Characterisation of phenotypic patterns in equine exercise-associated myopathies.

BACKGROUND: Equine exercise-associated myopathies are prevalent, clinically heterogeneous, generally idiopathic disorders characterised by episodes of myofibre damage that occur in association with exercise. Episodes are intermittent and vary within and between affected horses and across breeds. The aetiopathogenesis is often unclear; there might be multiple causes. Poor phenotypic characterisation hinders genetic and other disease analyses. OBJECTIVES: The aim of this study was to characterise phenotypic patterns across exercise-associated myopathies in horses. STUDY DESIGN: Historical cross-sectional study, with subsequent masked case-control validation study. METHODS: Historical clinical and histological features from muscle samples (n = 109) were used for k-means clustering and validated using principal components analysis and hierarchical clustering. For further validation, a blinded histological study (69 horses) was conducted comparing two phenotypic groups with selected controls and horses with histopathological features characterised by myofibrillar disruption. RESULTS: We identified two distinct broad phenotypes: a non-classic exercise-associated myopathy syndrome (EAMS) subtype was associated with practitioner-described signs of apparent muscle pain (p < 0.001), reluctance to move (10.85, p = 0.001), abnormal gait (p < 0.001), ataxia (p = 0.001) and paresis (p = 0.001); while a non-specific classic RER subtype was not uniquely associated with any particular variables. No histological differences were identified between subtypes in the validation study, and no identifying histopathological features for other equine myopathies identified in either subtype. MAIN LIMITATIONS: Lack of an independent validation population; small sample size of smaller identified subtypes; lack of positive control myofibrillar myopathy cases; case descriptions derived from multiple independent and unblinded practitioners. CONCLUSIONS: This is the first study using computational clustering methods to identify phenotypic patterns in equine exercise-associated myopathies, and suggests that differences in patterns of presenting clinical signs support multiple disease subtypes, with EAMS a novel subtype not previously described. Routine muscle histopathology was not helpful in sub-categorising the phenotypes in our population.

CONTEXTE: Les myopathies induites à l'exercice demeurent fréquentes, hétérogènes cliniquement et représentent des désordres idiopathiques caractérisés par des épisodes de dommages myofibrillaires en lien avec l'exercice. Les épisodes sont intermittents et varient à la fois chez le même cheval, entre chevaux et entre les différentes races. L'étiopathogénie demeure obscure et pourrait être multifactorielle. La pauvre caractérisation phénotypique des myopathies ne simplifie pas les analyses génétiques ni celles d'autres maladies. OBJECTIFS: Le but de cette étude est de caractériser les patrons phénotypiques en lien avec les myopathies induites à l'exercice chez le cheval. TYPE D'ÉTUDE: Étude transversale historique et étude subséquente de validation de cas témoins aveugle. MÉTHODES: Les facteurs clés cliniques et histologiques provenant d'échantillons de muscles (n = 109) ont été utilisés pour l'algorithme de K­moyennes et validés par le biais d'analyse des composantes principales et de classification hiérarchique. Pour validation additionnelle, une étude histologique à l'aveugle (69 chevaux) a été faite comparant les deux groupes phénotypiques avec des contrôles sélectionnés et des chevaux avec éléments histopathologiques caractérisés par de la discontinuité myofibrillaire. RÉSULTATS: Deux phénotypes distincts ont été identifiés: un premier sous­type de syndrome de myopathie induite à l'exercice non­classique (EAMS) associé à de la douleur musculaire telle que décrite par le praticien suivant le cheval (χ2 (df=1,n=109) = 19.33, p < 0.001), difficulté à se déplacer (χ2 (df=1,n=109) = 10.85, p = 0.001), démarche anormale (χ2 (df=1,n=109) = 34.61, p < 0.001), ataxie (χ2 (df=1,n=109) = 10.88, p = 0.001) et parésie (χ2 (df=1,n=109) = 10.88, p = 0.001); alors qu'un sous­type RER classique non­spécifique n'était associé à aucune variable en particulier. Aucune différente histologique n'a été identifié entre les sous­types dans l'étude de validation et aucune caractéristique histopathologique d'autres myopathies équines n'a été identifiées dans les différents sous­types. LIMITES PRINCIPALES: Aucune population indépendante pour validation; petite taille d'échantillon pour les sous­types peu nombreux identifiés; aucun cas contrôles positifs de myopathie fibrillaire; description des cas provenant de multiples praticiens indépendants et non­aveugles. CONCLUSION: Cette étude est la première utilisant des méthodes de regroupement informatique pour identifier des patrons phénotypiques de myopathies équines induites à l'exercice et suggère que des différences existent dans les patrons de signes cliniques en faveur de multiples sous­types de maladie, incluant EAMS qui représente un nouveau sous­type non décrit jusqu'à maintenant. L'histopathologie musculaire de routine n'a pas permis de sous­catégoriser les phénotypes dans cette population.

