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Osteoarthritis (OA) is a chronic debilitating condition that affects the whole joint. There are several sources of pain in OA that include the synovium, bone, including osteophytes and more recently bone marrow lesions (BML) that correlate with pain. Recent studies have shown that the bone compartment contributes to pain in OA through the development of OA-BMLs which are richly innervated and demonstrate angiogenesis. The synovium is also innervated in OA tissue and is another distinct source of pain, with imaging and genetic studies supporting the observation that synovitis is an important component of pain in OA. Previous studies using magnetic resonance imaging (MRI) have shown that bone marrow lesions (BMLs), observed as high intensity signal on T2 fat-suppressed imaging sequences, are commonly found in OA and are associated with progression of pain symptoms. Recent studies have described the genetic signature of BMLs and the characteristic histological changes of BML tissue. In this narrative review we describe the recent developments in the discovery of the gene expression profiles identified from BMLs. We also review the recently characterised histological changes from BMLs in large weight-bearing joints including the knee and hip. Finally, we discuss the implications of new genetic and histological findings in BML in the context of new developments for pharmacological therapies in OA.

Maternal hyperglycemia during pregnancy adversely affects maternal and child outcomes. While mechanisms are not fully understood, maternal circulating miRNAs may play a role. We examined whether continuous glucose levels and hyperglycemia subtypes (gestational diabetes, type 2 diabetes, and glucose intolerance) were associated with circulating miRNAs during late pregnancy. Seven miRNAs (hsa-miR-107, hsa-let-7b-5p, hsa-miR-126-3p, hsa-miR-181a-5p, hsa-miR-374a-5p, hsa-miR-382-5p, and hsa-miR-337-5p) were associated (p

Background Healthcare professionals have been slow to adopt health literacy practices. With the focus on organizational health literacy increasing, there is a need for accompanying workforce training. Aims: The Innovate to Communicate workshop aimed to increase participants’ knowledge and skills to (1) communicate using evidence-based health literacy practices e.g., plain language, chunking information, teach back, medicine review, and (2) integrate health literacy into structures, processes, and quality measures.Methods Health Literacy Collaborative of the Dallas Fort Worth Hospital Council, developed the ITC modules and workshop informed by the 10 Attributes of a Health Literate Organization and adult learning principles. We developed an interactive, engaging workshop that includes a didactic slide deck, exemplar videos, role-play scenarios, a Kahoot® game, and the Agency for Healthcare Research and Quality [AHRQ] Communication Observation Form.Results The ITC workshop was delivered at 7 virtual or in-person conferences with 250 participants. Of the total participants, 104 completed the workshop evaluation. Most reported that they see themselves using health literacy strategies in direct patient care (90%) with many participants feeling mostly or completely confident about using health literacy strategies such as plain language, chunking information, and teach back (81%) and doing one health literacy action in the next week (89%). The majority (92%) reported that the ITC workshop introduced them to at least one new health literacy resource that they had not used before. Most (93%) reported that they see themselves using the ITC workshop to train others and almost all (97%) reported that they were likely to recommend the ITC workshop to their colleagues. While 89% reported that the 1½ h workshop was the right amount of time, 11% reported that it was too short.Discussion The ITC was an interactive, engaging workshop that is available at no cost to others who are training healthcare professionals in health literacy.

ABSTRACTBackground: Experiencing sexual assault is associated with a significant increase in risk for developing posttraumatic stress disorder and related concerns (e.g. alcohol misuse). Cross-sectional and longitudinal evidence suggests that social support may be both broadly protective against and eroded by posttraumatic stress symptoms. However, little is known about how different aspects of social support and posttraumatic stress symptoms influence each other in the weeks and months immediately following sexual assault, when posttraumatic stress (PTS) symptoms first emerge.Objective: The present study assessed the day-to-day relationship between social support and PTS in a sample of distressed, alcohol-using, recently-assaulted female survivors participating in a clinical trial of an app-based intervention (N = 41).Method: Participants completed 3 weeks of daily diaries starting within 10 weeks of sexual assault. Mixed-effects models were used to examine prior-day and same-day relationships between PTS and four social support constructs (social contact, emotional support, pleasantness of social interactions, and talking about sexual assault).Results: Results indicate that higher quantity and pleasantness of social interactions over the full sampling period was associated with lower PTS symptoms on any given day. Experiencing better-than-typical social interactions on one day was associated with lower than typical PTS symptoms on that day and the next day. On days when participants discussed their sexual assault with others, they tended to be having higher than usual PTS symptoms.Conclusions: Findings suggest that increasing the quantity and pleasantness of social interactions soon after sexual assault might protect against worsening posttraumatic stress symptoms.Trial registration: ClinicalTrials.gov identifier: NCT03703258.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

