Childhood adiposity underlies numerous adult brain traits commonly attributed to midlife obesity.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study aimed to investigate whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We utilised a two-sample lifecourse Mendelian randomization study in 37,501 adults recruited to UK Biobank (UKB) imaging centers from 2014, with secondary analyses in 6,996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a GWAS of 407,741 UKB participants. Primary outcomes were adult total brain volume; grey matter volume, thickness, and surface area; white matter volume and hyperintensities; and hippocampus, amygdala, and thalamus volumes at mean age 55 in UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In UKB, individuals who were genetically-predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume (e.g. z-score difference in normalised brain volume per category increase in adiposity [95%CI] = -0.20 [-0.28, -0.12]; p = 4 × 10-6). These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null (e.g. adult z-score [95%CI] for total volume = 0.06 [-0.05,0.17]; p = 0.3). Observational analyses in ABCD showed a similar pattern of changes already present in those with a high BMI by age 10 (z-score [95%CI] = -0.10 [-0.13, -0.07]; p = 8 × 10-13), with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood (childhood z-score [95%CI] for intracranial volume = 0.14 [0.05,0.23]; p = 0.002), rather than smaller brain sizes per se. Our data suggest that persistence of early-life developmental differences across the lifecourse may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life.

Remimazolam for sedation and anesthesia in children: A scoping review.

BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, shows considerable promise in clinical practice. Its pharmacodynamic profile closely resembles that of midazolam, while its pharmacokinetic properties are similar to those of remifentanil. While research in adult populations continues to accumulate, the pace of pediatric studies is not as significant. This scoping review aims to systematically examine published studies, clinical trials, observational research, case reports, and relevant literature to provide a comprehensive understanding of remimazolam in pediatric sedation and anesthesia. By synthesizing the gathered evidence, we aim to identify gaps in the literature, guide future research endeavors, and inform clinical practices. METHODS: The review follows the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Review. A thorough search strategy was implemented across prominent peer-reviewed databases, with focused efforts to identify relevant grey literature. All primary studies involving the use of remimazolam in pediatric populations were included in this review. RESULTS: Eighteen studies were included in this analysis, comprising 2 randomized controlled trials, 4 prospective cohort trials, 12 case reports, and 692 children in total. CONCLUSION: This scoping review highlights the increasing interest in using remimazolam as a sedative or anesthetic for children. Although initial evidence indicates its effectiveness and safety, more research is necessary to fill knowledge gaps, establish standard protocols, and optimize its use in pediatric anesthesia and sedation. Addressing these challenges will enable clinicians to improve the quality of care and outcomes for pediatric patients undergoing sedation and anesthesia.

Effect of low-volume combined aerobic and resistance high-intensity interval training on vascular health in people with type 2 diabetes: a randomised controlled trial.

PURPOSE: We compared the effects of low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), combined moderate-intensity continuous training (C-MICT) and waitlist control (CON) on vascular health after 8-weeks of supervised training, and an additional 10-months of self-directed training, in adults with type 2 diabetes (T2D). METHODS: Sixty-nine low active adults with T2D were randomised to 8-weeks of supervised C-HIIT (3 times/week, 78-min/week), C-MICT (current exercise guidelines, 4 times/week, 210-min/week) or CON. CON underwent usual care for 8-weeks before being re-randomised to C-HIIT or C-MICT. This was followed by 10-months of self-directed training for participants in C-HIIT and C-MICT. Vascular outcomes were evaluated at baseline, 8-weeks, and 12-months. RESULTS: After 8-weeks, supervised C-HIIT significantly improved relative flow-mediated dilation (FMD) compared with CON (mean difference [MD] 0.8% [0.1, 1.4], p = 0.025). Although not significantly different from CON, the magnitude of change in relative FMD following 8-weeks of supervised C-MICT was similar (MD 0.8% [-0.1, 1.7], p = 0.080). There were no differences in haemodynamic indices, carotid-femoral pulse wave velocity (cfPWV), or aortic reservoir pressure between groups at 8-weeks. After 12-months, there was a significant reduction in haemodynamic indices (time effect, p < 0.05) for both C-HIIT and C-MICT, with no between-group difference. The reduction in cfPWV over 12-months was significantly greater in C-MICT than C-HIIT (group × time effect, p = 0.018). There was no difference in FMD over time or between groups at 12-months. CONCLUSIONS: Short-term supervised C-HIIT and C-MICT both increased brachial artery FMD compared with CON. Long-term C-HIIT and C-MICT were beneficial for improving haemodynamic indices, but not brachial artery FMD. C-MICT was superior to C-HIIT for improving cfPWV at 12-months. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier ACTRN12615000475549.

