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Background: Postgraduate medical training is undergoing major change, shortening and disrupting traditional practices. Scholarship remains highly valued, but increasingly difficult to fit in. Workplace-based Masters study offers a solution., Aims: We want consultants who are driven by enquiry, good teachers and team workers. Academic qualifications demonstrate trainees' commitment and expertise in competitive employment markets. Most Deaneries allow two sessions weekly for research/personal development, so this resource demands effective use., Methods: The good will, talent and commitment of colleagues are vital. A credible structured curriculum combines real-life consultant-level generic practice, with technical medical skills. Academic writing and practical assignments are assessed. Linking with a far-sighted academic institution brings vast expertise in education administration and delivery of accredited learning., Results: The course is more cost-effective than traditional study leave activities. Running part-time over 4 years fits with Higher Specialist Training. Structured programmes, over 9 month 'terms', fit with clinical rotations. Module leaders run yearly clinical modules alongside continuous generic modules. Clinical units are signed up to releasing trainees to attend. Evaluation is external to faculty, with highly favourable feedback., Conclusions: We believe training in academic disciplines underpins practice. With strong partnership working, planning and especially hard work, such a course is deliverable.

The academic discipline of kinesiology is relatively new (1960s) and is devoted to the study of human movement. The knowledge base and subject of study continues to develop and now includes inquiry regarding the impact of physical activity on health, society, and quality of life. The purpose of this course content evaluation was to identify kinesiology students' views on the addition of public health content in the curriculum. A lecture addressing the background history of public health, with supported reading, was given to forty students enrolled in an upper level Bachelor of Kinesiology-health course. Students were advised of the inclusion of this topic on the final exam and that their responses would be used to inform future direction of the course material. Students were asked to provide their opinion, through a written response to the question: Does public health belong in the Faculty of Kinesiology? A content analysis was employed and seven themes were identified from students' responses. The themes highlighted professional experience, enhanced leadership, and health promotion and physical activity's contribution to health. In summary, students positively evaluated the inclusion of public health within the kinesiology curriculum and perhaps this is not surprising given the scoring associated with the question. Despite this limitation, students provided insightful responses worthy of reflection that should be considered in a dialogue about the inclusion of public health content in the kinesiology curriculum.

The Latinx population in the United States is disproportionately affected by HIV. Our community-based participatory research partnership developed, implemented and evaluated a Spanish-language peer navigation intervention designed to increase HIV testing and condom use among social networks of immigrant Spanish-speaking Latinx gay, bisexual and other men who have sex with men (GBMSM) and transgender women (TW). We randomized 21 social networks of Latinx GBMSM and TW, ages 18-55 years, to the intervention, known as "HOLA," or a waitlist control group. Social network participants (n = 166) completed structured assessments at baseline and 12-month follow-up (24 months after baseline). Follow-up retention was 95%. Individual in-depth interviews with a sample of participants documented their intervention-related experiences, needs, and priorities to inform future research. At follow-up, "HOLA" participants reported increased HIV testing (adjusted odds ratio = 8.3; 95% CI = 3.0-23.0; P < 0.0001). All study participants reported increased condom use; there was no significant difference between HOLA and waitlist control participants. In-depth interviews identified critical intervention elements and impacts and community needs and priorities. The "HOLA" intervention is effective for increasing HIV testing among Latinx GBMSM and TW, an initial step within the HIV prevention and care continua, and may be adaptable to promote pre-exposure prophylaxis uptake.

Abstract Most simulations of electric field driven bioeffects have considered spherical cellular geometries or probed symmetrical structures for simplicity. This work assesses cellular transmembrane potential build-up and electroporation in a Jurkat cell that includes the endoplasmic reticulum (ER) and mitochondria, both of which have complex shapes, in response to external nanosecond electric pulses. The simulations are based on a time-domain nodal analysis that incorporates membrane poration utilizing the Smoluchowski model with angular-dependent changes in membrane conductivity. Consistent with prior experimental reports, the simulations show that the ER requires the largest electric field for electroporation, while the inner mitochondrial membrane (IMM) is the easiest membrane to porate. Our results suggest that the experimentally observed increase in intracellular calcium could be due to a calcium induced calcium release (CICR) process that is initiated by outer cell membrane breakdown. Repeated pulsing and/or using multiple electrodes are shown to create a stronger poration. The role of mutual coupling, screening, and proximity effects in bringing about electric field modifications is also probed. Finally, while including greater geometric details might refine predictions, the qualitative trends are expected to remain.

Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher-order control regions to lower-order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter-subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto-parietal network and lower-level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability.

Abstract Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a few other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad spectrum of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

Abstract MYCN-amplified RB1 wild-type (MYCN amp RB1 +/+) retinoblastoma is a rare and aggressive subtype, often resistant to standard therapies. Identifying unique MRI features is crucial for diagnosing this subtype, as biopsy is not recommended. This study aimed to differentiate MYCN amp RB1 +/+ from the most prevalent RB1 -/- retinoblastoma using pretreatment MRI and radiomics. Ninety-eight unilateral retinoblastoma patients (19 MYCN cases and 79 matched controls) were included. Tumors on T2-weighted MR images were manually delineated and validated by experienced radiologists. Radiomics analysis extracted 120 features per tumor. Several combinations of feature selection methods, oversampling techniques and machine learning (ML) classifiers were evaluated in a repeated fivefold cross-validation machine learning pipeline to yield the best-performing prediction model for MYCN. The best model used univariate feature selection, data oversampling (duplicating MYCN cases), and logistic regression classifier, achieving a mean AUC of 0.78 (SD 0.12). SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCN amp RB1 +/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCN amp RB1 +/+ and RB1 -/- retinoblastoma subtypes.

Abstract Moral injury has emerged as a construct of interest in healthcare workers’ (HCW) occupational stress and health. We conducted one of the first multidisciplinary, longitudinal studies evaluating the relationship between exposure to potentially morally injurious events (PMIEs), burnout, and turnover intentions. HCWs (N = 473) completed surveys in May of 2020 (T1) and again in May of 2021 (T2). Generalized Linear Models (robust Poisson regression) were used to test relative risk of turnover intentions, and burnout at T2 associated with PMIE exposure, controlling for T1 covariates. At T1, 17.67% reported they had participated in a PMIE, 41.44% reported they witnessed a PMIE and 76.61% reported feeling betrayed by healthcare or a public health organization. In models including all T1 PMIE exposures and covariates, T2 turnover intentions were increased for those who witnessed a PMIE at T1 (Relative Risk [RR] = 1.66, 95% Confidence Interval [CI] 1.17–2.34) but not those that participated or felt betrayed. T2 burnout was increased for those who participated in PMIE at T1 (RR = 1.38, 95%CI 1.03–1.85) but not those that witnessed or felt betrayed. PMIE exposure is highly prevalent among HCWs, with specific PMIEs associated with turnover intentions and burnout. Organizational interventions to reduce and facilitate recovery from moral injury should account for differences in the type of PMIE exposures that occur in healthcare work environments.

