B-cell-directed CAR-T cell therapy activates CD8+ cytotoxic CARneg bystander T-cells in non-human primates and patients.

CAR-T cells hold promise as a therapy for B-cell-derived malignancies, yet despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. While recent studies have explored the mechanisms of in vivo CAR-T cell function, little is understood about the activation of surrounding CARneg bystander T-cells and their potential to enhance tumor responses. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T-cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T-cells following B-cell targeted CAR-T cell therapy. Utilizing a highly translatable CD20 CAR NHP model, we observed a distinct population of activated CD8+ CARneg T-cells emerging during CAR-T cell expansion. These bystander CD8+ CARneg T-cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T-cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisagenlecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T-cells in a dose dependent manner. In vitro activated and patient-derived T-cells with the bystander phenotype efficiently killed leukemic cells through a TCR-independent mechanism. Collectively, this dataset provides the first comprehensive identification and profiling of CARneg bystander CD8+ T-cells following B-cell targeting CAR-T cell therapy and suggests a novel mechanism through which CAR-T cell infusion might trigger enhanced anti-leukemic responses.

Patient-Centered Outcomes in Bronchiolitis.

OBJECTIVES: We examined the impact of hospitalization for bronchiolitis on patient-centered outcomes across patients with varying levels of support. METHODS: The participants included primary caregivers of children aged 0 to 24 months hospitalized for bronchiolitis at an 150-bed tertiary care children's hospital. Data were collected using a 30-item questionnaire examining quality of life impact, adapted from the previously validated survey, the Impact of Bronchiolitis Hospitalization Questionnaire.1 The survey contained questions asking to what extent the hospitalization interfered with different aspects of care. After all surveys were collected, the patients were split into groups categorized by level of support and defined as no support, low support (low-flow nasal cannula only or nasogastric [NG] only), moderate support (high-flow nasal cannula without NG), high support (high-flow nasal cannula with NG support), and positive pressure (with or without NG support). Descriptive statistics were used to examine the distribution of mean impact scores across these groups. RESULTS: A total of 92 caregivers and their children were included. The mean impact score for variables of difficult to hold, difficult to bond, and breastfeeding disruption increased with greater levels of support with P values of P = .003, P = .04, and P < .001, respectively. CONCLUSIONS: We found that the impact on patient-reported outcomes varied by level of support, as defined here, among children hospitalized with bronchiolitis, with significant impacts being in areas of caregiver bonding, caregiver holding, and breastfeeding.

Preventable hand injuries: A national audit.

Little is known of the scale of avoidable injuries presenting to medical services on a national level in the UK. This study aimed to assess the type and incidence of preventable wrist and hand injuries (as defined by the core research team) at a national level in the UK. 28 UK hospitals undertook a service evaluation of all hand trauma cases presenting to their units over a 2 week period in early 2021 identifying demographical and aetiological information about injuries sustained. 1909 patients were included (184 children) with a median age of 40 (IQR 25-59) years. The commonest five types of injury were fractures of the wrist; single phalangeal or metacarpal fractures; fingertip injuries; and infection, with the most common mechanisms being mechanical falls and manual labour. This is the first extensive survey of preventable hand injuries in the UK, identifying a need for further work into prevention to reduce healthcare burden and cost. 50% of injuries presenting to hand surgeons are preventable, with the most common injuries being single fractures of the wrist, phalanx and metacarpal. Few preventable injuries were related to alcohol or narcotic intoxication. Further research is needed to identify how to initiate injury prevention measures for hand injuries, particularly focussed towards hand fracture prevention.

Interventions to reduce camel and small ruminant young stock morbidity and mortality in Ethiopia.

