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Abstract Background Synchronous malignant histiocytoses are rare conditions that occur concurrently with another hematologic neoplasm. Most reported cases are associated with B-cell lymphoproliferative disorders, while associations with T-cell hemopathies are less common. These two diseases may share mutations and/or cytogenetic anomalies, which can lead to malignant proliferations. In such cases, the term “secondary malignant histiocytosis” can be applied. Case description A 26-year-old patient was diagnosed with anaplastic lymphoma kinase negative anaplastic large cell lymphoma [ALK-ALCL] associated with synchronous malignant histiocytosis. Neoplastic cells were distinguished by the exclusivity of the rearrangement of TCR genes within the lymphoma cells, whereas mutations in the KRAS and TP53 genes affected mono-histiocytic cells. However, these two cells populations shared common chromosomal abnormalities. First line treatment protocol included Brentuximab vedotin, cyclophosphamide, doxorubicin, and methylprednisolone. Despite a partial clinical and biological response after cycle 1 of treatment, the patient was refractory at the end of cycle 2. Patient died in the intensive care unit from a multiple-organ failure related to lymphohistiocytic hemophagocytosis. Conclusion This case represents the first documented instance of synchronous malignant histiocytosis associated with anaplastic large cell lymphoma. Notably, the uniqueness of this case lies in the absence of TCR rearrangement in the histiocytic cells, despite the presence of shared chromosomal abnormalities with the lymphomatous cells indicating a common origin for both neoplastic proliferations. Considering the rarity of such occurrences, the use of histiocytosis targeted therapy alongside conventional lymphoma treatment warrants consideration in such a context.

Abstract Introduction Co-production involves researchers, practitioners and people with lived experience working in a collaborative manner, with shared power. The potential benefits of co-production are well documented. However, there is little research describing the experience of having been involved in co-production from the perspective of Experts By Lived Experience (EBLE). The aim of the present study is to explore the experiences of EBLE of obsessive-compulsive disorder (OCD) on their involvement in co-producing a blended intervention to prevent relapse for OCD. Methods Five EBLE took part in semi-structured interviews enquiring about their experiences of co-producing a relapse prevention intervention. Reflexive thematic analysis was used to analyse the data. Results Four themes were developed: (1) Welcome but unexpected therapeutic benefits; (2) The parameters of a safe space; (3) Genuine co-production brings meaningful change; and (4) Navigating the challenging terrain of co-production. Conclusions Overall, EBLE reported their involvement in the co-production process to have had positive impacts on both the development of the intervention and their own personal recovery journey. EBLE valued the safety created within the group, and the importance this had for allowing them to speak open and honestly about their experiences and the difficulties that can arise with the nature of the work.

Abstract Thin or ultra-thin dielectric layers have been widely used in various applications such as capacitors, piezo-electrics, and solar cells. This study explains the mechanism and chemistry of creating nano- and micron-sized openings in atomic-layer-deposited aluminum oxide-based dielectric layers using the alkali metal salt selenization technique. The necessary components for this mechanism are excess methyl groups present in the dielectric layer, supply of selenium and alkali metals, and a minimum annealing temperature. It is shown and explained that to create openings in the dielectric layer, heavier alkali halide metal salts require less energy, or - in other words - a lower annealing temperature. The overall hypothesis is explained via a thermodynamic approach with supportive thermochemical reactions. Thus, an easy way to engineer the dielectric layer to form openings at low temperatures is presented, beneficial for various applications like photovoltaics, optoelectronics, or micro-electro-mechanical systems (MEMS).

Despite the constant development of antimicrobial resistance (AMR), few new antimicrobials are currently becoming available clinically. Alternative approaches, such as different mechanisms to fund their use, are being explored to encourage development of new antimicrobials.

Abstract Aims Decision‐makers still predominantly focus on the perspective of non‐patient stakeholders, which may deviate from the unique perspective of heart failure (HF) patients. To enhance patient‐centred decision‐making, there is a need for more patient‐based evidence derived directly from the patients themselves. Hence, this study aimed to understand (i) HF patients' unmet medical needs and preferred treatment outcomes; (ii) patients' risk tolerance; and (iii) their information needs, uncertainties and satisfaction towards HF treatment. Methods This qualitative patient preference study consisted of a literature review with a systematic search strategy and semi‐structured interviews with HF patients, analysed using the framework method. During the interviews, patients were asked to rank a predefined list of disease and treatment‐related characteristics informed by the literature review and were able to spontaneously raise additional characteristics. Results The study included 14 Belgian HF patients (age range: 58–79, mean age: 72). (i) Regarding their unmet medical needs, HF patients reported that the most important unmet medical needs were shortness of breath and fatigue, as they negatively impact their quality of life (QoL) and independence. In the ranking exercise, patients prioritized improvements in QoL over improvements in life expectancy, whereby the following characteristics received the highest cumulative score: (1) independence, (2) shortness of breath, (3) impaired renal function, (4) survival, (5) fatigue, (6) risk of hospitalization and (7) communication with and between physicians. Patients most often spontaneously raise characteristics related to the general care process. Mechanism of action, route of administration, dose frequency and weight fluctuations scored among the least important characteristics. (ii) Regarding patients' risk tolerance towards HF treatment, some of the patients expressed zero tolerance for side effects, as they had not yet experienced any discomfort caused by the treatment or disease. (iii) Regarding their information needs, patients voiced their desire to receive practical and comprehensible advice orally from their physician because they highly value individualized treatment decision‐making. Patients also expressed uncertainties regarding whether the experienced effects were due to their treatment, disease, ageing or other comorbidities. Conclusions This study shows that, besides increasing life expectancy, HF patients prioritize improvements in symptoms and side effects reducing their QoL and independence, such as shortness of breath and fatigue. The patient‐relevant characteristics identified in this study, from the perspective of HF patients themselves, may be useful to inform clinical trial endpoint selection and guide downstream drug development, evaluation and clinical decision‐making towards addressing the unmet medical needs and treatment outcomes of importance to HF patients.

Abstract The endoplasmic reticulum (ER) is shaped by abundant membrane curvature-generating proteins that include the REEP family member REEP5. The REEP1 subfamily, consisting of four proteins in mammals (REEP1-4), is less abundant and lack a N-terminal region. Mutations in REEP1 and REEP2 cause Hereditary Spastic Paraplegia, but the function of these four REEP proteins remains enigmatic. Here we show that REEP1-4 reside in a unique vesicular compartment and identify features that determine their localization. Mutations in REEP1-4 that compromise curvature generation, including those causing disease, relocalize the proteins to the bulk ER. These mutants interact with wild-type proteins to retain them in the ER, consistent with their autosomal-dominant disease inheritance. REEP1 vesicles contain the membrane fusogen atlastin-1, but not general ER proteins. We propose that REEP1-4 generate these vesicles themselves by budding from the ER, and that they cycle back to the ER by atlastin-mediated fusion. The vesicles may serve to regulate ER tubule dynamics.

Abstract Sedimentary records of Early Pleistocene (~2.6–0.8 Ma) glaciations are sparse on shelves, yet trough mouth fans on adjacent continental slopes provide a continuous record of ice-sheet and climate development throughout the Quaternary. Here, we interpret high-quality 3D seismic reflection data combined with borehole and chronostratigraphic information from a shelf-slope setting in the southwestern Barents Sea to study meltwater and sediment inputs to the deep ocean, focusing on the onset of Pleistocene glaciations. Sandy deposits were brought to the slopes of the high-latitude Bear Island Fan by a preglacial contourite-turbidite system from ⁓2.6–2.4 Ma. Muddy glacigenic debris flows document the first shelf-edge glaciation at ⁓2.4 Ma. From 1.78–0.78 Ma, muddy turbidity-current- and debris-flow-derived sediments were delivered from shelf to slope via six tunnel valleys measuring up to 12 km in width and 200 m in depth. These tunnel valleys and associated downslope deposits formed during the 41-kyr climate cycles of the Early Pleistocene, and evidence abundant channelized, meltwater discharges from these glaciations. Following the mid-Pleistocene transition to 100-kyr cycles, a change in the style of glaciation is suggested by a change in landform and facies associations consistent with a reduced meltwater contribution. This study shows that the Norwegian-Barents shelf was extensively glaciated in the Early Pleistocene, with a first shelf-edge glaciation from ~2.4 Ma.