Innovative construction of the first reliable catalogue of bovine circular RNAs.

The aim of this study was to compare the circular transcriptome of divergent tissues in order to understand: i) the presence of circular RNAs (circRNAs) that are not exonic circRNAs, i.e. originated from backsplicing involving known exons and, ii) the origin of artificial circRNA (artif_circRNA), i.e. circRNA not generated in-vivo. CircRNA identification is mostly an in-silico process, and the analysis of data from the BovReg project (https://www.bovreg.eu/) provided an opportunity to explore new ways to identify reliable circRNAs. By considering 117 tissue samples, we characterized 23,926 exonic circRNAs, 337 circRNAs from 273 introns (191 ciRNAs, 146 intron circles), 108 circRNAs from small non-coding genes and nearly 36.6K circRNAs classified as other_circRNAs. Furthermore, for 63 of those samples we analysed in parallel data from total-RNAseq (ribosomal RNAs depleted prior to library preparation) with paired mRNAseq (library prepared with poly(A)-selected RNAs). The high number of circRNAs detected in mRNAseq, and the significant number of novel circRNAs, mainly other_circRNAs, led us to consider all circRNAs detected in mRNAseq as artificial. This study provided evidence of 189 false entries in the list of exonic circRNAs: 103 artif_circRNAs identified by total RNAseq/mRNAseq comparison using two circRNA tools, 26 probable artif_circRNAs, and 65 identified by deep annotation analysis. Extensive benchmarking was performed (including analyses with CIRI2 and CIRCexplorer-2) and confirmed 94% of the 23,737 reliable exonic circRNAs. Moreover, this study demonstrates the effectiveness of a panel of highly expressed exonic circRNAs (5-8%) in analysing the tissue specificity of the bovine circular transcriptome.

Features of databases that supported searching for rapid evidence synthesis during COVID-19: implications for future public health emergencies.

BACKGROUND: As evidence related to the COVID-19 pandemic surged, databases, platforms, and repositories evolved with features and functions to assist users in promptly finding the most relevant evidence. In response, research synthesis teams adopted novel searching strategies to sift through the vast amount of evidence to synthesize and disseminate the most up-to-date evidence. This paper explores the key database features that facilitated systematic searching for rapid evidence synthesis during the COVID-19 pandemic to inform knowledge management infrastructure during future global health emergencies. METHODS: This paper outlines the features and functions of previously existing and newly created evidence sources routinely searched as part of the NCCMT's Rapid Evidence Service methods, including databases, platforms, and repositories. Specific functions of each evidence source were assessed as they pertain to searching in the context of a public health emergency, including the topics of indexed citations, the level of evidence of indexed citations, and specific usability features of each evidence source. RESULTS: Thirteen evidence sources were assessed, of which four were newly created and nine were either pre-existing or adapted from previously existing resources. Evidence sources varied in topics indexed, level of evidence indexed, and specific searching functions. CONCLUSION: This paper offers insights into which features enabled systematic searching for the completion of rapid reviews to inform decision makers within 5-10 days. These findings provide guidance for knowledge management strategies and evidence infrastructures during future public health emergencies.

Review of valiltramiprosate (ALZ-801) for the treatment of Alzheimer's disease: a novel small molecule with disease modifying potential.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

BTK drives neutrophil activation for sterilizing antifungal immunity.

We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

Mobilizing community-driven health promotion through community granting programs: a rapid systematic review.