Comprehensive care programmes for children with medical complexity.

BACKGROUND: Children with medical complexity (CMC) represent a small, but growing, proportion of all children. Regardless of their underlying diagnosis, by definition, all CMC have similar functional limitations and high healthcare needs. It has been suggested that improving aspects of healthcare delivery for CMC improves health- and quality of life-related outcomes for children and their families and reduces healthcare-related expenditure. As a result, dedicated comprehensive care programmes have been established at many hospitals to meet the needs of CMC; however, it is unclear if such programmes are effective. OBJECTIVES: Our main objective was to assess the effectiveness of comprehensive care programmes that aim to improve care coordination and other aspects of health care for CMC and to assess whether the effectiveness of such programmes differs according to the programme setting and structure. We aimed to assess their effectiveness in relation to child and parent health, functioning, and quality of life, quality of care, number of healthcare encounters, unmet healthcare needs, and total healthcare-related costs. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and CINAHL in May 2023. We also searched reference lists, trial registries, and the grey literature. SELECTION CRITERIA: Randomised and non-randomised trials, controlled before-after studies, and interrupted time series studies were included. Studies that compared enrolment in a comprehensive care programme with non-enrolment in such a programme/treatment as usual were included. Participants were children that met the criteria for the definition of CMC, which is: having (i) a chronic condition, (ii) functional limitations, (iii) increased health and other service needs, and (iv) increased healthcare costs. Studies that included the following types of outcomes were included: health; quality of care; utilisation, coverage and access; resource use and costs; equity; and adverse outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed the risk of bias in each included study, and evaluated the certainty of evidence according to GRADE criteria. Where possible, data were represented in forest plots and pooled. We were unable to undertake a meta-analysis for comparisons and outcomes, so we used a structured synthesis approach. MAIN RESULTS: We included four studies with a total of 912 CMC as participants. All included studies were randomised controlled trials conducted in hospitals in the USA or Canada. Participants varied across the included studies; however, all four studies included children with complex and chronic illness and high healthcare needs. While the primary aim of the intervention was similar across all four studies, the components of the interventions differed: in the four studies, the intervention involved some element of care coordination; in two of the studies, it involved the child receiving care from a multidisciplinary team, while in one study, the intervention was primarily centred on access to an advanced practice nurse care coordinator and another study involved nurse a practitioner-paediatrician dyad partnering with families. The risk of bias in the four studies varied across domains, with issues primarily relating to the lack of blinding of participants, personnel, and outcome assessors, inadequate allocation concealment, and incomplete outcome data. Comprehensive care for CMC compared to usual care may make little to no difference to child health, functioning, and quality of life at 12 or 24 months (three studies with 404 participants) and we assessed the evidence for the outcomes in this category (child health-related quality of life and functional status) as being of low certainty. For CMC, comprehensive care probably makes little or no difference to parent health, functioning, and quality of life compared to usual care at 12 months (one study with 117 participants) and we assessed the evidence for this outcome as being of moderate certainty. Comprehensive care for CMC compared to usual care may slightly improve child and family satisfaction with, and perceptions of, care and service delivery at 12 months (three studies with 453 participants); however, we assessed the evidence for these outcomes as being of low certainty. For CMC, comprehensive care probably makes little or no difference to the number of healthcare encounters (emergency department visits) and the number of hospitalised days (hospital admissions) compared to usual care at 12 months (three studies with 668 participants), and we assessed the evidence for these outcomes as being of moderate certainty. Three of the included studies (668 participants) reported cost outcomes and had conflicting results, with one study reporting significantly lower healthcare costs at 12 months in the intervention group compared to the control group, one reporting no differences between groups, and the other study reporting a greater increase in total healthcare costs in the intervention group compared to the control group. Overall, comprehensive care may make little or no difference to overall healthcare costs in CMC; however, the methods used to measure total healthcare costs varied across studies and the certainty of the evidence relating to this outcome is low. No studies assessed the costs to the family. AUTHORS' CONCLUSIONS: The findings of this review should be treated with caution due to the limited amount and quality of the published research that was available to be included. Overall, the certainty of the evidence for the effectiveness of comprehensive care for CMC ranged from low to moderate across outcomes and there is currently insufficient evidence on which to draw strong conclusions. There is a need for more high-quality randomised trials with consistency of the target population and intervention components, methods of reporting outcomes, and follow-up periods, as well as full cost analyses, taking into account both costs to the family and costs to the healthcare system.

Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome.

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Mammographic density mediates the protective effect of early-life body size on breast cancer risk.

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

Surgical complications after fixation of minimally displaced lateral compression type 1 pelvic ring injuries.

PURPOSE: To review surgical complications after fixation of stress-positive minimally displaced (< 1 cm) lateral compression type 1 (LC1) pelvic ring injuries. METHODS: A retrospective study at a level one trauma center identified patients who received surgical fixation of isolated LC1 pelvic ring injuries. Surgical complications and additional procedures were reviewed. RESULTS: Sixty patients were included. The median age was 61 years (Interquartile range 40-70), 65% (n = 39) were women, and 57% (n = 34) had high-energy mechanisms. Anterior-posterior, posterior-only, and anterior-only fixation constructs were used in 77% (n = 46), 15% (n = 9), and 8% (n = 5) of patients. Anterior fixation was performed with rami screw fixation in 82% (49/60), external fixation in 2% (1/60), and open reduction and plate fixation in 2% (1/60). There were 15 surgical complications in 23% (14/60), and 12 additional procedures in 17% (10/60). Complications included loss of reduction ≥ 1 cm (8%), symptomatic hematomas (8%), symptomatic backout of unicortical retrograde rami screws (5%), deep infection of the pelvic space after a retrograde rami screw (1.6%), and iatrogenic L5 nerve injury (1.6%). All losses of reduction involved geriatric females with distal rami fractures sustained in ground-level falls. Loss of reduction was found to be more likely in patients with low energy mechanisms (proportional difference (PD) 62%, 95% confidence interval (CI) 18% to 76%; p = 0.01) and 2 versus 1 posterior pelvic screws (PD 36%; CI 0.4% to 75%; p = 0.03). CONCLUSIONS: Surgical complications and additional procedures routinely occurred after fixation of LC1 injuries. Patients should be appropriately counseled on the risks of surgical fixation of these controversial injuries. LEVEL OF EVIDENCE: Diagnostic, Level III.

Affective Symptoms in Pregnancy are Associated with the Vaginal Microbiome.

Composition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Identifying the sources of individual differences in the vaginal microbiome is therefore of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure. Data were based on a prospective longitudinal study of a diverse and medically healthy community sample of 275 mother-infant pairs. Affective symptoms and stress exposure and select measures of associated biomarkers (diurnal salivary cortisol, serum measures of sex hormones) were collected at each trimester; self-report, clinical, and medical records were used to collect detailed data on socio-demographic factors and health behavior, including diet and sleep. Vaginal microbiome samples were collected in the third trimester (34-40 weeks) and characterized by 16S rRNA sequencing. Identified taxa were clustered into three community state types (CST1-3) based on dissimilarity of vaginal microbiota composition. Results indicate that depressive symptoms during pregnancy were reliably associated with individual taxa and CST3 in the third trimester. Prediction of functional potential from 16S taxonomy revealed a differential abundance of metabolic pathways in CST1-3 and individual taxa, including biosynthetic pathways for the neuroactive metabolites, serotonin and dopamine. With the exception of bioavailable testosterone, no significant associations were found between symptoms- and stress-related biomarkers and CSTs. Our results provide further evidence of how prenatal psychological distress during pregnancy alters the maternal-fetal microbiome ecosystem that may be important for understanding maternal and child health outcomes.

