Search

Balance is paramount to safe and successful cycling, both in competition and recreation. Balance has been investigated in the return-to-cycling context, but its relationship to cycling performance is unknown. Our study aimed to analyse the relationship between balance, measured by common clinical balance tests, and cycling performance. Seven competitive cyclists participated in this cross-sectional correlational study. We collected field-based measures of cycling performance, including mean velocity, minimum and maximum velocity, mean corner speed, average lap time, and lean angle. Also, we measured balance via the balance error scoring system, the star excursion balance test, the lateral reach test, and the modified Bass test of dynamic balance. Strong correlations between cornering performance and cycling performance (r = 0.65–0.87, p < 0.01) were detected. Weak correlations between clinical balance tests and cycling performance (r = 0.33–0.53, p < 0.05) were observed. In conclusion, our study showed that improving cornering performance has the potential to improve overall cycling performance. We also found no clear correlations between our clinical balance tests and cycling performance. These weak correlations between postural control in standing and cycling performance suggest that standing balance and balancing during cycling are distinct motor control processes.

Abstract Up to 25% of the US population harbor Clostridioides difficile in the gut. Following antibiotic disruption of the gut microbiota, C. difficile can act as an opportunistic pathogen and induce potentially lethal infections. Consequently, reducing the colonization of C. difficile in at-risk populations is warranted, prompting us to identify and characterize a probiotic candidate specifically targeting C. difficile colonization. We identified Bacillus velezensis DSM 33864 as a promising strain to reduce C. difficile levels in vitro. We further investigated the effects of B. velezensis DSM 33864 in an assay including human fecal medium and in healthy or clindamycin-treated mouse models of C. difficile colonization. The addition of B. velezensis DSM 33864 to human fecal samples was shown to reduce the colonization of C. difficile in vitro. This was supported in vivo where orally administered B. velezensis DSM 33864 spores reduced C. difficile levels in clindamycin-treated mice. The commensal microbiota composition or post-antibiotic reconstitution was not impacted by B. velezensis DSM 33864 in human fecal samples, short-, or long-term administration in mice. In conclusion, oral administration of B. velezensis DSM 33864 specifically reduced C. difficile colonization in vitro and in vivo without adversely impacting the commensal gut microbiota composition.

Abstract It is challenging to regenerate periodontal tissues fully. We have previously reported a heparan sulfate variant with enhanced affinity for bone morphogenetic protein-2, termed HS3, that enhanced periodontal tissue regeneration in a rodent model. Here we seek to transition this work closer to the clinic and investigate the efficacy of the combination HS3 collagen device in a non-human primate (NHP) periodontitis model. Wire-induced periodontitis was generated in ten Macaca fascicularis, and defects were treated with Emdogain or collagen (CollaPlug) loaded with (1) distilled water, (2) HS low (36 µg of HS3), or (3) HS high (180 µg of HS3) for 3 months. At the endpoint, microscopic assessment showed significantly less epithelial down-growth, greater alveolar bone filling, and enhanced cementum and periodontal ligament regeneration following treatment with the HS-collagen combination devices. When evaluated using a periodontal regeneration assessment score (PRAS) on a scale of 0–16, collagen scored 6.78 (± 2.64), Emdogain scored 10.50 (± 1.73) and HS low scored 10.40 (± 1.82). Notably, treatment with HS high scored 12.27 (± 2.20), while healthy control scored 14.80 (± 1.15). This study highlights the efficacy of an HS-collagen device for periodontal regeneration in a clinically relevant NHP periodontitis model and warrants its application in clinical trials.

Abstract Background Spatiotemporal heterogeneity originating from genomic and transcriptional variation was found to contribute to subtype switching in isocitrate dehydrogenase-1 wild-type glioblastoma (GBM) prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) enables intraoperative visualization of infiltrative tumors outside the magnetic resonance imaging contrast-enhanced regions. The cell population and functional status of tumor responsible for enhancing 5ALA-metabolism to fluorescence-active PpIX remain elusive. The close spatial proximity of 5ALA-metabolizing (5ALA +) cells to residual disease remaining post-surgery renders 5ALA + biology an early a priori proxy of GBM recurrence, which is poorly understood. Methods We performed spatially resolved bulk RNA profiling (SPRP) analysis of unsorted Core, Rim, Invasive margin tissue, and FACS-isolated 5ALA + /5ALA − cells from the invasive margin across IDH-wt GBM patients (N = 10) coupled with histological, radiographic, and two-photon excitation fluorescence microscopic analyses. Deconvolution of SPRP followed by functional analyses was performed using CIBERSORTx and UCell enrichment algorithms, respectively. We further investigated the spatial architecture of 5ALA + enriched regions by analyzing spatial transcriptomics from an independent IDH-wt GBM cohort (N = 16). Lastly, we performed survival analysis using Cox Proportinal-Hazards model on large GBM cohorts. Results SPRP analysis integrated with single-cell and spatial transcriptomics uncovered that the GBM molecular subtype heterogeneity is likely to manifest regionally in a cell-type-specific manner. Infiltrative 5ALA + cell population(s) harboring transcriptionally concordant GBM and myeloid cells with mesenchymal subtype, -active wound response, and glycolytic metabolic signature, was shown to reside within the invasive margin spatially distinct from the tumor core. The spatial co-localization of the infiltrating MES GBM and myeloid cells within the 5ALA + region indicates PpIX fluorescence can effectively be utilized to resect the immune reactive zone beyond the tumor core. Finally, 5ALA + gene signatures were associated with poor survival and recurrence in GBM, signifying that the transition from primary to recurrent GBM is not discrete but rather a continuum whereby primary infiltrative 5ALA + remnant tumor cells more closely resemble the eventual recurrent GBM. Conclusions Elucidating the unique molecular and cellular features of the 5ALA + population within tumor invasive margin opens up unique possibilities to develop more effective treatments to delay or block GBM recurrence, and warrants commencement of such treatments as early as possible post-surgical resection of the primary neoplasm.

