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Abstract The microbiome is a key factor in the health, well-being, and success of vertebrates, contributing to the adaptive capacity of the host. However, the impact of geographic and biotic factors that may affect the microbiome of wild birds in polar environments is not well defined. To address this, we determined the bacterial 16S rRNA gene sequence profiles in faecal samples from pygoscelid penguin populations in the Scotia Arc, focusing on gentoo penguins. This mesopredatory group breeds in defined colonies across a wide geographic range. Since diet could influence microbiome structure, we extracted dietary profiles from a eukaryotic 18S rRNA gene sequence profile. The bacterial microbiome profiles were considered in the context of a diverse set of environmental and ecological measures. Integrating wide geographic sampling with bacterial 16S and eukaryotic 18S rRNA gene sequencing of over 350 faecal samples identified associations between the microbiome profile and a suite of geographic and ecological factors. Microbiome profiles differed according to host species, colony identity, distance between colonies, and diet. Interestingly there was also a relationship between the proportion of host DNA (in relation to total 18S rRNA gene signal) and the microbiome, which may reflect gut passage time. Colony identity provided the strongest association with differences in microbiome profiles indicating that local factors play a key role in the microbiome structure of these polar seabirds. This may reflect the influence of local transfer of microbes either via faecal-oral routes, during chick feeding or other close contact events. Other factors including diet and host species also associate with variation in microbiome profile, and in at least some locations, the microbiome composition varies considerably between individuals. Given the variation in penguin microbiomes associated with diverse factors there is potential for disruption of microbiome associations at a local scale that could influence host health, productivity, and immunological competence. The microbiome represents a sensitive indicator of changing conditions, and the implications of any changes need to be considered in the wider context of environmental change and other stressors.

Frontal plane ankle motion is important for balance in walking but is seldom controlled in robotic prostheses. This article describes the design, control and performance of a semi-active two-degree-of-freedom robotic prosthetic ankle. The mechanism uses a non-backdrivable wedge cam system based on rotating inclined planes, allowing actuation only during swing phases for low power, light weight and compactness. We present details of the mechanism and its kinematic and mechatronic control, and a benchtop investigation of the system’s speed and accuracy in ankle angle control. The two-axis ankle achieves angular reorientation movements spanning ±10 deg in any direction in less than 0.9 s. It achieves a plantarflexion/dorsiflexion error of 0.35 ± 0.27 deg and an inversion/eversion error of 0.29 ± 0.25 deg. Backdriven motion during walking tests is negligible. Strengths of the design include self-locking behavior for low power and simple kinematic control. Two-axis ankle angle control could enable applications such as balance augmentation, turning assistance, and wearable perturbation training.

Abstract We present a formally exact and simulation-free approach for the normalization of X-ray Thomson scattering (XRTS) spectra based on the f-sum rule of the imaginary-time correlation function (ITCF). Our method works for any degree of collectivity, over a broad range of temperatures, and is applicable even in nonequilibrium situations. In addition to giving us model-free access to electronic correlations, this new approach opens up the intriguing possibility to extract a plethora of physical properties from the ITCF based on XRTS experiments.

Abstract Background A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques. Methods We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires. Results RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose. Conclusions These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.

BackgroundIn the United States, colorectal cancer (CRC) is the third leading cause of cancer death among Black men. Compared to men of all other races or ethnicities, Black men have the lowest rates of CRC screening participation, which contributes to later-stage diagnoses and greater mortality. Despite CRC screening being a critical component of early detection and increased survival, few interventions have been tailored for Black men. ObjectiveThis study aims to report on the multistep process used to translate formative research including prior experiences implementing a national CRC education program, community advisory, and preliminary survey results into a culturally tailored mobile health (mHealth) intervention. MethodsA theoretically and empirically informed translational science public health intervention was developed using the Behavioral Design Thinking approach. Data to inform how content should be tailored were collected from the empirical literature and a community advisory board of Black men (n=7) and reinforced by the preliminary results of 98 survey respondents. ResultsA community advisory board identified changes for delivery that were private, self-paced, and easily accessible and content that addressed medical mistrust, access delays for referrals and appointments, lack of local information, misinformation, and the role of families. Empirical literature and survey results identified the need for local health clinic involvement as critical to screening uptake, leading to a partnership with local Federally Qualified Health Centers to connect participants directly to clinical care. Men surveyed (n=98) who live or work in the study area were an average of 59 (SD 7.9) years old and held high levels of mistrust of health care institutions. In the last 12 months, 25% (24/98) of them did not see a doctor and 16.3% (16/98) of them did not have a regular doctor. Regarding CRC, 27% (26/98) and 38% (37/98) of them had never had a colonoscopy or blood stool test, respectively. ConclusionsWorking with a third-party developer, a prototype mHealth app that is downloadable, optimized for iPhone and Android users, and uses familiar sharing, video, and text messaging modalities was created. Guided by our results, we created 4 short videos (1:30-2 min) including a survivor vignette, animated videos about CRC and the type of screening tests, and a message from a community clinic partner. Men also receive tailored feedback and direct navigation to local Federally Qualified Health Center partners including via school-based family clinics. These content and delivery elements of the mHealth intervention were the direct result of the multipronged, theoretically informed approach to translate an existing but generalized CRC knowledge–based intervention into a digital, self-paced, tailored intervention with links to local community clinics. Trial RegistrationClinicalTrials.gov NCT05980182; https://clinicaltrials.gov/study/NCT05980182

Summary: Background: PfSPZ Vaccine, a promising pre-erythrocytic stage malaria vaccine candidate based on whole, radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), has proven safe and effective in mediating sterile protection from malaria in malaria-naïve and exposed healthy adults. Vaccine-induced protection presumably depends on cellular responses to early parasite liver stages, but humoral immunity contributes. Methods: On custom-made Pf protein microarrays, we profiled IgG and IgM responses to PfSPZ Vaccine and subsequent homologous controlled human malaria infection (CHMI) in 21 Tanzanian adults with (n = 12) or without (n = 9) HIV infection. Expression of the main identified immunogens in the pre-erythrocytic parasite stage was verified by immunofluorescence detection using freshly purified PfSPZ and an in vitro model of primary human hepatocytes. Findings: Independent of HIV infection status, immunisation induced focused IgG and IgM responses to circumsporozoite surface protein (PfCSP) and merozoite surface protein 5 (PfMSP5). We show that PfMSP5 is detectable on the surface and in the apical complex of PfSPZ. Interpretation: Our data demonstrate that HIV infection does not affect the quantity of the total IgG and IgM antibody responses to PfCSP and PfMSP5 after immunization with PfSPZ Vaccine. PfMSP5 represents a highly immunogenic, so far underexplored, target for vaccine-induced antibodies in malaria pre-exposed volunteers. Funding: This work was supported by the Equatorial Guinea Malaria Vaccine Initiative (EGMVI), the Clinical Trial Platform of the German Center for Infection Research (TTU 03.702), the Swiss Government Excellence Scholarships for Foreign Scholars and Artists (grant 2016.0056) and the Interdisciplinary Center for Clinical Research doctoral program of the Tübingen University Hospital. The funders had no role in design, analysis, or reporting of this study.