Abstract Background Autologous bone grafts are essential in reconstructive oral and maxillofacial surgery, and depending on the donor site, they can be associated with specific harvesting morbidities. One of the most commonly applied bone grafts is the iliac crest bone graft, irrespective of other grafts, which might be associated with an easier surgical procedure or the possibility of harvesting them under local anaesthesia. Objective of the study is the clinical evaluation of proximal tibia bone grafts regarding their eligibility for maxillofacial bone grafting. Methods In this retrospective study, proximal tibia bone grafts were examined with regard to associated donor and recipient site morbidity and their suitability for alveolar ridge augmentation and rhinoplasty. Results In total, 21 tibia grafts were included. Fifty-seven percent of the bone grafts were used for alveolar ridge reconstruction, and 43% were used for augmentative rhinoplasty. No significant complications occurred during or after harvesting, but in 14.3% of the patients, minor wound healing disorders were recorded at the donor site, and in 19% of the patients, they were recorded at the recipient site. Statistically, patient sex, age, nicotine and alcohol abuse and metabolic diseases had no significant influence on the complication rate. Graft harvesting under local anaesthesia and at summer temperatures was associated with significantly more complications at the harvesting site (p

Abstract Background Rabies remains a major public health problem in low- and middle-income countries. However, human rabies deaths are rarely laboratory-confirmed or sequenced, especially in Africa. Five human rabies deaths from Tanzania and Kenya were investigated and the causative rabies viruses sequenced, with the aim of identifying implications for rabies control at individual, healthcare and societal levels. Case presentation The epidemiological context and care of these cases was contrasting. Four had a clear history of being bitten by dogs, while one had an unclear biting history. Two individuals sought medical attention within a day of being bitten, whereas three sought care only after developing rabies symptoms. Despite seeking medical care, none of the cases received complete post-exposure prophylaxis: one patient received only tetanus vaccination, one did not complete the post-exposure vaccination regimen, one followed an off-label vaccination schedule, and two did not receive any post-exposure vaccinations before the onset of symptoms. These cases highlight serious gaps in health-seeking behaviour, and in health systems providing appropriate care following risky exposures, including in the accessibility and effectiveness of post-exposure prophylaxis as it is administered in the region. Conclusions The viral genomic and epidemiological data confirms dog-mediated rabies as the cause of each of these deaths. The phylogenetic investigation highlights the transboundary circulation of rabies within domestic dog populations, revealing distinct rabies virus clades with evidence of regional spread. These findings underscore the importance of coordinated cross-border control efforts between the two countries. Urgent action is needed to improve awareness around the need for emergency post-exposure vaccines that should be accessible in local communities and administered appropriately, as well as investment in coordinated dog vaccination to control dog-mediated rabies, the underlying cause of these deaths. Graphical Abstract

Abstract Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key ‘don’t-eat-me’ molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.

BackgroundExtended reality (XR) technologies are increasingly being used to reduce health and procedural anxieties. The global effectiveness of these interventions is uncertain, and there is a lack of understanding of how patient outcomes might vary between different contexts and modalities. ObjectiveThis research used panoramic meta-analysis to synthesize evidence across the diverse clinical contexts in which XR is used to address common outcomes of health and procedural anxiety. MethodsReview-level evidence was obtained from 4 databases (MEDLINE, Embase, APA PsycINFO, and Epistemonikos) from the beginning of 2013 until May 30, 2023. Reviews that performed meta-analysis of randomized controlled trials relating to patient-directed XR interventions for health and procedural anxiety were included. Studies that analyzed physiological measures, or focused on technologies that did not include meaningful immersive components, were excluded. Furthermore, data were only included from studies that compared intervention outcomes against no-treatment or treatment-as-usual controls. Analyses followed a preregistered, publicly available protocol. Trial effect sizes were extracted from reviews and expressed as standardized mean differences, which were entered into a 3-level generalized linear model. Here, outcomes were estimated for patients (level 1), studies (level 2), and anxiety indications (level 3), while meta-regressions explored possible influences of age, immersion, and different mechanisms of action. Where relevant, the quality of reviews was appraised using the AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews, Revised Instrument) tool. ResultsData from 83 individual trials were extracted from 18 eligible meta-analyses. Most studies involved pediatric patient groups and focused on procedural, as opposed to general, health anxieties (eg, relating to needle insertion, dental operations, and acute surgery contexts). Interventions targeted distraction-, education-, and exposure-based mechanisms, and were provided via a range of immersive and nonimmersive systems. These interventions proved broadly effective in reducing patient anxiety, with models revealing significant but heterogeneous effects for both procedural (d=–0.75, 95% CI –0.95 to –0.54) and general health (d=–0.82, 95% CI –1.20 to –0.45) indications (when compared with nontreatment or usual-care control conditions). For procedural anxieties, effects may be influenced by publication bias and appear more pronounced for children (vs adults) and nonimmersive (vs immersive) technology interventions, but they were not different by indication. ConclusionsResults demonstrate that XR interventions have successfully reduced patient anxiety across diverse clinical contexts. However, significant uncertainty remains about the generalizability of effects within various unexplored indications, and existing evidence is limited in methodological quality. Although current research is broadly positive in this area, it is premature to assert that XR interventions are effective for any given health or procedural anxiety indication.

BackgroundThe rarity that is inherent in rare disease (RD) often means that patients and parents of children with RDs feel uniquely isolated and therefore are unprepared or unsupported in their care. To overcome this isolation, many within the RD community turn to the internet, and social media groups in particular, to gather useful information about their RDs. While previous research has shown that social media support groups are helpful for those affected by RDs, it is unclear what these groups are particularly useful or helpful for patients and parents of children with RDs. ObjectiveThis study aimed to identify what specific features of disease-related support groups (DRSGs) the RD community finds particularly useful or supportive and provide a set of recommendations to improve social media–based RD support groups based on this information. MethodsSemistructured qualitative interviews were performed with patients and parents of patients with RDs. Interview participants had to be at least 18 years of age at the time of the interview, be seen by a genetics specialist at a partner health care institution and be proficient in the English language. Social media use was not a prerequisite for participation, so interview participants ranged from extensive users of social media to those who chose to remain off all social media. All interviews were conducted by phone, recorded, and then transcribed. Interview transcripts were then coded using the 6 steps outlined by Braun and Clarke. Three researchers (TAD, SLV, and CMEH) performed initial coding. After this, the study team conducted a review of themes and all members of the team agreed upon a final analysis and presentation of data. ResultsWe conducted 31 interviews (mean age 40, SD 10.04 years; n=27, 87% were women; n=30, 97% were non-Hispanic White). Thematic analysis revealed that social media DRSG users identified the informational usefulness of these groups as being related to the gathering and sharing of specific information about an RD, clarification about the importance and meaning of certain symptoms, and obtaining insight into an RD’s progression and prognosis. Participants also identified that DRSGs were useful sources of practical information, such as tips and tricks about managing RD-related issues and concerns. In addition, participants found DRSGs to be a useful space for sharing their disease-related stories but also highlighted a feeling of exhaustion from overexposure and overuse of DRSGs. ConclusionsThis study identifies the usefulness of DRSGs for the RD community and provides a set of recommendations to improve future instances of DRSGs. These recommendations can be used to create DRSGs that are less prone to splintering into other DRSGs, thus minimizing the risk of having important RD-related information unhelpfully dispersed amongst a multitude of support groups.

Abstract Although parasitism is vital for ecosystem dynamics and food webs, the population effects of parasitism in the marine pelagic have received little attention. Pelagic copepods link primary producers and higher consumers in marine food webs and host numerous parasites that may affect reproduction, behavior, and survival. We present a simple model consisting of uninfected hosts, infected hosts, and the free‐living parasite stage and use it to investigate population dynamics and outbreak conditions of this host–parasite system. The host population growth is limited by a carrying capacity determined by resource availability and stoichiometric constraints. We parameterized the model for 10 copepod species with different traits but with the same Blastodinium‐like parasite. We derived a threshold ratio R0 for establishing infection, which showed that the parasite could invade and persist in all hosts. The ability of parasites to invade host populations largely depended on traits of free‐living spores and host density. From numerical analysis, we found that the parasite typically induced oscillations in the host population. Host traits were important for infection dynamics: High host growth rates mitigated some of the consequences of infection, and larger copepods were more susceptible to infection than smaller ones. The model implies that parasitism can impact the functional role of the copepod population in the ecosystem, and the system as a whole.

The gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood–brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients in vitro led to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.

Summary: Intestinal homeostasis is maintained through the combined functions of epithelial and immune cells that collaborate to preserve the integrity of the intestinal barrier. However, the mechanisms by which immune cell populations regulate intestinal epithelial cell (IEC) homeostasis remain unclear. Here, we use a multi-omics approach to study the immune-epithelial crosstalk and identify CD1d-restricted natural killer T (NKT) cells as key regulators of IEC biology. We find that NKT cells are abundant in the proximal small intestine and show hallmarks of activation at steady state. Subsequently, NKT cells regulate the survival and the transcriptional and cellular composition landscapes of IECs in intestinal organoids, through interferon-γ (IFN-γ) and interleukin-4 secretion. In vivo, lack of NKT cells results in an increase in IEC turnover, while NKT cell activation leads to IFN-γ-dependent epithelial apoptosis. Our findings propose NKT cells as potent producers of cytokines that contribute to the regulation of IEC homeostasis.

The field of transportation has undergone changes due to the advancements in technology and the pressing need for mobility solutions. As cities worldwide struggle with the challenges posed by population growth and environmental sustainability, it becomes imperative to introduce adaptive transportation options. The increasing traffic congestion in areas and concerns regarding air quality and carbon emissions emphasize the importance of finding sustainable solutions. In this regard we present the ''On demand shared use bike sharing system (OSABS)'' as an eco-friendly on-demand mobility alternative that has the potential to revolutionize transportation from its core. Self-driving bikes provide a solution by reducing traffic congestion and promoting sustainable modes of transport. Customers can easily reserve a bike through their smartphones and it comes directly to their location within the given time. The user will ride it manually and release it after usage. The bike then drives autonomously to the next destination. This service allows an environment-friendly door-to-door mobility solution.This scientific paper focuses on examining the viability of autonomous cargo bike-sharing as a solution for urban transportation. A simulation model has been built to reproduce the OSABS operation using a case study for the city of Magdeburg. Through a set of experiments with different demand scenarios, we analysed and discussed the profitability and feasibility of this new service. These findings would be valuable, in the conversation about the future of transportation through providing important insights into how autonomous bike-sharing systems could be effectively implemented.

It has been suggested that media and technology effectiveness in pedagogy is a myth. An intervention is not automatically effective simply by virtue of it being new. Yet, so often, initial hype leads to inflated expectations and subsequent disappointments. Virtual and augmented reality, the metaverse, and collaborative virtual learning environments that utilise an increasingly wide range of digital platforms have all made appearances within this narrative. However, initial failures to meet expectation, especially when value is taken for granted, should not condemn these technologies to being dismissed. With the burgeoning opportunity for heterogenic design (asynchronous and asymmetrical roles, tasks, interface platforms, user capabilities, etc.) their technical capabilities and pedagogic potential are too significant. The need is for deeper learning through meaningful experience, the latter facilitated through affective and cognitive engagement derived from user-experience factors that include presence, flow, and self-efficacy. The central assertion of this article is that the effectiveness of these technologies for learning can be greatly enhanced through user-centred software designs that focus upon evoking these factors. Hardware configurations and software designs should deliver training scenarios that are built upon research-informed interaction design. The twist here is that in this article, we look to the oft underappreciated field of auditory perception, specifically that pertaining to human interactions with (and through) digital technologies, to present a novel set of interaction design principles with the goal of enhancing extended reality collaborative learning.

Understanding the origin of eukaryotic cells is one of the most difficult problems in all of biology. A key challenge relevant to the question of eukaryogenesis is reconstructing the gene repertoire of the last eukaryotic common ancestor (LECA). As data sets grow, sketching an accurate genomics-informed picture of early eukaryotic cellular complexity requires provision of analytical resources and a commitment to data sharing. Here, we summarise progress towards understanding the biology of LECA and outline a community approach to inferring its wider gene repertoire. Once assembled, a robust LECA gene set will be a useful tool for evaluating alternative hypotheses about the origin of eukaryotes and understanding the evolution of traits in all descendant lineages, with relevance in diverse fields such as cell biology, microbial ecology, biotechnology, agriculture, and medicine. In this Consensus View, we put forth the status quo and an agreed path forward to reconstruct LECA's gene content.

IntroductionDepression is prevalent after traumatic brain injury (TBI). However, there is a lack of understanding of the brain-based correlates of depression post-TBI. This systematic review aimed to synthesize findings of structural and functional magnetic resonance imaging (MRI) studies to identify consistently reported neural correlates of depression post-TBI.MethodsA search for relevant published studies was conducted through OVID (MEDLINE, APA PsycINFO, and Embase), with an end date of August 3rd, 2023. Fourteen published studies were included in this review.ResultsTBI patients with depression exhibited distinct changes in diffusion- based white matter fractional anisotropy, with the direction of change depending on the acuteness or chronicity of TBI. Decreased functional connectivity (FC) of the salience and default mode networks was prominent alongside the decreased volume of gray matter within the insular, dorsomedial prefrontal, and ventromedial prefrontal cortices. Seven studies reported the correlation between observed neuroimaging and depression outcomes. Of these studies, 42% indicated that FC of the bilateral medial temporal lobe subregions was correlated with depression outcomes in TBI.DiscussionThis systematic review summarizes existing neuroimaging evidence and reports brain regions that can be leveraged as potential treatment targets in future studies examining depression post-TBI.

Abstract Volunteer recorders generate large amounts of biodiversity data through citizen science which is used in conservation planning and policy decision‐making. Unstructured sampling, where the volunteer can record what they want, where they want, leads to spatial unevenness in these data. While there are many statistical techniques to account for the resulting biases, it may be possible to improve datasets by directing a subset of recorders to sample in the most informative locations, known as adaptive sampling. We investigated the potential for adaptive sampling to improve the performance of species distribution models built on citizen science data using simulated ecological communities. We simulated ecological assemblages across Great Britain based on current butterfly data and modelled the distributions of each species. We then simulated the sampling of new data based on five adaptive sampling methods (one empirical method based simply on gap‐filling, and four model‐based methods using various measures from the model outputs) and one non‐adaptive method (a method in which recording continued in the current pattern), and re‐ran the species distribution models. In these, we also varied the rate of recording effort that was distributed according to adaptive sampling. The model predictions using the original and adaptively sampled data were compared to true species distributions to evaluate the performance of each method. We found that all adaptive sampling approaches improved model performance, with greatest improvement for model‐based approaches compared to the empirical sampling method (i.e. simple gap‐filling). All four model‐based adaptive sampling approaches provided similar benefits for model outputs. Improvements in model performance were greatest when the amount of adaptive sampling changed from no uptake to 1% uptake, indicating that only a small amount of change in recorder behaviour is needed to improve model performance. Directing volunteer recorders to places where records are most needed, based on information from model outputs, can improve species distribution models built on citizen science data, even with minimal uptake of suggested locations. Our results therefore suggest that adaptive sampling by recorders could be beneficial for real‐world citizen science datasets.

Abstract Classic galactosemia (CG) arises from loss‐of‐function mutations in the Galt gene, which codes for the enzyme galactose‐1‐phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low‐galactose diet, GALT's substrate galactose‐1‐phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides—galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1—were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

A new species of holothuroid, Pseudothyone labradorensis sp. nov. (order Dendrochirotida and family Sclerodactylidae), was discovered off the coast of Labrador (eastern Canada) at a depth of 740–969 m. Two specimens were described based on morphological and genetic parameters. Distinctive characters included pinkish body colour, presence of tube feet on a ‘tail’, supporting rod-shaped ossicles in the tube feet, and rod-shaped ossicles in the tentacles. To investigate its phylogenetic relationships, partial sequences of COI were obtained for the new species as well as for the type species P. raphanus and another North Atlantic species P. serrifera. According to the phylogenetic analysis, P. labradorensis sp. nov. appeared in a well-supported clade with P. raphanus and P. serrifera. Molecular data also suggest polyphyly of the genus, showing the Northeast Pacific species Pseudothyone belli recovered outside of the clade containing the type species. Pseudothyone labradorensis sp. nov. is the first species of the genus from the Northwest Atlantic. A key to the North Atlantic Pseudothyone is provided.

