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Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is an age-related neurodegenerative disorder caused by a premutation of the FMR1 gene on the X chromosome. Despite the pervasive physical and cognitive effects of FXTAS, no studies have examined language in symptomatic males and females, limiting utility as an outcome measure in clinical trials of FXTAS. The goal of this work is to determine (a) the extent to which male and female FMR1 premutation carriers with FXTAS symptoms differ in their language use and (b) whether language production predicts FXTAS symptoms. Thirty-one individuals with the FMR1 premutation (21M, 10F), ages 58–85 years with some symptoms of FXTAS, were recruited from a larger cross-sectional study. Participants completed a five-minute monologic language sample. Language transcripts were assessed for rate of dysfluencies, lexical-semantics, syntax, and speech rate. Multivariable linear and ordinal regressions were used to predict FXTAS-associated symptoms, cognitive functioning, and executive functioning. Males and females did not differ in their language use. Language production predicted FXTAS symptom severity, cognitive functioning, and executive functioning. Language production difficulties may co-occur with FXTAS-associated symptoms and may be a viable outcome measure in future clinical trials, with future research needed.

Background: The World Health Organization has updated its classification of haematolymphoid tumours to the new 5th edition. The International Consensus Classification is another group that has developed a separate classification system with similar but conflicting approaches. This led to a debate among haematologists about which classification system is more appropriate for clinical use. This article examines and compares these contrasting and concurring classifications, and provides insight into the utility of each system. Methods: Journal articles pertaining to WHO-HAEM4R, WHO-HAEM5 and ICC were searched for using the MEDLINE database, from November 2022 to November 2023. Original research articles and reviews were selected to compile this review. Results: The classification systems share many similarities with minor name changes and subgrouping. There are few instances where diagnostic grouping differs between the classifications, which could have clinical implications regarding treatment and enrolment in clinical trials. Conclusion: There is universal agreement about the need for objective criteria for the classification of haematolymphoid tumours. As a result, there have been considerable strides in the classification with regard to morphologic, immunophenotypic, molecular and cytogenetic characterisation. It is reassuring to have a stepwise approach to diagnosis, allowing developing countries to make appropriate diagnoses. Contribution: Harmonisation is needed for a universal diagnostic system for the benefit of the patient. Both classification systems have merit and either could be adopted by individual institutions at present. The authors appeal for interim advocacy measures to assure access to the specific diagnostic investigations in poorly resourced societies, pending more permanent and sustainable access.

Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the mouse genome in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this ‘privileged’ repertoire. Our experiments identify early transcription as a potential ‘epigenetic’ contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.

OBJECTIVES/GOALS: Ebolavirus disease survivors report persistent, debilitating health concerns dubbed Post-Ebola Syndrome (PES). Attention to PES in young survivors is lacking, we describe PES in pediatric EVD survivors in Eastern Sierra Leone. Additionally, we introduce our proposal investigating differential presentations of PES in pediatric survivors. METHODS/STUDY POPULATION: EVD survivors were enrolled a median of 2.5 years after resolution of disease. Survivors were eligible if listed in a national register maintained by the Sierra Leone Association of Ebola Survivors. Household contacts (HCs) were identified by survivors. Participants were assigned into three comparison groups: pediatric (7-11), adolescent (12-17) and young adult (18-25). A self-reported symptom questionnaire, and a physical exam were conducted. Variables were clustered within organ system and compared across groups. RESULTS/ANTICIPATED RESULTS: Pediatric survivors had lower levels of long-term sequelae compared to adolescents and young adults. Symptoms and abnormal physical exam signs increase with age. Musculoskeletal, psychiatric, ophthalmologic, and GI signs and symptoms were significantly different between groups. Pediatric survivors had significantly more persistent sequelae than age-matched HCs with no history of EVD; particularly within the cardiac/GI (p=.006) and psychiatric/neurological (p=.025) clusters. PES is heterogeneous with respect to age, calling for a deeper understanding of age-based differences. Even the youngest group of survivors experienced significantly more sequelae than HCs, highlighting the elevated symptom burden in these children over their peers. DISCUSSION/SIGNIFICANCE: Understanding mechanistic drivers will ultimately improve targeted treatments for PES. We will characterize symptom groups defining PES in children, determine the relationship between accelerated aging and PES in this population, and test how immune profiles associated with accelerated aging relate to the development of PES in children.

Objective: We sought to determine how the COVID-19 pandemic impacted academic health sciences library workshops. We hypothesized that health sciences libraries moved workshops online during the height of the pandemic and that they continued to offer workshops virtually after restrictions were eased. Additionally, we believed that attendance increased. Methods: In March 2022, we invited 161 Association of American Health Sciences Libraries members in the US and Canada to participate in a Qualtrics survey about live workshops. Live workshops were defined as synchronous; voluntary; offered to anyone regardless of school affiliation; and not credit-bearing. Three time periods were compared, and a chi square test of association was conducted to evaluate the relationship between time period and workshop format. Results: Seventy-two of 81 respondents offered live workshops. A chi square test of association indicated a significant association between time period and primary delivery method, chi-square (4, N=206) = 136.55, p< .005. Before March 2020, 77% of respondents taught in person. During the height of the pandemic, 91% taught online and 60% noted higher attendance compared to pre-pandemic numbers. During the second half of 2021, 65% of workshops were taught online and 43% of respondents felt that attendance was higher than it was pre-pandemic. Overall workshop satisfaction was unchanged (54%) or improved (44%). Conclusion: Most health sciences librarians began offering online workshops following the onset of the COVID-19 pandemic. More than half of respondents were still teaching online in the second half of 2021. Some respondents reported increased attendance with similar levels of satisfaction.