BACKGROUND: Effective health promotion responds to the unique needs of communities. Community granting programs that fund community-driven health promotion initiatives are a potential mechanism to meet those unique needs. While numerous community health-focused programs are available, the various strategies used by granting programs to foster engagement, administer grants and support awardees have not been systematically evaluated. This rapid systematic review explores the administration of community granting programs and how various program components impact process and population health outcomes. METHODS: A systematic search was conducted across three databases: Medline, SocINDEX, and Political Science Database. Single reviewers completed screening, consistent with a rapid review protocol. Studies describing or evaluating community granting programs for health or public health initiatives were included. Data regarding program characteristics were extracted and studies were evaluated for quality. A convergent integrated approach was used to analyze quantitative and qualitative findings. RESULTS: Thirty-five community granting programs, described in 36 studies, were included. Most were descriptive reports or qualitative studies conducted in the USA. Program support for grant awardees included technical assistance, workshops and training, program websites, and networking facilitation. While most programs reported on process outcomes, few reported on community or health outcomes; such outcomes were positive when reported. Programs reported that many funded projects were likely sustainable beyond program funding, due to the development of awardee skills, new partnerships, and securing additional funding. From the perspectives of program staff and awardees, facilitators included the technical assistance and workshops provided by the programs, networking amongst awardees, and the involvement of community members. Barriers included short timelines to develop proposals and allocate funds. CONCLUSIONS: This review provides a comprehensive overview of health-related community granting programs. Grant awardees benefit from technical assistance, workshops, and networking with other awardees. Project sustainability is enhanced by the development of new community partnerships and grant-writing training for awardees. Community granting programs can be a valuable strategy to drive community health, with several key elements that enhance community mobilization. REGISTRATION: PROSPERO #CRD42023399364.

Strategies to implement evidence-informed decision making at the organizational level: a rapid systematic review.

BACKGROUND: Achievement of evidence-informed decision making (EIDM) requires the integration of evidence into all practice decisions by identifying and synthesizing evidence, then developing and executing plans to implement and evaluate changes to practice. This rapid systematic review synthesizes evidence for strategies for the implementation of EIDM across organizations, mapping facilitators and barriers to the COM-B (capability, opportunity, motivation, behaviour) model for behaviour change. The review was conducted to support leadership at organizations delivering public health services (health promotion, communicable disease prevention) to drive change toward evidence-informed public health. METHODS: A systematic search was conducted in multiple databases and by reviewing publications of key authors. Articles that describe interventions to drive EIDM within teams, departments, or organizations were eligible for inclusion. For each included article, quality was assessed, and details of the intervention, setting, outcomes, facilitators and barriers were extracted. A convergent integrated approach was undertaken to analyze both quantitative and qualitative findings. RESULTS: Thirty-seven articles are included. Studies were conducted in primary care, public health, social services, and occupational health settings. Strategies to implement EIDM included the establishment of Knowledge Broker-type roles, building the EIDM capacity of staff, and research or academic partnerships. Facilitators and barriers align with the COM-B model for behaviour change. Facilitators for capability include the development of staff knowledge and skill, establishing specialized roles, and knowledge sharing across the organization, though staff turnover and subsequent knowledge loss was a barrier to capability. For opportunity, facilitators include the development of processes or mechanisms to support new practices, forums for learning and skill development, and protected time, and barriers include competing priorities. Facilitators identified for motivation include supportive organizational culture, expectations for new practices to occur, recognition and positive reinforcement, and strong leadership support. Barriers include negative attitudes toward new practices, and lack of understanding and support from management. CONCLUSION: This review provides a comprehensive analysis of facilitators and barriers for the implementation of EIDM in organizations for public health, mapped to the COM-B model for behaviour change. The existing literature for strategies to support EIDM in public health illustrates several facilitators and barriers linked to realizing EIDM. Knowledge of these factors will help senior leadership develop and implement EIDM strategies tailored to their organization, leading to increased likelihood of implementation success. REVIEW REGISTRATION: PROSPERO CRD42022318994.

Rethinking Data Collection Methods During the Pandemic: Development and Implementation of CATI for the All of Us Research Program.

The All of Us Research Program is a longitudinal cohort study aiming to build a diverse database to advance precision medicine. The COVID-19 pandemic hindered the ability of participants to receive in-person assistance at enrollment sites to complete digital surveys. Therefore, the program implemented Computer-Assisted Telephone Interviewing (CATI) to facilitate survey completion remotely to combat the disrupted data collection procedures. In January 2021, All of Us implemented a 1-year CATI Pilot supporting 9399 participants and resulting in 16 337 submitted surveys. The pilot showed that CATI was successful in increasing survey completion and retention activities for the All of Us Research Program, given the additional remote support offered to participants. Given the success of the CATI Pilot, multimodal survey administration will continue.