Abstract The adoption of transformer networks has experienced a notable surge in various AI applications. However, the increased computational complexity, stemming primarily from the self-attention mechanism, parallels the manner in which convolution operations constrain the capabilities and speed of convolutional neural networks (CNNs). The self-attention algorithm, specifically the matrix-matrix multiplication (MatMul) operations, demands a substantial amount of memory and computational complexity, thereby restricting the overall performance of the transformer. This paper introduces an efficient hardware accelerator for the transformer network, leveraging memristor-based in-memory computing. The design targets the memory bottleneck associated with MatMul operations in the self-attention process, utilizing approximate analog computation and the highly parallel computations facilitated by the memristor crossbar architecture. Remarkably, this approach resulted in a reduction of approximately 10 times in the number of multiply-accumulate (MAC) operations in transformer networks, while maintaining 95.47% accuracy for the MNIST dataset, as validated by a comprehensive circuit simulator employing NeuroSim 3.0. Simulation outcomes indicate an area utilization of 6895.7 $$\mu m^2$$ μ m 2 , a latency of 15.52 seconds, an energy consumption of 3 mJ, and a leakage power of 59.55 $$\mu W$$ μ W . The methodology outlined in this paper represents a substantial stride towards a hardware-friendly transformer architecture for edge devices, poised to achieve real-time performance.

Abstract Although abdominal aortic aneurysms (AAA) are more common in men, women are at greater risk for AAA growth/rupture. Vascular deformation mapping (VDM) utilizes deformable image registration to qualify and quantify 3D-AAA growth using computed tomography angiograms (CTA). In this study we leveraged VDM to investigate sex differences in AAA growth patterns. Patients with infra-renal AAA and ≥ 2 CTA were identified. Males and females were matched for age, hypertension, and smoking history. Patient characteristics, maximum diameter (Dmax), and AAA volume were obtained. CTA images were segmented, and VDM was conducted to quantify 3D AAA growth rate per year (GR, cm/year). Statistical shape modeling was utilized to compute mean aneurysm shapes and 3D GR. Average GR was evaluated at specific regions of the aortic surface for males and females. Seventeen males and 17 females were matched. At the individual level, there were no sex differences in changes in Dmax or AAA volume. However, females had larger GR across the anterior and right lateral AAA (1.33 vs 0.89 and 1.56 vs 0.74 cm/year, respectively), despite no difference in posterior or left lateral AAA GR. Despite comparable changes in Dmax, AAA volume, and GR magnitude, women demonstrated a more eccentric, anterior-predominant, AAA growth pattern.

Abstract Oral potentially malignant disorders (OPMDs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are typically obtained through invasive tissue biopsy. However, brush biopsy is a non-invasive method that has been utilized for identifying dysplastic cells in OPMD but its effectiveness in reflecting the genomic landscape of OPMDs remains uncertain. This pilot study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile and tumor evolution in a patient with both OPMD and OSCC. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal architectures in paired tissue and brush biopsy samples. The results showed that brush biopsy effectively captured 90% of SNVs and had similar CNA profiles as those seen in its paired tissue biopsies in all lesions. It was specific, as normal buccal mucosa did not share these genomic alterations. Interestingly, brush biopsy revealed shared SNVs and CNAs between the distinct OPMD and OSCC lesions from the same patient, indicating a common ancestral origin. Subclonal reconstruction confirmed this shared ancestry, followed by divergent evolution of the lesions. These findings highlight the potential of brush biopsies in accurately representing the genomic profile of OPL and OSCC, proving insight into reconstructing tumor evolution.

Abstract Recent advances in 3D printing have enabled the manufacture of porous electrodes which cannot be machined using traditional methods. With micron-scale precision, the pore structure of an electrode can now be designed for optimal energy efficiency, and a 3D printed electrode is not limited to a single uniform porosity. As these electrodes scale in size, however, the total number of possible pore designs can be intractable; choosing an appropriate pore distribution manually can be a complex task. To address this challenge, we adopt an inverse design approach. Using physics-based models, the electrode structure is optimized to minimize power losses in a flow reactor. The computer-generated structure is then printed and benchmarked against homogeneous porosity electrodes. We show how an optimized electrode decreases the power requirements by 16% compared to the best-case homogeneous porosity. Future work could apply this approach to flow batteries, electrolyzers, and fuel cells to accelerate their design and implementation.

Abstract Phylogenomic data are revolutionizing the field of insect phylogenetics. One of the most tenable and cost-effective methods of generating phylogenomic data is target enrichment, which has resulted in novel phylogenetic hypotheses and revealed new insights into insect evolution. Orthoptera is the most diverse insect order within polyneoptera and includes many evolutionarily and ecologically interesting species. Still, the order as a whole has lagged behind other major insect orders in terms of transitioning to phylogenomics. In this study, we developed an Orthoptera-specific target enrichment (OR-TE) probe set from 80 transcriptomes across Orthoptera. The probe set targets 1828 loci from genes exhibiting a wide range of evolutionary rates. The utility of this new probe set was validated by generating phylogenomic data from 36 orthopteran species that had not previously been subjected to phylogenomic studies. The OR-TE probe set captured an average of 1037 loci across the tested taxa, resolving relationships across broad phylogenetic scales. Our detailed documentation of the probe design and bioinformatics process is intended to facilitate the widespread adoption of this tool.

Abstract Nanomechanical oscillators are an alternative platform for computation in harsh environments. However, external perturbations arising from such environments may hinder information processing by introducing errors into the computing system. Here, we simulate the dynamics of three coupled Duffing oscillators whose multiple equilibrium states can be used for information processing and storage. Our analysis reveals that, within experimentally relevant parameters, error correcting dynamics can emerge, wherein the system’s state is robust against random external impulses. We find that oscillators in this configuration have several surprising and attractive features, including dynamic isolation of resonators exposed to extreme impulses and the ability to correct simultaneous errors.

