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A lot of startups struggle with whether they should hire a professional to create their video or just do it themselves. I ask, why not both? While I have a stake in the video production game, the truth is there's a time and place for both and more video is always better. It puts a face on a brand and helps connect people to other people. That is why video is so great. As mentioned there's a time and place for both, so when is the time and place? I usually recommend you use the 80/20 rule.
What the heck is the 80/20 rule?
The 80/20 rule is basically that you need professionally produced video as part of your content strategy to attract and educate people at the top of your marketing funnel. If you are creating lots of video content, this is your 20%. What makes up this 20%? These are your explainer videos, slick and quick product demos and all the content to help get viewers on the path to becoming customers.
The 80% is the "do it yourself" content. These are your webinar recordings, screenshare demos, off the cuff interviews, FAQ videos, and other support videos. These are for the viewers who are further down your marketing funnel and are getting closer to becoming customers. They aren't necessarily looking for the really polished stuff; they're looking to understand who they will be doing business with and what kind of support you'll be providing to them. The trick is to serve the right content to the right viewer.
Identifying the Audience
The 80/20 rule also applies to identifying your audience. It's just flipped. As you can see in the image above, many of the 80% are those browsing for information; the top of your marketing funnel. These are the tire kickers, the ones casually looking to see if your product or service is the solution they are looking for. They're in the discovery stage. These are the ones looking for that 20% professionally produced content. This is your explainer video featured on the home page quickly and easily breaking down what you do and if it will solve their problem in 90 seconds or less.
The 20% of your audience are those that are further down your marketing funnel. They've already watched that explainer video, been doing their research and now have you on a short list and are wondering about your organization, your support, etc. This is the 80% do it yourself content. The best part is, because they are further down your marketing funnel, their attention span is longer. They may be willing to sit through a 30 minute webinar recording because they have some level of intent. This content is a deeper dive. It's not on your home page. It should be on your blog or, depending upon its importance to the decision making process, possibly gated content so you can start to engage some of these very interested viewers.
Alright, that's a lot of numbers. I don't usually write many posts like this but I think the concept is important. If you get nothing else out of this, the takeaway is there is a place for both professionally produced content and the stuff you do yourself. You just need to know when and where to serve each type of video content up.


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Travel Girls
These cute girls: Lea, Lee and Lilou are going on a trip in India. They will travel by bus, train and airplane and they need a big luggage for their days on the trip. Help them choose different clothes for what the girls need and enjoy the game!
Tags: trip, friends, girls, travel, mygames4girls, mygames4girls, bus, train

subset: commoncrawl


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Oh, for more history written by biologists. The great thing about Guns, Germs and Steel is the detail: Jared Diamond starts with a proposition every good Guardian reader would wish to believe – that all humans are born with much the same abilities – and then proceeds to argue, through meticulous and logical steps, that the playing field of prehistory was anything but level.
The inequalities kicked off with the development of agriculture in one small part of the world, the so-called Fertile Crescent in what is now western Asia. Agriculture stimulates increasing population density, which means disease, which means acquired immunity. Civilisation requires the food surplus only agriculture can provide, but it also imposes a need for specialisation, for technology, for ingenuity. Competing civilisations (and they turned up soon enough in Europe and the Middle East) provoke an arms race.
So you start with stone tools and the raw materials for a Welsh rarebit and you end up with galleons, guns and measles, all of which helped 168 Spanish conquistadores in 1532 to overthrow an army of 80,000 Incas half way around the world.
But what was so special about the Fertile Crescent?
It had emmer and einkorn, species of grass with heavy seeds. Some individuals in these wild wheat ancestors had developed mutations that boded ill for their evolutionary survival. Instead of spilling their seed upon the ground, these doomed stalks kept their ears pricked, so to speak: their seed heads stayed neatly on the stem, long past ripening. This accident made them dish of the day for foraging nomads, and then ideal for the first, tentative plantations by the hunters and gatherers who so casually launched human civilisation some time after the end of the last ice age.
Pretty much the same mutation then occurred in certain wild pulses, which stayed in the pod, as a kind of packed lunch, rather than falling to the soil to multiply.
But it took more than one or two convenient plants that were ripe for the picking to get civilisation off the ground. The shuffling of the evolutionary pack dealt the hunter gatherers who happened to be living in eastern Turkey, the Levant and the valley of the Euphrates a whole suite of wild staples, all in that one huge curve of valley, hillside and floodplain: barley and lentils, olives, figs, sweet almonds, chickpeas, mustard and so on.
The seeds of wild wheat were not just big and easy to gather, they delivered the best nourishment. And not far away, contentedly chewing on a choice of the other wild grasses and pulses, were wild cattle, sheep and goats all suitable for domestication, and potentially docile swine as well.
So the groundbreaking farmers of the Fertile Crescent, with their makeshift mattocks, stone sickles and crude pestles and mortars, already had about them the makings of the first ploughman's lunch of bread and butter and cheese and beer; the first Mediterranean diet of wine, olive oil, peas and prosciutto; and everything for a beefburger except the tomatoes, ketchup and mayo.
Agricultural settlement also began independently in China and Mexico, because these places also had little packages of this and that – rice and soya, maize, beans and squash – from which to construct a cuisine and a culture.
Other places were not so fortunate. The entire continent of Africa produced a few scattered plants – coffee, millet, sorghum, groundnut and yams – but these species did not share the same climate so they could not all be grown in the same place. And not one large African mammal has ever been satisfactorily domesticated, even now. Meanwhile, the Fertile Crescent had four of them at the end of the last ice age, mooing and bleating and oinking for human attention.
And the same package of plants and animals that flourished in the Fertile Crescent could – with a bit of adjustment – do just as well on both sides of the Mediterranean, in the Alpine valleys, on the great European plain, and all the way to the Breton coast.
So the ploughman's lunch was not just a local meal: it could be exported from Nineveh to Nuneaton.
This is an exhilarating book. Not all the argument is quite as beautifully constructed as the passages that deal with plants and animals. Diamond's foray into human prehistory provoked the American Anthropological Association into devoting a whole session to examining the ideas he sets out in this book and more especially its sequel, Collapse.
The latter then became a scholarly Cambridge text which was reviewed in Science on 22 January. This particular issue of Science might have been edited with our club's choice in mind. The big feature focuses on evidence for permanent houses of stone, built by hunter-gatherers in the Fertile Crescent 14,500 years ago, long before the emergence of agriculture.
Another feature is devoted to the disappearance of Australia's giant marsupials, 40,000 years ago, around about the time the first bands of human hunters turned up. These extinctions – and similar megafaunal massacres happened in Eurasia too – left Australia and North America with no candidate creature for domestication, which is why the locals were better off with their old skills of hunting and gathering.
If I have a problem, it is with Diamond's prologue. On page 22 of Guns, Germs and Steel, he argues that people in New Guinea today who have never been exposed to passive televisual entertainment, and with every stimulus to think for themselves, might even be, because of their environment, mentally more able than Westerners. This seems to concede that some lineal groups can be innately "better" than others, which is the starting point for all racist claims.
Damn, can he have meant that? Surely it was to see off such thinking that prompted a club member to propose this book in the first place?
For March, something that really does add up. Ian Stewart has suggested that even his fellow scientists don't really appreciate the profound importance of mathematics. Professor Stewart recently delivered his own two-fisted mathematical punch with his Cabinet of Mathematical Curiosities (2008) and Hoard of Mathematical Treasures (2009). Both are huge fun. Grab one and enjoy it. I'll look at both on Friday 19 March


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Smucker Sales & Service has been a family owned business since 1979! Our many years of experience allows us to assist you in finding the best product to fit your needs as well as install and maintain your power generating equipment. Smucker Sales and Service offer service and maintenance on each product. All products are backed with our 24 hour emergency service!
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Christmas Present Breakdown
We scored some great gifts that we're going to integrate into our bedroom and we want to show you what we got:
From left to right, top to bottom:
- Silk frayed pillow from West Elm in a silver color (on sale)
- Studded velvet pillow from West Elm in charcoal (on sale)
- Zinc-color letter "J" (for Jones!) from Restoration Hardware (total splurge)
- Black-and-white crystal vase from Dale Tiffany – via Joss & Main (PS: if you click through our website to register, we get a small credit when you buy something)
- Sweater pillow cover from West Elm… West Elm actually calls it "sculpted origami" but we think it looks more like a sweater
Naturally, we are planning to put the pillows on our bed. We want the bed to be the focus of our bedroom and piling up the pillows really helps draw attention to it. The best part is that using pillows does not require us to invest a lot of money to get a big impact. We're not sure how we're going to use the vase and the metal "J" yet, but when we decide, we'll let you know!
Inspired by our new Christmas presents, we are going to turn our focus back to decorating our bedroom. We have a plan in the works to DIY a headboard. Krister does the constructing in our house (Kristin does more
buying decorating). Unfortunately, Krister is tied up with fixing the suspension in the truck, so you won't see the new headboard for a while.
We'll do a few "tables scapes" (for lack of a better word) on existing surfaces in the bedroom. Also, we're on the hunt for a nightstand, bedding, and some photo frames to help spruce the room up. As always, we'll keep you posted.