Background Bioacoustic monitoring is an effective and minimally invasive method to study wildlife ecology. However, even the state-of-the-art techniques for analyzing birdsongs decrease in accuracy in the presence of extraneous signals such as anthropogenic noise and vocalizations of non-target species. Deep supervised source separation (DSSS) algorithms have been shown to effectively separate mixtures of animal vocalizations. However, in practice, recording sites also have site-specific variations and unique background audio that need to be removed, warranting the need for site-specific data. Methods Here, we test the potential of training DSSS models on site-specific bird vocalizations and background audio. We used a semiautomated workflow using deep supervised classification and statistical cleaning to label and generate a site-specific source separation dataset by mixing birdsongs and background audio segments. Then, we trained a deep supervised source separation (DSSS) model with this generated dataset. Because most data is passively-recorded and consequently noisy, the true isolated birdsongs are unavailable which makes evaluation challenging. Therefore, in addition to using traditional source separation (SS) metrics, we also show the effectiveness of our site-specific approach using metrics commonly used in ornithological analyses such as automated feature labeling and species-specific trilateration accuracy. Results Our approach of training on site-specific data boosts the source-to-distortion, source-to-interference, and source-to-artifact ratios (SDR, SIR, and SAR) by 9.33 dB, 24.07 dB, and 3.60 dB respectively. We also find our approach allows for automated feature labeling with single-digit mean absolute percent error and birdsong trilateration accuracy with a mean simulated trilateration error of 2.58 m. Conclusion Overall, we show that site-specific DSSS is a promising upstream solution for wildlife audio analysis tools that break down in the presence of background noise. By training on site-specific data, our method is robust to unique, site-specific interference that caused previous methods to fail.

Abstract Most binocular vision models assume that the two eyes sum incompletely. However, some facilitatory cortical neurons fire for only one eye, but amplify their firing rates if both eyes are stimulated. These ‘binocular gate’ neurons closely resemble subthreshold multisensory neurons. Binocular amplification for binocular gate neurons follows a power law, with a compressive exponent. Unexpectedly, this rule also applies to facilitatory true binocular neurons; although driven by either eye, binocular neurons are well modeled as gated amplifiers of their strongest monocular response, if both eyes are stimulated. Psychophysical data follows the same power law as the neural data, with a similar exponent; binocular contrast sensitivity can be modeled as a gated amplification of the more sensitive eye. These results resemble gated amplification phenomena in multisensory integration, and other non-driving modulatory interactions that affect sensory processing. Models of incomplete summation seem unnecessary for V1 facilitatory neurons or contrast sensitivity. However, binocular combination of clearly visible monocular stimuli follows Schrödinger’s nonlinear magnitude-weighted average. We find that putatively suppressive binocular neurons closely follow Schrödinger’s equation. Similar suppressive multisensory neurons are well documented but seldom studied. Facilitatory binocular neurons and mildly suppressive binocular neurons are likely neural correlates of binocular sensitivity and binocular appearance respectively.

Objectives To systematically review and synthesise evidence on the effectiveness and implementation barriers/facilitators of pharmacist-led interventions to promote medicines optimisation and reduce overprescribing in UK primary care.Design Systematic review.Setting UK primary care.Methods We searched MEDLINE, Embase, CINAHL PsycINFO and The Cochrane Library for UK-based studies published between January 2013 and February 2023. Targeted searches for grey literature were conducted in May 2023. Quantitative and qualitative studies (including conference abstracts and grey literature) that addressed a relevant intervention and reported a primary outcome related to changes in prescribing were eligible for inclusion. Quality of included studies was assessed using the Multiple Methods Appraisal Tool. We performed a narrative synthesis, grouping studies by publication status, setting and type of data reported (effectiveness or implementation).Results We included 14 peer-reviewed journal articles and 11 conference abstracts, together with 4 case study reports. The journal articles reported 10 different interventions, 5 delivered in general practice, 4 in care homes and 1 in community pharmacy. The quality of evidence was higher in general practice than in care home settings. It was consistently reported that the intervention improved outcomes related to prescribing, although the limited number of studies and wide range of outcomes reported made it difficult to estimate the size of any effect. Implementation was strongly influenced by relationships between pharmacists and other health and care professionals, especially general practitioners. Implementation in care homes appeared to be more complex than in general practice because of differences in systems and ‘culture’ between health and social care.Conclusions Pharmacist-led interventions have been reported to reduce overprescribing in primary care settings in the UK but a shortage of high-quality evidence means that more rigorous studies using high-quality designs are needed. More research is also needed in community pharmacy settings; to assess intervention effects on patient outcomes other than prescribing and to investigate how reducing overprescribing can impact health inequalities.PROSPERO registration number CRD42023396366.

Abstract Over the past several decades, substantial ground has been gained in understanding the biology of sex differences. With new mandates to include sex as a biological variable in NIH-funded research, greater knowledge is forthcoming on how sex chromosomes, sex hormones, and social and societal differences between sexes can affect the pathophysiology of health and disease. A detailed picture of how biological sex impacts disease pathophysiology will directly inform clinicians in their treatment approaches and challenge canonical therapeutic strategies. Thus, a profound opportunity to explore sex as a variable in personalized medicine now presents itself. While many sex differences are apparent in humans and have been described at length, we are only beginning to see how such differences impact disease progression, treatment efficacy, and outcomes in obesity, type 2 diabetes, and cardiovascular disease. Here, we briefly present the most salient and convincing evidence of sex differences in type 2 diabetes detection, diagnostics, disease course, and therapeutics. We then offer commentary on how this evidence can inform clinicians on how to approach the clinical workup and management of different patients with diabetes. Finally, we discuss some gaps that remain in the literature and propose several research questions to guide basic and translational researchers as they continue in this growing area of scientific exploration.

Background/Objectives: Effective communication between patients and healthcare providers is essential for informed decision making in cancer care. Communication aids that can help prostate cancer patients optimize their involvement in treatment care planning are not widely used in the U.S. This research details the adaptation and validation process of a patient prompt list for localized prostate cancer patients undergoing treatment decisions. Methods: This process occurred in three steps: Step 1 involved gathering usable questions from the literature; in Step 2, we evaluated the tool’s content via expert (N = 6) feedback; and in Step 3, we assessed the usefulness of the prompt list with patients (N = 30). Results: Sixty percent of candidate questions (20/33) were retained for inclusion after achieving acceptable item-level content validity index (range: 0.83–1.00) and scale-level content validity index (S-CVI = 0.96) scores. The final 20 questions were classified into 5 domains (1: Treatment Options and Information, 2: Side Effects, Risks, and Recovery, 3: Emotional and Social Support, 4: Logistical and Practical Concerns, and 5: Future Health Considerations) through a card sorting exercise with a subset of patients (N = 3) and providers (N = 2). Most patients rated the prompt list as “useful or very useful” both to themselves (80%, N = 24) and to other men presenting with prostate cancer (83%, N = 25). Conclusions: The participatory process used to develop and validate the prompt list offers insights for the development of similar tools.

