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Abstract The use of supplementary cementitious materials (SCMs) is a key method used to reduce the embodied carbon of cement-based materials. Uncertainty in traditional SCM markets has led to increased interest in alternative, natural SCM materials. In this work, biosilica derived from freshly cultured diatom frustules (grown by Thalassiosira pseudonana and Phaeodactylum tricornutum) was assessed as an alternative SCM for the first time. The chemical reactivity of each biosilica source was assessed using a small-scale version of ASTM C1897 (the R3 test) previously developed by the authors. The chemical reactivity of T. pseudonana frustules was relatively high (i.e., greater than that of blast furnace slag, but lower than that of metakaolin). P. tricornutum frustules exhibited a lower chemical reactivity, similar to a Class F fly ash. Results demonstrate the potential to grow highly reactive biominerals using diatoms and highlight the potential tunability of diatom biosilica for use as a novel, sustainable SCM.

Abstract The complex dynamics of protein expression in plasma during hyperacute HIV-1 infection and its relation to acute retroviral syndrome, viral control, and disease progression are largely unknown. Here, we quantify 1293 blood plasma proteins from 157 longitudinally linked plasma samples collected before, during, and after hyperacute HIV-1 infection of 54 participants from four sub-Saharan African countries. Six distinct longitudinal expression profiles are identified, of which four demonstrate a consistent decrease in protein levels following HIV-1 infection. Proteins involved in inflammatory responses, immune regulation, and cell motility are significantly altered during the transition from pre-infection to one month post-infection. Specifically, decreased ZYX and SCGB1A1 levels, and increased LILRA3 levels are associated with increased risk of acute retroviral syndrome; increased NAPA and RAN levels, and decreased ITIH4 levels with viral control; and increased HPN, PRKCB, and ITGB3 levels with increased risk of disease progression. Overall, this study provides insight into early host responses in hyperacute HIV-1 infection, and present potential biomarkers and mechanisms linked to HIV-1 disease progression and viral load.

Marek’s disease virus (MDV) has become an increasingly virulent pathogen in the poultry industry despite vaccination efforts to control it. Brazil has experienced a significant rise of Marek’s disease (MD) outbreaks in recent years. Our study aimed to analyze the complete meq gene sequences to understand the molecular epidemiological basis of MD outbreaks in Brazilian vaccinated layer farms. We detected a high incidence rate of visceral MD (67.74%) and multiple circulating MDV strains. The most prevalent and geographically widespread genotype presented several clinical and molecular characteristics of a highly virulent strain and evolving under positive selective pressure. Phylogenetic and phylogeographic analysis revealed a closer relationship with strains from the USA and Japan. This study sheds light on the circulation of MDV strains capable of infecting vaccinated birds. We emphasize the urgency of adopting preventive measures to manage MDV outbreaks threatening the poultry farming industry.

Abstract Background Indices of tumor heterogeneity on somatostatin receptor PET/CT scans may potentially serve as predictive biomarkers of treatment efficacy in neuroendocrine tumor (NET) patients undergoing [177Lu]Lu-DOTA-TATE PRRT. Methods NET patients who underwent [177Lu]Lu-DOTA-TATE therapy at the University of Iowa from August 2018 to February 2021 were retrospectively evaluated. Radiomic features on the pre-PRRT somatostatin receptor PET/CT were evaluated using a custom MIM Software® LesionID workflow. Conventional PET/CT metrics of tumor burden, such as somatostatin receptor expression and tumor volume, were calculated in addition to the indices of tumor heterogeneity for each lesion (intra-lesional) and then summarized across all lesions throughout the body (inter-lesional). Endpoints included post-PRRT 24-month time to progression (TTP) and overall survival (OS). Cox regression models were used to assess the predictive ability of the imaging factors on post-PRRT 24-month TTP and OS. LASSO-penalized Cox regression was used to build a multivariable model for each outcome. Results Eighty patients with a mean age of 65.1 years were included, with most (71.3%) completing 4 cycles of PRRT. Median TTP was 19.1 months, and OS at 60 months was 50%. A large degree of variability between patients was evidenced for imaging features related to somatostatin receptor expression. On multivariable analysis, total receptor expression and mean liver-corrected SUVmean were selected for 24-month TTP. The model was not able to significantly predict progression (C-statistic = 0.58, 95% CI 0.50–0.62). Total receptor expression and mean skewness were selected for OS. The resulting model was able to significantly predict death (C-statistic = 0.62, 95% CI 0.53–0.67), but the predictive ability was limited, as evidenced by the low C-statistic. Conclusions Our exploratory analysis provides preliminary results showing that imaging indices of inter- and intra-tumor heterogeneity from pretreatment PET/CT images may potentially predict treatment efficacy in NET patients undergoing [177Lu]Lu-DOTA-TATE therapy. However, prospective evaluation in a larger cohort is needed to further assess whether a comprehensive characterization of tumor heterogeneity within a patient can help guide treatment decisions.

Inclisiran is a synthetic small interfering RNA (siRNA) that inhibits the production of proprotein convertase subtilisin/ kexin 9 (PCSK9) in hepatocytes by silencing the translation of PCSK9 mRNA. The result of this mechanism is a decrease in PCSK9 synthesis resulting in decreased degradation of the LDL receptor, leading to more LDL receptors being available to clear LDL cholesterol (LDL-C) from the circulation. Inclisiran received FDA approval in 2021 and EMA approval in 2020. The indication for inclisiran use is as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidaemia, including those with heterozygous familial hypercholesterolaemia to reduce LDL-C. Inclisiran has demonstrated consistent LDL-C lowering in the range of 44–54%. Furthermore, inclisiran has been demonstrated to be a safe medication with indications of significant or serious adverse events when compared to placebo. Inclisiran is given as an initial subcutaneous dose followed by a repeat dose at 3 months and every 6 months thereafter. The 2022 American College of Cardiology Expert Consensus Decision Pathway includes inclisiran as an option for non-statin therapy in addition to maximally tolerated statin therapy in those at very high risk of atherosclerotic cardiovascular disease or those with LDL-C >190 mg/ dL. The ORION-4, VICTORION-1 PREVENT and VICTORION-2 PREVENT trials are ongoing and designed to evaluate the ability of inclisiran to reduce major cardiovascular events in addition to LDL-C lowering but will not be completed for a few years.

Children with lived cancer experience encounter adversity, therefore experiences promoting psychosocial health are necessary. This pilot study determined the impact of recreational oncology camps (ROC) on resilience, hope, social support, and mental well-being in youth who have lived with cancer. Youth (6–18 years) with cancer experience enrolled in an 11-day session of ROC (Muskoka, Ontario, Canada) were invited to participate. Participants completed a survey [Children’s Hope Scale (CHS), Child and Youth Resilience Measure (CYRM-R), Social Provisions Scale (SPS-5), and Short Warwick–Edinburgh Mental Wellbeing Scale (SWEMWBS)] on the first (T1) and last day (T2) of camp, and 3 months post-camp (T3). Repeated-measures ANOVAs evaluated differences in survey scores among time points. Ten participants (14.1 ± 2.5 years) were included in the analysis. CHS scores at T3 were lower than T1 and T2 (F = 9.388, p = 0.008). CYRM-R, SPS-5, and SWEMWBS scores were high but did not differ between time points. Hope decreased 3 months post-camp, suggesting a need for continued psychosocial support. Overall, the ROC environment is associated with positive psychosocial health.