Electrical Impedance Tomography as a monitoring tool during weaning from mechanical ventilation: an observational study during the spontaneous breathing trial.

BACKGROUND: Prolonged weaning from mechanical ventilation is associated with poor clinical outcome. Therefore, choosing the right moment for weaning and extubation is essential. Electrical Impedance Tomography (EIT) is a promising innovative lung monitoring technique, but its role in supporting weaning decisions is yet uncertain. We aimed to evaluate physiological trends during a T-piece spontaneous breathing trail (SBT) as measured with EIT and the relation between EIT parameters and SBT success or failure. METHODS: This is an observational study in which twenty-four adult patients receiving mechanical ventilation performed an SBT. EIT monitoring was performed around the SBT. Multiple EIT parameters including the end-expiratory lung impedance (EELI), delta Tidal Impedance (ΔZ), Global Inhomogeneity index (GI), Rapid Shallow Breathing Index (RSBIEIT), Respiratory Rate (RREIT) and Minute Ventilation (MVEIT) were computed on a breath-by-breath basis from stable tidal breathing periods. RESULTS: EELI values dropped after the start of the SBT (p < 0.001) and did not recover to baseline after restarting mechanical ventilation. The ΔZ dropped (p < 0.001) but restored to baseline within seconds after restarting mechanical ventilation. Five patients failed the SBT, the GI (p = 0.01) and transcutaneous CO2 (p < 0.001) values significantly increased during the SBT in patients who failed the SBT compared to patients with a successful SBT. CONCLUSION: EIT has the potential to assess changes in ventilation distribution and quantify the inhomogeneity of the lungs during the SBT. High lung inhomogeneity was found during SBT failure. Insight into physiological trends for the individual patient can be obtained with EIT during weaning from mechanical ventilation, but its role in predicting weaning failure requires further study.

Iodine(III)-Catalyzed Oxidative Cyclization of Aryl Amines to Construct N-Alkylbenzimidazoles.

An I(III)-catalyzed oxidative cyclization reaction using selectfluor as the oxidant was developed that converts ortho-substituted anilines to benzimidazoles. The mild reaction requires as little as 0.5 mol % of iodobenzene, and its scope is broad: electron-withdrawing or electron-releasing groups on the aniline portion are tolerated, and cyclic or acyclic N-alkylamines are permitted as ortho-substituents. Preliminary mechanistic investigations suggest that benzimidazole formation occurs via cationic reactive intermediates, and an intramolecular kinetic isotope effect of 1.98 ± 0.05 was measured.

Availability and stock-outs of paediatric antiretroviral treatment formulations at health facilities in Kenya and Uganda.

INTRODUCTION: The large number of deaths among children with HIV is driven by poor antiretroviral treatment (ART) coverage among this cohort. The aim of the study was to assess the availability and stock-outs of paediatric and adult ART formulations in Kenya and Uganda across various regions and types of health facilities. METHODS: A survey on availability and stock-outs of paediatric ART at health facilities was adapted from the standardized Health Action International-WHO Medicine Availability Monitoring Tool. All preferred and limited-use formulations, and three phased-out formulations according to the 2021 WHO optimal formulary list were included in the survey, as well as a selection of adult ART formulations suitable for older children, adolescents, and adults. Availability data were collected in June-July 2022 and stock-out data were obtained over the previous year from randomly selected public and private-not-for-profit (PNFP) facilities registered to dispense paediatric ART across six districts per country. All data were analysed descriptively. RESULTS: In total, 144 health facilities were included (72 per country); 110 were public and 34 PNFP facilities. Overall availabilities of preferred paediatric ART formulations were 52.2% and 63.5% in Kenya and Uganda, respectively, with dolutegravir (DTG) 10 mg dispersible tablets being available in 70.2% and 77.4% of facilities, respectively, and abacavir/lamivudine dispersible tablets in 89.8% and 98.2% of facilities. Of note, availability of both formulations was low (37.5% and 62.5%, respectively) in Kenyan PNFP facilities. Overall availabilities of paediatric limited-use products were 1.1% in Kenya and 1.9% in Uganda. At least one stock-out of a preferred paediatric ART formulation was reported in 40.0% of Kenyan and 74.7% of Ugandan facilities. Nevirapine solution stock-outs were reported in 43.1% of Ugandan facilities, while alternative formulations for postnatal HIV prophylaxis were not available. CONCLUSIONS: Recommended DTG-based first-line ART for children across all ages was reasonably available at health facilities in Kenya and Uganda, with the exception of Kenyan PNFP facilities. Availability of paediatric ART formulations on the limited-use list was extremely low across both countries. Stock-outs were reported regularly, with the high number of reported stock-outs of neonatal ART formulations in Uganda being most concerning.