Objectives To explore the experience of accessing Long COVID community rehabilitation from the perspectives of people with Long COVID and general practitioners (GPs).Design Qualitative descriptive study employing one-to-one semistructured virtual interviews analysed using the framework method.Setting Four National Health Service Scotland territorial health boards.Participants 11 people with Long COVID (1 male, 10 female; aged 40–65 (mean 53) and 13 GPs (5 male, 8 female).Results Four key themes were identified: (1) The lived experience of Long COVID, describing the negative impact of Long COVID on participants’ health and quality of life; (2) The challenges of an emergent and complex chronic condition, including uncertainties related to diagnosis and management; (3) Systemic challenges for Long COVID service delivery, including lack of clear pathways for access and referral, siloed services, limited resource and a perceived lack of holistic care, and (4) Perceptions and experiences of Long COVID and its management, including rehabilitation. In this theme, a lack of knowledge by GPs and people with Long COVID on the potential role of community rehabilitation for Long COVID was identified. Having prior knowledge of rehabilitation or being a healthcare professional appeared to facilitate access to community rehabilitation. Finally, people with Long COVID who had received rehabilitation had generally found it beneficial.Conclusions There are several patient, GP and service-level barriers to accessing community rehabilitation for Long COVID. There is a need for greater understanding by the public, GPs and other potential referrers of the role of community rehabilitation professionals in the management of Long COVID. There is also a need for community rehabilitation services to be well promoted and accessible to the people with Long COVID for whom they may be appropriate. The findings of this study can be used by those (re)designing community rehabilitation services for people with Long COVID.

Purpose Pregnancy and the postpartum period are increasingly recognised as sensitive windows for cardiometabolic disease risk. Growing evidence suggests environmental exposures, including endocrine-disrupting chemicals (EDCs), are associated with an increased risk of pregnancy complications that are associated with long-term cardiometabolic risk. However, the impact of perinatal EDC exposure on subsequent cardiometabolic risk post-pregnancy is less understood. The Environmental Reproductive and Glucose Outcomes (ERGO) Study was established to investigate the associations of environmental exposures during the perinatal period with post-pregnancy parental cardiometabolic health.Participants Pregnant individuals aged ≥18 years without pre-existing diabetes were recruited at

Information seeking anxiety is a multidimensional construct that is operationalized as having elements of worry, confusion, and disorganization. Much remains unknown about the ways information seeking anxiety operates among cancer patients in the United States. This study investigated the application of the information seeking anxiety concept among prostate cancer patients by documenting their assessment experiences and examining relationships between information seeking anxiety and treatment information search behaviors. A purposive sample of African American and Caucasian men ( N = 63) within 5 years of being diagnosed with localized disease (stage T1 or T2) were recruited to participate through cancer registries, advertisements, and word-of-mouth. Participants completed a self-administered survey with items that collected demographic information, treatment information-seeking behaviors, and information seeking anxiety evaluations. All surveys were completed in one sitting and a majority of men (82.5%, N = 52) completed the information seeking anxiety assessment with no assistance. During their first interactions with available sources of information (e.g., doctors, internet, peers), most survivors (95.2%, N = 60) reported some level of information seeking anxiety. Specifically, 55.5% ( N = 35) were confused about what to look for, 60.3% ( N = 38) were worried they would not find the right information, 55.5% ( N = 35) were uncomfortable with the search process, and 49.2% ( N = 31) reported being disorganized. The composite information seeking anxiety measure was moderately correlated with men’s self-reported time to start searching for treatment information ( p = .02; r = .306). Information seeking anxiety appears to delay the treatment information gathering activities of prostate cancer survivors with localized disease. This previously undocumented barrier to the delivery of prostate cancer care services should be investigated in other studies with larger and more diverse samples.

Melioidosis, caused by the environmental gram-negative bacterium Burkholderia pseudomallei, usually develops in adults with predisposing conditions and in Australia more commonly occurs during the monsoonal wet season. We report an outbreak of 7 cases of melioidosis in immunocompetent children in Australia. All the children had participated in a single-day sporting event during the dry season in a tropical region of Australia, and all had limited cutaneous disease. All case-patients had an adverse reaction to oral trimethoprim/sulfamethoxazole treatment, necessitating its discontinuation. We describe the clinical features, environmental sampling, genomic epidemiologic investigation, and public health response to the outbreak. Management of this outbreak shows the potential benefits of making melioidosis a notifiable disease. The approach used could also be used as a framework for similar outbreaks in the future.

Abstract Soft sensors that can discriminate shear and normal force could help provide machines the fine control desirable for safe and effective physical interactions with people. A capacitive sensor is made for this purpose, composed of patterned elastomer and containing both fixed and sliding pillars that allow the sensor to deform and buckle, much like skin itself. The sensor differentiates between simultaneously applied normal force and shear using summation and differences of signals from four deformable capacitors. Cross talk from shear to normal force is less than 2.5%, and between shear axes is less than 10%. Normal and shear stress sensitivity is 0.49 kPa and 0.31 kPa respectively, with a minimum displacement resolution of 40 μm. In addition, finger proximity is detectable at a range of up to 15 mm. The operation is demonstrated on a simple gripper holding a cup. The combination of features and the straightforward fabrication method make this sensor a candidate for implementation as a sensing skin for humanoid robotics applications.

Abstract Vertebrate color vision is predominantly mediated by the presence of multiple cone photoreceptor subtypes that are each maximally sensitive to different wavelengths of light. Thyroid hormone (TH) has been shown to be essential in the spatiotemporal patterning of cone subtypes in many species, including cone subtypes that express opsins that are encoded by tandemly replicated genes. TH has been shown to differentially regulate the tandemly replicated lws opsin genes in zebrafish, and exogenous treatments alter the expression levels of these genes in larvae and juveniles. In this study, we sought to determine whether gene expression in cone photoreceptors remains plastic to TH treatment in adults. We used a transgenic lws reporter line, multiplexed fluorescence hybridization chain reaction in situ hybridization, and qPCR to examine the extent to which cone gene expression can be altered by TH in adults. Our studies revealed that opsin gene expression, and the expression of other photoreceptor genes, remains plastic to TH treatment in adult zebrafish. In addition to retinal plasticity, exogenous TH treatment alters skin pigmentation patterns in adult zebrafish after 5 days. Taken together, our results show a remarkable level of TH-sensitive plasticity in the adult zebrafish.