Abstract Background Technology-based assessments using 2D virtual reality (VR) environments and goal-directed instrumented tasks can deliver digital health metrics describing upper limb sensorimotor function that are expected to provide sensitive endpoints for clinical studies. Open questions remain about the influence of the VR environment and task complexity on such metrics and their clinimetric properties. Methods We aim to investigate the influence of VR and task complexity on the clinimetric properties of digital health metrics describing upper limb function. We relied on the Virtual Peg Insertion Test (VPIT), a haptic VR-based assessment with a virtual manipulation task. To evaluate the influence of VR and task complexity, we designed two novel tasks derived from the VPIT, the VPIT-2H (VR environment with reduced task complexity) and the PPIT (physical task with reduced task complexity). These were administered in an observational longitudinal study with 27 able-bodied participants and 31 participants with multiple sclerosis (pwMS, VPIT and PPIT only) and the value of kinematic and kinetic metrics, their clinimetric properties, and the usability of the assessment tasks were compared. Results Intra-participant variability strongly increased with increasing task complexity (coefficient of variation + 56%) and was higher in the VR compared to the physical environment (+ 27%). Surprisingly, this did not translate into significant differences in the metrics’ measurement error and test–retest reliability across task conditions (p > 0.05). Responsiveness to longitudinal changes in pwMS was even significantly higher (effect size + 0.35, p

Abstract Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Abstract A finite element model was developed for assessing the efficacy of rugby body padding in reducing the risk of sustaining cuts and abrasions. The model was developed to predict the onset of damage to a soft tissue simulant from concentrated impact loading (i.e., stud impact) and compared against a corresponding experiment. The damage modelling techniques involved defining an element deletion criterion, whereby those on the surface of the surrogate were deleted if their maximum principal stress reached a predefined value. Candidate maximum principal stress values for element deletion criteria were identified independently from puncture test simulations on the soft tissue simulant. Experimental impacts with a stud were carried out at three energies (2, 4 and 6 J), at three angular orientations (0°, 15° and 30°) and compared to corresponding simulations. Suitable maximum principal stress values for element deletion criteria settings were first identified for the 4 J impact, selecting the candidates that best matched the experimental results. The same element deletion settings were then applied in simulations at 2 and 6 J and the validity of the model was further assessed (difference

In this work, the diversity of the genus Orbiniella in the Nordic Seas and the North Atlantic waters south of Iceland is studied based on the analyses of molecular markers (mitochondrial COI, 16S rDNA and nuclear ITS2) and morphological characters. Our results showed the presence of at least five genetic lineages in the studied material which could also be morphologically identified by their segmental annulation patterns, the number and the shape of acicular spines, and the length and the shape of pygidial lobes. The species name Orbiniella petersenae is assigned to one of the lineages restricting its geographical and vertical distribution to the deep-sea areas north of Iceland and Jan Mayen, and three lineages are described as new species (i.e., Orbiniella griegi Meca & Budaeva, sp. nov., Orbiniella mayhemi Meca & Budaeva, sp. nov., and Orbiniella parapari Meca & Budaeva, sp. nov.) elevating the number of known species in the genus to 25. Three deep-sea species of Orbiniella in our study are reported only north of the Greenland-Iceland-Scotland Ridge, one deep-sea species found south of the ridge. A single shallow-water species is distributed along the ridge and on the Norwegian shelf.

Abstract Background The Global Fund partnered with the Zimbabwean government to provide end-to-end support to strengthen the procurement and supply chain within the health system. This was accomplished through a series of strategic investments that included infrastructure and fleet improvement, training of personnel, modern equipment acquisition and warehouse optimisation. This assessment sought to determine the effects of the project on the health system. Methods This study employed a mixed methods design combining quantitative and qualitative research methods. The quantitative part entailed a descriptive analysis of procurement and supply chain data from the Zimbabwe healthcare system covering 2018 – 2021. The qualitative part comprised key informant interviews using a structured interview guide. Informants included health system stakeholders privy to the Global Fund-supported initiatives in Zimbabwe. The data collected through the interviews were transcribed in full and subjected to thematic content analysis. Results Approximately 90% of public health facilities were covered by the procurement and distribution system. Timeliness of order fulfillment (within 90 days) at the facility level improved from an average of 42% to over 90% within the 4-year implementation period. Stockout rates for HIV drugs and test kits declined by 14% and 49% respectively. Population coverage for HIV treatment for both adults and children remained consistently high despite the increasing prevalence of people living with HIV. The value of expired commodities was reduced by 93% over the 4-year period. Majority of the system stakeholders interviewed agreed that support from Global Fund was instrumental in improving the country's procurement and supply chain capacity. Key areas include improved infrastructure and equipment, data and information systems, health workforce and financing. Many of the participants also cited the Global Fund-supported warehouse optimization as critical to improving inventory management practices. Conclusion It is imperative for governments and donors keen to strengthen health systems to pay close attention to the procurement and distribution of medicines and health commodities. There is need to collaborate through joint planning and implementation to optimize the available resources. Organizational autonomy and sharing of best practices in management while strengthening accountability systems are fundamentally important in the efforts to build institutional capacity.

Microturbellarian flatworms comprise a diverse assemblage amongst meiofauna. These animals primarily exhibit carnivorous feeding habits, preying on various organisms, such as crustaceans, annelids and even other microturbellarians. However, details of their diet are poorly known. This study represents the first documentation of a proseriate preying upon a rhabdocoel. The proseriate was extracted from the sediment and studied alive. Within its digestive tract, structures of the reproductive systems of its prey were observed and identified as belonging to Phonorhynchopsis haegheni, a predatory turbellarian as well. No remains of any other organisms were detected. This finding underscores the relevance of Proseriata as top-level predators within the meiofaunal trophic web, a role that warrants further consideration beyond what has been previously acknowledged.

Objectives Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination.Methods In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3–6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells.Results Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients.Conclusion Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses.Trial registration number NL8900.

