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In this report we have examined the ability of small resting B cells to act as antigen-presenting cells (APC) to antigen-specific MHC-restricted T cells as assessed by either T cell proliferation or T cell-dependent B cell stimulation. We found that 10 of 14 in vitro antigen-specific MHC-restricted T cell clones and lines and three of four T cell hybridomas could be induced to either proliferate or secrete IL-2 in the presence of lightly irradiated (1,000 rads) purified B cells and the appropriate foreign antigen. All T cell lines and hybridomas were stimulated to proliferate or make IL-2 by macrophage- and dendritic cell-enriched populations and all T cells tested except one hybridoma caused B cell activation when stimulated with B cells as APC. Furthermore, lightly irradiated, highly purified syngeneic B cells were as potent a source of APC for inducing B cell activation as were low density dendritic and macrophage-enriched cells. Lymph node T cells freshly taken from antigen-primed animals were also found to proliferate when cultured with purified B cells and the appropriate antigen. Thus, small resting B cells can function as APC to a variety of T cells. This APC function was easily measured when the cells were irradiated with 1,000 rads, but was greatly diminished or absent when they were irradiated with 3,300 rads. Thus, the failure of some other laboratories to observe this phenomenon may be the result of the relative radiosensitivity of the antigen-presenting function of the B cells. In addition, this radiosensitivity allowed us to easily distinguish B cell antigen presentation from presentation by the dendritic cell and macrophage, as the latter was resistant to 3,300 rads. Finally, one T cell clone that failed to proliferate when B cells were used as APC was able to recruit allogeneic B cells to proliferate in the presence of syngeneic B cells and the appropriate antigen. This result suggests that there are at least two distinct pathways of activation in T cells, one that leads to T cell proliferation and one that leads to the secretion of B cell recruitment factor(s).

The frequency of murine B lymphocytes that respond to antibodies directed against membrane IgM was measured. These anti-mu antibodies induced all, or almost all, resting B cells to enlarge over the first 24 h of stimulation. This probably represents the transition from the resting state (G0) to active transit through the cell cycle. In contrast, only a fraction of these cells, approximately 60% for BDF1 mice, continued through the cell cycle into S phase. This is consistent with previous experiments that had suggested there were some types of B cells that did not proliferate in response to anti-mu. The results presented here demonstrate that many, perhaps all, of these nonresponding B cells, both from normal mice and from mice with the xid defect, actually do respond to the presence of anti-mu by going through early parts of the cell cycle. These cells appear to become blocked at some point before the beginning of S phase, perhaps requiring a signal from a T cell or a macrophage to continue through the cell cycle. Thus, the role of antigen may be to prepare all B cells for proliferation. Different subpopulations of B cells may then require different regulatory signals before actually proliferating or before differentiating into antibody-secreting cells.

Resting B lymphocytes are activated, proliferate, and differentiate into antibody-secreting cells when cultured with long-term lines of major histocompatibility complex (MHC)-restricted, antigen-specific T cell in the presence of the antigen for which the T cells are specific. Under optimal conditions, essentially all B cells are activated and approximately 35% enter S phase in the absence of antigens for which the B cells are specific. Activation and proliferation are observed in cells from both normal mice and mice with the xid-determined immune defect. Highly purified B cells bearing Ia molecules for which the T cells are "cospecific" can present antigen to T cells with the resulting T cell stimulation leading to the activation and proliferation of the antigen-presenting B cells. However, B cells that do not bear Ia molecules for which the T cells are cospecific are also activated and proliferate if antigen and a source of antigen-presenting B cells or macrophage-rich cells of proper histocompatibility type are present. Thus, resting B cells, both normal and "xid", can be activated by non-MHC restricted factors without receptor cross-linkage. Experiments are presented that support the concept that local production and action of such unrestricted activating factors may be responsible for the MHC-restriction of T cell-B cell interaction seen in many circumstances.

Abstract Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with adiposity. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively. Linear mixed models were used to estimate the effect of the interventions on circulating proteins. Twenty-three proteins were altered in a consistent direction after both bariatric surgery and caloric restriction, suggesting that these proteins are modulated by weight change, independent of intervention type. We also integrated Mendelian randomisation (MR) estimates of the effect of BMI on proteins measured by SomaLogic from a UK blood donor cohort as a third line of causal evidence. These MR estimates provided further corroborative evidence for a role of BMI in regulating the levels of six proteins including alcohol dehydrogenase-4, nogo receptor and interleukin-1 receptor antagonist protein. These results indicate the importance of triangulation in interrogating causal relationships; further study into the role of proteins modulated by weight in disease is now warranted.