Abstract Background The active involvement of patients and the public in the design and delivery of health research has been increasingly encouraged, if not enforced. Knowledge of how this is realised in practice, especially where children and young people (CYP) are concerned, is limited, partly due to the low level of reporting of patient and public involvement (PPI) in general. The aim of this work was to assess how researchers funded by the National Institute for Health and Care Research (NIHR) report the involvement of CYP in the design and conduct of child health research to better understand the opportunities offered to CYP, and the realities of involvement in practice. Methods A participation matrix, analysis framework and accompanying tools were adapted from existing frameworks, including a child-rights informed framework, the Guidance for Reporting Involvement of Patients and the Public Checklist Short Form (GRIPP2SF), and NIHR reporting expectations. Child-focused research reports were identified from the NIHR Journals Library, including any interventional or observational study involving CYP aged 0–

Abstract Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10–15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p

Abstract Background Viral therapies developed for cancer treatment have classically prioritized direct oncolytic effects over their immune activating properties. However, recent clinical insights have challenged this longstanding prioritization and have shifted the focus to more immune-based mechanisms. Through the potential utilization of novel, inherently immune-stimulating, oncotropic viruses there is a therapeutic opportunity to improve anti-tumor outcomes through virus-mediated immune activation. PV001-DV is an attenuated strain of Dengue virus (DEN-1 #45AZ5) with a favorable clinical safety profile that also maintains the potent immune stimulatory properties characterstic of Dengue virus infection. Methods In this study, we utilized in vitro tumor killing and immune multiplex assays to examine the anti-tumor effects of PV001-DV as a potential novel cancer immunotherapy. Results In vitro assays demonstrated that PV001-DV possesses the ability to directly kill human melanoma cells lines as well as patient melanoma tissue ex vivo. Importantly, further work demonstrated that, when patient peripheral blood mononuclear cells (PBMCs) were exposed to PV001-DV, a substantial induction in the production of apoptotic factors and immunostimulatory cytokines was detected. When tumor cells were cultured with the resulting soluble mediators from these PBMCs, rapid cell death of melanoma and breast cancer cell lines was observed. These soluble mediators also increased dengue virus binding ligands and immune checkpoint receptor, PD-L1 expression. Conclusions The direct in vitro tumor-killing and immune-mediated tumor cytotoxicity facilitated by PV001-DV contributes support of its upcoming clinical evaluation in patients with advanced melanoma who have failed prior therapy.

Abstract Background Randomised controlled trials are often beset by problems with poor recruitment and retention. Information to support decisions on trial participation is usually provided as printed participant information sheets (PIS), which are often long, technical, and unappealing. Multimedia information (MMI), including animations and videos, may be a valuable alternative or complement to a PIS. The Trials Engagement in Children and Adolescents (TRECA) study compared MMI to PIS to investigate the effects on participant recruitment, retention, and quality of decision-making. Methods We undertook six SWATs (Study Within A Trial) within a series of host trials recruiting children and young people. Potential participants in the host trials were randomly allocated to receive MMI-only, PIS-only, or combined MMI + PIS. We recorded the rates of recruitment and retention (varying between 6 and 26 weeks post-randomisation) in each host trial. Potential participants approached about each host trial were asked to complete a nine-item Decision-Making Questionnaire (DMQ) to indicate their evaluation of the information and their reasons for participation/non-participation. Odds ratios were calculated and combined in a meta-analysis. Results Data from 3/6 SWATs for which it was possible were combined in a meta-analysis (n = 1758). Potential participants allocated to MMI-only were more likely to be recruited to the host trial than those allocated to PIS-only (OR 1.54; 95% CI 1.05, 2.28; p = 0.03). Those allocated to combined MMI + PIS compared to PIS-only were no more likely to be recruited to the host trial (OR = 0.89; 95% CI 0.53, 1.50; p = 0.67). Providing MMI rather than PIS did not impact on DMQ scores. Once children and young people had been recruited to host trials, their trial retention rates did not differ according to intervention allocation. Conclusions Providing MMI-only increased the trial recruitment rate compared to PIS-only but did not affect DMQ scores. Combined MMI + PIS instead of PIS had no effect on recruitment or retention. MMIs are a useful tool for trial recruitment in children and young people, and they could reduce trial recruitment periods.

Abstract Background MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1: c.-11C > T and one MLH1: c.-[28A > G; 7C > T] carriers and three MLH1 methylated EOCRCs ( T carriers and MLH1 methylated EOCRCs clustered with the constitutional MLH1 epimutation CRCs but not with the sporadic MLH1 methylated CRCs. Furthermore, monoallelic MLH1 methylation and APC promoter hypermethylation in tumour were observed in both MLH1 epimutation and germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs. Mosaic constitutional MLH1 methylation in MLH1: c.-11C > T carriers and 1 of 3 MLH1 methylated EOCRCs was identified by methylation-sensitive ddPCR. Conclusions Mosaic MLH1 epimutation underlies the CRC aetiology in MLH1: c.-11C > T germline carriers and a subset of MLH1 methylated EOCRCs. Tumour profiling and ultra-sensitive ddPCR methylation testing can be used to identify mosaic MLH1 epimutation carriers.

The Coastal California Gnatcatcher (Polioptila californica californica), a federally threatened species, is a flagship species for regional conservation planning in southern California (USA). An inhabitant of coastal sage scrub vegetation, the gnatcatcher has declined in response to habitat loss and fragmentation, exacerbated by catastrophic wildfires. We documented the status of gnatcatchers throughout their California range and examined post-fire recovery of gnatcatchers and their habitat. We used GIS to develop a habitat suitability model for Coastal California Gnatcatchers using climate and topography covariates and selected over 700 sampling points in a spatially balanced manner. Bird and vegetation data were collected at each point between March and May in 2015 and 2016. Presence/absence of gnatcatchers was determined during three visits to points, using area searches within 150 x 150 m plots. We used an occupancy framework to generate Percent Area Occupied (PAO) by gnatcatchers, and analyzed PAO as a function of time since fire. At the regional scale in 2016, 23% of the points surveyed were occupied by gnatcatchers, reflecting the effect of massive wildfires in the last 15 years. Similarly, PAO in the post-fire subset of points was 24%, with the highest occupancy in unburned (last fire

Objective When considering proposals to improve diets, it is important to understand how factors like price and income can affect saturated fat (SF) intake and demand. In this study, we examine and estimate the influence of price and income on intake across 160 countries, by age and sex, and derive sensitivity measures (price elasticities) that vary by age, sex and world region.Design We econometrically estimate intake responsiveness to income and prices across countries, accounting for differences by world region, age and sex. Intake data by age, sex and country were obtained from the 2018 Global Dietary Database. These data were then linked to global price data for select food groups from the World Bank International Comparison Programme and income data from the World Development Indicators Databank (World Bank).Results Intake differences due to price were highly significant, with a 1% increase in price associated with a lower SF intake (% energy/d) of about 4.3 percentage points. We also find significant differences across regions. In high-income countries, median (age 40) intake reductions were 1.4, 0.8 and 0.2 percentage points, given a 1% increase in the price of meat, dairy, and oils and fats, respectively. Price elasticities varied with age but not sex. Intake differences due to income were insignificant when regional binary variables were included in the analysis.Conclusion The results of this study show heterogeneous associations among prices and intake within and across countries. Policymakers should consider these heterogeneous effects as they address global nutrition and health challenges.