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State names 311 Four Star schools
A total of 311 schools statewide, including about 100 in the metropolitan Indianapolis area, have earned Four Star Awards for 2012-13.
Each year, the Indiana Department of Education recognizes schools that perform in the upper 25th percentile of schools in three ISTEP-based categories.
"Winning this award required excellent work by teachers, administrators, students and parents throughout the year, and on behalf of the entire Indiana Department of Education, I send them my sincere congratulations," said state Superintendent of Public Instruction Glenda Ritz.
Here's a list of Four Star schools in the metro Indianapolis area:
Boone County
• Zionsville: Eagle Elementary; Pleasant View Elementary; Stonegate Elementary; Union Elementary; Zionsville High; Zionsville Middle.
Hamilton County
• Carmel Clay: Carmel High; Carmel Middle; Cherry Tree Elementary; Clay Middle; College Wood Elementary; Creekside Middle; Prairie Trace Elementary; Smoky Row Elementary; Towne Meadow Elementary; West Clay Elementary; Woodbrook Elementary.
• Hamilton Southeastern: Brooks School Elementary; Durbin Elementary; Fall Creek Intermediate; Fishers High; Fishers Junior High; Geist Elementary; Hamilton Southeastern High; Hamilton Southeastern Junior High; Lantern Road Elementary; New Britton Elementary; Riverside Junior High; Thorpe Creek Elementary.
• Noblesville: Hinkle Creek Elementary; Noblesville High; Noblesville West Middle.
• Westfield-Washington: Maple Glen Elementary; Oak Trace Elementary; Shamrock Springs Elementary; Westfield High; Westfield Middle.
Hancock County
• Eastern Hancock: Eastern Hancock High.
• Greenfield-Central: Community Junior High; Eden Elementary; Harris Elementary; Weston Elementary.
• Mt. Vernon: Mt. Vernon High.
• Southern Hancock: New Palestine High; Doe Creek Middle.
Hendricks County
• Avon: Avon High; Avon Intermediate East; Avon Intermediate West; Avon Middle North; Avon Middle South; Hickory Elementary; White Oak Elementary.
• Brownsburg: Brown Elementary; Brownsburg East Middle; Brownsburg High; Brownsburg West Middle; Eagle Elementary; White Lick Elementary.
• Danville: Danville High.
• Mill Creek: Cascade Elementary; Cascade Senior High; Mill Creek West Elementary.
• Northwest Hendricks: North Salem Elementary; Pittsboro Elementary; Tri-West Middle; Tri-West Senior High.
> Plainfield: Brentwood Elementary; Central Elementary; Clarks Creek Elementary; Plainfield Middle; Plainfield High; Van Buren Elementary.
Marion County
• Franklin Township: Bunker Hill Elementary; Franklin Central High.
• Indianapolis: Center for Inquiry II; Crispus Attucks Medical Magnet High; Merle Sidener Gifted Academy.
• Perry Township: Rosa Parks-Edison Elementary.
• Wayne Township: Ben Davis University High.
Johnson County
• Center Grove: Center Grove Elementary; Center Grove High; Center Grove Middle Central; Maple Grove Elementary; Sugar Grove Elementary.
• Clark-Pleasant: Break-O-Day Elementary, New Whiteland; Clark Pleasant Intermediate; Clark Pleasant Middle.
• Franklin: Union Elementary.
• Greenwood: Greenwood High.
Calvary Christian, Indianapolis; Flanner House Elementary, Indianapolis; Herron High, Indianapolis; Holy Cross Lutheran, Indianapolis; Lutheran High, Indianapolis; Oaks Academy, Indianapolis; Tindley Accelerated, Indianapolis.
• Archdiocese of Indianapolis: Bishop Chatard High; Brebeuf Jesuit Preparatory; Cathedral High; Christ The King; Immaculate Heart of Mary; Roncalli High; St. Luke; St. Pius X; St. Simon The Apostle; St. Thomas Aquinas, all Indianapolis; St. Susanna, Plainfield.
• Diocese of Lafayette: Guerin Catholic High, Noblesville; Our Lady of Grace, Noblesville; Our Lady of Mount Carmel, Carmel; St. Louis de Montfort, Fishers; St. Maria Goretti, Westfield.
Call Star reporter Barb Berggoetz at (317) 444-6294. Follow her on Twitter: @barbberg.


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Punjab CM Amarinder Singh promises jobs, debt relief for landless farmers
Punjab CM urges PM Modi not to go ahead with 'anti-farmer legislation'
Congress MP trains guns on Punjab DGP over withdrawal of police security
Punjab minister, two MLAs test Covid-19 positive ahead of assembly session
Punjab allows shops dealing in non-essential shops to open on Saturdays
Terming the Essential Commodities (Amendment) Act 2020, passed by the Lok Sabha on Tuesday, a "direct and deliberate assault" by the Centre on the interests of the farmers, Punjab Chief Minister Amarinder Singh said his Congress will challenge it in court.
Riding roughshod over the concerns of the farmers, the Modi government, of which the Shiromani Akali Dal is a constituent, has imposed a Central law on a state subject, thus eroding the federal structure of the country, he said.
"We will challenge it in court," he said.
Asserting that he will not allow the interests of the farmers to be compromised in this "shameless" manner, Amarinder Singh claimed the enactment of the legislation is clearly a step towards abolition of the MSP regime.
"It is a conspiracy on the part of the BJP-led NDA government to destroy Punjab and its farmers," he said, declaring that the Congress will fight this attack on the state's interests tooth and nail.
"The legislation talks of encouraging competition among farmers. Do they really expect the poor farmers, who are only competing with themselves for survival every day, to rival big corporates for protecting their interests?" he asked.
Noting that the enactment, along with the other two farm ordinances that the Centre has already tabled in the Lok Sabha, was in line with the recommendations of the Shanta Kumar committee, Amarinder Singh pointed out that the same committee had also suggested dismantling of the MSP regime.
It is evident that the NDA government is now moving towards the elimination of the MSP system, which is the lifeline of the farmers, he said, adding that the Congress will not allow the interests of the farming community to be trampled in this manner.
The very survival of the farmers is at stake, he warned.
The Chief Minister also took on SAD chief Sukhbir Badal, who was reportedly present in the House when the bill was passed by a voice vote, for failing to protect the interests of Punjab's farmers, whose messiah he claimed his party to be.
Sukhbir Badal and his SAD were clearly party to the treachery of the Union government, which has paved the way, through the passage of this bill, for taking away the rights of the farmers, who have fed the nation and given it food security for decades, he added.
"Will you quit the ruling coalition at the Centre, or will you continue to wait outside their doors for any crumbs they throw your way?" Amarinder Singh asked Sukhbir Badal, adding that the Akalis had totally and irrevocably failed their own state yet again.
Taking a dig at Sukhbir Badal's remarks that the SAD would live up to the legacy of senior party leaders who had stood with the farmers before him, the Chief Minister said the only legacy that the incumbent Akali chief was promoting was of a party that will always put its own interests over those of Punjab's people, particularly the farmers.
(Only the headline and picture of this report may have been reworked by the Business Standard staff; the rest of the content is auto-generated from a syndicated feed.)
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First Published: Wed, September 16 2020. 06:16 IST


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[Updated Monday, April 15, 2019] One Apex Legends fan took it a step further with the 3D printing of a Loot Tick. Check out this awesome Apex Legends Loot Tick video that will leave you satisfied.
3D Printing
Last month we shared the designs of some 3D printed Apex Legends items done by a talented bunch over at Thingiverse. For those who never heard of the website before, it's a site dedicated to sharing user-created design files. Most of the files found there are 3D printable, and there are a lot of video game related files. A bunch of talented designers have been putting together some great Apex Legends design files, such as Wraiths Kunai Knife, and a life sized P2020. Well one fan took it a step further and made a real life functional loot tick.
Functional Apex Legends Loot Tick
We've featured a 3D printed loot tick model a while back. The seller of that loot tick took the design files off of Thingiverse and 3D printed it. The final product was a mini version that was around 3×3 inches. It was solid all around and you weren't able to move any of the loot tick parts. Well, one Apex Legends fan (reddit user u/TheLAhearts) took it a step further and 3D printed a more functional (and bigger) loot tick. However, he added an additional feature that's no one has ever seen before. Check out the satisfying video below.
The funny thing about the video is that the builder had to create two new legs as they broke in the video.
Where did the User Get the Design From?
The design in the video was created by Jon Jopling at Thingiverse. He goes by the name Jonnyo85 on the site, and the design above can be found here: https://www.thingiverse.com/thing:3426481 . The 3D print in the video was done at 100%, while the model in the Thingiverse page is at 50%.
If you're interested in printing the model shown in the video, just follow the link above. Thanks to Jon for pointing out the original design link.
Link to Reddit post.
Did you enjoy reading This Awesome Apex Legends Loot Tick Video Will Leave You Satisfied? Read Game Life on the GO: Follow us on Twitter @GameLifeHQ


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Streaming giant Netflix has added a new stud to its stable of original series: animated adult comedy BoJack Horseman from Michael Eisner's Tornante. The 12-episode series will launch in mid-2014 across all Netflix territories. Created by Raphael Bob-Waksberg, the show will be animated by L.A.'s ShadowMachine (Robot Chicken). The main character was designed by graphic artist Lisa Hanawalt.
The 2D series revolves around whiskey-swigging humanoid horse BoJack (voiced by Will Arnett), legendary star of the '90s sitcom Horsin' Around, who deals with his personal crises with the help of human sidekick Todd (Breaking Bad's Aaron Paul) and feline agent and ex-lover Princess Caroline (Amy Sedaris). BoJack Horseman will be exec produced by creator Bob-Waksberg, Steven A. Cohen, Noel Bright, Arnett and Paul.
"As a studio executive involved in successful sitcoms like Happy Days, Barney Miller and Cheers, I always regretted BoJack wasn't on my team," Eisner joked in a statement. "But now, with Tornante in the saddle, BoJack is exactly where he belongs, in full creative control, and on Netflix."