Abstract Introduction Essentially all women and babies irrespective of their economic and social status should reach their full potential for health and well-being. The study assessed the readiness of mothers and their preparedness for birth across three disadvantaged rural districts in Ghana. Methods A multi-centre quantitative survey from January to December 2018 using a multistage sampling approach was employed. Using a structured questionnaire data from mothers attending antenatal and postnatal clinics in three main ecological zones of Ghana were collected. Women who provided informed consent were consecutively recruited until the sample size was achieved. For categorical data, summary tables, proportions and percentage are presented. Multivariate logistic regression analysis determined the effect of selected characteristics on birth preparedness. Ethics approval was obtained from the Navrongo Health Research Centre. Results A total of 1058 mothers were enrolled: 33.6%, 33.4% and 33.0% respectively from the Ada west, Upper Denkyira west and Builsa south districts. About 94% of the women had prior knowledge of birth preparedness. Approximately 22.6% (95%CI 20.1, 25. 2) of the mothers were assessed to have poor birth preparedness: 8.0% in Builsa south, 27.8% in Ada west and 31.7% in Upper Denkyira west. Prenatal and postnatal data showed no statistically significant difference in poor preparedness (21.9% vs 23.3%; p-value > 0.05). Maternal age, employment status, religious affiliation and parity were not associated with birth preparedness (p-value > 0.05). Area of study (P

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high – that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

BackgroundNeuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients.Methods27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments.Results13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all.ConclusionsOur prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.

Introduction: Environmental exposures, such as ambient air pollution and household fuel use affect health and under-5 mortality (U5M) but there is a paucity of data in the Global South. This study examined early-life exposure to ambient particulate matter with a diameter of 2.5 µm or less (PM2.5), alongside household characteristics (including self-reported household fuel use), and their relationship with U5M in the Navrongo Health and Demographic Surveillance Site (HDSS) in northern Ghana. Methods: We employed Satellite-based spatiotemporal models to estimate the annual average PM2.5 concentrations with the Navrongo HDSS area (1998 to 2016). Early-life exposure levels were determined by pollution estimates at birth year. Socio-demographic and household data, including cooking fuel, were gathered during routine surveillance. Cox proportional hazards models were applied to assess the link between early-life PM2.5 exposure and U5M, accounting for child, maternal, and household factors. Findings: We retrospectively studied 48,352 children born between 2007 and 2017, with 1872 recorded deaths, primarily due to malaria, sepsis, and acute respiratory infection. Mean early-life PM2.5 was 39.3 µg/m3, and no significant association with U5M was observed. However, Children from households using “unclean” cooking fuels (wood, charcoal, dung, and agricultural waste) faced a 73 % higher risk of death compared to those using clean fuels (adjusted HR = 1.73; 95 % CI: 1.29, 2.33). Being born female or to mothers aged 20–34 years were linked to increased survival probabilities. Interpretation: The use of “unclean” cooking fuel in the Navrongo HDSS was associated with under-5 mortality, highlighting the need to improve indoor air quality by introducing cleaner fuels.

Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in “kick and kill” strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the “kick” rather than the “kill” arm of this HIV cure approach.

Abstract Background Routine program data indicates positivity rates under 2% from HIV testing services (HTS) at sites supported by Centre for Health Solutions-Kenya in Central Kenya. Achieving the UNAIDS 95:95:95 goals requires continuous identification of people living with HIV in an environment of diminishing resources. We assessed non-clinical and clinical characteristics of persons who tested HIV-positive aimed at improving the process of HTS through Provider-Initiated HIV Testing & Counseling (PITC). Methods We conducted a retrospective analysis of routine PITC program data collected between October 2018 and September 2019 from six health facilities located in three counties in central Kenya. Stratification was based on county and facility volume. A multivariable logistic regression model, clustered adjusted for facility using robust standard errors, was used to determine predictors of a positive HIV result. Results The total sample was 80,693 with an overall positivity rate of 1.2%. Most, (65.5%), were female and 6.1% were

