Burden of hereditary transthyretin amyloidosis on quality of life

INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis is a progressive, degenerative disease, with peripheral neuropathy, cardiomyopathy, and other clinical manifestations. In this study we examine the impact of hATTR amyloidosis on quality of life (QOL). METHODS: Neuropathy-specific QOL, measured with the Norfolk QOL-Diabetic Neuropathy questionnaire, was compared between patients with hATTR amyloidosis and patients with type 2 diabetes, whereas generic QOL, measured with the 36-item Short Form Health Survey version 2 (SF-36v2), was compared between patients with hATTR amyloidosis, the general population, and patients with chronic diseases. RESULTS: Neuropathy-specific QOL for patients with hATTR amyloidosis was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation. Generic QOL was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure. DISCUSSION: Patients with hATTR amyloidosis show significant burden on QOL, particularly in physical functioning. Muscle Nerve 60: 169-175, 201

Prenormative verification and validation of a protocol for measuring magnetite–maghemite ratios in magnetic nanoparticles

An important step in establishing any new metrological method is a prenormative interlaboratory study, designed to verify and validate the method against its stated aims. Here, the 57Fe Mössbauer spectrometric ‘centre of gravity’ (COG) method was tested as a means of quantifying the magnetite/maghemite (Fe3O4/γ-Fe2O3) composition ratio in biphasic magnetic nanoparticles. The study involved seven laboratories across Europe and North and South America, and six samples—a verification set of three microcrystalline mixtures of known composition, and a validation set of three nanoparticle samples of unknown composition. The spectra were analysed by each participant using in-house fitting packages, and ex post facto by a single operator using an independent package. Repeatability analysis was performed using Mandel’s h statistic and modified Youden plots. It is shown that almost all (83/84) of the Mandel h statistic values fall within the 0.5% significance level, with the one exception being borderline. Youden-based pairwise analysis indicates the dominance of random uncertainties; and in almost all cases the data analysis phase is only a minor contributor to the overall measurement uncertainty. It is concluded that the COG method is a robust and promising candidate for its intended purpose

Preliminary safety study for an equine (Equus caballus) vaccine against sperm acrosome associated 3 protein

In the United States, the wild horse population exceeds the recommended carrying capacity by about 60,000 horses. • Current contraceptive methods include: surgical (removal of ovaries), hormonal (progesterone, GnRH), and immunologic (porcine zona pellucida, GnRH). • SPACA3 is a sperm surface membrane protein involved in sperm-egg plasma membrane adhesion and fusion during fertilization, and has been identified in men, cattle, sheep, and deer. • SPACA3 has also been identified in the granulosa cells and ooplasm in dogs and cats

Optimizing Wellness in Academic Emergency Medicine

Introduction Academic Emergency Physicians (EPs) face additional unique challenges in optimizing wellness compared to community EPs. Objective Our objective was to explore specific individual and systems challenges that academic EPs encounter that affect their wellbeing and professional fulfillment in emergency medicine (EM). Methods An expert group of academic EPs convened in 2019 at the annual meeting of the Society of Academic Emergency Medicine to investigate the overall causes of burnout in healthcare providers, the effects of burnout on the healthcare system, specific causes of burnout in EM, and the distinct challenges facing academic emergency physicians. Results We outline specific causes of burnout in EM and the effects of burnout on the healthcare system. Scholarly productivity pressures, variable reimbursement gaps, time allotment, and work-life balance are challenges facing academic EPs. Conclusion Understanding the unique challenges of academic EPs in optimizing wellness is vital to inform future research and effective interventions

