From mutation to mechanism: deciphering the molecular function of genetic variants linked to human ageing

Many of the leading causes of death in humans, such as cardiovascular disease, type 2 diabetes and Alzheimer’s disease are influenced by biological mechanisms that become dysregulated with increasing age. Hence, by targeting these ageing-related mechanisms, we may be able to improve health in old age. Ageing is partly heritable and genetic studies have been moderately successful in identifying genetic variants associated with ageing-related phenotypes (lifespan, healthspan and longevity). To decipher the mechanisms by which the identified variants influence ageing, studies that focus on their functional validation are vital. In this perspective, we describe the steps that could be taken in the process of functional validation: (1) in silico characterisation using bioinformatic tools; (2) in vitro characterisation using cell lines or organoids; and (3) in vivo characterisation studies using model organisms. For the in vivo characterisation, it is important to focus on translational phenotypes that are indicative of both healthspan and lifespan, such as the frailty index, to inform subsequent intervention studies. The depth of functional validation of a genetic variant depends on its location in the genome and conservation in model organisms. Moreover, some variants may prove to be hard to characterise due to context-dependent effects related to the experimental environment or genetic background. Future efforts to functionally characterise the (newly) identified genetic variants should shed light on the mechanisms underlying ageing and will help in the design of targeted interventions to improve health in old age

Regulated Commercial Harvest to Manage Overabundant White-Tailed Deer: An Idea to Consider?

Dramatic growth in numbers of white-tailed deer (Odocoileus virginianus) and declines in hunter recruitment have challenged our ability to manage deer populations through traditional methods. We surveyed all state wildlife agencies and estimate the current abundance of white-tailed deer in North America exceeds 30 million. States currently are issuing record numbers of permits to hunters to increase harvest of white-tailed deer. Unfortunately, hunter participation has been declining in North America during the past two decades. Traditional methods of population management have been ineffective in reducing numbers of deer sufficiently in some environments. Regulated commercial harvest would help state wildlife agencies manage overabundant populations of white-tailed deer and allow licensed hunters to sell all or parts of harvested deer. We anticipate that many will criticize regulated commercial harvest of deer and claim that it is contrary to the North American Model of Wildlife Conservation (NAMWC). We feel, however, that regulated commercial harvest meets all seven of the pillars of the NAMWC: 1) Wildlife is a natural resource of the public trust (state wildlife agencies will manage deer and deer would continue to be a public resource). 2) No commercial use of wildlife [a direct reaction to exploitive and unsustainable market hunting in the 18th and 19th Centuries; commercial markets currently exist for other natural resources (e.g., furbearers, fish, timber); contemporary conservation values would not allow overexploitation; a framework for regulations, monitoring, and enforcement already is in place in every state]. 3) Democratic rule of law to regulate use of wildlife (commercial harvest of white-tailed deer would be highly regulated by wildlife agencies through public processes). 4) Hunting opportunity for all (anyone legally able to hold a deer hunting license would be eligible to apply for a Commercial Deer Harvest License (CDHL), CDHL programs would be implemented only where recreational hunting is inefficient or inappropriate). 5) No frivolous use of wildlife (CDHLs will be used to generate food and other products, management would address risks to human health and safety and losses of agricultural resources to deer). 6) Wildlife is an international resource [has little to do with our proposed idea of managing overabundant resident populations of white-tailed deer, but a CDHL program may be applicable to any overabundant species, including internationally migratory species, such as snow geese (Chen caerulescens)]. 7) Science-based wildlife policy (a CDHL program would rely on science and research-based data to estimate densities before, during, and after commercial harvest). A CDHL program should be managed and distributed by state wildlife agencies, issue permits only to qualified individuals, enable harvest of an allotment of deer in areas targeted for population reduction, and permit the sale of whole carcasses and parts of harvested deer. Administration of a CDHL program will be taxing. State agencies are understaffed, but administrative and enforcement frameworks already exist for commercial harvest of publicly owned natural resources (e.g. furbearers, fish, timber) and the processing and handling of meat (e.g., USDA inspections). Revenue generated by CDHL programs could be directed back to agencies and personnel that administer and oversee programs. We anticipate several issues that must be addressed for regulated commercial harvest of deer to be accepted by agencies, hunters, and the public. State laws and regulations will need to be reviewed and some will have to be changed. Some will argue that we do not have the strength, stamina, or political will necessary to implement such broad sweeping changes. On the other hand, many wildlife managers will appreciate having an alternative tool for managing overabundant populations of white-tailed deer. Several benefits (reduce overabundant populations of deer; source of healthy, natural, green, locally-produced protein; economic growth, entrepreneurship, and market expansion; and public engagement and appreciation) and concerns (privatization of wildlife; overexploitation; food safety; competition with existing commodities; law enforcement; challenges of changing laws, regulations, and attitudes) are associated with this concept. We encourage a professional discussion of regulated commercial harvest to address the issue of overabundant white-tailed deer

