Disease duration in autosomal dominant familial Alzheimer disease

OBJECTIVE: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. METHODS: Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed. RESULTS: Estimated mean survival was 11.6 (10.4–12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1. CONCLUSIONS: Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD

Ectopic A-lattice seams destabilize microtubules

Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe

Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153137/1/lt25681.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153137/2/lt25681_am.pd

Postcopulatory sexual selection

The female reproductive tract is where competition between the sperm of different males takes place, aided and abetted by the female herself. Intense postcopulatory sexual selection fosters inter-sexual conflict and drives rapid evolutionary change to generate a startling diversity of morphological, behavioural and physiological adaptations. We identify three main issues that should be resolved to advance our understanding of postcopulatory sexual selection. We need to determine the genetic basis of different male fertility traits and female traits that mediate sperm selection; identify the genes or genomic regions that control these traits; and establish the coevolutionary trajectory of sexes

T‐cell epitope content comparison (EpiCC) of swine H1 influenza A virus hemagglutinin

Background: Predicting vaccine efficacy against emerging pathogen strains is a significant problem in human and animal vaccine design. T‐cell epitope cross‐conservation may play an important role in cross‐strain vaccine efficacy. While influenza A virus (IAV) hemagglutination inhibition (HI) antibody titers are widely used to predict protective efficacy of 1 IAV vaccine against new strains, no similar correlate of protection has been identified for T‐cell epitopes. Objective: We developed a computational method (EpiCC) that facilitates pairwise comparison of protein sequences based on an immunological property—T‐cell epitope content—rather than sequence identity, and evaluated its ability to classify swine IAV strain relatedness to estimate cross‐protective potential of a vaccine strain for circulating viruses. Methods: T‐cell epitope relatedness scores were assessed for 23 IAV HA sequences representing the major H1 swine IAV phylo‐clusters circulating in North American swine and HA sequences in a commercial inactivated vaccine (FluSure XP®). Scores were compared to experimental data from previous efficacy studies. Results: Higher EpiCC scores were associated with greater protection by the vaccine against strains for 23 field IAV strain vaccine comparisons. A threshold for EpiCC relatedness associated with full or partial protection in the absence of cross‐reactive HI antibodies was identified. EpiCC scores for field strains for which FluSure protective efficacy is not yet available were also calculated. Conclusion: EpiCC thresholds can be evaluated for predictive accuracy of protection in future efficacy studies. EpiCC may also complement HI cross‐reactivity and phylogeny for selection of influenza strains in vaccine development

Can Plan Recommendations Improve the Coverage Decisions of Vulnerable Populations in Health Insurance Marketplaces?

OBJECTIVE: The Affordable Care Act's marketplaces present an important opportunity for expanding coverage but consumers face enormous challenges in navigating through enrollment and re-enrollment. We tested the effectiveness of a behaviorally informed policy tool--plan recommendations--in improving marketplace decisions. STUDY SETTING: Data were gathered from a community sample of 656 lower-income, minority, rural residents of Virginia. STUDY DESIGN: We conducted an incentive-compatible, computer-based experiment using a hypothetical marketplace like the one consumers face in the federally-facilitated marketplaces, and examined their decision quality. Participants were randomly assigned to a control condition or three types of plan recommendations: social normative, physician, and government. For participants randomized to a plan recommendation condition, the plan that maximized expected earnings, and minimized total expected annual health care costs, was recommended. DATA COLLECTION: Primary data were gathered using an online choice experiment and questionnaire. PRINCIPAL FINDINGS: Plan recommendations resulted in a 21 percentage point increase in the probability of choosing the earnings maximizing plan, after controlling for participant characteristics. Two conditions, government or providers recommending the lowest cost plan, resulted in plan choices that lowered annual costs compared to marketplaces where no recommendations were made. CONCLUSIONS: As millions of adults grapple with choosing plans in marketplaces and whether to switch plans during open enrollment, it is time to consider marketplace redesigns and leverage insights from the behavioral sciences to facilitate consumers' decisions

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Acute Toxicity and General Pharmacological Action of QGC EXT

It has been shown that QGC isolated and purified from Rumecis folium found protective effects of gastritis and esophagitis which EXT is an ethanol extract of it. We examined acute toxicity and the general pharmacological action of QGC EXT to search for any side effects of it in rats, mice, guinea pigs, and cats. In a single dose toxicity study, QGC EXT didn't show toxicological effects in rats and mice, and the LD50 was over 5 g/kg in both animals, and there were also no changes in weight, feed and water intake during these toxicological experimental periods. We examined the general pharmacological action on central controlled behavior responses, and peripheral organs including blood pressure, heart rate, respiration and gastrointestinal system, We found that there were no significant changes in body temperature, locomotors activity, stereotyped behaviors, sleeping time, and convulsion. In other studies, writhing reaction, normal body temperature, there did not appear to be any changes. The large intestine movement and electrical field stimulation-induced contraction was not changes by its EXT. In addition, the influences on blood pressure, heart rates, and respiration by QGC EXT were not found. These results indicate that QGC EXT may be very safe as a new drug, since its LD50 was very high over 5 g/kg and any side effects were not found

Understanding communication networks in the emergency department

<p>Abstract</p> <p>Background</p> <p>Emergency departments (EDs) are high pressure health care settings involving complex interactions between staff members in providing and organising patient care. Without good communication and cooperation amongst members of the ED team, quality of care is at risk. This study examined the problem-solving, medication advice-seeking and socialising networks of staff working in an Australian hospital ED.</p> <p>Methods</p> <p>A social network survey (Response Rate = 94%) was administered to all ED staff (n = 109) including doctors, nurses, allied health professionals, administrative staff and ward assistants. Analysis of the network characteristics was carried out by applying measures of density (the extent participants are concentrated), connectedness (how related they are), isolates (how segregated), degree centrality (who has most connections measured in two ways, in-degree, the number of ties directed to an individual and out-degree, the number of ties directed from an individual), betweenness centrality (who is important or powerful), degree of separation (how many ties lie between people) and reciprocity (how bi-directional are interactions).</p> <p>Results</p> <p>In all three networks, individuals were more closely connected to colleagues from within their respective professional groups. The problem-solving network was the most densely connected network, followed by the medication advice network, and the loosely connected socialising network. ED staff relied on each other for help to solve work-related problems, but some senior doctors, some junior doctors and a senior nurse were important sources of medication advice for their ED colleagues.</p> <p>Conclusions</p> <p>Network analyses provide useful ways to assess social structures in clinical settings by allowing us to understand how ED staff relate within their social and professional structures. This can provide insights of potential benefit to ED staff, their leaders, policymakers and researchers.</p

Attentional learning helps language acquisition take shape for atypically developing children, not just children with Autism Spectrum Disorders

The shape bias-generalising labels to same shaped objects-has been linked to attentional learning or referential intent. We explore these origins in children with typical development (TD), autism spectrum disorders (ASD) and other developmental disorders (DD). In two conditions, a novel object was presented and either named or described. Children selected another from a shape, colour or texture match. TD children choose the shape match in both conditions, children with DD and 'high-verbal mental age' (VMA) children with ASD (language age > 4.6) did so in the name condition and 'low-VMA' children with ASD never showed the heuristic. Thus, the shape bias arises from attentional learning in atypically developing children and is delayed in ASD