TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

BackgroundDuring the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health.AimTo determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality.Design and settingThis was a 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all communty dwelling participants (n = 6241/8732, response rate 71.5%).MethodCox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided health care because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records.ResultsOf 5656 respondents, one-fifth avoided health care because of the COVID-19 pandemic (n = 1143). Compared with non-avoiders, those who avoided health care more often reported symptoms of depression (n = 357, 31.2% versus n = 554, 12.3%) and anxiety (n = 340, 29.7% versus n = 549, 12.2%), and more often rated their health as poor to fair (n = 336, 29.4% versus n = 457, 10.1%) . Those who avoided health care had an increased adjusted risk of all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] = 1.01 to 1.67), which remained nearly identical after adjustment for history of any non-communicable disease (HR 1.20, 95% CI = 0.93 to 1.54). However, this association attenuated after additional adjustment for mental and physical self-perceived health factors (HR 0.93, 95% CI = 0.71 to 1.20).ConclusionThis study found an increased risk of all-cause mortality among individuals who avoided health care during COVID-19. These individuals were characterised by poor mental and physical self-perceived health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care to limit health disparities, inside and beyond healthcare crises.

BackgroundCOVID-19 pandemic restrictions may have influenced behaviours related to weight.AimTo describe patterns of weight change among adults living in England with type 2 diabetes (T2D) and/or hypertension during the pandemic.Design and settingAn observational cohort study using the routinely collected health data of approximately 40% of adults living in England, accessed through the OpenSAFELY service inside TPP.MethodClinical and sociodemographic characteristics associated with rapid weight gain (>0.5 kg/m2/year) were investigated using multivariable logistic regression.ResultsData were extracted on adults with T2D (n = 1 231 455, 43.9% female, and 76.0% White British) or hypertension (n = 3 558 405, 49.7% female, and 84.3% White British). Adults with T2D lost weight overall (median δ = −0.1 kg/m2/year [interquartile range {IQR} −0.7–0.4]). However, rapid weight gain was common (20.7%) and associated with the following: sex (male versus female: adjusted odds ratio [aOR] 0.78 [95% confidence interval {CI} = 0.77 to 0.79]); age (older age reduced odds, for example, aged 60–69 years versus 18–29 years: aOR 0.66 [95% CI = 0.61 to 0.71]); deprivation (least deprived Index of Multiple Deprivation [IMD] quintile versus most deprived IMD quintile: aOR 0.87 [95% CI = 0.85 to 0.89]); White ethnicity (Black versus White: aOR 0.95 [95% CI = 0.92 to 0.98]); mental health conditions (for example, depression: aOR 1.13 [95% CI = 1.12 to 1.15]); and diabetes treatment (non-insulin treatment versus no pharmacological treatment: aOR 0.68 [95% CI = 0.67 to 0.69]). Adults with hypertension maintained stable weight overall (median δ = 0.0 kg/m2/year [IQR −0.6–0.5]); however, rapid weight gain was common (24.7%) and associated with similar characteristics as in T2D.ConclusionAmong adults living in England with T2D and/or hypertension, rapid pandemic weight gain was more common among females, younger adults, those living in more deprived areas, and those with mental health conditions.

BackgroundBetween 2003 and 2018, incident prescriptions of beta-blockers for anxiety increased substantially, particularly for young adults. National Institute for Health and Care Excellence guidance for anxiety does not recommend beta-blockers, probably due to a lack of evidence to support such use. Recent reports have highlighted the potential risks of beta-blockers.AimTo understand when and why GPs prescribe beta-blockers for people with anxiety.Design and settingIn-depth interviews with 17 GPs in Bristol and the surrounding areas.MethodInterviews were held by telephone or video call. A topic guide was used to ensure consistency across interviews. Interviews were audio-recorded, transcribed verbatim, and analysed thematically.ResultsMany GPs viewed beta-blockers as ‘low risk’, particularly for young adults. Some GPs viewed beta-blockers as an alternative to benzodiazepines, acting quickly and not leading to dependence. GPs reflected that some patients appeared to want an ‘immediate fix’ to their symptoms, which GPs thought beta-blockers could potentially offer. This is salient in light of substantial waiting lists for talking therapies and delays in antidepressants taking effect. GPs described how some patients seemed more willing to try beta-blockers than antidepressants, as patients did not perceive them as ‘mental health drugs’ and therefore viewed them as potentially more acceptable and less stigmatising. Further, GPs viewed beta-blockers as ‘patient-led’, with patients managing their own dose and frequency, without GP input.ConclusionMany GPs believe that beta-blockers have a role to play in the management of anxiety. Given recent increases in the prescribing of these drugs in primary care, there is a need to assess their safety and effectiveness as a treatment for people with anxiety disorders.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.