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A significant difference was found in Hamilton Rating Scale for Depression score changes between the GG group and GA + AA group at week 6. The score change was −14 (95% confidence interval, −19 to −11) for the GG genotype and was −11 (95% confidence interval, −15 to −6) for the GA + AA genotypes (P = .006 by Mann-Whitney U test). Each box displays the median, 75th percentile, and 25th percentile values; horizontal bars indicate the highest and lowest observed values. NET indicates norepinephrine transporter.
A significant difference was found in Hamilton Rating Scale for Depression score changes between the ll group and ls + ss group at week 6. The score change was −12 (95% confidence interval, −16.5 to −9) for the ll genotype and was −6.5 (95% confidence interval, −8.75 to −5) for ls + ss genotypes (P<.001 by Mann-Whitney U test). Each box displays the median, 75th percentile, and 25th percentile values; horizontal bars indicate the highest and lowest observed value. 5-HTT indicates serotonin transporter gene.
Customize your JAMA Network experience by selecting one or more topics from the list below.
Kim H, Lim S, Kim S, et al. Monoamine Transporter Gene Polymorphisms and Antidepressant Response in Koreans With Late-Life Depression. JAMA. 2006;296(13):1609–1618. doi:10.1001/jama.296.13.1609
© 2022
Author Affiliations: Departments of Psychiatry (Drs H. Kim and D. Kim) and Laboratory Medicine and Genetics (Dr J.-W. Kim), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Center for Clinical Research (Ms Lim) and Biostatistics Unit (Dr S. Kim), Samsung Biomedical Research Institute, Seoul, Korea; Department of Food and Nutrition, Myongji University, Yongin, Korea (Dr Chang); and Pacific Behavioral Research Foundation, Carmel, Calif (Dr Carroll).
Context Polymorphisms in the serotonin transporter gene (5-HTT) may influence antidepressant response to selective serotonin reuptake inhibitors (SSRIs). The norepinephrine transporter (NET) is the analogous target for norepinephrine reuptake inhibitors (NRIs).
Objective To determine whether antidepressant responses to SSRIs or NRIs are associated with genetic polymorphisms of the corresponding monoamine transporters.
Design, Setting, and Patients A 6-week naturalistic treatment study with blinded outcome evaluation of 241 Korean inpatients and outpatients with major depression at an academic psychiatry service. Patients were recruited to the study from March 1998 through February 2003.
Interventions Treatment with an SSRI (fluoxetine or sertraline; n = 136) or an NRI (nortriptyline; n = 105) antidepressant. Adherence was assessed by measuring plasma concentration at 4 weeks. Patients were genotyped for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), 5-HTT intron 2 s/l variation, and NET G1287A variation of exon 9.
Main Outcome Measures An SSRI and NRI response (defined as ≥50% decrease in Hamilton Rating Scale for Depression score at 6 weeks).
Results NRI response was associated with the NET G1287A polymorphism (odds ratio [OR], 7.54; 95% confidence interval [CI], 2.53-22.49; P<.001). An SSRI response was associated with the 5-HTT intron 2 s/l variation (OR, 20.11; 95% CI, 4.27-94.74; P<.001). The 5-HTTLPR was also associated with an SSRI response (OR, 3.34; 95% CI, 1.41-7.91; P = .006). In contrast to studies in white patients, the favorable allele for SSRI response was S 5-HTTLPR. The S5-HTTLPR was associated also with NRI response (OR, 3.73; 95% CI, 1.32-10.53; P = .01). The NET polymorphism was not associated with an SSRI response. The NET G1287A GG genotype (56% of the population) was associated with better response to the NRI (83.3% [35/42]) than to SSRI (58.7% [44/75]) (OR, 3.52; 95% CI, 1.39-8.95; P = .006). Some genotype combinations were associated with high rates of antidepressant response and others with low rates of response.
Conclusions Monoamine transporter gene polymorphisms were associated with response to antidepressants with homologous monoamine transporter targets. Combinations of polymorphisms were informative for response and nonresponse. Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment.
Initial drug treatments fail in 30% to 40% of patients with major depression. Pharmacogenetic prediction of response is one possibility for improving the efficiency of antidepressant treatment. A number of studies have shown that s/l polymorphisms in the serotonin transporter gene (5-HTT) promoter region variation (5-HTTLPR) might predict treatment outcomes to selective serotonin reuptake inhibitors (SSRIs) such as antidepressant response1-7 and adverse events.8,9
However, ethnic variation as well as choice of drug may influence genetic effects on antidepressant response. In white populations,1-5,10 depressed patients with the long allele 5-HTTLPR genotypes (sl and ll) generally show a greater response to SSRIs than those with a short allele genotype (ss). However, studies in Japanese and Korean populations6,7 report an association in the opposite direction. The effect of this polymorphism on treatment outcome may also depend on the mechanism of antidepressant action.2,7,11 A significant association between allelic variation of 5-HTTLPR and antidepressant response was found with fluvoxam ine,1,7 paroxetine2 or sertraline,10 but not with fluvoxamine plus pindolol,1 or nortriptyline,2 or milnacipran.12
In a previous study,6 we found that allelic variation of the 5-HTT gene was associated with variation in antidepressant response to SSRIs. Herein we extend that approach to allelic variation of the norepinephrine transporter (NET), which is the target of the norepinephrine reuptake inhibitor (NRI) class of antidepressant drugs. Due to reported interactions between the monoamine systems, we also included the dopamine transporter (DAT) polymorphism.13 Based on previous studies, we chose 5-HTTLPR and intron 2 variable number of tandem repeats (VNTR) of the 5-HTT gene1,5; the G1287A polymorphism in exon 9, the C296T polymorphism (Thr99Ile) in exon 2, and the G1432A (Gly478Ser) in exon 10 of the NET gene14,15; and the 3′-untranslated region VNTR of the DAT gene13 as candidate gene variants for the prediction of antidepressant responses. The C296T and G1432A polymorphisms of NET and 3′-untranslated region VNTR of the DAT gene were excluded from the analysis because minor alleles of these polymorphisms were relatively uncommon (<5% of the population).
As our primary hypothesis, we predicted significant associations between NRI efficacy and NET polymorphisms and between SSRI efficacy and 5-HTT polymorphisms. If confirmed, these associations could provide a basis for the differential pharmacogenetic prediction of antidepressant response by the mode of the mechanism. In secondary analyses, we compared the NRI and SSRI response rates by genotype. In additional secondary analyses, we examined combinations of polymorphisms and NRI or SSRI response. We chose nortriptyline as the NRI and fluoxetine or sertraline as the SSRI because these are the agents most commonly used to treat late-life depression in Korea. In addition to treatment response, we also monitored adverse events to antidepressants by the UKU Side Effect Rating Scale.16
All patients were of unrelated Korean ancestry. These patients were a completely separate sample from our previous report.6 Patients were eligible if they were at least 18 years of age. Eligible patients were enrolled in the Clinical Trials Program of the Samsung Medical Center Geropsychiatry and Affective Disorder Clinics (Seoul, Korea). They received a semistructured diagnostic interview, the Samsung Psychiatric Evaluation Schedule.6 The affective disorder section of the Samsung Psychiatric Evaluation Schedule uses the Korean version of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.17 At least 1 family member who is living with the patient was interviewed to supplement the patient's report of symptoms, behaviors, level of functioning, duration of episode, and recent treatments. Patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for major depressive episode. Diagnoses were confirmed by a board certified psychiatrist on the basis of the Samsung Psychiatric Evaluation Schedule, case review notes, and other relevant data. A minimum baseline 17-item Hamilton Rating Scale for Depression (HAM-D) score of 15 was required. No patient had received psychotropic medication within 2 weeks of the study or fluoxetine within 4 weeks. Potential study participants were excluded for pregnancy, significant medical conditions, abnormal laboratory baseline values, unstable psychiatric features (eg, suicidal), history of alcohol or drug dependence, seizures, head trauma with loss of consciousness, neurological illness, or concomitant Axis I psychiatric disorder. The protocol was approved by the ethics review board of the Samsung Medical Center. Signed informed consent was obtained from all participants.
A total of 241 patients were enrolled from March 1998 through February 2003. Patients were assigned by a clinician to either an NRI (nortriptyline) or an SSRI (fluoxetine or sertraline). The clinician's drug choice was based on anticipated adverse effects of nortriptyline in at-risk individuals rather than by the symptomatic characteristics of the patients. Factors that determined use of fluoxetine or sertraline in preference to nortriptyline were frailty, osteoporosis, a history of falls, and known cardiovascular disease, including hypotensive episodes. A total of 105 patients received nortriptyline and 136 patients received an SSRI (fluoxetine [n = 51] or sertraline [n = 85]). Dose titration was completed within 2 weeks. Doses were titrated into the usual clinical range based on initial tolerability and adverse effects. The final daily median dosages were 55.0 mg/d of nortriptyline (interquartile range [IQR], 47.5-70.0 mg/d; range, 35.0-100.0 mg/d); 30.0 mg/d of fluoxetine (IQR, 20.0-40.0 mg/d; range, 20.0-50.0 mg/d); and 75.0 mg/d of sertraline (IQR, 75.0-100.0 mg/d; range, 50.0-100.0 mg/d). These are typical clinical doses for Asian populations and they result in comparable plasma drug levels as do higher drug dosages in white populations.18 Trough serum samples to measure NRI and SSRI levels were drawn at the end of week 4. A 1- to 2-mg dose of lorazepam could be prescribed at bedtime for insomnia.
Patients were seen by a psychiatrist, who monitored their adverse events by the UKU Side Effect Rating Scale16 at weeks 0, 0.5, 1, 2, 4, and 6. The 17-item HAM-D was administered by a single trained rater every 2 weeks. The rater and genotyper were blinded to the hypotheses of the study and to drug assignment. To maintain the blind, a trained research coordinator managed the data and schedules. The HAM-D and genotype data were not disclosed to the psychiatrist and the rater was blinded to the genotype data. Response was defined as a 50% or greater decrease in the HAM-D score at 6 weeks. Remission was defined as a HAM-D score of less than 8 at 6 weeks.19
Figure 1 shows the flow of patients through the study. A total of 208 patients (86%) completed the 6-week treatment trial. Sixteen patients who received the NRI and 17 patients who received an SSRI dropped out of the study. Eight patients who received nortriptyline, 3 patients who received fluoxetine, and 5 patients who received sertraline discontinued treatment based on lack of efficacy or intolerable adverse effects. Six patients were excluded because their plasma drug concentrations were undetectable, consistent with nonadherence. Four patients were excluded because their plasma drug concentrations were consistent with extensive drug metabolism: <200 ng/mL for fluoxetine/norfluoxetine and <30 ng/mL for sertraline).20 Seven patients failed to attend scheduled clinic visits. The clinical characteristics of the dropouts did not differ significantly from the completers who received either SSRI or the NRI (data not shown). These 33 dropouts were excluded from the data analyses.
Genomic DNA was extracted from whole blood using a Wizard Genomic Purification kit (Promega, Madison, Wis). Patients were genotyped for 5-HTT promoter region s/l variation (5-HTTLPR), 5-HTT intron 2 s/l variation, and NET G1287A variation of exon 9.