Abstract Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Many screens have been conducted to find inhibitors for the Hedgehog signaling pathway – a developmental pathway with many implications in health and disease – yielding many hits but only few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We develop a PROTAC based on Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using this Hedgehog Pathway PROTAC (HPP) we identify and validate BET bromodomains as the cellular targets of HPI-1. Furthermore, we find that HPP-9 is a long-acting Hedgehog pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that answers the longstanding question of the cellular target of HPI-1 and yields a PROTAC that acts on the Hedgehog pathway.

In 2008, bacilli from 2 Hansen disease (leprosy) cases were identified as a new species, Mycobacterium lepromatosis. We conducted a systematic review of studies investigating M. lepromatosis as a cause of HD. Twenty-one case reports described 27 patients with PCR–confirmed M. lepromatosis infection (6 dual M. leprae/M. lepromatosis): 10 case-patients in the United States (7 originally from Mexico), 6 in Mexico, 3 in the Dominican Republic, 2 each in Singapore and Myanmar, and 1 each in Indonesia, Paraguay, Cuba, and Canada. Twelve specimen surveys reported 1,098 PCR–positive findings from 1,428 specimens, including M. lepromatosis in 44.9% (133/296) from Mexico, 3.8% (5/133) in Colombia, 12.5% (10/80) in Brazil, and 0.9% (2/224) from the Asia-Pacific region. Biases toward investigating M. lepromatosis as an agent in cases of diffuse lepromatous leprosy or from Mesoamerica precluded conclusions about clinicopathologic manifestations and geographic distribution. Current multidrug treatments seem effective for this infection.

Background: The Western Cape province in South Africa has a high age-standardised mortality from cancer. Most literature reports significantly poorer access to healthcare, more advanced cancers and worse survival for rural and remote populations. This study investigates if significant disparities exist with regard to stage at presentation and overall survival of patients with head and neck cancer (HNC) between geographical areas within the Western Cape province in South Africa. Methods: A retrospective chart review was conducted on all patients managed at the Combined ENT Head and Neck Oncology clinic at Groote Schuur from January 2010 to December 2014. Ethics approval was granted by the University of Cape Town Human Research Ethics Committee (HREC, 351-2017). Results: Although we observed no significant difference in TNM clinical stages or overall survival between metropolitan and remote patients, there were statistically and clinically significant differences in terms of both stages of HNC and overall survival between some individual metropolitan and remote areas. The remote area of Eden had a median overall survival of more than 6 months less than that of the Southern subdistrict of the City of Cape Town. Conclusion: Differences in HNC stages and overall survivals between some subdistricts of the City of Cape Town and remote areas are not only statistically significant but also clinically relevant. Contribution: This article highlights the need to improve on diagnostic and referral pathways for management of patients with HNC in the Western Cape.

The mechanisms driving dynamics of many epidemiologically important mosquito-borne pathogens are complex, involving combinations of vector and host factors (e.g., species composition and life-history traits), and factors associated with transmission and reporting. Understanding which intrinsic mechanisms contribute most to observed disease dynamics is important, yet often poorly understood. Ross River virus (RRV) is Australia's most important mosquito-borne disease, with variable transmission dynamics across geographic regions. We used deterministic ordinary differential equation models to test mechanisms driving RRV dynamics across major epidemic centers in Brisbane, Darwin, Mandurah, Mildura, Gippsland, Renmark, Murray Bridge, and Coorong. We considered models with up to two vector species (Aedes vigilax, Culex annulirostris, Aedes camptorhynchus, Culex globocoxitus), two reservoir hosts (macropods, possums), seasonal transmission effects, and transmission parameters. We fit models against long-term RRV surveillance data (1991-2017) and used Akaike Information Criterion to select important mechanisms. The combination of two vector species, two reservoir hosts, and seasonal transmission effects explained RRV dynamics best across sites. Estimated vector-human transmission rate (average β = 8.04x10-4per vector per day) was similar despite different dynamics. Models estimate 43% underreporting of RRV infections. Findings enhance understanding of RRV transmission mechanisms, provide disease parameter estimates which can be used to guide future research into public health improvements and offer a basis to evaluate mitigation practices.

The fundus is unique in that it is the only part of the body that allows for a noninvasive and uninterrupted view of vasculature and nervous tissue. Utilization of this can be a powerful tool in uncovering salient incidental findings which point to underlying systemic diseases, and for monitoring response to therapy. Retinal venules and arterioles allow the clinician to assess changes in vascular color, diameter, outline, and tortuosity. The retina and optic nerve may exhibit changes associated with increased or decreased thickness, inflammatory infiltrates, hemorrhages, and detachments. While some retinal manifestations of systemic disease may be nonspecific, others are pathognomonic, and may be the presenting sign for a systemic illness. The examination of the fundus is an essential part of the comprehensive physical examination. Systemic diseases which may present with retinal abnormalities include a variety of disease classifications, as represented by the DAMNIT-V acronym, for Degenerative/Developmental, Anomalous, Metabolic, Neoplastic, Nutritional, Inflammatory (Infectious/Immune-mediated/ischemic), Toxic, Traumatic and Vascular. This review details systemic illnesses or syndromes that have been reported to manifest in the fundus of companion animals and discusses key aspects in differentiating their underlying cause. Normal variations in retinal anatomy and morphology are also considered.

[This corrects the article DOI: 10.1371/journal.pntd.0010696.].