Abstract Introduction Mental health problems are a considerable public health issue and spending time in nature has been promoted as a way to access a range of psychological benefits leading to the development of nature‐based interventions for people with severe and enduring mental health problems. Less, however, is understood about the potential benefits and efficacy of day‐to‐day routine access to outdoor green and blue spaces for mental health service users. Methods Using a mixed‐methods design between April and October 2021, we explored the benefits and barriers to spending time outdoors with a purposive sample of mental health service users (N = 11) using qualitative interviews and an online general population survey (N = 1791). Qualitative evidence highlighted the restorative benefits of nature and identified a number of barriers associated with fears around personal safety, social anxiety, fatigue and lack of motivation. COVID‐19 had also restricted access to green and blue spaces. Having social contact and support encouraged people to spend time outdoors. In the quantitative survey, self‐report and standardised measures (the Patient Health Questionnaire and the Warwick–Edinburgh Wellbeing Scale) were used to assess past and current mental wellbeing. Findings Statistically significant differences were found between wellbeing and the use of green and blue spaces. Those with mental health problems spent time outdoors because they: felt guilty; wanted to reduce their anxiety; or rely on someone for encouragement. Those without mental health problems endorsed more positively framed reasons including relaxation, improving physical health or getting exercise. Barriers for people with mental health problems involved safety concerns, feeling anxious and having a poor self‐image. These findings give insight into motivations for an outdoor activity to help inform the design of public mental health interventions. Conclusion Further work is required to improve access and safety to promote the benefits of green and blue spaces for everyone. Patient or Public Contribution The research team included expert experienced researchers with a mental health service provider (Praxis Care) and they were involved in the development of the research idea, funding application, design, data collection, analysis, writing up and dissemination activities.

Abstract In this paper, we present the results of lab and pilot-scale testing of a continuously enhanced backscattering, or Rayleigh enhanced fiber cable that can improve distributed acoustic sensing performance. In addition, the Rayleigh-enhanced fiber is embedded within a tight buffered cable configuration to withstand and be compatible for field applications. The sensing fiber cable exhibits a Rayleigh enhancement of 13 dB compared to standard silica single-mode fiber while maintaining low attenuation of ≤ 0.4 dB/km. We built a phase-sensitive optical time domain reflectometry system to interrogate the enhanced backscattering fiber cable both in lab and pilot-scale tests. In the laboratory experiment, we analyzed the vibration performance of the enhanced backscattering fiber cable and compared it with the standard single-mode telecom fiber. Afterward, we field validated for natural gas pipeline vibration monitoring using a 4-inch diameter steel pipeline operating at a fixed pressure level of 1000 psi, and a flow rate of 5, 10, 15, and 20 ft/s. The feasibility of gas pipeline monitoring with the proposed enhanced backscattering fiber cable shows a substantial increase in vibration sensing performance. The pilot-scale testing results demonstrated in this paper enable pipeline operators to perform accurate flow monitoring, leak detection, third-party intrusion detection, and continuous pipeline ground movement.

Surgery of the aortic arch remains a complex procedure, with neurological events such as stroke remaining its most dreaded complications. Changes in surgical technique and the continuous innovation in neuroprotective strategies have led to a significant decrease in cerebral and spinal events. Different modes of cerebral perfusion, varying grades of hypothermia, and a number of pharmacological strategies all aim to reduce hypoxic and ischemic cerebral injury, yet there is no evidence indicating the clear superiority of one method over another. While surgical results continue to improve, novel hybrid and interventional techniques are just entering the stage and the question of optimal neuroprotection remains up to date. Within this perspective statement, we want to shed light on the current evidence and controversies of cerebral protection in aortic arch surgery, as well as what is on the horizon in this fast-evolving field. We further present our institutional approach as a large tertiary aortic reference center.