NETPolymorphism. The G1287A polymorphism in exon 9 was amplified by primers 8F (5′-TCCAGGGAGACCCTAATTCC) and 8R (5′-TTGACTTTATTGAAATGCGGC) and digested by the restriction enzyme, Sau96I. Polymerase chain reaction was performed in a total volume of 25 μL that contained 40 ng of genomic DNA, 0.2 mM of dNTP, 10 pmol of primers, 10 mM of tris hydrochloric acid (pH, 8.3), 50 mM of potassium chloride, 3.5 mM of magnesium chloride, 0.1% of Triton-X100, and 0.5 U of Taq polymerase. The polymerase chain reaction condition was 1 cycle of predenaturation at 94°C for 5 minutes, 40 cycles at 94°C for 30 seconds, 57°C for 45 seconds, and 72°C for 45 seconds in series, and 1 cycle of postelongation at 72°C for 10 minutes. The expanded products were digested at 37°C for 1 hour with a restriction enzyme and detected in 12% polyacrylamide gel. Depending on the polymorphic Sau96I site, either a 1287A (113 + 97 + 31 bp) or 1287G (113 + 76 + 31 + 21 bp) fragment was produced.
5-HTTPolymorphism. The VNTR polymorphism in the intron 2 region and the 5-HTTLPR (5-HTT–linked polymorphic region) element in the promoter region were also detected through polymerase chain reaction amplification as described previously.6 The 9 and 10 VNTRs were designated as short alleles and the 12 VNTR was designated as the long allele of the 5-HTT intron 2; the 14 copy of 5-HTTLPR was designated as the short allele and copies 16, 18, 20, and 22 were designated as long alleles.
Plasma levels of nortriptyline, fluoxetine/norfluoxetine, and sertraline were quantified by previously described methods with liquid chromatography tandem mass spectrometry.20-22
Means and SDs, ranges of continuous variables, and proportions of categorical variables are presented as descriptive statistics. The Mann-Whitney U test was used for continuous variables because they were not normally distributed and the χ2 test was used for categorical variables. Hardy-Weinberg equilibrium was tested by the χ2 test. Power analyses were performed to examine if the number of patients was sufficient to produce a statistically significant result, given a true difference. The Fisher exact test was used for comparisons of the genotype and allele frequencies between the antidepressant responders and nonresponders. All 3 genes were entered in the multiple logistic regression model to evaluate the influence of each gene on the response to the medication, adjusting for other genes. The Bonferroni correction was applied for multiple testing. Results were considered significant at P<.05 after this correction. The P values from the Bonferroni correction are stated with the corrected values. The Fisher exact test was used to conduct limited exploratory, post hoc analyses by using a permutation method for multiple testing to examine response rates in relation to genotype combinations. The same method was used to compare differential response to NRI or SSRI by genotype. Measures of linkage disequilibrium were calculated using the Gold program.23 All statistical analyses were performed using SAS software version 9.13 (SAS Institute Inc, Cary, NC).
There were no major differences by sex, number of episodes, age at onset, or HAM-D scores before or after treatment between the NRI-treated and SSRI-treated groups (Table 1). Patients treated with SSRIs were older (mean [SD] age, 59.9 [12.6] years) than those treated with nortriptyline (mean [SD] age, 55.8 [12.4] years). The mean age at onset of major depressive disorder was in the early to mid-50s (Table 1). Rate of response to antidepressants was 124 (60%) of 208 patients who completed the 6-week treatment trial; 55 (62%) of 89 patients who received the NRI and 69 (58%) of 119 patients who received an SSRI (P = .58). Rate of remission did not differ by drug class (26 [29%] of 89 in NRI group vs 34 [29%] of 119 in SSRI group). The overall distribution of response, remission, and nonresponse did not differ by drug class (P = .84).
Genotype distribution for each monoamine transporter polymorphism was not significantly different between the NRI group and SSRI group (Table 2), and was not significantly different within the SSRI group (fluoxetine vs sertraline). The choice of drug in the SSRI group (fluoxetine vs sertraline) had no effect on drug responsiveness (P = .56). Genotypes were unrelated to dropout status or summed total score of the UKU Side Effect Rating Scale in either treatment group. There were no statistical differences in genotype distributions between early onset depression (age ≤59 years) and late-onset depression (age ≥60 years) (P = .25 for the 5-HTTLPR; P = .82 for 5-HTT intron 2; and P = .97 for NET G1287A). Comparisons between younger (age ≤59 years) and older (age ≥60 years) patients were similarly nonsignificant (P = .30, P = .35, and P = .44, respectively).
The mean (SD) plasma levels for responders and nonresponders were 116 (21) ng/mL and 123 (23) ng/mL for nortriptyline; 789 (236) ng/mL and 802 (206) ng/mL for fluoxetine/norfluoxetine; and 75 (29) ng/mL and 72 (28) ng/mL for sertraline and were not significantly different between responders and nonresponders. The responders did not differ significantly by lorazepam dosages from the nonresponders who received either an SSRI (P = .71) or the NRI (P = .46).
The genotype frequencies in the NRI-treated group for the 5-HTTLPR (P = .23), 5-HTT intron 2 (P>.99), and NET G1287A polymorphisms (P = .34) were in Hardy-Weinberg equilibrium. For the power analysis in the NRI-treated group, the response rate of patients with the GG genotype was predicted to be 80% and the response rate of patients with the GA plus AA genotypes was predicted to be 50%. Based on 42 patients with GG genotype and 47 patients with GA plus AA genotypes, the power to detect this difference of 30% is 80% under the significance level of .05.
Response to NRI was strongly associated with the NET G1287A polymorphism (odds ratio [OR], 7.54; 95% confidence interval [CI], 2.53-22.49; P<.001 by multiple logistic regression). A response rate of 83.3% (35/42) was associated with the GG genotype, which was significantly greater than the response rate of 42.6% (20/47) in the GA plus AA genotypes (P = .01; Table 3). The GA and AA genotypes were combined for this analysis because the 1287AA genotype was found in only 6 patients. The reduction in HAM-D score after 6 weeks of NRI treatment was greater in the GG genotype than in the GA plus AA genotypes (P = .006; Figure 2).
The NRI response was also associated with the 5-HTTLPR polymorphism (OR, 3.73; 95% CI, 1.32-10.53; P = .01 by multiple logistic regression). The favorable allele for the NRI response was s allele of 5-HTTLPR polymorphism (P = .003; Table 3). A response rate of 76% (38/50) to the NRI was associated with the ss genotype of the 5-HTTLPR polymorphism. In comparison, the response rates to the NRI were 48% (14/29) in those with the sl genotype and 30% (3/10) in patients who carried the ll genotype. The frequency of the 5-HTTLPRss genotype was significantly higher in the NRI responders than in the nonresponders (P = .006). The l/s polymorphism of 5-HTT intron 2 region had no relationship with the NRI response (OR, 3.34; 95% CI, 0.70-15.91; P = .13 by multiple logistic regression).
Within the SSRI-treated group, the genotype frequencies for the polymorphisms of the 5-HTTLPR (P = .83), 5-HTT intron 2 (P>.99), and NET G1287A (P = .40) were in Hardy-Weinberg equilibrium. For the power analysis, the response rate of the patients with ll genotype in 5-HTT intron 2 was assumed to be 70% compared with 30% in the patients with ls plus ss genotypes. Based on 97 patients with ll and 22 patients with ls plus ss, the power of detecting this difference of 40% is 90% under the significance level of .05.
The genotype distribution and allele frequencies in the SSRI responders and nonresponders appear in Table 3. Response to SSRI was significantly associated with the polymorphisms of the 5-HTT intron 2 and the 5-HTTLPR. Patients with the ll genotype of 5-HTT intron 2 had a 69% (67/97) rate of response to SSRIs compared with only 9% (2/22) for the other 2 genotypes combined (P = .01). The 5-HTT intron 2 polymorphism showed the strongest association with SSRI response among the monoamine transporter gene polymorphisms (OR, 20.11; 95% CI, 4.27-94.74; P<.001 by multiple logistic regression). Figure 3 shows the difference in HAM-D score reduction after 6 weeks of SSRI medication between the two 5-HTT intron 2 genotype groups (ll genotype vs ls+ss genotype, P<.001). Response to SSRI was also significantly associated with polymorphism of the 5-HTTLPR (OR, 3.34; 95% CI, 1.41-7.91; P = .006). Patients with the ss genotype at this site had a 71% (50/70) rate of response to SSRI compared with rates of 40% (17/42) with the ls genotype and 29% (2/7) with the ll genotype (ss genotype vs sl + ll genotypes, P = .003; Table 3). Polymorphisms in the 5-HTTLPR and 5-HTT intron 2 regions in our study population are in partial linkage disequilibrium (r2 = 0.04; D′ = .40), which indicates that 5-HTTLPR and 5-HTT intron 2 may play independent roles in determining drug response. The NET G1287A polymorphism showed no association with response to SSRI drugs (OR, 0.84; 95% CI, 0.34-2.09; P = .71 by multiple logistic regression).
Although it was not a primary focus of this study, we compared the response rates to NRI and SSRI by genotype (Table 3). Only 1 strong association was detected: patients carrying the GG polymorphism of NET G1287A had a higher response rate of 83.3% to NRI treatment (35/42) than the rate of 58.7% to SSRI treatment (44/75), which is a statistically significant difference (OR, 3.52; 95% CI, 1.39-8.95; P = .006 by χ2).
We examined combinations of 2 significant polymorphisms for their association with response to each class of drug. Patients carrying unfavorable genotypes of both polymorphisms (NET G1287A polymorphism A + 5-HTTLPR l) showed the lowest response rate among 4 genotype combination groups on NRI response (Table 4). The response rate of this group (21.7%) was significantly lower than those of the other 3 genotype groups (NET A + 5-HTTLPRss, 62.5%, P = .02; NET GG + 5-HTTLPRl, 75.0%, P = .008; and NET GG + 5-HTTLPRss, 88.5%, P<.001). In the SSRI group, patients carrying favorable genotypes of both 5-HTT intron 2 ll and 5-HTTLPRss had the highest response rate to SSRIs. The response rate of this genotype group to SSRIs (77.4%) was significantly higher than those of the other 3 genotype groups (5-HTT intron 2 ll + 5-HTTLPRl, 54.3%, P = .06; 5-HTT intron 2 s + 5-HTTLPRss, 25.0%, P = .01; and 5-HTT intron 2 s + 5-HTTLPRl, 0%, P<.001).
Our results indicate that (1) antidepressant response to NRI is principally associated with the NET G1287A polymorphism; (2) response to NRI is also secondarily related to the 5-HTTLPR polymorphism; (3) response to SSRI is associated with the 5-HTT intron 2 and 5-HTTLPR polymorphism; and (4) response to SSRI is not related to the NET G1287A polymorphisms. Thus, our primary hypotheses were confirmed and extended.
We observed significant associations of NRI efficacy with NET G1287A polymorphism and of SSRI efficacy with 5-HTT polymorphisms. These findings support the concept that pharmacologically selective antidepressants act primarily through homologous neurotransmitter mechanisms. Thus, our findings are consistent with observations that selective depletion of monoamines leads to relapse in patients who have responded to the homologous monoamine transporter inhibitors.24,25 Our results support our primary hypothesis that responses to NRI and SSRI are significantly associated with their respective transporter polymorphisms.
Our data revealed that the NET G1287A polymorphism plays a major role in the NRI antidepressant response. This polymorphism was reported by Stober et al26 to have no functional consequences and to lack significant associations with major depression, bipolar disorder, schizophrenia, alcohol dependence, or panic disorder.27-30 However, this polymorphism is associated with the cerebrospinal fluid concentration of 3-methoxy-4-hydrophenylglycol, a major norepinephrine metabolite,13 and with the response to methylphenidate, a drug with noradrenergic action, in attention-deficit/hyperactivity disorder.31 The association between the NET polymorphisms and the antidepressant response was previously examined in Japanese patients by Yoshida et al.12 They reported that the NET T182C polymorphism was associated with a superior response to milnacipran, a serotonin and norepinephrine reuptake inhibitor, and that the NET G1287A polymorphism was associated with the onset of response but not the final clinical improvement. Thus, our data add to the basis for considering that the NET G1287A polymorphism does have functional consequences.