Morbidity and mortality of young stock is a challenge for livestock producers globally. In Ethiopia, where camels and small ruminants (sheep and goats) are essential smallholder and pastoral livestock, young stock losses can cause severe consequences to livelihoods. This pilot study, part of a Government-led Young Stock Mortality Reduction Consortium project, was undertaken to identify and evaluate interventions to reduce young stock mortality in mixed crop-livestock and pastoral production systems in Ethiopia. Pastoralists and mixed crop-livestock farmers were enrolled by convenience sampling across four regions. Households were sampled with questionnaire surveys to establish baseline mortality risk and prevalence of diarrhoea and respiratory disease in animals younger than one year, and followed longitudinally over a one-year period, with final evaluations conducted from March to July 2020. Mortality risk and prevalence of diarrhoea and respiratory disease before and after implementation were compared using Poisson regression models including household as random effect. Prior to intervention, median camel mortality, prevalence of diarrhoea, and respiratory disease across production systems in the different households was 0.4, 0.44 and 0.2, respectively. This compared to median pastoralist small ruminant mortality risk and prevalence of diarrhoea and respiratory disease of 0.45, 0.32 and 0.18, respectively. Post-intervention, median camel mortality, prevalence of diarrhoea and respiratory disease dropped to 0.1, 0.08 and 0. Similarly, more than half of the small ruminant households reported no mortality, and no cases of diarrhoea or respiratory disease. In camels, rate ratios of mortality risk, prevalence of diarrhoea, and respiratory disease post-intervention compared to the baseline were 0.41, 0.41 and 0.37. In small ruminants, rate ratios were 0.33, 0.35 and 0.46. All reductions were statistically significant (p < 0.01). Generally, pastoralists experienced higher mortality and disease prevalence compared to mixed crop-livestock smallholders, and the effect of intervention was slightly higher in pastoralist households. The pilot study findings demonstrated highly significant reductions in mortality and risk of diarrhoea and respiratory disease post-interventions. However, not all households benefitted from the interventions, with a few households reporting increased mortality and morbidity. Many households had very few animals which made it challenging to measure impact and the study was conducted over a single year, without a control group, so between year effects could not be accounted for in the reductions observed. These findings should contribute to improved livestock productivity in Ethiopia.

Statistics for the hand surgeon. Part 1: principles and application to hand surgery research.

Hand surgeons have the potential to improve patient care, both with their own research and by using evidenced-based practice. In this first part of a two-part article, we describe key steps for the analysis of clinical data using quantitative methodology. We aim to describe the principles of medical statistics and their relevance and use in hand surgery, with contemporaneous examples. Hand surgeons seek expertise and guidance in the clinical domain to improve their practice and patient care. Part of this process involves the critical analysis and appraisal of the research of others.

Statistics for the hand surgeon. Part 2: avoiding common pitfalls.

In this second of a two-part article, we describe some of the common statistical pitfalls encountered in hand surgery research. These include dichotomania, the 'Table 2 fallacy', p-hacking, regression to the mean, overfitting and unaccounted data clustering. We explain the impact of these pitfalls on hand surgery research and describe techniques to avoid them. The aim of this two-part article was to provide a starting point for hand surgeons to refer to when conducting or analysing research and provide resources and references for interested readers to explore.

Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4ß7 in conventional T cells while preserving α4ß7 in regulatory T cells, with findings suggesting increased ß1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4ß7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.

Working Through Stigma: A Constructivist Grounded Theory of Delivering Health Services to Diverse 2SLGBTQ Populations.

Previous research inadequately explores processes and factors influencing the delivery of health services to sexual and gender minorities in ways that equitably attend to the infinite diversity held by these groups. This study employed Intersectionality and Critical Theories to inform Constructivist Grounded Theory methods and methodology; social categories of identity were strategically adopted to explore domains of power operating across multiple forms of oppression, think through subjective realities, and generate a nuanced rendering of power relations influencing health service delivery to diverse 2SLGBTQ populations in a Canadian province. Semi-structured interviews were conducted and the co-constructed theory of Working Through Stigma, with three interrelated concepts, depending on context, resolving histories, and surviving the situation, was generated. The theory depicts the concerns of participants and what they do about power relations influencing health service delivery and broader social contexts. While the negative impacts of stigma were widely and diversely experienced by patients and providers, ways of working within power relations emerged that would be impossible if stigma was not present, highlighting opportunities to positively impact those from stigmatized groups. As such, Working Through Stigma is a theory that flouts the tradition of stigma research; it offers theoretical knowledge that can be used to work within power relations upholding stigma in ways that increase access to quality health services for those whose historical underservicing can be attributed to stigma. In doing so, the stigma script is flipped and strategies for working against practices and behaviours that uphold cultural supremacies may be realized.

Creating psychological safety in interprofessional simulation for health professional learners: a scoping review of the barriers and enablers.