Abstract Background Breeding of lettuce (Lactuca sativa L.), the most important leafy vegetable worldwide, for enhanced disease resistance and resilience relies on multiple wild relatives to provide the necessary genetic diversity. In this study, we constructed a super-pangenome based on four Lactuca species (representing the primary, secondary and tertiary gene pools) and comprising 474 accessions. We include 68 newly sequenced accessions to improve cultivar coverage and add important foundational breeding lines. Results With the super-pangenome we find substantial presence/absence variation (PAV) and copy-number variation (CNV). Functional enrichment analyses of core and variable genes show that transcriptional regulators are conserved whereas disease resistance genes are variable. PAV-genome-wide association studies (GWAS) and CNV-GWAS are largely congruent with single-nucleotide polymorphism (SNP)-GWAS. Importantly, they also identify several major novel quantitative trait loci (QTL) for resistance against Bremia lactucae in variable regions not present in the reference lettuce genome. The usability of the super-pangenome is demonstrated by identifying the likely origin of non-reference resistance loci from the wild relatives Lactuca serriola, Lactuca saligna and Lactuca virosa. Conclusions The super-pangenome offers a broader view on the gene repertoire of lettuce, revealing relevant loci that are not in the reference genome(s). The provided methodology and data provide a strong basis for research into PAVs, CNVs and other variation underlying important biological traits of lettuce and other crops.

Abstract Climate disruption today represents a threat to the environment and sustainable development. Climate-Smart Agriculture (CSA) is an appropriate adaptation approach to climate change. It allows producers to improve their production and act on their food security, despite the conditions of climate change while limiting the causes arising from agriculture. The objective of this study is to evaluate the impact of CSA, through the use of harvest residues in cassava fields, on the income and food security of cassava producing households in Savalou. The three-stage sampling method made it possible to draw a random sample of 360 cassava producers including 180 users of pigeon pea, mucuna and peanut harvest residues. The average income from cassava production during the last 12 months (until July 2023) is 366,400 FCFA with 387,340 FCFA for beneficiaries compared to 322,060 FCFA for non-beneficiaries. The impact analysis was done with the matching method based on propensity scores. The results of this impact study showed that this adoption contributes to improving income from cassava production by 35,135 FCFA and household food security by 0.10 points, on average per household per year. It would therefore be useful to promote and improve this type of agriculture, in order to ensure sustainable development of the agricultural sector and improve food security.

Abstract Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions.

Abstract Background Research is needed to better understand the specific challenges for autistic learners in informal STEM learning settings. This study aimed to increase inclusion in STEM museums, with a larger goal of increasing the impact (i.e., learning and application of knowledge during and after visits) of informal STEM learning settings for autistic youth. We conducted an online parent attitudes survey with 93 parents of autistic adolescents and 53 parents of adolescents in the general population to better understand the experiences of autistic adolescents when visiting STEM-related museums. Parent responses informed professional development training for museum staff at four partner museums, which taught strategies to better support autistic learners. Then, autistic adolescents (n = 20) and their parents were randomly assigned to visit one partner and one control museum. They were asked to report their experiences through an online survey and semi-structured interviews. Results Participants who completed the parent attitudes survey indicated significantly lower inclusion, engagement, and general impact of STEM museum visits among autistic adolescents compared to the general population comparison group. Parents of adolescents who visited partner and control museums reported higher STEM impact during visits to partner museums; however, parent-reported inclusion, engagement, and general impact did not differ significantly between partner and control museums. Qualitative analysis identified four themes (Spectrum of Museum Impact; Adolescent-Environment Fit; Barriers to Engagement, and Barrier Breakers), providing context for quantitative findings. Conclusions Findings underscore the need for increased inclusion for autistic individuals in informal STEM learning environments like museums. This project demonstrated feasibility of professional development training of forward-facing staff and identified several themes that should inform future efforts to improve inclusion in informal STEM learning settings.

Abstract Background The COVID-19 pandemic led to dramatic changes in the lives of children that impact cardiometabolic health. Cities and counties had varying policies with respect to school closure, recreational programs, and efforts to mitigate food insecurity and economic distress. Our objective was to evaluate changes in BMI-z score and prevalence of overweight/obesity prior to and during the pandemic among children in San Francisco, CA, where public schools were closed for 18-months. Methods This was an electronic medical record-based retrospective cohort study. We included 15,401 children, 4–17 years of age at study onset. Our exposure was time into each of three time periods: (1) March 2018-February 2019; (2) March 2019-February 2020; (3) March 2020-August 2021 (the pandemic period of school closure). Generalized estimating equations (GEE) were used to assess changes in BMI-z score and overweight/obesity across the three time periods. We assessed for effect modification by age-category, insurance status, and race/ethnicity. Results Mean BMI-z score increased by 0.06 per year in time period 2, the year prior to the pandemic (p

Abstract Induced pluripotent stem cell (iPSC)-derived mesenchymal stromal cells (iMSCs) offer a promising alternative to primary mesenchymal stromal cells (MSCs) and their derivatives, particularly extracellular vesicles (EVs), for use in advanced therapy medicinal products. In this study we evaluated the immunomodulatory and regenerative potential of iMSCs as well as iMSC-EVs, alongside primary human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Our findings demonstrate that iMSCs exhibit comparable abilities to hUCMSCs in regulating lymphocyte proliferation and inducing an anti-inflammatory phenotype in monocytes. We also observed decreased TNFα levels and increased IL-10 induction, indicating a potential mechanism for their immunomodulatory effects. Furthermore, iMSC-EVs also showed effective immunomodulation by inhibiting T cell proliferation and inducing macrophage polarization similar to their parental cells. Additionally, iMSC-EVs exhibited pro-regenerative potential akin to hUCMSC-EVs in in vitro scratch assays. Notably, priming iMSCs with pro-inflammatory cytokines significantly enhanced the immunomodulatory potential of iMSC-EVs. These results underscore the considerable promise of iMSCs and iMSCs-EVs as an alternate source for MSC-derived therapeutics, given their potent immunomodulatory and regenerative properties.

Abstract Background Heart failure is a major global health challenge incurring a high rate of mortality, morbidity and hospitalisation. Effective medicines management at the time of hospital discharge into the community could reduce poor outcomes for people with heart failure. Within the Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT) programme, the Medicines at Transitions Intervention (MaTI) was co-designed to improve such transitions, with a cluster randomised controlled trial to test effectiveness. The MaTI includes a patient toolkit and transfer of discharge medicines information to community pharmacy. This paper aims to determine the degree to which the intervention was delivered, and identify barriers and facilitators experienced by staff for the successful implementation of the intervention. Methods The study was conducted in six purposively selected intervention sites. A mixed-methods design was employed using hospital staff interviews, structured and unstructured ward observations, and routine trial data about adherence to the MaTI. A parallel mixed analysis was applied. Qualitative data were analysed thematically using the Framework method. Data were synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research (CFIR). Results With limited routines of communication between ward staff and community pharmacy, hospital staff found implementing community pharmacy-related steps of the intervention challenging. Staff time was depleted by attempts to bridge system barriers, sometimes leading to steps not being delivered. Whilst the introduction of the patient toolkit was often completed and valued as important patient education and a helpful way to explain medicines, the medicines discharge log within it was not, as this was seen as a duplication of existing systems. Within the CFIR the most applicable constructs were identified as ‘intervention complexity’ and ‘cosmopolitanism’ based on how well hospitals were networked with community pharmacies, and the availability of hospital resources to facilitate this. Conclusion The MaTI was generally successfully implemented, particularly the introduction of the toolkit. However, implementation involving community pharmacy was more challenging and more effective communication systems are needed to support wider implementation. Trial registration 11/04/2018 ISRCTN66212970. https://www.isrctn.com/ISRCTN66212970 .