The 5-HTTLPR polymorphism had significant associations with both the SSRI (P = .003) and nortriptyline responses (P = .006). Few studies have examined the relationship between the 5-HTTLPR polymorphism and NRI response. Pollock et al2 examined this polymorphism and response to nortriptyline in 23 patients and found no differences. Tsapakis et al32 reported a trend association between the 5-HTTLPR and response to tricyclic antidepressant treatment. Our study is the largest to date to show that the 5-HTTLPR is associated with a response to nortriptyline as well as to an SSRI. We see this finding as consistent with preclinical studies that indicate facilitation of multiple neurotransmitter systems by antidepressant agents.33,34 "Cross-talk" between the noradrenergic and serotonergic systems may explain why drugs acting selectively on either one or other of these systems are both active at relieving symptoms of depression.35
The observed association of the 5-HTTLPR polymorphism with the response to both NRIs and SSRIs may signal a more general association of this polymorphism with response to multiple interventions for depression, including drugs of several classes, placebo, sleep deprivation, and light therapy. It was reported in a white population that patients with the long allele (especially ll genotype) of 5-HTTLPR are more responsive to placebo, sleep deprivation, and light therapy as well as more responsive to drug than those with the short allele.4,36
In this independent sample, we replicated our finding6 that a variable repeat sequence of 5-HTTLPR is associated with response to SSRI drugs in depressed patients (P = .003; Table 3), although the favorable allelic variant for response again is at odds with studies in white patients.1-5 The reason for this ethnic difference remains unclear. However, the data suggest several speculations. First, allelic frequencies for 5-HTTLPR in Korean and Japanese populations differ greatly from white populations. The allele frequency of l variant 5-HTTLPR in Korean and Japanese populations is about 25%6,7,37,38 compared with about 55% in white populations.1-3,39 If we assumed from studies of white patients that the l variant 5-HTTLPR is the favorable allele for response to SSRIs, we might expect a low rate of response of Korean and Japanese patients to those agents. However, a consistent finding is that 60% to 70% of depressed patients respond to SSRI drugs in multicenter clinical trials regardless of ethnic group.40-43 Thus, other genetic explanations for this ethnic difference must be sought.
The second speculation is that 5-HTTLPR is linked with unknown functional variants. It may be an associated marker in linkage disequilibrium with a functional site, rather than a functional polymorphism itself. The authentic functional sequence variants may be in strong linkage disequilibrium with the l allele in whites and also in linkage disequilibrium with the s allele in Koreans. Similarly, there may be a functional site closely linked with the second intronic VNTR in the Korean population (but not in the white population) that is associated with SSRI response. Different ethnic populations may have other polymorphisms in linkage disequilibrium with 5-HTT polymorphisms.
Moreover, it may not be possible to explain the ethnic difference by analyzing only these 2 polymorphisms. Thus, although studies to date have focused on these 2 polymorphisms of the 5-HTT gene, the ethnic variation observed between this study and others suggests that these alleles are only indirectly responsible for the observed interactions with treatment response. New approaches that include whole gene sequencing or entire single nucleotide polymorphism (SNP) analyses are needed to identify the responsible loci. In this regard, we note that the current SNP database from the National Center for Biotechnology Information Web site shows 111 SNPs in the 5-HTT gene, and all of these should be considered in the search for functional polymorphisms. Our finding illustrates the importance of comparing ethnic groups to confirm candidate pharmacogenetic markers.
As to the prediction of differential drug response, our preliminary data analysis suggests that patients carrying the GG polymorphism of NET G1287A will have a statistically significantly superior rate of response to NRI treatment than to SSRI treatment (83.3% vs 58.7% [P = .006]; OR, 3.52 [95% CI, 1.39-8.95]). As this genetic subgroup comprised 56% of the population (117/208 cases), this result may prove to have salience for clinical practice. This preliminary finding needs to be tested in studies specifically designed to examine differential response to drug class by genotype.
At least some of the individual variation in antidepressant treatment outcome has a genetic basis.44 Although the functional influence of these transporter polymorphisms is not fully understood, it is related to the transcription of individual genes. The l and s variants of the promoter polymorphism have functional differences in modulating transcription of the 5-HTT gene as well as subsequent 5-HTT availability.45 These allele-specific functional differences have been confirmed in human tissues including the brain.46,47 Thus, the 5-HTT polymorphisms might influence response to treatment by modulating transcription of 5-HTT, a direct target of SSRIs.
Our exploratory post hoc analyses point to the predictive potential of combinations of polymorphisms. Two significant polymorphisms, NET G1287A and 5-HTTLPR, contributed to the prediction of NRI response. For instance, in patients carrying the A allele of the NET G1287A polymorphism, the rate of response to nortriptyline was 43% (20/47) (Table 4). After stratifying by the 5-HTTLPR polymorphism, however, the rates of response to nortriptyline were 63% (15/24) in those with the combination of NET A plus 5-HTTLPRss and only 22% (5/23) in those with the combination of NET A plus 5-HTTLPRl (P = .02). For SSRIs, two 5-HTT polymorphisms contributed to the prediction of response, with no contribution from NET polymorphism. As the number of favorable genotypes (ss in 5-HTTLPR and ll in 5-HTT intron 2) increased, the response rate to SSRIs increased (77.4% for 2 favorable genotypes, 54.3% and 25.0% for 1 favorable genotype, and 0% for no favorable genotype). Notwithstanding the small size of the subgroup samples for these secondary analyses, these differential response rates by polymorphism combination are statistically significant or nearly so and they are potentially clinically meaningful.
It is also interesting that the effect of the 5-HTT intron 2 polymorphism varies by drug. That is, even within a single gene, the association between this polymorphism and outcome is drug-class specific. Likewise, the effect of the NET G1287A polymorphism is drug-class specific.
The primary limitation of this study is its seminaturalistic design, in which the antidepressant was selected by clinician's choice, driven by safety considerations, and titrated to a final dosage based on therapeutic responses or intolerable adverse effects. However, the data confirm that choice of drug was not related to the underlying genotypes. The 2 treatment groups did not differ meaningfully in their demographic or clinical features, and the primary hypotheses did not involve a comparison between the drugs. Moreover, compliance with treatment was checked by drug plasma levels at 4 weeks, and outcome was evaluated by a trained rater who was blinded to both drug status and genotype.
The second limitation of this study is the absence of a placebo-treated group. Because we do not know the rate of nonspecific or nondrug attributable response, we cannot determine from the present data whether subgroups with high rates of response (Table 3 and Table 4) reflect specific drug effects or combinations of drug effect with high nonspecific response rates. Stronger inference is possible with respect to the subgroups in which low rates of response were seen. These groups must have a low placebo-response rate as well as a low drug-response rate. In future studies it will be important to resolve this issue of nonspecific drug response in relation to genotype. Nevertheless, the naturalistic design of our study reflects the de facto conditions of managing depression in primary care, in which drugs are a first-line treatment and placebo is not used.48 Whether these monoamine transporter genotypes additionally predict response to placebo or to psychotherapy of depression remains to be studied.
Our patients were mostly elderly (77% age >50 years), and most (60%) had late-onset illnesses with few previous depressive episodes. Eighty-eight percent of all cases were in their first or second lifetime episode of depression. We adopted strict criteria for a previous major depressive episode, excluding minor depression or dysthymia. It is unclear whether late-life depression has distinctive genetic contributions. It is generally accepted that familial risk for an affective disorder is reduced after age 50 years and that patients with late-onset depression are less likely to have psychiatric comorbidity and more likely to have medical comorbidity. However, studies have demonstrated that depression symptoms in older adults might be more heritable than previously thought,49 and that early onset and late-onset groups do not differ from each other in genotype frequency distribution of the two 5-HTT gene polymorphisms.50,51 Likewise, it is not known whether antidepressant response and pharmacogenetic effects are affected by age in general or by the age at onset.52,53 We found no differences in genotype distributions between early onset (126 patients aged ≤59 years) and late-onset (82 patients aged ≥60 years) by χ2 tests for 5-HTTLPR (P = .25), 5-HTT intron 2 (P = .82), and NET G1287A (P = .97). The result was similar when we compared genotype distributions between mid-life (89 patients aged ≤59 years) and later in life (119 patients aged ≥60 years) by χ2 tests for 5-HTTLPR (P = .30), 5-HTT intron 2 (P = .35), and NET G1287A (P = .44). As for treatment response, some previous pharmacogenetic studies reported similar results with elderly and younger patients when controlling for ethnicity and drug.4,8,54
Despite these limitations, this study demonstrates that the responses to antidepressants with different targets have significant associations with homologous monoamine transporter gene polymorphisms. Our data confirm a relationship between SSRI response and 5-HTT polymorphisms, and establish an association between NRI response and the NET G1287A polymorphism. We also found that the 5-HTTLPRs/l variation plays a role in the treatment of depression with both NRI and SSRI agents. The results of this study need to be confirmed in other populations, using selective NRIs other than nortriptyline. Additional studies in younger populations with depression are also needed.
Corresponding Author: Doh Kwan Kim, MD, PhD, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Kangnam-gu, Seoul 135-710, Korea (email@example.com).
Author Contributions: Dr D. Kim had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: H. Kim, Lim, S. Kim, J. Kim, Chang, Carroll, D. Kim.
Acquisition of data: H. Kim, Lim, J. Kim, Chang, D. Kim.
Analysis and interpretation of data: H. Kim, S. Kim, Carroll, D. Kim.
Drafting of the manuscript: H. Kim, Lim, S. Kim, Chang, Carroll, D. Kim.
Critical revision of the manuscript for important intellectual content: H. Kim, S. Kim, J. Kim, Carroll, D. Kim.
Statistical analysis: H. Kim, S. Kim, Carroll, D. Kim.
Obtained funding: D. Kim.
Administrative, technical, or material support: H. Kim, Lim, Chang, D. Kim.
Study supervision: J. Kim, D. Kim.
Financial Disclosures: Dr D. Kim reported receiving drug-trial related clinical research grants from Lilly, Organon, and Pfizer. Dr Carroll reported being a consultant to AstraZeneca, Becton Dickinson, Bristol-Myers Squibb, Cato Research, Cyberonics, DuPont, GlaxoSmithKline, Ives Laboratories, Janssen, Lilly, National Medical Laboratories, Novartis, Pfizer, Roche, Servier, Shire, Skila, and Wyeth; receiving research support from Janssen, Pfizer, and Wyeth; and receiving speaker honoraria from Abbott, Janssen, Lilly, Pfizer, and Wyeth. No other authors reported financial disclosures.
Funding/Support: This study was supported by grant 03-PJ10-PG13-GD01-0002 from the Korea Health Research and Development Project, Ministry of Health and Welfare, Republic of Korea.
Role of the Sponsor: The Ministry of Health and Welfare, Republic of Korea, did not have any involvement in the design of the study, nor was it involved in the data management and analysis, manuscript preparation, and review or approval of the manuscript.