There is increasing pressure on social media companies to reduce the spread of misinformation on their platforms. However, they would prefer not to be the arbiters of truth as the truth can be subjective or otherwise hard to determine. Instead, they would prefer that social media users themselves show better discernment when deciding which information to share. Here we show that allowing people to share only those social media posts that they have indicated are true significantly improves sharing discernment, as measured by the difference in the probability of sharing true information versus the probability of sharing false information. Because it doesn’t require social media companies to be the arbiters of truth, this self-censorship intervention can be employed in situations where social media companies suspect that individuals are propagating misinformation but are not sufficiently confident in their suspicions to directly censor the individuals involved. As such, self-censorship can usefully supplement externally imposed (i.e. traditional) censorship in reducing the propagation of false information on social media platforms.

Perceptual training has been shown to be an effective and rapid way of training people to make simple diagnoses using medical images. However, it appears to be less effective at training people to make more complex diagnoses that require non-binary judgements. In the present study, we investigated whether perceptual training could be augmented to make it more effective and what factors limited its effectiveness. In Experiment 1, we created artificial stimuli that were designed to simulate liver ultrasound images to assess perceptual learning for a complex task that involved judgements on a 7-point scale. Whilst performance improved somewhat with training, we found that incorporating annotations into the training provided no benefits. Additionally, contrary to our expectations, training that was structured in a stepped fashion was detrimental to learning. In Experiment 2, we found that perceptual learning in a simple task with shaded disks was most impacted by the extent to which the brightness levels of each disk were discriminable but that attending to multiple locations did not result in a significant cost to performance. Our findings show that augmenting perceptual training does not increase learning and that learning is less when the relevant features are harder to discriminate.

There is an urgent need for countries to transition their national food and land-use systems toward food and nutritional security, climate stability, and environmental integrity. How can countries satisfy their demands while jointly delivering the required transformative change to achieve global sustainability targets? Here, we present a collaborative approach developed with the FABLE—Food, Agriculture, Biodiversity, Land, and Energy—Consortium to reconcile both global and national elements for developing national food and land-use system pathways. This approach includes three key features: (1) global targets, (2) country-driven multi-objective pathways, and (3) multiple iterations of pathway refinement informed by both national and international impacts. This approach strengthens policy coherence and highlights where greater national and international ambition is needed to achieve global goals (e.g., the SDGs). We discuss how this could be used to support future climate and biodiversity negotiations and what further developments would be needed.

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.

PurposeSocial support may have benefits on cardiovascular health (CVH). CVH is evaluated using seven important metrics (Life's Simple 7; LS7) established by the American Heart Association (e.g., smoking, diet). However, evidence from longitudinal studies is limited and inconsistent. The objective of this study is to examine the longitudinal relationship between social support and CVH, and assess whether psychosocial risks (e.g., anger and stress) modify the relationship in a racially/ethnically diverse population.MethodsParticipants from three harmonized cohort studies - Jackson Heart Study, Mediators of Atherosclerosis in South Asians Living in America, and Multi-Ethnic Study of Atherosclerosis - were included. Repeated-measures modified Poisson regression models were used to examine the overall relationship between social support (in tertiles) and CVH (LS7 metric), and to assess for effect modification by psychosocial risk.ResultsAmong 7724 participants, those with high (versus low) social support had an adjusted prevalence ratio (aPR) and 95% confidence interval (CI) for ideal or intermediate (versus poor) CVH of 0.99 (0.96-1.03). For medium (versus low) social support, the aPR (95% CI) was 1.01 (0.98-1.05). There was evidence for modification by employment and anger. Those with medium (versus low) social support had an aPR (95% CI) of 1.04 (0.99-1.10) among unemployed or low anger participants. Corresponding results for employed or high anger participants were 0.99 (0.94-1.03) and 0.97 (0.91-1.03), respectively.ConclusionOverall, we observed no strong evidence for an association between social support and CVH. However, some psychosocial risks may be modifiers. Prospective studies are needed to assess the social support-CVH relationship by psychosocial risks in racially/ethnically diverse populations.

BackgroundCarbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms.MethodsTo overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years.ResultsOur CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment.ConclusionsCollectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.

Background: The Collaboration for Evidence-based Healthcare and Public Health in Africa (CEBHA+) developed and offered a course on evidence-based public health (EBPH) in five sub-Saharan African (SSA) countries to enhance individual and institutional capacity. Aim: This study aims to assess, compare and learn from implementing the CEBHA+ EBPH course using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework and Practical, Robust, Implementation and Sustainability Model (PRISM). Setting: This study involved CEHBA+ partner universities in five countries in SSA. Methods: We developed a framework that draws on signalling questions for RE-AIM and PRISM dimensions. Country teams reflected on, discussed and mapped unique experiences. Using this framework, we then elicited common themes across countries and distilled country-specific experiences through virtual discussions. Results: Across countries, 130 public health practitioners, researchers and students completed the course (Reach). The course increased EBPH knowledge and skills and the capacity to teach EBPH and resulted in immediate opportunities for applying skills (Effectiveness). Hybrid offering in two countries presented challenges regarding Internet connectivity and hybrid discussions. Facilitators had previous training in teaching EBPH. While learning material was the same across countries, the content was adapted to represent local public health priorities (Implementation, Adoption). Course materials have informed other related training leading to spin-offs (Maintenance). Institutionalisation is dependent on external funding. Conclusion: Strengthening EBPH capacity across contexts is feasible. Curricula containing both core and contextualised elements create an authentic learning environment. Formal evaluations should be embedded within capacity-strengthening initiatives. Contribution: This is the first study evaluating EBPH training in SSA using an implementation science lens, offering learning about context-relevant adaptations that assist with plans for sustainability and scale.

Attention and reward are functions that are critical for the control of behavior, and massive multi-region neural systems have evolved to support the discrete computations associated with each. Previous research has also identified that attention and reward interact, though our understanding of the neural mechanisms that mediate this interplay is incomplete. Here, we review the basic neuroanatomy of attention, reward, and cholinergic systems. We then examine specific contexts in which attention and reward computations interact. Building on this work, we propose two discrete neural circuits whereby acetylcholine, released from cell groups located in different parts of the brain, mediates the impact of stimulus-reward associations as well as motivation on attentional control. We conclude by examining these circuits as a potential shared loci of dysfunction across diseases states associated with deficits in attention and reward.

Purpose: The construction industry is a diverse sector with exposure to multiple psychosocial and environmental workplace hazards that increase the risk of injury. This scoping review aims to consolidate the existing literature on the physical and psychosocial determinants influencing the risk of occupational physical injuries among construction workers globally. Methods: A scoping review was conducted using the PRISMA extension checklist guided. Literature searches were performed between June and October 2023 in electronic academic databases. Results: A total of 77 studies were identified, encompassing various geographical regions, including North America (n = 29), Africa (n = 18), Europe (n = 12), Asia (n = 9), the Middle East (n = 5), and Oceania (n = 4). The review identified physical and psychosocial factors in 3 domains influencing occupational physical injuries: workplace physical environment (eg, exposure to physical hazards, availability and utilization of personal protective equipment, company size, and job type), workplace culture (eg, psychosocial stressors, gender-related barriers, migrant and ethnic disparities, educational background), and physical wellbeing, health and aging (eg, age, obesity, sleep quality, marital stats, and physical health status). Notably, workers from social minority groups (eg, women, ethnic and migrant workers) of young (