Abstract Capacitation is an essential post-testicular maturation event endowing spermatozoa with fertilizing capacity within the female reproductive tract, significant for fertility, reproductive health, and contraception. By using a human-relevant large animal model, the domestic boar, this study focuses on furthering our understanding of the involvement of the ubiquitin-proteasome system (UPS) in sperm capacitation. The UPS is a universal, evolutionarily conserved, cellular proteome-wide degradation and recycling machinery, that has been shown to play a significant role in reproduction during the past two decades. Herein, we have used a bottom-up proteomic approach to (i) monitor the capacitation-related changes in the sperm protein levels, and (ii) identify the targets of UPS regulation during sperm capacitation. Spermatozoa were capacitated under proteasomal activity-permissive and inhibiting conditions and extracted sperm proteins were subjected to high-resolution mass spectrometry. We report that 401 individual proteins differed at least two-fold in abundance (P

Abstract Youth screen media activity is a growing concern, though few studies include objective usage data. Through the longitudinal, U.S.-based Adolescent Brain Cognitive Development (ABCD) Study, youth (mage = 14; n = 1415) self-reported their typical smartphone use and passively recorded three weeks of smartphone use via the ABCD-specific Effortless Assessment Research System (EARS) application. Here we describe and validate passively-sensed smartphone keyboard and app use measures, provide code to harmonize measures across operating systems, and describe trends in adolescent smartphone use. Keyboard and app-use measures were reliable and positively correlated with one another (r = 0.33) and with self-reported use (rs = 0.21–0.35). Participants recorded a mean of 5 h of daily smartphone use, which is two more hours than they self-reported. Further, females logged more smartphone use than males. Smartphone use was recorded at all hours, peaking on average from 8 to 10 PM and lowest from 3 to 5 AM. Social media and texting apps comprised nearly half of all use. Data are openly available to approved investigators ( https://nda.nih.gov/abcd/ ). Information herein can inform use of the ABCD dataset to longitudinally study health and neurodevelopmental correlates of adolescent smartphone use.

Abstract A theoretical perspective on grandiose narcissism suggests four forms of it (sanctity, admiration, heroism, rivalry) and states that these forms conduce to different ways of thinking and acting. Guided by this perspective, we examined in a multinational and multicultural study (61 countries; N = 15,039) how narcissism forms are linked to cognitions and behaviors prompted by the COVID-19 pandemic. As expected, differences in cognitions and behaviors across narcissism forms emerged. For example, higher narcissistic rivalry predicted lower likelihood of enactment of COVID-19 prevention behaviors, but higher narcissistic sanctity predicted higher likelihood of enactment of COVID-19 prevention behaviors. Further, whereas the heroism, admiration, and rivalry narcissism forms acted in a typically antisocial manner, with high narcissism predicting greater endorsement of unfounded health beliefs, the sanctity form acted in a prosocial manner, with higher narcissism being linked to lower endorsement of unfounded COVID-19 health beliefs. Thus, the findings (a) support the idea of four narcissism forms acting differently, and (b) show that these differences reflect a double-edged sword, sometimes linking to an anti-social orientation, and sometimes linking to a pro-social orientation.

Abstract Background Engagement and partnership with consumers and communities throughout research processes produces high quality research meeting community needs and promoting translation of research into improved policy and practice. Partnership is critical in research involving Aboriginal and/or Torres Strait Islander people (First Nations Peoples) to ensure cultural safety. We present lessons from the design, implementation and progress of the National Health and Medical Research Council funded INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on hemodialysis (INFERR) clinical trial. Main body The trial was designed to understand the benefits and harms of iron therapy in First Nations Australians on haemodialysis with anaemia and hyperferritinaemia. The lack of evidence for treatment was discussed with patients who were potential participants. A key element ensuring safe conduct of the INFERR trial was the establishment of the Indigenous Reference Groups (IRGs) comprising of dialysis patients based in the Top End of Australia and Central Australia. Two IRGs were needed based on advice from First Nations communities and researchers/academics on the project regarding local cultural differences and approaches to trial conduct. The IRGs underpin culturally safe trial conduct by providing input into study materials and translating study findings into effective messages and policies for First Nations dialysis patients. Throughout the trial conduct, the IRGs’ role has developed to provide key mechanisms for advice and guidance regarding research conduct both in this study and more broadly. Support provided to the IRGs by trial First Nations Research Officers and independent First Nations researchers/academics who simplify research concepts is critical. The IRGs have developed feedback documents and processes to participants, stakeholders, and the renal units. They guarantee culturally safe advice for embedding findings from the trial into clinical practice guidelines ensuring evidence-based approaches in managing anaemia in haemodialysis patients with hyperferritinaemia. Conclusion Active consumer and community partnership is critical in research conduct to ensure research impact. Strong partnership with consumers in the INFERR clinical trial has demonstrated that First Nations Consumers will engage in research they understand, that addresses health priorities for them and where they feel respected, listened to, and empowered to achieve change.

Abstract Background The tumor microenvironment is profoundly heterogeneous particularly when comparing sites of metastases. Establishing the extent of this heterogeneity may provide guidance on how best to design lipid-based drug delivery systems to treat metastatic disease. Building on our previous research, the current study employs a murine model of metastatic cancer to explore the distribution of ~ 100 nm liposomes. Methods Female NCr nude mice were inoculated with a fluorescently labeled, Her2/neu-positive, trastuzumab-resistant breast cancer cell line, JIMT-1mkate, either in the mammary fat pad to create an orthotopic tumor (OT), or via intracardiac injection (IC) to establish tumors throughout the body. Animals were dosed with fluorescent and radio-labeled liposomes. In vivo and ex vivo fluorescent imaging was used to track liposome distribution over a period of 48 h. Liposome distribution in orthotopic tumors was compared to sites of tumor growth that arose following IC injection. Results A significant amount of inter-vessel heterogeneity for DiR distribution was observed, with most tumor blood vessels showing little to no presence of the DiR-labelled liposomes. Further, there was limited extravascular distribution of DiR liposomes in the perivascular regions around DiR-positive vessels. While all OT tumors contained at least some DiR-positive vessels, many metastases had very little or none. Despite the apparent limited distribution of liposomes within metastases, two liposomal drug formulations, Irinophore C and Doxil, showed similar efficacy for both the OT and IC JIMT-1mkate models. Conclusion These findings suggest that liposomal formulations achieve therapeutic benefits through mechanisms that extend beyond the enhanced permeability and retention effect.