Abstract Infection has emerged as the chief cause of non‐relapse mortality (NRM) post CD19‐targeting chimeric antigen receptor T‐cell therapy (CAR‐T) therapy. Even though up to 50% of patients may remain infection‐free, many suffer multiple severe, life‐threatening, or fatal infectious events. The primary aim of this study was to explore severe and life‐threatening infections post licensed CAR‐T therapy in large B‐cell lymphoma, with a focus on the role of disease burden and disease sites in assessing individual risk. We sought to understand the cohort of patients who experience ≥2 infections and those at the highest risk of infectious NRM. Our analysis identifies a higher disease burden after bridging therapy as associated with infection events. Those developing ≥2 infections emerged as a uniquely high‐risk cohort, particularly if the second (or beyond) infection occurred during an episode of immune effector cell‐associated neurotoxicity syndrome (ICANS) or while on steroids and/or anakinra for ICANS. Herein, we also describe the first reported cases of “CAR‐T cold sepsis,” a phenomenon characterized by the lack of an appreciable systemic inflammatory response at the time of detection of infection. We propose a risk‐based strategy to encourage heightened clinician awareness of cold sepsis, with a view to reducing NRM.

BackgroundA COVID-19 hospital guideline was implemented across all 18 acute hospitals in Wales in March 2020, promoting ward management of COVID pneumonitis and data collected across the first 3 Waves of the pandemic (Wave 1 March 1st 2020 to November 1st 2020, Wave 2 November 2st 2020 to February 21st 2021 and Wave 3 June 1st 2021 to December 14th 2021). The aim of this paper is to compare outcomes for patients by admission setting and type of ventilatory support given, with a particular focus on CPAP therapy.MethodsThis is a retrospective observational study of those aged over 18 admitted to hospital with community acquired COVID-19 between March 2020 and December 2021. The outcome of interest was in-hospital mortality. Univariate logistic regression models were used to compare crude outcomes across the waves. Multivariable logistic regression models were used to assess outcomes by different settings and treatments after adjusting for Wave, age, sex, co-morbidity and deprivation.ResultsOf the 7,803 records collected, 5,887 (75.4%) met the inclusion criteria. Analysis of those cases identified statistically significant outcome improvements across the waves for all patients combined (Waves 1 to 3: 31.5% to 18.8%, pConclusionsThere were successive reductions in mortality in inpatients over the three Waves reflecting new treatments and better management of complications. Mortality for those requiring CPAP was similar in respiratory wards and ICUs after adjusting for differences in their respective patient populations.

IntroductionDue to hypoxic vasoconstriction, perfusion is interesting in the lungs. Magnetic Resonance Imaging (MRI) perfusion imaging based on Dynamic Contrast Enhancement (DCE) has been demonstrated in patients with Chronic Obstructive Pulmonary Diseases (COPD) using visual scores, and quantification methods were recently developed further. Inter-patient correlations of echo time-dependent observed T1 [T1(TE)] have been shown with perfusion scores, pulmonary function testing, and quantitative computed tomography. Here, we examined T1(TE) quantification and quantitative perfusion MRI together and investigated both inter-patient and local correlations between T1(TE) and quantitative perfusion.Methods22 patients (age 68.0 ± 6.2) with COPD were examined using morphological MRI, inversion recovery multi-echo 2D ultra-short TE (UTE) in 1–2 slices for T1(TE) mapping, and 4D Time-resolved angiography With Stochastic Trajectories (TWIST) for DCE. T1(TE) maps were calculated from 2D UTE at five TEs from 70 to 2,300 μs. Pulmonary Blood Flow (PBF) and perfusion defect (QDP) maps were produced from DCE measurements. Lungs were automatically segmented on UTE images and morphological MRI and these segmentations registered to DCE images. DCE images were separately registered to UTE in corresponding slices and divided into corresponding subdivisions. Spearman’s correlation coefficients were calculated for inter-patient correlations using the entire segmented slices and for local correlations separately using registered images and subdivisions for each TE. Median T1(TE) in normal and defect areas according to QDP maps were compared.ResultsInter-patient correlations were strongest on average at TE2 = 500 μs, reaching up to |ρ| = 0.64 for T1 with PBF and |ρ| = 0.76 with QDP. Generally, local correlations of T1 with PBF were weaker at TE2 than at TE1 or TE3 and with maximum values of |ρ| = 0.66 (from registration) and |ρ| = 0.69 (from subdivision). In 18 patients, T1 was shorter in defect areas than in normal areas, with the relative difference smallest at TE2.DiscussionThe inter-patient correlations of T1 with PBF and QDP found show similar strength and TE-dependence as those previously reported for visual perfusion scores and quantitative computed tomography. The local correlations and median T1 suggest that not only base T1 but also the TE-dependence of observed T1 in normal areas is closer to that found previously in healthy volunteers than in defect areas.

Abstract Hells Bells are underwater secondary carbonates discovered in sinkholes (cenotes) southeast of Cancun on the north-eastern Yucatán peninsula, Mexico. These authigenic calcite precipitates, reaching a length of up to 4 m, most likely grow in the pelagic redoxcline. Here we report on detailed 230Th/U-dating and in-depth geochemical and stable isotope analyses of specimens from cenotes El Zapote, Maravilla and Tortugas. Hells Bells developed since at least ~ 8000 years ago, with active growth until present day. Initial (234U/238U) activity ratios (δ234U0) in Hells Bells calcite decreas from 55 to 15‰ as sea level converges toward its present state. The temporal evolution of the geochemistry and isotope composition of Hells Bells calcites thus appears to be closely linked to sea-level rise and reflects changing hydrological conditions (desalinization) of the aquifer. We suggest that decelerated leaching of excess 234U from the previously unsaturated bedrock traces Holocene relative sea-level rise. Considering this proxy, the resulting mean sea-level reconstruction contains half as much scatter, i.e. improves by a factor of two, when compared to previously published work for the period between 8 and 4 ky BP.