Abstract Magnetically shielded rooms (MSRs) use multiple layers of materials such as MuMetal to screen external magnetic fields that would otherwise interfere with high precision magnetic field measurements such as magnetoencephalography (MEG). Optically pumped magnetometers (OPMs) have enabled the development of wearable MEG systems which have the potential to provide a motion tolerant functional brain imaging system with high spatiotemporal resolution. Despite significant promise, OPMs impose stringent magnetic shielding requirements, operating around a zero magnetic field resonance within a dynamic range of ± 5 nT. MSRs developed for OPM-MEG must therefore effectively shield external sources and provide a low remnant magnetic field inside the enclosure. Existing MSRs optimised for OPM-MEG are expensive, heavy, and difficult to site. Electromagnetic coils are used to further cancel the remnant field inside the MSR enabling participant movements during OPM-MEG, but present coil systems are challenging to engineer and occupy space in the MSR limiting participant movements and negatively impacting patient experience. Here we present a lightweight MSR design (30% reduction in weight and 40–60% reduction in external dimensions compared to a standard OPM-optimised MSR) which takes significant steps towards addressing these barriers. We also designed a ‘window coil’ active shielding system, featuring a series of simple rectangular coils placed directly onto the walls of the MSR. By mapping the remnant magnetic field inside the MSR, and the magnetic field produced by the coils, we can identify optimal coil currents and cancel the remnant magnetic field over the central cubic metre to just |B|= 670 ± 160 pT. These advances reduce the cost, installation time and siting restrictions of MSRs which will be essential for the widespread deployment of OPM-MEG.

BackgroundFatigue is a subjective, complex and multi-faceted phenomenon, commonly experienced as tiredness. However, pathological fatigue is a major debilitating symptom associated with overwhelming feelings of physical and mental exhaustion. It is a well-recognized manifestation in chronic inflammatory rheumatic diseases, such as Sjögren’s Syndrome and Systemic Lupus Erythematosus and an important predictor of patient’s health-related quality of life (HRQoL). Patient reported outcome questions are the key instruments to assess fatigue. To date, there is no consensus about reliable quantitative assessments of fatigue.MethodObservational data for a period of one month were collected from 296 participants in the United States. Data comprised continuous multimodal digital data from Fitbit, including heart rate, physical activity and sleep features, and app-based daily and weekly questions covering various HRQoL factors including pain, mood, general physical activity and fatigue. Descriptive statistics and hierarchical clustering of digital data were used to describe behavioural phenotypes. Gradient boosting classifiers were trained to classify participant-reported weekly fatigue and daily tiredness from multi-sensor and other participant-reported data, and extract a set of key predictive features.ResultsCluster analysis of Fitbit parameters highlighted multiple digital phenotypes, including sleep-affected, fatigued and healthy phenotypes. Features from participant-reported data and Fitbit data both contributed as key predictive features of weekly physical and mental fatigue and daily tiredness. Participant answers to pain and depressed mood-related daily questions contributed the most as top features for predicting physical and mental fatigue, respectively. To classify daily tiredness, participant answers to questions on pain, mood and ability to perform daily activities contributed the most. Features related to daily resting heart rate and step counts and bouts were overall the most important Fitbit features for the classification models.ConclusionThese results demonstrate that multimodal digital data can be used to quantitatively and more frequently augment pathological and non-pathological participant-reported fatigue.

BackgroundEmotion dysregulation is key to the development and maintenance of chronic pain, feeding into a cycle of worsening pain and disability. Dialectical behavioral therapy (DBT), an evidence-based treatment for complex transdiagnostic conditions presenting with high emotion dysregulation, may be beneficial to manage and mitigate the emotional and sensory aspects of chronic pain. Increasingly, DBT skills training as a key component of standard DBT is being delivered as a stand-alone intervention without concurrent therapy to help develop skills for effective emotion regulation. A previous repeated-measure single-case trial investigating a novel technologically driven DBT skills training, internet-delivered DBT skills training for chronic pain (iDBT-Pain), revealed promising findings to improve both emotion dysregulation and pain intensity. ObjectiveThis randomized controlled trial aims to examine the efficacy of iDBT-Pain in comparison with treatment as usual to reduce emotion dysregulation (primary outcome) for individuals with chronic pain after 9 weeks and at the 21-week follow-up. The secondary outcomes include pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, posttraumatic stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. The trial also examines the acceptability of the iDBT-Pain intervention for future development and testing. MethodsA total of 48 people with chronic pain will be randomly assigned to 1 of 2 conditions: treatment and treatment as usual. Participants in the treatment condition will receive iDBT-Pain, consisting of 6 live web-based group sessions led by a DBT skills trainer and supervised by a registered psychologist and the iDBT-Pain app. Participants in the treatment-as-usual condition will not receive iDBT-Pain but will still access their usual medication and health interventions. We predict that iDBT-Pain will improve the primary outcome of emotion dysregulation and the secondary outcomes of pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. A linear mixed model with random effects of individuals will be conducted to investigate the differences between the baseline, 9-week (primary end point), and 21-week (follow-up) assessments as a function of experimental condition. ResultsRecruitment started in February 2023, and the clinical trial started in March 2023. Data collection for the final assessment is planned to be completed by July 2024. ConclusionsIf our hypothesis is confirmed, our findings will contribute to the evidence for the efficacy and acceptability of a viable intervention that may be used by health care professionals for people with chronic pain. The results will add to the chronic pain literature to inform about the potential benefits of DBT skills training for chronic pain and will contribute evidence about technologically driven interventions. Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12622000113752; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383208&isReview=true International Registered Report Identifier (IRRID)PRR1-10.2196/41890

