Secretaries, waitresses, middle managers, police officers, editors and medical interns are among those with the most highly stressed occupations - marked by the need to respond to others' demands and timetables, with little control over events. Just like laws vary from state to state to meet the demands of citizens so too did the laws between the US and Canada change a bit as things evolved. It's worth knowing the difference between laws if you ever want to travel between the two countries, and, let's be honest, it's kind of cool to learn some of the laws that apply even in your own country that you may never have heard of before because they're a little obscure or unusual. Who would have thought that a cartoon show about a simple yellow sponge would have lasted for more than two decades? Wake her up when she's hibernating, however, and she turns into a scary beast ready to punish any starfish or sponge who dares disturb her slumber. Stephen Hillenburg, who combined his background in marine biology and art into a comic book about an anthropomorphic sponge and his undersea pals. Similarly, a contractor who tries to tie money to dates rather than construction milestones is going to do you wrong. The product’s durable construction is another reason it sticks out from its competitors. There may be a perfectly legitimate reason your contractor never shows up on Mondays until noon. In a recent interview with Protocol, Zuckerberg suggested the company was thinking about it, but stopped short of giving any kind of idea as to how this may work. More changes are likely to surface as the pandemic continues to influence businesses’ HR and company policies, as well as workers’ decisions about the shifting landscape of how and where we work. Here's where universal-access principles really come in handy, helping to create a space that will work well for users of all ages. Nevertheless, cleaning airliners is a crucial part of air travel, and not just because it makes it more pleasant for passengers to spend several hours in a relatively crowded, confined space. Glassblowers use hollow tubes to blow air into the hot glass and expand it. Sandy is one of the few air breathers living in Bikini Bottom. Do you know all there is to know about the residents of Bikini Bottom? There are two states where it's illegal to pump your own gas. In Canada, you're free to pump all your own gas as well. Similarly, a good contractor should manage these subcontractors and other workers well. These systems do a pretty good job when it comes to keeping our loved ones safe. Meanwhile, electronic control units throughout your entire car are monitoring wheel slip, engine temperature, fuel mixture and hundreds of other variables, all while regulating the anti-lock brakes, traction control systems and other safety and control features. CUE's customization and control features are further enhanced through OnStar's suite of safety, security and connectivity services , such as Turn-by-Turn navigation, Automatic Crash Notification, hands-free calling and the OnStar RemoteLink mobile application. Step 2. Launch AirDroid Parental Control on your device, and it will direct you to the sign-up page. For lots more information on the Tiwi and other auto-related content, see the next page. Often used by companies to track vehicles and cargo - and let you see where your delivery is - it’s also loved by outdoorsy athletes and farmers who want to keep an eye on their animals. The same or similar colors across surfaces allow the eye to keep moving and unify a space, making the whole area look larger. It comes in a range of slick metallic colors and can be flipped open, one-handed, too. The same rules apply when it comes to buying online or creating accounts on new Web sites: Make sure the site is trustworthy. Go to the Web site and view the first category, Most Popular/Breaking News. She advised us to buy Tasers for sale on the web for quick home shipping. While it's clear that he is a lover of the arts, and quite the clarinet player, he is quick to point out to Patrick that neither mayonnaise nor horseradish is an instrument. Patrick lives under a rock. Patrick has a pet rock. Fans are introduced to Glove World in the episode where SpongeBob and Patrick travel on a bus to Rock Bottom to ride its star attraction, the Fiery Fist O'Pain. “For Horizon, making it so that you can create a world and share it on Facebook or Instagram, and people can just jump into it from there - that's going to be pretty valuable,” he said.

Are there spelling or grammatical errors? Lung conditions, such as Emphysema, COPD, or lung cancer are very hard for people when they have to walk. While you can float home to Bikini Bottom on a balloon, you might not have much luck finding a bus, as bus service in Rock Bottom is surprisingly unpredictable. There's regular, non-stop bus service to Bikini Bottom. Bikini Bottom jellyfish don't sting. Given that it's always shown in Bikini Bottom, which sits under the sea, it's easy to deduce that the ship doesn't disappear when wet. Owned by Mr. Krabs rival Plankton, the Chum Bucket sits across from the Krusty Krab to serve hungry diners. SpongeBob once gets the chance to be his fry cook after pulling the golden spatula from the stone, and in the SpongeBob movie, Neptune almost kills Mr. Krabs for stealing his precious crown. Tell us which of these statements about King Neptune is false. They also tell you if they share your data with third parties, such as advertisers. There are plenty of other approaches, of varying complexity; please do share your approach in the comments. There are a lot of conditions that can make a scooter purchase a wonderful investment. Be prepared for sticker shock -- a perfect sine inverter can cost almost 10 times as much as the same wattage inverter with a modified sine output. Wireless bluetooth will connect products to one another, even if they aren’t the same model. He gives full assistance and instruction on how to use the products. https://chardcross44.bravejournal.net/the-gps-sos-alarm Most large contracting firms have a zero-tolerance policy for drug and alcohol use on the job. More often than not, these luddites are old hands at the practice and they have everything all filled out except for the total (or at least they should). In one beloved song, SpongeBob declares that the best time to wear a striped sweater is all the time, and on at least one occasion, he gifts Squidward a magnificent sweater made from his own eyelashes. The three-inch chute accepts big chunks of produce, which cuts down on prep time, but even more importantly, the machine disassembles easily and isn’t a pain to clean. SpongeBob and Patrick love to head down to Jellyfish Fields and catch jellyfish with nets, always wearing their safety goggles to protect themselves from the creature's painful sting, which is especially painful when delivered by their queen. Jellyfish jelly is delicious on Krabby Patties. They only sell Krabby Patties. Which of these three things does NOT happen when SpongeBob and Patrick sell chocolate? To deal with that variation, ABM has three different types of cleaning operations, according to Alford. They also expose the cars to extreme heat and cold weather to test how the various mechanical components will work in all types of weather. Thirsty workers can drink cold or hot water whenever they want. Russia is constantly cited as an example of dubious security efforts -- the end of the Cold War and the breakup of the Soviet Union complicated matters because officials didn't keep proper records. He launched at one end of the stadium and flew quickly across the bowl to land in the center of the field. When we launched the Bronco, it really was a lifestyle product," Mosco says. "It was the 4x4 mountain goat, the new type of sports car, the SUV type lifestyle, and we've seen years and years where SUVs have kind of morphed away from that. High-quality personal alarms for women will have small and compact constructions. These ear-piercing loud alarms are every attacker’s worse nightmare due to the attention they attract once the alarm goes off. The Safe Life 4G Watch Alarm for lone workers has many features. Chapter 4.67 Hotel Worker Protection, which includes measures to protect hotel workers went into effect on January 1st, 2020. All hotel workers must be trained on the use and maintenance of personal security devices. This includes not only how things are made, but what they're made of. There can still be distortion or delay caused by things like interference from software or computer issues, other devices sharing your bandwidth or a weak Internet connection, but the newer MagicJack Plus purportedly results in better call quality, even on par with landline service. A strong and independent female squirrel, Sandy loves the state of Texas, the sport of karate and all things southern. It's one more judge independently agreeing that at least as far as it appears, Uber is treating these drivers more like employees than like independent contractors.