Background People with severe mental illness who experience co-occurring substance use experience poor outcome including suicide, violence, relapses and use of crisis services. They struggle to access care and treatment due to a lack of an integrated and co-ordinated approach which means that some people can fall between services. Despite these concerns, there is limited evidence as to what works for this population. Objectives To undertake a realist evaluation of service models in order to identify and refine programme theories of what works under what contexts for this population. Design Realist synthesis and evaluation using published literature and case study data. Setting Mental health, substance use and related services that had some form of service provision in six locations in the United Kingdom (five in England and one in Northern Ireland). Participants People with lived experience of severe mental illness and co-occurring substance use, carers and staff who work in the specialist roles as well as staff in mental health and substance use services. Results Eleven initial programme theories were generated by the evidence synthesis and in conjunction with stakeholders. These theories were refined through focus groups and interviews with 58 staff, 25 service users and 12 carers across the 6 case study areas. We identified three forms of service provision (network, consultancy and lead and link worker); however, all offered broadly similar interventions. Evidence was identified to support most of the 11 programme theories. Theories clustered around effective leadership, workforce development and collaborative integrated care pathways. Outcomes that are meaningful for service users and staff were identified, including the importance of engagement. Limitations The requirement for online data collection (due to the COVID-19 pandemic) worked well for staff data but worked less well for service users and carers. Consequently, this may have reduced the involvement of those without access to information technology equipment. Conclusion The realist evaluation co-occurring study provides details on how and in what circumstances integrated care can work better for people with co-occurring severe mental health and alcohol/drug conditions. This requires joined-up policy at government level and local integration of services. We have also identified the value of expert clinicians who can support the workforce in sustaining this programme of work. People with co-occurring severe mental health and alcohol/drug conditions have complex and multifaceted needs which require a comprehensive and long-term integrated approach. The shift to integrated health and social care is promising but will require local support (local expert leaders, network opportunities and clarity of roles). Future work Further work should evaluate the effectiveness and cost-effectiveness of service models for this group. Study registration This study is registered as PROSPERO CRD42020168667. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128128) and is published in full in Health Technology Assessment; Vol. 28, No. 67. See the NIHR Funding and Awards website for further award information. Plain language summary People who experience serious mental illness (the kind that affects people’s daily life and needs long-term support) can also have problems with drugs and alcohol. This can affect access to care and treatment and result in a crisis. We wanted to develop a better understanding of how services could help those with co-occurring serious mental health and alcohol/drug conditions (or COSMHAD for short). To answer these questions, we carried out the following: We gathered information from publications to identify what treatments are available for co-occurring severe mental health and alcohol/drug conditions and which aspects of these were useful (evidence synthesis). We asked services across the United Kingdom about the local provision for people with co-occurring severe mental health and alcohol/drug conditions. We conducted focus groups in six locations with service users, carers and staff about their experiences of care for co-occurring severe mental health and alcohol/drug conditions. What we found There are very few services in the United Kingdom that currently provide a service for people with co-occurring severe mental health and alcohol/drug conditions. We identified a set of factors that are likely to promote better outcomes for people with co-occurring severe mental health and alcohol/drug conditions including commitment from leaders across organisations to address this issue and support staff training. A local expert clinical leader was seen to be important in enabling closer working between mental health and substance use. Service users and carers recognised that when care was co-ordinated, and staff demonstrated empathy and compassion, they were more likely to engage in treatment. Further work will be needed to evaluate how helpful some of the aspects of the models of care are in helping people in their recovery goals. Scientific summary Background Approximately 30–50% of people with serious mental health illness (SMI) have a coexisting alcohol/drug condition, leading to significant negative health and social outcomes. Despite the scale of these co-occurring conditions, there is limited evidence to inform treatment, with the evidence that is available failing to provide a definitive answer as to how services and treatments should be best delivered to improve health and other outcomes for this diverse group. Objectives The aim of this project was to use a realist approach to understand what works, how, for whom and in what circumstances by synthesising data from published and grey literature, mapping and describing the characteristics of UK services and service provision, and undertaking in-depth focus groups and interviews in locations picked to be representative of the range of provision identified in the mapping and review of the literature. The outcome was a set of refined programme theories (PTs), which underpin an explanatory framework that can be used to inform future research, policy and practice. Methods We conducted a series of distinct, yet interrelated work packages (WPs) to achieve our research objectives. Work package 1: development of programme theories The aim of WP1 was to (1) map the literature to provide a systematic overview of the nature of the published and grey literature on types of service provision for people with co-occurring severe mental health and alcohol/drug conditions (COSMHAD) and (2) develop realist PTs for interventions and service models for COSMHAD. An a priori protocol was registered with PROSPERO. In phase 1, in consultation with stakeholders (including clinical experts in COSMHAD and those with lived experience), we elicited a set of initial PTs in a workshop and analysed policy documents and articles describing COSHMAD services in practice in the UK. In phase 2, we followed the five stages for realist synthesis. A total of 172 papers were included in the synthesis. Work package 2: service mapping Work package 2a: mapping of United Kingdom co-occurring severe mental health and alcohol/drug conditions services The aim of WP2 was to gather information on the availability of COSMHAD treatment across the UK. To achieve this, information was gathered by direct requests to relevant health and social care organisations, either as speculative e-mails or as Freedom of Information requests. In addition, internet searches for relevant services were also conducted. The initial information requests were sent by e-mail in March 2020 and had to be halted due to the start of the coronavirus disease 2019 (COVID-19) pandemic. A second wave of requests was sent in October 2020 to organisations that had not responded. The information requested included the details of the approach/treatment pathway for COSMHAD that each organisation commissioned/provided, and whether treatment was commissioned/provided specifically for COSMHAD, knowledge of any other COSMHAD service being provided in the same location, and name and contact details of the organisation’s COSMHAD lead (if there was one). Work package 2b: service audit/survey Using the information gathered during the national mapping, 16 organisations were identified as providing COSMHAD services. This was on the basis that their response indicated that there was some form of dedicated resource (typically in the form of specifically funded staff roles) to deliver the COSMHAD model. The 16 services were asked to provide more detail using an online audit form. This included items on the approach to treatment, the range of treatments offered, staff training/supervision, commissioning and funding of COSMHAD services, and health economic data. This survey was sent to a key member of staff in each of the organisations to complete, with the option of a follow-up telephone call to aid response rates. The data were used to identify models of service delivery. Work package 3: refining programme theories The purpose of WP3 was to test and refine the PTs developed in WP1 in real-world settings. Six case study sites were selected that represented examples from the three types of service models identified in WP2. Staff were recruited and consented to participate in online focus groups. Service users and carers were approached by clinical staff in the service to inform them of the study and to pass on contact details to the realist evaluation co-occurring (RECO) researcher. The RECO researcher would then contact and discuss the project, and if they were interested, they would give informed consent. Service users and carers participated in online focus groups and individual interviews. One carer focus group was face to face. Topic guides were developed from the 11 PTs that were developed in the realist synthesis, and all the interviews and focus groups were conducted using realist interviewing style. All interviews were recorded using Microsoft Teams and the auto-transcription facility. The transcripts were anonymised and analysed in NVivo. Results Work package 1: realist synthesis A set of 11 refined PTs were identified from the literature and these broadly fell into three interconnecting categories: committed leadership; clear expectations regarding COSMHAD from mental health and substance use workforces; and clear processes to co-ordinate care. Work package 2: service mapping The initial mapping identified that most areas of the UK offer some form of integrated care or treatment pathway for people with COSMHAD. However, only 16 services indicated that they offered more than an agreed pathway and offered something more tangible. The information provided from the audit of the services was used to broadly divide into three main models of delivery: Network – this is a broad collection of staff from a range of local services that share agreed care pathways and come together for network meetings and shared training. Consultancy – a specialist team that provides consultancy to the mainstream mental health services, including joint assessment, advice on care planning and clinical management and continuous professional development (CPD) training. Lead and link – this model is led by a clinical expert leader (often a consultant nurse or equivalent) with ‘link workers’ or ‘champions’ based across the mental health service to support this role. However, there was significant variation in the level of investment in terms of dedicated staff. Six sites were selected to be case studies. Work package 3: case studies A total of 58 staff, 25 service users and 12 carers participated in the focus groups and interviews. Data were obtained that supported 10 out of 11 PTs. There were limited data regarding pre-registration/undergraduate training (despite prompts) because the participants had no connection to the curriculum development and delivery for nursing, allied health, social care or medical training. Some of the PTs had more supporting evidence than others. The main findings were that positive attitudes including empathy and compassion were seen as a critical context for engaging people in services. Positive attitudes were influenced by access to CPD training, and also ongoing support and supervision in practice. It was important that people could see that the clinical skills taught in CPD worked effectively in practice. This was also promoted by working alongside (shadowing) a clinical expert in COSMHAD. The role of a clinical expert (most commonly a consultant nurse in COSMHAD) was rated highly by the staff for a number of reasons, including keeping COSMHAD on the agenda both clinically and strategically; having an oversight of the whole care pathway; and fostering relationships between key agencies (such as substance use, housing, etc.). The expert lead also offered a training and supervision programme within the organisation, and in some cases facilitated local special interest networks which included peer support, sharing expertise across disciplines, and building interagency and interdisciplinary relationships. The quality of these inter-agency relationships was seen to be critical for integrating care for COSMHAD. Clear and collaborative care pathways that were needs led, person-centred and holistic were important. The service users and carers reported that fragmented local services were really difficult to navigate, and therefore service users often ended up falling through the gaps, increasing the need for crisis care including the police, ambulance service and emergency rooms, none of which is satisfactory in helping people to move forward with their recovery. For effective integrated care to occur, there was a clear need for organisational commitment to this agenda at a senior strategic level (including local commissioning) as well as commitment in operational managers. This commitment ensures investment in posts (such as the expert leaders); protected time for staff to access training, supervision and network meetings; and mandating standards of care for people with COSMHAD. In addition, there needs to be a commitment to recruiting and retaining the workforce that have the requisite knowledge, skills and values. This also links to the need to ensure that pre-registration education for nurses and allied health professionals as well as psychiatry and psychology includes content in working with COSMHAD, as well as offering placements where health and social care students get positive experience of assessing and planning care for people with COSMHAD. Carers felt that they carried a lot of the burden of caring for their loved one, and often felt excluded from the care team. They found that peer support was very helpful, but they too would benefit from more clarity in the care pathways and consistency of approach. Discussion Despite over two decades of attention and policy guidance to improve responses to people with COSMHAD, the mapping revealed a lack of investment in specific roles to support care pathways, workforce development and quality of care. Most of the services we identified had been in existence in some form or another for many years and were driven by enthusiastic champions with fragile funding, and often limited strategic or organisational support. Models of care were generally based on an expert lead role plus link workers (dedicated roles) or local champions (not dedicated roles, but supplemental to their role) to support the work within the service as well as co-ordinating services across several agencies. In addition to leadership and supporting care pathways, all of the case studies offered in-house training and consultation. One of the case studies involved a dedicated team of clinicians who offered consultation and training only, as opposed to carrying out any direct clinical work. One model operated as a network of link workers but was missing the strategic lead as that post had not been filled following the departure of the previous lead. The RECO study has been able to identify the important contexts under which integrated care can be provided (mechanism) which produces positive outcomes for service users (and their carers). It is clear that COSMHAD needs to be prioritised as a service development issue and this requires drivers from national and local policy-makers and commissioners. NHS mental health providers should be the main provider with key responsibilities for people with serious and enduring mental health problems irrespective of other comorbidities (in this case alcohol and or drugs). Staff in mental health services should have a minimum level of knowledge and skills regarding the interface between mental health and substance use. Training alone, without clinical supervision and/or other practice-based learning opportunities, is likely to be insufficient. The RECO study demonstrates how valued and multifaceted the role of the clinical expert is in promoting good practice for COSMHAD. They need senior organisational level support for this work. Strengths This is the first study to use realist methods to identify the contexts under which mechanisms work and identify the types of outcomes that are meaningful for staff, service users and carers. The PTs were generated from a number of sources (stakeholder consultation, literature and document synthesis and primary data) using robust methodology. This is also one of the first studies to include the lived experience of being a service user and carer and triangulate with the staff data. We sampled case studies across three types identified from mapping the broader UK service provision. Limitations The study was impacted by COVID-19. The national response to COVID-19 in health and social care impacted on responses to requests for information in the UK mapping exercise. Therefore, there may have been additional services in existence that we did not identify. Due to social distancing and various national and regional lockdowns, the data collection was almost entirely conducted online. While we collected our target sample of staff, we did not recruit to target for the service user and carer focus groups and interviews. Online methods were a barrier to some people. However, the data from the service user and carers were obtained across most of the sites and were sufficient to answer the research questions. Conclusion Co-occurring serious mental illness and substance use is a common phenomenon in mental health care, yet the mental health, substance use and related services remain ill-equipped to meet the needs of people with COSMHAD. The RECO study provides details on how and in what circumstances integrated care can work better for people with COSMHAD. This requires joined-up policy at government level and local integration of services. We have also identified the value of expert clinicians who can support the workforce in sustaining this programme of work. People with COSMHAD have complex and multifaceted needs which require a comprehensive and long-term integrated approach. The shift to integrated health and social care is promising but will require local support (local expert leaders, network opportunities and clarity of roles). Future research should focus on evaluating whole system approaches as opposed to reductionist individual interventions. This includes establishing the cost-effectiveness of key components of the COSMHAD models. Study registration This study is registered as PROSPERO CRD42020168667. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128128) and is published in full in Health Technology Assessment; Vol. 28, No. 67. See the NIHR Funding and Awards website for further award information.