AimAssess whether school-based teacher-led screening is effective at identifying children with motor difficulties.MethodsTeachers tested 217 children aged between 5 and 11 years old, after a one hour training session, using a freely available tool (FUNMOVES). Four classes (n = 91) were scored by both researchers and teachers to evaluate inter-rater reliability. Researchers assessed 22 children using the Movement Assessment Battery for Children (MABC-2; considered to be the 'gold standard' in Europe for use as part of the diagnostic process for Developmental Coordination Disorder) to assess concurrent and predictive validity.ResultsInter-rater reliability for all individual activities within FUNMOVES ranged from 0.85-0.97 (unweighted Kappa; with 95%CI ranging from 0.77-1). For total score this was lower (κ = 0.76, 95%CI = 0.68-0.84), however when incorporating linear weighting, this improved (κ = 0.94, 95%CI = 0.89-0.99). When evaluating FUNMOVES total score against the MABC-2 total score, the specificity (1, 95%CI = 0.63-1) and positive predictive value (1; 95%CI = 0.68-1) of FUNMOVES were high, whereas sensitivity (0.57, 95%CI = 0.29-0.82) and negative predictive values (0.57, 95%CI = 0.42-0.71) were moderate. Evaluating only MABC-2 subscales which are directly related to fundamental movement skills (Aiming & Catching, and Balance) improved these values to 0.89 (95%CI = 0.52-1) and 0.93 (95%CI = 0.67-0.99) respectively.InterpretationTeacher-led screening of fundamental movement skills (via FUNMOVES) is an effective method of identifying children with motor difficulties. Such universal screening in schools has the potential to identify movement difficulties and enable earlier intervention than the current norm.

Given the increasing prevalence of online data collection, it is important to know how behavioral data obtained online compare to samples collected in the laboratory. This study compares online and in-person measurement of speech perception in older children and adolescents. Speech perception is important for assessment and treatment planning in speech-language pathology; we focus on the American English /ɹ/ sound because of its frequency as a clinical target. Two speech perception tasks were adapted for web presentation using Gorilla: identification of items along a synthetic continuum from rake to wake, and category goodness judgment of English /ɹ/ sounds in words produced by various talkers with and without speech sound disorder. Fifty typical children aged 9-15 completed these tasks online using a standard headset. These data were compared to a previous sample of 98 typical children aged 9-15 who completed the same tasks in the lab setting. For the identification task, participants exhibited smaller boundary widths (suggestive of more acute perception) in the in-person setting relative to the online setting. For the category goodness judgment task, there was no statistically significant effect of modality. The correlation between scores on the two tasks was significant in the online setting but not in the in-person setting, but the difference in correlation strength was not statistically significant. Overall, our findings agree with previous research in suggesting that online and in-person data collection do not yield identical results, but the two contexts tend to support the same broad conclusions. In addition, these results suggest that online data collection can make it easier for researchers connect with a more representative sample of participants.

Objectives The Bronchiolitis Endotracheal Surfactant Study (BESS) is a randomised controlled trial to determine the efficacy of endo-tracheal surfactant therapy for critically ill infants with bronchiolitis. To explore acceptability of BESS, including approach to consent within a limited time frame, we explored parent and staff experiences of trial involvement in the first two bronchiolitis seasons to inform subsequent trial conduct.Design A mixed-method embedded study involving a site staff survey, questionnaires and interviews with parents approached about BESS.Setting Fourteen UK paediatric intensive care units.Participants Of the 179 parents of children approached to take part in BESS, 75 parents (of 69 children) took part in the embedded study. Of these, 55/69 (78%) completed a questionnaire, and 15/69 (21%) were interviewed. Thirty-eight staff completed a questionnaire.Results Parents and staff found the trial acceptable. All constructs of the Adapted Theoretical Framework of Acceptability were met. Parents viewed surfactant as being low risk and hoped their child’s participation would help others in the future. Although parents supported research without prior consent in studies of time critical interventions, they believed there was sufficient time to consider this trial. Parents recommended that prospective informed consent should continue to be sought for BESS. Many felt that the time between the consent process and intervention being administered took too long and should be ‘streamlined’ to avoid delays in administration of trial interventions. Staff described how the training and trial processes worked well, yet patients were missed due to lack of staff to deliver the intervention, particularly at weekends.Conclusion Parents and staff supported BESS trial and highlighted aspects of the protocol, which should be refined, including a streamlined informed consent process. Findings will be useful to inform proportionate approaches to consent in future paediatric trials where there is a short timeframe for consent discussions.Trial registration number ISRCTN11746266.

Objectives This study aimed to explore the perceptions and experiences of barriers and facilitators to accessing Long COVID community rehabilitation.Design We used a qualitative descriptive design over two rounds of data collection with three participant groups: (1) people with experience of rehabilitation for Long COVID (PwLC); (2) National Health Service (NHS) staff delivering and/or managing community rehabilitation services (allied health professionals (AHPs)) and (3) NHS staff involved in strategic planning around Long COVID in their health board (Long COVID leads).Setting Four NHS Scotland territorial health boards.Participants 51 interviews: eight Long COVID leads (11 interviews); 15 AHPs (25 interviews) and 15 PwLC (15 interviews).Results Three key themes were identified: (1) accessing care for PwLC, (2) understanding Long COVID and its management and (3) strengths and limitations of existing Long COVID rehabilitation services.Conclusions Organisational delivery of Long COVID community rehabilitation is complex and presents multiple challenges. In addition, access to Long COVID community rehabilitation can be challenging. When accessed, these services are valued by PwLC but require adequate planning, publicity and resource. The findings presented here can be used by those developing and delivering services for people with Long COVID.