Abstract Immunological adaptions during pregnancy play a crucial role in healthy fetal development. Aberrant immune modifications however contribute to adverse pregnancy outcomes, which may be driven by maternal factors such as previous pregnancies and BMI. This secondary analysis of the MicrobeMom2 RCT investigates the changes to maternal inflammatory biomarkers derived from serum and stimulated peripheral blood mononuclear cells (PBMCs) during pregnancy, and the effects of previous pregnancies (parity) and BMI on maternal immune responses. Changes in immune and metabolic biomarkers from early (11–15 weeks’ gestation) to late (28–32 weeks’ gestation) pregnancy were compared using paired t-tests. Participants were then split by parity (nulliparous, parous) and BMI (BMI = 25), and the relationship between parity and BMI with immune biomarker levels was examined using independent t-tests, paired t-tests, ANCOVA, and linear regression. Equivalent non-parametric tests were used for skewed data. Recruited women (n = 72) were on average 31.17 (SD ± 4.53) years of age and 25.11 (SD ± 3.82) BMI (kg/m2). Of these, 51 (70.8%) had a previous term pregnancy. Throughout gestation, PBMC cytokines displayed contrasting trends to serum, with a dampening of immune responses noted in PBMCs, and enhanced production of cytokines observed in the serum. Significant decreases in PBMC derived TNF-α, IL-10 and IFN-γ were seen from early to late pregnancy. Serum C3, IL-17A, IL-6, TNF-α, CD163, GDF-15 and leptin increased throughout gestation. First pregnancy was associated with higher levels of leptin in late pregnancy, while parous women showed significant decreases in PBMC derived TNF-α, IL10, and IFN-γ with gestation. Differences in levels of C3, IL-17A, TNF-α, GDF-15 and leptin were observed across BMI groups. Overall, serum-derived cytokines exhibit contrasting levels to those derived from stimulated PBMCs. Maternal immune responses undergo significant changes from early to late pregnancy, which are influenced by parity and BMI. These differences aid our understanding as to why first-time mothers are at greater risk of placental disease such as pre-eclampsia and fetal growth restriction.

Abstract Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone. Therefore, we adopted a combined in vivo-in silico approach and developed an ordinary differential equation model of acute liver disease able to predict the host response to injury and potential interventions. The Mdm2fl/fl mouse model of senescence-driven liver injury was used to generate a quantitative dynamic characterisation of the key cellular players (macrophages, endothelial cells, myofibroblasts) and extra cellular matrix involved in liver injury. This was qualitatively captured by the mathematical model. The mathematical model was then used to predict injury outcomes in response to milder and more severe levels of senescence-induced liver injury and validated with experimental in vivo data. In silico experiments using the validated model were then performed to interrogate potential approaches to enhance regeneration. These predicted that increasing the rate of macrophage phenotypic switch or increasing the number of pro-regenerative macrophages in the system will accelerate the rate of senescent cell clearance and resolution. These results showcase the potential benefits of mechanistic mathematical modelling for capturing the dynamics of complex biological systems and identifying therapeutic interventions that may enhance our understanding of injury-repair mechanisms and reduce translational bottlenecks.

Abstract Biocatalysis has been widely employed for the generation of carbon-carbon/heteroatom stereocentres, yet its application in chiral C(sp3)–S bond construction is rare and limited to enzymatic kinetic resolutions. Herein, we describe the enantioselective construction of chiral C(sp3)–S bonds through ene-reductase biocatalyzed conjugate reduction of prochiral vinyl sulfides. A series of cooperative sequential/concurrent chemoenzymatic and biocatalytic cascades have been developed to access a broad range of chiral sulfides, including valuable β-hydroxysulfides bearing two adjacent C(sp3)–S and C(sp3)–O stereocentres, in a stereoconvergent manner with good to excellent yields (up to 96%) and enantioselectivities (up to >99% ee). Notably, this biocatalytic strategy allows to overcome the long-standing shortcomings of catalyst poisoning and C(sp2)/C(sp3)–S bond cleavage faced in transition-metal-catalyzed hydrogenation of vinyl sulfides. Finally, the potential of this methodology is also exemplified by its broader application in the stereoconvergent assembly of chiral C(sp3)–N/O/Se bonds with good to excellent enantioselctivities.

Synbiotics are mixtures of prebiotics and probiotics that enhance the activity of probiotic bacteria when co-administered to provide greater benefits to the host. Traditionally, the synbiotics that have been discovered enhance gut probiotic strains and are nutritionally complex molecules that survive digestive breakdown until they reach the later stages of the intestinal tract. Here, we screened and identified sugars or sugar substitutes as synbiotics for the oral probiotic strains Streptococcus salivarius BLIS K12 and BLIS M18. Using a modified deferred antagonism assay, we found that 0.5% (w/v) galactose and 2.5% (w/v) raffinose were the best candidates for use as synbiotics with BLIS K12 and M18, as they trigger enhanced antimicrobial activity against a range of bacteria representing species from the mouth, gut, and skin. Using reverse transcriptase quantitative PCR, we found that this enhanced antimicrobial activity was caused by the upregulation of the lantibiotic genes salA, salB, and sal9 in either K12 or M18. This led to the conclusion that either 2.5% (w/v) raffinose or 0.5% (w/v) galactose, respectively, are suitable synbiotics for use in conjunction with BLIS K12 and M18 to enhance probiotic performance.

Purpose Nonneurogenic chronic urinary retention is an uncommon problem in young female individuals, and a well characterised causes is Fowler syndrome (primary disorder of urethral sphincter relaxation). Intermittent catheterisation is often challenging, and gold standard treatment sacral neuromodulation is not widely available. Urethral sphincter botulinum toxin injection has been shown to be effective cross-sectionally, however little is known about long-term outcomes. Methods Female individuals presenting with urinary retention due to Fowler syndrome were reviewed retrospectively from a single tertiary referral centre over an 11-year period (2010–2021). One hundred units of onabotulinum toxin A (BoTX-A) was injected into the striated urethral sphincter in a divided dose by the periurethral approach. Efficacy and side effects were assessed 4 weeks after injection. Results Thirty-three female individuals with a mean age of 40.1±14.1 years received 165 unique urethral sphincter BoTX-A injections over 11 years. Nineteen individuals (57.6%) presented in acute urinary retention, and 28 (84.8%) were reliant on catheterisation. Twenty-one individuals (64%) responded to BoTX-A injections and had a significantly raised baseline maximum urethral closure pressure (MUCP), compared to nonresponders (114.6 cm H2O, P=0.012). Side effects were reported following 19 injections (11.5%) however, were mild and transient. Fifteen individuals received more than 1 botulinum toxin injection (median, 3 injections), with a median interval of 112 days (interquartile range) and efficacy persisted following repeat injections and no safety concerns were seen. Conclusions Sphincter botulinum toxin through the periurethral approach is safe and effective following repeat injections, and offers a low-cost, minimally invasive alternative to managing female chronic urinary retention due to Fowler syndrome, particularly when there was a high baseline MUCP.