COVID-19 vaccination was launched in March 2021 in Uganda and initially prioritized persons >50 years of age, persons with underlying conditions, healthcare workers, teachers, and security forces. However, uptake remained low 5 months after the program launch. Makerere University’s Infectious Diseases Institute supported Uganda’s Ministry of Health in optimizing COVID-19 vaccination uptake models by using point-of-care, place of worship, and place of work engagement and the Social Assistance Grant for Empowerment model in 47 of 135 districts in Uganda, where we trained influencers to support mobilization for vaccination outreach under each model. During July–December, vaccination rates increased significantly in targeted regions, from 92% to 130% for healthcare workers, 40% to 90% for teachers, 25% to 33% for security personnel, 6% to 15% for persons >50 years of age, and 6% to 11% for persons with underlying conditions. Our approach could be adopted in other targeted vaccination campaigns for future pandemics.

Abstract As genomic databases expand and artificial intelligence tools advance, there is a growing demand for efficient characterization of large numbers of proteins. To this end, here we describe a generalizable pipeline for high-throughput protein purification using small-scale expression in E. coli and an affordable liquid-handling robot. This low-cost platform enables the purification of 96 proteins in parallel with minimal waste and is scalable for processing hundreds of proteins weekly per user. We demonstrate the performance of this method with the expression and purification of the leading poly(ethylene terephthalate) hydrolases reported in the literature. Replicate experiments demonstrated reproducibility and enzyme purity and yields (up to 400 µg) sufficient for comprehensive analyses of both thermostability and activity, generating a standardized benchmark dataset for comparing these plastic-degrading enzymes. The cost-effectiveness and ease of implementation of this platform render it broadly applicable to diverse protein characterization challenges in the biological sciences.

Abstract Nonpharmaceutical interventions (NPIs) implemented during the COVID-19 pandemic have disrupted the dynamics of respiratory syncytial virus (RSV) on a global scale; however, the cycling of RSV subtypes in the pre- and post-pandemic period remains poorly understood. Here, we used a two subtype RSV model supplemented with epidemiological data to study the impact of NPIs on the two circulating subtypes, RSV-A and RSV-B. The model is calibrated to historic RSV subtype data from the United Kingdom and Finland and predicts a tendency for RSV-A dominance over RSV-B immediately following the implementation of NPIs. Using a global genetic dataset, we confirm that RSV-A has prevailed over RSV-B in the post-pandemic period, consistent with a higher R0 for RSV-A. With new RSV infant monoclonals and maternal and elderly vaccines becoming widely available, these results may have important implications for understanding intervention effectiveness in the context of disrupted subtype dynamics.

Abstract Background: Solving complex research challenges requires innovative thinking and alternative approaches to traditional methods. One such example is the problem of arm and hand, or upper limb function in multiple sclerosis (MS), a neurological condition affecting approximately 2.9 million people worldwide and more than 150,000 in the United Kingdom. Historically, clinical trials and research have focused on mobility and walking ability. This excludes a large number of patients who are wheelchair users, limiting their quality of life and restricting access to possibly helpful medications. To address this issue, the ThinkHand campaign was launched in 2016, aiming to raise awareness about the importance of upper limb function in MS and develop alternative ways to measure, record, and account for hand and arm function changes. Main body: The campaign utilised innovative strategies at scientific conferences and online surveys to engage people affected by MS, healthcare professionals, charities, and researchers in discussing the importance of preserving upper limb function. Through co-design and interdisciplinary collaboration, the campaign developed new tools like the low-cost cardboard version of the Nine-Hole Peg Test, facilitating remote monitoring of hand function. Additionally, the campaign co-created the “Under & Over” rehabilitation tool, allowing individuals with advanced MS to participate in a remote rehabilitation program. The impact of the ThinkHand campaign has been significant, helping to shift the focus of both academic and industry-supported trials, including the O’HAND and ChariotMS trials, both using upper limb function as their primary end point. The campaign’s patient-centred approach highlighted the importance of recognising patients’ perspectives in research and challenged established assumptions and practices. It demonstrated the effectiveness of interdisciplinary collaboration, systems thinking, and co-creation with stakeholders in tackling complex problems. Conclusion: The ThinkHand campaign provides valuable insights for health research practices. By involving patients at all stages, researchers can gain a deeper understanding of the impact of disease on their lives, identify gaps and focus research on their needs. Experimentation and iteration can lead to innovative solutions, and openness to unconventional methods can drive widespread change. The ThinkHand campaign exemplifies the potential of patient-centred approaches to address complex research challenges and revolutionise the field of MS research and management. Embracing such approaches will contribute to more inclusive and impactful research in the future.

Abstract Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8–10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.

Abstract Sociodemographic and lifestyle factors (sleep, physical activity, and sedentary behavior) may predict obesity risk in early adolescence; a critical period during the life course. Analyzing data from 2971 participants (M = 11.94, SD = 0.64 years) wearing Fitbit Charge HR 2 devices in the Adolescent Brain Cognitive Development (ABCD) Study, glass box machine learning models identified obesity predictors from Fitbit-derived measures of sleep, cardiovascular fitness, and sociodemographic status. Key predictors of obesity include identifying as Non-White race, low household income, later bedtime, short sleep duration, variable sleep timing, low daily step counts, and high heart rates (AUCMean = 0.726). Findings highlight the importance of inadequate sleep, physical inactivity, and socioeconomic disparities, for obesity risk. Results also show the clinical applicability of wearables for continuous monitoring of sleep and cardiovascular fitness in adolescents. Identifying the tipping points in the predictors of obesity risk can inform interventions and treatment strategies to reduce obesity rates in adolescents.

Abstract Due to growing interest in the investigation of exercise induced sweat biomarkers to assess an individual’s health and the increasing prevalence of tattoos in the world’s population, investigators sought to determine whether local sweat concentrations and excretion rates of epidermal growth factor (EGF), interleukin (IL) -1α, IL-6, IL-8, cortisol, glucose, blood urea nitrogen (BUN), and lactate differ between tattooed and contralateral non-tattooed skin during exercise. Sixteen recreational exercisers [female (50%)] (age = 25–48 years) with ≥ 1 unilateral permanent tattoo [median tattoo age = 6 years, IQR = 5] on the arm/torso completed an outdoor group fitness session. There were no significant differences between tattooed and non-tattooed skin for sweat EGF, IL-1α, IL-8, cortisol, glucose, BUN, or lactate concentrations. There were no significant differences between tattooed and non-tattooed skin for sweat EGF, IL-1α, IL-8, cortisol, glucose, BUN, or lactate excretion rate. Findings suggest that permanent tattoos older than 1 year may not impact local sweat EGF, IL-1α, IL-8, cortisol, glucose, BUN, and lactate concentrations or excretion rates during exercise. Clinical trial identifier NCT04920266 was registered on June 9, 2021.