Background: Since 2003, the MLA Membership Committee has facilitated an in-person mentoring program called Colleague Connection at the annual meeting. The program hinged on meeting attendance, so members who could not attend were excluded. The 2020 virtual meeting created an opportunity to rethink the Colleague Connection experience. Three members of the Membership Committee developed an expanded and virtual version of the mentoring program. Case Presentation: Colleague Connection was promoted via the MLA ’20 vConference Welcome Event, MLAConnect, and email lists. The 134 participants were matched based on same-chapter preference, library type, practice area interest, and years of experience. Mentees chose mentor-mentee or peer pairs, resulting in 4 peer matchings and 65 mentor-mentee matchings. Pairs were encouraged to meet monthly, and conversation prompts were provided. A Wrap-Up Event was held for participants to talk about their experiences and network. A survey evaluated the program and sought suggestions for improvement. Conclusion: The online format boosted participation, and the format change was well received. In the future, a formal orientation meeting and communication plan can ensure pairs make their initial connections and provide clarity about program details, expectations, timelines, and contact information. The type of pairings and size of the program are important considerations for the feasibility and sustainability of a virtual mentoring program.

Abstract Rare diseases often result in delays in diagnosis. It is important to recognize conditions that have features of both inborn errors of immunity and predispose to myeloid neoplasia. Here we report a patient with GATA2 deficiency that presented with disseminated non‐tuberculous mycobacterial infection and pancytopenia secondary to myelodysplastic syndrome.

Global declines in bird and arthropod abundance highlights the importance of understanding the role of food limitation and arthropod community composition for the performance of insectivorous birds. In this study, we link data on nestling diet, arthropod availability and nesting performance for the Coastal Cactus Wren (Campylorhynchus brunneicapillus sandiegensis), an at-risk insectivorous bird native to coastal southern California and Baja Mexico. We used DNA metabarcoding to characterize nestling diets and monitored 8 bird territories over two years to assess the relationship between arthropod and vegetation community composition and bird reproductive success. We document a discordance between consumed prey and arthropod biomass within nesting territories, in which Diptera and Lepidoptera were the most frequently consumed prey taxa but were relatively rare in the environment. In contrast other Orders (e.g., Hemiptera, Hymenoptera)were abundant in the environment but were absent from nestling diets. Accordingly, variation in bird reproductive success among territories was positively related to the relative abundance of Lepidoptera (but not Diptera), which were most abundant on 2 shrub species (Eriogonum fasciculatum, Sambucus nigra) of the 9 habitat elements characterized (8 dominant plant species and bare ground). Bird reproductive success was in turn negatively related to two invasive arthropods whose abundance was not associated with preferred bird prey, but instead possibly acted through harassment (Linepithema humile; Argentine ants) and parasite transmission or low nutritional quality (Armadillidium vulgare; "pill-bug"). These results demonstrate how multiple aspects of arthropod community structure can influence bird performance through complementary mechanisms, and the importance of managing for arthropods in bird conservation efforts.

Abstract Background Intra-regional cultural and linguistic differences are common in low- and middle-income countries. To sensitise undergraduate medical students to the social and contextual determinants of health to achieve the ‘health for all’ goal, these countries must focus on innovative teaching methods. The early introduction of a Community Orientation Program (COP) as a Community-based Medical Education (CBME) method could be a game changing strategy. In this paper the methods, evaluation, and implication of the COP in an Indian setting are described. Methods The curriculum of the COP was developed based on the analysis, design, development, implementation, and evaluation (ADDIE) model for educational intervention. In this learner-centric and supervised educational program, the key aim was to focus on developing students’ communication skills, observation power and enhancing their motivation for learning through collaborative learning. To meet the objectives of the COP, a situated learning model under the constructivism theory was adopted. Results Between 2016 and 2019, 557 students were trained through the COP by visiting more than 1300 households in ten villages. To supplement the students’ observations in the community, more than 150 small group discussions, a health education programme for the community and summary presentations were conducted. The students’ feedback indicated the need to improve the clinical examinations demonstration quality and increase the number of instruments for clinical examinations. More than 80% of students felt that the program would assist them to improve their communication skills, their understanding of the various socio-demographic factors associated with the common diseases, and it will enable them to respect the local culture during their clinical practice. Conclusions Early initiation of the COP as a CBME method in the undergraduate medical curriculum in an Indian setting has shown promising results. Further evidence is required to adopt such a program routinely for under-graduate medical teaching in the low- and middle- income settings.

Introduction Chronic pain, defined as pain persisting longer than 3 months, is more than an unpleasant sensory experience. Persistent negative emotions and emotional comorbidities, such as depression and anxiety, plague people with chronic pain leading to worsening pain intensity and increasing disability. While cognitive–behavioural therapy (CBT) is the gold standard psychological treatment, recent evidence highlights that CBT lacks efficacy for the physical and emotional aspects of chronic pain. Increasingly, researchers are investigating emotion-centric psychological therapies. While treatment modalities vary, these interventions frequently target understanding emotions, and train individuals for an emotionally adaptive response. The aim of this systematic review and meta-analysis is to quantify the efficacy of emotion-centric interventions for the physical and emotional characteristics of chronic pain.Methods/analysis Electronic databases (EMBASE, PubMed, PsychINFO, Cochrane Central Register of Controlled Trials, CINAHL and Web of Science) will be systematically searched from inception to 28 April 2022 for randomised controlled trials. Studies that compare an emotion-centric intervention with another form of treatment or placebo/control for adults (≥18 years old) with chronic pain will be included. All treatment modes (eg, online or in-person), any duration and group-based or individual treatments will be included. Studies that do not investigate at least one emotion-centric treatment will be excluded. The primary outcome is pain intensity. Secondary outcomes include emotion dysregulation, depression, anxiety, affect, safety and intervention compliance. A quantitative synthesis using a random effects meta-analysis will be adopted. Risk of bias will be evaluated using Cochrane Risk of Bias V.2.0 with the certainty of evidence assessed according to Recommendation, Assessment, Development and Evaluation. Data permitting, subgroup analysis will be conducted for intervention type and pain condition.Ethics and dissemination Ethical approval is not required for this systematic review. Results may inform an efficacy study examining a new emotion-centric intervention for chronic pain. Dissemination will be through peer-reviewed publications and in conference presentations.PROSPERO registration number CRD42021266815.

Abstract Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

Abstract Here, we discuss the presence and roles of heterogeneity in the development of uveal melanoma. Both genetic and cellular heterogeneity are considered, as their presence became undeniable due to single cell approaches that have recently been used in uveal melanoma analysis. However, the presence of precursor clones and immune infiltrate in uveal melanoma have been described as being part of the tumour already decades ago. Since uveal melanoma grow in the corpus vitreous, they present a unique tumour model because every cell present in the tumour tissue is actually part of the tumour and possibly plays a role. For an effective treatment of uveal melanoma metastasis, it should be clear whether precursor clones and normal cells play an active role in progression and metastasis. We propagate analysis of bulk tissue that allows analysis of tumour heterogeneity in a clinical setting.

Abstract Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease with limited therapeutic options. We retrospectively analyzed the effects of a comprehensive 4-week inpatient pulmonary rehabilitation (PR) program in 58 patients with advanced LAM (FEV1: 45 ± 34%predicted, 6-min walk distance (6MWD): 338 ± 167 m). Exercise performance (6MWD: + 49 ± 50 m; p

Summary: Background: SARS-CoV-2 lineages are continuously evolving. As of December 2021, the AY.4.2 Delta sub-lineage represented 20 % of sequenced strains in the UK and had been detected in dozens of countries. It has since then been supplanted by Omicron. The AY.4.2 spike displays three additional mutations (T95I, Y145H and A222V) in the N-terminal domain when compared to the original Delta variant (B.1.617.2) and remains poorly characterized. Methods: We compared the Delta and the AY.4.2 spikes, by assessing their binding to antibodies and ACE2 and their fusogenicity. We studied the sensitivity of an authentic AY.4.2 viral isolate to neutralizing antibodies. Findings: The AY.4.2 spike exhibited similar binding to all the antibodies and sera tested, and similar fusogenicity and binding to ACE2 than the ancestral Delta spike. The AY.4.2 virus was slightly less sensitive than Delta to neutralization by a panel of monoclonal antibodies; noticeably, the anti-RBD Imdevimab showed incomplete neutralization. Sensitivity of AY.4.2 to sera from vaccinated individuals was reduced by 1.3 to 3-fold, when compared to Delta. Interpretation: Our results suggest that mutations in the NTD remotely impair the efficacy of anti-RBD antibodies. The spread of AY.4.2 was not due to major changes in spike fusogenicity or ACE2 binding, but more likely to a partially reduced neutralization sensitivity. Funding: The work was funded by Institut Pasteur, Fondation pour la Recherche Médicale, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, ANRS, the Vaccine Research Institute, Labex IBEID, ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR.

During the Covid-19 pandemic, older people have been in the spotlight of the public debate. Given their higher risk of severe outcomes of the disease, they have been described as especially vulnerable and as a burden to others and society. We thus wanted to investigate how older people’s perception of their own age, that is their subjective age, as well as their Covid-19 related risks and worries were related during the pandemic and whether these relationships varied according to participants’ subjective health. We used data from the longitudinal CRISIS study which was conducted in the Grand-Duchy of Luxembourg in June and October 2020. Participants were aged 60–98 and responded on questionnaires regarding their subjective age, worry of falling ill with Covid-19, perceived risk of contracting the virus, perceived risk of falling seriously ill if they contracted Covid-19, as well as their subjective health and covariates. Three cross-lagged panel models were constructed to explore the longitudinal, bidirectional relationships between the variables. Cross-sectionally, a higher subjective age was related to more perceived risk of a serious course of disease. Longitudinally, subjective age and worry did not show any significant association over time, and neither did subjective age and perceived risk of contracting the virus. However, subjective health significantly moderated the relationship of worry and subjective age, showing different trajectories in the relationship depending on whether subjective health was good or bad. Higher perceived risk of falling seriously ill increased subjective age over time. Again, subjective health moderated this relationship: the perceived risk of falling seriously ill affected subjective age only for those with better subjective health. Our findings show the interactive relationship between subjective age and Covid-19 related cognitions and emotions and provide guidance for identifying older people that are most susceptible for negative age-related communication during the pandemic.

Squamous cell carcinoma (SCC) seriously compromises the health and welfare of affected horses. Although robust evidence points to equine papillomavirus type 2 (EcPV2) causing genital lesions, the etiopathogenesis of equine SCC is still poorly understood. We screened a series of SCCs from the head-and-neck (HN), (peri-)ocular and genital region, and site-matched controls for the presence of EcPV2-5 and herpesvirus DNA using type-specific EcPV PCR, and consensus nested herpesvirus PCR followed by sequencing. EcPV2 DNA was detected in 45.5% of HN lesions, 8.3% of (peri-)ocular SCCs, and 100% of genital tumors, whilst control samples from tumor-free horses except one tested EcPV-negative. Two HNSCCs harbored EcPV5, and an ocular lesion EcPV4 DNA. Herpesvirus DNA was detected in 63.6%, 66.6%, 47.2%, and 14.2% of horses with HN, ocular, penile, and vulvar SCCs, respectively, and mainly identified as equine herpesvirus 2 (EHV2), 5 (EHV5) or asinine herpesvirus 5 (AsHV5) DNA. In the tumor-free control group, 9.6% of oral secretions, 46.6% of ocular swabs, 47% of penile samples, and 14.2% of vaginal swabs scored positive for these herpesvirus types. This work further highlights the role of EcPV2 as an oncovirus and is the first to provide information on the prevalence of (gamma-)herpesviruses in equine SCCs.

The sharing of research data is essential to ensure reproducibility and maximize the impact of public investments in scientific research. Here, we describe OpenNeuro, a BRAIN Initiative data archive that provides the ability to openly share data from a broad range of brain imaging data types following the FAIR principles for data sharing. We highlight the importance of the Brain Imaging Data Structure standard for enabling effective curation, sharing, and reuse of data. The archive presently shares more than 600 datasets including data from more than 20,000 participants, comprising multiple species and measurement modalities and a broad range of phenotypes. The impact of the shared data is evident in a growing number of published reuses, currently totalling more than 150 publications. We conclude by describing plans for future development and integration with other ongoing open science efforts.

There is an urgent need for accurate, scalable and cost-efficient models of the tumor microenvironment. Here, we detail how to fabricate and use the metabolic microenvironment chamber (MEMIC) – a 3D-printed ex vivo model of intratumoral heterogeneity. A major driver of the cellular and molecular diversity in tumors is accessibility to the blood stream. Whereas perivascular tumor cells have direct access to oxygen and nutrients, cells further from the vasculature must survive under progressively more ischemic environments. The MEMIC simulates this differential access to nutrients, allow co-culturing any number of cell types, and it is optimized for live imaging and other microscopy-based analyses. Owing to a modular design and full experimental control, the MEMIC provides insights into the tumor microenvironment that would be difficult to obtain via other methods. As proof of principle, we show that cells sense gradual changes in metabolite concentration leading to predictable molecular and cellular spatial patterns. We propose the MEMIC as a complement to standard in vitro and in vivo experiments, diversifying the tools available to accurately model, perturb and monitor the tumor microenvironment.

Projection neurons (PNs) in the mammalian olfactory bulb (OB) receive input from the nose and project to diverse cortical and subcortical areas. Morphological and physiological studies have highlighted functional heterogeneity, yet no molecular markers have been described that delineate PN subtypes. Here, we used viral injections into olfactory cortex and fluorescent nucleus sorting to enrich PNs for high-throughput single nucleus and bulk RNA deep sequencing. Transcriptome analysis and RNA in situ hybridization identified distinct mitral and tufted cell populations with characteristic transcription factor network topology, cell adhesion, and excitability-related gene expression. Finally, we describe a new computational approach for integrating bulk and snRNA-seq data and provide evidence that different mitral cell populations preferentially project to different target regions. Together, we have identified potential molecular and gene regulatory mechanisms underlying PN diversity and provide new molecular entry points into studying the diverse functional roles of mitral and tufted cell subtypes.

Background Coronavirus disease 2019 (COVID-19) can result in a large variety of chronic health issues such as impaired lung function, reduced exercise performance and diminished quality of life. Our study aimed to investigate the efficacy, feasibility and safety of pulmonary rehabilitation in COVID-19 patients and to compare outcomes between patients with a mild/moderate and a severe/critical course of the disease. Methods Patients in the post-acute phase of a mild to critical course of COVID-19 admitted to a comprehensive 3-week inpatient pulmonary rehabilitation programme were included in this prospective, observational cohort study. Several measures of exercise performance (6-min walk distance (6MWD)), lung function (forced vital capacity (FVC)) and quality of life (36-question short-form health survey (SF-36)) were assessed before and after pulmonary rehabilitation. Results 50 patients were included in the study (24 with mild/moderate and 26 with severe/critical COVID-19). On admission, patients had a reduced 6MWD (mild: median 509 m, interquartile range (IQR) 426–539 m; severe: 344 m, 244–392 m), an impaired FVC (mild: 80%, 59–91%; severe: 75%, 60–91%) and a low SF-36 mental health score (mild: 49 points, 37–54 points; severe: 39 points, 30–53 points). Patients attended a median (IQR) 100% (94–100%) of all provided pulmonary rehabilitation sessions. At discharge, patients in both subgroups improved in 6MWD (mild/moderate: +48 m, 35–113 m; severe/critical: +124 m, 75–145 m; both p