AbstractObjective Athletes are susceptible to acute respiratory tract infections, including SARS-CoV-2, which can affect cardiovascular function. We aimed to evaluate the impact of COVID-19 infection and quarantine on cardiac function in male and female collegiate athletes.Methods We conducted a single-center, prospective, case-control study and performed transthoracic echocardiography in a diverse group of convalescent SARS-CoV-2-positive athletes following a 10–14–day quarantine, matched to non-SARS-CoV-2 athletes. Data collection occurred from August 1, 2020, to May 31, 2021.Results We evaluated 61 SARS-CoV-2-positive athletes (20 ± 1 years, 39% female) and 61 controls (age 20 ± 2 years, 39% female). Echocardiography in SARS-CoV-2-positive athletes was performed on average 40 ± 38 days after infection diagnosis. All SARS-CoV-2-positive athletes had clinically normal systolic left ventricular function (LVEF > 50%). However, SARS-CoV-2-positive athletes exhibited mildly lower LVEF compared to controls (65 ± 6% vs. 72 ± 8%, respectively, p

Abstract Background Extra-intestinal pathogenic Escherichia coli (ExPEC) are a leading cause of bloodstream and urinary tract infections worldwide. Over the last two decades, increased rates of antibiotic resistance in E. coli have been reported, further complicating treatment. Worryingly, specific lineages expressing extended-spectrum β-lactamases (ESBLs) and fluoroquinolone resistance have proliferated and are now considered a serious threat. Obtaining contemporary information on the epidemiology and prevalence of these circulating lineages is critical for containing their spread globally and within the clinic. Methods Whole-genome sequencing (WGS), phylogenetic analysis, and antibiotic susceptibility testing were performed for a complete set of 2075 E. coli clinical isolates collected from 1776 patients at a large tertiary healthcare network in the USA between October 2019 and September 2020. Results The isolates represented two main phylogenetic groups, B2 and D, with six lineages accounting for 53% of strains: ST-69, ST-73, ST-95, ST-131, ST-127, and ST-1193. Twenty-seven percent of the primary isolates were multidrug resistant (MDR) and 5% carried an ESBL gene. Importantly, 74% of the ESBL-E.coli were co-resistant to fluoroquinolones and mostly belonged to pandemic ST-131 and emerging ST-1193. SNP-based detection of possible outbreaks identified 95 potential transmission clusters totaling 258 isolates (12% of the whole population) from ≥ 2 patients. While the proportion of MDR isolates was enriched in the set of putative transmission isolates compared to sporadic infections (35 vs 27%, p = 0.007), a large fraction (61%) of the predicted outbreaks (including the largest cluster grouping isolates from 12 patients) were caused by the transmission of non-MDR clones. Conclusion By coupling in-depth genomic characterization with a complete sampling of clinical isolates for a full year, this study provides a rare and contemporary survey on the epidemiology and spread of E. coli in a large US healthcare network. While surveillance and infection control efforts often focus on ESBL and MDR lineages, our findings reveal that non-MDR isolates represent a large burden of infections, including those of predicted nosocomial origins. This increased awareness is key for implementing effective WGS-based surveillance as a routine technology for infection control.

Abstract Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

Plain English summary Patient and Public Involvement (PPI) is important for high-quality research. It makes research more relevant to patients, and makes the results more useful for the health service. To make patient involvement effective, we need skilled staff with experience of involving lay members in research, as well as engaging researchers in PPI activities. There is little guidance about staff time needed to recruit and support lay members and researchers properly. This means that we still do not understand the true cost of including patients and the public in research, and we often under cost this in funding applications. As an example, we reflect on how the Asthma UK Centre for Applied Research (AUKCAR) has organised staff to support for its patient involvement. We give some thoughts on how to cost PPI staff time in funding applications. By focusing attention on the team behind the lay volunteers, we hope to encourage a much-needed discussion about the support involved, and deliver more patient benefits. The AUKCAR experience can be adapted to other research topics and contexts.

Abstract Bacterial phytopathogens living on the surface or within plant tissues may experience oxidative stress because of the triggered plant defense responses. Although it has been suggested that polyamines can defend bacteria from this stress, the mechanism behind this action is not entirely understood. In this study, we investigated the effects of oxidative stress on the polyamine homeostasis of the plant pathogen Pseudomonas syringae and the functions of these compounds in bacterial stress tolerance. We demonstrated that bacteria respond to H2O2 by increasing the external levels of the polyamine putrescine while maintaining the inner concentrations of this compound as well as the analogue amine spermidine. In line with this, adding exogenous putrescine to media increased bacterial tolerance to H2O2. Deletion of arginine decarboxylase (speA) and ornithine decarboxylate (speC), prevented the synthesis of putrescine and augmented susceptibility to H2O2, whereas targeting spermidine synthesis alone through deletion of spermidine synthase (speE) increased the level of extracellular putrescine and enhanced H2O2 tolerance. Further research demonstrated that the increased tolerance of the ΔspeE mutant correlated with higher expression of H2O2-degrading catalases and enhanced outer cell membrane stability. Thus, this work demonstrates previously unrecognized connections between bacterial defense mechanisms against oxidative stress and the polyamine metabolism.

Despite clear evidence of the public health benefits of the human papillomavirus (HPV) vaccine in preventing HPV-related cancers and genital warts, underutilization of HPV vaccination in the United States persists. Interventions targeting multi-level determinants of vaccination behavior are crucial for improving HPV vaccination rates. The study’s purpose was to implement and evaluate the adapted Adolescent Vaccination Program (AVP), a clinic-based, multi-level, multi-component intervention aimed at increasing HPV vaccine initiation and completion rates in a five-clinic pediatric network in Bexar County, Texas. The adaptation process was guided by established frameworks and involved formative work with clinic stakeholders. The study utilized a quasi-experimental single group pre- and post- study design, with an external comparison data using the National Immunization Survey-Teen (NIS-Teen) datasets for the same time period to examine the AVP’s effect on HPV vaccination initiation and completion. A series of interrupted time series analyses (ITSA) compared the clinic system patient outcomes (HPV vaccination initiation and completion rates) in the post-intervention to the general adolescent population (NIS-Teen). Of the 6438 patients (11–17 years) with clinic visits during the 3-year study period, HPV vaccination initiation rates increased from 64.7% to 80.2% (p < 0.05) and completion rates increased from 43.2% to 60.2% (p < 0.05). The AVP was effective across various demographic and economic subgroups, demonstrating its generalizability. ITSA findings indicated the AVP improved HPV vaccination initiation and completion rates in clinic settings and that AVP strategies facilitated resilience during the pandemic. The minimal adaptation required for implementation in a new clinic system underscores its feasibility and potential for widespread adoption.

Abstract The body is intrinsic to our sense of self and as such, any theoretical account of the self should also include contributions of the body. This Collection incorporates a series of papers that demonstrate the inextricable relationship between body and self. The papers include studies of body illusions and studies of observed differences in bodily experience in participants with psychiatric and physical conditions. Papers in the Collection also address methodological issues, because measuring and manipulating the bodily self does not come without challenges; subjective experiences are difficult to capture empirically. Making progress on these methodological limitations is crucial to further develop experimental design and thus our understanding of self-body relations.