Abstract Background Impaired muscle function has been identified as a risk factor for declining cognitive function and cardiovascular health, both of which are risk factors for late‐life dementia (after 80 years of age). We examined whether hand grip strength and timed‐up‐and‐go (TUG) performance, including their change over 5 years, were associated with late‐life dementia events in older women and whether any associations provided independent information to Apolipoprotein E ℇ4 (APOE ℇ4) genotype. Methods Grip strength and TUG were assessed in community‐dwelling older women (mean ± SD; age 75.0 ± 2.6 years) at baseline (n = 1225) and 5 years (n = 1052). Incident 14.5‐year late‐life dementia events (dementia‐related hospitalization/death) were obtained from linked health records. Cardiovascular risk factors (Framingham Risk Score), APOE genotyping, prevalent atherosclerotic vascular disease and cardiovascular‐related medications were evaluated at baseline. These were included in multivariable‐adjusted Cox‐proportional hazards models assessing the relationship between muscle function measures and late‐life‐dementia events. Results Over follow‐up, 207 (16.9%) women had a late‐life dementia event. Compared with women with the highest grip strength (Quartile [Q] 4, 25.8 kg), those with the lowest grip strength (Q1, 16.0 kg) had greater hazard for a late‐life dementia event (HR 2.27 95% CI 1.54–3.35, P 10.2 s) provided independent information to the presence of an APOE ℇ4 allele (n = 280, 22.9%). Compared with women with no weakness and no APOE ℇ4 allele, those with weakness and APOE ℇ4 allele had a greater hazard (HR 3.19 95% CI 2.09–4.88, P

Abstract Introduction The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. Methods The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. Results Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. Conclusion We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. Trial registration BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

Abstract Introduction The use of faecal microbiota transplantation (FMT) to eradicate intestinal carriage of multidrug-resistant organisms (MDRO) has been described in case reports and small case series. Although few in numbers, these patients suffer from recurrent infections that may exacerbate both the patients’ comorbidities and their healths. In the current study, we hypothesized that FMT for MDRO-related urinary tract infections (UTIs) reduces hospitalisations and associated costs. Methods In a cohort of patients referred for FMT from 2015 to 2020, we selected all patients who had consecutively been referred for eradication of MRDO carriage with UTIs. An early economic assessment was performed to calculate hospital-related costs. The overall study cohort was registered at ClinicalTrials, study identifier NCT03712722. Results We consecutively included five patients with UTIs caused by MDROs. Four of the patients were renal transplant recipients. Patients were followed for median 126 days (range 60–320), where the follow-up duration for each patient was aligned with the number of days from the first UTI to FMT. The median number of UTIs per patient dropped from 4 to 0. Investigating hospital costs, hospital admission days dropped by 87% and monthly hospital costs by 79%. Conclusions FMT was effective in reducing the occurrence of UTIs and mediated a marked reduction in hospital costs. We suggest that this strategy is cost-effective. Trial Registration ClinicalTrials, study identifier NCT03712722. Graphical Abstract

Abstract Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10–09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10–10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10–09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10–08, MAF = 0.006, sex-interaction P = 9.8 × 10–07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10–08, MAF = 0.004, sex-interaction P = 1.3 × 10–03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

‘The induction and coordination of immune cells in response to SARS-CoV-2 infection are critical in the immunopathology of COVID-19. Here the authors use a rhesus macaque model of SARS-CoV-2 infection and show key populations of macrophage drive the inflammatory cytokine production in the alveolar space’.

Dengue virus (DENV) is a continuing global threat that puts half of the world’s population at risk for infection. This mosquito-transmitted virus is endemic in over 100 countries. When a mosquito takes a bloodmeal, virus is deposited into the epidermal and dermal layers of human skin, infecting a variety of permissive cells, including keratinocytes, Langerhans cells, macrophages, dermal dendritic cells, fibroblasts, and mast cells. In response to infection, the skin deploys an array of defense mechanisms to inhibit viral replication and prevent dissemination. Antimicrobial peptides, pattern recognition receptors, and cytokines induce a signaling cascade to increase transcription and translation of pro-inflammatory and antiviral genes. Paradoxically, this inflammatory environment recruits skin-resident mononuclear cells that become infected and migrate out of the skin, spreading virus throughout the host. The details of the viral–host interactions in the cutaneous microenvironment remain unclear, partly due to the limited body of research focusing on DENV in human skin. This review will summarize the functional role of human skin, the cutaneous innate immune response to DENV, the contribution of the arthropod vector, and the models used to study DENV interactions in the cutaneous environment.

IntroductionPlant species often exhibit significant variation in functional traits in populations along elevational gradients to cope with varying stress conditions. While plant development has been assumed to be most limited by a single resource, growing evidence suggests the potential for interactions of co-limiting resources to impact plant performance. Here, we aimed to determine how light, nitrogen, and water availability influence the growth and physiology of different populations of koa (Acacia koa), a tree species of concern that occurs across a large elevational gradient in tropical Hawaii, United States.MethodsPopulations from three seed sources [low (L), mid (M), and high (H) elevation] were grown in a controlled greenhouse experiment and exposed to co-limiting light, water, and nutrient (nitrogen) conditions. Light response, gas exchange, water status, resource use efficiency, nutrients and shoot non-structural carbohydrate concentrations, and growth and biomass allocation responses were quantified.ResultsWe found that resource co-limitation sometimes interacted to determine responses of the measured parameters. In general, the low elevation (L) koa population was more sensitive to conditions where both moisture and nutrients were limiting, while the high elevation (H) koa population was more sensitive to conditions where either light and moisture or light and nitrogen were co-limiting. The M population performed well overall regardless of resource limitation.DiscussionOur findings lend support to the theory that multiple resources limit growth and physiology of populations rather than the traditional view of a single resource limiting performance. Therefore, the possibility that multiple resource limitations drive population differences should be considered when developing population-based guidelines for forest and tree species restoration.