Abstract Objective To investigate the prevalence and sociodemographic associations of online dating in a demographically diverse U.S. national cohort of early adolescents. Methods We analyzed cross-sectional data from the Adolescent Brain Cognitive Development Study (Year 2, 2018–2020, ages 11–12; N = 10,157). Multivariable logistic regression analyses were employed to estimate associations between sociodemographic factors (e.g., age, sex, race/ethnicity, sexual orientation, household income, parental education) and early adolescent-reported online dating behaviors. Results Overall, 0.4% (n = 38) of participants reported ever using a dating app. Males (AOR 2.72, 95% CI 1.11–6.78) had higher odds of online dating compared to females, and sexual minority identification (e.g., lesbian, gay, or bisexual; AOR 12.97, 95% CI 4.32–38.96) was associated with greater odds of online dating compared to heterosexual identification. Conclusion Given the occurrence of online dating among early adolescents despite age restrictions, interventions might address age misrepresentation. Adolescent sexual health education may consider incorporating anticipatory guidance on online dating, especially for males and sexual minorities. Future research could further investigate online dating patterns from early to late adolescence and associated health effects.

Abstract Background This study was initiated and co-designed by a Participant and Public Involvement (PPI) group attached to HOMESIDE, a randomized controlled trial that investigated music and reading interventions for people living with dementia and their family caregivers across five countries: Australia, Germany, Norway, Poland, and the UK. The aim was to capture experiences of PPI across the five countries, explore the benefits and challenges of PPI in dementia research, and identify contributions made to the study. Methods We surveyed PPI members and academic researchers who collaborated on the HOMESIDE study. The survey was co-designed through consultation with PPI members and academics, alongside a small scoping literature review. Survey questions covered four topics: (1) expectations for PPI, (2) perceived contributions of PPI to the research study, (3) benefits and challenges of PPI, and (4) recommendations for future PPI in dementia research. Results There were 23 responses, representing 50% of the PPI members (n = 16) and 29% of academics (n = 7). PPI was found to be beneficial to the research and individuals involved. Contributions to the research included supporting recruitment and publicity, advising on the design of participant-facing materials, guiding the design and delivery of the interventions, and identifying cultural differences affecting research delivery. PPI members benefited from building connections, sharing experiences and receiving support, learning about dementia and research, and gaining new unexpected experiences. Academics learned about the realities of living with dementia, which they felt informed and grounded their work. Several challenges were identified, including the need for clear expectations and objectives, inconsistency of PPI members across research stages, limitations of meeting online versus in-person, scheduling difficulties, and language barriers. Conclusions This study identifies important considerations for implementing PPI within dementia studies and international healthcare research more broadly. Our findings guided the development of five recommendations: (1) involve PPI members as early as possible and throughout the research process; (2) create a space for constructive criticism and feedback; (3) have clear tasks, roles, and expectations for PPI members; (4) involve PPI members with a diverse range of experiences and backgrounds; and (5) embed infrastructure and planning to support PPI.

Abstract One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Open day activities rarely give applicants a real sense of the practical and intellectual work that goes on in university chemistry departments. We devised an experiment for year 13 (age 17-18) students based on the size-dependent colours of gold nanoparticles and linked this to current research in diagnostic medicine. The experience was designed to demonstrate the benefits of nanotechnology but it did so through the allure of gold. (Contains 5 figures and 1 table.)

Black men in the United States face disproportionately high rates of firearm violence, leading to death and disability more often than males of other racial/ethnic groups. Managing life after such injuries involves significant challenges in daily activities, employment, and pain management. Despite the critical impacts of firearm-related disabilities on Black men, their experiences remain largely unexplored by disability scholars, public health researchers, and practitioners. This oversight is alarming, as Black men with firearm-acquired disabilities encounter considerable structural barriers to achieving health and social objectives. Our team focuses on: (a) the experiences of Black men with firearm-acquired disabilities, (b) the lack of literature on their lived realities, and (c) new pathways for disability and public health research. Recognizing and addressing the invisibility of violently injured Black men in research is crucial for advancing equity, social justice, and representation across society. We argue that disability justice is a vital starting point for acknowledging the social experiences of gunshot wound survivors. More research is needed to understand the experiences of these young Black men who have been largely ignored in public health and disability narratives. It is essential for clinicians and policymakers to grasp how this neglect affects conventional views on health, accessibility, and well-being, underscoring the need for a more inclusive and equitable approach.

Summary: Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID. Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.). Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events. Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions. Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

Introduction: Older adults are at risk of developing new or worsened disability when hospitalized for acute medical illness. This study is a secondary analysis of the STAND-Cph trial on the effect of a simple strength training intervention initiated during hospitalization and continued after discharge. We investigated the between-group difference in change in functional performance outcomes, the characteristics of patients who experienced a relevant effect of the intervention, and the characteristics of those who were compliant with the intervention, using an expanded sample size as protocolized. Methods: The STAND-Cph was a randomized controlled trial conducted at a major Danish university hospital. Acutely admitted older adult patients (65+) from the Emergency Department were randomized to the intervention group receiving progressive strength training and a protein supplement during and after hospitalization (12 sessions over 4 weeks) or control group receiving usual care. The primary outcome was the de Morton Mobility Index assessed at baseline and 4 weeks after discharge. The secondary outcomes were 24-h mobility (assessed by ActivPAL accelerometers), isometric knee-extension strength, 30 s. sit-to-stand performance, and habitual gait speed. Results: Between September 2013 and September 2018, a total of 158 patients were included and randomized to either the intervention group (N = 80; mean age 79.9 ± 7.6 years) or the control group (N = 78; mean age 80.8 ± 7.4 years). We found no significant between-group difference in change in our primary outcome (p > 0.05). Both the intention-to-treat (difference in change 0.14 Nm/kg (95 % CI 0.03;0.24), p = 0.01) and the per protocol (difference in change 0.16 Nm/kg (95 % CI 0.04;0.29), p = 0.008) analyses showed that between baseline and 4 weeks, knee-extension strength increased significantly more in the intervention group than in the control group. Also, the per protocol analysis showed that the intervention group increased their daily number of steps significantly more than the control group (difference in change 1088 steps (95 % CI 44; 2132); p = 0.04). When examining subgroups of patients, we found no significant differences neither between those who experienced a clinically relevant improvement in the de Morton Mobility Index and those who did not, nor between those who were compliant and those who were not. Conclusion: This exploratory analysis indicates that while simple progressive strength training and protein supplementation does not improve functional performance assessed by the de Morton Mobility Index, it can benefit specific facets of physical activity and muscle strength among geriatric patients.

Amegakaryocytic thrombocytopenia is a rare hematologic disorder characterized by a profound reduction in platelet production due to the near absence of megakaryocytes, leading to severe thrombocytopenia. This case report elucidates the diagnostic and therapeutic challenges encountered in managing such rare hematological conditions alongside significant cardiovascular disease. We detail the case of a patient who presented with chest pain and was diagnosed with non-ST elevation myocardial infarction (NSTEMI). Subsequent investigations revealed severe thrombocytopenia and underlying triple vessel disease, complicating immediate surgical intervention. Initial management strategies aimed at treating presumed immune thrombocytopenia proved ineffective. A definitive diagnosis of amegakaryocytic thrombocytopenia was established following a bone marrow biopsy. Despite treatment adjustments, including the administration of thrombopoietin agonists and immunosuppression, platelet counts improved but did not reach levels safe for coronary artery bypass grafting (CABG). This case underscores the critical importance of achieving adequate hematologic stability prior to surgical procedures in patients with complex cardio-hematologic profiles to minimize perioperative risks and optimize patient outcomes, illustrating the ongoing challenges in managing severe thrombocytopenia in cardiac patients.

BackgroundDespite the increased accessibility and availability of technology in recent years, equality and access to health-related technology remain limited to some demographics. In particular, patients who are older or from rural communities represent a large segment of people who are currently underusing mobile health (mHealth) solutions. System usability continues to hinder mHealth adoption among users with nontraditional digital literacy. ObjectiveThis study aims to investigate if state-of-the-art mobile app interfaces from open-source libraries provide sufficient usability for rural patients with cancer, with minimal design changes and forgoing the co-design process. MethodsWe developed Assuage (Network Reconnaissance Lab) as a research platform for any mHealth study. We conducted a pilot study using Assuage to assess the usability of 4 mobile user interfaces (UIs) based on open-source libraries from Apple’s ResearchKit and CareKit. These UIs varied in complexity for reporting distress symptoms. Patients with cancer were recruited at the Markey Cancer Center, and all research procedures were conducted in person. Participants completed the distress assessment using a randomly selected UI in Assuage with little to no assistance. Data were collected on participant age, location, mobile app use, and familiarity with mHealth apps. Participants rated usability with the System Usability Scale (SUS), and usability issues were documented and compared. A one-way ANOVA was used to compare the effect of the UIs on the SUS scores. ResultsWe recruited 30 current or postsurgery patients with cancer for this pilot study. Most participants were aged >50 years (24/30, 80%), from rural areas (25/30, 83%), had up to a high school education (19/30, 63%), and were unfamiliar with mHealth apps (21/30, 70%). General mobile app use was split, with 43% (14/30) of the patients not regularly using mobile apps. The mean SUS score across the UIs was 75.8 (SD 22.2), with UI 3 and UI 4 achieving an SUS score ≥80, meeting the industry standard for good usability of 80. Critical usability issues were related to data input and navigation with touch devices, such as scale-format questions, vertical scrolling, and traversing multiple screens. ConclusionsThe findings from this study show that most patients with cancer (20/30, 67%) who participated in this study rated the different interfaces of Assuage as above-average usability (SUS score >68). This suggests that Apple’s ResearchKit and CareKit libraries can provide usable UIs for older and rural users with minimal interface alterations. When resources are limited, the design stage can be simplified by omitting the co-design process while preserving suitable usability for users with nontraditional technical proficiency. Usability comparable to industry standards can be achieved by considering heuristics for interface and electronic survey design, specifically how to segment and navigate surveys, present important interface elements, and signal gestural interactions.

Background In the UK, one in four patients are in work at the time of their hip or knee replacement surgery. These patients receive little support about their return to work (RTW). There is a need for an occupational support intervention that encourages safe and sustained RTW which can be integrated into National Health Service practice. We developed a two-arm intervention trial, based on a feasibility study, to assess whether an occupational support intervention (the OPAL (Occupational support for Patients undergoing Arthroplasty of the Lower limb) intervention) is effective in supporting a reduced time to full, sustained RTW compared with usual care in patients undergoing hip and knee replacement.Methods and analysis This is a multicentre, individually randomised controlled superiority trial comparing the OPAL intervention to usual care. 742 working adults listed for elective primary hip or knee replacement, who intend to RTW, will be randomised to the OPAL intervention or usual care. The intervention comprises: (1) multimedia information resources; and (2) support from a designated RTW coordinator. The primary outcome is time until ‘full’ sustained RTW without sick leave for a consecutive 4-week period. Secondary outcomes are: time to any RTW, measures of functional recovery, number of ‘sick days’ between surgery and ‘full’ sustained RTW and the use of workplace modifications to facilitate their return. A health economic evaluation and a mixed methods process evaluation will assess cost-effectiveness and the implementation, fidelity and acceptability of the intervention, respectively. Outcomes will be collected at baseline, 3, 6, 9 and 12-month follow-up time points, as well as a monthly RTW questionnaire.Ethics and dissemination Dissemination will focus on supporting the wider adoption and implementation of the intervention (if effective) and will target groups for whom the results will be relevant. This trial was approved by West Midlands—Edgbaston REC 23/WM/0013.Trial registration number ISRCTN13694911.

Introduction: Lung cancer is the leading cause of cancer death among American Indian and Alaska Native (AI/AN) people, and AI/AN people have the highest rate of smoking of any racial or ethnic group in the US. There is limited research to inform culturally-relevant strategies for lung cancer prevention inclusive of lung cancer screening (LCS). The objective of this study was to understand determinants of LCS and tobacco cessation care in at-risk urban-dwelling AI/ANs. Materials and Methods: This was a mixed-methods community-based participatory research study including complimentary qualitative discussions and surveys conducted in Seattle, Washington, USA from 2022 to 2023. The study measures and analytic approach integrated the Consolidated Framework for Implementation Research and Tribal Critical Race Theory and qualitative transcripts were analyzed using thematic analysis. Participants were self-identified AI/AN people who were age ≥ 40 and had ≥ 10-year history of commercial cigarette smoking. Results: Forty-five participants completed surveys and participated in discussions, 48% were female, the median age was 58 and median smoking history was 24 pack-years of commercial cigarette use. Themes revealed prominent barriers to LCS care including access, costs, awareness, and fear. Many reported previous negative and discriminatory encounters within and outside the health system which may also serve as barriers. Most participants endorsed cancer screening and increased education, recommending Indigenous-centered, delivered, and tailored programs, as well barrier-directed support. Conclusions: In a broad sample of at-risk urban-dwelling AI/AN people, our findings suggest enthusiasm for preventive care but several complex barriers. Participants endorsed culturally-tailored programs which could provide relevant education and address barriers.