Abstract Pregnancy is a time of great physical and psychological change. As well as prominent changes in the external appearance of the body, such as the baby bump, there are also substantial changes taking place within the body. Our awareness of, and attention towards, internal bodily signals (interoception) is thought to have a direct impact on how we feel about our bodies. Therefore, understanding how our experience of these interoceptive signals might change during pregnancy may have important implications for maternal wellbeing. This study examined body satisfaction and interoceptive sensibility (subjective experience of interoception) in pregnant and non-pregnant women with and without children. Feelings towards pregnancy-specific changes in body satisfaction and interoceptive sensibility were also examined in women in their first pregnancy (primigravida) and subsequent pregnancies (multigravida). It was found that pregnancy did not directly impact levels of body satisfaction, instead pregnant and non-pregnant women with children reported less satisfaction with their bodies compared to those without children. Primigravida women were more satisfied with the appearance of pregnancy specific bodily changes compared to multigravida women. Interestingly, these differences in body satisfaction in those with children (pregnant and non-pregnant) were mediated by the extent to which women trusted their bodies (measure of interoceptive sensibility). All other pregnancy related changes in interoceptive sensibility and body satisfaction were either non-significant or had small effect sizes. These results may suggest body trust as an important factor to support during the transition to parenthood in order to improve body satisfaction in mothers.

Objectives Patient and public involvement (PPI) in clinical research has a well-established infrastructure in the UK, and while there has been good progress within pharmaceutical-industry-sponsored research, further improvements are still needed. This review aims to share learnings from quality assessments of historical PPI projects within Pfizer UK to inform future projects and drive PPI progress in the pharmaceutical industry.Design and setting Internal assessments of Pfizer UK PPI projects were conducted to identify all relevant projects across the medicines development continuum between 2017 and 2021. Five sample projects were developed into case studies.Outcome measure Retrospective quality assessments were performed using the Patient Focused Medicines Development (PFMD) Patient Engagement Quality Guidance (PEQG) tool. Recommendations for improvement were developed.Results Retrospective case study analysis and quality framework assessment revealed benefits of PPI to both Pfizer UK and to external partners, as well as challenges and learnings to improve future practice. Recommendations for improvement based on these findings focused on processes and procedures for PPI, group dynamics and diversity for PPI activities, sharing of expertise, the importance of bidirectional and timely feedback, and the use of understandable language in materials.Conclusions PPI in medicines development is impactful and beneficial but is still being optimised in the pharmaceutical industry. Using the PFMD PEQG tool to define gaps, share learnings and devise recommendations for improvement helps to ensure that PPI is genuine and empowering, rather than tokenistic. Ultimately, these recommendations should be acted on to further embed PPI as an integral part of medicines development and health research within the pharmaceutical industry. This article includes a plain language summary in the supplement.

Introduction The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?’ This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.Methods and analysis We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.Ethics and dissemination This study was approved by the Yorkshire and The Humber—Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.Trial registration number ISRCTN41647111.

Introduction A substantial proportion of COVID-19 survivors continue to have symptoms more than 3 months after infection, especially of those who required medical intervention. Lasting symptoms are wide-ranging, and presentation varies between individuals and fluctuates within an individual. Improved understanding of undulation in symptoms and triggers may improve efficacy of healthcare providers and enable individuals to better self-manage their Long Covid. We present a protocol where we aim to develop and examine the feasibility and usability of digital home monitoring for capturing daily fluctuation of symptoms in individuals with Long Covid and provide data to facilitate a personalised approach to the classification and management of Long Covid symptoms.Methods and analysis This study is a longitudinal prospective cohort study of adults with Long Covid accessing 10 National Health Service (NHS) rehabilitation services in the UK. We aim to recruit 400 people from participating NHS sites. At referral to study, 6 weeks and 12 weeks, participants will complete demographic data (referral to study) and clinical outcome measures, including ecological momentary assessment (EMA) using personal mobile devices. EMA items are adapted from the COVID-19 Yorkshire Rehabilitation Scale items and include self-reported activities, symptoms and psychological factors. Passive activity data will be collected through wrist-worn sensors. We will use latent class growth models to identify trajectories of experience, potential phenotypes defined by co-occurrence of symptoms and inter-relationships between stressors, symptoms and participation in daily activities. We anticipate that n=300 participants provide 80% power to detect a 20% improvement in fatigue over 12 weeks in one class of patients relative to another.Ethics and dissemination The study was approved by the Yorkshire & The Humber—Bradford Leeds Research Ethics Committee (ref: 21/YH/0276). Findings will be disseminated in peer-reviewed publications and presented at conferences.Trial registration number ISRCTN15022307.

Introduction There are few empirically supported social and emotional well-being programmes for First Nations adolescents, and we found none targeting those living in Aboriginal communities in remote areas of Australia. The dearth of social and emotional well-being programmes is concerning given that adolescents in remote Australia are at much greater risk of mental disorder and suicide. Our pragmatic community-based research intervention ‘Enabling Dads and Improving First Nations Adolescent Mental Health’ is designed by and for First Nations people living in remote communities to promote and support the parenting role and examine the interconnection between men’s parenting knowledge and adolescent mental health. The aim is to improve adolescent mental health by strengthening the participating father’s empowerment, parenting confidence and engagement in the parenting role. The words Aboriginal, First Nation and Indigenous are applied interchangeably, as appropriate, throughout the article.Methods and analysis The intervention is currently being conducted in five remote First Nations communities in Far North Queensland, Australia. The project is funded by the Medical Research Future (MRFF UNSW RG200484), and staff recruitment and training began in early December 2020. The aim is to recruit 100 men and dyad adolescents, that is, in each of the five community sites, we will recruit 20 men and adolescent dyads at baseline. To date, we have complete data collection in one community, and fieldwork will begin in the final community in September 2023.The intervention involves a pragmatic randomised controlled trial, using a novel and culturally designed and manualised parenting programme with men (Strong Fathers, SF). The comparison group is receiving a culturally congruent and familiar yarning/relaxation (YR) condition. The SF component focuses on reinforcing knowledge related to parenting adolescents, promoting father’s empowerment, and increasing their confidence and engagement with the adolescent. The second component systematically measures and examines differences in adolescent social and emotional well-being before and after their father’s involvement in either the SF or YR. The adolescent is blind to the father’s group allocation. The outcome measures for the men include parenting knowledge, attitudes and beliefs; a First Nations measure for empowerment; the Harvard Trauma Questionnaire (Indigenous) used to assess post-traumatic stress disorder symptoms; and alcohol use. The adolescent mental health outcomes are measured by a culturally congruent social and emotional well-being measure.Ethics and dissemination Ethics approval was granted from the Aboriginal Health and Medical Research Council of Australia: Human Research Ethics Committee (1711/20). Results will be verbally shared at community meetings and conferences, and reports will be produced for community stakeholder use. Data will be available for community-controlled health services and stakeholders. Findings will also be published in peer-reviewed journals, and summaries will be provided to the funders of the study as well as male participants and adolescents.

Herpes simplex virus type 2 (HSV-2) coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2–infected and bystander 2D10 cells. Bulk and single-cell RNA-Seq studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2–infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms, including upregulation of MALAT1 to release epigenetic silencing.