BackgroundEngaging men in psychotherapy is essential in male suicide prevention efforts, yet to date, efforts to upskill mental health practitioners in delivering gender-sensitized therapy for men have been lacking. To address this, we developed Men in Mind, an e-learning training program designed to upskill mental health practitioners in engaging men in therapy. ObjectiveThis study involves an in-depth analysis of the user experience of the Men in Mind intervention, assessed as part of a randomized controlled trial of the efficacy of the intervention. MethodsFollowing completion of the intervention, participants provided qualitative (n=392) and quantitative (n=395) user experience feedback, focused on successes and suggested improvements to the intervention and improvements to their confidence in delivering therapy with specific subpopulations of male clients. We also assessed practitioner learning goals (n=242) and explored the extent to which participants had achieved these goals at follow-up. ResultsParticipants valued the inclusion of video demonstrations of skills in action alongside the range of evidence-based content dedicated to improving their insight into the engagement of men in therapy. Suggested improvements most commonly reflected the desire for more or more diverse content, alongside the necessary adaptations to improve the learning and user experience. Participants also commonly reported improved confidence in assisting men with difficulty articulating their emotions in therapy and suicidal men. ConclusionsThe evidence obtained from this study aids in plans to scale Men in Mind and informs the future development of practitioner training interventions in men’s mental health. International Registered Report Identifier (IRRID)RR2-10.1186/s40359-022-00875-9

Tuberculosis remains a major health threat globally and a more effective vaccine than the current Bacillus Calmette Guerin (BCG) is required, either to replace or boost it. The Spore-FP1 mucosal vaccine candidate is based on the fusion protein of Ag85B-Acr-HBHA/heparin-binding domain, adsorbed on the surface of inactivated Bacillus subtilis spores. The candidate conferred significant protection against Mycobacterium. tuberculosis challenge in naïve guinea pigs and markedly improved protection in the lungs and spleens of animals primed with BCG. We then immunized rhesus macaques with BCG intradermally, and subsequently boosted with one intradermal and one aerosol dose of Spore-FP1, prior to challenge with low dose aerosolized M. tuberculosis Erdman strain. Following vaccination, animals did not show any adverse reactions and displayed higher antigen specific cellular and antibody immune responses compared to BCG alone but this did not translate into significant improvement in disease pathology or bacterial burden in the organs.

Summary: Highly pathogenic avian influenza A H5N1 viruses cause high mortality in humans and have pandemic potential. Effective vaccines and treatments against this threat are urgently needed. Here, we have refined our previously established model of lethal H5N1 infection in cynomolgus macaques. An inhaled aerosol virus dose of 5.1 log10 plaque-forming unit (pfu) induced a strong febrile response and acute respiratory disease, with four out of six macaques succumbing after challenge. Vaccination with three doses of adjuvanted seasonal quadrivalent influenza vaccine elicited low but detectable neutralizing antibody to H5N1. All six vaccinated macaques survived four times the 50% lethal dose of aerosolized H5N1, while four of six unvaccinated controls succumbed to disease. Although vaccination did not protect against severe influenza, vaccinees had reduced respiratory dysfunction and lower viral load in airways compared to controls. We anticipate that our macaque model will play a vital role in evaluating vaccines and antivirals against influenza pandemics.

Background: Women treated for cervical precancerous lesions have up to a 30 % increased risk of developing cervical cancer compared to women in the general population. The aim of this study was to identify predictors for adherence to follow-up among women treated for precancerous lesions of the cervix in Cameroon. Materials and Methods: The study design was a retrospective cohort analysis of a five-year follow-up for women in Cameroon who were initially treated for cervical precancer lesions in 2013. Logistic regression models were used to determine factors associated with adherence to post-treatment follow-up. Statistical significance was set at p

Abstract Background Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. Methods Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. Results In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. Conclusions These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

Metal–organic frameworks have demonstrated promise for the storage and release of biologically active gases. Here, an in situ single crystal X-ray diffraction study using synchrotron radiation elucidates the binding mechanisms and geometries of nitric oxide and carbon monoxide gases in activated frameworks Ni-CPO-27 and Co-4,6-dihydroxyisophthalate.

The brain-expressed receptor GPR10 is involved in energy homeostasis in mice. Here the authors identify rare loss of function variants in GPR10 in people with severe obesity and showed that one of these variants causes obesity when modelled in mice, suggesting that future studies could explore GPR10 as a potential target for weight-loss therapy.

Long noncoding RNA molecules are RNA transcripts long thought to remain untranslated. In this study, the authors demonstrate that certain lncRNA can be translated into peptides that are immunogenic to CD8+ T cells and promote anti-tumour responses when delivered as vaccine vectors in mice.

The genetic basis of primary sclerosing cholangitis has only been partially uncovered. Here, the authors perform a multitrait genome-wide association study to provide insight into the genetic etiology of primary sclerosing cholangitis risk and possible therapeutic drug targets.

Implementing online learning in a higher education environment requires an analysis of learning outcomes and their impact on students, lecturers, and the institutions that administer the learning. The implementation of online learning shows that the learning process takes place and the readiness of lecturers and students to implement online learning. The impact given by online learning is in the form of GPA and student perceptions of the learning process they experience. Based on the research results, various findings were obtained, including that mastery of online learning LMS was not optimal, learning outcomes in the form of GPA were relatively high, students' perceptions of online learning were still low, especially in terms of lecturer readiness and students' confidence in their competence after participating in learning.