Interprofessional simulation-based education (IP-SBE) supports the acquisition of interprofessional collaborative competencies. Psychologically safe environments are necessary to address socio-historical hierarchies and coercive practices that may occur in IP-SBE, facilitating fuller student participation. A scoping review was conducted to understand the barriers and enablers of psychological safety within IP-SBE. Research papers were eligible if they included two or more undergraduate and/or post-graduate students in health/social care qualifications/degrees and discussed barriers and/or enablers of psychological safety within simulation-based education. Sources of evidence included experimental, quasi-experimental, analytical observational, descriptive observational, qualitative, and mixed-methodological peer-reviewed studies. English or English-translated articles, published after January 1, 1990, were included. Data were extracted by two members of the research team. Extraction conflicts were resolved by the principal investigators. In total, 1,653 studies were screened; 1,527 did not meet inclusion criteria. After a full-text review, 99 additional articles were excluded; 27 studies were analyzed. Psychological safety enablers include prebriefing-debriefing by trained facilitators, no-blame culture, and structured evidenced-based simulation designs. Hierarchy among/between professions, fear of making mistakes, and uncertainty were considered barriers. Recognition of barriers and enablers of psychological safety in IP-SBE is an important first step towards creating strategies that support the full participation of students in their acquisition of IPC competencies.

A Virtual Fracture Clinic Pathway for Managing Suspected Paediatric Scaphoid Fractures.

INTRODUCTION: The mismanagement of an occult scaphoid fracture is a significant concern in patients presenting with anatomical snuffbox tenderness and no radiographic signs of injury. AIM: This study investigated whether a virtual fracture clinic (VFC) could improve care efficiency and expedite management decisions surrounding suspected pediatric scaphoid fractures. METHOD: Data was reviewed for patients referred via the VFC for suspected scaphoid fractures at a local trauma unit over 19 months. Patients received an "appointment" in VFC. Based on their notes and imaging, patients were referred to an outpatient clinic for repeat radiographs within two weeks (if initial radiographs demonstrated no fracture). Patients with unremarkable second x-rays were contacted and informed to mobilize and return if the pain persisted at four weeks. RESULTS: The pathway received 175 referrals; 114 male, 61 female, mean age 14 years, range 9-17) with 42 scaphoid fractures diagnosed, 35 (83.3%) on first x-ray, and 7 (16.7%) occult fractures. The pathway managed all patients as intended; 71 patients were seen face-to-face in the clinic due to age or pathology picked up on the first x-ray, and 104 required repeat radiographs. Following the second radiograph, 78 patients were discharged directly. Twenty-six patients required further review in a face-to-face clinic after their second radiograph. CONCLUSION: VFC appears to be a safe and efficient method of managing patients with suspected scaphoid fractures on short-term follow-up analysis. This cohort presents no 'missed' injuries and therefore appears safe compared to conventional treatment pathways.

Reducing Calf Mortality in Ethiopia.

Morbidity and mortality of young stock present economic and production challenges to livestock producers globally. In Ethiopia, calf morbidity and mortality rates, particularly due to diarrhea and respiratory disease, are high, limiting production, incomes, and the ability of farmers to improve their livelihoods. In this paper, we present findings from the combined experience of the Young Stock Mortality Reduction Consortium, which conducted epidemiological and intervention testing in calves across three production systems. This innovative alliance identified Cryptosporidium parvum and E. Coli K99 as the most common causes of diarrhea in pastoral and peri-urban calves; Strongyloides spp. as the most common fecal parasite in mixed crop-livestock and peri-urban calves; and bovine adenovirus, parainfluenza virus-3, and bovine respiratory syncytial virus as the most common respiratory pathogens in peri-urban calves. Furthermore, by improving producer knowledge with respect to fundamental livestock husbandry, feeding, housing, and neonatal care practices, calf mortality risk across production systems was reduced by 31.4 to 71.4% compared to baseline (between 10.5 and 32.1%), whereas risk of diarrhea was reduced by 52.6-75.3% (baseline between 11.4 and 30.4%) and risk of respiratory disease was reduced by 23.6-80.8% (baseline between 3.3 and 16.3%). These findings have informed scaling strategies and can potentially contribute to improved livestock productivity and human livelihoods in Ethiopia.

Serious adverse event rates and reoperation after arthroscopic shoulder surgery: population based cohort study.