Abstract Merkel cell carcinoma (MCC) is a rare neuroendocrine cutaneous cancer, with incidence of less than 1/100,000, low survival rates and variable response to chemotherapy or immunotherapy. Herein we explore the application of patient tumor organoids (PTOs) in modeling personalized research in this rare malignancy. Unsorted and non-expanded MCC tumor cells were isolated from surgical specimens and suspended in an ECM based hydrogel, along with patient matched blood and lymph node tissue to generate immune enhanced organoids (iPTOs). Organoids were treated with chemotherapy or immunotherapy agents and efficacy was determined by post-treatment viability. Nine specimens from seven patients were recruited from December 2018-January 2022. Establishment rate was 88.8% (8/9) for PTOs and 77.8% (7/9) for iPTOs. Histology on matched patient tissues and PTOs demonstrated expression of MCC markers. Chemotherapy response was exhibited in 4/6 (66.6%) specimens with cisplatin and doxorubicin as the most effective agents (4/6 PTO sets) while immunotherapy was not effective in tested iPTO sets. Four specimens from two patients demonstrated resistance to pembrolizumab, correlating with the corresponding patient’s treatment response. Routine establishment and immune enhancement of MCC PTOs is feasible directly from resected surgical specimens allowing for personalized research and exploration of treatment regimens in the preclinical setting.

Plain English Summary All major problems, including complex global problems such as air pollution and pandemics, require reliable data sharing between disciplines in order to respond effectively. Such problems require evidence-informed collaborative methods, multidisciplinary research and interventions in which the people who are affected are involved in every stage. However, there is currently no standardised way to share information about initiatives and problem-solving across and between fields such as health, environment, basic science, manufacturing, education, media and international development. A multi-disciplinary international team of over 100 citizens, experts and data-users has been involved in co-creating STARDIT to help everyone in the world share, find and understand information about collective human actions, which are referred to as ‘initiatives’. STARDIT is an open access data-sharing system to standardise the way that information about initiatives is reported, including information about which tasks were done by different people. Reports can be updated at all stages, from planning to evaluation, and can report impacts in many languages, using Wikidata. STARDIT is free to use, and data can be submitted by anyone. Report authors can be verified to improve trust and transparency, and data checked for quality. STARDIT can help create high-quality standardised information on initiatives trying to solve complex multidisciplinary global problems. Among its main benefits, STARDIT offers those carrying out research and interventions access to standardised information which enables well-founded comparisons of the effectiveness of different methods. This article outlines progress to date; current usage; information about submitting reports; planned next steps and how anyone can become involved.

Abstract Background In physiotherapy there is a growing body of literature exploring the benefits simulation could have in the university-setting, prior to the commencement of work-integrated learning. MASK-ED™ simulation is one form of simulation that could be beneficial for student learning and improve performance in the clinical setting. MASK-ED™ simulation involves an educator donning a silicone mask and portraying a patient role that has been specifically developed to meet learning objectives. Objective To evaluate the effectiveness of MASK-ED™ simulation compared to role-play with peers for training pre-clinical physiotherapy students. Methods A single-centre, single-blind, cluster randomized trial with concealed allocation, between group post-measures, and intention-to-treat analysis was conducted at an Australian university between February 2018 – January 2021. Participants were 144 physiotherapy students, cluster randomized by tutorial groups (exp n = 70, con n = 74), undertaking their neurological curricula. The experimental group was exposed to MASK-ED™ simulation in five out of a potential thirty-two tutorials (16%) whilst the control continued with role-play with peers. The primary outcome measure was Assessment of Physiotherapy Practice scores from the students’ rehabilitation work-integrated learning clinical placement. These were compared between the experimental and control groups using Mann–Whitney U tests. Secondary outcome measures include practical and written examination scores. These were compared between groups via independent t-tests. Participant satisfaction surveys were also administered to the experimental group. Results One hundred thirty-two participants’ (exp n = 62, con n = 72) results were analyzed. There were no significant differences between the experimental and control groups for Assessment of Physiotherapy Practice scores (p = 0.699–0.995). There were no significant differences found between the groups, across the secondary outcome measures. Participants found MASK-ED™ simulation was somewhat helpful for preparing them for clinical practice, however felt that a group setting was not as effective as a one-on-one encounter would have been. Conclusions MASK-ED™ simulation was no more effective than role-play with peers in preparing physiotherapy students for work-integrated learning. The influence of the design of simulation on effective learning and the number of classroom-based simulation encounters required to impact clinical performance requires further investigation.

How the body and brain respond to a gentle stroke dynamically changes depending on how familiar someone is with the other person.

Abstract Background Robotic-assisted surgeries have gradually become the standard of care for many procedures, especially in the field of urology. Despite the widespread use of robotic assistance in surgeries, data on its postoperative complications are extremely limited. We detail a rare presentation of fulminant Clostridium difficile colitis requiring surgical intervention in a patient with a solitary ectopic pelvic kidney who underwent a robotic-assisted pyelolithotomy. Highlights of the most recent management recommendations for C. difficile infection are also presented. Case presentation A 26-year-old Caucasian woman who underwent a robot-assisted pyelolithotomy of a pelvic kidney developed tachycardia, leukocytosis, and severe diarrhea 2 days following surgery. Because of her long history of antibiotic use, her severe symptoms were concerning for C. difficile colitis. This was confirmed by a C. difficile toxin test and a computed tomography scan. She was given recommended antibiotics, but her condition progressively deteriorated. The patient developed fulminant colitis and toxic megacolon, for which she underwent an exploratory laparotomy with subtotal abdominal colectomy and ileostomy creation on the twelfth day of her hospitalization. She fully recovered and was discharged 3 weeks after her subtotal colectomy. Conclusion Although robotic surgeries have been shown to have several advantages, risk of postsurgical complications remains. We present a rare case of fulminant C. difficile colitis that complicated a robotic-assisted pyelolithotomy. Active prevention, early detection, and optimization of management are essential to preventing unfavorable outcomes.

Abstract The aims of the current study, therefore, were to compare (1) free-living MPS and (2) muscle and metabolic adaptations to resistance exercise in South Asian and white European adults. Eighteen South Asian and 16 White European men were enrolled in the study. Free-living muscle protein synthesis was measured at baseline. Muscle strength, body composition, resting metabolic rate, VO2max and metabolic responses (insulin sensitivity) to a mixed meal were measured at baseline and following 12 weeks of resistance exercise training. Free-living muscle protein synthesis was not different between South Asians (1.48 ± 0.09%/day) and White Europeans (1.59 ± 0.15%/day) (p = 0.522). In response to resistance exercise training there were no differences, between South Asians and White Europeans, muscle mass, lower body strength or insulin sensitivity. However, there were differences between the ethnicities in response to resistance exercise training in body fat, resting carbohydrate and fat metabolism, blood pressure, VO2max and upper body strength with responses less favourable in South Asians. In this exploratory study there were no differences in muscle protein synthesis or anabolic and metabolic responses to resistance exercise, yet there were less favourable responses in several outcomes. These findings require further investigation.

Abstract Background Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. Results Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. Conclusions The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org