Objective Diarrhoea remains a leading cause of morbidity and death among under-5 children in Kenya, despite multipronged policy and programme initiatives to increase access to treatment. This study interrogates the comprehensiveness and adequacy of Kenya’s policies, frameworks and action plans for diarrheal management and prevention. The study seeks to identify policy and practice gaps that need to be filled to strengthen diarrhoea treatment and prevention among under-5 children in Kenya.Design Our study is a landscape analysis, which seeks to identify the gaps in the current Kenya diarrheal policy, frameworks and action plans. The critical questions included their comprehensiveness, the availability of elaborate treatment, management and prevention solutions, together with updatedness, building on evidence from extant literature on key pathways to infection relating to man-animal environmental interaction, which are critical in enteric infection prevention initiatives.Data sources We conducted an internet search of databases of Government of Kenya’s Ministry of Health; relevant websites/publications of international organisations and groups (Centre for Disease Control and Prevention, UNICEF and WHO) and published and grey literature (Google searches, Google Scholar and PubMed).Eligibility criteria Included are publicly available key national diarrheal policy frameworks, plans, strategies, laws, institutional frameworks and operational guidelines that inform pertinent questions on the adequacy of policy and practice and preventive policy updates and actions. Further, peer-reviewed and grey literature on diarrheal morbidity and mortality and diarrheal prevention and management are included. The analysis excluded any information that was not referenced on the internet nor obtained from the internet.Data extraction and synthesis The review team extracted the key provisions of the policy guidelines guided by a checklist and questions around the adequacy of existing national policies in addressing the determinants, prevention and treatment interventions of enteric infections and diarrhoea among under-5 children in the country. The checklist covered Kenyan background and diarrhoea situation analysis, policy objectives, policy strategies and policy implementation.Results The analysis identified a corpus of strategies for the management of diarrhoea at multiple levels: health facilities, communities and households. The policies highlighted advocacy, health communication and social mobilisation, as well as logistics management and prevention strategies. However, the triangulation of evidence from the policy provisions and extant literature identified critical policy gaps in diarrhoea prevention and management in Kenya, particularly the lack of focus on zoonotic pathways to enteric infection, environment-pathogen linkages and operationalisation of the roles of social determinants of health and related services. The policy documents had limited focus on rapid diagnosis, vaccine development and deployment, together with weak funding commitment towards implementation and unclear pathways to funding responsibilities.Conclusion Policies are central to guiding programmatic actions towards effective enteric and diarrhoea prevention and management measures in Kenya. This study shows the need for policy updates to reflect pathways to enteric infections not covered in the current policy guidelines. Further, there is a need to strengthen the treatment and management of infection through rapid diagnosis, vaccine development and deployment, and strong funding commitment towards implementation together with clear funding responsibilities. Together, these will be vital in strengthening the current policy provisions and addressing other pathways to the prevention of enteric infections relating to zoonotic, environment-pathogen linkages and social determinants of health in Kenya and other low-income and middle-income countries.Trial registration number NCT05322655.

Instrument-assisted soft tissue mobilization (IASTM) techniques use specialized hand-held instruments for applying controlled mechanical forces to the body with the goal of facilitating healing, improving range of motion, and reducing pain. Nevertheless, an optimal range of forces for achieving clinical outcomes has yet to be established. A barrier to advancing research on IASTM force optimization is the lack of commercially available instruments that quantify treatment forces. The aim of the current study was to assess the feasibility of attaching a flexible force sensor to a commercially available IASTM instrument to obtain valid force measurements. The validity of this novel approach was assessed by comparing data between the flexible force sensor and a force plate during a simulated treatment. Intraclass correlation coefficients, linear regression models, and Bland Altman plots all indicated excellent agreement between the force plate and flexible sensor when the instrument was used at 45°, 65°, and 90° treatment angles. Agreement between measures decreased when the instrument was held at 30°. Thus, commercially available instruments with attached sensors could make force measurement more accessible and feasible for a wider range of research settings, facilitating the advancement of IASTM research and ultimately informing clinical decision-making to improve patient care.

Abstract P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7, abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1β release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.

Abstract Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFβ/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFβ/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFβ-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFβ–YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

Abstract Trait impulsivity represents a tendency to take action without forethought or consideration of consequences. This trait is multifaceted and can be decomposed into attentional, motor and non-planning subtypes of impulsivity. The purpose of the current study was to investigate how subtypes of trait impulsivity responded to different degrees of threat within room-scale virtual reality (VR) with respect to behaviour and level of physiological activation. Thirty-four participants were required to negotiate a virtual environment (VE) where they walked at height with the continuous threat of a virtual ‘fall.’ Behavioural measures related to the speed of movement, interaction frequency and risk were collected. Participants also wore ambulatory sensors to collect data from electrocardiogram (ECG) and electrodermal activity (EDA). Our results indicated that participants who scored highly on non-planning impulsivity exhibited riskier behaviour and higher skin conductance level (SCL). Participants with higher motor impulsivity interacted with more objects in the VE when threat was high, they also exhibited contradictory indicators of physiological activation. Attentional impulsivity was associated with a greater number of falls across the VE. The results demonstrate that subtypes of trait impulsivity respond to threats via different patterns of behaviour and levels of physiological activation, reinforcing the multifaceted nature of the trait.

Abstract Dreaming is a universal human behavior that has inspired searches for meaning across many disciplines including art, psychology, religion, and politics, yet its function remains poorly understood. Given the suggested role of sleep in emotional memory processing, we investigated whether reported overnight dreaming and dream content are associated with sleep-dependent changes in emotional memory and reactivity, and whether dreaming plays an active or passive role. Participants completed an emotional picture task before and after a full night of sleep and they recorded the presence and content of their dreams upon waking in the morning. The results replicated the emotional memory trade-off (negative images maintained at the cost of neutral memories), but only in those who reported dreaming (Dream-Recallers), and not in Non-Dream-Recallers. Results also replicated sleep-dependent reductions in emotional reactivity, but only in Dream-Recallers, not in Non-Dream-Recallers. Additionally, the more positive the dream report, the more positive the next-day emotional reactivity is compared to the night before. These findings implicate an active role for dreaming in overnight emotional memory processing and suggest a mechanistic framework whereby dreaming may enhance salient emotional experiences via the forgetting of less relevant information.

