Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms

Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses in both delayed and premature aging. To test the relevance of these processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen over the entire murine adult lifespan and subsequently confirmed these findings on an independent aging cohort. The majority of genes showed similar expression changes in all four organs, indicating a systemic transcriptional response with aging. This systemic response included the same biological processes that are triggered in progeroid and long-lived mice. However, on a genome-wide scale, transcriptomes of naturally aged mice showed a strong association to progeroid but not to long-lived mice. Thus, endocrine and metabolic changes are indicative of “survival” responses to genotoxic stress or starvation, whereas genome-wide associations in gene expression with natural aging are indicative of biological age, which may thus delineate pro- and anti-aging effects of treatments aimed at health-span extension

Self-medication with antibiotics for the treatment of menstrual symptoms in southwest Nigeria: a cross-sectional study

Background: Self-medication with antibiotics is an important factor contributing to the development of bacterial antibiotic resistance. The purpose of this study was to evaluate the prevalence of self-medication with antibiotics for the treatment of menstrual symptoms among university women in Southwest Nigeria. Methods: A cross-sectional survey was administered to female undergraduate and graduate students (n = 706) at four universities in Southwest Nigeria in 2008. The universities were selected by convenience and the study samples within each university were randomly selected cluster samples. The survey was self-administered and included questions pertaining to menstrual symptoms, analgesic and antibiotic use patterns, and demographics. Data were analyzed using descriptive statistics and logistic regression. Results: The response rate was 95.4%. Eighty-six percent (95% CI: 83-88%) of participants experienced menstrual symptoms, and 39% (95% CI: 36-43%) reported using analgesics to treat them. Overall, 24% (95% CI: 21-27%) of participants reported self-medicated use of antibiotics to treat the following menstrual symptoms: cramps, bloating, heavy bleeding, headaches, pimples/acne, moodiness, tender breasts, backache, joint and muscle pain. Factors associated with this usage were: lower levels of education (Odds Ratio (OR): 2.8, 95% CI: 1.1-7.1, p-value: 0.03); nonscience major (OR: 1.58, 95% CI: 1.03-2.50, p-value: 0.04); usage of analgesics (OR: 3.17, 95% CI: 2.07-4.86, p-value: <0.001); and mild to extreme heavy bleeding (OR: 1.64, 95% CI: 1.01-2.67, p-value: 0.05) and pimples/acne (OR: 1.57, 95% CI: 0.98-2.54, p-value: 0.06). Ampicillin, tetracycline, ciprofloxacin and metronidazole were used to treat the most symptoms. Doctors or nurses (6%, 95% CI: 4-7%), friends (6%, 95% CI: 4-7%) and family members (7%, 95% CI: 5-8%) were most likely to recommend the use of antibiotics for menstrual symptoms, while these drugs were most often obtained from local chemists or pharmacists (10.2%, 95% CI: 8-12%). Conclusions: This is the first formal study to report that approximately 1 out of 4 university women surveyed in Southwest Nigeria self-medicate with antibiotics to treat menstrual symptoms. This practice could provide monthly, low-dose exposures to antibiotics among users. Further studies are necessary to evaluate the impacts of selfmedication on student health

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses

Background Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). Methods and findings Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86–0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34–0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90–1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40–0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. Conclusions In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Oral l-menthol reduces thermal sensation, increases work-rate and extends time to exhaustion, in the heat at a fixed rating of perceived exertion

PurposeThe study investigated the effect of a non-thermal cooling agent, l-menthol, on exercise at a fixed subjective rating of perceived exertion (RPE) in a hot environment.MethodEight male participants completed two trials at an exercise intensity between ‘hard’ and ‘very hard’, equating to 16 on the RPE scale at ~35 °C. Participants were instructed to continually adjust their power output to maintain an RPE of 16 throughout the exercise trial, stopping once power output had fallen by 30%. In a randomized crossover design, either l-menthol or placebo mouthwash was administered prior to exercise and at 10 min intervals. Power output, VO2, heart rate, core and skin temperature was monitored, alongside thermal sensation and thermal comfort. Isokinetic peak power sprints were conducted prior to and immediately after the fixed RPE trial.ResultsExercise time was greater (23:23 ± 3:36 vs. 21:44 ± 2:32 min; P = 0.049) and average power output increased (173 ± 24 vs. 167 ± 24 W; P = 0.044) in the l-menthol condition. Peak isokinetic sprint power declined from pre-post trial in the l-menthol l (9.0%; P = 0.015) but not in the placebo condition (3.4%; P = 0.275). Thermal sensation was lower in the l-menthol condition (P = 0.036), despite no changes in skin or core temperature (P > 0.05).Conclusion These results indicate that a non-thermal cooling mouth rinse lowered thermal sensation, resulting in an elevated work rate, which extended exercise time in the heat at a fixed RPE

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone