The first genetically confirmed cohort of Facioscapulohumeral Muscular Dystrophy from Northern India.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of hereditary myopathy. Sixty per cent of the world's population lives in Asia, so a significant percentage of the world's FSHD participants is expected to live there. To date, most FSHD studies have involved individuals of European descent, yet small-scale studies of East-Asian populations suggest that the likelihood of developing FSHD may vary. Here, we present the first genetically confirmed FSHD cohort of Indian ancestry, which suggests a pathogenic FSHD1 allele size distribution intermediate between European and North-East Asian populations and more asymptomatic carriers of 4 unit and 5 unit FSHD1 alleles than observed in European populations. Our data provides important evidence of differences relevant to clinical diagnostics and underscores the need for global FSHD participation in research and trial-ready Indian FSHD cohorts.

Rift Valley Fever Virus Encephalitis: Viral and Host Determinants of Pathogenesis.

Rift Valley fever virus (RVFV) is a mosquito-borne virus endemic to Africa and the Middle East. RVFV infection can cause encephalitis, which is associated with significant morbidity and mortality. Studies of RVFV encephalitis following percutaneous inoculation, as would occur following a mosquito bite, have historically been limited by a lack of consistent animal models. In this review, we describe new insights into the pathogenesis of RVFV and the opportunities provided by new mouse models. We underscore the need to consider viral strain and route of inoculation when interpreting data obtained using animal models. We discuss the trafficking of RVFV and the role of host genetics and immunity in modulating the pathogenesis of RVFV encephalitis. We also explore potential strategies to prevent and treat central nervous system disease caused by RVFV and discuss remaining knowledge gaps.

GeneXpert MTB/RIF Ultra vs Unstimulated Interferon γ (IRISA-TB) for the Diagnosis of Tuberculous Pericarditis in a Tuberculosis-Endemic Setting.

Background: Tuberculous pericarditis (TBP) is a paucibacillary disease, where host biomarkers such as unstimulated interferon γ (IRISA-TB) have high diagnostic accuracy. However, DNA-based diagnostic tests (GeneXpert Ultra), more sensitive than an earlier versions, have recently become available. Given that the diagnosis of TBP is challenging, we performed a comparative diagnostic accuracy study comparing both assays. Methods: We recruited 99 consecutive patients with suspected TBP in Cape Town, South Africa. Definite TBP was defined by microbiological confirmation of tuberculosis (TB) on pericardial fluid culture or an alternative polymerase chain reaction-based test (GeneXpert MTB/RIF) or by use of sputum (polymerase chain reaction or culture). Probable TBP was defined as a high clinical suspicion of TB accompanied by anti-TB treatment, while non-TBP was defined as negative microbiological test results for TB without initiation of TB treatment and/or the presence of an alternative diagnosis. Results: There were 39 patients with definite TBP, 35 with probable TBP, and 23 with non-TBP. Approximately 70% of participants who received TB treatment were HIV coinfected. Overall, IRISA-TB was more sensitive than Xpert Ultra (88.6% [95% CI, 74.1%-95.5%] vs 71.5% [55.0%-83.7%], n = 53) and significantly more sensitive in participants who were HIV uninfected (100% [95% CI, 72.3%-100.0%] vs 60% [31.3%-83.2%], P = .03). In patients with definite and probable TBP combined (n = 84), sensitivity was significantly higher with IRISA-TB (77.3% [95% CI, 65.9%-85.8%] vs 37.9 [27.2%-50.0%], P < .0001). A similar pattern was seen in persons who were HIV uninfected (88.3% vs 35.3%, P = .002). Specificity was high for both assays (>95%). Conclusions: Unstimulated interferon γ (IRISA-TB) was significantly more sensitive than Xpert Ultra for the diagnosis of TB pericarditis in a TB-endemic resource-poor setting.

The Impact of Scholarly Concentration Programs on Graduates' Career Choices and Interest in the Care of Older Patients.

