A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.

Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease2-4. Fructose intake triggers de novo lipogenesis in the liver4-6, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases8. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota9, and this supplies lipogenic acetyl-CoA independently of ACLY10. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.

Model for an Academic Medicine Interest Group: A student-led initiative.

Academic physicians are responsible for the education of medical students, residents, and other practicing physicians through clinical rotations lectures, seminars, research, and conferences. Therefore, the increasing need to recruit academic physicians holds immense value within the healthcare system. Academic Medicine Interest Group (AMIG) is a collective made up of students who share an interest in the growth and advancement of academic medicine. We present a guide and model on establishing an AMIG. We found that AMIG fostered professional growth by providing leadership, research, and teaching opportunities. Strategic planning, effective leadership, and group organization were all necessary for the success of the group.

Native American ancestry and breast cancer risk in Colombian and Mexican women: ruling out potential confounding through ancestry-informative markers.

BACKGROUND: Latin American and Hispanic women are less likely to develop breast cancer (BC) than women of European descent. Observational studies have found an inverse relationship between the individual proportion of Native American ancestry and BC risk. Here, we use ancestry-informative markers to rule out potential confounding of this relationship, estimating the confounder-free effect of Native American ancestry on BC risk. METHODS AND STUDY POPULATION: We used the informativeness for assignment measure to select robust instrumental variables for the individual proportion of Native American ancestry. We then conducted separate Mendelian randomization (MR) analyses based on 1401 Colombian women, most of them from the central Andean regions of Cundinamarca and Huila, and 1366 Mexican women from Mexico City, Monterrey and Veracruz, supplemented by sensitivity and stratified analyses. RESULTS: The proportion of Colombian Native American ancestry showed a putatively causal protective effect on BC risk (inverse variance-weighted odds ratio [OR] = 0.974 per 1% increase in ancestry proportion, 95% confidence interval [CI] 0.970-0.978, p = 3.1 × 10-40). The corresponding OR for Mexican Native American ancestry was 0.988 (95% CI 0.987-0.990, p = 1.4 × 10-44). Stratified analyses revealed a stronger association between Native American ancestry and familial BC (Colombian women: OR = 0.958, 95% CI 0.952-0.964; Mexican women: OR = 0.973, 95% CI 0.969-0.978), and stronger protective effects on oestrogen receptor (ER)-positive BC than on ER-negative and triple-negative BC. CONCLUSIONS: The present results point to an unconfounded protective effect of Native American ancestry on BC risk in both Colombian and Mexican women which appears to be stronger for familial and ER-positive BC. These findings provide a rationale for personalised prevention programmes that take genetic ancestry into account, as well as for future admixture mapping studies.

Alternative Abdominal Wall Plication Techniques: A Review of Current Literature.

Abdominoplasty is one of the most common procedures performed in plastic surgery. By removing redundant skin and fat tissue, body contouring narrows the waist and achieves a naturally flattened appearance. To achieve this, one technique frequently utilized is plication of the abdominal rectus sheath. Although abdominal wall plication is commonly performed during abdominoplasty, there is a lack of consensus regarding which plication method provides the best outcomes. Each variation addresses some of the common intraoperative and postoperative complications of abdominoplasty. These include extended operating time, rupture of the plication, epigastric bulging, and patient postoperative dissatisfaction. Many plication techniques have been described in the literature, but no single technique has been adopted by plastic surgeons as the gold standard. Here we present a narrative comparison of current published literature reporting novel or modified abdominoplasty plication techniques. This includes diagrams of each procedure, sutures utilized, and key concepts of each plication technique. Discussion regarding how these modifications change operating time, alter epigastric bulging, and improve the ability to narrow the waist is provided. The purpose of this paper is to provide a concise source document for plastic surgeons to reference when choosing a plication method to use during abdominoplasty.

Health conditions among Navy divers at end of service: a retrospective cohort study.