The Biosecurity Risks of International Forest Tree Seed Movements

Funding Information: Anne Chandelier was funded by the Belgian Federal Service Health, Food Chain and Environment (project RF21/6344 ALERTSEED). Funding Information: René Eschen was supported by CABI. CABI is an international intergovernmental organisation, and we gratefully acknowledge the core financial support from our member countries (and lead agencies) including the UK (Foreign, Commonwealth & Development Office), China (Chinese Ministry of Agriculture and Rural Affairs), Australia (Australian Centre for International Agricultural Research), Canada (Agriculture and Agri-Food Canada), Netherlands (Directorate-General for International Cooperation) and Switzerland (Swiss Agency for Development and Cooperation). See https:// www. cabi. org/ about- cabi/ who- we- work- with/ key- donors/ for full details. Funding Information: Helena Bragança was supported by INIAV IP and FCT (Portugal) through the R&D Unit “GREEN-IT-Bioresources for Sustainability” (UIDB/04551/2020 and UIDP/04551/2020) and LS4FUTURE Associated Laboratory (LA/P/0087/2020). Funding Information: Guro Brodal and Venche Talgø were funded by the Norwegian Institute of Bioeconomy Research (NIBIO). Funding Information: Thomas L. Cech and Katharina Schwanda were financially supported by the Austrian Federal Ministry of Agriculture, Forestry, Regions and Water Management (BML), Stubenring 1, 1010 Vienna, Austria. Funding Information: This study was carried out within the Agritech National Research Center and received funding from the European Union Next-GenerationEU (PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR)—MISSIONE 4 COMPONENTE 2, INVESTIMENTO 1.4—D.D. 1032 17/06/2022, CN00000022). This manuscript reflects only the authors’ views and opinions neither the European Union nor the European Commission can be considered responsible for them. Funding Information: Ana Pérez-Sierra was funded by the Department for Environment, Food & Rural Affairs (DEFRA) and Forest Research (UK). Funding Information: This study was supported by Partnerskap Alnarp Project 1407, SLU Forest Damage Centre and Kungl. Skogs-och Lantbruksakademien KSLA Grant CF2022-0022. Funding Information: Open Access funding provided by Lib4RI – Library for the Research Institutes within the ETH Domain: Eawag, Empa, PSI & WSL. Iva Franić was funded by the Swiss National Science Foundation Grant number P500PB_211040. Publisher Copyright: © 2023, The Author(s).Purpose of Review: Because tree seeds have been considered a low-risk pathway for the spread of plant pathogenic fungi, their international movement is not subject to strict phytosanitary regulation. However, recent studies have provided scientific evidence that the biosecurity risk of seed trade may not be as negligible as assumed. This review summarises current knowledge about seed trade activity across the world and seed-borne plant pathogenic fungi and highlights knowledge gaps that need to be filled to mitigate the risk of spreading tree pathogens via seeds. Recent Findings: Several outbreaks of severe tree diseases in natural forests and plantations worldwide have been linked to fungal pathogens spread by seed trade. Indeed, recent studies based on modern sequencing technologies have shown that tree seeds harbour highly diverse fungal communities, including well-known pathogens and fungal taxa belonging to unknown species. While it has become clear that even apparently healthy seeds can carry potentially pathogenic fungi, the likelihood of seed-borne pathogens being introduced and becoming established, spreading and causing impact in the new environment is still unclear which challenges the assessment of the phytosanitary risk posed by seed trade. Summary: Our analyses show that large amounts of tree seeds have been traded among countries and continents. Based on published literature, the risk of spreading pathogenic fungi via tree seed movement is high. However, the role of the taxonomically and functionally diverse fungal communities associated with seeds is still poorly understood. In particular, more research is needed to assess the likelihood of seed-borne fungi being transmitted to the seedlings and spreading and causing impact in the new environment.publishersversionpublishe

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.This research was funded by Akcea Therapeutics and Ionis Pharmaceuticals, Incinfo:eu-repo/semantics/publishedVersio

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Multivariate analysis of food consumption profiles in crisis settings.

Preventing malnutrition is one of the primary objectives of many humanitarian agencies, and household surveys are regularly employed to monitor food insecurity caused by political, economic, or environmental crises. Consumption frequencies for standard food groups are often collected to characterize the depth of food insecurity in a community and measure the impact of food assistance programs, producing a vector of bounded, correlated counts for each household. While aggregate indicators are typically used to summarize these results with a single statistic, they can be difficult to interpret and provide insufficient detail to judge the effectiveness of assistance programs. To address these limitations, we have developed a multivariate modeling framework for consumption frequency data. We introduce methods to update baseline models for the analysis of the smaller and more variable surveys typically collected in crisis settings, and we present an application of our approach to national consumption data collected in Yemen in 2014 and 2016 by the World Food Programme. The approach provides more nuanced and interpretable information about consumption changes in response to shocks and the effectiveness of humanitarian assistance