Remimazolam for sedation and anesthesia in children: Protocol for a scoping review.

BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, holds significant promise in clinical practice. Its pharmacodynamic profile closely mirrors that of midazolam, while its pharmacokinetics properties bear resemblance to remifentanil. Research in adult populations continues to accumulate, but the pediatric studies' pace is not significant. This scoping review aims to methodically scrutinize published studies, clinical trials, observational research, case reports, and pertinent literature to offer a comprehensive insight into the existing understanding of remimazolam in pediatric sedation and anesthesia. The synthesis of gathered evidence will discern lacunae in the literature, direct forthcoming investigations, and enlighten clinical practices. METHODS: The review will adhere to the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) for Scoping Review. A meticulous search strategy will be executed across prominent peer-reviewed databases, with concerted efforts to identify relevant gray literature. All primary investigations involving the administration of remimazolam in pediatric populations will be encompassed within the scope of this review. RESULTS: The encompassed studies will be elucidated through a narrative synopsis, complemented by descriptive statistical analyses of quantitative data where deemed applicable. CONCLUSION: The planned scoping review aims to delineate the existing evidence regarding the utilization of remimazolam in pediatric anesthesia and sedation. It will discern areas of knowledge deficiency, provide guidance for future inquiries, and enhance clinical practices within the field.

Future of Dutch NGS-Based Newborn Screening: Exploring the Technical Possibilities and Assessment of a Variant Classification Strategy.

In this study, we compare next-generation sequencing (NGS) approaches (targeted panel (tNGS), whole exome sequencing (WES), and whole genome sequencing (WGS)) for application in newborn screening (NBS). DNA was extracted from dried blood spots (DBS) from 50 patients with genetically confirmed inherited metabolic disorders (IMDs) and 50 control samples. One hundred IMD-related genes were analyzed. Two data-filtering strategies were applied: one to detect only (likely) pathogenic ((L)P) variants, and one to detect (L)P variants in combination with variants of unknown significance (VUS). The variants were filtered and interpreted, defining true/false positives (TP/FP) and true/false negatives (TN/FN). The variant filtering strategies were assessed in a background cohort (BC) of 4833 individuals. Reliable results were obtained within 5 days. TP results (47 patient samples) for tNGS, WES, and WGS results were 33, 31, and 30, respectively, using the (L)P filtering, and 40, 40, and 38, respectively, when including VUS. FN results were 11, 13, and 14, respectively, excluding VUS, and 4, 4, and 6, when including VUS. The remaining FN were mainly samples with a homozygous VUS. All controls were TN. Three BC individuals showed a homozygous (L)P variant, all related to a variable, mild phenotype. The use of NGS-based workflows in NBS seems promising, although more knowledge of data handling, automated variant interpretation, and costs is needed before implementation.

Fully closed and automated enrichment of primary blood dendritic cells for cancer immunotherapy.

Dendritic cell (DC) vaccination is a promising approach to induce tumor-specific immune responses in cancer patients. Until recently, most DC vaccines were based on in vitro-differentiated monocyte-derived DCs. However, through development of efficient isolation techniques, the use of primary blood dendritic cell subsets has come within reach. Manufacturing of blood-derived DCs has multiple advances over monocytes-derived DCs, including more standardized isolation and culture protocols and shorter production processes. In peripheral blood, multiple DC subsets can be distinguished based on their phenotype and function. Plasmacytoid DC (pDC) and myeloid/conventional DCs (cDC) are the two main DC populations, moreover cDC can be further subdivided into CD141/BDCA3+ DC (cDC1) and CD1c/BDCA1+ DC (cDC2). In three separate clinical DC vaccination studies in melanoma and prostate cancer patients, we manufactured DC vaccines consisting of pDCs only, cDC2s only, or a combination of pDC and cDC2s, which we called natural DCs (nDC). Here, we describe a fully closed and automated GMP-compliant method to enrich naturally circulating DCs and present the results of enrichment of primary blood DCs from aphaeresis products of 8 healthy donors, 21 castrate-resistant prostate cancer patients, and 112 stage III melanoma patients. Although primary blood DCs are relatively scarce in aphaeresis material, our results show that it is feasible to isolate highly pure pDC, cDC2, or nDC with sufficient yield to manufacture DC vaccines for natural DC-based immunotherapy.