Abstract Ionic transport through porous membranes and porous materials has received enormous attention due to its importance to many applications. An innovative methodology is proposed to study ion diffusion and ion sieving through mesoporous silica membranes (shells). The mobility of fluorescently labeled core particles within a hollow porous shell, filled with an index‐matched electrolyte solution, is observed using confocal laser scanning microscopy. The core motion range, i.e., the area explored by the core within the hollow compartment, sensitively changed depending on the local ionic concentration. Monitoring transitions in the core motion range is a practical way to detect which ions can migrate through the shells and on what timescale. For instance, lithium and chloride ions easily diffused through the porous silica shells, resulting in a core motion range that changed relatively quickly upon change of the ion concentrations outside of the shell. However, the motion range changed significantly slower upon changing to a bigger cation (tetraoctylammonium ion). This proof of principle experiment can be explained by the Gibbs‐Donnan effect, revealing that the detection of core motion ranges is a good probe to measure both ion diffusion and ion sieving through porous membranes.

IntroductionLow- and middle-income countries bear disproportionate burdens from excessive alcohol consumption, yet have fewer resources to identify and intervene with risky drinkers. Low-cost screening and brief intervention (SBI) models offer a tool for addressing this health problem and reducing disparities.MethodsIn this mixed-methods study, trained pseudo-patients visited health clinics in Zacatecas, Mexico, where a novel SBI model was used with trained nonmedical health educators (HEs) conducting SBI in waiting areas. Pseudo-patients, who provided responses to the AUDIT-C screening items designed to trigger a brief intervention (BI), waited for HEs to engage them in an SBI encounter. Data on HEs’ behaviors, SBI components provided, and contextual characteristics were coded from audio recordings of the encounters using an SBI checklist and from pseudo-patient interviews.ResultsQuantitative analyses examined the consistency in pseudo-patients’ targeted AUDIT-C scores and those documented by HEs as well as the frequency of delivery of SBI components. Across 71 interactions, kappas between HEs’ scores and the targeted AUDIT-C scores ranged from 0.33 to 0.45 across AUDIT-C items; it was 0.16 for the total AUDIT-C. In 41% of interactions, the HEs recorded total AUDIT-C scores that accurately reflected the targeted scores, 45% were below, and 14% exceeded them. Analyses of checklist items and transcripts showed that HEs demonstrated desired interpersonal skills (attentive, empathetic, professional) and provided general information regarding risks and recommendations about reducing consumption. In contrast, personalized BI components (exploring pseudo-patients’ personal challenges and concerns about reducing drinking; making a plan) occurred much less frequently. Pseudo-patient interviews revealed contextual factors (noise, lack of privacy) that may have negatively affected SBI interactions.DiscussionUsing trained nonmedical persons to administer SBI holds promise to increase its reach. However, ongoing training and monitoring, prioritizing comprehensive BIs, eliminating contextual barriers, and electronic delivery of screening may help ensure high quality delivery.

ABSTRACT We are still largely reliant on pesticides for the suppression of arthropod pests which threaten human health and food production, but the recent rise of evolved resistance among important pest species has reduced pesticide efficacy. Despite this, our understanding of strategies that effectively limit the evolution of resistance remains weak. Male‐killing sex ratio distorting microbes (SRDMs), such as Wolbachia and Spiroplasma, are common among arthropod species. Previous theoretical work has suggested that they could limit adaptive potential in two ways: first, because by distorting sex ratios they reduce the effective population size, and second, because infected females produce no male offspring which restricts gene flow. Here we present the results of a novel experiment in which we test the extent by which these two mechanisms limit the adaptive response of arthropods to pesticide. Using a fully factorial design, we manipulated the adult sex ratio of laboratory populations of Drosophila melanogaster, both in the presence and absence of SRDMs, and exposed these populations to six generations of pesticide poisoning. This design allows the effects of SRDMs on sex ratio and their effects on gene flow to be estimated separately. After six generations, individuals from populations with even sex ratios displayed a higher resistance to pesticide relative to individuals from female‐biased populations. By contrast, we found no effect of the presence of SRDMs in host populations on pesticide resistance independent of sex ratio. In addition, males were more susceptible to pesticide than females—this was true of flies from both naïve and previously exposed populations. These findings provide the first empirical proof of concept that sex ratio distortion arising from SRDMs can limit adaptation to pesticides, but cast doubt on the theoretical effect of male‐killers limiting adaptation by disrupting gene flow.

IntroductionPost-acute COVID syndrome (PACS) is a growing concern, given its impact on mental health and quality of life. However, its effects on cerebral white matter remain poorly understood, particularly in non-hospitalized cohorts. The goals of this cross-sectional, observational study were to examine (1) whether PACS was associated with distinct alterations in white matter microstructure, compared to symptom-matched non-COVID viral infection; and (2) whether microstructural alterations correlated with indices of post-COVID emotional health.MethodsData were collected for 54 symptomatic individuals who tested positive for COVID-19 (mean age 41 ± 12 yrs., 36 female) and 14 controls who tested negative for COVID-19 (mean age 41 ± 14 yrs., 8 female), with both groups assessed an average of 4–5 months after COVID testing. Diffusion magnetic resonance imaging data were collected, and emotional health was assessed via the NIH emotion toolbox, with summary scores indexing social satisfaction, well-being and negative affect.ResultsDespite similar symptoms, the COVID-19 group had reduced mean and axial diffusivity, along with increased mean kurtosis and neurite dispersion, in deep white matter. After adjusting for social satisfaction, higher levels of negative affect in the COVID-19 group were also correlated with increased mean kurtosis and reduced free water in white matter.DiscussionThese results provide preliminary evidence that indices of white matter microstructure distinguish PACS from symptomatic non-COVID infection. Moreover, white matter effects seen in PACS correlate with the severity of emotional sequelae, providing novel insights into this highly prevalent disorder.