Introduction Difficulties in emotional regulation are key to the development and maintenance of chronic pain. Recent evidence shows internet-delivered dialectic behaviour therapy (iDBT) skills training can reduce emotional dysregulation and pain intensity. However, further studies are needed to provide more definitive evidence regarding the efficacy of iDBT skills training in the chronic pain population.Methods and analysis A single-case experimental design (SCED) with multiple baselines will be used to examine the efficacy of a 4-week iDBT-Pain skills training intervention (iDBT-Pain intervention) to reduce emotional dysregulation and pain intensity in individuals with chronic pain. The iDBT-Pain intervention encompasses two components: (1) iDBT-Pain skills training sessions (iDBT-Pain sessions) and (2) the iDBT-Pain skills training web application (iDBT-Pain app). Three individuals with chronic pain will be recruited and randomly allocated to different baseline phases (5, 9 or 12 days). Following the baseline phase, participants will receive six 60–90 min iDBT-Pain sessions approximately 4 or 5 days apart, delivered by a psychologist via Zoom. To reinforce learnings from the iDBT-Pain sessions, participants will have unlimited use of the iDBT-Pain app. A 7-day follow-up phase (maintenance) will follow the intervention, whereby the iDBT-Pain sessions cease but the iDBT-Pain app is accessible. Emotional regulation, as the primary outcome measure, will be assessed using the Difficulties in Emotion Regulation Scale. Pain intensity, as the secondary outcome measure, will be assessed using a visual analogue scale. Generalisation measures will assess psychological state factors (depression, anxiety and coping behaviour), alongside sleep quality, well-being and harm avoidance. SCEDs are increasingly considered effective designs for internet-delivered psychological interventions because SCED enables the investigation of interindividual variability in a heterogeneous population such as chronic pain.Ethics and dissemination This trial was approved by the University of New South Wales (HC200199). Results will be published in peer-reviewed journals.Trial registration number ACTRN12620000604909.

Abstract We assessed the calming effect of doppel, a wearable device that delivers heartbeat-like tactile stimulation on the wrist. We tested whether the use of doppel would have a calming effect on physiological arousal and subjective reports of state anxiety during the anticipation of public speech, a validated experimental task that is known to induce anxiety. Two groups of participants were tested in a single-blind design. Both groups wore the device on their wrist during the anticipation of public speech, and were given the cover story that the device was measuring blood pressure. For only one group, the device was turned on and delivered a slow heartbeat-like vibration. Participants in the doppel active condition displayed lower increases in skin conductance responses relative to baseline and reported lower anxiety levels compared to the control group. Therefore, the presence, as opposed to its absence, of a slow rhythm, which in the present study was instantiated as an auxiliary slow heartbeat delivered through doppel, had a significant calming effect on physiological arousal and subjective experience during a socially stressful situation. This finding is discussed in relation to past research on responses and entrainment to rhythms, and their effects on arousal and mood.

The purpose of this study was to describe the ocular findings, structural ocular complications, and vision impairment in a cohort of Lassa fever survivors in Kenema, Sierra Leone. A retrospective, uncontrolled, cross-sectional study of 31 Lassa fever survivors (62 eyes) who underwent an ophthalmic evaluation in January 2018 at the Kenema Government Hospital in Kenema, Sierra Leone was performed. Data collection included demographic information, ocular/systemic symptoms, visual acuity (VA), and ophthalmic examination findings. Main outcome measures included anterior and posterior segment ophthalmic manifestations and level of VA impairment in Lassa fever survivors. Anterior segment findings included cataract (18%) and pterygium (2%), while posterior segment manifestations consisted of glaucoma (6%), preretinal hemorrhage (2%), and lattice degeneration (2%). Findings suggestive of prior sequelae of uveitis included chorioretinal scarring (5%), retinal fibrosis (3%), and vitreous opacity (2%). Visual acuity was normal/mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind by the World Health Organization (WHO) criteria. Median VA was worse in Lassa fever survivors with ophthalmic disease findings (p

IntroductionStandard multidrug-resistant tuberculosis (MDR-TB) treatment is lengthy, toxic, and insufficiently effective. New drugs and a shorter treatment regimen (SCR) are now recommended. However, patient and health-care worker (HCW) perspectives regarding the SCR are unknown. We aimed to determine the views and experiences of patients with MDR-TB and HCW regarding the SCR in Karakalpakstan, Uzbekistan.MethodsIn a qualitative study, we conducted 48 in-depth interviews with 24 people with MDR-TB and 20 HCW, purposively recruited to include those with a range of treatment-taking experiences and employment positions. Data were analysed thematically using Nvivo 12, to identify emergent patterns, concepts, and categories. Principles of grounded theory were drawn upon to generate findings inductively from participants' accounts.ResultsAll patients viewed the SCR favourably. The SCR was seen as enabling an expedited return to work, studies, and "normality". This reduced the burden of treatment and difficulties with treatment fatigue. The SCR appeared to improve mental health, ease difficulties with TB-related stigma, and foster improved adherence. While patients wanted shorter treatment, it was also important that treatment be tolerable and effective. However, HCW doubted the appropriateness and effectiveness of the SCR, which influenced their confidence in prescribing the regimen.ConclusionThe SCR was said to benefit treatment completion and patients' lives. HCW concerns about SCR appropriateness and effectiveness may influence who receives the regimen. These are important considerations for SCR implementation and MDR-TB treatment developments, and dissonance between patient and HCW perspectives must be addressed for successful implementation of shorter regimens in the future.

The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. CpG methylation in the TERT promoter (TERTp) was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to facilitate binding of transcription factor ETS/TCF and subsequent TERT expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and chromatin accessibility) and genetic (promoter mutations) mechanisms in regulating TERT gene expression in healthy skin samples and in melanoma cell lines (n = 61). We unexpectedly observed that the methylation of TERTp was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with either high methylation or intermediate methylation in combination with TERT mutations. TERTp methylation was positively correlated with chromatin accessibility and TERT mRNA expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to high methylation throughout the promoter or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T or C250T mutations.