α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.

Advancements in immunotherapy in the perioperative setting have revolutionised the treatment of resectable nonsmall cell lung cancer (NSCLC). Here we present the methodology and results of the clinical trial CheckMate 816 demonstrating the benefit of neoadjuvant therapy with nivolumab plus chemotherapy compared with chemotherapy alone. Furthermore, this article discusses the implications for future practice in resectable NSCLC and the need for future research.

The leak caught national intelligence officials by surprise and led to an embarrassing Air Force Inspector General investigation.

This is not a joke, the subscription to ExpressVPN is at an unprecedented price. We'll tell you everything you need to know so you don't miss out on its Black Friday offer.

NATWEST has moved to reduce the UK Government’s stake in the bank after buying back a significant tranche of shares from the Treasury in what it described as a “another important milestone”, it was announced this morning.

Scotland was second out of 12 UK nations and regions on one key measure

A rural housing project branded as ‘truly transformative’ has been completed

The technology will deliver enhanced day-to-day and major incident response capability

Join Anna Marie, Chris, Josh, and Kelley this week, as things get a little weirder than usual. A sticky soda fracas kicks off the show. Meanwhile, Kelley runs the news section for the first time, which is good since Chris stomps off after discovering this is definitely the worst timeline of them all. And don't forget, #JRPGJuly continues for one more week!

The post RPG Cast – Episode 551: “I Don’t Want the Moe Future” appeared first on RPGamer.

We're rounding up two weeks of news with Robert, Kelley, Jonathan, Chris, and Anna Marie. Everything is delayed, so in response everything else is...also delayed...? Can we just cancel the rest of 2020 and skip right to next year, please?

The post RPG Cast – Episode 561: “Pour Some Syrup on Me” appeared first on RPGamer.

Anna Marie practices equal opportunity violence. Kelley fawns over Sidon Shark (do do do do). Robert is the destroyer of Vitas. Josh is stress. Chris does some Neo Vision shaming. And Alex wonders why he allows this podcast on the site.

The post RPG Cast – Episode 571: “Hospital Hat Trick” appeared first on RPGamer.

It's another explicit week, as Sam calls Chris poopy. Anna Marie can't understand Dutch (even though she likes to think she does), while Pascal imagines he's eating a sausage. Josh is slowly falling under the spell of Mass Effect Stockholm Syndrome, and somehow Chris is equally obsessed with shoes, jeggings, and dead Google products. Save us.

The post RPG Cast – Episode 581: “Love Me, I Himbo” appeared first on RPGamer.

Alex, Anna Marie, Chris, and Kelley come together to discuss the news of the week. #JRPGJuly is well underway for everyone on the cast. Anna Marie makes every evil choice she can. Alex dives into Anime: The Game. Chris shouldn't be playing Elder Scrolls Online because his arm hurts, and yet he still is? Meanwhile, we lost Kelley somewhere in the wastelands when she wandered off to hug all the monsties.

The post RPG Cast – Episode 591: “Save the Baby? Eat the Baby?” appeared first on RPGamer.

Josh and Scotty get into a father-son slap fight. Kelley ascends to divinity playing Picross. Johnathan sees how much his ZHP is worth and has to go make a transaction in a back alley. And Chris tries to justify life without a back button.

The post RPG Cast – Episode 601: “Tactical Baking RPG” appeared first on RPGamer.

Chris dies a lot. Then some more. Then Kelley explains how digimon are vegan to Chris. Then Sam explains how books work to Chris (with a lot of cursing). Then Josh explains how birthmarks work to Chris. Then Anna Marie explains how cosplaying works to Chris. Then Chris gets dunked on some more by a boss. Then the show ends.

The post RPG Cast – Episode 607: “Extra Life 2021” appeared first on RPGamer.

Chris embraces our cyberpunk subscription overlords. Josh kills the innkeeper (accidentally). Meanwhile Robert plunges down the .Hack hole.