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A Method To Write Brilliant Essays
At the beginning of transition to separate food it is difficult for some to eat schnitzel, cutlet or fish fillet without habitual garnish (potatoes, makaron or bread, however in the course of reorganization the feeling of discomfort quickly will pass. Anyway begin a lunch with a big portion of salad. Further it is possible to include vegetable broth or vegetable cream soup, any portion of meat or fish or the eggs or soy dish added with a large number of vegetables. At desire as a dessert eat unsweetened fruit.


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About me
Team leader of year 1 to 6 at Maniototo Area School. Teacher of year 1. Interested in leading teachers to meet the needs of all students through increasing student choice, control and self direction. I have two boys, a cat, a dog and a husband whose full time job is supporting the family.


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Daniel Kreisman is an Associate Professor of Economics at Georgia State University. His research addresses topics in labor economics, education finance and education policy. He is also Director of CTEx - a consortium of researchers and state partners working to inform the future of high school Career and Technical Education in the US.
Dan holds a PhD in Public Policy from the University of Chicago, and a BA in History and Philosophy from Tulane. Before graduate school Dan taught high school English in New Orleans.
He became a Research Fellow in October 2018.


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By Stephanie Helmer
Posted in Education, Market development
2019 was already the year where Ampoules gradually became better known, but according to the beauty experts, ampoules will really break through in 2020. After all, every skin is different and therefore needs its own approach. The skin can use a boost in its time.
What are Ampoules?
Ampoules are glass tubes and contain high concentrations of a specific active substance, such as vitamins A or C, hyaluronic acid, .. And can then be used as a supplement to the day cream.
This allows you to solve very specific problems. More and more brands, such as Vichy, Collistar and Sisley for example, have launched ampoules last year. The ampoule is used in one go, in contrast to a serum that is often provided with a dropper and is massaged with a few drops at a time. After the ampoule or serum, the day cream and the foundation follows.
Eberlin Biocosmetics, a brand used by several beauty salons, also works with ampoules. Not only can the ampoules be used under the cream, the beautician can also personalize a cream. For example, a nourishing day cream that also contains extra ampoules that have an effect on hydration and / or strengthening. This creates a very powerful and functional cream.
Then use a booster under your foundation for that night out, then the result will be amazing.
Which Ampoule suits me best?
Eberlin has ampoules in the BioMolecular Complexes Line
BMC – Firming – firming with sagging skin
BMC – C Activator – for a fresh appearance with tired skin
BMC – Moisterizer – for dehydrated skin
BMC – Protein – lack of muscle tension, malnourished skin
BMC – Xebor – for oily skin with acne
The daily use of a serum can be supplemented with ampoules a few times a year. So it is better not to wait until the skin screams, but assume an average of 4 times a year in the form of a small cure.
Wondering which ampoule fits your skin best? Ask your beautician about it.
For more information about Eberlin for the salon; www.elisabethcosmetics.com


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Big Brother 2013 Spoilers: Finale Interviews (VIDEOS)|
Big Brother 2013 started off with so much hope and promise and we all thought it would be a longer summer and a great season on Big Brother 15. What we were left with was one of the most controversial seasons and a lot of people anxiously wait for it to end or not even making it to the end to watch. It happens, but I have been providing videos of the interviews with Jeff Schroeder after the finale and now I am combining the last five into on Big Brother 2013 spoilers post.
I found the season to be enjoyable, even though it was tough to cover at times. We had some characters that is for sure and here are the videos for the remaining five and links to the other videos:
Nick Uhas
Jessie Kowalski
Kaitlin Barnaby
Jeremy McGuire
David Girton
As far as the other videos, here are links to all my posts from today:
- Aaryn Gries
- Amanda Zuckerman
- Andy Herren
- Candice Stewart
- Elissa Slater
- GinaMarie Zimmerman
- Helen Kim
- Howard Overby
- Judd Daugherty
- McCrae Olson
- Spencer Clawson
I hope you enjoyed them all. Some of them were very good and entertaining!
Join us on Big Big Brother for all your Big Brother 2013 spoilers, news, recaps, previews, pictures and much more! Find us on Twitter and keep up with us on Facebook. Don't forget Big Brother 15 live feeds for even more Big Brother fun, but uncensored! Every sign up helps support this site to keep bringing you Big Brother 15 spoilers, news and gossip all season long.
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12 Responses to "Big Brother 2013 Spoilers: Finale Interviews (VIDEOS)"
A big thank you Todd…hopefully next year will be much better!
Great job Todd!! 🙂
Thank you Todd!
Thanks, Todd.
LMAO… when I finally found this page the last 2 weeks , I was really excited , reading the post and Todd doing such a great job.. but it did not take but one of my comments on naming the ppl getting fired , that the ( as they put it ) ppl been here all season , to jump.my ass , and say I did not know what I was talking about !! REALLY ???? They made fun of me saying oh dumb ass believes EVERYTHING on the net !! Well , well , well , … GUESS WHO IS LAUGHING NOW !! They said they new Andy was wich I told them.he never was full time.anyway , but they made fun of me on the rest of them… so those bullets can kiss it !! I WAS RIGHT !! Todd you are awesome but the ppl who sit up and comment all day all.night , need to check themselves , just cause a newbie makes a TRUE COMMENT OR ANY COMMEMT ThEY GO CRAZY !! I will have to find a diff. Site next year , as many of others said ,cause your followers are just plain mean , ignorant , and need education , similar to half of bb15 house guest..This post excludes LILLY , SHE WAS AWESOME .. AND CAN CONFIRM.ME.GETTING MY ADS JUMPED.FOR.BOOK I REASON !! Night ..
Last sentence.. should have said she can confirm me getting my ass jumped.for.NO REASON..
Really!?! I caught the gist of what you were saying, but this uneducated person (not really) found your post hard to understand. Anyhow, who shit in your lunch pail today? Why don't you just upload all of your info so that we can all be in the know? No one said you were wrong, we just don't believe it, & that's our prerogative. I for one don't believe everything I hear.
Thanks for all your efforts getting these interviews posted, Todd!!!
Boy, that Nick can talk, eh? Still say he would have been interesting to have a round longer. Wouldn't mind him back again for a second chance.
Hey, everyone, watch Kaitlyn's interview!!! She could be a BBB fan! Maybe she's REALLY Jan Jan…!
AWESOME JOB!!!! I didn't find the website until about the 4th or 5th week and became an immediate fan. Next season, if I can figure out how to do it, I will be sure to sign up so I can support the site. Know you brought a lot of enjoyment to a house bound old lady. THANK YOU!!!
Thanks so much Todd, and to everyone else on this site! You have all made this season tolerable! hehe 😉 Much love and see you all next year for sure!!!