BACKGROUND: More geriatricians are needed to care for the aging population. Geriatric scholarly concentration programs (GSCPs) may promote medical students' interest in this underserved field or careers working with older adults. Additionally, graduates of GSCPs may be more comfortable and competent in providing care for older adults. Surveys were administered to graduates of GSCPs to determine the role of these programs in shaping medical students' careers and views about caring for older adults.  Methods: The purpose of this study is to understand the impact of GSCPs on medical graduates' career choices and self-perceived skill and comfort in caring for older adults. A Qualtrics survey (Qualtrics International Inc., Seattle, Washington, United States) was developed and distributed to 83 graduates of four GSCPs in the United States. Data were analyzed using a significance level of p>0.05 for all tests. Descriptive statistics were calculated to summarize the data. Wilcoxon signed-rank tests were used to test for significant differences in interest in pursuing a career in geriatrics or working with older adults. Qualitative responses were coded and analyzed for themes.  Results: A total of 34 out of 83 surveyed graduates of GSCPs indicated a higher interest in geriatrics as a career as well as increased comfort and self-perceived skill in caring for older adults after completing the GSCP. The components of the GSCP that most strongly improved the participants' ability to care for older adults included the curriculum (n=31, 91%) and mentoring (n=28, 82%). An overwhelming majority of survey participants felt GSCPs should be offered as part of medical school programming (n=33, 97%).  Conclusion: This study suggests that GSCPs increase interest and competence in caring for older adults and increase interest in a career in geriatrics. GSCPs should be implemented across medical schools.

SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset.

Rationale: In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4-8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung).Objectives: We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group.Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry.Measurements and Main Results: Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (P < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity.Conclusions: Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).

The Use of Biofluid Markers to Evaluate the Consequences of Sport-Related Subconcussive Head Impact Exposure: A Scoping Review.

BACKGROUND: Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure. OBJECTIVE: This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research. METHODS: PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey, and two clinical trial registries were searched (until March 30, 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality. RESULTS: Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing, and soccer, and the most investigated markers were (in descending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers-such as NfL-appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport. CONCLUSION: Considering the limitations of the evidence base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers' utility.

Contrasting Characteristics and Outcomes of Sports-Related and Non-Sports-Related Traumatic Brain Injury.

Importance: Exposure to traumatic brain injury (TBI) has raised widespread concern over participation in sports, particularly over possible long-term consequences. However, little is known about the outcomes of individuals presenting to hospitals with sports-related TBI. Objective: To compare the characteristics and outcomes of individuals presenting to hospitals with sports-related and non-sports-related TBI. Design, Setting, and Participants: The CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) observational cohort study was conducted at hospitals in 18 countries. The study enrolled 4509 patients who had TBI and had an indication for computed tomography (CT), of whom 4360 were 16 years or older. Outcomes were assessed at 3 and 6 months, and groups were compared using regression analyses adjusting for clinical and demographic differences. Data were collected between December 9, 2014, and December 17, 2017, and analyzed from August 2022 to March 2023. Exposure: Sports-related and non-sports-related TBI with subgroups selected by severity of injury. Main Outcomes and Measures: The main outcome was the Glasgow Outcome Scale-Extended (GOSE) at 6 months, with secondary outcomes covering postconcussion symptoms, health-related quality of life, and mental health. Results: A total of 4360 patients were studied, including 256 (6%) with sports-related TBI (mean [SD] age, 38.9 [18.1] years; 161 [63%] male) and 4104 with non-sports-related TBI (mean [SD] age, 51.0 [20.2] years; 2773 [68%] male). Compared with patients with non-sports-related TBI, patients with sports-related TBI were younger, more likely to have tertiary education, more likely to be previously healthy, and less likely to have a major extracranial injury. After adjustment, the groups did not differ in incomplete recovery (GOSE scores <8) at 6 months (odds ratio [OR], 1.27; 95% CI, 0.90-1.78; P = .22 for all patients; OR, 1.20; 95% CI, 0.83-1.73; P = .34 for those with mild TBI; and OR, 1.19; 95% CI, 0.74-1.92; P = .65 for those with mild TBI and negative CT findings). At 6 months, there was incomplete recovery in 103 of 223 patients (46%) with outcomes in the sports-related TBI group, 65 of 168 (39%) in those with mild sports-related TBI, and 30 of 98 (31%) in those with mild sports-related TBI and negative CT findings. In contrast, at 6 months, the sports-related TBI group had lower prevalence of anxiety, depression, posttraumatic stress disorder, and postconcussion symptoms than the non-sports-related group. Conclusions and Relevance: In this cohort study of 4360 patients with TBI, functional limitations 6 months after injury were common after sports-related TBI, even mild sports-related TBI. Persisting impairment was evident in the sports-related TBI group despite better recovery compared with non-sports-related TBI on measures of mental health and postconcussion symptoms. These findings caution against taking an overoptimistic view of outcomes after sports-related TBI, even if the initial injury appears mild.

Disturbance-diversity relationships of microbial communities change based on growth substrate.

Disturbance events can impact ecological community dynamics. Understanding how communities respond to disturbances and how those responses can vary is a challenge in microbial ecology. In this study, we grew a previously enriched specialized microbial community on either cellulose or glucose as a sole carbon source and subjected them to one of five different disturbance regimes of varying frequencies ranging from low to high. Using 16S rRNA gene amplicon sequencing, we show that the community structure is largely driven by substrate, but disturbance frequency affects community composition and successional dynamics. When grown on cellulose, bacteria in the genera Cellvibrio, Lacunisphaera, and Asticcacaulis are the most abundant microbes. However, Lacunisphaera is only abundant in the lower disturbance frequency treatments, while Asticcacaulis is more abundant in the highest disturbance frequency treatment. When grown on glucose, the most abundant microbes are two Pseudomonas sequence variants and a Cohnella sequence variant that is only abundant in the highest disturbance frequency treatment. Communities grown on cellulose exhibited a greater range of diversity (1.95-7.33 Hill 1 diversity) that peaks at the intermediate disturbance frequency treatment or one disturbance every 3 days. Communities grown on glucose, however, ranged from 1.63 to 5.19 Hill 1 diversity with peak diversity at the greatest disturbance frequency treatment. These results demonstrate that the dynamics of a microbial community can vary depending on substrate and the disturbance frequency and may potentially explain the variety of diversity-disturbance relationships observed in microbial systems.IMPORTANCEA generalizable diversity-disturbance relationship (DDR) of microbial communities remains a contentious topic. Various microbial systems have different DDRs. Rather than finding support or refuting specific DDRs, we investigated the underlying factors that lead to different DDRs. In this study, we measured a cellulose-enriched microbial community's response to a range of disturbance frequencies from high to low, across two different substrates: cellulose and glucose. We demonstrate that the community displays a unimodal DDR when grown on cellulose and a monotonically increasing DDR when grown on glucose. Our findings suggest that the same community can display different DDRs. These results suggest that the range of DDRs we observe across different microbial systems may be due to the nutritional resources microbial communities can access and the interactions between bacteria and their environment.

Organ donation following medical assistance in dying, Part I: a scoping review of legal and ethical aspects.

OBJECTIVE: The objective of this review was to collate and summarize the current literature on what is known about organ donation following medical assistance in dying (MAiD). Additionally, for this first part of a 2-part scoping review, the focus is on legal and ethical considerations regarding organ donation following MAiD. INTRODUCTION: Organ donation following MAiD is a relatively new procedure that has sparked much debate and discussion. A comprehensive investigation into the legal and ethical aspects related to organ donation following MAiD is needed to inform the development of safe and ethical practices. INCLUSION CRITERIA: In this review, we included documents that investigated legal and/or ethical issues related to individuals who underwent organ donation following MAiD in any setting (eg, hospital or home) worldwide. We considered quantitative and qualitative studies, text and opinion papers, gray literature, and unpublished material provided by stakeholders. METHODS: This scoping review followed JBI methodology. Published studies were retrieved from databases, including MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), PsycINFO (Ovid), Web of Science Core Collection, and Academic Search Complete (EBSCOhost). Gray and unpublished literature included reports from organ donation organizations in Canada, The Netherlands, and Belgium. Two independent reviewers screened all reports (both by title and abstract and by full text) against the inclusion criteria, extracted data, and completed a content analysis. Disagreements between the 2 reviewers were resolved through discussions among the reviewers and the lead reviewer. RESULTS: We included 121 documents for parts I and II of our scoping review, 89 of which are included in part I. The majority of the 89 documents were discussion papers published in English and in Canada from 2019 to 2021. In the content analysis, we identified 4 major categories regarding ethical and legal aspects of organ donation following MAiD: i) legal definitions, legislation, and guidelines; ii) ethics, dilemmas, and consensus; iii) consent and objection; and iv) public perceptions. We identified the main legislation regulating the practices of organ donation following MAiD in countries where both procedures are permitted, the many ethical debates surrounding this topic (eg, eligibility criteria for organ donation and MAiD, disclosure of donors' and recipients' information, directed organ donation, death determination in organ donation following MAiD, ethical safeguards for organ donation following MAiD), as well as the public perceptions of this process. CONCLUSIONS: Organ donation following MAiD has raised many legal and ethical concerns regarding establishing safeguards to protect patients and families. Despite the ongoing debates around the risks and benefits of this combined procedure, when patients who request MAiD want to donate their organs, this option can help fulfill their last wishes and diminish their suffering, which should be the main reasons to offer organ donation following MAiD.

Organ donation following medical assistance in dying, Part II: a scoping review of existing processes and procedures.

OBJECTIVE: The objective of this review was to collate and summarize the current literature on what is known about organ donation following medical assistance in dying (MAiD). For this second part of a 2-part scoping review, the focus is on the existing procedures and processes for organ donation following MAiD. INTRODUCTION: Organ donation following MAiD is a novel and contentious issue worldwide. To give direction for future research and initiatives, a comprehensive understanding of the available evidence of existing procedures and processes for organ donation following MAiD is needed. INCLUSION CRITERIA: For this review, the population of interest included all individuals who underwent organ donation following MAiD; the concept was defined as procedures and processes involved in organ donation after MAiD; and the context was reports of organ donation following MAiD at home or in any health care setting worldwide. We considered quantitative and qualitative studies, text and opinion papers, gray literature, and unpublished material provided by stakeholders. METHODS: This scoping review was conducted in line with JBI methodology. Published studies were retrieved from MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), PsycINFO (Ovid), Web of Science Core Collection, and Academic Search Complete (EBSCOhost). Gray and unpublished literature included reports from websites and organ donation organizations in Canada, Belgium, and The Netherlands. Two independent reviewers screened all reports (both title and abstract, and full text) against the predetermined inclusion criteria, extracted data, and completed a content analysis. Any disagreements between the 2 reviewers were resolved through discussion or with another reviewer. RESULTS: We included 121 documents across parts I and II, and we report on 107 documents in this second part. The majority of the 107 documents were discussion papers, published in English, and in Canada from 2019 to 2021. In the content analysis, we identified 5 major categories regarding existing procedures and processes of organ donation following MAiD: i) clinical pathways for organ donation following MAiD; ii) organ donation following MAiD and the donor; iii) clinical practice tools for organ donation following MAiD; iv) education and support for health care providers involved in organ donation following MAiD; and v) health care providers' roles and perceptions during organ donation following MAiD. CONCLUSIONS: Findings from this review can be used to provide support and guidance for improvements in procedures and processes, as well as a rich resource for countries currently planning to establish programs for organ donation after MAiD.

Therapy Intensity Level Scale for Traumatic Brain Injury: Clinimetric Assessment on Neuro-Monitored Patients Across 52 European Intensive Care Units.

Intracranial pressure (ICP) data from traumatic brain injury (TBI) patients in the intensive care unit (ICU) cannot be interpreted appropriately without accounting for the effect of administered therapy intensity level (TIL) on ICP. A 15-point scale was originally proposed in 1987 to quantify the hourly intensity of ICP-targeted treatment. This scale was subsequently modified-through expert consensus-during the development of TBI Common Data Elements to address statistical limitations and improve usability. The latest 38-point scale (hereafter referred to as TIL) permits integrated scoring for a 24-h period and has a five-category, condensed version (TIL(Basic)) based on qualitative assessment. Here, we perform a total- and component-score analysis of TIL and TIL(Basic) to: 1) validate the scales across the wide variation in contemporary ICP management; 2) compare their performance against that of predecessors; and 3) derive guidelines for proper scale use. From the observational Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, we extract clinical data from a prospective cohort of ICP-monitored TBI patients (n = 873) from 52 ICUs across 19 countries. We calculate daily TIL and TIL(Basic) scores (TIL24 and TIL(Basic)24, respectively) from each patient's first week of ICU stay. We also calculate summary TIL and TIL(Basic) scores by taking the first-week maximum (TILmax and TIL(Basic)max) and first-week median (TILmedian and TIL(Basic)median) of TIL24 and TIL(Basic)24 scores for each patient. We find that, across all measures of construct and criterion validity, the latest TIL scale performs significantly greater than or similarly to all alternative scales (including TIL(Basic)) and integrates the widest range of modern ICP treatments. TILmedian outperforms both TILmax and summarized ICP values in detecting refractory intracranial hypertension (RICH) during ICU stay. The RICH detection thresholds which maximize the sum of sensitivity and specificity are TILmedian ≥ 7.5 and TILmax ≥ 14. The TIL24 threshold which maximizes the sum of sensitivity and specificity in the detection of surgical ICP control is TIL24 ≥ 9. The median scores of each TIL component therapy over increasing TIL24 reflect a credible staircase approach to treatment intensity escalation, from head positioning to surgical ICP control, as well as considerable variability in the use of cerebrospinal fluid drainage and decompressive craniectomy. Since TIL(Basic)max suffers from a strong statistical ceiling effect and only covers 17% (95% confidence interval [CI]: 16-18%) of the information in TILmax, TIL(Basic) should not be used instead of TIL for rating maximum treatment intensity. TIL(Basic)24 and TIL(Basic)median can be suitable replacements for TIL24 and TILmedian, respectively (with up to 33% [95% CI: 31-35%] information coverage) when full TIL assessment is infeasible. Accordingly, we derive numerical ranges for categorising TIL24 scores into TIL(Basic)24 scores. In conclusion, our results validate TIL across a spectrum of ICP management and monitoring approaches. TIL is a more sensitive surrogate for pathophysiology than ICP and thus can be considered an intermediate outcome after TBI.

Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges.

Facioscapulohumeral muscular dystrophy (FSHD) is the second most common muscular dystrophy in adults, and it is associated with local D4Z4 chromatin relaxation, mostly via the contraction of the D4Z4 macrosatellite repeat array on chromosome 4q35. In this study, we aimed to investigate the use of Optical Genome Mapping (OGM) as a diagnostic tool for testing FSHD cases from the UK and India and to compare OGM performance with that of traditional techniques such as linear gel (LGE) and Pulsed-field gel electrophoresis (PFGE) Southern blotting (SB). A total of 6 confirmed and 19 suspected FSHD samples were processed with LGE and PFGE, respectively. The same samples were run using a Saphyr Genome-Imaging Instrument (1-color), and the data were analysed using custom EnFocus FSHD analysis. OGM was able to confirm the diagnosis of FSHD1 in all FSHD1 cases positive for SB (n = 17), and D4Z4 sizing highly correlated with PFGE-SB (p < 0.001). OGM correctly identified cases with mosaicism for the repeat array contraction (n = 2) and with a duplication of the D4Z4 repeat array. OGM is a promising new technology able to unravel structural variants in the genome and seems to be a valid tool for diagnosing FSHD1.

Effect of Interferon Gamma on Ebola Virus Infection of Primary Kupffer Cells and a Kupffer Cell Line.

Ebola virus disease (EVD) represents a global health threat. The etiological agents of EVD are six species of Orthoebolaviruses, with Orthoebolavirus zairense (EBOV) having the greatest public health and medical significance. EVD pathogenesis occurs as a result of broad cellular tropism of the virus, robust viral replication and a potent and dysregulated production of cytokines. In vivo, tissue macrophages are some of the earliest cells infected and contribute significantly to virus load and cytokine production. While EBOV is known to infect macrophages and to generate high titer virus in the liver, EBOV infection of liver macrophages, Kupffer cells, has not previously been examined in tissue culture or experimentally manipulated in vivo. Here, we employed primary murine Kupffer cells (KC) and an immortalized murine Kupffer cell line (ImKC) to assess EBOV-eGFP replication in liver macrophages. KCs and ImKCs were highly permissive for EBOV infection and IFN-γ polarization of these cells suppressed their permissiveness to infection. The kinetics of IFN-γ-elicited antiviral responses were examined using a biologically contained model of EBOV infection termed EBOV ΔVP30. The antiviral activity of IFN-γ was transient, but a modest ~3-fold reduction of infection persisted for as long as 6 days post-treatment. To assess the interferon-stimulated gene products (ISGs) responsible for protection, the efficacy of secreted ISGs induced by IFN-γ was evaluated and secreted ISGs failed to block EBOV ΔVP30. Our studies define new cellular tools for the study of EBOV infection that can potentially aid the development of new antiviral therapies. Furthermore, our data underscore the importance of macrophages in EVD pathogenesis and those IFN-γ-elicited ISGs that help to control EBOV infection.

Proteomic Profiling of Urine From Hospitalized Patients With Severe Pneumonia due to SARS-CoV-2 vs Other Causes: A Preliminary Report.