OBJECTIVE: To provide clinicians and patients with accurate risk estimates of serious adverse events after common elective shoulder arthroscopic procedures, including reoperation within one year. DESIGN: Population based cohort study. SETTING: Hospital Episode Statistics for NHS England, including civil registration mortality data from the Office for National Statistics. PARTICIPANTS: 288 250 arthroscopic shoulder procedures performed in 261 248 patients aged ≥16 years between 1 April 2009 and 31 March 2017. Elective procedures were grouped into subacromial decompression, rotator cuff repair, acromioclavicular joint excision, glenohumeral stabilisation, and frozen shoulder release. MAIN OUTCOME MEASURES: The primary outcomes were rates of serious adverse events (mortality, pulmonary embolism, pneumonia, myocardial infarction, acute kidney injury, stroke, and urinary tract infection) requiring inpatient care within 90 days post-surgery. Secondary outcomes were specific adverse event rates at 90 days, and reoperations (including for deep infection) within one year. RESULTS: The overall rate of complications within 90 days after arthroscopic shoulder surgery (including reoperation) was low at 1.2% (95% confidence interval 1.2% to 1.3%), with one in 81 patients at risk, and varied according to type of procedure, from 0.6% (0.5% to 0.8%) for glenohumeral stabilisation to 1.7% (1.5% to 1.8%) for frozen shoulder release. After adjustment for age, comorbidities, and sex, no effect of procedure type was observed. Pneumonia was the most common adverse event (0.3%, 0.3% to 0.4%), with one in 303 patients at risk. Pulmonary embolic events were rare, at 0.1% (0.1% to 0.1%), with one in 1428 patients at risk. At one year, the overall rate for reoperation was 3.8% (3.8% to 3.9%), with one in 26 patients at risk, ranging from 2.7% (2.5% to 3.0%) for glenohumeral stabilisation to 5.7% (5.4% to 6.1%) for frozen shoulder release. The overall rate of further surgery for deep infection was low, at 0.1% (0.1% to 0.1%), with one in 1111 patients at risk, but was higher after rotator cuff repair (0.2%, 0.2% to 0.2%), with one in 526 patients at risk. Over the study period the number of arthroscopic shoulder procedures increased, except for subacromial decompression, which decreased. CONCLUSIONS: The findings of this study suggest that risks of serious adverse events associated with common shoulder arthroscopy procedures are low. Nevertheless, serious complications do occur, and include the risk of reoperation in one in 26 patients within one year. STUDY REGISTRATION: Clinical. TRIALS: gov NCT03573765.

Development and external validation of prediction models for adverse health outcomes in rheumatoid arthritis: A multinational real-world cohort analysis.

BACKGROUND: Identification of rheumatoid arthritis (RA) patients at high risk of adverse health outcomes remains a major challenge. We aimed to develop and validate prediction models for a variety of adverse health outcomes in RA patients initiating first-line methotrexate (MTX) monotherapy. METHODS: Data from 15 claims and electronic health record databases across 9 countries were used. Models were developed and internally validated on Optum® De-identified Clinformatics® Data Mart Database using L1-regularized logistic regression to estimate the risk of adverse health outcomes within 3 months (leukopenia, pancytopenia, infection), 2 years (myocardial infarction (MI) and stroke), and 5 years (cancers [colorectal, breast, uterine] after treatment initiation. Candidate predictors included demographic variables and past medical history. Models were externally validated on all other databases. Performance was assessed using the area under the receiver operator characteristic curve (AUC) and calibration plots. FINDINGS: Models were developed and internally validated on 21,547 RA patients and externally validated on 131,928 RA patients. Models for serious infection (AUC: internal 0.74, external ranging from 0.62 to 0.83), MI (AUC: internal 0.76, external ranging from 0.56 to 0.82), and stroke (AUC: internal 0.77, external ranging from 0.63 to 0.95), showed good discrimination and adequate calibration. Models for the other outcomes showed modest internal discrimination (AUC < 0.65) and were not externally validated. INTERPRETATION: We developed and validated prediction models for a variety of adverse health outcomes in RA patients initiating first-line MTX monotherapy. Final models for serious infection, MI, and stroke demonstrated good performance across multiple databases and can be studied for clinical use. FUNDING: This activity under the European Health Data & Evidence Network (EHDEN) has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806968. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Coronavirus and Paramyxovirus Shedding by Bats in a Cave and Buildings in Ethiopia.

Bats are important hosts of zoonotic viruses with pandemic potential, including filoviruses, MERS-Coronavirus (CoV), SARS-CoV -1, and likely SARS-CoV-2. Viral infection and transmission among wildlife are dependent on a combination of factors that include host ecology and immunology, life history traits, roosting habitats, biogeography, and external stressors. Between 2016 and 2018, four species of insectivorous bats from a readily accessed roadside cave and buildings in Ethiopia were sampled and tested for viruses using consensus PCR assays for five viral families/genera. Previously identified and novel coronaviruses and paramyxoviruses were identified in 99 of the 589 sampled bats. Bats sampled from the cave site were more likely to test positive for a CoV than bats sampled from buildings; viral shedding was more common in the wet season; and rectal swabs were the most common sample type to test positive. A previously undescribed alphacoronavirus was detected in two bat species from different taxonomic families, sampling interfaces, geographic locations, and years. These findings expand knowledge of the range and diversity of coronaviruses and paramyxoviruses in insectivorous bats in Ethiopia and reinforce that an improved understanding of viral diversity and species-specific shedding dynamics is important for designing informed zoonotic disease surveillance and spillover risk reduction efforts.