In recent years, there has been many efforts to establish a comprehensive theoretical framework explaining the working mechanisms involved in perception-action integration. This framework stresses the importance of the immediate past on mechanisms supporting perception-action integration. The present study investigates the neurophysiological principles of dynamic perception-action bindings, particularly considering the influence of the immediate history on action control mechanisms. For this purpose, we conducted an established stimulus-response binding paradigm during EEG recording. The SR-task measures stimulus-response binding in terms of accuracy and reaction time differences depending on the degree of feature overlap between conditions. Alpha, beta and theta band activity in distinct time domains as well as associated brain regions were investigated applying time-frequency analyses, a beamforming approach as well as correlation analyses. We demonstrate, for the first time, interdependencies of neuronal processes relying on the immediate past. The reconfiguration of an action seems to overwrite immediately preceding processes. The analyses revealed modulations of theta (TBA), alpha (ABA) and beta band activity (BBA) in connection with fronto-temporal structures supporting the theoretical assumptions of the considered conceptual framework. The close interplay of attentional modulation by gating irrelevant information (ABA) and binding and retrieval processes (TBA) is reflected by the correlation of ABA in all pre-probe-intervals with post-probe TBA. Likewise, the role of BBA in maintaining the event file until retrieval is corroborated by BBA preceding the TBA-associated retrieval of perception-action codes. Following action execution, TBA shifted towards visual association cortices probably reflecting preparation for upcoming information, while ABA and BBA continue to reflect processes of attentional control and information selection for goal-directed behavior. The present work provides the first empirical support for concepts about the neurophysiological mechanisms of dynamic management of perception and action.

Summary: Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Summary: Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value