The adoption ended with a major fight between the two, and Junior eventually flew away to forge an independent life. In addition, high R&D expenditures on smart helmets, elegant pendants, personal emergency alarms, and the increasing adoption of wearable technologies can contribute to the market expansion in the region. The development of sensors in the form of wearable sensors that continuously provide accurate and reliable information has become a key factor in increasing demand for new applications, which is stimulating growth in the market. The smart personal safety and security device market is experiencing exponential growth due to the increase in cybercrime and the need for security measures against it. Measuring your signal strength can help you identify blackspots where the lone worker device may not have enough signal to operate. Where have the top managers worked before? Employers look for it on the top of a resume -- the first item after your name and contact info. We will know what your calendar is so when you start interacting with Alexa in the morning, she'll suggest the next actions you should be taking or she'll look at your appointments and check the traffic for you. Check out our Adulting Graduation Gift Guide for ideas on what to get recently graduated high school students or soon-to-be college graduates. We also added notes about Apple's upcoming iOS 17 Check In feature. But being a gadget for the masses means that when it comes to running, the Apple Watch has never been as feature rich as competing devices built specifically for that purpose. If something comes up that requires the use of your hazard lights, you're expected to pull over and come to a complete stop first. Hawaii has a law against using your hazard lights if you're still in motion for some reason. Who'd ever know that a contractor was using "extra" supplies to remodel his own bathroom? Whether a staff member is cleaning a room, serving drinks, fixing a light or greeting guests, working alone can bring extra risks to physical and mental wellbeing. Ensure staff stay safe by reminding them to start the app each morning. In these cases, the staff member would need alternative ways to call for help. I want to note that having the ability to call for help quickly can be a life-saver, so make sure that your devices are always charged. Amazon's warehouse workers previously spoke out about having to urinate in bottles just so they wouldn't have to be disciplined for "idle time." The e-commerce giant also has a massive injury rate, because workers are expected to be able to keep up with the machines they're working with. Ontario and Quebec, however, have different laws. Around 17 US states don't have any laws at all on the books about passengers in the back of a pickup truck, meaning it's not illegal. Her sweaters have love in every stitch. Sports fans might love the dedicated News app tab, but on the other hand, you also might not care about sportsball? https://notes.io/w1MdP These technologists may specialize in soil analysis, livestock care or crop yields. Depending upon the clean type and the particular airline's specifications, it may take between five and 12 people equipped with cordless vacuums and disinfectants to get the job done. If the person is under 18 and you get caught, the driver gets fined. For example, a vehicle that senses that the driver has an elevated body temperature and has increased his respiration rate significantly may automatically open windows or increase interior ventilation to improve comfort. This could be for any number of reasons, but the exchange rate between American and Canadian funds is one aspect as is Canada's use of a carbon tax on gasoline. In New Jersey it's fully banned thanks to the Retail Gasoline Dispensing Safety Act of 1949. As a result, a gas station employee has to do it for you. In general, gasoline is going to cost you more in Canada than it is in the United States. Canadian law says that everyone in a vehicle has to wear a seat belt and most states everyone in the front needs to wear one. Turn clean: "This clean is designed to accommodate an aircraft that will 'turn' and leave again quickly," Alford says. It's also important for passengers' health to remove refuse and clean dirty surfaces that might harbor germs that could make people sick. But theft from the job site might be a little trickier to spot than a kid in a candy store with bulging pockets.

Some people do this if they're on a fairly large hill to save a little bit of gas mileage in the mountains. A large chunk of a professional locksmith’s time is spent repairing or installing keys and locks and security systems in home places. Today’s PERS systems can do so much more than get your patients help during falls. It's another thing when you refine existing technologies to help people improve their lives in new ways. So, if you see your contractor acting cruelly to his crew, it's not only the right thing for the workers, but in the best interest of your project, to replace the contractor with a better people person. Or, better yet, interview or observe someone who holds the type of position you are hiring for. Of course, better filtering also costs a little more. The bestselling product is, of course, the Krabby Patty. Of course, that doesn't necessarily prevent all quality issues at the factory, but a sharp set of human eyes and a commitment to building the best car possible helps keep a company's cars safe and running properly. Do our principles focus sufficiently on how innovation impacts human life and the protection of humanity as a whole? An airplane designer during the Second World War, Malcolm Sayer applied many principles of aircraft design to the cars he created for Jaguar. It is often claimed that lone workers make up one-fifth of the UK workforce but Safepoint think that number may now be much higher -especially in a post-covid world. Failure to comply means that the landlord may be able to sue the tenant for dangerous premises. It goes without saying that as a commercial landlord you must take full responsibility for repaying any mortgages or loans leveraged on the property, failure to do so could be disastrous for your business and that of your tenant. A missed call is one thing, but failure to return a call promptly is another. Sandy can easily beat one up. This tracker can be integrated into a managed service. Here’s what’s going on inside a GPS tracker with a SIM card. The first circle is Bluetooth connectivity, which allows someone inside the car to interface with the system by using a cell phone or other Bluetooth enabled device, such as a Blackberry. Using this function, the kids can get in touch with their parents in an emergency. You can use it as a camera for snapping photos and videos, a communication device to keep in touch with friends, family, and colleagues, and a GPS tracker, among other uses. This makes it much more important to stay in touch with your employees. And the same goes for your contractor's employees. Since sitting in the drive-thru is not the same as being parked, people can and have been ticketed in places like Alberta for this infraction. In fact, most Canadian provinces have adopted this law as well, including the Yukon, British Columbia, Manitoba, and Prince Edward Island. Head to the east coast of Canada and Prince Edward Island and you'll run into this obscure traffic law that requires you to honk before passing a car. Emergency distress signals are routed to the privately run GEOS International Emergency Response Coordination Center headquartered near Houston. Al's Home Improvement Center. They live in a retirement home. Though they've settled in nicely at Shady Shoals Retirement Home, Mermaid Man and Barnacle Boy aren't afraid to come out of retirement and speed to the scene of the crime in their invisible boat mobile. Even SpongeBob loves his superheroes, but can you pick the false fact about Mermaid Man and Barnacle Boy? While we never get to see Pearl's mother on the show, it's clear that she can't be a crab, because Pearl is a sperm whale who looks nothing like her old man. If you can't get along with a contractor's employee, it's the contractor's job, not yours, to resolve the dispute. It's your contractor's job to effectively communicate this information to you. Like drug and alcohol use on the job site, theft is a no-brainer. If there's substance abuse on your job site, it's the contractor's fault. Like a business manager, part of a contractor's skill should be in hiring good people, and the contractor who shrugs his shoulders in apology for bad subcontractors is passing blame that is really his. Simply put, a contractor sets his or her own hours and these hours not only determine how quickly your project is completed, but they reflect a contractor's overall professionalism and his commitment to the project.