OBJECTIVE:Chronic suppurative otitis media (CSOM) is a chronic infectious disease with worldwide prevalence that causes hearing loss and decreased quality of life. As current (antibiotic) treatments often unsuccessful and antibiotic resistance is emerging, alternative agents and/or strategies are urgently needed. We considered the synthetic antimicrobial and anti-biofilm peptide P60.4Ac to be an interesting candidate because it also displays anti-inflammatory activities including lipopolysaccharide-neutralizing activity. The aim of the present study was to investigate the safety and efficacy of ototopical drops containing P60.4Ac in adults with CSOM without cholesteatoma. METHODS:We conducted a range-finding study in 16 subjects followed by a randomized, double blinded, placebo-controlled, multicentre phase IIa study in 34 subjects. P60.4Ac-containing ototopical drops or placebo drops were applied twice a day for 2 weeks and adverse events (AEs) and medication use were recorded. Laboratory tests, swabs from the middle ear and throat for bacterial cultures, and audiometry were performed at intervals up to 10 weeks after therapy. Response to treatment was assessed by blinded symptom scoring on otoscopy. RESULTS:Application of P60.4Ac-containing ototopical drops (0.25-2.0 mg of peptide/ml) in the ear canal of patients suffering from CSOM was found to be safe and well-tolerated. The optimal dose (0.5 mg of peptide/ml) was selected for the subsequent phase IIa study. Safety evaluation revealed only a few AEs that were unlikely related to study treatment and all, except one, were of mild to moderate intensity. In addition to this excellent safety profile, P60.4Ac ototopical drops resulted in a treatment success in 47% of cases versus 6% in the placebo group. CONCLUSION:The efficacy/safety balance assessed in the present study provides a compelling justification for continued clinical development of P60.4Ac in therapy-resistant CSOM.

Euphorbia usambarica is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from Euphorbia species have been shown to have activity against latent HIV-1, the major source of HIV-1 persistence despite antiretroviral therapy. We performed bioactivity-guided isolation to identify 15 new diterpenoids (1–9, 14–17, 19, and 20) along with 16 known compounds from E. usambarica with HIV-1 latency reversal activity. Euphordraculoate C (1) exhibits a rare 6/6/3-fused ring system with a 2-methyl-2-cyclopentenone moiety. Usambariphanes A (2) and B (3) display an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure. 4β-Crotignoid K (14) revealed a 250-fold improvement in latency reversal activity compared to crotignoid K (13), identifying that configuration at the C-4 of tigliane diterpenoids is critical to HIV-1 latency reversal activity. The primary mechanism of the active diterpenoids 12–14 and 21 for the HIV-1 latency reversal activity was activation of PKC, while lignans 26 and 27 that did not increase CD69 expression, suggesting a non-PKC mechanism. Accordingly, natural constituents from E. usambarica have the potential to contribute to the development of HIV-1 eradication strategies.

ABSTRACT IMPACT: This real-world study of what students value in crisis leadership fills an important gap in the literature and may inform future leadership development programs in undergraduate medical education. OBJECTIVES/GOALS: Leadership training is of growing importance and prevalence in medical education. The COVID-19 pandemic provides a unique insight into the qualities students value in leaders. Our qualitative study examined these leadership themes and provides a grounding for future development of leadership programs. METHODS/STUDY POPULATION: A conventional qualitative approach was used in order to allow open expression of ideas related to leadership in a pandemic. The authors developed a 5 free-text question survey instrument aimed to uncover student perceptions of leadership both during the current pandemic and in crises in general. A participant pilot was performed in order to ensure readability and ease of understanding. We used thematic analysis to examine the content of the survey responses, and inductive coding of the responses allowed identification of emerging themes. Medical students at the University of Michigan were surveyed. RESULTS/ANTICIPATED RESULTS: In total, 162 students completed the survey. The demographic characteristics of participants are shown in Table 1. Median age was 25 years old (range, 22-39). There was good representation from the 4 classes in the medical school with 20-30% from each medical school class and 5% of dual degree students. Thematic analysis demonstrated that students value personal characteristics of excellence in their leaders with an orientation towards helping other people. Students believe that leaders must know how to interpret and use information and then that these leaders must be able to communicate expertly to guide organizations. The final theme that emerged is that effective leaders must commit to decisive action. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study took place at a time of unprecedented crises and response examples were grounded in this real-world practice of leadership. These results and themes that emerged fill a critical gap and may facilitate future curriculum development for medical students and trainees.

Alveolar echinococcosis (AE) is caused by the intermediate stage of Echinococcus multilocularis. We aimed to correlate computed tomography (CT) data with histology to identify distinct characteristics for different lesion types. We classified 45 samples into five types with the Echinococcus multilocularis Ulm Classification for Computed Tomography (EMUC-CT). The various CT lesions exhibited significantly different histological parameters, which led us to propose a progression model. The initial lesion fit the CT type IV classification, which comprises a single necrotic area with the central located laminated layer, a larger distance between laminated layer and border zone, a small fibrotic peripheral zone, and few small particles of Echinococcus multilocularis (spems). Lesions could progress through CT types I, II, and III, characterized by shorter distances between laminated layer and border zone, more spems inside and surrounding the lesion, and a pronounced fibrotic rim (mostly in type III). Alternatively, lesions could converge to a highly calcified, regressive state (type V). Our results suggest that the CT types mark sequential stages of the infection, which progress over time. These distinct histological patterns advance the understanding of interactions between AE and human host; moreover, they might become prognostically and therapeutically relevant.