Abstract Land trusts have historically selected many project sites opportunistically, awaiting communication from willing sellers or donors interested in conserving their land. However, in light of the multiple ecological crises faced by land trusts, including climate change, biodiversity loss, and habitat destruction, there is a growing awareness of the need to practice land conservation with an increased pace, scale, and efficacy. In answer to that challenge, we provide one example of how a land trust can adopt methodology for the strategic selection of land protection project sites. Strategic land conservation, as demonstrated in this paper, involves thoughtful prioritization of the attributes of future conservation project sites. Following prioritization, spatial analysis of the region is conducted to identify sites that meet the prioritized attributes, in this case, resilience to climate change. The case study explored in this paper is the 2020 Strategic Land Conservation Plan created by Southwest Michigan Land Conservancy and its partners.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics.

Background: Despite positive outcomes in controlled trials, organizations have been slow to adopt health literacy practices. The purpose of the Communicate to CARE (Clear Communication, Achieve Understanding with Teach-Back, Receptive to our patient family needs, Empathetic care delivery) study was to use theories and strategies from implementation science to scale up health literacy practices in a pediatric Ears, Nose, and Throat (ENT) clinic. Brief Description of Activity: Expanding on previous efforts that simply reflected on barriers, the CARE team identified barriers within the local context pre-implementation to select strategies to directly address barriers during health literacy implementation. The RE-AIM framework was used to evaluate the reach, effectiveness, adoption, implementation, and maintenance of health literacy practices. Implementation: Over 18 months, the CARE team delivered multiple implementation strategies, including external facilitator, microlessons, preparing champions, audit and feedback, local consensus discussions, and small test of change. We tailored health literacy practices to clinic team roles to accommodate the clinic workflow. Results: ENT team mean ratings on acceptability, appropriateness, and feasibility remained >4 indicating a high likelihood of successful implementation. Caregiver always ratings significantly increased from baseline to 12 months for easy-to-understand medication instructions (74%–96%), test results (54%–96%), know what to do if had questions (89%–96%), and encouraged to talk about health problems (76%–90%). Caregiver ratings dropped slightly at 18 months, indicating a need for booster training. While one third of caregivers reported Teach-Back practice across all time periods, the ENT team reported increased practice from baseline (42%), 6 (61%) and 12 months (70%). Lessons Learned: Over the first 12 months, the external facilitator delivered implementation strategies with weekly contact, tapering contact over the final 6 months. The local champion became engaged in the CARE study through a quality improvement project with meaningful outcomes for the clinic and an incentivization program for scholarly endeavors. Lunch and learn sessions helped build relationships between the CARE and ENT team to discuss and problem solve issues. The 5-item CAHPS health literacy composite proved to be sensitive to changes during implementation of health literacy practices. Integrating these items into standard follow up surveys with patients and families would help realize the return on investment for health literacy implementation. [HLRP: Health Literacy Research and Practice. 2024;8(3):e166–e174.]

Background: General practice has one of the most diverse medical training programmes in terms of sex and ethnic background. However, this diversity of race and ethnicity is not reflected in academic GP careers, with just 17% (n = 81/473) of academic GPs being from racially minoritised groups, according to the Medical Schools Council. Aim: To determine whether GP academic clinical fellow (ACF) trainees from racially minoritised backgrounds are proportionally represented, compared with the non-academic training programme, using the annual GP ACF conference as a proxy. Design & setting: A retrospective analysis of conference programmes from national academic GP training conferences from 2018–2023 and demographic data obtained from Health Education England (HEE). Method: Using conference programmes and online searches, demographic information on conference speakers was obtained and a freedom of information request was made to HEE for the demographics of GP ACFs for corresponding years. This was compared with demographic data of GP trainees and academics. Results: On average, there were 40 speakers each year at the conference. White females (average 20.2 speakers each year) were the most well represented group, followed by White males (average 12.5), Asian females (average 3.3), Asian males (average 1.8), Black males (average 0.7), and Black females (average 0.3). HEE data from 2022 revealed that 27 (71.1%) of the 38 (excluding five who did not state their ethnicity) ACFs were White British. Conclusion: GP academia should be more representative of the non-academic GP training scheme. Work needs to be done to understand and overcome the structural barriers to recruiting from racially minoritised groups.