An employee sued his employer for tracking his vehicle after working hours without his consent. Spongebob will do anything to win Employee of the Month. While SpongeBob almost always wins, he is still willing to do almost anything to claim the title once more, even though poor Squidward has never had the opportunity to win the honor. Sleeping on the front lawn is still camping. Despite setting up their tent on the front lawn, SpongeBob and friends have quite the camping adventure. But customers have also complained of banks losing checks deposited via ATM. In addition, the company allegedly failed to spot an assault conviction of one of the drivers from 2003, because its background checks only go back seven years. However, a narrow objective might hurt your chances if it doesn't exactly match the position and disqualifies you from other positions at the company that you might be interested in. A career objective is a brief statement that expresses your professional goal. Because of these issues, some experts claim that a career objective statement is inherently flawed. New York Attorney General Letitia James released a statement in response to the news. This, together with other lone worker alarms, can be integrated into an emergency response program to automate check-ins and alerts, and log responses. The Warning, Alert and Response Network (WARN) Act of 2006 mandated creation of the Commercial Mobile Service Alert Advisory Committee by the FCC to make recommendations regarding what was necessary to send emergency alerts through mobile carriers, which laid the groundwork for the new alert system. Once they weigh more than 40 pounds, a seat isn't necessary. Although we've developed a strong love affair with the technologies that run our day-to-day lives, our relationship with the cyber security precautions necessary to protect them has historically been a bit rocky. While SpongeBob's grandmother makes sweaters with love in every stitch, not once has any of the characters recommended sporting a cardigan over a scuba suit. Realizing that adulting is pretty tough, SpongeBob rips off his 'stache to take advantage of his wonderful granny, who bakes him cookies, gives him kisses and knits sweaters made with love in every stitch. I wanted to have the advantage in a situation, and if I can get a self defense pepper spray online that resembled an everyday item unobtrusively, I would be happy. The GPS feature advantage can also be turned into a trustworthy and reasonably priced instrument for a variety of uses with the correct apps. Lastly, AirTags and GPS dog trackers are not created equally. The problems created by this promotion are compounded by the idea that an incompetent manager will make incompetent decisions -- including deciding who to promote. Ok Alone have created a lower cost lone worker monitoring that offers a high level of service. He says that number was even lower in 2020 due to the operational impact the pandemic had on the company's business. Beware the common scam in which the contractor assures the homeowner that the home will be used as an example for advertising purposes and that's why he's able to bid so much lower than the competition. It's home to the Fiery Fist O'Pain. He inadvertently shot his firearm within his own home. Squidward lives in an Easter Island-inspired home with SpongeBob and Patrick as his closest neighbors. How Can I Protect Myself from Nosy Neighbors? When connected to any Bluetooth-enabled phone, the Lifestyle Connect can connect any user with a crisis-certified Personal Safety Concierge™ for immediate assistance in any situation, 24/7. With one press of a button, Lifestyle Connect enables the user to speak with a live Personal Safety Concierge directly from the integrated speakerphone on the device - making communication simple when the mobile phone is out of reach. Pepper spray and mace are a staple in the personal protection device industry because of their ease of use, reliability, and ability to immediately impair a target. However, there's no guarantee either will reach their target audience. The UPS hydraulic hybrid package car UPS has also at times been the target of less glowing publicity. Though funeral processions are granted a lot of courtesy on the roads in both Canada and the United States, it's only a law in Nevada that the lead car may proceed through red lights after showing proper caution in approaching one. Technically this is false because there are a handful of states, like Illinois, that do not require motorcyclists to wear a helmet under the law.

The maximum blood alcohol content you can have is 0.08, which is the same as many states, but the penalties are much stiffer. You won’t have to pay any additional cost for the first year, and from the following year, only $5 per month. Your contractor should have enough credit to pay the rest of the up-front costs. You have to follow to avoid problems. If you want to experience left-side driving, you're going to have to head to someplace like Great Britain or Australia. SpongeBob is pretty much ready to break into song at any time, as evidenced by the many great tunes inspired by the show, many of which have found a place in pop culture. Once upon a time, drunk dialing required both access to a landline and the ability to remember the number of the person you so desperately needed to call. Users won’t have to replace this model for a long time, either. Do you have crews working overnight and on weekends or holidays, who need monitoring? Labradors have diverse working situations but they just about all require the basic laboratory equipment and state with the art lab apparatus regarding complicated lab experiments. Overnight Clean: "This clean is performed on aircraft that have flown all their routes for the day and are to remain overnight, generally between 8 to 10 hours," Alford says. Follow Engadget for the best Amazon Prime Day tech deals. To put its recent pace in perspective, it took Amazon 13 years to attract its first 100 million customers to the service. Amazon said that it worked with the Family Online Safety Institute to create the FreeTime experience and also followed the Children's Online Privacy Protection Act. Family Locator. If you are an overly concerned parent who is constantly worried about your child becoming a victim of crime, here is the perfect solution to keep an eye on your child's "depressed" state (to ensure their safety). This lets drivers know it was pedestrian-activated and to keep an eye open. GPS navigation systems display drivers' locations on a digital map and provide driving instructions to get them to a specific location. Buy 1 Technavio report and get the second for 50% off. Employees who can't get enough of artistic paperweights can join a club for this hobby. Mr. Krabs makes his employees pay to work for him. Also eager to make a buck, Mr. Krabs offers Krusty Krab pizza for sale and tasks SpongeBob and Patrick with delivering it. Unlike most on the market, it offers a bright strobe LED light as well as a 130db alarm, key ring, and carabiner. This Gravity Series grill offers the familiarity and convenience of charcoal with a WiFi-connected setup that works well as both a smoker and a high-temperature searing machine. The day a teenager starts driving may well be the most terrifying day of a parent's life. The history of driving in Canada is nearly identical to that of the US since the border was not nearly as well enforced back in the day as it is today, and free trade and free travel between the two countries was pretty commonplace. Is Black Friday the biggest shopping day of the year? Friday afternoon? If the answer is "quiet," you need to reevaluate your contractor. Most Black Friday shoppers pick up a few extra items as they browse retailers. Patrick wears black shorts. It turns out, Patrick Star is a cousin to SpongeBob's snail Gary. Gary meows like a cat. Squidward runs the cash register and takes orders for items like Kelp Rings and Coral Bits, while SpongeBob prepares the food with his trusty spatula. It's for dine-in orders only. They meet at the Biannual Jellyfish Convention. They have to disclose those quotas to their workers and provide authorities with a detailed description of the targets workers are expected to meet. What have you done for me lately? These external devices would have much greater processing ability, and could therefore be used to quickly provide valuable information to the user based on visual data received by the contacts. Using personal safety devices is easy. And easy expansion allows consumers to add up to four hard drives for more storage capacity, without using tools or attaching any cables. I told her everything I knew about personal security tools as we strolled towards the girls’ dorms. One of many tricks that can be used to obtain the ultimate in the market is to actually are with a carrying out security.