PURPOSE: To identify the most prevalent health conditions among divers during their last year of Navy service. METHODS: For this retrospective descriptive study we used data from the Dive Jump Reporting System to identify 4,623 active-duty divers who separated between 2008 and 2018. Medical records, dive histories, and personnel files were merged, linked and analyzed at the individual level. RESULTS: On average, 420 divers separated each year. Among the separating divers, 99% were male, 26% were aged 25 to 29 years old with a mean age of 35 (SD = 9, range 18 to 65). The major medical categories with the highest numbers of divers affected were: musculoskeletal system diseases (prevalence rate (PR) = 515.2 per 1,000 divers/year); nervous system (PR = 411.9); injury and poisonings (PR = 249.8); and mental disorders (PR = 237.3). Of the 50 specific conditions that affected the most divers the top four were joint disorders (PR = 34.5), disorders of refraction and accommodation (PR = 30.1), back disorders (PR = 26.8) and organic sleep disorders (PR = 21.6). Compared to divers with fewer than 29 dives, divers with 49-plus dives were about twice as likely to have diagnoses related to symptoms involving head and neck. CONCLUSIONS: The study found high rates of conditions such as musculoskeletal disorders, joint and back disorders, and some mental health related disorders. Special warfare divers have high rates of hearing loss, and other disorders of ear. The results show the need and to develop and implement group-specific mitigation programs.

Prescription medication use and trends for U.S. Navy submariners from 2007 to 2018.

Introduction: This is the first study to examine population medication prescription rates among U.S. submariners by common therapeutic classifications. Methods: Individual-level pharmacy records during the years 2007 to 2018 were extracted from the Military Health System's Pharmacy Data Transaction Service (PDTS) file. Demographic and military factors captured from Navy personnel files were linked to PDTS records. Logistic regression models were used to identify characteristics and trends associated with prevalence. Published total rates for other active-duty components were compared to submariner rates. Results: There were data for 50,720 submariners, among whom 576,782 prescriptions were filled. Prevalence rates decreased significantly from 2007-2018 among most drug classes. Central nervous system agents accounted for 31% of the total prescriptions, followed by 12% for eye, ear, nose, and throat preparations, and 10% for anti-infective agents. Higher prescription rates were associated with being enlisted, younger, a woman, lower-ranked, or Hispanic. The mean yearly prescription rate was 2.7 per submariner, less than half of the overall rate of all military components. Conclusion: The survival benefit of HBO2 therapy observed in our unadjusted analysis suggests that there may be therapeutic benefits of HBO2 in treating COVID-19 hypoxia as an adjunct to standard care.

FACSHuman, a software program for creating experimental material by modeling 3D facial expressions.

This paper presents the FACSHuman software program, a tool for creating facial expression materials (pictures and videos) based on the Facial Action Coding System (FACS) developed by Ekman et al. (2002). FACSHuman allows almost all the Action Units (AUs) described in the FACS Manual to be manipulated through a three-dimensional modeling software interface. Four experiments were conducted to evaluate facial expressions of emotion generated by the software and their theoretical efficiency regarding the FACS. The first study (a categorization task of facial emotions such as happiness, anger, etc.) showed that 85% of generated pictures of emotional expressions were correctly categorized. The second study showed that only 82% of the most-used AUs were correctly matched. In the third experiment, two independent FACS coders rated 47 AUs generated by FACSHuman using the standard methodology used in this kind of task (AU identification). Results showed good-to-excellent codification rates (64% and 85%). In the last experiment, 54 combinations of AU were evaluated by the same FACS coders. Results showed good-to-excellent codification rates (68-82%). Results suggested that FACSHuman could be used as experimental material for research into nonverbal communication and emotional expression.

Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides.

Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a challenge. We report here the first general approach to this transformation. The key to productive, selective cross-coupling is the use of a small amount of iodide or bromide along with a recently reported ligand, pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN). The scope of the reaction is demonstrated with 35 examples (63 ± 16% average yield), and we show that the Br- and I- additives act as cocatalysts, generating a low, steady-state concentration of more-reactive alkyl bromide/iodide.

Nickel-Catalyzed Addition of Aryl Bromides to Aldehydes To Form Hindered Secondary Alcohols.

Transition-metal-catalyzed addition of aryl halides across carbonyls remains poorly developed, especially for aliphatic aldehydes and hindered substrate combinations. We report here that simple nickel complexes of bipyridine and PyBox can catalyze the addition of aryl halides to both aromatic and aliphatic aldehydes using zinc metal as the reducing agent. This convenient approach tolerates acidic functional groups that are not compatible with Grignard reactions, yet sterically hindered substrates still couple in high yield (33 examples, 70% average yield). Mechanistic studies show that an arylnickel, and not an arylzinc, adds efficiently to cyclohexanecarboxaldehyde, but only in the presence of a Lewis acid co-catalyst (ZnBr2).

Interaction between genetic ancestry and common breast cancer susceptibility variants in Colombian women.

Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1022 Colombian BC cases and 1023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC) = 0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC = 0.58) or the combined effect of all 13 associated risk variants (AUC = 0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants.

Opioid Overdose Prevention Programs Providing Naloxone to Laypersons - United States, 2014.