Abstract Background Peer workers are people with personal experience of mental distress, employed within mental health services to support others with similar experiences. Research has identified a range of factors that might facilitate or hinder the introduction of new peer worker roles into mental health services. While there is mixed evidence for the effectiveness of peer worker delivered interventions, there are no studies exploring how implementation might be associated with effect. Methods This was a qualitative comparative case study using data from interviews with 20 peer workers and their five supervisors. Peer workers delivered peer support for discharge from inpatient to community mental health care as part of a randomised controlled trial. In the trial, level of participant engagement with peer support was associated with better outcome (hospital readmission). Study sites with higher levels of engagement also had higher scores on a measure of fidelity to peer support principles. We compared data from sites with contrasting levels of engagement and fidelity using an analytical framework derived from implementation theory. Results In high engagement-high fidelity sites, there was regular work with clinical teams preparing for working alongside peer workers, and a positive relationship between staff on inpatient wards and peer workers. The supervisor role was well resourced, and delivery of peer support was highly consistent with the intervention manual. In low engagement-low fidelity sites peer workers were employed in not-for-profit organisations to support people using public mental health services and in rural areas. Supervisors faced constrained resources and experienced barriers to joint working between organisations. In these sites, peer workers could experience challenging relationships with ward staff. Issues of geography and capacity limited opportunities for supervision and team-building, impacting consistency of delivery. Conclusions This study provides clear indication that implementation can impact delivery of peer support, with implications for engagement and, potentially, outcomes of peer worker interventions. Resourcing issues can have knock-on effects on consistency of delivery, alongside challenges of access, authority and relationship with clinical teams, especially where peer workers were employed in not-for-profit organisations. Attention needs to be paid to the impact of geography on implementation. Trial registration ISRCTN registry number ISRCTN10043328, registered 28 November 2016.

Abstract Background Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. Methods To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. Results We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. Conclusion The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.

Abstract The role of the cerebral cortex in self-initiated versus sensory-driven movements is central to understanding volitional action. Whether the differences in these two movement classes are due to specific cortical areas versus more cortex-wide engagement is debated. Using wide-field Ca2+ imaging, we compared neural dynamics during spontaneous and motorized treadmill locomotion, determining the similarities and differences in cortex-wide activation and functional connectivity (FC). During motorized locomotion, the cortex exhibits greater activation globally prior to and during locomotion starting compared to spontaneous and less during steady-state walking, during stopping, and after termination. Both conditions are characterized by FC increases in anterior secondary motor cortex (M2) nodes and decreases in all other regions. There are also cortex-wide differences; most notably, M2 decreases in FC with all other nodes during motorized stopping and after termination. Therefore, both internally- and externally-generated movements widely engage the cortex, with differences represented in cortex-wide activation and FC patterns.

Health. Disability. Vulnerability. These words are often used when discussing the risks of climate disruption. These discussions warn of the potential for climate impacts to “undermine 50 years of gains in public health” (as stated by the Lancet Countdown on Climate Change). Increasingly, such discussions also acknowledge climate injustice, examining who will benefit or lose out from climate change, how and why. The embodied vulnerability of disabled people is often assumed within such discussions, with less consideration of the social, economic or political conditions that create this vulnerability. By bringing disability justice and disability studies into correspondence with care, environmental and climate justice scholarship, this reflective paper challenges the master narratives that blur differentiated experiences of disability and climate impacts into a single story of inevitable vulnerability. Recognising disabled people as knowers, makers and agents of change, it calls for transformative climate action, underpinned by values of solidarity, mutuality and care.

Abstract Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT). Methods We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events. Results At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported. Conclusion Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018).

Abstract Halide solid electrolytes do not currently display ionic conductivities suitable for high-power all-solid-state batteries. We explore the model system A2ZrCl6 (A = Li, Na, Cu, Ag) to understand the fundamental role that A-site chemistry plays on fast ion transport. Having synthesised the previously unknown Ag2ZrCl6 we reveal high room temperature ionic conductivities in Cu2ZrCl6 and Ag2ZrCl6 of 1 × 10−2 and 4 × 10−3 S cm−1, respectively. We introduce the concept that there are inherent limits to ionic conductivity in solids, where the energy and number of transition states play pivotal roles. Transport that involves multiple coordination changes along the pathway suffer from an intrinsic minimum activation energy. At certain lattice sizes, the energies of different coordinations can become equivalent, leading to lower barriers when a pathway involves a single coordination change. Our models provide a deeper understanding into the optimisation and design criteria for halide superionic conductors.

Abstract Dynamin-like GTPase proteins, including myxoma (Mx) and guanylate-binding proteins (GBPs), are among the many interferon stimulated genes induced following viral infections. While studies report that human (h)GBPs inhibit different viruses in vitro, few have convincingly demonstrated that mouse (m)GBPs mediate antiviral activity, although mGBP-deficient mice have been used extensively to define their importance in immunity to diverse intracellular bacteria and protozoa. Herein, we demonstrate that individual (overexpression) or collective (knockout (KO) mice) mGBPs of the chromosome 3 cluster (mGBPchr3) do not inhibit replication of five viruses from different virus families in vitro, nor do we observe differences in virus titres recovered from wild type versus mGBPchr3 KO mice after infection with three of these viruses (influenza A virus, herpes simplex virus type 1 or lymphocytic choriomeningitis virus). These data indicate that mGBPchr3 do not appear to be a major component of cell-intrinsic antiviral immunity against the diverse viruses tested in our studies.

Abstract Previous studies showed that accelerated enhanced recovery programs (ERPs) with discharge 1–3 days after colorectal surgery are feasible for specific patients without compromising patients’ safety. This study aimed to examine the incidence, severity, and treatment of complications after treatment according to an accelerated ERP (CHASE). This accelerated ERP consisted of adjustments in pre-, peri- and postoperative care. Patients treated according to the CHASE protocol were compared to a retrospective cohort of patients who received standard ERAS care. The primary outcome was the rate of severe complications. The overall complication rates were similar in both cohorts (CHASE 30.7% vs ERAS 31.4%, p = 0.958) as well as severe complications (CHASE 20.9% vs ERAS 21.4%, p = 0.950). Among the 113 patients with a complicated course, the readmission rate was significantly higher in the CHASE cohort (41.9% vs 21.4%, p = 0.020). LOS after readmission was longer in the CHASE cohort (p = 0.018), but the total LOS was shorter (4 versus 6 days, p = 0.001). This study demonstrates that accelerated recovery can be safe for ASA I-II patients and has the potential to become a standard of care. Moreover, the CHASE protocol proved to be beneficial in terms of total LOS for patients with complications.