Outcome measurement in adult flexor tendon injury: A systematic review.

BACKGROUND: Defining the optimal, evidence-based management of flexor tendon injury remains challenging. Lack of consensus on which measures to use to assess the outcome of interventions is a key issue, especially with regard to patient-reported outcome measures (PROMs). This systematic review defines the landscape of outcome measurement in studies on interventions for flexor tendon injuries to guide future research. METHODS: A PRISMA-compliant systematic review was conducted using bespoke search strategies applied to MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL and AMED. A protocol was developed and registered prospectively (CRD42020186780). We identified all studies describing adult patients undergoing interventions for acute hand flexor tendon injuries. RESULTS: Of the 4844 studies, 114 studies met the final inclusion criteria for evaluating the outcomes of 8127 participants with 9071 injured digits. Studies included 24 randomised controlled trials, 19 cohort studies and 61 case series. Nine different PROMs were used in 24 studies (22%): three site-specific PROMs, one generic quality-of-life measure and four visual analogue scales. Clinician-reported outcome measures were used in 103 studies (96%), such as the range of motion reported in 102 studies (94%). Adverse outcomes were reported in 96 studies (89%), with the most frequently reported adverse outcomes being tendon rupture and infection. Re-operation was reported in 21 studies (19%). The most frequently reported health economic outcome measure was the length of work absence, reported in ten studies (9%). CONCLUSIONS: There is variability in the use of outcome measures used to study interventions for flexor tendon injuries. An independent systematic review of the psychometric properties of the identified outcome measures and a specific multi-stakeholder consensus process may support optimal choice and standardisation for future studies.

The association of bariatric surgery and Dupuytren's disease: a propensity score-matched cohort study.

We aimed to assess the association between bariatric surgery and incident Dupuytren's disease (DD) using propensity score-matched cohort studies among Swedish nationwide healthcare registries. Patients aged 30-79 years who underwent bariatric surgery 2006-2019 were matched on their propensity scores, up to two obese bariatric surgery-free (unexposed) patients. We applied Cox proportional hazard regression to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the risk of DD overall, in subgroups of age, sex, bariatric surgery type and duration of follow-up. Among 34,959 bariatric surgery patients and 54,769 propensity score-matched obese patients, the risk of DD was increased in bariatric surgery patients compared with obese unexposed patients (HR 1.30, 95% CI 1.02-1.65), among women (HR 1.36; 1.00-1.84); those undergoing gastric bypass (HR 1.33; 1.04-1.71) and those with >5 years follow-up (HR 1.63; 1.14-2.34). Our results suggest that substantial weight loss is associated with an increased risk of DD in an obese population.Level of evidence: III.

Variation in patient information and rehabilitation regimens after flexor tendon repair in the United Kingdom.

Introduction: There is clinical uncertainty regarding the optimal method of rehabilitation following flexor tendon repair. Many splint designs and rehabilitation regimens are reported in the literature; however, there is insufficient evidence to support the use of any one regimen. The aim of this study was to describe rehabilitation guidelines used in the United Kingdom (UK) following zone I/II flexor tendon repair. Methods: Using a cross-sectional design, hand units in the UK were invited to complete a short survey and to upload their flexor tendon rehabilitation guidelines and patient information material. Approval was granted by the British Association of Hand Therapists. Data were extracted in duplicate, using a pre-piloted form, and analysed using descriptive statistics. Results: Thirty-five hand units responded (21%), providing 52 treatment guidelines. Three splinting regimens were described, and all involved early active mobilisation: (i) long dorsal-blocking splint (DBS); (ii) short DBS; and (iii) relative motion flexion splint. Duration of full-time splint wear ranged from 4 to 6 weeks. There were variations in splint design and composition of home exercise programmes, particularly for the long DBS. Where reported, recommended return to driving ranged from 8 to 12 weeks, and return to light work activities ranged from 5 to 10 weeks. Discussion: Treatment guidelines varied across UK hand therapy departments, suggesting that patients receive differing advice about how to protect, move and use their hand after zone I/II flexor tendon repair. The disparity in splint wear duration, home exercise frequency and prescribed functional restrictions raises potential financial and social implications for patients. Future research should explore rehabilitation burden in addition to clinical outcomes.