The post RPG Cast – Episode 610: “No One Should Learn Japanese from Super Robot Wars” appeared first on RPGamer.

Robert tells us who the babby daddy is. Kelley plays Dark Souls Tetris. Chris designs a very special bidet. And you get to breed with a ditto. Have fun!

The post RPG Cast – Episode 611: “All the Bidoofs I Released Before” appeared first on RPGamer.

Josh demands justice for Jorts. Chris is deployed to the circus wars. And Kelley assures us that Fang sniper is real. We'll see you in 2022. Don't butter your cats!

The post RPG Cast – Episode 612: “He Must Have Put Skill Points Into Broom Handle” appeared first on RPGamer.

Chris gets caught up on Columbo while queueing for FFXIV. Eclipse steals the show from Kelley by opening the Chrome dev tools. And Josh sells all his Spoony Bard NFTs.

The post RPG Cast – Episode 613: “Nancy New Year” appeared first on RPGamer.

Kelley finds out that Alice is made of Lego. Josh asks if his cat even lifts, bro. Chris puts everything into the Final Fantasy XVI bucket. And everyone gets KEMCO shamed.

The post RPG Cast – Episode 614: “The Burned Pirated Disc Is a Feature” appeared first on RPGamer.

Kelley ruins Warcraft by including Conker. Chris mortgages his Xbox. Josh's cat won't let him control his Xbox. And Microsoft has announced their new Candy Crush themed Windows 12.

The post RPG Cast – Episode 615: “The New Dialga Looks Like My Brother’s Broken Vacuum Cleaner” appeared first on RPGamer.

Jonathan Stringer joins us in an attempt to sell his copy of Mugen Souls. Josh is launching his Kickstarter for his new documentary, Legacy of the Bitcoins. And Chris has lost his Epic Games launcher, thanks Windows 11.

The post RPG Cast – Episode 616: “Garland Does It His Way” appeared first on RPGamer.

Chris has a normal amount of coffee on his shirt. Kelley conks her cat on the head with a controller. And Josh thinks Maglam Lord is a contraceptive device.

The post RPG Cast – Episode 617: “Yoko Taro Made This While Queuing for His Raid” appeared first on RPGamer.

This week on RPG Cast, Chris asks Anna to go fix her truckers. Josh wants to date the robots. And Kelley has a hot Raymond.

The post RPG Cast – Episode 618: “Kirby’s Oral Fixation” appeared first on RPGamer.

Kelley graduates from Canada. Josh discovers Tactics Advance is an isekai. Meanwhile Chris calculates the skill check for suplexing a train.

The post RPG Cast – Episode 619: “That One Time I Got Reincarnated as a Canadian Yankee in King Arthur’s Court” appeared first on RPGamer.

Kelley puts a price on a good nap. Josh complains about Pokémon (someone has to). And Chris's true Dark Souls adventure begins with his dryer.

The post RPG Cast – Episode 621: “My Elden Ring Fever Dreams” appeared first on RPGamer.

Josh uses a cat carrier as an impromptu shield. Kelley learns that her husband's Steamdeck RNG is improved if she's not around. Meanwhile, Chris's turtles are always having mating season.

The post RPG Cast – Episode 631: “God of Diablo” appeared first on RPGamer.

Chris takes his horse in for an oil change. Kelley droplifts bootleg amiibos at Target. Josh fantasizes about Nopon Tom Cruise.

The post RPG Cast – Episode 641: “It’s a Vestigial Wheel” appeared first on RPGamer.

Kelley annoys her cat by looking at her feet. Chris scratches his nose with elbow spikes. Josh wonders how fast his computer can emulate Saturn. And Phil needs surgery because of Monster Hunter.

The post RPG Cast – Episode 651: “I’m Sub-Entitled” appeared first on RPGamer.

Tam plays the waifu games for the "plot." Chris teaches his cats to play DDR. Kelley blames everyone else for her Vampire Survivors addiction.

The post RPG Cast – Episode 661: “I Got Addicted to the Pentagram” appeared first on RPGamer.

Chris walks in on Anna playing Tactics Ogre. Alex is head of the elemental winds. And Kelley's cat stole a banana.

The post RPG Cast – Episode 669: “The 1 of 1 Ring to Rule Them All” appeared first on RPGamer.