As the pandemic continues to pose challenges to global public health, developing effective predictive models has become an urgent research topic. This study aims to explore the application of multi-objective optimization methods in selecting infectious disease prediction models and evaluate their impact on improving prediction accuracy, generalizability, and computational efficiency. In this study, the NSGA-II algorithm was used to compare models selected by multi-objective optimization with those selected by traditional single-objective optimization. The results indicate that decision tree (DT) and extreme gradient boosting regressor (XGBoost) models selected through multi-objective optimization methods outperform those selected by other methods in terms of accuracy, generalizability, and computational efficiency. Compared to the ridge regression model selected through single-objective optimization methods, the decision tree (DT) and XGBoost models demonstrate significantly lower root mean square error (RMSE) on real datasets. This finding highlights the potential advantages of multi-objective optimization in balancing multiple evaluation metrics. However, this study’s limitations suggest future research directions, including algorithm improvements, expanded evaluation metrics, and the use of more diverse datasets. The conclusions of this study emphasize the theoretical and practical significance of multi-objective optimization methods in public health decision support systems, indicating their wide-ranging potential applications in selecting predictive models.

Background Errors associated with failures in filing, actioning and communicating blood test results can lead to delayed and missed diagnoses and patient harm. This study aimed to audit how blood tests in primary care are filed, actioned and communicated in primary care, to identify areas for patient safety improvements.Methods UK primary care clinicians were recruited through the Primary Care Academic CollaboraTive (PACT). PACT members audited 50 recent sets of blood tests from their practice and retrospectively extracted data on blood test result coding, actioning and communication. PACT members received a practice report, showing their own results, benchmarked against other participating practices.Results PACT members from 57 general practices across all four UK nations collected data on 2572 patients who had blood tests in April 2021. In 89.9% (n=2311) they agreed with the initial clinician’s actioning of blood tests; 10.1% disagreed, either partially (7.1%) or fully (3.0%).In 44% of patients (n=1132) an action (eg, ‘make an appointment’) was specified by the filing clinician. This action was carried out in 89.7% (n=1015/1132) of cases; in 6.8% (n=77) the action was not carried out, in 3.5% (n=40) it was unclear. In the 117 cases where the test result had not been actioned 38% (n=45) were felt to be at low risk of harm, 1.7% (n=2) were at high risk of harm, 0.85% (n=1) came to harm.Overall, in 47% (n=1210) of patients there was no evidence in the electronic health records that results had been communicated. Out of 1176 patients with one or more abnormal results there was no evidence of test communication in 30.6% (n=360). There were large variations between practices in rates of actioning and communicating tests.Conclusion This research demonstrates variation in the way blood test results are actioned and communicated, with important patient safety implications.

Aims Recommendations from the NHS and the Royal College of Psychiatrists advise that patients receive a copy of all correspondence that is sent on to the GP. Often, within psychiatric services, letters are not routinely sent to patients. To improve communication with patients and their carers, the Aneurin Bevan Learning Disability team have been writing letters directly to patients and sending a copy to the GP. There is limited use of jargon, and the complexity of the language aims to reflect the individual's reading level. This study aimed to gain feedback from local GPs on the new letter format to ensure effective communication between teams. Methods We contacted Primary Care Services in the local area to gain feedback on how our clinic letters were being processed, we were informed that letters are reviewed by an admin team and only sent on to GPs if there are specific tasks to action, meaning that many of our letters remain unread. We identified 16 GP practices in the Torfaen and Monmouthshire area and sent a survey by email to gain feedback on the new correspondence style. The survey was sent out three times within a 12-month period. Results Of 16 GP practices just 6 responded, with just 1 GP stating that they had noticed a change in the letter style. 50% of GPs felt they received relevant information in the letters from the CLDT. The comments were largely positive with suggestions reflecting changes that have already been made. There is no feedback that suggests GPs feel they are not receiving adequate clinical information. Conclusion The lack of response may highlight how infrequently GPs are reviewing the letters from the CLDT confirming the importance of prioritising doctor–patient correspondence. The limited communication from GP to CLDT emphasises the need for improvement in liaison between secondary and primary care services. The lack of negative feedback about the letters is encouraging. There is no feedback that suggests GPs feel they are not receiving adequate clinical information and clear feedback that GPs want clear and accessible information, particularly regarding specific actions for GPs. A clear limitation of this work is the lack of response to our survey. Reviewing these letters from our team is a very small proportion of a GPs workload, more time may be needed to ensure GPs have had contact with our team and are able to provide more detailed feedback.