Changes to Public Health Surveillance Methods Due to the COVID-19 Pandemic: Scoping Review.

BACKGROUND: Public health surveillance plays a vital role in informing public health decision-making. The onset of the COVID-19 pandemic in early 2020 caused a widespread shift in public health priorities. Global efforts focused on COVID-19 monitoring and contact tracing. Existing public health programs were interrupted due to physical distancing measures and reallocation of resources. The onset of the COVID-19 pandemic intersected with advancements in technologies that have the potential to support public health surveillance efforts. OBJECTIVE: This scoping review aims to explore emergent public health surveillance methods during the early COVID-19 pandemic to characterize the impact of the pandemic on surveillance methods. METHODS: A scoping search was conducted in multiple databases and by scanning key government and public health organization websites from March 2020 to January 2022. Published papers and gray literature that described the application of new or revised approaches to public health surveillance were included. Papers that discussed the implications of novel public health surveillance approaches from ethical, legal, security, and equity perspectives were also included. The surveillance subject, method, location, and setting were extracted from each paper to identify trends in surveillance practices. Two public health epidemiologists were invited to provide their perspectives as peer reviewers. RESULTS: Of the 14,238 unique papers, a total of 241 papers describing novel surveillance methods and changes to surveillance methods are included. Eighty papers were review papers and 161 were single studies. Overall, the literature heavily featured papers detailing surveillance of COVID-19 transmission (n=187). Surveillance of other infectious diseases was also described, including other pathogens (n=12). Other public health topics included vaccines (n=9), mental health (n=11), substance use (n=4), healthy nutrition (n=1), maternal and child health (n=3), antimicrobial resistance (n=2), and misinformation (n=6). The literature was dominated by applications of digital surveillance, for example, by using big data through mobility tracking and infodemiology (n=163). Wastewater surveillance was also heavily represented (n=48). Other papers described adaptations to programs or methods that existed prior to the COVID-19 pandemic (n=9). The scoping search also found 109 papers that discuss the ethical, legal, security, and equity implications of emerging surveillance methods. The peer reviewer public health epidemiologists noted that additional changes likely exist, beyond what has been reported and available for evidence syntheses. CONCLUSIONS: The COVID-19 pandemic accelerated advancements in surveillance and the adoption of new technologies, especially for digital and wastewater surveillance methods. Given the investments in these systems, further applications for public health surveillance are likely. The literature for surveillance methods was dominated by surveillance of infectious diseases, particularly COVID-19. A substantial amount of literature on the ethical, legal, security, and equity implications of these emerging surveillance methods also points to a need for cautious consideration of potential harm.

Addressing Circadian Disruptions in Visually Impaired Paralympic Athletes.

PURPOSE: Transmeridian travel is common for elite athletes participating in competitions and training. However, this travel can lead to circadian misalignment wherein the internal biological clock becomes desynchronized with the light-dark cycle of the new environment, resulting in performance decrement and potential negative health consequences. Existing literature extensively discusses recommendations for managing jet lag, predominantly emphasizing light-based interventions to synchronize the internal clock with the anticipated time at the destination. Nevertheless, visually impaired (VI) athletes may lack photoreceptiveness, diminishing or nullifying the effectiveness of this therapy. Consequently, this invited commentary explores alternative strategies for addressing jet lag in VI athletes. CONCLUSIONS: VI athletes with light perception but reduced visual acuity or visual fields may still benefit from light interventions in managing jet lag. However, VI athletes lacking a conscious perception of light should rely on gradual shifts in behavioral factors, such as meal timing and exercise, to facilitate the entrainment of circadian rhythms to the destination time. Furthermore, interventions like melatonin supplementation may prove useful during and after travel. In addition, it is recommended that athlete guides adopt phase-forward or phase-back approaches to synchronize with the athlete, aiding in jet-lag management and optimizing performance.

Vaccination against neoantigens induced in cross-priming cDC1 in vivo.