Introduction: Diagnosing Tuberculosis (TB) in children is difficult as they do not expectorate sputum on their own, and the sample is usually paucibacillary. Hence, alternative sampling methods like Gastric juice Aspiration (GA), which is the widely accepted method, and Induced Sputum (IS) collection, a more novel approach, are used. The IS method has several advantages, such as being less invasive, not requiring inpatient admission, causing less discomfort, and not necessitating overnight fasting, compared to the GA method. Aim: To evaluate IS against GA for diagnosing TB using XpertMTB/RIF assay, as well as mycobacterial culture, in children aged between 2 and 15 years. Materials and Methods: This cross-sectional study was conducted in the Department of Paediatrics at Christian Medical College and Hospital, Vellore, Tamil Nadu, India from June 2019 to March 2020, involving 138 children aged between 2 and 15 years who were being evaluated for TB. GA samples were collected after an overnight fast, and on the same day, atleast two hours later, IS samples were collected by trained staff. Both samples underwent mycobacterial smear and culture using the Mycobacteria Growth Indicator Tube (MGIT) method and Xpert MTB/RIF assay. Confirmation of pulmonary TB was based on atleast one of these tests being positive. The ‘Wong-Baker’ Visual Analogue Scale (VAS) was individually administered to each patient to compare the discomfort associated with GA and IS procedures. The differences in yield between IS and GA were tested for significance using the Two-sample test of proportions with a significance level set at 5%. McNemar's χ2 test was employed to compare matched observations. The Mann-Whitney test was used for comparing continuous variables, and the Chi-Square test for categorical variables. Cohen’s Kappa (κ) was used to assess interobserver agreement between the sampling methods using the different tests. Results: Out of the 138 cases recruited with suspected pulmonary TB, the diagnosis was microbiologically confirmed in 13 cases (9.4%). The overall diagnostic yield was 12/138 (8.7%) for GA and 10/138 (7.2%) for IS. In children under 10 years, GA outperformed IS with all three cases being positive by GA and none by IS. For those aged 10 years and above, 10 children (100%) tested positive with IS, while nine children (90%) were positive with GA. According to the Wong-Baker VAS measuring discomfort during the procedure, IS was favoured over GA (p-value

During October 2021–June 2023, a total of 392 cases of acute hepatitis of unknown etiology in children in the United States were reported to Centers for Disease Control and Prevention as part of national surveillance. We describe demographic and clinical characteristics, including potential involvement of adenovirus in development of acute hepatitis, of 8 fatally ill children who met reporting criteria. The children had diverse courses of illness. Two children were immunocompromised when initially brought for care. Four children tested positive for adenovirus in multiple specimen types, including 2 for whom typing was completed. One adenovirus-positive child had no known underlying conditions, supporting a potential relationship between adenovirus and acute hepatitis in previously healthy children. Our findings emphasize the importance of continued investigation to determine the mechanism of liver injury and appropriate treatment. Testing for adenovirus in similar cases could elucidate the role of the virus.

Salmonella enterica serovar Infantis presents an ever-increasing threat to public health because of its spread throughout many countries and association with high levels of antimicrobial resistance (AMR). We analyzed whole-genome sequences of 5,284 Salmonella Infantis strains from 74 countries, isolated during 1989–2020 from a wide variety of human, animal, and food sources, to compare genetic phylogeny, AMR determinants, and plasmid presence. The global Salmonella Infantis population structure diverged into 3 clusters: a North American cluster, a European cluster, and a global cluster. The levels of AMR varied by Salmonella Infantis cluster and by isolation source; 73% of poultry isolates were multidrug resistant, compared with 35% of human isolates. This finding correlated with the presence of the pESI megaplasmid; 71% of poultry isolates contained pESI, compared with 32% of human isolates. This study provides key information for public health teams engaged in reducing the spread of this pathogen.

Highly pathogenic avian influenza (HPAI) viruses have potential to cross species barriers and cause pandemics. Since 2022, HPAI A(H5N1) belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected poultry, wild birds, and mammals across North America. Continued circulation in birds and infection of multiple mammalian species with strains possessing adaptation mutations increase the risk for infection and subsequent reassortment with influenza A viruses endemic in swine. We assessed the susceptibility of swine to avian and mammalian HPAI H5N1 clade 2.3.4.4b strains using a pathogenesis and transmission model. All strains replicated in the lung of pigs and caused lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission was only observed with mammalian isolates. Mammalian adaptation and reassortment may increase the risk for incursion and transmission of HPAI viruses in feral, backyard, or commercial swine.

Abstract 24-h shift (24 hS) exposed emergency physicians to a higher stress level than 14-h night shift (14 hS), with an impact spreading on several days. Catecholamines are supposed to be chronic stress biomarker. However, no study has used catecholamines to assess short-term residual stress or measured them over multiple shifts. A shift-randomized trial was conducted to study urinary catecholamines levels of 17 emergency physicians during a control day (clerical work on return from leave) and two working day (14 hS and 24 hS). The Wilcoxon matched-pairs test was utilized to compare the mean catecholamine levels. Additionally, a multivariable generalized estimating equations model was employed to further analyze the independent relationships between key factors such as shifts (compared to control day), perceived stress, and age with catecholamine levels. Dopamine levels were lower during 24 hS than 14 hS and the control day. Norepinephrine levels increased two-fold during both night shifts. Epinephrine levels were higher during the day period of both shifts than on the control day. Despite having a rest day, the dopamine levels did not return to their normal values by the end of the third day after the 24 hS. The generalized estimating equations model confirmed relationships of catecholamines with workload and fatigue. To conclude, urinary catecholamine biomarkers are a convenient and non-invasive strong measure of stress during night shifts, both acutely and over time. Dopamine levels are the strongest biomarker with a prolonged alteration of its circadian rhythm. Due to the relation between increased catecholamine levels and both adverse psychological effects and cardiovascular disease, we suggest that emergency physicians restrict their exposure to 24 hS to mitigate these risks.