Aims To identify if COVID-19 has changed the experience for patients under the care of Crisis Resolution Home Treatment teams (HTT). To identify if COVID-19 altered the response for HTT patients in the context of Personality Disorder (PD). To provide useful demographic and experiential information about patients using HTT with PD during crisis. Methods Data regarding the demographics of patients with personality disorders under the care of the Croydon crisis home treatment team were collected retrospectively for two, predetermined time windows. The first window was pre-COVID-19 (26/03/2019–25/03/2020) and the second window was during COVID-19 (26/03/2020–25/03/2021). The demographics of patients with personality disorder referred to the team during these two time periods included were compared. Results More patients with personality disorder were referred to the Croydon HTT during COVID-19 (n = 82) when compared with the window before (n = 58). The proportion of referred patients with Emotionally Unstable Personality Disorder (EUPD) was constant before and during COVID-19. The average length of stay reduced from 22.6 days before COVID-19 to 18.7 days during COVID-19. The proportion of rejected referrals to the HTT of patients with personality disorder increased during COVID-19. Finally, the proportion of BAME (Black, Asian, Minority Ethnicity) referrals of patients with personality disorder increased during COVID when compared with before, with this finding not being replicated in any other ethnic group. Conclusion Increased numbers of referrals may indicate worsening mental health in the community. This may have been compounded by an inability of community mental health teams and inpatient services to meet such an increase in demand for services. An overall reduction in inpatient admissions during COVID-19 supports this idea. There was a relatively larger drop in duration of admission for patient with personality disorder during COVID-19, when compared with all patients. This may be due to staff feeling unable to offer quick management for patients with personality disorder. Subsequently, staff may have selectively discharged such patients earlier. The rate of rejected referrals to the Croydon HTT was consistently higher than the acceptances both pre- and post- COVID-19. Therefore, HTT clinicians may feel unable to adequately treat PD. In conclusion, the number of referrals to the HTT increased during COVID-19, however, with a reduced average duration of stay with HTT for patients. The rejection rates for personality disorder patients were consistently higher than for other patient groups, both before and during COVID-19. Additionally, the proportion of patients with personality disorder from BAME backgrounds increased during COVID-19.

ABSTRACT Asexual replication in the apicomplexan Sarcocystis neurona involves two main developmental stages: the motile extracellular merozoite and the sessile intracellular schizont. Merozoites invade host cells and transform into schizonts that undergo replication via endopolygeny to form multiple (64) daughter merozoites that are invasive to new host cells. Given that the capabilities of the merozoite vary significantly from the schizont, the patterns of transcript levels throughout the asexual lifecycle were determined and compared in this study. RNA-Seq data were generated from extracellular merozoites and four intracellular schizont development time points. Of the 6,938 genes annotated in the S. neurona genome, 6,784 were identified in the transcriptome. Of these, 4,111 genes exhibited significant differential expression between the merozoite and at least one schizont development time point. Transcript levels were significantly higher for 2,338 genes in the merozoite and 1,773 genes in the schizont stages. Included in this list were genes encoding the secretory pathogenesis determinants (SPDs), which encompass the surface antigen and SAG-related sequence (SAG/SRS) and the secretory organelle proteins of the invasive zoite stage (micronemes, rhoptries, and dense granules). As anticipated, many of the S. neurona SPD gene transcripts were abundant in merozoites. However, several SPD transcripts were elevated in intracellular schizonts, suggesting roles unrelated to host cell invasion and the initial establishment of the intracellular niche. The hypothetical genes that are potentially unique to the genus Sarcocystis are of particular interest. Their conserved expression patterns are instructive for future investigations into the possible functions of these putative Sarcocystis-unique genes.IMPORTANCEThe genus Sarcocystis is an expansive clade within the Apicomplexa, with the species S. neurona being an important cause of neurological disease in horses. Research to decipher the biology of S. neurona and its host-pathogen interactions can be enhanced by gene expression data. This study has identified conserved apicomplexan orthologs in S. neurona, putative Sarcocystis-unique genes, and gene transcripts abundant in the merozoite and schizont stages. Importantly, we have identified distinct clusters of genes with transcript levels peaking during different intracellular schizont development time points, reflecting active gene expression changes across endopolygeny. Each cluster also has subsets of transcripts with unknown functions, and investigation of these seemingly Sarcocystis-unique transcripts will provide insights into the interesting biology of this parasite genus.