The conventional type 1 dendritic cells (cDC1) play a pivotal role in protective immunity against pathogens and cancer. However, their low frequency in the blood and tissues limits their use in immune therapy. We have recently described a method to vaccinate against neoantigens that are induced in tumor cells by targeted delivery of a TAP siRNA to dendritic cells using a TLR9 binding CpG oligonucleotide. Since TLR9 is also expressed in immune suppressive myeloid populations TLR9 targeting could reduce the effectiveness of this approach. Here, we describe a modular multivalent antibody platform to target the TAP siRNA to resident Clec9a expressing cDC1 and show that it leads to selective and sustained TAP downregulation in cDC1 and inhibits tumor growth in mice more effectively than CpG targeted siRNA. To induce DC maturation an agonistic CD40 antibody was administered to the siRNA treated mice. To obviate the need for a second drug formulation and reduce the risk of toxicity, we exploited the multivalent nature of this targeting platform to co-deliver the TAP siRNA and a DC maturation agent, a CpG containing oligonucleotide, to cDC1 in vivo and show that it was more effective than Clec9a targeting of TAP siRNA in combination with CD40 antibody. This study describes a way to manipulate the function of cDC1 cells in vivo using a broadly applicable antibody-based targeting platform to deliver multiple biological agents to specific cells in vivo to potentiate (immune) therapy and to probe the biology of specific cell types in their natural settings.

Mice expressing nonpolymerizable fibrinogen have reduced arterial and venous thrombosis with preserved hemostasis.

ABSTRACT: Elevated circulating fibrinogen levels correlate with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% ferric chloride (FeCl3) challenges compared with wild-type (FgaWT/WT) mice, but this protection was lost, with injuries driven by higher concentrations of FeCl3. In contrast, fibrinogen-deficient (Fga-/-) mice showed no evidence of occlusion, even with high-concentration FeCl3 challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in FgaWT/WT, FgaWT/EK, and FgaEK/EK mice, consistent with preserved fibrinogen-platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, FgaWT/EK and FgaEK/EK mice had preserved hemostasis in multiple models as well as normal wound healing times after skin incision, unlike Fga-/- mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.

An outbreak of Salmonella Typhimurium associated with the consumption of raw liver at an Eid al-Adha celebration in Wales (UK), July 2021.

In July 2021, Public Health Wales received two notifications of salmonella gastroenteritis. Both cases has attended the same barbecue to celebrate Eid al-Adha, two days earlier. Additional cases attending the same barbecue were found and an outbreak investigation was initiated. The barbecue was attended by a North African community's social network. On same day, smaller lunches were held in three homes in the social network. Many people attended both a lunch and the barbecue. Cases were defined as someone with an epidemiological link to the barbecue and/or lunches with diarrhoea and/or vomiting with date of onset following these events. We undertook a cohort study of 36 people attending the barbecue and/or lunch, and a nested case-control study using Firth logistic regression. A communication campaign, sensitive towards different cultural practices, was developed in collaboration with the affected community. Consumption of a traditional raw liver dish, 'marrara', at the barbecue was the likely vehicle for infection (Firth logistic regression, aOR: 49.99, 95%CI 1.71-1461.54, p = 0.02). Meat and offal came from two local butchers (same supplier) and samples yielded identical whole genome sequences as cases. Future outbreak investigations should be relevant to the community affected by considering dishes beyond those found in routine questionnaires.

A versatile nuclei extraction protocol for single nucleus sequencing in non-model species-Optimization in various Atlantic salmon tissues.

The use of single cell sequencing technologies has exploded over recent years, and is now commonly used in many non-model species. Sequencing nuclei instead of whole cells has become increasingly popular, as it does not require the processing of samples immediately after collection. Here we present a highly effective nucleus isolation protocol that outperforms previously available method in challenging samples in a non-model specie. This protocol can be successfully applied to extract nuclei from a variety of tissues and species.

Recent advances in the genomic resources for sheep.

Sheep (Ovis aries) provide a vital source of protein and fibre to human populations. In coming decades, as the pressures associated with rapidly changing climates increase, breeding sheep sustainably as well as producing enough protein to feed a growing human population will pose a considerable challenge for sheep production across the globe. High quality reference genomes and other genomic resources can help to meet these challenges by: (1) informing breeding programmes by adding a priori information about the genome, (2) providing tools such as pangenomes for characterising and conserving global genetic diversity, and (3) improving our understanding of fundamental biology using the power of genomic information to link cell, tissue and whole animal scale knowledge. In this review we describe recent advances in the genomic resources available for sheep, discuss how these might help to meet future challenges for sheep production, and provide some insight into what the future might hold.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.

Cellular heterogeneity of the developing worker honey bee (Apis mellifera) pupa: a single cell transcriptomics analysis.