ObjectivesTo estimate the cost-effectiveness to the US Veterans Health Administration (VA) of the use of complementary and integrative health (CIH) approaches by younger Veterans with chronic musculoskeletal disorder (MSD) pain.PerspectiveVA healthcare system.MethodsWe used a propensity score-adjusted hierarchical linear modeling (HLM), and 2010-2013 VA administrative data to estimate differences in VA healthcare costs, pain intensity (0-10 numerical rating scale), and opioid use between CIH users and nonusers. We identified CIH use in Veterans' medical records through Current Procedural Terminology, VA workload tracking, and provider-type codes.ResultsWe identified 30,634 younger Veterans with chronic MSD pain as using CIH and 195,424 with no CIH use. CIH users differed from nonusers across all baseline covariates except the Charlson comorbidity index. They also differed on annual pre-CIH-start healthcare costs ($10,729 versus $5,818), pain (4.33 versus 3.76), and opioid use (66.6% versus 54.0%). The HLM results indicated lower annual healthcare costs (-$637; 95% CI: -$1,023, -$247), lower pain (-0.34; -0.40, -0.27), and slightly higher (less than a percentage point) opioid use (0.8; 0.6, 0.9) for CIH users in the year after CIH start. Sensitivity analyses indicated similar results for three most-used CIH approaches (acupuncture, chiropractic care, and massage), but higher costs for those with eight or more CIH visits.ConclusionsOn average CIH use appears associated with lower healthcare costs and pain and slightly higher opioid use in this population of younger Veterans with chronic musculoskeletal pain. Given the VA's growing interest in the use of CIH, further, more detailed analyses of its impacts are warranted.

PURPOSE:To provide population-based reference values for cervical spinal canal parameters and vertebral body (VB) width and to study their associations with sex, age, body height, body weight and body mass index (BMI) using MRI. METHODS:Cross-sectional analyses included data from 2,453 participants, aged 21-89 years, of the population-based Study of Health in Pomerania (SHIP) who underwent whole-body MRI at 1.5 Tesla between July 2008 and March 2011. A standardised reading was performed for the C2-C7 cervical spine levels at sagittal T2 TSE weighted sequences. RESULTS:Reference intervals for spinal canal parameters were similar in males and females, while VB width was on average 2.1-2.2 mm larger in males. Age effects were only substantial regarding VB width with a 0.5 mm per ten-year age increase. Body height effects were only substantial regarding the osseous spinal canal and VB width. Body weight and BMI effects are mostly not substantial. CONCLUSIONS:Our study provides MRI-based reference values for the cervical spinal canal parameters in an adult Caucasian population. Except for VB width, associations with sex, age and somatometric measures are mostly small and thus have only limited clinical implications. Some available cut-off values may need a revision because they likely overestimate risks.

BackgroundPerinatal and newborn complications are major risk factors for unfavorable fetal and neonatal outcomes. Gestational dating and growth monitoring can be instrumental in the identification and management of high-risk pregnancies and births. The INTERGROWTH-21st Project developed the first global standards for gestational dating and fetal and newborn growth monitoring, supplying a toolkit for clinicians. This study aimed to assess the feasibility and acceptability of the first known implementation study of these standards in a low resource setting.MethodsThe study was performed in two 12-month phases from March 2016 to March 2018 at Jacaranda Health, a private maternity hospital in peri-urban Nairobi, Kenya. In-depth interviews, focus group discussions and a provider survey were utilized to evaluate providers' experiences during implementation. Client chart data, for pregnant women attending antenatal care and/or delivering at Jacaranda Health along with their newborns, were captured to assess uptake and effect of the standards on clinical decision-making.ResultsFacility-level support and provider buy-in proved to be critical factors driving the success of implementing the standards. However, additional support was needed to strengthen capacity to conduct and interpret ultrasounds and maintain motivation among providers. We observed a significant increase in the uptake of obstetric ultrasounds, particularly gestational dating, during the implementation of the standards. Although no significant changes were detected in the identification of high-risk pregnancies, referrals and deliveries by Cesarean section during implementation, we did observe a significant reduction in inductions for post-date. No significant barriers were reported regarding the use of the newborn standards. Over 80% of providers advocated for the standards to remain in place with some enhancements related mainly to training, advocacy and procurement.ConclusionsThe findings are timely with increasing global adoption of the standards and the challenging and multi-faceted nature of translating new, evidence-based guidelines into routine clinical practice.

Objective: The research assessed online learning modules designed to teach health professions students evidence-based practice (EBP) principles in an interprofessional context across two institutions. Methods: Students from nine health professions at two institutions were recruited to participate in this pilot project consisting of two online learning modules designed to prepare students for an in-person case-based interprofessional activity. Librarians and an instructional designer created two EBP modules. Students’ competence in EBP was assessed before and after the modules as well as after the in-person activity. Students evaluated the online learning modules and their impact on the students’ learning after the in-person session. Results: A total of 39 students from 8 health professions programs participated in the project. Average quiz scores for online EBP module 1 and module 2 were 83% and 76%, respectively. Following completion of the learning modules, adapted Fresno test of competence in EBP scores increased (p=0.001), indicating that the modules improved EBP skill competence. Student evaluations of the learning modules were positive. Students indicated that they acquired new information skills that contributed to their ability to develop a patient care plan and that they would use these information skills in their future clinical practice. Conclusions: Online EBP learning modules were effective in developing EBP knowledge and skills for health professions students. Using the same modules ensured that students from different health professions at different stages of their professional programs had consistent knowledge and enabled each student to fully engage in an interprofessional evidence-based activity. Student feedback indicated the modules were valued and beneficial.