Introduction & Background Menstruation affects half the population, yet its patterns and management are greatly under-researched. A regular and functioning menstrual cycle is considered an important vital sign and menstrual-related issues can be strong indicators of both reproductive and wider health issues. This project explores a novel health data source - shopping data history - to study how individuals manage menstrual symptoms such as pain, intensity of flow, mental health, and other issues, and explore potential social inequalities in these management strategies. Objectives & Approach We present a conceptual framework of studying management of menstruation symptoms using shopping data. The core objectives of this research are to enhance our understanding of menstrual management strategies and potential inequalities in these whilst evaluating the utility and acceptability of shopping data for future female reproductive health research. Our research will focus on harnessing loyalty card data from UK supermarkets and pharmaceutical retailers to provide insights into the management of menstrual symptoms at a national level. We will study retail data to identify products and patterns of purchasing which may be relevant to menstrual management and conduct surveys for linkage with shopping data. The public will be consulted to investigate attitudes towards shopping data for health research and inform interpretations of patterns in the data. Relevance to Digital Footprints This project contributes to advancing of understanding of using digital data for health research on an important societal challenge. We investigate the practical applications for menstrual health and other female reproductive health issues, with scope to enact meaningful change. Conclusions & Implications By analysing shopping behaviour, combined with survey data and area-level socioeconomic data, we aim to identify regions of the UK and individual characteristics which influence the risk of experiencing menstrual symptoms and ability to manage these within a high-income context. Our research will contribute to understanding of menstrual management strategies for women and people who menstruate, and associated inequalities.

Genetic markers for acne are being studied to create personalized treatments based on an individual’s genes, and the field is benefiting from the application of artificial intelligence (AI) techniques. One such AI tool, the Q-learning algorithm, is increasingly being utilized by medical researchers to delve into the genetics of acne. In contrast to previous methods, our research introduces a Q-learning model that is adaptable to diverse sample groups. This innovative approach involves preprocessing data by identifying differentially expressed genes and constructing gene-gene connectivity networks. The key advantage of using the Q-learning model lies in its ability to transform acne gene data into Markovian domains, which are essential for selecting relevant genetic markers. Performance evaluations of our Q-learning model have shown high accuracy and specificity, although there may be some sensitivity variations. Notably, this research has identified specific genes, such as CD86, AGPAT3, TMPRSS11D, DSG3, TNFRSF1B, PI3, C5AR1, and KRT16, as being acne-related through biological verification and text data mining. These findings underscore the potential of AI-driven Q-learning models to revolutionize the study of acne genetics. In conclusion, our Q-learning model offers a promising approach for the selection of acne-related genetic markers, despite minor sensitivity fluctuations. This research highlights the transformative potential of Q-learning in advancing our understanding of the genetics underlying acne, paving the way for more personalized and effective treatments in the future.