Drug overdose deaths in the United States have more than doubled since 1999. During 2013, 43,982 drug overdose deaths (unintentional, intentional [suicide or homicide], or undetermined intent) were reported. Among these, 16,235 (37%) were associated with prescription opioid analgesics (e.g., oxycodone and hydrocodone) and 8,257 (19%) with heroin. For many years, community-based programs have offered opioid overdose prevention services to laypersons who might witness an overdose, including persons who use drugs, their families and friends, and service providers. Since 1996, an increasing number of programs provide laypersons with training and kits containing the opioid antagonist naloxone hydrochloride (naloxone) to reverse the potentially fatal respiratory depression caused by heroin and other opioids. In July 2014, the Harm Reduction Coalition (HRC), a national advocacy and capacity-building organization, surveyed 140 managers of organizations in the United States known to provide naloxone kits to laypersons. Managers at 136 organizations completed the survey, reporting on the amount of naloxone distributed, overdose reversals by bystanders, and other program data for 644 sites that were providing naloxone kits to laypersons as of June 2014. From 1996 through June 2014, surveyed organizations provided naloxone kits to 152,283 laypersons and received reports of 26,463 overdose reversals. Providing opioid overdose training and naloxone kits to laypersons who might witness an opioid overdose can help reduce opioid overdose mortality.

The Reddit cannabis subjective highness rating scale: Applying computational social science to explore psychological and environmental correlates of naturalistic cannabis use.

Social media data provide unprecedented access to discussions of active, naturalistic, and often real-time cannabis use in an era of cannabis policy liberalization. The aim of this study was to explore psychological and environmental correlates of cannabis effects by applying computational social science approaches to a large dataset of unprompted reports of naturalistic cannabis use with corresponding self-reported numerical ratings of subjective highness. Post title text was extracted via the Pushshift dataset from N = 328,865 posts to the r/trees Reddit community, where posters self-assess and disclose how high they feel on a scale from 1 to 10 (M = 6.9, SD = 1.8). Structural topic modelling and Linguistic Inquiry and Word Count (LIWC) dictionary-based approaches were applied to identify (1) frequently discussed topics and (2) text indicative of 5 psychological processes (affective, social, cognitive, perceptual, biological), respectively, as well as to examine relationships between subjective highness and (1) topic prevalence and (2) psychological process word counts. A 40-topic model was selected for interpretation based on semantic coherence and exclusivity. The most discussed topics in a 40-topic model were characterized by references to smoking places, social contexts, positive affect, cognitive states, as well as food and media consumed. In LIWC dictionary analyses, words mentioning affective, social, and cognitive processes were referenced more often than perceptual or body processes. Posters reported greater subjective highness when using language that referred to in-person social environments and lower subjective highness when using language that referred to online social environments and positive affect psychological states. This examination of unprompted online reports of naturalistic cannabis use identified textual content referring to affect and to other people as being associated with perceived effects of cannabis. These affective and social aspects of the cannabis use experience were salient to active posters in this online community and should be integrated into experience sampling methods and behavioral pharmacology research, as well as public health messaging.

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.

Sirtuins, a class of highly conserved histone/protein deacetylases, are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled both transcriptionally and translationally and via localization within the cell. While Sirtiun proteins are implicated with aging, how their levels are regulated during aging across cell types and eliciting tissue specific age-related cellular changes is unclear. Here, we demonstrate that SIRT7 is targeted for degradation during senescence and liver aging. To uncover the significance of SIRT7 loss, we performed proteomics analysis and identified a new SIRT7 interactor, the HMG box protein NUCKS1. We found that the NUCKS1 transcription factor is recruited onto chromatin during senescence and this is mediated by SIRT7 loss. Further, depletion of NUCKS1 delayed senescence upon DNA damage leading to reduction of inflammatory gene expression. Examination of NUCKS1 transcriptional regulation during senescence revealed gene targets of transcription factors NFKB1, RELA, and CEBPß. Consistently, in both Sirt7 KO mouse liver and in naturally aged livers, Nucks1 was recruited to chromatin. Further, Nucks1 was bound at promoters and enhancers of age-related genes, including transcription factor Rela, and, moreover, these bound sites had increased accessibility during aging. Overall, our results uncover NUCKS1 as a novel interactor of SIRT7, and show that loss of SIRT7 during senescence and liver aging promotes NUCKS1 chromatin binding to regulate metabolic and inflammatory genes.

Stool protein mass spectrometry identifies biomarkers for the early detection of diffuse-type gastric cancer.