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Will there be life after Wolfowitz?
Unloved and demoralised, the bank still has work to do, especially in Africa
WHEN Paul Wolfowitz was named as president of the World Bank just two years ago, optimists compared him to another of the Pentagon's controversial sons, Robert McNamara. Perhaps, like the mastermind of the Vietnam war, Mr Wolfowitz would quit the rubble of a failed conflict to build a righteous empire of aid. But now Mr Wolfowitz is likened less to a benign emperor than to Caesar's suspect spouse.
As recrimination swirls around him, squabbles over his future are dragging on. As The Economist went to press, the bank's executive directors—civil servants who oversee the bank on behalf of member governments—had yet to pass judgment on the deal Mr Wolfowitz struck for his girlfriend, Shaha Riza, in August 2005. A bank employee, she was not allowed to keep her job when he took his. Prompted by his directors, Mr Wolfowitz posted Ms Riza outside the bank—and gave her a promotion. The terms he set proved too rich for bank staff, and some donor governments, to stomach.
At this month's spring meetings, the 24 ministers who steer the institution showed both indignation and indecision. The Americans who appointed Mr Wolfowitz have not abandoned him, and the European donors who want him out seem to will the end but not the means. Mr Wolfowitz is so far refusing to make it easy for them. He seems unmoved by an unprecedented ministerial communiqué, voicing fears about the bank's credibility and the motivation of its staff.
Both have been badly damaged. In their rage, the staff have shed all deference and discretion. Some heckled their president to his face in the vast atrium of the bank's headquarters; others have written to bank directors urging them to seek his resignation. One of his two deputies, Graeme Wheeler, has reportedly advised him to jump, and other senior staff are considering leaving if he doesn't.
Why did the bank's people desert their boss so dramatically? Some insiders have known for a while that Ms Riza left on cushy terms. In January 2006, a whistleblower calling himself "John Smith" sent an e-mail to the bank's directors, complaining about the $180,000 salary the bank was paying her in her new job at the State Department. The board's ethics committee looked into it, and found the e-mails told them nothing new. Mr Smith warned them of a "trial by the media" if they did not act. Sure enough, the Washington Post last month reported that Ms Riza was now getting $193,590, more than the secretary of state. Disgruntled staff finally had the tip of a spear they had wanted to throw at Mr Wolfowitz for some time.
He came to the bank tainted by his role as a champion of the Iraq war. Opposition to the war, he still thinks, explains much of the hostility to him. "For people who disagree with things they associate with me in my previous job," he said on April 12th, "I am not in my previous job."
The truth is perhaps more subtle. Some of the bank's professionals complain that he is too secure in his own insights, unimpressed by the accumulated wisdom of the institution. That intellectual temperament may explain both his enthusiasm for invading Iraq and his lack of support in an institution that prides itself on its expertise. Moreover, if Mr Wolfowitz entered the bank expecting to fight his corner against a staunchly anti-war staff, his expectation may have been self-fulfilling. Certainly his underlings dislike the sectarian style Mr Wolfowitz seems to share with the man who appointed him.
If Mr Wolfowitz is an overconfident thinker, he also seems an insecure manager, too impressed by bumptious aides. The career staff resent his richly rewarded inner circle, drafted in from his past. They say Kevin Kellems, his press flak, and Robin Cleveland, his right-hand woman, make too much money (about $250,000 a year, tax-free). Staff are fond of sharing stories about Ms Cleveland's aggressive style, some of which no doubt improve in the telling. "I am very focused," she counters, exasperated by the rumour mill. "I am not asking for sympathy so much as fairness," but "no one cares about that at this point."
Two intimates hardly constitute "an army of Bush administration retreads", as Mr Wolfowitz points out. But some of his attempts to widen the gene pool have proved disastrous. According to leaked e-mails, Juan José Daboub, a former conservative finance minister of El Salvador named last year as the bank's managing director, last month ordered that all reference to family planning be expunged from the bank's aid strategy for Madagascar. This is a country where, the bank said in 2004, the use of modern contraceptives is stagnant and sexually transmitted disease abounds. "I am biting my tongue to avoid saying something impolitic," a bank official wrote at the time.
Demoralised, the bank is also compromised. Mr Wolfowitz has espoused a policy of "zero tolerance" towards graft and corruption in the bank's staff and activities. The "actions of even a very small number of individuals can tarnish the reputation of an entire organisation," he wrote in the latest report of the bank's internal investigations unit. The unit last year found two people guilty of a conflict of interest; both were banned from bank employment. Moreover, the bank allocates aid to the poorest countries according to a formula in which "governance", broadly defined, plays much the biggest role. Mr Wolfowitz's underlings must rate a country's state apparatus on a scale of one to six, and justify their scores to the government under scrutiny. Where people are promoted according to personal ties rather than merit, the bank gives a score of only two out of six; where ombudsmen and auditors exist, but lack authority, the bank gives a score of just three. So by its own measure, the bank might not now deserve much support.
See you, or pass
That is a sad state of affairs, because the bank needs support. In June it will turn to donors at a gathering in Mozambique, asking them to pledge money to its self-loan agency, the International Development Association (IDA), for the three years starting in mid-2008. If it is not to shrink in real terms, it must raise at least $18.4 billion from 42 governments, each of which wants to see the others' cards first.
That sum is only about the same as the bonuses paid last year in the City of London. But even before this week's scandal, some donors appeared stand-offish. Indeed, as of January 31st Mr Wolfowitz's political sponsors in America had yet to pay the bank $525m they still owed from previous funding rounds (though some of that money is in America's recently passed 2008 budget).
Mr Wolfowitz apologised for his indiscretion only once during the meetings. But he twice chided bank donors for their own lapses. They "are in danger of not fulfilling their promises" to double aid to Africa, he said on April 16th. That "would be a tragic mistake", he noted three days before.
The begathon is haunted by one of Mr Wolfowitz's early triumphs. In September 2005 the bank agreed to forgive the debts of many of its poorest borrowers. Mr Wolfowitz then helped persuade the bank's donors to compensate it "dollar-for-dollar" for debt repayments it would no longer receive. That will add another $6.1 billion for this funding round. But America, Canada, Japan and Italy among others are being slow to meet these commitments.
The danger is that the president's troubles will provide unsympathetic governments with an alibi for backsliding. If the bank lacks motivation and credibility, they will say, can it be as effective as it should be? And if it cannot, should not a responsible donor put its money elsewhere? There are now over 230 international organisations, funds and initiatives, the bank calculates. The United Nations agencies and the European Commission are now bigger donors than IDA (although not in the poorest countries). And Hilary Benn, Britain's development minister, said this month that regional lenders, like the African Development Bank, have more "legitimacy" in the eyes of the governments they help.
The bank manages "common funds for common purposes", as its president likes to say. That is a handicap when it peddles itself to donors. The first lesson of fundraising is limit yourself to a single cause. The American President's Emergency Plan for AIDS Relief, one of many funds now dedicated to a narrow aim, does what it says on the tin. IDA, on the other hand, is the sum of 82 strategies, each supposedly cooked up by poor countries themselves. It pays for hundreds of projects, from demobilising gunmen in Burundi to, yes, promoting contraception in Madagascar.
Harder to raise, such monies are nonetheless more useful to poor countries than earmarked dollars. In Rwanda, for example, HIV/AIDS is contained, carried by 3% of the population. Other killers, however, claim the lives of almost 12% of infants before their first birthday. And yet $46m of aid to Rwanda's health sector is earmarked for AIDS, whereas only $1m goes to fighting childhood illnesses of all kinds.
When IDA was invented in the 1960s, it was one of about a dozen donors in the average poor country. Now it jostles with over 30. This can put an intolerable burden on a country's slim corps of capable civil servants. Each donor exploits the best people to ensure the success of its own projects, lest another donor exploit them first. The bank may be no better than others at building clinics or laying roads. But in a hopelessly fragmented aid industry, "IDA is the glue that holds all this together," as Mr Wolfowitz said.
As they perused memos and messages from the Riza affair, journalists may have missed another fact released by the bank. The world's poor, judged by its $1-a-day yardstick, now number fewer than 1 billion, down by over 250m since 1990. If only Mr Wolfowitz, or his replacement, could win as sweet a settlement for IDA as he got for his friend, that total might fall a bit further. At the end of the affair, that is what will matter most.
This article appeared in the International section of the print edition under the headline "Will there be life after Wolfowitz?"
International April 21st 2007
From the April 21st 2007 edition
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Its propaganda is deceptive, multilingual and well-funded. But does it work?
An election that could make the global internet safer for autocrats
Vladimir Putin is keen to see a Russian lead the International Telecommunication Union


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In school and in the workplace, there are individuals who continuously lift the spirits of those around them and inspire others to join them in achieving success. As a Film/TV student, Shea Al-Khair was extremely eager to study film production and spent many extra hours going above and beyond for class projects. Shea's consistently positive outlook, as well as his passion for cinematography, inspired his classmates to embrace creativity. Shea encouraged his colleagues to excel, and offered a hand in any way possible, whether it was help editing or simply offering constructive criticism.
During his internship with the video technologies company Vistek during an event at the Metro Toronto Convention Centre, Shea stood out from the crowd. His shining personality and affinity for video production and postproduction caught the eye of Vistek marketing staff, who later recommended him for employment in his field. Shea is currently employed at Vistek as a marketing and warehouse assistant.
BRANTFORD, July, 2021 – Today, the Ministry of Colleges and Universities announced its Acting Director and Superintendent of Private Career Colleges, Travis Coulter, is stepping into a new […]Read More


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Have you read the current issue?
VIDEO of the past conference.
Collective monograph HERE
In cooperation with the EJF-Academy for Education and International Cooperation, the University College of Business in Prague would like to invite you to an international conference dedicated to disabled citizens in tourism (as passengers and employees) in order to contribute to further improvement in this area within the Czech Republic and Germany.
Another aim of the conference is to map and evaluate the barrier/barrier-free situation in selected destinations in the Czech Republic and Germany through field research, observation, the content analysis of documents and literary research. The issue of the disabled in tourism and their requirements will be simultaneously monitored. An integral part of the project is the issue of human resources in relation to the topic. Everyone somehow affected by or interested in the topic is invited. Send your papers for the conference in Czech, English or German by the deadline of 15 November 2019. The selected papers will be included in the peer-reviewed proceedings. Papers can only be definitively included in the proceedings after payment of the conference fee. The collection of papers will receive an ISBN and be submitted for review for indexing in scientific databases. The recommended length of the paper is 8 to 10 standard pages, including a bibliography (maximum 10 pages), and abstract of no more than 250 words.
More information about the international conference can be found in the invitation/application – download here.
The program of the international conference can be downloaded here.
I graduated with a bachelor's degree from the College of European and Regional Studies in České Budějovice and transferred to UCB in Prague to do my master's degree. Great choice – UCB is much more like a public school and the quality of lecturers is 100% better. For example, my teacher Mrs. Palatková is someone to know in tourism.
At UCB, I learned to be independent and gained experience in the field. Wherever we entered student competitions, we walked away with awards. During my studies I became part of the organizational structure of several projects in tourism. I can't wait to start working full time.
I graduated from UCB, now I teach here. Much has changed over the years. The school is constantly moving forward, focusing more on gaining practice, the subjects are more professional and tightly focused. Although the competition on the market is huge, UCB is doing very well and I can heartily recommend it.
Schools graduated from: School of Performing Arts, PALESTRA Academy of Physical Education and Sport, University College of Business. Motto: Don't be a jerk in life or liar on stage! "So which title do you use?" "None." Laughter. "More important is what I have in my head."
UCB is one of the few schools in the Czech Republic that really does offer experience. During our studies, we worked on projects where the results were then taken up by the National Monuments Institute. Many lectures were also given by external lecturers, so we learned how things really work in the world.
She works as a Program Coordinator at Smaller Earth. In 2009, she did an internship in New York. She lived in England for three and a half years and worked for an Australian travel agency. Work never bothered Simona, so when she was given the chance to go to America to work as kitchen help, she didn't hesitate for a moment. She got experience, made new friends, and traveled around the United States with the money she earned. This opened the door to job opportunities in Spain and England. She's working today.
He studied aviation theory at Oxford Aviation Academy. He completed his practical training in the Czech Republic and Poland. He holds a CPL/ME/IR pilot license. As a child, Jakub dreamed of becoming a pilot one day. He faced a twisting road to it and had to sacrifice a lot. He started off by studying Marketing Communication at the University of Finance and Administration in Prague, then moved to Airline Management at UCB. To save time and money on pilot training, he started his own company. Today he is within reach of his dream.
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Cochin or Kochi is the one significant port city that long history of being the major port for trades of many goods. It is one of the most ancient cities in the country that also has a glorious history to tell. Meanwhile, the city is also a popular tourist destination, particularly among the history buffs. Visit the city to explore every aspect of it, and for accommodation choose from best Cochin hotels.
Cochin is one amongst the cities in southern India that has a lot to offer to the backpackers across In-dia. Being ruled by the Portuguese, Dutch, Mysore rulers, and the British, the city is one city where several cultures and religions from all across the world melt and mix. The city has been marking a ma-jor spot in the books on Indian history since long. The city has a long history of being a major trading port since the early medieval era when it opened the trade route between countries in the East with the countries in the West.
The Dutch, Arabs, Chinese, Portuguese, and British used the city to trade large amount goods and items. However, the trade items for which the ancient city finds most prominence are the Exotic Indian spices, which include: cinnamon, pepper, cardamom, and cloves. Meanwhile, a good to know fact about the city, more specifically the Cochin Spice Exchange is that of the total pepper and spice trade in the country, the Cochin/Kochi Spice Exchange accounts for 90 percent.
Cochin is the colonial version of the word Kochi, and many still prefer to call the city with that name. The city is located on one of the most strategic locations on the country's mainland, which is on the west coast in the southern part of India's mainland. So geographically it is the coasts of the city where ends the Indian mainland and starts the vast Arabian Sea. Based on this fact and since the city was a beautiful, prosperous port, it was given the epithet of the Queen of the Arabian Sea.
The city is amongst the handful of cities where colonization took place the first. Thus, also making the city to receive some of the first European structures which also includes the first church ever built on Indian soil. The church is called St. Francis Church. Apart from that, Cochin is also the city where the famous explorer Vasco-da-Gama died while he was on his third visit to the city. There still exist proofs of the fact that his was buried in the St. Francis Church, which were later taken back to his homeland, Portugal.
Another cool fact about the city is that it is in Kochi where the oldest fort built by the Europeans exist. The fort is called Pallipuram Fort and still is in an excellent state of preservation. The fort is situated in the northern part of the Vypeen Island in the Ernakulum district. It is a must see when in the city. The good thing is that being a major landmark the fort is easy to access. Plus, there exist a couple of Cochin hotels that offer transportations to the fort.
Apart from the fort, the other well-known attractions of the city that a must-visit include: Cherai Beach, Chottanikkara Temple, Marine Drive, Mattancherry Palace, Chinese Fishing Nets, Shiva Temple, Bol-gatty Palace, Museum of Kerala History, Jew Town, Hill Palace Museum, Kashi Art Caf, Princess Street, Subhash Park, Paradesi Synagogue, Indian Naval Maritime Museum, and Willingdon Island. The good thing is that all these tourist spots are easily accessible via roads. Several taxis, rickshaws, and local buses are available for the convenience of the visitors. Meanwhile, there is a couple of good 3 Star hotels in Cochin situated in the vicinity of many tourist sites.


