Population Impact & Efficiency of Benefit‐Targeted Versus Risk‐Targeted Statin Prescribing for Primary Prevention of Cardiovascular Disease

BACKGROUND: Benefit-targeted statin prescribing may be superior to risk-targeted statin prescribing (the current standard), but the impact and efficiency of this approach are unclear. METHODS AND RESULTS: We analyzed the National Health and Nutrition Examination Survey (NHANES) using an open-source model (the Prevention Impact and Efficiency Model) to compare targeting of statin therapy according to expected benefit (benefit-targeted) versus baseline risk (risk-targeted) in terms of projected population-level impact and efficiency. Impact was defined as relative % reduction in atherosclerotic cardiovascular disease in the US population for the given strategy compared to current statin treatment patterns; and efficiency as the number needed to treat over 10 years (NNT10, average and maximum) to prevent each atherosclerotic cardiovascular disease event. Benefit-targeted moderate-intensity statin therapy at a treatment threshold of 2.3% expected 10-year absolute risk reduction could produce a 5.7% impact (95% confidence interval, 4.8-6.7). This is approximately equivalent to the potential impact of risk-targeted therapy at a treatment threshold of 5% 10-year atherosclerotic cardiovascular disease risk (5.6% impact [4.7-6.6]). Whereas the estimated maximum NNT10 is much improved for benefit-targeted versus risk-targeted therapy at these equivalent-impact thresholds (43.5 vs 180), the average NNT10 is nearly equivalent (24.2 vs 24.6). Reaching 10% impact (half the Healthy People 2020 impact objective, loosely defined) is theoretically possible with benefit-targeted moderate-intensity statins of persons with expected absolute risk reduction >2.3% if we expand age eligibility and account for treatment of all persons with diabetes mellitus or with low-density lipoprotein >190 mg/dL (impact=12.4%; average NNT10=23.0). CONCLUSIONS: Benefit-based targeting of statin therapy provides modest gains in efficiency over risk-based prescribing and could theoretically help attain approximately half of the Healthy People 2020 impact goal with reasonable efficiency

Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells

To prevent rereplication of genomic segments, the eukaryotic cell cycle is divided into two nonoverlapping phases. During late mitosis and G1 replication origins are “licensed” by loading MCM2-7 double hexamers and during S phase licensed replication origins activate to initiate bidirectional replication forks. Replication forks can stall irreversibly, and if two converging forks stall with no intervening licensed origin—a “double fork stall” (DFS)—replication cannot be completed by conventional means. We previously showed how the distribution of replication origins in yeasts promotes complete genome replication even in the presence of irreversible fork stalling. This analysis predicts that DFSs are rare in yeasts but highly likely in large mammalian genomes. Here we show that complementary strand synthesis in early mitosis, ultrafine anaphase bridges, and G1-specific p53-binding protein 1 (53BP1) nuclear bodies provide a mechanism for resolving unreplicated DNA at DFSs in human cells. When origin number was experimentally altered, the number of these structures closely agreed with theoretical predictions of DFSs. The 53BP1 is preferentially bound to larger replicons, where the probability of DFSs is higher. Loss of 53BP1 caused hypersensitivity to licensing inhibition when replication origins were removed. These results provide a striking convergence of experimental and theoretical evidence that unreplicated DNA can pass through mitosis for resolution in the following cell cycle

Tumor predisposition in mice mutant for p63 and p73: Evidence for broader tumor suppressor functions for the p53 family

Summaryp63 and p73 are functionally and structurally related to the tumor suppressor p53. However, their own role in tumor suppression is unclear. Given the p53-like properties of p63 and p73, we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63+/−;p73+/− mice develop spontaneous tumors. Loss of p63 and p73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and p73 displayed higher tumor burden and metastasis compared to p53+/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported

Asymmetric ketone hydroboration catalyzed by alkali metal complexes derived from BINOL ligands

The ability of alkali metal complexes featuring functionalized BINOL-derived ligands to catalyze ketone hydroboration reactions was explored. The reduced products were formed in excellent yield and with variable enantioselectivities dependent upon the nature of the ligand and the alkali metal cation

Animal Research beyond the Laboratory:Report from a Workshop on Places Other than Licensed Establishments (POLEs) in the UK

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Research involving animals that occurs outside the laboratory raises an array of unique challenges. With regard to UK legislation, however, it receives only limited attention in terms of official guidelines, support, and statistics, which are unsurprisingly orientated towards the laboratory environment in which the majority of animal research takes place. In September 2019, four social scientists from the Animal Research Nexus program gathered together a group of 13 experts to discuss nonlaboratory research under the Animals (Scientific Procedures) Act (A(SP)A) of 1986 (mirroring European Union (EU) Directive 2010/63/EU), which is the primary mechanism for regulating animal research in the UK. Such nonlaboratory research under the A(SP)A often occurs at Places Other than Licensed Establishments (POLEs). The primary objective of the workshop was to assemble a diverse group with experience across a variety of POLEs (e.g., wildlife field sites, farms, fisheries, veterinary clinics, zoos) to explore the practical, ethical, and regulatory challenges of conducting research at POLEs. While consensus was not sought, nor reached on every point of discussion, we collectively identified five key areas that we propose require further discussion and attention. These relate to: (1) support and training; (2) ethical review; (3) cultures of care, particularly in nonregulated research outside of the laboratory; (4) the setting of boundaries; and (5) statistics and transparency. The workshop generated robust discussion and thereby highlighted the value of focusing on the unique challenges posed by POLEs, and the need for further opportunities for exchanging experiences and sharing best practice relating to research projects outside of the laboratory in the UK and elsewhere

Relationships between home ventilation rates and respiratory health in the Colorado Home Energy Efficiency and Respiratory Health (CHEER) study.