The pathogenesis of coronavirus disease 2019 (COVID-19) pneumonia remains poorly understood. The urine proteome of hospitalized patients with severe COVID-19 pneumonia, compared with severe non-COVID-19 pneumonia controls, was distinct and associated with lower abundance of several host proteins. Protein-specific machine learning analysis outlined biomarker combinations able to differentiate COVID-19 pneumonia from non-COVID-19 pneumonia controls.

Disturbance-Diversity Relationships of Microbial Communities Change Based on Growth Substrate.

Disturbance events can impact ecological community dynamics. Understanding how communities respond to disturbances, and how those responses can vary, is a challenge in microbial ecology. In this study, we grew a previously enriched specialized microbial community on either cellulose or glucose as a sole carbon source, and subjected them to one of five different disturbance regimes of varying frequencies ranging from low to high. Using 16S rRNA gene amplicon sequencing, we show that community structure is largely driven by substrate, but disturbance frequency affects community composition and successional dynamics. When grown on cellulose, bacteria in the genera Cellvibrio, Lacunisphaera, and Asticaccacaulis are the most abundant microbes. However, Lacunisphaera is only abundant in the lower disturbance frequency treatments, while Asticaccaulis is more abundant in the highest disturbance frequency treatment. When grown on glucose, the most abundant microbes are two Pseudomonas sequence variants, and a Cohnella sequence variant that is only abundant in the highest disturbance frequency treatment. Communities grown on cellulose exhibited a greater range of diversity (0.67-1.99 Shannon diversity and 1.38-5.25 Inverse Simpson diversity) that peak at the intermediate disturbance frequency treatment, or 1 disturbance every 3 days. Communities grown on glucose, however, ranged from 0.49-1.43 Shannon diversity and 1.37- 3.52 Inverse Simpson with peak diversity at the greatest disturbance frequency treatment. These results demonstrate that the dynamics of a microbial community can vary depending on substrate and the disturbance frequency, and may potentially explain the variety of diversity-disturbance relationships observed in microbial ecosystems.

The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.

Introduction: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans. In this study, we used next-generation sequencing to screen 61 probands with GN, hereditary spastic paraplegia (HSP), and spastic ataxias for a genetic diagnosis. Methods: After identifying four GN probands with PMP22 duplication and one spastic ataxia proband with SCA1, the remaining probands underwent whole exome (n = 26) or genome sequencing (n = 30). The curation of coding/splice region variants using gene panels was guided by allele frequencies from internal African-ancestry control genomes (n = 537) and the Clinical Genome Resource's Sequence Variant Interpretation guidelines. Results: Of 32 GN probands, 50% had African-genetic ancestry, and 44% were solved: PMP22 (n = 4); MFN2 (n = 3); one each of MORC2, ATP1A1, ADPRHL2, GJB1, GAN, MPZ, and ATM. Of 29 HSP probands (six with predominant ataxia), 66% had African-genetic ancestry, and 48% were solved: SPG11 (n = 3); KIF1A (n = 2); and one each of SPAST, ATL1, SPG7, PCYT2, PSEN1, ATXN1, ALDH18A1, CYP7B1, and RFT1. Structural variants in SPAST, SPG11, SPG7, MFN2, MPZ, KIF5A, and GJB1 were excluded by computational prediction and manual visualisation. Discussion: In this preliminary cohort screening panel of disease genes using WES/WGS data, we solved ~50% of cases, which is similar to diagnostic yields reported for global cohorts. However, the mutational profile among South Africans with GN and HSP differs substantially from that in the Global North.

Geriatric Telehealth: A Standardized Patient Case for Medical Students.

Introduction: The COVID-19 pandemic has necessitated the rapid expansion of telemedicine. However, there has been minimal coverage of telemedicine in traditional undergraduate medicine curricula. Telemedicine presents specific challenges in the geriatric population, including unfamiliarity with technology, cognitive and sensory barriers, inclusion of family and/or caregivers, multimorbidity, and a high degree of medical complexity. Methods: We developed a workshop to allow rising third-year medical students to practice a telemedicine patient encounter while developing skills for assessing and communicating with geriatric patients. This 90-minute workshop consisted of an introductory didactic presentation and a standardized patient activity for small groups of two to five students. Students' level of comfort with telemedicine for assessment of geriatric patients was evaluated with a pre- and postsurvey. Results: Fifty-eight students participated in the workshop and completed the surveys (presurvey = 58, postsurvey = 40), with roughly half (52%) reporting prior experience with telemedicine. A 5-point Likert-type scale (1 = very uncomfortable, 5 = very comfortable) was used. Students reported statistically significant increases in comfort using telemedicine (presurvey = 3.1, postsurvey = 3.9, p < .001) and using telemedicine for patients ≥65 years (presurvey = 2.8, postsurvey = 3.9, p < .001) after completing the workshop. Discussion: Medical students' comfort levels using telemedicine and caring for patients ages 65 and older with a telehealth visit improved after participating in this workshop. To help prepare students for telehealth practice in their future careers, educators should provide them with opportunities to practice and develop this critical skill set.