Abstract Background In Vietnam and other global settings, men who have sex with men (MSM) have become the population at greatest risk of HIV infection. Although HIV pre-exposure prophylaxis (PrEP) has been implemented as a prevention strategy, PrEP outcomes may be affected by low persistence and adherence among MSM with unhealthy alcohol use. MSM have a high prevalence of unhealthy alcohol use in Vietnam, which may affect PrEP outcomes. Methods Design: We will conduct a two-arm hybrid type 1 effectiveness-implementation randomized controlled trial of a brief alcohol intervention (BAI) compared to the standard of care (SOC) at the Sexual Health Promotion (SHP) clinic Hanoi, Vietnam. Participants: Sexually active MSM (n=564) who are newly initiating PrEP or re-initiating PrEP and have unhealthy alcohol use will be recruited and randomized 1:1 to the SOC or BAI arm. A subgroup of participants (n=20) in each arm will be selected for longitudinal qualitative interviews; an additional subset (n=48) in the BAI arm will complete brief quantitative and qualitative interviews after completion of the BAI to assess the acceptability of the intervention. Additional implementation outcomes will be assessed through interviews with clinic staff and stakeholders (n=35). Intervention: Study participants in both arms will receive standard care for PrEP clients. In the BAI arm, each participant will receive two face-to-face intervention sessions and two brief booster phone sessions, based on cognitive behavioral therapy and delivered in motivational interviewing informed style, to address their unhealthy alcohol use. Outcomes: Effectiveness (PrEP and alcohol use) and cost-effectiveness outcomes will be compared between the two arms. Intervention implementation outcomes (acceptability, feasibility, adoption) will be assessed among MSM participants, clinic staff, and stakeholders. Discussion This proposed trial will assess an alcohol intervention for MSM with unhealthy alcohol use who initiate or re-initiate PrEP, while simultaneously preparing for subsequent implementation. The study will measure the effectiveness of the BAI for increasing PrEP persistence through reducing unhealthy alcohol use in a setting where excessive alcohol consumption is a normative behavior. If effective, implementation-focused results will inform future scale-up of the BAI in similar settings. Trial registration NCT06094634 on clinicaltrials.gov. Registered 16 October 2023.

Abstract Childhood maltreatment (CM) is thought to be associated with altered responses to social stimuli and interpersonal signals. However, limited evidence exists that CM is linked to larger comfortable interpersonal distance (CID) – the physical distance humans prefer towards others during social interactions. However, no previous study has investigated this association in a comprehensive sample, yielding sufficient statistical power. Moreover, preliminary findings are limited to the European region. Finally, it is unclear how CM affects CID towards different interaction partners, and whether CID is linked to social functioning and attachment. To address these outstanding issues, adults (N = 2986) from diverse cultures and socio-economic strata completed a reaction time task measuring CID towards an approaching stranger and friend. Higher CM was linked to a larger CID towards both friends and strangers. Moreover, insecure attachment and less social support were associated with larger CID. These findings demonstrate for the first time that CM affects CID across countries and cultures, highlighting the robustness of this association.

Abstract Hypervirulent Klebsiella pneumoniae (HvKP) is an emerging bacterial pathogen causing invasive infection in immune-competent humans. The hypervirulence is strongly linked to the overproduction of hypermucoviscous capsule, but the underlying regulatory mechanisms of hypermucoviscosity (HMV) have been elusive, especially at the post-transcriptional level mediated by small noncoding RNAs (sRNAs). Using a recently developed RNA interactome profiling approach iRIL-seq, we interrogate the Hfq-associated sRNA regulatory network and establish an intracellular RNA-RNA interactome in HvKP. Our data reveal numerous interactions between sRNAs and HMV-related mRNAs, and identify a plethora of sRNAs that repress or promote HMV. One of the strongest HMV repressors is ArcZ, which is activated by the catabolite regulator CRP and targets many HMV-related genes including mlaA and fbp. We discover that MlaA and its function in phospholipid transport is crucial for capsule retention and HMV, inactivation of which abolishes Klebsiella virulence in mice. ArcZ overexpression drastically reduces bacterial burden in mice and reduces HMV in multiple hypervirulent and carbapenem-resistant clinical isolates, indicating ArcZ is a potent RNA inhibitor of bacterial pneumonia with therapeutic potential. Our work unravels a novel CRP-ArcZ-MlaA regulatory circuit of HMV and provides mechanistic insights into the posttranscriptional virulence control in a superbug of global concern.

Despite their prevalence in almost all publicly orientated conservation settings, sign design receives limited attention in the research literature. We used a remote eye-tracking device to test how visitors read educational signs, maps, and species signage. Three designs, plus a plain-text control sign, were tested for each sign type. Sign content was based on Brackenhurst Botanic Garden, Kenya, and included four different information texts (156–256 words long) and a species information text (64 words long). Four presentations of extinction threat status were also tested as were depictions of trail routes on maps. Data were collected from 51 participants at six cultural venues across Nottingham, U.K. Signs positioned centre-left of an exhibit were read first. Information on the left-hand side of signs was read first and dwelled upon the longest. Signs with a single large image and a single block of text were generally preferred, and images were most frequently recalled. Extinction threat status was most frequently viewed and best recalled from green–red thermometer diagrams and least from the IUCN red list diagram. Map routes were clearest when presented as coloured solid lines. This study indicates the potential benefit of eye-tracking research for measuring sign use and assisting in sign design.

Abstract Introduction Dermatomyositis (DM) is a rare systemic autoimmune disease characterized by a distinctive debilitating skin rash and skeletal muscle weakness. It is unclear if existing clinical outcome assessment (COA) measures include the concepts of priority to patients and those necessary to fully capture improvements in the active cutaneous manifestations of DM. This study aimed to develop the Cutaneous Dermatomyositis Investigator Global Assessment (CDM-IGA), a de novo IGA, for use in clinical trials of adult DM. Methods Eight DM clinical experts participated in 60-min qualitative interviews consisting of concept elicitation and cognitive debriefing methodologies. Concept elicitation comprised open-ended questions with follow-up probes to explore clinicians’ experiences of treating patients with DM, the impact of symptoms on patients’ quality of life, and the severity levels of disease characteristics to explore DM progression. Cognitive debriefing required the clinical experts to perform a review of the CDM-IGA, designed to assess the severity of cutaneous disease activity of DM. After the interviews, a consensus meeting with three clinical experts was held to agree on any outstanding issues relating to the CDM-IGA. Results The CDM-IGA was iteratively developed using the opinions of nine clinical experts. Feedback provided by all clinicians agreed that erythema was the main active cutaneous manifestation of DM and should be the primary characteristic on the CDM-IGA, split by erythema color and extent. To determine cutaneous disease severity, experts suggested adding a metric called secondary changes, which combined erosion/ulceration and lichenification, which could modify the patient’s final score. Three clinical experts suggested that a photo-guide to support assessments of erythema across different skin tones could be beneficial. Conclusions A novel CDM-IGA was developed for use with adult patients with DM in clinical trials, based on an iterative development process that combined qualitative feedback from clinical experts of DM and importantly adult patients living with DM.