BACKGROUND: As societies adopt green building practices to reduce energy expenditures and emissions that contribute to climate change, it is important to consider how such building design changes influence health. These practices typically focus on reducing air exchange rates between the building interior and the outdoor environment to minimize energy loss, the health effects of which are not well characterized. This study aims to evaluate the relationship between air exchange rates and respiratory health in a multi-ethnic population living in low-income, urban homes. METHODS: The Colorado Home Energy Efficiency and Respiratory Health (CHEER) study is a cross-sectional study that enrolled 302 people in 216 non-smoking, low-income single-family homes, duplexes and town-homes from Colorado's Northern Front Range. A blower door test was conducted and the annual average air exchange rate (AAER) was estimated for each home. Respiratory health was assessed using a structured questionnaire based on standard instruments. We estimated the association between AAER and respiratory symptoms, adjusting for relevant confounders. RESULTS: Air exchange rates in many homes were high compared to prior studies (median 0.54 air changes per hour, range 0.10, 2.17). Residents in homes with higher AAER were more likely to report chronic cough, asthma and asthma-like symptoms, including taking medication for wheeze, wheeze that limited activities and dry cough at night. Allergic symptoms were not associated with AAER in any models. The association between AAER and asthma-like symptoms was stronger for households located in areas with high potential exposure to traffic related pollutants, but this was not consistent across all health outcomes. CONCLUSIONS: While prior studies have highlighted the potential hazards of low ventilation rates in residences, this study suggests high ventilation rates in single-family homes, duplexes and town-homes in urban areas may also have negative impacts on respiratory health, possibly due to the infiltration of outdoor pollutants.</p

Twisting the arm: structural constraints in bicyclic expanded-ring N-heterocyclic carbenes

A series of diaryl, mono-aryl/alkyl and dialkyl mono- and bicyclic expanded-ring N-heterocyclic carbenes (ER-NHCs) have been prepared and their complexation to Au(I) investigated through the structural analysis of fifteen Au(NHC)X and/or [Au(NHC)2]X complexes. The substituted diaryl 7-NHCs are the most sterically encumbered with large buried volume (%VB) values of 40–50% with the less flexible six-membered analogues having %VB values at least 5% smaller. Although the bicyclic systems containing fused 6- and 7-membered rings (6,7-NHCs) are constrained with relatively acute NCN bond angles, they have the largest %VB values of the dialkyl derivatives reported here, a feature related to the fixed conformation of the heterocyclic rings and the compressional effect of a pre-set methyl substituent

The redshift and mass dependence on the formation of the Hubble sequence at z > 1 from CANDELS/UDS

In this paper we present a detailed study of the structures and morphologies of a sample of 1188 massive galaxies with M-* >= 10(10) M-circle dot between redshifts z = 1 and 3 within the Ultra Deep Survey (UDS) region of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) field. Using this sample we determine how galaxy structure and morphology evolve with time, and investigate the nature of galaxy structure at high redshift. We visually classify our sample into discs, ellipticals and peculiar systems and correct for redshift effects on these classifications through simulations. We find significant evolution in the fractions of galaxies at a given visual classification as a function of redshift. The peculiar population is dominant at z > 2 with a substantial spheroid population, and a negligible disc population. We compute the transition redshift, z(trans), where the combined fraction of spheroidal and disc galaxies is equal to that of the peculiar population, as z(trans) = 1.86 +/- 0.62 for galaxies in our stellar mass range. We find that this transition changes as a function of stellar mass, with Hubble-type galaxies becoming dominant at higher redshifts for higher mass galaxies (z(trans) = 2.22 +/- 0.82), than for the lower mass galaxies (z(trans) = 1.73 +/- 0.57). Higher mass galaxies become morphologically settled before their lower mass counterparts, a form of morphological downsizing. We furthermore compare our visual classifications with the Sersic index, the concentration, asymmetry and clumpiness (CAS) parameters, star formation rate and rest-frame U - B colour. We find links between the colour of a galaxy, its star formation rate and how extended or peculiar it appears. Finally, we discuss the negligible z > 2 disc fraction based on visual morphologies and speculate that this is an effect of forming disc appearing peculiar through processes such as violent disc instabilities or mergers. We conclude that to properly define and measure high-redshift morphology and structure a new and more exact classification scheme is needed