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Spare with me 5 minutes of your life. Play the song below and close your eyes.
That's Yuna with Deeper Conversation. Never in my life I get goosebumps when I hit Play. Most artist takes days to fully assimilate with my ear drums. She only took 3 minutes!
I know I missed the bus to her concert, but hey, better late than never.
Ninie was the first to recommend Yuna. I googled, but half way through, I found out Yuna's myspace. Myspace and me is like water and oil. Out the window she goes.
Few months passed, Laila recommended. She even sent Yuna's tunes via Email. Somehow I couldn't play those songs on Winamp or iTune. Another fate barrier.
Yesterday, Sarah wrote about Yuna. The song played automatically, I was rather forced against my will to listen. I was about to hit CTRL + W, her voice suddenly pulls me deep in my seat, caressing my subconscious mind. Before I knew it, I had to hold my jaw from touching the ground.
Tudung, Malaysians, whatever, I don't give a damn. She's too good to miss.
I hope with me forcing you to listen, will pave a golden road for her.
ps: I bet her boyfriend is one insecure alpha male.
pss: I'd love to make a parody of this song, since she asks a lot of Qs.
psss: Please Yuna, release the chords! I want to learn! Ok, maybe after your Euro tour.
pssss: There was actually more than 3 people who recommended Yuna. I couldn't remember.


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Obama Stronger Among White Voters than Gore or Kerry
July 24, 2008 Election '08
AlterNet is a nonprofit organization and does not make political endorsements. The opinions expressed by its writers are their own.
Remember all of the talk about Barack Obama's unique weakness among White voters? I noted the absurdity of this assertion earlier this month, but I thought it would be worth passing on a portion of professor Alan Abramowitz's analysis on the issue.
So does Barack Obama have a problem with white voters? The answer is a resounding "yes." And so has every other Democratic presidential candidate in the past forty years. The last Democratic candidate for president to win a majority of the white vote was Lyndon Johnson in 1964. Al Gore lost the white vote by 12 points in 2000. John Kerry lost the white vote by 17 points in 2004.
Based on five national polls that have been conducted this month -- Gallup, Newsweek, Quinnipiac, CBS/New York Times, and ABC/Washington Post -- Barack Obama is currently trailing John McCain by an average of nine points among white voters. So Obama is doing much better than John Kerry and a little better than Al Gore. In fact, the only Democratic presidential candidates in the past four decades who have done better among white voters were Jimmy Carter in 1976 and Bill Clinton in 1992 and 1996. Not coincidentally, they were also the only successful Democratic presidential candidates in the past four decades. Based on his current showing in the polls, Barack Obama may well be the next one. With whites expected to comprise less than 80 percent of the 2008 electorate, and with a 20-1 margin among black voters and a 2-1 margin among Hispanic voters, Obama's current nine point deficit among white voters would translate into a decisive victory in November.Shocking, no ... the numbers not lining up with the narrative pushed by a large segment of the punditry. Would it be better if Obama were able to secure a greater share of the White vote? Sure. But politics is about building coalitions, and there is no one single path to success that runs only through the support of White voters in America. Democrats can and repeatedly have secured pluralities and even majorities within the broader electorate even while carrying a minority of the White vote -- and, frankly, it seems more likely than not at this juncture that Obama will win in such a manner this year, too.
AlterNet is a nonprofit organization and does not make political endorsements. The opinions expressed by its writers are their own.


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ATLANTA – For some, helping to get out the vote during Georgia's U.S. Senate runoffs meant writing checks for campaigns. Others signed up to canvass neighborhoods or make calls for campaign phone banks. Brandon Litman took a different approach by making thousands of pieces of art to connect the Democratic candidates with voters.
The 39-year-old artist from Brooklyn, New York, packed up his spray paint and traveled to Atlanta in early December amid a critical election overtime period in Georgia. Control of the U.S. Senate was at stake in what Litman called "the most important runoff elections of our lifetimes."
His plan: to create and give away art that would inspire voters to turn out for Democratic Senate contenders Jon Ossoff and Raphael Warnock.
For weeks leading up to the Jan. 5 election, Litman churned out handmade posters featuring likenesses of Ossoff and Warnock. Boosted by a coalition of Black and younger voters, the challengers went on to defeat Georgia's two Republican senators and hand the Senate majority to Democrats as President-elect Joe Biden takes office. Georgia certified the results Tuesday.
After arriving in Atlanta last month, Litman started showing up at Ossoff and Warnock campaign rallies, painting custom yard signs for supporters. He would sometimes set up shop under an overpass in downtown Atlanta, where passersby would stop and wait in line for a free poster. Litman soon connected with the Ossoff campaign, which let him tag along to events in other Georgia cities.
Litman, known on social media as @voteruthless, would chat with prospective voters and let them choose their favorite colors for the customized portraits. They would watch him work through clouds of spray paint, and within a few minutes the posters would be done.
Ellen Foster, Ossoff's campaign manager, credited Litman with bringing "a lot of excitement to the campaign trail." She called his efforts "an organic and fresh way to engage voters while also creating buzz for this movement."
Litman had previously done artwork featuring 2016 Democratic presidential nominee Hillary Clinton and the late Supreme Court Justice Ruth Bader Ginsberg. But he said none of them were as popular as his work centered on the Georgia Senate races. By the time the campaigns ended, he figured he had produced about 3,500 posters.
"I've refined this get-out-the-vote model of co-creating politically themed art over the past few years," Litman said. "It is so powerful in attracting people, young and old and all backgrounds."


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Thursday, 9 November 2017
When Staff are Injured at Work
Winter is upon us! Are you aware of what to do if an employee slips and falls or is injured at work? Whether or not time is lost due to injury, both the supervisor and staff member are responsible to report the incident or injury within 72 hours to the WCB. Find more information on WCB processes and links to forms on our WCB Reporting web page. WCB and Homewood Health partner to support staff in their recovery while the Return to Work Consultants facilitate the return to work when an injury has resulted in a time loss from work, or there is a need for modification as result of the injury. More information about the health recovery supports available can be found on the Injury and Illness web page.
Posted by Jeffrey Klassen Labels: Hiring and Managing, Nov 2017 Newsletter


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Last month, the small spot at Second and Pine that was once home to the Artful Dodger re-opened its doors as Society Hill Society. The restaurant might have a slightly confusing name, but the menu is straightforward. Running the kitchen is former Jose Garces employee Yun Fuentes.
We caught up with Fuentes to chat about his buzzy new restaurant, and his path to opening it.
How's it going so far at Society Hill Society?
Really well so far. We had a great opening — even though we went through what every restaurant goes through in an opening. The feedback has been positive. It feels like a workshop right now: We see what the guests want from us and we work from there.
You have Headhouse Farmers Market right at your door. Are you utilizing that for your menu?
For brunch we are definitely able to incorporate it, since the market is once a week. One of the things I put on the menu was an omelet, but I leave it open and feature one or two things that I can get from the market, like baby Tuscan Kkle. Before the brunch service was over we sold out of that. It felt so nice to be able to go to the market right away and give the farmers feedback.
Before Society Hill Society, you were most recently at Rosa Blanca, right?
Yes. I worked for Garces for close to five years. I did many restaurants and wore many hats. I went from making salads at Amada to cooking every dish. Then I was asked to be a chef at Tinto and Village Whiskey. Working with Garces was a pleasure. It was the first job I got in Philadelphia and now I call Philadelphia my home.
Where did you move from?
Oh, I came from life! I was everywhere. North Carolina, and before that I was hoping around islands and Puerto Rico – I'm from Puerto Rico. Then I was in New York for four years. I wanted to make my way back to New York, but I fell in love with the city.