Abstract Background The emergency department (ED) is a vital source of healthcare for individuals living with sickle cell disease (SCD). Prior research indicates that during the COVID-19 pandemic some individuals with SCD avoided the ED for fear of acquiring COVID-19 or delayed visiting the ED by self-management of symptoms or pain crisis at home. The purpose of the current study was to understand ED utilization rates before and during the pandemic among individuals living with SCD. Methods We conducted a retrospective cohort study using population-based SCD surveillance systems in California, Georgia, Michigan, and Tennessee to assess the impact of the pandemic on ED utilization among people with SCD by (1) analyzing trends in monthly ED utilization from January 2019 - December 2020, with specific attention given to immediate changes at the onset of the pandemic; and (2) calculating changes in the volume of utilization by comparing the total ED visits made from March - December 2020 to the same period in 2019, both overall and by demographic characteristics. Results Across all states, a decline in ED utilization during the onset of the pandemic was seen, with the largest decline seen in those under age 10. By December 2020, utilization rates were higher than their lowest observed month of April 2020, but had not fully returned to pre-COVID levels. During the pandemic, ED visits in each state decreased by as much as 25%, and the number of people with any ED utilization decreased by as much as 26%. Conclusions This study confirms and extends the existing literature related to the impact of the pandemic on healthcare utilization patterns in the US, in a unique population with increased healthcare needs.

Abstract The ancestral sarbecovirus giving rise to SARS-CoV-2 is posited to have originated in bats. While SARS-CoV-2 causes asymptomatic to severe respiratory disease in humans, little is known about the biology, virus tropism, and immunity of SARS-CoV-2-like sarbecoviruses in bats. SARS-CoV-2 has been shown to infect multiple mammalian species, including various rodent species, non-human primates, and Egyptian fruit bats. We show that SARS-CoV-2 can utilize Jamaican fruit bat (Artibeus jamaicensis) ACE2 spike for entry in vitro. Therefore, we investigate the Jamaican fruit bat as a possible in vivo model to study reservoir responses. We find that SARS-CoV-2 Delta does not efficiently replicate in Jamaican fruit bats in vivo. We observe infectious viruses in the lungs of only one animal on day 1 post-inoculation and find no evidence of shedding or seroconversion. This is possibly due to host factors restricting virus egress after aborted replication. Furthermore, we observe no significant immune gene expression changes in the respiratory tract but do observe changes in the intestinal metabolome after inoculation. This suggests that, despite its broad host range, SARS-CoV-2 is unable to infect all bat species, and Jamaican fruit bats are not an appropriate model to study SARS-CoV-2 reservoir infection.

Abstract Khat, a naturally growing stimulant, has seen a significant increase in both consumption and cultivation in eastern Ethiopia. This reliance on khat in the region comes despite its known physiological complications, with users unable to restrict khat use due to its pervasive impact on their livelihood. This qualitative study sought to understand the meaning that those in eastern Ethiopia attribute to khat and explore their firsthand experiences with the substance. In June and July of 2023, six unstructured interviews were conducted among residents of the Haramaya District in Ethiopia. To promote a holistic comprehension of the participants’ lived experiences, an interpretative phenomenological analysis approach was employed when collecting and analyzing the data. Participant responses were coded independently from one another by two different researchers identifying superordinate and corresponding subordinate themes. Among the participants, six superordinate themes were captured: economic backbone of the region, market disruption & fluctuation, pesticide use, societal relationships around khat, applications of khat, and access to healthcare. The participants’ responses indicated that the normalization of khat use, coupled with the downplaying of its addictive potential, has established a framework where khat consumption is not only allowed but, in some cases, even encouraged. The unique interplay between communal practice and individual preservation creates a cyclical effect of using khat to supplement energy to farm khat and then sell or stimulate further work on their farm. This study illuminates the transitionfrom what was once the traditional or spiritual use of khat, to a more practical use for ensuring economic livelihood.

Abstract Background Portable gamma cameras are being developed for nuclear medicine procedures such as thyroid scintigraphy. This article introduces Seracam® – a new technology that combines small field of view gamma imaging with optical imaging – and reports its performance and suitability for small organ imaging. Methods The count rate capability, uniformity, spatial resolution, and sensitivity for 99mTc are reported for four integrated pinhole collimators of nominal sizes of 1 mm, 2 mm, 3 mm and 5 mm. Characterisation methodology is based on NEMA guidelines, with some adjustments necessitated by camera design. Two diagnostic scenarios – thyroid scintigraphy and gastric emptying – are simulated using clinically relevant activities and geometries to investigate application-specific performance. A qualitative assessment of the potential benefits and disadvantages of Seracam is also provided. Results Seracam’s performance across the measured characteristics is appropriate for small field of view applications in nuclear medicine. At an imaging distance of 50 mm, corresponding to a field of view of 77.6 mm × 77.6 mm, spatial resolution ranged from 4.6 mm to 26 mm and sensitivity from 3.6 cps/MBq to 52.2 cps/MBq, depending on the collimator chosen. Results from the clinical simulations were particularly promising despite the challenging scenarios investigated. The optimal collimator choice was strongly application dependent, with gastric emptying relying on the higher sensitivity of the 5 mm pinhole whereas thyroid imaging benefitted from the enhanced spatial resolution of the 1 mm pinhole. Signal to noise ratio in images was improved by pixel binning. Seracam has lower measured sensitivity when compared to a traditional large field of view gamma camera, for the simulated applications this is balanced by advantages such as high spatial resolution, portability, ease of use and real time gamma-optical image fusion and display. Conclusion The results show that Seracam has appropriate performance for small organ 99mTc imaging. The results also show that the performance of small field of view systems must be considered holistically and in clinically appropriate scenarios.

Background: The current standard-of-care pathology report relies only on lengthy written text descriptions without a visual representation of the resected cancer specimen. This study demonstrates the feasibility of incorporating virtual, three-dimensional (3D) visual pathology reports to improve communication of final pathology reporting. Materials and methods: Surgical specimens are 3D scanned and virtually mapped alongside the pathology team to replicate grossing. The 3D specimen maps are incorporated into a hybrid visual pathology report which displays the resected specimen and sampled margins alongside gross measurements, tumor characteristics, and microscopic diagnoses. Results: Visual pathology reports were created for 10 head and neck cancer cases. Each report concisely communicated information from the final pathology report in a single page and contained significantly fewer words (293.4 words) than standard written pathology reports (850.1 words, p

Background: Maintaining an appropriate depth of anaesthesia is important for avoiding adverse effects from undermedication or overmedication during surgery. Electroencephalography (EEG) has become increasingly used to achieve this balance. Investigating the predictive power of intracranial EEG (iEEG) and scalp EEG for different levels of sedation could increase the utility of EEG monitoring. Methods: Simultaneous iEEG, scalp EEG, and Observer's Assessment of Alertness/Sedation (OAA/S) scores were recorded during emergence from anaesthesia in seven patients undergoing placement of intracranial electrodes for medically refractory epilepsy. A deep learning model was constructed to predict an OAA/S score of 0–2 vs 3–5 using iEEG, scalp EEG, and their combination. An additional five patients with only scalp EEG data were used for independent validation. Models were evaluated using the area under the receiver-operating characteristic curve (AUC). Results: Combining scalp EEG and iEEG yielded significantly better prediction (AUC=0.795, P