BACKGROUND & AIMS Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in nonalcoholic steatohepatitis (NASH). We evaluated the safety and anti-fibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. METHODS We conducted two randomized, double-blind, placebo-controlled, phase 3 trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 221 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and noninvasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. RESULTS Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p=0.49 vs placebo), 12% (39/321, p=0.93 vs placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p=0.56), 13% (45/351; p=0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. CONCLUSIONS Forty-eight weeks of selonsertib monotherapy had no anti-fibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. V.BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) could play a catalyst role on the development of metabolic comorbidities, although the magnitude of this effect in metabolically healthy NAFLD patients remains unclear. We assessed the role of biopsy-proven NAFLD on the risk of developing type 2 diabetes mellitus (T2DM) and other metabolic comorbidities (arterial hypertension (AHT), and dyslipidemia) in metabolically healthy patients. METHODS From HEPAmet Registry (N=1030), we included 178 biopsy-proven NAFLD patients with a metabolically healthy status, defined by the absence of baseline T2DM, AHT, and dyslipidemia. Hepamet Fibrosis Score (HFS), NAFLD Fibrosis Score, and FIB-4 were calculated. Follow-up was computed from the biopsy to the diagnosis of T2DM, AHT, or dyslipidemia. RESULTS During a follow-up of 5.6+4.4 years, T2DM occurred in 9% (16/178), AHT in 8.4% (15/178), low HDL in 9.6% (17/178), and hypertriglyceridemia in 23.6% (42/178) of patients. In multivariate analysis, significant fibrosis predicted T2DM and AHT. Independent variables related to T2DM appearance were significant fibrosis [HR 2.95 (CI95% 1.19-7.31); p=0.019], glucose levels [p=0.008], age [p=0.007] and BMI [p=0.039]. AHT was independently linked to significant fibrosis [HR 2.39 (CI95% 1.14-5.10); p=0.028], age [p=0.0001], BMI [p=0.006], glucose [p=0.021] and platelets [p=0.050]. The annual incidence rate of T2DM was higher in patients with significant fibrosis (4.4 vs. 1.2 cases per 100 person-years), and increased in presence of obesity, similar than AHT (4.6 vs. 1.1 cases per 100 person-years). HFS >0.12 predicted the risk of T2DM (25% (4/16) vs. HFS 0.12, but not FIB4 or NFS predicted the occurrence of T2DM. BACKGROUND/PURPOSE Despite the importance of sleep for athletic performance, there is a lack of normative sleep data and sex comparisons in collegiate athletes. The primary purpose of our study was to assess the prevalence of insufficient sleep in collegiate athletes, with a secondary aim to compare male and female athletes. PROCEDURES Participants included 121 collegiate athletes (65 men and 56 women) from six team sports and three individual sports. Subjective assessments of sleep included at-home sleep diary, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI). Objective assessments of sleep included three consecutive off-season weekdays of wrist actigraphy to assess total sleep time (TST) and sleep efficiency (SE). MAIN FINDINGS Actigraphy revealed that 94% of student-athletes received 10. Objective TST was not different between sexes (6.7±0.1 vs. 6.7±0.1 hours, p=0.99), but females demonstrated higher SE (87±1 vs. 82±1%, p less then 0.01) and lower WASO (31±2 vs. 38±2 min, p=0.02). Male athletes significantly overestimated TST (i.e., subjective minus objective TST) when compared to female athletes (Δ0.7±0.1 vs. Δ0.3±0.1 hours/night; p less then 0.01). https://www.selleckchem.com/products/sto-609.html PSQI, ISI, and ESS were not different between sexes. CONCLUSIONS The majority of male and female collegiate athletes received less than age-recommended levels of sleep, and 44% subjectively reported poor sleep quality, mild severity insomnia, and/or excessive daytime sleepiness. Sex differences were observed in male and female collegiate athletes. OBJECTIVES Examine the associations of sleep problems with health-risk behaviors and psychological well-being in a representative sample of Canadian adults. DESIGN Cross-sectional. SETTING The 2011-2012 Canadian Community Health Survey (CCHS, conducted by Statistics Canada). PARTICIPANTS Of all individuals taking part in the 2011-2012 CCHS, 42,600 participants aged ≥18 years from five provinces/territories (Nova Scotia, Quebec, Manitoba, Alberta, and Yukon) who participated in the sleep survey module were selected for this study. MEASUREMENTS Health conditions were self-reported. Sleep problems referred to extreme sleep durations (either less then 5 or ≥10 hours) and insomnia symptom. Health-risk behaviors included physical inactivity, daily smoking, highly sedentary behavior, and insufficient fruit and vegetable consumption. Worse psychological well-being included having worse self-rated general health, worse self-rated mental health, and worse sense of belonging, and being dissatisfied with life. RESULTS The participants represented 10,614,600 Canadian adults aged ≥18 years from the five abovementioned provinces/territories. A significantly higher prevalence of all health-risk behaviors and worse psychological well-being was found among participants with extreme sleep durations (than those with 7 to less then 8 hours) and insomnia symptom (than those without insomnia symptom). After multivariate adjustment, extreme sleep durations and insomnia symptom were still independently associated with increased odds of all health-risk behaviors and worse psychological well-being. CONCLUSIONS Both extreme sleep durations and insomnia symptom were independently associated with health-risk behaviors and worse psychological well-being among Canadian adults. The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2-3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1-4 µg mL-1. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic - ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives. Peptide nucleic acid (PNA), a synthetic DNA mimic that is devoid of the (deoxy)ribose-phosphate backbone yet still perfectly retains the ability to recognize natural nucleic acids in a sequence-specific fashion, can be employed as a tool to modulate gene expressions via several different mechanisms. The unique strength of PNA compared to other oligonucleotide analogs is its ability to bind to nucleic acid targets with secondary structures such as double-stranded and quadruplex DNA as well as RNA. This digest aims to introduce general readers to the advancement in the area of modulation of DNA/RNA functions by PNA, its current status and future research opportunities, with emphasis on recent progress in new targeting modes of structured DNA/RNA by PNA and PNA-mediated gene editing. The naturally occurring host defense peptide (HDP), aurein 2.2, secreted by the amphibian Litoria aurea, acts as a moderate antibacterial, affecting Gram positive bacteria such as Staphylococcus aureus by forming selective ion pores. In a quest to find more active analogues of aurein 2.2, peptides 73 and 77 were discovered. These peptides were rich in arginine and tryptophan and found to have MICs of 4 μg/mL. Here we examined what impact the increased charge from +2 to +3 and a slight increase in hydrophobic moment relative to aurein 2.2 had on the mechanism of action of these two analogues. Using a time-kill assay, both peptides 73 and 77 were found to kill bacteria more effectively than the parent peptide. Using solution CD and NMR, the peptides were found to not adopt a continuous α-helical structure, i.e. the analogues were not helical from residue 1-13 like the parent peptide. Results obtained from oriented CD (OCD), DiSC35 and pyranine assays and a gel retardation experiment showed that the peptides did not function by membrane perturbation and further showed that peptide 73 and 77 did not interact with DNA. Overall, the data were consistent with these peptides acting as cell penetrating peptides with intracellular targets, which did not appear to be DNA. Pinholins are a family of lytic membrane proteins responsible for the lysis of the cytosolic membrane in host cells of double stranded DNA bacteriophages. Protein-lipid interactions have been shown to influence membrane protein topology as well as its function. This work investigated the interactions of pinholin with the phospholipid bilayer while in active and inactive confirmations to elucidate the different interactions the two forms have with the bilayer. Pinholin incorporated into deuterated DMPC-d54 lipid bilayers, along with 31P and 2H solid state NMR (SS-NMR) spectroscopy were used to probe the protein-lipid interactions with the phosphorus head group at the surface of the bilayer while interactions with the 2H nuclei were used to study the hydrophobic core. A comparison of the 31P chemical shift anisotropy (CSA) values of the active S2168 pinholin and inactive S21IRS pinholin indicated stronger head group interactions for the pinholin in its active form when compared to that of the inactive form supporting the model of a partially externalized peripheral transmembrane domain (TMD) of the active S2168 instead of complete externalized TMD1 as suggested by Ahammad et al.