Abstract Background Critically unwell babies in intensive care units may develop acute renal failure. Options for renal replacement therapy are limited by their small size and available technology. Objectives To determine the clinical efficacy, outcomes and safety profile of the NIDUS® (a novel infant haemodialysis device) for babies under 8 kg, compared with current renal replacement therapy. Design A clinical investigation using a non-blinded cluster stepped wedge design with paediatric intensive care units randomised to sequences. Setting Paediatric intensive care units in six UK hospitals. Participants Children under 8 kg who required renal replacement therapy for fluid overload or biochemical disturbance. Interventions Continuous renal replacement therapy was provided by the usual methods: peritoneal dialysis and continuous haemofiltration (during control periods) and by the NIDUS (during intervention periods), a novel device designed for babies with a smaller circuit and filter and volumetric control of ultrafiltration. Main outcome measures Primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances, accuracy of reported ultrafiltration and mortality. Data sources Bedside study data collected by weighing bags of fluid entering and leaving the device were entered into the study database along with case descriptors. Some secondary outcome data was collected via the Paediatric Intensive Care Audit Network. Results Ninety-seven participants were recruited by study closure, 62 to control and 35 to intervention. The primary outcome was obtained from 62 control but only 21 intervention patients, largely because of technical difficulties using NIDUS. The analysis comparing the available primary outcomes showed that ultrafiltration with NIDUS was closer to that prescribed than with control: standard deviations controls 18.75, intervention 2.95 (ml/hour), adjusted ratio 0.13, 95% confidence interval (0.03 to 0.71); p = 0.018. The mean clearances for creatinine, urea and phosphate were lower on peritoneal dialysis than NIDUS, which were in turn lower than continuous veno-venous haemofiltration. The variability in the clearances was in the same order. Of the 62 control patients, 10 died (2/62 on peritoneal dialysis; 7/13 on continuous haemofiltration) before discharge from paediatric intensive care unit (16%), compared with 12 out of 35 (34%) in the NIDUS group: p = 0.04, 95% confidence interval for difference (0 to 36%). Harms No important adverse events occurred and the NIDUS has an acceptable safety profile compared with other renal replacement therapies in this critically ill population with multi-organ failure. Mortality was lowest for Peritoneal Dialysis, highest for continuous haemofiltration, with the NIDUS in-between. Only one serious adverse device event which was reported to the Medicines and Healthcare products Regulatory Agency. Conclusions NIDUS works effectively, delivering appropriate blood clearances and accurate, controllable fluid removal (ultrafiltration), indicating that it has an important place alongside other dialysis modalities for infant renal replacement therapy. Future work Findings from this study indicate some modifications are required to NIDUS to improve usability. Further studies on use of the NIDUS device in other populations of babies for example those with chronic renal failure, and long-term outcomes are required. Trial registration This trial is registered as ISRCTN 13787486. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 14/23/26) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 1. See the NIHR Funding and Awards website for further award information. Plain language summary Why do this study? Some children in intensive care are so poorly that their kidneys do not work well, and they need help, called dialysis, to get rid of fluid and chemicals from their blood. For babies, we currently use peritoneal dialysis, where fluid is cycled in and out of the tummy, or adapted machines designed for bigger children (continuous veno-venous haemofiltration). A new machine, the NIDUS® (Allmed, www.allmedgroup.com), was developed specifically for babies weighing under 8 kg with much smaller tubing. NIDUS worked well when studied in Newcastle but needed testing elsewhere. What was the question? How well does NIDUS work compared to other dialysis methods? What are the problems? What did we do? The study was done in six paediatric intensive care units who used their usual dialysis methods (=control) in the first part of the study and then later swapped to using the NIDUS (=intervention). What did we find? We recruited 97 participants, 62 to control (49 peritoneal dialysis, 13 continuous veno-venous haemofiltration) and 35 intervention (NIDUS). We found NIDUS provided much better control of fluid removal. The CVVH machines were more efficient at blood cleaning than NIDUS, which was better than peritoneal dialysis. What does this mean? We learnt a lot about babies needing kidney support in paediatric intensive care units and that all methods have advantages and disadvantages. We showed that NIDUS could be very useful for some participants because it cleans blood effectively and gives accurate, controllable fluid removal. We have gathered important information to help us improve NIDUS to make it easier to use and run. Many parents responded to our questionnaire and most told us they felt it was acceptable to be approached about taking part in research despite the circumstances. This is very important for future research studies. We are very grateful to families for their generosity in becoming involved in this study. Scientific summary Background Critically unwell babies in paediatric intensive care units (PICUs) may develop acute renal failure and require management with renal replacement therapy. Although mortality and morbidity vary and are related to the underlying diagnosis, survival of babies in paediatric intensive care is worse for those with fluid overload. Babies requiring renal replacement treatment present specific therapeutic challenges because of their small size and the current technology available. Difficulties with vascular access and blood flows, fluid balance, loss of circuits, filter clotting and hypotensive episodes at initiation are all described in the literature. The need for new solutions and improved technology is well recognised. Continuous veno-venous haemofiltration (CVVH) machines in use in the UK at the time of this study are not approved for use in babies weighing 80%) were similar. The median (IQR) age in controls 10.5 (7, 38) days was similar to that in the intervention group 11 (7, 61) days; the range of age of participants was between 1 and 477 days (approximately 15 months). The median (IQR) weights 3.2 (2.9, 3.9) and 3.7 (3.1, 5.6) kg were similar between control and intervention. Availability of primary outcome The primary outcome was available on all 62 control patients but only 21 of the 35 intervention patients. This was due to a range of reasons including difficulties in obtaining the information needed to compute the UF rate (accurate timing and weighing data) and technical difficulties using the NIDUS: full details are in the report. Precision of UF Analysis comparing the 62 control patients with the 21 intervention patients with a primary outcome showed that UF with the NIDUS was closer to that prescribed than with control: standard deviations (SDs) controls 18.75, intervention 2.95 (ml/hour), adjusted ratio 0.13, 95% confidence interval (0.03 to 0.71); p = 0.018. For the NIDUS and CVVH devices, an important measure was to compare the difference between the actual fluid removal measured and that reported by the device. This had a mean closer to zero for the NIDUS than CVVH (means −0.44 vs. 11.6 ml/hour, respectively), with less variation in NIDUS than CVVH (SDs 3.2 vs. 28.4 ml/hour). Biochemical clearances The initial intention was to compare clearance rate on NIDUS with the control group. However, for these variables combining PD and CVVH in this way proved to be misleading because NIDUS clearances rates were intermediate between those of PD and CVVH. The clearance for creatinine on PD was smaller and less variable (mean 0.08, SD 0.03 ml/min/kg) than on the NIDUS (mean 0.46, SD 0.30 ml/min/kg), which was in turn smaller and less variable than for CVVH (mean 1.20, SD 0.72 ml/min/kg). The pattern was repeated for urea: PD (0.12, 0.06), NIDUS (0.48, 0.30) and CVVH (1.15, 0.67), all in ml/min/kg, and also for phosphate: PD (0.07, 0.04), NIDUS (0.44, 0.27) and CVVH (1.16, 0.71), all in ml/min/kg. All pairwise treatment comparisons of means and of SDs gave p