Background: Positive margins are frequently observed in total laryngectomy (TL) specimens. Effective communication of margin sampling sites and final margin status between surgeons and pathologists is crucial. In this study, we evaluate the utility of multimedia visual pathology reports to facilitate interdisciplinary discussion of margin status in laryngeal cancer surgery. Methods: Ex vivo laryngeal cancer surgical specimens were three-dimensional (3D) scanned before standard of care pathological analysis. Using computer-aided design software, the 3D model was annotated to reflect inking, sectioning, and margin sampling sites, generating a visual pathology report. These reports were distributed to head and neck surgeons and pathologists postoperatively. Results: Fifteen laryngeal cancer surgical specimens were 3D scanned and virtually annotated from January 2022 to December 2023. Most specimens (73.3%) were squamous cell carcinomas (SCCs). Among the cases, 26.7% had final positive surgical margins, whereas 13.3% had close margins, defined as

Objectives: Given the complex role of immunity in dengue severity, we aimed to review the clinical course of dengue infection in immunocompromised patients. Methods: We conducted a systematic review of studies reporting outcomes among immunocompromised patients with laboratory-confirmed dengue infection. Meta-analysis using the Mantel-Haenszel method (fixed effects) was performed for studies with control groups. We registered the study with PROSPERO (No. CRD42021258930). Results: We included 115 studies. Among these, 30 studies compared immunocompromised (cases) and nonimmunocompromised (control) patients, focusing mainly on children (n = 22 studies) with malnutrition (n=18). Immunocompromised patients had a higher likelihood of dengue complications (OR 1.87; 95% CI: 1.04-3.35]) but a lower likelihood of severe dengue (OR 0.83; 95% CI: 0.69-1.00]. No significant difference in mortality was observed. In the 85 studies focused solely on immunocompromised patients, severe dengue and mortality rates were 9% and 4%, respectively, mostly among adult solid organ transplant recipients and those with inflammatory diseases. Immunosuppressive treatment alterations and temporary graft dysfunction were reported. Conclusion: Immunocompromised patients have an increased risk of dengue-related complications. However, definitive conclusions about the comparative severity of dengue across different immunocompromised patient groups are limited by a lack of robust data, highlighting the need for well-designed future studies.

The ovarian reserve consists of a limited supply of primordial follicles (PFs), each containing an oocyte surrounded by a layer of granulosa cells (GCs). PFs are relatively quiescent and must remain viable for a long period, thereby making them susceptible to environmental and lifestyle influences. Given the widespread prevalence of e-cigarette use, this study aimed to investigate the effects of nicotine and its metabolite cotinine in a mouse model and to elucidate the mechanisms by which nicotine influences the ovarian reserve. Neonatal ovaries were cultured for 7-days in nicotine or cotinine reflective of concentrations in plasma of e-cigarette users. From histological evaluation, nicotine or cotinine had no impact on the number of PFs or early growing follicles; however, the medium (15 ng/ml) and high (45 ng/ml) concentrations of nicotine (but not cotinine) caused a small reduction in oocyte and GC size within PFs relative to controls (0 ng/ml; both P

Purpose: Physical activity (PA) is an important determinant of skeletal health. In young adults with type 1 diabetes (T1D) fracture risk is increased, yet few studies have examined the PA and bone health relationship. Therefore, this pilot cross-sectional study characterized PA levels and their association with bone parameters measured by high resolution peripheral quantitative computed tomography (HR-pQCT) in young adults with T1D. Methods: HR-pQCT (Xtreme CTII) was used to measure bone outcomes at the distal tibia and radius, and accelerometery (ActiGraph GT3X) recorded daily minutes of light and moderate-vigorous physical activity (MVPA). Quadratic regression analyses were conducted with a p-value ≤ 0.05 considered significant. Results: PA data from 19 young adults (23.1 ± 1.9 years) with T1D was analyzed. Over half (63 %) of participants completed ≥150 min of MVPA per week, however, most measured activity time per day (57 %) was spent in sedentary pursuits. Significant non-linear associations were found between the duration of MVPA and several trabecular bone parameters at the tibia. Conclusions: In young adults with T1D, MVPA may have site specific (tibia) and compartment specific (trabecular) non-linear associations with bone. Further studies should confirm these findings, which may help inform evidence-based exercise recommendations to optimize bone health in young adults with T1D.

Summary: Background: Physical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear. Methods: We carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race. Findings: We found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (Padj = 0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (Padj

Biofilms are a highly complex community of microorganisms embedded in a protective extracellular polymeric substance (EPS). Successful biofilm control requires a variety of approaches to better understand the structure-function relationship of the EPS matrix. Magnetic resonance imaging (MRI) is a versatile tool which can measure spatial structure, diffusion, and flow velocities in three dimensions and in situ. It is well-suited to characterize biofilms under natural conditions and at different length scales. MRI contrast is dictated by T1 and T2 relaxation times which vary spatially depending on the local chemical and physical environment of the sample. Previous studies have demonstrated that MRI can provide important insights into the internal structure of biofilms, but the contribution of major biofilm components—such as proteins, polysaccharides, and cells—to MRI contrast is not fully understood. This study explores how these components affect contrast in T1-and T2-weighted MRI by analyzing artificial biofilms with well-defined properties modeled after aerobic granular sludge (AGS), compact spherical biofilm aggregates used in wastewater treatment. MRI of these biofilm models showed that certain gel-forming polysaccharides are a major source of T2 contrast, while other polysaccharides show minimal contrast. Proteins were found to reduce T2 contrast slightly when combined with polysaccharides, while cells had a negligible impact on T2 but showed T1 contrast. Patterns observed in the model biofilms served as a reference for examining T2 and T1-weighted contrast in the void spaces of two distinct AGS granules, allowing for a qualitative evaluation of the EPS components which may be present. Further insights provided by MRI may help improve understanding of the biofilm matrix and guide how to better manage biofilms in wastewater, clinical, and industrial settings.

Objective: Young people with post-traumatic stress disorder experience difficulties in social and interpersonal domains. We examined whether the best-evidenced treatments of PTSD for children and young people (Trauma-focussed Cognitive Behavioural Therapy or Eye Movement Desensitisation and Reprocessing; aged 5–25) improve social or interpersonal factors in randomised controlled trials, compared to a comparator condition.Method: The review was preregistered on PROSPERO (CRD42023455615; 18th August 2023). Web of Science Core Collection, EMBASE, CINAHL, Pubmed, PsycINFO, Cochrane Central Register of Controlled Trials and PTSDPubs were searched, and data were extracted for social and interpersonal outcomes post treatment. A random effect meta-analysis was conducted to obtain between-group pooled effect size estimates.Results: The search resulted in 792 studies, of which 17 met our inclusion criteria (N = 2498). Our meta-analysis included 13 studies which investigated social skills and functioning, revealing a small but non-significant effect favouring the evidence-based treatment versus comparison (g = .20, 95% CI [−0.03, 0.44], p = .09). We narratively synthesised six studies which reported other social-related outcomes (e.g. perceptions of social support), and four out of six reported improved social domain outcomes for the evidence-based PTSD treatment condition. There was a large amount of heterogeneity, with no evidence that this could be explained by moderators.Conclusion: Few trials report on social and interpersonal outcomes, and where they are reported the evidence is mixed. It may be that trauma-focused therapies for PTSD need to be adapted in some circumstances, so that they address social and interpersonal deficits often seen in children and young people with PTSD.