Characterizing the Causal Pathway From Childhood Adiposity to Right Heart Physiology and Pulmonary Circulation Using Lifecourse Mendelian Randomization.

BACKGROUND: Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging. METHODS AND RESULTS: In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end-diastolic volume: ß=0.24 [95% CI, 0.15-0.33]; P=3×10-7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat-free mass and childhood height, respectively. CONCLUSIONS: Our findings suggest that, although childhood body size has a long-term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse.

University students' access to mental health services: A qualitative study of the experiences of health service professionals through the lens of candidacy in England.

OBJECTIVES: In order to develop a better understanding of students' access to mental health services, we explored the experiences of health care professionals interacting with university students with mental health problems. METHODS: We interviewed 23 professionals working across university advice and counselling services, NHS general practice, crisis, and psychological services in North and East London between June 2022 and January 2023. Our approach drew on reflexive thematic analysis and the principles of abductive analysis. The notion of candidacy - that is, how different needs are deemed deserving of health service attention - was particularly helpful to our understanding of the ongoing phenomenon of interest in the data. RESULTS: Each student's access to mental health support was highly contingent on the student's dynamic social context and the pressures and organisation of the local health system. Professionals described how different students viewed different needs as deserving of health service attention. Which students reached the professional's service depended on the resources and relationships a student could draw upon, and the service's relative permeability. Once there, what action professionals took was strongly influenced by the professional's service expertise, resource constraints, the relationships the professional's service had with other organisations, the students' wishes, and whether students regarded treatment offers as acceptable. CONCLUSIONS: Candidacy offers a useful lens to view university students' access to mental health support. Access appears to be an increasingly intricate task for students, given the fragmented service landscape, surging demand for mental health care and challenges of emerging adulthood. Our findings suggest that policy goals to increase use of mental health services are unlikely to improve outcomes for students without policy makers and health systems giving holistic consideration of inter-service relationships and available resources.

Systematic evaluation of B-cell clonal family inference approaches.

The reconstruction of clonal families (CFs) in B-cell receptor (BCR) repertoire analysis is a crucial step to understand the adaptive immune system and how it responds to antigens. The BCR repertoire of an individual is formed throughout life and is diverse due to several factors such as gene recombination and somatic hypermutation. The use of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using next generation sequencing enabled the generation of full BCR repertoires that also include rare CFs. The reconstruction of CFs from AIRR-seq data is challenging and several approaches have been developed to solve this problem. Currently, most methods use the heavy chain (HC) only, as it is more variable than the light chain (LC). CF reconstruction options include the definition of appropriate sequence similarity measures, the use of shared mutations among sequences, and the possibility of reconstruction without preliminary clustering based on V- and J-gene annotation. In this study, we aimed to systematically evaluate different approaches for CF reconstruction and to determine their impact on various outcome measures such as the number of CFs derived, the size of the CFs, and the accuracy of the reconstruction. The methods were compared to each other and to a method that groups sequences based on identical junction sequences and another method that only determines subclones. We found that after accounting for data set variability, in particular sequencing depth and mutation load, the reconstruction approach has an impact on part of the outcome measures, including the number of CFs. Simulations indicate that unique junctions and subclones should not be used as substitutes for CF and that more complex methods do not outperform simpler methods. Also, we conclude that different approaches differ in their ability to correctly reconstruct CFs when not considering the LC and to identify shared CFs. The results showed the effect of different approaches on the reconstruction of CFs and highlighted the importance of choosing an appropriate method.