It is estimated that animals pollinate 87.5% of flowering plants worldwide and that managed honey bees (Apis mellifera) account for 30-50% of this ecosystem service to agriculture. In addition to their important role as pollinators, honey bees are well-established insect models for studying learning and memory, behavior, caste differentiation, epigenetic mechanisms, olfactory biology, sex determination, and eusociality. Despite their importance to agriculture, knowledge of honey bee biology lags behind many other livestock species. In this study, we have used scRNA-Seq to map cell types to different developmental stages of the worker honey bee (prepupa at day 11 and pupa at day 15) and sought to determine their gene expression signatures. To identify cell-type populations, we examined the cell-to-cell network based on the similarity of the single-cells transcriptomic profiles. Grouping similar cells together we identified 63 different cell clusters of which 17 clusters were identifiable at both stages. To determine genes associated with specific cell populations or with a particular biological process involved in honey bee development, we used gene coexpression analysis. We combined this analysis with literature mining, the honey bee protein atlas, and gene ontology analysis to determine cell cluster identity. Of the cell clusters identified, 17 were related to the nervous system and sensory organs, 7 to the fat body, 19 to the cuticle, 5 to muscle, 4 to compound eye, 2 to midgut, 2 to hemocytes, and 1 to malpighian tubule/pericardial nephrocyte. To our knowledge, this is the first whole single-cell atlas of honey bees at any stage of development and demonstrates the potential for further work to investigate their biology at the cellular level.

Genetic characterisation of the Connemara pony and the Warmblood horse using a within-breed clustering approach.

BACKGROUND: The Connemara pony (CP) is an Irish breed that has experienced varied selection by breeders over the last fifty years, with objectives ranging from the traditional hardy pony to an agile athlete. We compared these ponies with well-studied Warmblood (WB) horses, which are also selectively bred for athletic performance but with a much larger census population. Using genome-wide single nucleotide polymorphism (SNP) and whole-genome sequencing data from 116 WB (94 UK WB and 22 European WB) and 36 CP (33 UK CP and 3 US CP), we studied the genomic diversity, inbreeding and population structure of these breeds. RESULTS: The k-means clustering approach divided both the CP and WB populations into four genetic groups, among which the CP genetic group 1 (C1) associated with non-registered CP, C4 with US CP, WB genetic group 1 (W1) with Holsteiners, and W3 with Anglo European and British WB. Maximum and mean linkage disequilibrium (LD) varied significantly between the two breeds (mean from 0.077 to 0.130 for CP and from 0.016 to 0.370 for WB), but the rate of LD decay was generally slower in CP than WB. The LD block size distribution peaked at 225 kb for all genetic groups, with most of the LD blocks not exceeding 1 Mb. The top 0.5% harmonic mean pairwise fixation index (FST) values identified ontology terms related to cancer risk when the four CP genetic groups were compared. The four CP genetic groups were less inbred than the WB genetic groups, but C2, C3 and C4 had a lower proportion of shorter runs of homozygosity (ROH) (74 to 76% < 4 Mb) than the four WB genetic groups (80 to 85% < 4 Mb), indicating more recent inbreeding. The CP and WB genetic groups had a similar ratio of effective number of breeders (Neb) to effective population size (Ne). CONCLUSIONS: Distinct genetic groups of individuals were revealed within each breed, and in WB these genetic groups reflected population substructure better than studbook or country of origin. Ontology terms associated with immune and inflammatory responses were identified from the signatures of selection between CP genetic groups, and while CP were less inbred than WB, the evidence pointed to a greater degree of recent inbreeding. The ratio of Neb to Ne was similar in CP and WB, indicating the influence of popular sires is similar in CP and WB.

The international reference system for beta-particle emitting radionuclides: Validation through the pilot study CCRI(II)-P1.Co-60.

The Bureau International des Poids et Mesures (BIPM) is developing a new transfer instrument to extend its centralized services for assessing the international equivalence of radioactive standards to new radionuclides. A liquid scintillation counter using the triple/double coincidence ratio method is being studied and tested in the CCRI(II)-P1.Co-60 pilot study. The pilot study, involving 13 participating laboratories with primary calibration capabilities, validated the approach against the original international reference system based on ionization chambers, which has been in operation since 1976. The results are in agreement and an accuracy suitable for purpose, below 5×10-4, is achieved. The pilot study also reveals an issue when impurities emitting low-energy electrons are present in the standard solution, which have a different impact on liquid scintillation counting compared to other primary measurement methods.