BackgroundTranscranial temporal interference stimulation (tTIS) is a new, emerging neurostimulation technology that utilizes two or more electric fields at specific frequencies to modulate the oscillations of neurons at a desired spatial location in the brain. The physics of tTIS offers the advantage of modulating deep brain structures in a non-invasive fashion and with minimal stimulation of the overlying cortex outside of a selected target. As such, tTIS can be effectively employed in the context of therapeutics for the psychiatric disease of disrupted brain connectivity, such as major depressive disorder (MDD). The subgenual anterior cingulate cortex (sgACC), a key brain center that regulates human emotions and influences negative emotional states, is a plausible target for tTIS in MDD based on reports of its successful neuromodulation with invasive deep brain stimulation.MethodsThis pilot, single-site, double-blind, randomized, sham-controlled interventional clinical trial will be conducted at St. Michael’s Hospital – Unity Health Toronto in Toronto, ON, Canada. The primary objective is to demonstrate target engagement of the sgACC with 130 Hz tTIS using resting-state magnetic resonance imaging (MRI) techniques. The secondary objective is to estimate the therapeutic potential of tTIS for MDD by evaluating the change in clinical characteristics of participants and electrophysiological outcomes and providing feasibility and tolerability estimates for a large-scale efficacy trial. Thirty participants (18–65 years) with unipolar, non-psychotic MDD will be recruited and randomized to receive 10 sessions of 130 Hz tTIS or sham stimulation (n = 15 per arm). The trial includes a pre- vs. post-treatment 3T MRI scan of the brain, clinical evaluation, and electroencephalography (EEG) acquisition at rest and during the auditory mismatch negativity (MMN) paradigm.DiscussionThis study is one of the first-ever clinical trials among patients with psychiatric disorders examining the therapeutic potential of repetitive tTIS and its neurobiological mechanisms. Data obtained from this trial will be used to optimize the tTIS approach and design a large-scale efficacy trial. Research in this area has the potential to provide a novel treatment option for individuals with MDD and circuitry-related disorders and may contribute to the process of obtaining regulatory approval for therapeutic applications of tTIS.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT05295888.

Abstract Background Delayed discharge is problematic. It is financially costly and can create barriers to delivering best patient care, by preventing return to usual functioning and delaying admissions of others in need. This systematic review aimed to collate existing evidence on delayed discharge in psychiatric inpatient settings and to develop understanding of factors and outcomes of delays in these services. Methods A search of relevant literature published between 2002 and 2022 was conducted on Pubmed, PsycInfo and Embase. Studies of any design, which published data on delayed discharge from psychiatric inpatient care in high income countries were included. Studies examining child and adolescent, general medical or forensic settings were excluded. A narrative synthesis method was utilised. Quality of research was appraised using the Mixed Methods Appraisal Tool (MMAT). Results Eighteen studies from England, Canada, Australia, Ireland, and Norway met the inclusion criteria. Six main reasons for delayed discharge were identified: (1) accommodation needs, (2) challenges securing community or rehabilitation support, (3) funding difficulties, (4) family/carer factors, (5) forensic considerations and (6) person being out of area. Some demographic and clinical factors were also found to relate to delays, such as having a diagnosis of schizophrenia or other psychotic disorder, cognitive impairment, and increased service input prior to admission. Being unemployed and socially isolated were also linked to delays. Only one study commented on consequences of delays for patients, finding they experienced feelings of lack of choice and control. Four studies examined consequences on services, identifying high financial costs. Conclusion Overall, the findings suggest there are multiple interlinked factors relevant in delayed discharge that should be considered in practice and policy. Suggestions for future research are discussed, including investigating delayed discharge in other high-income countries, examining delayed discharge from child and forensic psychiatric settings, and exploring consequences of delays on patients and staff. We suggest that future research be consistent in terms used to define delayed discharge, to enhance the clarity of the evidence base. Review registration number on PROSPERO 292515. Date of registration 9th December 2021.

Abstract To better understand molecular aspects of equine endometrial function, there is a need for advanced in vitro culture systems that more closely imitate the intricate 3-dimensional (3D) in vivo endometrial structure than current techniques. However, development of a 3D in vitro model of this complex tissue is challenging. This study aimed to develop an in vitro 3D endometrial tissue (3D-ET) with an epithelial cell phenotype optimized by treatment with a Rho-associated protein kinase (ROCK) inhibitor. Equine endometrial epithelial (eECs) and mesenchymal stromal (eMSCs) cells were isolated separately, and eECs cultured in various concentrations of Rock inhibitor (0, 5, 10 µmol) in epithelial medium (EC-medium) containing 10% knock-out serum replacement (KSR). The optimal concentration of Rock inhibitor for enhancing eEC proliferation and viability was 10 µM. However, 10 µM Rock inhibitor in the 10% KSR EC-medium was able to maintain mucin1 (Muc1) gene expression for only a short period. In contrast, fetal bovine serum (FBS) was able to maintain Muc1 gene expression for longer culture durations. An in vitro 3D-ET was successfully constructed using a collagen-based scaffold to support the eECs and eMSCs. The 3D-ET closely mimicked in vivo endometrium by displaying gland-like eEC-derived structures positive for the endometrial gland marker, Fork headbox A2 (FOXA2), and by mimicking the 3D morphology of the stromal compartment. In addition, the 3D-ET expressed the secretory protein MUC1 on its glandular epithelial surface and responded to LPS challenge by upregulating the expression of the interleukin-6 (IL6) and prostaglandin F synthase (PGFS) genes (P

To report a new species of sandfly, Sergentomyia (Neophlebotomus) ashwanii sp. nov. (Diptera: Psychodidae) from Western Ghats, India. A systematic sandfly survey was conducted in the Thrissur and Kollam districts of Kerala, India using mechanical aspirators, light and sticky traps, both indoor and outdoor habitats, for a period of one year. Deoxyribonucleic acid barcoding of samples was performed targeting mitochondrial cytochrome oxidase I (COI) gene and sequence generated was subjected to phylogenetic analysis. Sergentomyia (Neophlebotomus) ashwanii, a new sandfly species is recorded and described in this communication. A single row of 10-12 pointed teeth in the cibarium with 4-6 small denticles or fore-teeth are the key characteristics that is distinctive from other members of the subgenus Neophlebotomus. Mitochondrial COI barcode followed by phylogenetic analysis of the nucleotide sequence confirms that specimens of the species belong to the same taxonomic group while the genetic distance (14.2%) with the congeners established it to be a different species. The Western Ghats' being an important biodiversity hotspot and has dearth of systematic entomological surveys on sandflies. The current study tried to fill the void and also report a new sandfly species.

Abstract Background The Ehlers-Danlos Syndromes (EDS) are a group of connective tissue disorders that are hereditary in nature and characterized by joint hypermobility and tissue fragility. The complex nature of this unique patient population requires multidisciplinary care, but appropriate centers for such care do not exist in large portions of the country. Need for more integrated services has been identified in Chicagoland, or Chicago and its suburbs. In order to explore and begin to address barriers to seeking appropriate care facing EDS patients in this region, we developed an online survey which we circulated through EDS social media groups for Chicagoland patients. Results Three hundred and nine unique respondents participated. We found that there exists a strong medical need for and interest in the development of a center in the region, and participants reported that, if made available to them, they would make extensive and regular use of such a facility. Conclusions We conclude that the establishment of a collaborative medical center specializing in the diagnosis and treatment of EDS, Hypermobility Spectrum Disorder, and related disorders in the Chicagoland area would greatly benefit patients by providing comprehensive care, alleviate the burden on overworked healthcare providers, and contribute to the sustainability of medical facilities.