The production of ribosomes is a precisely orchestrated energy consuming cellular process of highest priority. Here, the authors use cryo-EM to show that bacterial ribosomal subunits, self-assembled from their purified RNA and protein components, mature along parallel pathways.

Globally, major efforts are being made to restore peatlands to maximise their resilience to anthropogenic climate change, which puts continuous pressure on peatland ecosystems and modifies the geography of the environmental envelope that underpins peatland functioning. A probable effect of climate change is reduction in the waterlogged conditions that are key to peatland formation and continued accumulation of carbon (C) in peat. C sequestration in peatlands arises from a delicate imbalance between primary production and decomposition, and microbial processes are potentially pivotal in regulating feedbacks between environmental change and the peatland C cycle. Increased soil temperature, caused by climate warming or disturbance of the natural vegetation cover and drainage, may result in reductions of long-term C storage via changes in microbial community composition and metabolic rates. Moreover, changes in water table depth alter the redox state and hence have broad consequences for microbial functions, including effects on fungal and bacterial communities especially methanogens and methanotrophs. This article is a perspective review of the effects of climate change and ecosystem restoration on peatland microbial communities and the implications for C sequestration and climate regulation. It is authored by peatland scientists, microbial ecologists, land managers and non-governmental organisations who were attendees at a series of three workshops held at The University of Manchester (UK) in 2019–2020. Our review suggests that the increase in methane flux sometimes observed when water tables are restored is predicated on the availability of labile carbon from vegetation and the absence of alternative terminal electron acceptors. Peatland microbial communities respond relatively rapidly to shifts in vegetation induced by climate change and subsequent changes in the quantity and quality of below-ground C substrate inputs. Other consequences of climate change that affect peatland microbial communities and C cycling include alterations in snow cover and permafrost thaw. In the face of rapid climate change, restoration of a resilient microbiome is essential to sustaining the climate regulation functions of peatland systems. Technological developments enabling faster characterisation of microbial communities and functions support progress towards this goal, which will require a strongly interdisciplinary approach.

Abstract Background Men account for three-quarters of all suicide deaths in many Western nations including Australia. Whilst extensive research has examined risk factors for suicidal ideation and behaviour in men, protective factors remain underexplored, particularly social support, resilience and coping behaviours. Such factors are important to examine particularly in the context of COVID-19, where enforced isolation (among other negative lifestyle effects) has created widespread risk for the development of suicidal ideation. This mixed-methods study aimed to examine associations of various protective factors with suicidal ideation in men, using data from an online survey conducted during the COVID-19 pandemic. In addition, we aimed to qualitatively investigate men’s self-reported protective strategies when experiencing suicidal thoughts and behaviour. Methods A convenience sample of 700 men (age M = 50.3 years; SD = 15.2 years) responded to an online survey including quantitative measures of suicidal ideation, planning and attempt, alongside employment and relationship status, coping, social support, resilience, and a qualitative free-text item gauging men’s self-reported protective strategies. Multinomial logistic regression was applied to compare odds of sub-categories of suicide risk (ideation; planning) according to protective factors. Qualitative responses were analysed via thematic analysis. Results Men in a relationship, and those lower in emotion-focused and avoidant coping reported lower odds of suicidal ideation. Maintaining employment throughout the pandemic was protective against suicidal ideation and planning; as was greater perceived social support from friends. Greater self-reported resilience was protective against suicidal ideation and planning. Qualitative analyses led to the development of two themes: coping and connecting, reflecting men’s intra- and interpersonal management strategies; and sustaining selflessness, where men’s imaginings of the collateral damage of their suicidal behaviour was protective against action on suicidal thoughts or plans. Conclusions Findings of this study speak to the nuanced roles of interpersonal connections, resilience and coping behaviours in protecting against suicidal ideation and planning in men. In addition, qualitative insights further cement men’s identification with familial protector and/or provider roles as protective against suicidal action.

Abstract Background The On–Off, or long flash, full field electroretinogram (ERG) separates retinal responses to flash onset and offset. Depending on degree of dark-adaptation and stimulus strength the On and Off ERG can be shaped by rod and cone photoreceptors and postreceptoral cells, including ON and OFF bipolar cells. Interspecies differences have been shown, with predominantly positive Off-response in humans and other primates and a negative Off-response in rodents and dogs. However, the rod signaling pathways that contribute to these differential responses have not been characterized. In this study, we designed a long flash protocol in the dog that varied in background luminance and stimulus strength allowing for some rod components to be present to better characterize how rod pathways vary from scotopic to mesopic conditions. Results With low background light the rod a-wave remains while the b-wave is significantly reduced resulting in a predominantly negative waveform in mesopic conditions. Through modeling and subtraction of the rod-driven response, we show that rod bipolar cells saturate with dimmer backgrounds than rod photoreceptors, resulting in rod hyperpolarization contributing to a large underlying negativity with mesopic backgrounds. Conclusions Reduction in rod bipolar cell responses in mesopic conditions prior to suppression of rod photoreceptor responses may reflect the changes in signaling pathway of rod-driven responses needed to extend the range of lighting conditions over which the retina functions.

Abstract Background Malaria in western Kenya is currently characterized by sustained high Plasmodial transmission and infection resurgence, despite positive responses in some areas following intensified malaria control interventions since 2006. This study aimed to evaluate long-term changes in malaria transmission profiles and to assess patterns of asymptomatic malaria infections in school children aged 5–15 years at three sites in western Kenya with heterogeneous malaria transmission and simultaneous malaria control interventions. Methods The study was conducted from 2018 to 2019 and is based on data taken every third year from 2005 to 2014 during a longitudinal parasitological and mosquito adult surveillance and malaria control programme that was initiated in 2002 in the villages of Kombewa, Iguhu, and Marani. Plasmodium spp. infections were determined using microscopy. Mosquito samples were identified to species and host blood meal source and sporozoite infections were assayed using polymerase chain reaction. Results Plasmodium falciparum was the only malaria parasite evaluated during this study (2018–2019). Asymptomatic malaria parasite prevalence in school children decreased in all sites from 2005 to 2008. However, since 2011, parasite prevalence has resurged by > 40% in Kombewa and Marani. Malaria vector densities showed similar reductions from 2005 to 2008 in all sites, rose steadily until 2014, and decreased again. Overall, Kombewa had a higher risk of infection compared to Iguhu (χ 2 = 552.52, df = 1, P

Photovoice offers creative participatory action methods for conveying community strengths and challenges with the goal of addressing health inequities. Accelerated by COVID-19 restrictions, photovoice has increasingly become virtual, and this shift has given rise to new considerations including navigating online recruitment and data collection, e-participatory action trends and working with multi-site large qualitative data sets. Within these contexts, the current article discusses the case for and against virtual photovoice, drawing from a large study comprising 110 men’s experiences of, and perspectives about, equitable and sustainable intimate partner relationships. The findings are shared across three themes. The first theme, e-Efficiencies and concessions contrasts increased recruitment reach and data collection cost-savings with vulnerabilities to phishing and challenges for working with participants’ wide-ranging internet literacies and practices. Theme two, Participatory action changed , chronicles the participants’ varied relationships to photography including sourcing third-party and archived photographs. Revealed also were privacy concerns whereby some participants opted for audio only interviews and/or restricted the use of their photographs. The third theme, Reckoning breadth and depth in a large dataset , discusses emergent study design considerations including analytics for interpreting and contextually representing large multi-site projects that are made possible through virtual photovoice. While technological advances and COVID-19 have forged photovoice virtually, the case for and against this trend reveals complex considerations that will likely manifest a continuum of approaches ranging virtual, hybrid and in-person models. In summary, we suggest that integral to weighing the case for and against virtual photovoice researchers will need to thoughtfully adapt to changing technologies, as well as potential post COVID-19 tilts for returning to in-person.

As interest in animal-assisted therapy (AAT) and canine-assisted psychotherapy (CAP) grows, there are increasing calls for the management of related health, safety, and welfare concerns for canines, providers, and clients. Existing health and safety guidelines lack empirical support and are, at times, contradictory. Welfare is increasingly prioritized; however, tools to monitor and manage welfare are underutilized and under-reported. The aim of this study was to provide expert consensus on the minimum health, safety, and welfare standards required to develop and deliver a CAP group program to adolescents experiencing common mental health disorders. Diverse AAT experts were recruited globally. Using Delphi methodology, over two rounds, 40 panelists reached a consensus agreement to include 32 items from a possible 49 into the minimum standards. Health and safety measures included risk assessment, veterinary screening, preventative medicine, training in infection control, and first aid. Welfare measures included training in welfare assessment, documentation of welfare, and flexible, individualized responses to promote wellbeing. Intestinal screening for parasites and the prohibition of raw food were not supported. Flexible and individualized assessment and management of canine welfare were supported over fixed and time-limited work schedules. Clinical practice implications are discussed, and recommendations are made.

The complexity and uncertainty of construction projects contribute to low efficiency in the construction industry. This research applied the Takt-time planning method to optimize the construction working process, and proposed a risk control framework based on Value at Risk (VaR) and Conditional Value at Risk (CVaR) approaches to explore and predict a project schedule and cost performance under different scenarios. This research selected a high-rise residential building project for a case study and collected 1672 productivity data samples. Arena Simulation models were established based on 90 combinations of labor assignments to assess Takt-time planning strategies’ impact on project performance in four scenarios. The VaR and CVaR evaluations at 75% and 90% confidence levels were compared to balance project benefits and risks. Without any overtime or additional workers, this research found a Takt-time planning method that can reduce the project duration by 20.2% and labor costs by 2.1% at the same time, using a labor assignment of 12 bar placers, 12 carpenters, and 5 pipefitters. The findings can assist construction managers to achieve a shorter duration, reduced cost, and safer work environment, which will be very effective and beneficial to improve project overall performance.

We report a theoretical study of dielectric properties of models of amorphous Boron Nitride, using interatomic potentials generated by machine learning. We first perform first-principles simulations on small (about 100 atoms in the periodic cell) sample sizes to explore the emergence of mid-gap states and its correlation with structural features. Next, by using a simplified tight-binding electronic model, we analyse the dielectric functions for complex three dimensional models (containing about 10.000 atoms) embedding varying concentrations of sp ^1 , sp ^2 and sp ^3 bonds between B and N atoms. Within the limits of these methodologies, the resulting value of the zero-frequency dielectric constant is shown to be influenced by the population density of such mid-gap states and their localization characteristics. We observe nontrivial correlations between the structure-induced electronic fluctuations and the resulting dielectric constant values. Our findings are however just a first step in the quest of accessing fully accurate dielectric properties of as-grown amorphous BN of relevance for interconnect technologies and beyond.