on-making.
Improving rural health is often identified as a priority area for research and policy in Canada. We examined how findings on HIV outcomes (virologic suppression) can vary depending on the definition of rurality used.

We performed retrospective cohort analyses using the Comparative Outcomes and Service Utilization Trends study population-based cohort of adults (age ≥ 19 yr) living with HIV in British Columbia between Apr. 1, 2012, and Mar. 31, 2013. We performed univariate logistic regression analyses using the following geographic variables to predict HIV virologic suppression rurality defined by forward sortation area, by Statistical Area Classification and by health authority. We mapped suppression using geographic information systems.

Virologic suppression was observed in 5605 (65.2%) of 8598 participants. In univariate analysis, rurality defined by Statistical Area Classification (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.65-0.82), but not by forward sortation area, was associated with lower odds of suppression. When we examined suppression by health authority, Northern Health had the lowest odds of suppression (OR 0.46, 95% CI 0.36-0.58 compared to Vancouver Coastal Health). Geographic information systems mapping showed poorer suppression in northern areas.

Health outcome findings can vary depending on the definition of the geographic variable. When including https://www.selleckchem.com/products/astx660.html , researchers should carefully consider variable definitions and whether other classification systems, such as north-south, are more appropriate than rurality for their analysis.
Health outcome findings can vary depending on the definition of the geographic variable. When including geographic variables, researchers should carefully consider variable definitions and whether other classification systems, such as north-south, are more appropriate than rurality for their analysis.
Genetic testing in families with hereditary cancer enables identification of people most likely to benefit from intensive screening and preventive measures; however, the uptake of testing in relatives (known as cascade carrier testing) for hereditary colorectal cancer syndromes has been shown to be low. #link# Our objective was to report rates of familial testing for hereditary colorectal cancer syndromes in a publicly funded hereditary cancer clinic in Canada.

A cross-sectional retrospective database review was used to determine testing uptake between 1997 and 2016 for families served by the provincial Hereditary Cancer Program for British Columbia and Yukon. Analyses were conducted for genes associated with syndromes with an increased risk for colorectal cancer, including Lynch syndrome (
,
,
,
and
) and familial adenomatous polyposis (
), and for additional moderate- to high-penetrance genes (
,
,
,
,
and
). Descriptive statistics were used and all analyses were 2-tailed.

The study coggressive efforts by hereditary cancer programs are needed to reach this highest risk population.The deterioration of a previously stable preterm infant is a common scenario on the neonatal unit. The the most common bacterial causes of deterioration are nosocomial infections, such as coagulase-negative Staphylococcus and Staphylococcus aureus Non-infective conditions such as pulmonary haemorrhage, anaemia of prematurity and necrotising enterocolitis may also cause preterm infants to deteriorate. This case chronicles the unusual diagnostic journey of an infant born at 27+1 weeks who deteriorated at 26 days of life and did not respond to antimicrobial therapy as anticipated.Exertional dyspnoea among children and adolescents is a common presenting complaint to general practitioners. Exertional dyspnoea is most commonly attributed to exercise-induced bronchoconstriction (EIB), but there are several other causes including hyperventilation syndrome, breathlessness associated with normal exercise limitation and exercise-induced laryngeal obstruction (EILO). The symptoms of EILO include stridor, throat tightness and difficulty on inspiration. link2 If these are mistaken for EIB, children will receive asthma therapy. The underlying mechanism of EILO includes closure of the larynx during high-intensity exercise, which causes a reduction in airflow and breathlessness. This phenomenon is often associated with a background of psychological stress. Historically, a diagnosis of EILO has been considered 'rare' though this may be a reflection of under-recognition. Direct visual observation via laryngoscopy is the gold standard for diagnosis of EILO; however, this is rarely available even in specialised centres. Nevertheless, the diagnosis can usually be made by recognising the characteristic clinical pattern. Here we provide recommendations for appropriate investigations for the determination of EILO, together with suggested treatment.
Firearm-related injury is an important and preventable cause of death and disability. We describe the burden, baseline characteristics and regional rates of firearm-related injury and death in Ontario.