Background: Perceived social support is an established predictor of post-traumatic stress disorder (PTSD) after exposure to a traumatic event. Gender is an important factor that could differentiate responses to social support, yet this has been little explored. Symptoms of complex PTSD are also common following trauma but have been under-researched in this context. Large scale studies with culturally diverse samples are particularly lacking.Objectives: In a multi-country sample, we examined: (a) gender differences in perceived social support and both posttraumatic stress symptom severity (PTSS) and complex posttraumatic stress symptom severity (CPTSS); (b) associations between social support and PTSS/CPTSS; and (c) the potential moderating role of gender in the relationship between perceived social support and trauma-related distress.Method: A total of 2483 adults (Mage = 30yrs, 69.9% females) from 39 countries, who had been exposed to mixed trauma types, completed the Multidimensional Scale of Perceived Social Support and the International Trauma Questionnaire (which captures PTSS/CPTSS). Regression analyses examined associations between gender, perceived social support, and PTSS/CPTSS; and tested for gender by social support interactions in predicting PTSS/CPTSS scores. Models were adjusted for age and socioeconomic status.Results: In our cross-country sample, females had greater PTSS/CPTSS than males (B = .23 [95% CI 0.16, 0.30], p

Background: As physical function and physical activity are often compromised among children and adolescents undergoing acute cancer treatment, psychometrically robust and feasible assessment tools are needed. The aim of this study is to evaluate the construct validity, responsiveness and feasibility of one physical activity assessment tool (Fitbit Inspire); and six physical function assessment tools (Movement ABC-2, Timed Up and Go, 30-s Chair Stand, Timed Rise from the Floor, Timed Up and Down Stairs, 6-min Walk Test) for children undergoing acute cancer treatment. Methods: A prospectively-registered, mixed methods, single-group study evaluated measurement properties against a priori hypothesis using Consensus-based Standards for the selection of health status Measurement Instruments (COSMIN) framework. Feasibility was assessed quantitively (a priori thresholds), and qualitatively (semi-structured interviews, focus-groups). Results: Twenty children/adolescents (median age 13 ​± ​5 years, various cancer diagnoses), 20 parents and 16 clinicians participated. Fitbit was feasible to assess daily steps only, had evidence of construct validity, tendency to overestimate step count and adequate evidence of responsiveness (compared to Actigraph). The 30-s Chair stand, 6-min Walk Test and Timed Up and Go were feasible and showed evidence of construct validity and responsiveness. To maximise feasibility, consideration of timing and intent of assessment are crucial. Conclusion: Fitbit has limitations as a physical activity assessment tool. The 30-s Chair Stand, 6-min Walk Test and Timed Up and Go were feasible to use and showed favourable measurement properties to assess physical function.

ABSTRACTPrecision engineering of the gut microbiome holds promise as an effective therapeutic approach for diseases associated with a disruption in this microbial community. Engrafting a live biotherapeutic product (LBP) in a predictable, controllable manner is key to the consistent success of this approach and has remained a challenge for most LBPs under development. We recently demonstrated high-level engraftment of Bifidobacterium longum subsp. infantis (B. infantis) in adults when co-dosed with a specific prebiotic, human milk oligosaccharides (HMO). Here, we present a cellular kinetic-pharmacodynamic approach, analogous to pharmacokinetic-pharmacodynamic-based analyses of small molecule- and biologic-based drugs, to establish how HMO controls expansion, abundance, and metabolic output of B. infantis in a human microbiota-based model in gnotobiotic mice. Our data demonstrate that the HMO dose controls steady-state abundance of B. infantis in the microbiome, and that B. infantis together with HMO impacts gut metabolite levels in a targeted, HMO-dependent manner. We also found that HMO creates a privileged niche for B. infantis expansion across a 5-log range of bacterial inocula. These results demonstrate remarkable control of both B. infantis levels and the microbiome community metabolic outputs using this synbiotic approach, and pave the way for precision engineering of desirable microbes and metabolites to treat a range of diseases.

Stigma that people with HIV who inject drugs experience negatively impacts HIV and substance use care, but stigma’s association with sharing injection equipment is not known. This is a cross-sectional analysis of data from two studies of people with HIV reporting drug injection (N = 319) in St. Petersburg, Russia (September 2018-December 2020). We used logistic regression to examine associations between HIV stigma and substance use stigma scores (categorised into quartiles) and past 30-day equipment sharing, adjusting for demographic and clinical characteristics. Secondary analyses examined associations of arrest history and social support with sharing equipment. Almost half (48.6%) of participants reported sharing injection equipment. Among groups who did and did not share, mean HIV stigma (2.3 vs 2.2) and substance use stigma (32 vs 31) scores were similar. Adjusted analyses detected no significant associations between HIV stigma quartiles (global p-value = 0.85) or substance use stigma quartiles (global p-value = 0.51) and sharing equipment. Neither arrest history nor social support were significantly associated with sharing equipment. In this cohort, sharing injection equipment was common and did not vary based on stigma, arrest history, or social support. To reduce equipment sharing, investments in sterile injection equipment access in Russia should be prioritised over interventions to address stigma.

Salmonella enterica serovar Panama, a causative agent of non-typhoidal salmonellosis (NTS), is one of several serovars that causes invasive NTS disease (iNTS) in humans. S. Panama is an understudied pathogen, with its pathobiology poorly understood. It is a predominant iNTS serovar in Australia, a high-income country with high rates of salmonellosis, where S. Panama has been documented to have a high odds ratio (13.9-15.26) for causing iNTS. This study investigates the genomic epidemiology and antimicrobial resistance profiles of all S. Panama isolates recovered in Victoria, Australia, between 2000 and 2021. We examined the infection dynamics of S. Panama in seven isolates, representing the genetic diversity of the study population. Two sub-lineages, encompassed within a previously described Asian lineage, were identified. Multi-drug resistance (resistance to ≥3 drug classes) was detected in 46 (51.7%) Australian isolates. The plasmid-mediated colistin resistance gene, mcr1.1, was detected in one Australian S. Panama isolate, carried by an IncI plasmid previously reported in Salmonella and Escherichia coli isolates collected from poultry in South-East Asia. Examination of the intracellular replication dynamics of S. Panama isolates demonstrated diverse phenotypes. In THP-1 derived macrophages, despite low host cell uptake, S. Panama showed higher replication rates over time compared to S. enterica serovar Typhimurium. However, a causative genotype could not be identified to explain this observed phenotype. This study provides insights into the S. Panama isolates circulating in Australia over two-decades, finding that 78% were linked to international travel suggesting importation in Australia. It shows MDR was common in this iNTS serovar, and colistin resistance reported for the first time. It provides the first data on the host-pathogen interactions of S. Panama in Australia, which will aid our collective understanding of the pathobiology of S. Panama and iNTS serovars more broadly.