Abstract Subterranean habitats are generally very stable environments, and as such evolutionary transitions of organisms from surface to subterranean lifestyles may cause considerable shifts in physiology, particularly with respect to thermal tolerance. In this study we compared responses to heat shock at the molecular level in a geographically widespread, surface-dwelling water beetle to a congeneric subterranean species restricted to a single aquifer (Dytiscidae: Hydroporinae). The obligate subterranean beetle Paroster macrosturtensis is known to have a lower thermal tolerance compared to surface lineages (CT max 38 °C cf. 42–46 °C), but the genetic basis of this physiological difference has not been characterized. We experimentally manipulated the thermal environment of 24 individuals to demonstrate that both species can mount a heat shock response at high temperatures (35 °C), as determined by comparative transcriptomics. However, genes involved in these responses differ between species and a far greater number were differentially expressed in the surface taxon, suggesting it can mount a more robust heat shock response; these data may underpin its higher thermal tolerance compared to subterranean relatives. In contrast, the subterranean species examined not only differentially expressed fewer genes in response to increasing temperatures, but also in the presence of the experimental setup employed here alone. Our results suggest P. macrosturtensis may be comparatively poorly equipped to respond to both thermally induced stress and environmental disturbances more broadly. The molecular findings presented here have conservation implications for P. macrosturtensis and contribute to a growing narrative concerning weakened thermal tolerances in obligate subterranean organisms at the molecular level.

Abstract To characterize maxillofacial, otorhinolaryngological and oral manifestations of Hansen’s disease (HD), we conducted a cross-sectional study in 21 current patients attending the Unidade Básica de Saúde de Jardim América, Espírito Santo, Brazil and 16 former patients resident at Pedro Fontes Hospital using data from computed tomography imaging, rhinoscopy, and oroscopy. Maxillofacial characteristics were compared with 37 controls. Differences in bone alterations across the three groups were determined mainly by severe resorption/atrophy being more frequent in former HD patients, with severe resorption/atrophy of the anterior alveolar process of maxilla in 50.0% (8/16) of former patients, 28.6% (6/21) of current patients and 10.8% (4/37) of controls and of nasal bones and aperture in 31.3% (5/16) of former patients compared with 0/21 current patients and two controls. There were no substantial differences in otorhinolaryngological and oroscopic findings between the two patient groups. HD patients had more tooth loss than the age-matched control group. Maxillofacial, otorhinolaryngological and oroscopic finding scores were strongly correlated only in current HD patients. Correlation between otorhinolaryngological and maxillofacial scores suggests that protocols for HD patient assessment and follow-up could include otorhinolaryngological evaluation, with radiological imaging where necessary, subject to replication of our findings in a larger study.

Abstract Overhead line conductors can generate audible noise across a wide frequency spectrum as a result of elevated electric fields at the conductor surface. Such fields are enhanced by the presence of surface defects, insects, water drops and pollution. Within this paper, the impact of a superhydrophobic coating on the audible noise produced by an overhead line conductor is examined. Noise levels from a conductor coated with a superhydrophobic coating were compared to those from a bare conductor in a semi‐anechoic chamber. The conductors were energised at voltages to provide surface electric fields ranging from 6 kV/cm to 21 kV/cm (rms). With a continuous water spray system depositing droplets on the conductor surface, the frequency domain sound pressure level, overall sound pressure levels and corona discharge magnitude were measured. It is demonstrated that the use of a superhydrophobic coating reduced audible noise levels and corona discharge magnitude, especially at electric fields above 14 kV/cm. The image analysis suggests that the water drop size distribution and the position of surface droplets on the conductor circumference play an important role in the magnitude of audible noise.

SARS-CoV-2 variants have accumulated multiple defining mutations within their spike glycoproteins. Here, the authors report a structural basis for broad neutralization of several variants by a heavy chain antibody fragment and provide a mutational analysis focusing on antibody evasion, receptor engagement, and spike protein structure.

AimsA number of anti-retroviral therapies (ART) have been implicated in potentially contributing to HIV-associated bone disease. The aim of this study was to evaluate the effect of combination ART on the fracture healing process.MethodsA total of 16 adult male Wistar rats were randomly divided into two groups (n = eight each): Group 1 was given a combination of Tenfovir 30 mg, Lamivudine 30 mg, and Efavirenz 60 mg per day orally, whereas Group 2 was used as a control. After one week of medication preload, all rats underwent a standardized surgical procedure of mid-shaft tibial osteotomy fixed by intramedullary nail with no gap at the fracture site. Progress in fracture healing was monitored regularly for eight weeks. Further evaluations were carried out after euthanasia by micro-CT, mechanically and histologically. Two blinded orthopaedic surgeons used the Radiological Union Scoring system for the Tibia (RUST) to determine fracture healing.ResultsThe fracture healing process was different between the two groups at week 4 after surgery; only two out of eight rats showed full healing in Group 1 (ART-treated), while seven out of eight rats had bone union in Group 2 (control) (p = 0.040). However, at week eight postoperatively, there was no statistical difference in bone healing; seven out of eight progressed to full union in both groups.ConclusionThis study demonstrated that combination ART resulted in delayed fracture healing at week 4 after surgery in rats, but did not result in the development of nonunion.Cite this article: Bone Joint Res 2022;11(8):585–593.

Addressing health disparities has become a central remit for conducting health research. In the following paper, we explore the conceptual and methodological challenges posed by the call to recruit medically underserved populations. This exploration of challenges is undertaken from the perspective of social science researchers embedded in a large clinical genomics research study. We suggest that these challenges are found in respect to the development of recruiting strategies, analysis of the data in respect to understanding and interpreting the experiences of being medically underserved, and in comparing the experiences of being medically underserved compared to not being underserved. By way of conclusion, it is argued that there is an important role for social scientists with large health research studies which, if achieved successfully, can benefit study teams and society as a whole.

A cross-trait meta-analysis of several genome-wide association studies suggest that Alzheimer’s disease shares a common genetic basis (including 7 shared loci) and underlying biological pathways with gastrointestinal tract disorders.