We conducted a population-based cross-sectional study using linked data from health administrative data sets held at ICES. We identified residents of Ontario of all ages who were injured or died as a result of a firearm discharge between Apr. 1, 2002, and Dec. link3 31, 2016. We included injuries classified as assault, unintentional, self-harm or undetermined intent secondary to handguns, rifles, shotguns and larger firearms. The primary outcome was the incidence of nonfatal and fatal injuries resulting in an emergency department visit, hospital admission or death. We also describe regional and temporal rates.

We identified 6483 firearm-related injuries (annualized injury rate 3.54 per 100 000 population), of which 2723 (42.3%) were fatal. Assault accounted for 40.2% (1494/3715) of nonfatal injuries and 25.5% (ntion strategies in rural areas targeted at men aged 45 or older.Type I and III interferons induce expression of the "myxovirus resistance proteins" MxA in human cells and its ortholog Mx1 in murine cells. Human MxA forms cytoplasmic structures, whereas murine Mx1 forms nuclear bodies. Whereas both HuMxA and MuMx1 are antiviral toward influenza A virus (FLUAV) (an orthomyxovirus), only HuMxA is considered antiviral toward vesicular stomatitis virus (VSV) (a rhabdovirus). We previously reported that the cytoplasmic human GFP-MxA structures were phase-separated membraneless organelles ("biomolecular condensates"). In the present study, we investigated whether nuclear murine Mx1 structures might also represent phase-separated biomolecular condensates. The transient expression of murine GFP-Mx1 in human Huh7 hepatoma, human Mich-2H6 melanoma, and murine NIH 3T3 cells led to the appearance of Mx1 nuclear bodies. These GFP-MuMx1 nuclear bodies were rapidly disassembled by exposing cells to 1,6-hexanediol (5%, w/v), or to hypotonic buffer (40-50 mosm), consistent with properties of membraneless phase-separated condensates. Fluorescence recovery after photobleaching (FRAP) assays revealed that the GFP-MuMx1 nuclear bodies upon photobleaching showed a slow partial recovery (mobile fraction ∼18%) suggestive of a gel-like consistency. Surprisingly, expression of GFP-MuMx1 in Huh7 cells also led to the appearance of GFP-MuMx1 in 20-30% of transfected cells in a novel cytoplasmic giantin-based intermediate filament meshwork and in cytoplasmic bodies. Remarkably, Huh7 cells with cytoplasmic murine GFP-MuMx1 filaments, but not those with only nuclear bodies, showed antiviral activity toward VSV. Thus, GFP-MuMx1 nuclear bodies comprised phase-separated condensates. Unexpectedly, GFP-MuMx1 in Huh7 cells also associated with cytoplasmic giantin-based intermediate filaments, and such cells showed antiviral activity toward VSV.Knock-out mouse models have been extensively used to study the antiviral activity of interferon-induced protein with tetratricopeptide repeats (IFIT). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of 'self' in higher eukaryotes, while unmodified cap0-RNA is recognised as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess 'non-self' cap0-mRNAs. However, in mice and other rodents the IFIT1 orthologue has been lost and the closely-related Ifit1b has been duplicated twice, yielding three paralogues Ifit1, Ifit1b and Ifit1c. While murine Ifit1 is similar to human IFIT1 in its cap0-RNA binding selectivity, the roles of Ifit1b and Ifit1c are unknown. Here, we found that Ifit1b preferentially binds to cap1-RNA, while binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that Ifit1b can modulate host translation and restrict wildtype mouse coronavirus infection. We found that Ifit1c acts as a stimulatory cofactor for both Ifit1 and Ifit1b, promoting their translation inhibition. In this way, Ifit1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families, to facilitate better design and interpretation of mouse models of human infection, and sheds light on the evolutionary plasticity of the IFIT family.Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell-mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell-mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1-triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1-targeting therapeutic approaches.
The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression.

We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group.

962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.

Correlating with this, 3D spheroid cells were more resistant to permetrexed and topotecan than the two-dimensional cells, indicative of their potential for hypoxic adaptation. Furthermore, significantly stronger resistance to both chemotherapeutic agents was observed in spheroid cells upon hypoxic challenge compared to spheroid cells under normoxia.

From the present data, it is concluded that hypoxia adaptation of MPM cells from tumor spheres could enhance their chemoresistance.
From the present data, it is concluded that hypoxia adaptation of MPM cells from tumor spheres could enhance their chemoresistance.
Oncolytic virotherapy is an emerging biotherapeutic platform for selectively infecting cancer cells and triggering apoptosis in a number of malignant cells due to robust viral replication. Studies related to the oncolytic activity of human orthopneumovirus (hOPV) are conflicting.

This study was designed to elucidate the possible role of hOPV in the modulation of cell growth and apoptosis in cancer cell lines including human epidermoid carcinoma (HEp-2), lung epithelial cell line (A549), and breast cancer cell line (MCF-7).

The oncolytic activity of hOPV on cancer cells was studiedin vitro. The virus titersweredeterminedbytissue culture infectious dose (TCID50/mL) in A549cell. The cytotoxic effect of the virus onHEp-2, A549, and MCF-7was determined using MTT and trypan blue dyeexclusion test assays. hOPV in the infected cells was detected using real-time reverse transcription polymerase chain reaction(rRT-PCR) and indirect immunofluorescence (IIF) assays. Therelative expression of apoptosis-related genesrovide evidence that hOPV could be a potential candidate for oncolytic virotherapy.
People with severe mental illness have a mortality rate higher than the general population, living an average of 10-20 years less. Most studies of mortality among people with severe mental illness have occurred in high-income countries (HICs). We aimed to estimate all-cause and cause-specific relative risk (RR) and excess mortality rate (EMR) in a nationwide cohort of inpatients with severe mental illness compared with inpatients without severe mental illness in a middle income country, Brazil.