ObjectivesTo date, there is no evidence regarding the safety of automated titanium fastener compared with hand-tied knots for prosthesis fixation in infective endocarditis.MethodsBetween January 2016 and December 2022, a total of 220 patients requiring surgery for infective endocarditis were included in this retrospective analysis. The primary study endpoint was re-endocarditis during follow-up. The secondary study endpoints included stroke onset, all-cause mortality, and a composite outcome of either re-endocarditis, stroke, or all-cause mortality during follow-up.ResultsSuture-securing with an automated titanium fastener was performed in 114 (51.8%) patients, whereas the conventional technique of hand knot-tying was used in 106 (48.2%) patients. The risk of re-endocarditis was significantly lower in the automated titanium fastener group, as shown in a multivariable proportional competing risk regression model (adjusted sub-hazard ratio 0.33, 95% confidence interval 0.11–0.99, p = 0.048). The multivariable Cox proportional hazards regression analysis showed that the automated titanium fastener group was not associated with an increased risk of stroke-onset or attaining the composite outcome, respectively, (adjusted hazard ratio 0.54, 95% confidence interval 0.27–1.08, p = 0.082), (adjusted hazard ratio 0.65, 95% confidence interval 0.42–1.02, p = 0.061). Also, this group was not associated with an increased risk of all-cause mortality, as demonstrated in the multivariable Poisson regression analysis (adjusted incidence-rate ratio 1.42, 95% confidence interval 0.83–2.42, p = 0.202).ConclusionsThe use of automated titanium fastener device seems to be safe for infective endocarditis. Analyses of larger cohorts are required.

Abstract Goal-directed behavior requires integrated mental representations of perceptions and actions. The neurophysiological underpinnings of these processes, however, are not yet understood. It is particularly undetermined, which oscillatory activities in which brain regions are involved in the management of perception-action representations. We examine this question with a focus on response inhibition processes and show that the dynamics of perception-action representations reflected in theta band activity (TBA) are particularly evident in the supplementary motor area and the occipito-temporal cortex. Mental representations coded in alpha band activity (ABA) during perception-action integration are associated with the occipito-temporal cortex. Crucially, perception-action representations are exchanged between theta and alpha frequency bands. The results imply that ABA functions as dynamic top-down control over binding, retrieval and reconfiguration processes during response inhibition, which in turn are reflected by TBA. Our study thus highlights how the interplay of oscillatory activity enables the management of perception-action representations for goal-directed behavior.

(Series Information) European Papers - A Journal on Law and Integration, 2023 8(1), 81-84 | European Forum Highlight of 16 May 2023 | (Abstract) German-speaking scholarship on EU law is coined, to a significant extent, by relevant decisions of constitutional courts in German-speaking countries. The translation of these decisions into other languages contributes strongly to broaden the legal discourse, as it allows also non-German-speaking members of the scientific community or of courts in other Member States to read and to reflect upon them. Against this background, in this Highlight we take a look at the translation policy of the German Bundesverfassungsgericht (BVerfG) and the Austrian Verfassungsgerichtshof (VfGH). For the sake of comparison, we also take a look at how the French Conseil constitutionnel (CC) – as an example for a constitutional court of a non-German-speaking Member State – approaches this question. While in all three cases the number of provided translations has increased considerably over the past 25 years, it turns out that the BVerfG and the VfGH translate mostly into English. The CC, however, does not only translate (proportionally) more decisions, but also it translates them into different languages, very prominently into German, thereby inviting German-speaking scholarship and German-speaking judges to take account of it. The provision of translations by courts seems to be more than a service to ‘interested third parties’. It turns out to be a tool to pursue the specific interests of a court as well.

Abstract Background Most studies investigating the association between physical activity (PA) and the risk of type 2 diabetes are derived from self-reported questionnaires, with limited evidence using device-based measurements. Therefore, this study aimed to investigate the dose–response relationship between device-measured PA and incident type 2 diabetes. Methods This prospective cohort study included 40,431 participants of the UK Biobank. Wrist-worn accelerometers were used to estimate total, light, moderate, vigorous and moderate-to-vigorous PA. The associations between PA and incident type 2 diabetes were analysed using Cox-proportional hazard models. The mediating role of body mass index (BMI) was tested under a causal counterfactual framework. Results The median follow-up period was 6.3 years (IQR: 5.7–6.8), with 591 participants developing type 2 diabetes. Compared to those achieving 600 min/week were at 49% (95% CI 62–32%), 62% (95% CI 71–50%) and 71% (95% CI 80–59%) lower risk of type 2 diabetes, respectively. For vigorous PA, compared to those achieving 75 min/week were at 38% (95% CI 48–33%), 48% (95% CI 64–23%) and 64% (95% CI 78–42%) lower type 2 diabetes risk, respectively. Twelve per cent and 20% of the associations between vigorous and moderate PA and type 2 diabetes were mediated by lower BMI, respectively. Conclusions PA has clear dose-response relationship with a lower risk of type 2 diabetes. Our findings support the current aerobic PA recommendations but suggest that additional PA beyond the recommendations is associated with even greater risk reduction. Trial registration The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (Ref 11/NW/0382 on June 17, 2011).