Abstract Neutrophil released peptidyl arginine deiminase 4 (PAD4) converts arginine residues on plasma proteins into citrulline. Here, we developed an assay to quantify citrullinated fibrinogen. We employed a biotin‐conjugated phenylglyoxal (biotin‐phenylglyoxal (PG)) compound that selectively labels citrulline. Patient samples were derived from a multicenter prospective cohort study that aimed to identify cancer patients at high risk for venous thromboembolism (VTE). Our data show that cancer patients have higher (median 2‐fold increased) citrullinated fibrinogen levels when compared to normal human plasma and a cohort of healthy donors. Our results show that citrullination of fibrinogen is a common posttranslational modification in patients with cancer.

EU policies, such as the EU biodiversity strategy 2030 and the Birds and Habitats Directives, demand unbiased, integrated and regularly updated biodiversity and ecosystem service data. However, efforts to monitor wildlife and other species groups are spatially and temporally fragmented, taxonomically biased, and lack integration in Europe. To bridge this gap, the MAMBO project will develop, test and implement enabling tools for monitoring conservation status and ecological requirements of species and habitats for which knowledge gaps still exist. MAMBO brings together the technical expertise of computer science, remote sensing, social science expertise on human-technology interactions, environmental economy, and citizen science, with the biological expertise on species, ecology, and conservation biology. MAMBO is built around stakeholder engagement and knowledge exchange (WP1) and the integration of new technology with existing research infrastructures (WP2). MAMBO will develop, test, and demonstrate new tools for monitoring species (WP3) and habitats (WP4) in a co-design process to create novel standards for species and habitat monitoring across the EU and beyond. MAMBO will work with stakeholders to identify user and policy needs for biodiversity monitoring and investigate the requirements for setting up a virtual lab to automate workflow deployment and efficient computing of the vast data streams (from on the ground sensors, and remote sensing) required to improve monitoring activities across Europe (WP4). Together with stakeholders, MAMBO will assess these new tools at demonstration sites distributed across Europe (WP5) to identify bottlenecks, analyze the cost-effectiveness of different tools, integrate data streams and upscale results (WP6). This will feed into the co-design of future, improved and more cost-effective monitoring schemes for species and habitats using novel technologies (WP7), and thus lead to a better management of protected sites and species.

Background: Plant-based protein supplements often contain lower amounts of leucine and other essential amino acids (EAAs), potentially making them less effective in stimulating muscle protein synthesis (MPS) than animal-based proteins. Combining plant proteins could improve the EAA profile and more effectively support MPS. Objectives: The aim of this study was to determine the effect of a novel plant-based blend protein (PBP), PBP with added leucine (PBP + Leu) to levels equivalent to whey protein isolate (WHEY) on aminoacidemia and MPS responses in young men and women. We hypothesized that PBP + Leu would stimulate MPS equivalent to WHEY, and both would be greater than PBP. Methods: We employed a randomized, double-blind, crossover study consisting of 3 separate study visits to compare PBP, PBP + Leu, and WHEY. To measure MPS response to ingestion of the supplements, a primed continuous infusion of L-[ring13C6] phenylalanine was administered for 8 h at each study visit. Skeletal muscle tissue and blood samples were collected to measure aminoacidemia and MPS. Results: All protein supplements increased mixed MPS above postabsorptive levels (P < 0.001). However, MPS increase following ingestion of PBP was less than that following ingestion of PBP + Leu (P = 0.002) and WHEY (P = 0.046). There were no differences in MPS between PBP + Leu and WHEY (P = 0.052). Conclusions: Consumption of PBP isolate with added leucine stimulated MPS to a similar extent as whey protein in young men and women. PBPs containing higher leucine content promote anabolism to a similar extent as animal-based proteins.This study was registered at clinicaltrials.gov as NCT05139160.

Nanoplastics can cause severe malformations in chicken embryos. To improve our understanding of the toxicity of nanoplastics to embryos, we have studied their biodistribution in living chicken embryos. We injected the embryos in the vitelline vein at stages 18–19. We injected polystyrene nanoparticles (PS-NPs) tagged with europium- or fluorescence. Their biodistribution was tracked using inductively-coupled plasma mass spectrometry on tissue lysates, paraffin histology, and vibratome sections analysed by machine learning algorithms. PS-NPs were found at high levels in the heart, liver and kidneys. Furthermore, PS-NPs crossed the endocardium of the heart at sites of epithelial-mesenchymal transformation; they also crossed the liver endothelium. Finally, we detected PS-NPs in the allantoic fluid, consistent with their being excreted by the kidneys. Our study shows the power of the chicken embryo model for analysing the biodistribution of nanoplastics in embryos. Such experiments are difficult or impossible in mammalian embryos. These findings are a major advance in our understanding of the biodistribution and tissue-specific accumulation of PS-NPs in developing animals.

Summary: Human leukocyte antigen (HLA) class-I molecules present fragments of the cellular proteome to the T cell receptor (TCR) of cytotoxic T cells to control infectious diseases and cancer. The large number of combinations of HLA class-I allotypes and peptides allows for highly specific and dedicated low-affinity interactions to a diverse array of TCRs and natural killer (NK) cell receptors. Whether the divergent HLA class-I peptide complex is exclusive for interactions with these proteins is unknown. Using genome-wide CRISPR-Cas9 activation and knockout screens, we identified peptide-specific HLA-C∗07 combinations that can interact with the surface molecules CD55 and heparan sulfate. These interactions closely resemble the HLA class-I interaction with the TCR regarding both the affinity range and the specificity of the peptide and HLA allele. These findings indicate that various proteins can specifically bind HLA class-I peptide complexes due to their polymorphic nature, which suggests there are more interactions like the ones we describe here.

BackgroundDespite the potential to significantly reduce complications, many patients do not consistently receive diabetes preventive care. Our research team recently applied user-centered design sprint methodology to develop a patient portal intervention empowering patients to address selected diabetes care gaps (eg, no diabetes eye examination in last 12 months). ObjectiveThis study aims to evaluate the effect of our novel diabetes care gap intervention on completion of selected evidence-based diabetes preventive care services and secondary outcomes. MethodsWe are conducting a pragmatic randomized controlled trial of the effect of the intervention on diabetes care gaps. Adult patients with diabetes mellitus (DM) are recruited from primary care clinics affiliated with Vanderbilt University Medical Center. Participants are eligible if they have type 1 or 2 DM, can read in English, are aged 18-75 years, have a current patient portal account, and have reliable access to a mobile device with internet access. We exclude patients with medical conditions that prevent them from using a mobile device, severe difficulty seeing, pregnant women or women who plan to become pregnant during the study period, and patients on dialysis. Participants will be randomly assigned to the intervention or usual care. The primary outcome measure will be the number of diabetes care gaps among 4 DM preventive care services (diabetes eye examination, pneumococcal vaccination, hemoglobin A1c, and urine microalbumin) at 12 months after randomization. Secondary outcomes will include diabetes self-efficacy, confidence managing diabetes in general, understanding of diabetes preventive care, diabetes distress, patient portal satisfaction, and patient-initiated orders at baseline, 3 months, 6 months, and 12 months after randomization. An ordinal logistic regression model will be used to quantify the effect of the intervention on the number of diabetes care gaps at the 12-month follow-up. For dichotomous secondary outcomes, a logistic regression model will be used with random effects for the clinic and provider variables as needed. For continuous secondary outcomes, a regression model will be used. ResultsThis study is ongoing. Recruitment was closed in February 2022; a total of 433 patients were randomized. Of those randomized, most (n=288, 66.5%) were non-Hispanic White, 33.5% (n=145) were racial or ethnic minorities, 33.9% (n=147) were aged 65 years or older, and 30.7% (n=133) indicated limited health literacy. ConclusionsThe study directly tests the hypothesis that a patient portal intervention—alerting patients about selected diabetes care gaps, fostering understanding of their significance, and allowing patients to initiate care—will reduce diabetes care gaps compared with usual care. The insights gained from this study may have broad implications for developing future interventions to address various care gaps, such as gaps in cancer screening, and contribute to the development of effective, scalable, and sustainable approaches to engage patients in chronic disease management and prevention. Trial RegistrationClinicalTrials.gov NCT04894903; https://classic.clinicaltrials.gov/ct2/show/NCT04894903 International Registered Report Identifier (IRRID)DERR1-10.2196/56123