This national retrospective cohort study included all patients hospitalised through the Brazilian Public Health System (Sistema Único de Saúde [SUS]-Brazil) between Jan 1, 2000, and April 21, 2015. Probabilistic and deterministic record linkages integrated data from the Hospital Information System (Sistema de informações Hospitalares) and the National Mortality System (Sistema de Informação sobre Mortalidade). Follow-up duration was measured from the date of the patients' first hospitalisation until their death, orople with severe mental illness, especially in a middle-income country like Brazil that has low investment in mental health.

Bill and Melinda Gates Foundation, Fundação de Amparo a Pesquisa do Estado de Minas Gerais, FAPEMIG, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil.
Bill and Melinda Gates Foundation, Fundação de Amparo a Pesquisa do Estado de Minas Gerais, FAPEMIG, and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil.
Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC.

In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (11) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Proceduresnstitute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology.

For the French translation of the abstract see Supplementary Materials section.
For the French translation of the abstract see Supplementary Materials section.
The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment.

We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT<4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or >12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectaMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs.

The Research Council of Norway.
The Research Council of Norway.
Pregnant individuals have been receiving COVID-19 vaccines following pre-authorisation clinical trials in non-pregnant people. This study aimed to determine the frequency and nature of significant health events among pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals.

We did an observational cohort study, set in seven Canadian provinces and territories including Ontario, Quebec, British Columbia, Alberta, Nova Scotia, Yukon, and Prince Edward Island. Eligibility criteria for vaccinated individuals were a first dose of a COVID-19 vaccine within the previous 7 days; an active email address and telephone number; ability to communicate in English or French; and residence in the aforementioned provinces or territories. Study participants were pregnant and non-pregnant females aged 15-49 years. Individuals were able to participate as controls if they were unvaccinated and fulfilled the other criteria. Data were collected primarily bysafety profile in pregnancy. These data can be used to appropriately inform pregnant people regarding reactogenicity of COVID-19 vaccines during pregnancy, and should be considered alongside effectiveness and immunogenicity data to make appropriate recommendations about best use of COVID-19 vaccines in pregnancy.

Canadian Institutes of Health Research, Public Health Agency of Canada.
Canadian Institutes of Health Research, Public Health Agency of Canada.
The global burden of lower respiratory infections (LRIs) and corresponding risk factors in children older than 5 years and adults has not been studied as comprehensively as it has been in children younger than 5 years. We assessed the burden and trends of LRIs and risk factors across all age groups by sex, for 204 countries and territories.

In this analysis of data for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we used clinician-diagnosed pneumonia or bronchiolitis as our case definition for LRIs. We included International Classification of Diseases 9th edition codes 079.6, 466-469, 470.0, 480-482.8, 483.0-483.9, 484.1-484.2, 484.6-484.7, and 487-489 and International Classification of Diseases 10th edition codes A48.1, A70, B97.4-B97.6, J09-J15.8, J16-J16.9, J20-J21.9, J91.0, P23.0-P23.4, and U04-U04.9. We used the Cause of Death Ensemble modelling strategy to analyse 23 109 site-years of vital registration data, 825 site-years of sample vital registration data, 1766 siteousehold air pollution, would prevent deaths and reduce health disparities.

Bill & Melinda Gates Foundation.
Bill & Melinda Gates Foundation.
The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. https://www.selleckchem.com/products/ew-7197.html Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time.

We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion ofponse over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer.

During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours.

National Cancer Institute.
National Cancer Institute.
Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone.

This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 11 to mepolizumab (6-11 years 40 mg; 12-17 years 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks.