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of GC or individuals with hereditary diffuse GC (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of stool from a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells (known as TCON mice) identified differentially abundant proteins compared to littermate controls. Immunoblot assays validated a panel of proteins including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP) as enriched in TCON stool compared to littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression as compared to littermate controls. Proteomic mass spectrometry of stool obtained from HDGC patients with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 (TPM2) relative to stool from healthy sex and age-matched donors. Chemical inhibition of ASAH2 using C6-urea ceramide was toxic to GC cell lines and patient derived-GC organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, suggesting a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features which correlated with patient tumors. Here we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC.

Cerebral Venous Sinus Thrombosis Following an mRNA COVID-19 Vaccination and Recent Oral Contraceptive Use.

Rising concerns of cerebral venous sinus thrombosis (CVST) and other forms of venous thromboembolism have been associated with the SARS-CoV-2 vaccinations. Adverse effects with vector-based vaccines are well documented in the literature, while less is known about the mRNA vaccines. This report documents a case of CVST in a 32-year-old female patient who received her second Pfizer mRNA COVID-19 vaccination 16 days prior to hospital admission and had started oral combined contraceptives approximately 4 months beforehand. Clinicians should be cognizant of the possibility that mRNA vaccines, when combined with other risk factors like oral contraceptive pill use, may enhance one's hypercoagulable status.

Creation of an Application to Increase Surgical Resident Operative Case Coverage.

PURPOSE: Studies have shown that the confidence of surgical residents to perform procedures after completing residency can be affected by their volume of operative experiences. Many surgical residencies span multiple hospitals with a multitude of attendings providing additional educational opportunities available via cross-coverage. This study aims to evaluate the use of a mobile application (app) for operative cross-coverage to improve surgical opportunities in a large surgical residency program and decrease the number of uncovered cases. METHODS: An app allowing for uncovered cases to be sent to all surgical residents was used starting March 2022. A survey was completed by residents pre- and postapp implementation. A retrospective chart review was conducted of all general surgery procedures at the 2 major hospital systems 4 months before and after implementation to evaluate resident case coverage. RESULTS: In the preapp survey, 71% (27/38) of residents noted cross-covering 1 or more cases a month with 90% (34/38) reporting, they were unaware of all cases available. In the postapp survey, 100% of residents reported better awareness of available cases, 97% (35/36) reported uncovered cases were more easily accessible, 100% felt the app simplified finding coverage, and 100% wanted to continue the app long-term. On retrospective review, 7210 cases were identified in the preapp and postapp period with an increased volume of cases in the postapp period. After implementation of the case coverage app, there was a significant increase in total case coverage (p = <0.001) as well as a significant increase in coverage of endoscopic (p = 0.007), laparoscopic (p = 0.025), open (p = 0.015) and robotic cases (p = <0.001). CONCLUSIONS: This study shows the impact that technological innovation can play in the education and operative experiences of surgical residents. This can be used to improve operative experiences of residents in various surgical fields in any training program throughout the country.

A Cohort Study Assessing the Impact of Anki as a Spaced Repetition Tool on Academic Performance in Medical School.

Introduction: Anki is an application that capitalizes upon the techniques of spaced repetition and is increasingly utilized by medical students for examination preparation. This study examines the impact of Anki usage in a medical school curriculum on academic performance. Secondary objectives analyzed individual Anki utilization and a qualitative assessment of Anki use. Methods: A cohort-control study was conducted at Boonshoft School of Medicine. One hundred thirty first-year medical students were enrolled in an Anki utilization training program from July 2021 to September 2021. Training included educational Anki courses and subsequent survey data collection over Anki usage. Data variables included all course final examinations, the Comprehensive Basic Science Exam (CBSE), individual Anki user statistics, nationally standardized exams scores, and Qualtrics surveys on student perceived ease of use. Results: Seventy-eight students reported using Anki for at least one of the exams, and 52 students did not use Anki for any exam. Anki users scored significantly higher across all four exams: Course I (6.4%; p < 0.001); Course II (6.2%; p = 0.002); Course III (7.0%; p = 0.002); and CBSE (12.9%; p = 0.003). Students who reported higher dependency on Anki for studying performed significantly better on the Course I, II, and CBSE exams. Conclusion: Anki usage may be associated with an increase in standardized examination scores. This supports Anki as an evidence-based spaced repetition and active retrieval learning modality for medical school standardized examinations. There was little correlation between its specific statistical markers and examination performance. This is pertinent to physicians and medical students alike as the learning and preservation of biomedical knowledge is required for examinations and effective clinical care.