Effectiveness of a Simulated Pack to Manipulate Wolf Movements

Bioboundaries, also called biofences, are deterrents that attempt to exploit certain innate behaviors to exclude wildlife from target areas. We hypothesized that human-deployed scent marks and playbacks of foreign howls could simulate a territorial gray wolf (Canis lupus) pack impinging on a resident pack, thereby causing the resident pack to move. During summer 2010, we deployed a simulated-pack bioboundary near 3 wolf packs in northern Wisconsin and monitored their movements relative to 3 wolf packs experiencing a sham treatment, to control for effects of human presence. We analyzed wolves’ locations (≥1 location per week) and used linear models with mixed effects to examine distance from the rendezvous site as a function of treatment (sham or experimental) and phase of treatment (before or after treatment was initiated), while accounting for variations in individual wolves. We found little evidence that biofences, as configured and deployed in this study, caused wolves to change use of their territory

Гипотензивный эффект факоэмульсификации катаракты у больных с некомпенсированной первичной открытоугольной глаукомой

Нами було досліджено вплив факоемульсифікації катаракти з імплантацією інтраокулярної лінзи на внутришньоочний тиск (ВОТ). Обстежено та прооперовано 44 ока (36 людей) хворих на катаракту зпідвищеннимвнутриочним тиском, який тримався на тлі прийому двох чи більше гіпотензивних препаратах, та з відкритим кутом передньої камери.Очі були поділені на дві групи: у першу групу увійшли очі з псевдоесфоліативним синдромом, друга – без псевдо ексфоліацій. Більш виражене зниження внутрішньоочного тиску спостерігалося на очах з псевдоексфоліативним синдромом (32,4%) ніж на очах без нього (27,6%). В результаті проведеного лікування крім нормалізації офтальмотонуса вдалося зменшити кількість застосовуваних гіпотензивних препаратів або повністю відійти від них на оперованих очах.Факоемульсифікація катаракти є ефективною методикою нормалізації ВОТ у хворих з ПВКГ і катарактою та може рекомендуватися як метод першого вибору в тактиці лікування даної групи пацієнтів.We have investigated the effect of phacoemulsification of cataract with implantation of intraocular lenses on intraocular pressure (IOP). Examined and operated 44 eyes (36 patients) with cataract and high intraocular pressure, which was kept in the background taking two or more antihypertensive medications, and an open anterior chamber angle. Eyes were divided into two groups: first group included eyes with psevdoesfoliation syndrome, the second – with out pseudoeksfoliation. A marked reduction of intraocular pressure was observed in eyes with PEX syndrome (32.4%) thanineyeswithout (27.6%). As a result of treatment but normalization of IOP managed to reduce the number of antihypertensive drugs used or completely away from them on the operated eyes. Phacoemulsification of the cataract is an effective method of normalization of IOP in patients with POAG and cataract and be recommended as a method of first choice in tactics of treatment of this patient group

An International Prospective Cohort Study To Validate 2 Prediction Rules for Infections Caused by Third-generation Cephalosporin-resistant Enterobacterales

Background The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections. Methods In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points. Results 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non–3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75–.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient. Conclusions A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance

Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Copy number variation associates with mortality in long-lived individuals:a genome-wide assessment

Pathophysiology, epidemiology and therapy of agein