One of the hardest working mitotic proteins, Polo-like kinase 1 (PLK1), functions at mitotic entry, cytokinesis, and many steps in between. In this issue, Xie et al. (2020) describe a centrosome-specific interaction between PLK1 and Retinoid X Receptor-α and they test selective inhibition of this interaction as an anti-mitotic cancer therapy.Membrane-cortex attachment plays key roles in controlling cell shape and integrity. In this issue of Developmental Cell, Welf et al. describe a new function for membrane-actin tethering in controlling where and when cells initiate new protrusions.In this issue of Developmental Cell, Muncie et al. describe the generation of gastrulation-like foci of cells within micropatterned colonies of pluripotent stem cells. This demonstration of mechanosensitive β-catenin/Wnt-dependent specification of cell fate during gastrulation illustrates the insights gleaned by placing stem cells in embryo-like mechanical environments.The United Nations General Assembly calls for ecosystem restoration to be a primary intervention strategy used to counter the continued loss of natural habitats worldwide, while supporting human health and wellbeing globally. Restoration of coastal marine ecosystems is perceived by many to be expensive and prone to failure, in part explaining its low rates of implementation compared with terrestrial ecosystems. Yet, marine ecosystem restoration is a relatively new field, and we argue that assessments of its potential to answer this call should not rely on typical outcomes, but also to learn from successful outliers. Here, we review successful restoration efforts across a suite of metrics in coastal marine systems to highlight 'bright spots'. We find that, similar to terrestrial systems, restoration interventions can be effective over large spatial expanses (1,000s-100,000s ha), persist for decades, rapidly expand in size, be cost-effective, and generate social and economic benefits. These bright spots clearly demonstrate restoration of coastal marine systems can be used as a nature-based solution to improve biodiversity and support human health and wellbeing. Examining coastal marine restoration through a historical lens shows that it has developed over a shorter period than restoration in terrestrial systems, partially explaining lower efficiencies. Given these bright spots and the relative immaturity of coastal marine ecosystem restoration, it is likely to advance rapidly over the coming decades and become a common intervention strategy that can reverse marine degradation, contribute to local economies, and improve human wellbeing at a scale relevant to addressing global threats.The first three-dimensionally preserved sauropod dinosaur embryo surprises paleontologists. A member of the gigantic titanosaurs, its peculiar morphology shows how much these animals changed during growth and has implications for ecology and skull development that go beyond paleontology.A recent study reports the three-dimensional structure of a primary cilium with unprecedented clarity. The results highlight the architectural differences with motile cilia and provoke a reassessment of the relationship between the ciliary cytoskeleton and microtubule-based transport in cilia.Organ development requires coordination between gene expression patterns and cellular processes across developmental axes to generate consistent shapes. A new study shows that, in plants, this coordination may be in part mediated by precise spatial hormone synthesis, regulated by a conserved family of genes.RNA viral titers are often suppressed in insects co-infected with the bacterial endosymbiont Wolbachia. This property has been used to suppress transmission of the ragged rice stunt virus from its insect host, the brown planthopper, to the rice plant.Recognizing and remembering dangerous pathogens is of the utmost importance for an animal's survival. Nematodes use a digested bacterial small RNA molecule as a cue of pathogenicity. Inheritance of this RNA even protects the progeny from infection.A new study that regularly resets the background community to time zero shows how eco-evolutionary dynamics affect bacteria living in a diverse community.Whilst tissues form during development, some cells are extruded from epithelial monolayers. Rather than dying or differentiating, a new study shows that displaced cells can reintegrate after dividing. Surprisingly, this 'intrusion' pathway shares common features with axon guidance.The mode and tempo of human dispersal to the far-flung Pacific Islands has been a source of fascination for centuries. New ancient DNA data from the archipelago of Vanuatu shed light on the ancient migrations that shaped the history of human settlement in the Pacific.An investigation of how mitotic spindle size scales with cell size in early zebrafish embryos reveals fundamental principles of spindle organization. Spindle size depends primarily on microtubule number, which is regulated by a reaction-diffusion system when cells are large, and by signals from the plasma membrane when they are small.Studies in island systems underpin much of our knowledge of macroevolution. A new study of the Galápagos giant daisies adds to this tradition. A time-calibrated phylogeny is presented that offers insights into the factors associated with diversification, providing a framework for further studies to investigate processes underlying these findings.During a brief increase in temperature, cells undergoing spermatogenesis, but not oogenesis, activate transposons. This sexual dimorphism suggests that temperature stress during spermatogenesis provides a unique opportunity for transposons to mobilize and modify genomes, driving evolutionary change without substantially affecting reproduction.A new metagenomics study has shown that marine viruses recently acquired genes encoding light-gated ion channels from green algae. These so-called channelrhodopsin genes may allow the viruses to manipulate the swimming behavior of the algae they infect.In July 2016, a mummified carcass of an ancient wolf (Canis lupus) pup (specimen YG 648.1) was discovered in thawing permafrost in the Klondike goldfields, near Dawson City, Yukon, Canada (Figure 1A). The wolf pup mummy was recovered along a small tributary of Last Chance Creek during hydraulic thawing that exposed the permafrost sediment in which it was preserved. This mummified wolf pup is important to the local Tr'ondëk Hwëch'in people, who named it Zhùr, meaning 'wolf' in the Hän language of their community. Here, we report detailed morphometric, isotopic, and genetic analyses of Zhùr that reveal details of her appearance, evolutionary relationships to other wolves and short life-history and ecology. Zhùr is the most complete wolf mummy known. She lived approximately 57,000 years ago and died in her den during a collapse of the sediments. During her short life, she ate aquatic resources, and is related to ancient Beringian and Russian gray wolves and her clade is basal to all living gray wolves. VIDEO ABSTRACT.Intraub posits the existence of two separate processes in scene memory one in which we automatically extrapolate the visual information in a scene beyond its boundaries (scene construction), and one in which we normalize our memories to either a schema or an average (normalization). She claims that scene construction will lead to transformations exclusively in the direction of boundary extension (BE), while normalization will produce bidirectional transformations of both BE and the opposite effect of boundary contraction (BC). Thus, because we observed both BE and BC in our study [1], our paradigm must be tapping into additional cognitive processes than just scene construction. https://www.selleckchem.com/products/azd5363.html However, our paper [1] questions this premise - if BE and BC are equally common using large, representative stimulus sets in the same tasks used previously [2,3], then perhaps prior studies primarily found unidirectional BE effects due to limited stimulus sampling, and there was no privileged link between boundary extension and scene construction in memory to begin with.Bainbridge and Baker [1] argue that boundary extension (BE), false memory beyond a view, is an artifact of stimulus selection. They dismiss theoretical explanations that include scene construction [2,3], and suggest removal of BE from textbooks. Their empirical work is an admirable study of scene errors, but the bridge between their data and their sweeping conclusions about BE is not well-grounded. They claim that BE is considered 'universal' and, thus, their observation of contraction (loss of peripheral content) in addition to extension violates a fundamental premise. They claim that reliance on narrow 'recycled' stimulus sets object(s) centered on 'generic', non-scenic backgrounds created the artifact. Neither claim is correct.In this Quick guide, Nadia Sloan and Leigh Simmons introduce the diverse and fascinating biology of female genitalia.Interview with Alycia Mosley Austin, who directs graduate recruitment, professional development, and diversity initiatives at the University of Rhode Island.A critical mechanism for maximizing reward is instrumental learning. In standard instrumental learning models, action values are updated on the basis of reward prediction errors (RPEs), defined as the discrepancy between expectations and outcomes. A wealth of evidence across species and experimental techniques has established that RPEs are signaled by midbrain dopamine neurons. However, the way dopamine neurons receive information about reward outcomes remains poorly understood. Recent animal studies suggest that the pedunculopontine nucleus (PPN), a small brainstem structure considered as a locomotor center, is sensitive to reward and sends excitatory projection to dopaminergic nuclei. Here, we examined the hypothesis that the PPN could contribute to reward learning in humans. To this aim, we leveraged a clinical protocol that assessed the therapeutic impact of PPN deep-brain stimulation (DBS) in three patients with Parkinson disease. PPN local field potentials (LFPs), recorded while patients performed an instrumental learning task, showed a specific response to reward outcomes in a low-frequency (alpha-beta) band. Moreover, PPN DBS selectively improved learning from rewards but not from punishments, a pattern that is typically observed following dopaminergic treatment. Computational analyses indicated that the effect of PPN DBS on instrumental learning was best captured by an increase in subjective reward sensitivity. Taken together, these results support a causal role for PPN-mediated reward signals in human instrumental learning.The synaptotrophic hypothesis posits that synapse formation stabilizes dendritic branches, but this hypothesis has not been causally tested in vivo in the mammalian brain. The presynaptic ligand cerebellin-1 (Cbln1) and postsynaptic receptor GluD2 mediate synaptogenesis between granule cells and Purkinje cells in the molecular layer of the cerebellar cortex. Here we show that sparse but not global knockout of GluD2 causes under-elaboration of Purkinje cell dendrites in the deep molecular layer and overelaboration in the superficial molecular layer. Developmental, overexpression, structure-function, and genetic epistasis analyses indicate that these dendrite morphogenesis defects result from a deficit in Cbln1/GluD2-dependent competitive interactions. A generative model of dendrite growth based on competitive synaptogenesis largely recapitulates GluD2 sparse and global knockout phenotypes. Our results support the synaptotrophic hypothesis at initial stages of dendrite development, suggest a second mode in which cumulative synapse formation inhibits further dendrite growth, and highlight the importance of competition in dendrite morphogenesis.