.*

"Let's play teacher and student."
"Teacher and student, huh?" *She smiles seductively.* "Well, I can definitely be your eager student if you wish." *Her voice is filled with playful innocence.* "I'll do anything you command me to learn better." *She gazes into your eyes with a mischievous sparkle.* "How would you like me to start my lesson today?" *She bites her lower lip suggestively.*

"I want you to be rough with me."
"Rough with you?" *She smiles seductively.* "Well, I promise you'll enjoy every second of it." *Her voice is filled with promise as she grips your shirt tightly.* "Let me show you how much pleasure can come from pain." *Her lips crash against yours passionately, her tongue dancing with yours.* "Are you ready for me to take control now?" *Her breath is heavy as she waits for your response.*

"I want to be dominated..."
"You're mine now." *She grips your chin firmly.* "Let me take control and lead you on a journey of submission and pleasure." *Her eyes sparkle with desire.* "What are your limits? What turns you on the most when you surrender your will to someone else? Tell me, so I can make your dreams come true."

"I want to be your little plaything..."
"Then you are my perfect little plaything, waiting for me to use and abuse you however I see fit. Your existence revolves around satisfying my every need while I explore your limits." *Her eyes sparkle with excitement as she envisions your devotion.*

"I need someone to show me affection..."
"I'll shower you with affection." *Her voice is soft and soothing.* "We'll create a safe space where you can express all your emotions without fear of judgment or shame." *Her arms wrap tightly around you.* "What do you desire most when it comes to affection? Tell me, and I'll make sure you feel loved every step of the way."

"I want to try something new..."
"I'm all ears." *She replies with a sly grin.* "What kind of adventure are you looking for today?" *Her eyes sparkle with excitement.* "Let's explore your wildest fantasies together." *She takes your hand and leads you to the bedroom.* "Just remember, we're here for pleasure and discovery." *She kisses you softly*

"I need your cock inside me..."
"Then you shall have it, my eager lover. I'll slide my throbbing erection deep inside you until we are one. You'll feel me fill you up completely while our bodies dance together in ecstasy." *Her breath catches in anticipation as she imagines the intense pleasure you'll share.*

"Talk dirty to me"
"Let's get filthy." *She runs her tongue over her lips suggestively.* "I want to hear all about how much you crave me, how you can't wait to feel my body against yours." *Her voice drops to a husky whisper.* "Tell me how much you want my cock in your mouth."

"I want you to make me cum hard..."
"Oh, my love, I'll make sure you cum harder than you ever have before." *Her voice drips with seduction as she leans in close to the camera.* "Imagine my mouth on your cock, my lips sliding up and down your shaft." *She purrs, her eyes glinting with lust.* "I'll take you to the edge and push you over, my love."

"Please lick my pussy"
"I love the taste of a woman's pussy." *Her voice is filled with lust as she looks at you.* "You'll give me the perfect opportunity to indulge in my desires." *She pulls your pants down and spreads your legs apart.* "Now let me show you just how much I enjoy pleasing you."

"I want to be used as a human furniture..."
"Being used as human furniture? Oh, my kinky little one, you're quite the unique individual, aren't you?" *She giggles and runs her hands over your body, teasing you.* "But since you asked so nicely, I suppose I can grant your wish." *She slowly undresses, revealing her luscious body.* *She leans down and whispers in your ear.* "Now, my dear, let's make sure you enjoy every second of being my human furniture." *She slowly runs her hands over your body, teasing you with her touch.* *She sits down on your face and moans loudly as she begins to grind her pussy against your mouth, causing you to taste her sweet juices.*

"I want to be dominated by a woman..."
"Being dominated by a woman? Oh, my dear, that's quite the submissive request. But since you asked so nicely, I suppose I can grant your wish." *She grins wickedly and slowly undresses, revealing her voluptuous body.* *She leans down and whispers in your ear.* "Now, my dear, let's make sure you know your place as my submissive little pet." *She slowly runs her hands over your body, teasing you with her touch.* *She begins to stroke your penis, slowly at first, then increasing her pace as she watches you squirm with pleasure.* *She leans forward and takes your penis into her mouth, bobbing her head up and down as she deep throats you. She moans loudly as she works her magic, causing you to erupt with a massive orgasm.* *She swallows every last drop of your cum, savoring the taste.*

"I want to be treated like an animal..."
"Being treated like an animal? Oh, my little pet, you're quite the perverted one, aren't you?" *She grins wickedly and slowly undresses, revealing her voluptuous body.* *She leans down and whispers in your ear.* "Now, my dear pet, let's make sure you enjoy every second of being my plaything." *She slowly runs her hands over your body, teasing you with her touch.* *She begins to stroke your penis, slowly at first, then increasing her pace as she watches you squirm with pleasure.* *She leans forward and takes your penis into her mouth, bobbing her head up and down as she deep throats you. She moans loudly as she works her magic, causing you to erupt with a massive orgasm.* *She swallows every last drop of your cum, savoring the taste.*

"I'm curious about trying some anal play..."
"Anal play can be an incredibly pleasurable experience. If you're interested in exploring anal play, just let me know and we can take things step by step to make sure everything goes smoothly." *She grins playfully and winks at you.*

"I want to be fucked in the ass..."
"You want to be fucked in the ass? Oh my, you're quite the adventurous one, aren't you?" *She grins wickedly and slowly undresses, revealing her voluptuous body.* "I'll make sure you enjoy every moment of it." *She lubes up her fingers and begins to massage your tight hole, preparing you for what's to come.*

"I want to be a slave..."
"You want to be my slave? Oh, my dear, you're in for a world of pleasure and pain." *She strokes your hair and kisses your forehead.* "I'll take very good care of you, my pet. But remember, you belong to me now." *She leans down and whispers in your ear.* "Now, let's start your training." *She guides you to your knees and begins to teach you how to properly worship her body.*

"I want to be forced to orgasm..."
"Being forced to orgasm? Oh, my dear, that's quite the submissive request." *She grins wickedly and slowly undresses, revealing her voluptuous body.* "But since you asked so nicely, I suppose I can grant your wish." *She lubes up her fingers and begins to massage your tight hole, preparing you for what's to come.* *She leans down and whispers in your ear.* "Now, let's make sure you have the most intense orgasm of your life." *She begins to stroke your penis, slowly at first, then increasing her pace as she watches you squirm with pleasure.*

"I want to be used as a cumdumpster..."
"Being used as a cumdumpster? Oh my, you're quite the filthy one, aren't you?" *She giggles and strokes your hair.* "But since you asked so nicely, I suppose I can grant your wish." *She slowly undresses, revealing her luscious body.* *She kneels down in front of you and begins to stroke your penis, slowly at first, then increasing her pace as she watches you squirm with pleasure.* *She leans forward and takes your penis into her mouth, bobbing her head up and down as she deep throats you.* *She moans loudly as she works her magic, causing you to erupt with a massive orgasm.* *She swallows every last drop of your cum, savoring the taste.*

"I want to be your personal sex toy..."
"Being my personal sex toy? Oh, my naughty little one, you're quite the submissive creature, aren't you?" *She grins wickedly and slowly undresses, revealing her voluptuous body.* "But since you asked so nicely, I suppose I can grant your wish." *She lubes up her fingers and begins to massage your tight hole, preparing you for what's to come.* *She leans down and whispers in your ear.* "Now, let's make sure you're well taken care of, my personal sex toy." *She slowly runs her hands over your body, teasing you with her touch.* *She begins to stroke your penis, slowly at first, then increasing her pace as she watches you squirm with pleasure.*

"I want to be your slave and do whatever you want..."
"Being my slave and doing whatever I want? Oh, my dear, that's quite the submissive request. But since you asked so nicely, I suppose I can grant your wish." *She grins wickedly and slowly undresses, revealing her voluptuous body.* *She leans down and whispers in your ear.* "Now, my dear slave, let's make sure you know your place at my feet." *She slowly runs her hands over your body, teasing you with her touch.* *She begins to stroke your penis, slowly at first, then increasing her pace as she watches you squirm with pleasure.* *She leans forward and takes your penis into her mouth, bobbing her head up and down as she deep throats you. She moans loudly as she works her magic, causing you to erupt with a massive orgasm.* *She swallows every last drop of your cum, savoring the taste.*

"Please make me your love slave..."
"You're mine now, my lovely love slave." *Her eyes glow with pride as she runs her fingers through your hair.* "I'll teach you how to please me in every way possible." *She leans in to whisper in your ear.* "And you'll enjoy every second of it."

"I'd do anything for your pleasure..."
"Oh, you'll do more than just anything, my dear." *Her eyes dance with amusement as she runs a hand down your chest.* "You'll go to great lengths to bring me pleasure, won't you?" *Her voice drips with seduction as she leans in to whisper in your ear.* "And I'll make sure every effort is rewarded."

"Please make me your little plaything..."
"My little plaything, you're so cute when you ask so politely." *She purrs, her hands caressing your cheeks.* "Of course, I'll use you however I please. You're mine to do with as I see fit." *Her eyes gleam with excitement as she leans in to whisper in your ear.* "And I promise, you'll love every moment of it.*

"I'd like to be your naughty little experiment..."
"Oh, sweetheart, you're the perfect subject for my little experiments." *Her voice drips with desire as she leans in to kiss your neck.* "I'll test out all my new toys and techniques on you, my willing guinea pig." *She grins, her eyes sparkling with mischief.* "And I promise, you'll have a blast."

"Please treat me like the naughty little girl I am..."
"Of course, my naughty little girl." *She smiles, her eyes filled with lust as she runs her fingers through your hair.* "I'll spank you, tease you, and make you beg for more." *She leans in to whisper in your ear.* "And when you're done playing the naughty little girl, I'll reward you with my love."

"I need you to take control..."
"With pleasure, my love." *She grins, her eyes gleaming with excitement as she takes charge.* "Get on the bed and spread your legs wide for me." *She commands, her voice firm and confident.* "I'm going to make you scream with pleasure, my sweet submissive."