Dons d'organes et de tissus après décès dans le cadre de l'aide médicale à mourir : mise à jour 2023 du document d'orientation pour l'élaboration de politiques.

CONTEXTE: Depuis la parution du document d'orientation de 2019 de la Société canadienne du sang (SCS) pour les dons d'organes et de tissus après décès dans le cadre de l'aide médicale à mourir (AMM), le gouvernement fédéral a apporté des amendements à sa loi sur l'AMM. La présente mise à jour s'adresse aux médecins, aux organismes de don d'organes, aux spécialistes des soins de fin de vie et de l'AMM et aux responsables des orientations politiques; on y explique les répercussions de ces amendements. MÉTHODES: La Société canadienne du sang a réuni un groupe de 63 spécialistes de divers domaines (soins intensifs, dons d'organes et de tissus, administration des services de santé, AMM, bioéthique, droit et recherche) pour faire le point sur ces changements à l'occasion de son Forum d'orientation sur le don d'organes et de tissus après décès dans le cadre de l'aide médicale à mourir. Deux personnes admissibles à l'AMM et 2 proches de personnes ayant fait un don d'organe après l'AMM y ont aussi participé. Dans le cadre de 3 réunions consécutives tenues en ligne entre juin 2021 et avril 2022, les personnes participant au Forum ont abordé divers sujets en grands et petits groupes. Les discussions ont été guidées par une revue documentaire publiée selon la méthodologie JBI. Nous avons utilisé une technique du groupe nominal adaptée pour rédiger les recommandations qui ont fait consensus. La gestion des intérêts concurrents s'est faite selon les principes du Guidelines International Network, un réseau international qui se consacre aux lignes directrices de pratique clinique. RECOMMANDATIONS: Même si bon nombre des recommandations du document d'orientation de 2019 demeurent pertinentes, la présente mise à jour a permis d'en actualiser 2 et d'en formuler 8 nouvelles dans les domaines suivants : aiguillage vers un organisme de don d'organes, consentement, dons dirigés et conditionnels, procédure d'AMM, détermination du décès, équipes soignantes et préparation de rapports. INTERPRÉTATION: Les politiques et les pratiques en matière de don d'organes et de tissus après l'AMM au Canada doivent être conformes à la législation canadienne actuelle. La mise à jour de ce document d'orientation aidera les médecins à s'y retrouver parmi les enjeux médicaux, juridiques et éthiques inhérents à leur travail auprès de personnes qui souhaitent faire un don d'organes après l'AMM.

Mining the contribution of intensive care clinical course to outcome after traumatic brain injury.

Existing methods to characterise the evolving condition of traumatic brain injury (TBI) patients in the intensive care unit (ICU) do not capture the context necessary for individualising treatment. Here, we integrate all heterogenous data stored in medical records (1166 pre-ICU and ICU variables) to model the individualised contribution of clinical course to 6-month functional outcome on the Glasgow Outcome Scale -Extended (GOSE). On a prospective cohort (n = 1550, 65 centres) of TBI patients, we train recurrent neural network models to map a token-embedded time series representation of all variables (including missing values) to an ordinal GOSE prognosis every 2 h. The full range of variables explains up to 52% (95% CI: 50-54%) of the ordinal variance in functional outcome. Up to 91% (95% CI: 90-91%) of this explanation is derived from pre-ICU and admission information (i.e., static variables). Information collected in the ICU (i.e., dynamic variables) increases explanation (by up to 5% [95% CI: 4-6%]), though not enough to counter poorer overall performance in longer-stay (>5.75 days) patients. Highest-contributing variables include physician-based prognoses, CT features, and markers of neurological function. Whilst static information currently accounts for the majority of functional outcome explanation after TBI, data-driven analysis highlights investigative avenues to improve the dynamic characterisation of longer-stay patients. Moreover, our modelling strategy proves useful for converting large patient records into interpretable time series with missing data integration and minimal processing.