IntroductionChildcare center closures during COVID-19 impacted education for approximately 40 million children nationwide. Unfortunately, COVID-19 restrictions significantly limited the extent that outside personnel could provide in-person support to educators, resulting in the need for innovative approaches to meet childcare centers’ needs. A virtual robotic telepresence approach was applied to early childhood consultation models to promote child resilience while mitigating COVID-19 risks. The goal of this study was to examine how training influenced consultants’ and childcare staff uptake of the virtual robotic telepresence consultation approach and their acceptance of this technology.MethodsTen early childhood consultants received multimedia/simulation training and weekly communities of practice related to virtual telepresence robotic consultation. Telepresence robotic consultation equipment was deployed to 16 childcare centers in a diverse multilingual metropolitan area as a part of a larger randomized controlled trial. Consultants trained childcare staff (14 center directors and 58 teachers) on how to receive virtual telepresence robotic consultation. Demographic information and measures of technology acceptability and uptake were collected from childcare staff and consultants. A mixed methods approach was used including multilevel modeling and focus groups to examine consultation uptake, acceptability, barriers, and facilitators of virtual telepresence robotic consultation implementation.ResultsConsultants and childcare staff generally perceived the virtual telepresence consultation approach to be useful and easy to use. Consultant perceptions of the acceptability of technology did not change over time. Childcare staff, center, and consultant factors impacted the uptake of the virtual robotic telepresence consultation approach and childcare staff acceptance of the technology. Focus groups revealed that consultants believed that additional hands-on training with childcare staff would have benefited implementation and expressed a desire for a hybrid approach for consultation.DiscussionPerceptions of telepresence robotic consultation acceptability are discussed, including future recommendations for training.

Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the ex vivo introduction of a missing gene into patients’ own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.

Purpose: Swallow-related motion of the larynx is most significant in the cranio-caudal directions and of` short duration. Conventional target definition for radical radiation therapy includes coverage of the whole larynx. This study longitudinally examined respiration- and swallow-related laryngeal motions using cine-magnetic resonance imaging. We further analyzed the dosimetry to organs at risk by comparing 3D-conformal radiation therapy (3D-CRT), volumetric modulated arc therapy (VMAT), and intensity modulated radiation therapy (IMRT) techniques. Methods: Fifteen patients with T1-2 N0 glottic squamous cell carcinomas were prospectively recruited for up to 3 cine-MRI scans on the Elekta Unity MR-Linear accelerator, at the beginning, middle, and end of a course of radical radiation therapy. Swallow frequency and motion of the hyoid bone, cricoid and thyroid cartilages, and vocal cords were recorded during swallow and rest. Adapted treatment volumes consisted of gross tumor volume + 0.5-1 cm to a clinical target volume with an additional internal target volume (ITV) for personalized resting-motion. Swallow-related motion was deemed infrequent and was not accounted for in the ITV. We compared radiation therapy plans for 3D-CRT (whole larynx), VMAT (whole larynx), and VMAT and IMRT (ITV for resting motion). Results: Resting- and swallow-related motions were most prominent in the cranio-caudal plane. There were no significant changes in the magnitude of motion over the course of radiation therapy. There was a trend of a progressive reduction in the frequency of swallow. Treatment of partial larynx volumes with intensity modulated methods significantly reduced the dose to carotid arteries, compared with treatment of whole larynx volumes. Robustness analysis demonstrated that when accounting for intrafraction swallow, the total dose delivered to the ITV/planning target volume was maintained at above 95%. Conclusions: Swallow-related motions are infrequent and accounting for resting motion in an ITV is sufficient. VMAT/IMRT techniques that treat more conformal targets can significantly spare critical organs at risk such as the carotid arteries and thyroid gland, potentially reducing the risk of carotid artery stenosis-related complications and other long-term complications.

Single Electron Pump (SEP) devices that can deliver single electrons at high frequencies are fabricated using two different gate geometries. The pump quantum dot (QD) can be defined either using two finger gates where the pump operates in what is known as the conventional pumping regime (CPR), or alternatively, the QD can be designed with the use of a single finger gate and split gate, where the pump operates in the long pumping regime (LPR). Here we investigate pump-maps produced in both the CPR and LPR under the effects of a low magnetic field (1 T to −1 T) and observe both the evolution of the pump-map and pump accuracy. Measurements were carried out in a cryogen free dilution refrigeration system with the use of a superconducting magnetic. Clear discrepancies between the behaviour of current in the different regimes can be seen indicating a fundamental difference in the operation of the pumps in the two different pumping regimes.

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein-protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.