Abstract Identifying systems failures and contributing to a safety culture is the Association of American Colleges (AAMC’s) thirteenth Entrustable Professional Activity (EPA). While most curricula teach Patient Safety (PS) and Quality Improvement (QI) principles, student participation in live QI/PS activities remains limited. This workshop enabled late Clerkship phase students to apply these Health Systems Science (HSS) principles to real adverse patient event cases through team-based simulation. This 3-h capstone included both a didactic review of QI, PS, and TeamSTEPPS® tools and an experiential component where student-led interactive small group discussions were augmented by resident and faculty preceptors. Collaboratively, students composed an adverse patient event report, conducted a Root Cause Analysis (RCA) during role-play, and proposed error prevention ideas after identifying systems problems. In April 2020, the in-person workshop became fully virtual due to the COVID-19 pandemic. A statistically significant increase in ability to identify Serious Safety Events, Escalation Chain of Command, and define a Plan-Do-Study-Act (PDSA) cycle was observed. Comfort with RCA increased from 48 to 87% and comfort with TeamSTEPPS® principles increased from 68% to 85.5% This novel capstone provided students with the tools to synthesize HSS concepts through problem-solving processes and recognize EPA 13’s importance. Their increased capability to identify appropriate chain of command, escalate concerns, and recognize serious adverse patient events also has training and practice readiness implications.

Abstract Background This paper reports on results of a health system strengthening implementation research initiative conducted the Upper East Region of northern Ghana. Transformative interventions to accelerate and strengthen the health delivery were implemented that included empowering community leaders and members to actively participate in health delivery, strengthening the referral systems through the provision of community transport systems, providing basic medical equipment to community clinics, and improving the skills of critical health staff through training. Methods A mixed method design was used to evaluate the impact of the interventions. A quantitative evaluation employed a flexible research design to test the effects of various component activities of the project. To assess impact, a pre-versus–post randomized cluster survey design was used. Qualitative research was conducted with focus group data and individual in depth interviews to gauge the views of various stakeholders associated with the implementation process. Results After intervention, significant improvements in key maternal and child health indicators such as antenatal and postnatal care coverage were observed and increases in the proportion of deliveries occurring in health facilities and assisted by skilled health personnel relative to pre-intervention conditions. There was also increased uptake of oral rehydration salts (ORS) for treatment of childhood diarrhoea, as well as marked reductions in the incidence of upper respiratory infections (URI). Conclusions A pre-and post-evaluation of impact suggests that the programme had a strong positive impact on the functioning of primary health care. Findings are consistent with the proposition that the coverage and content of the Ghana Community-based Health Planning and Services programme was improved by program interventions and induced discernable changes in key indicators of health system performance.

The European mining bee species Andrena lathyri (Andrenidae) is a narrow specialist of flowers of Lathyrus and Vicia (Fabaceae), from which both females and males gain nectar by primary nectar robbing. Both sexes are equipped with a unique proboscis, which is much longer and more strongly angled than in most other Andrena bees including the most closely related species. The comparison between the shape of the proboscis and the interior of the host flowers combined with field observations revealed that the specialised mouthparts of A. lathyri precisely correspond to the dimensions of the flower interior and the position of the nectary, representing one of the few known examples of a morphological adaptation to primary nectar robbing in bees. For nectar uptake, the bee’s head is inserted laterally under the standard petal before it is moved towards the flower base, thereby slitting the calyx longitudinally to a depth necessary to reach the nectary from inside the flower with the specialised proboscis. Nectar-robbing individuals of A. lathyri are able to adapt their behaviour to the different calyx lengths of their host flower species by slitting the calyx over varying distances. Except for the slit in the calyx, primary nectar robbing by A. lathyri does not damage any flower parts allowing for normal fruit development.

Abstract High-dose alcohol intoxication reduces cognitive control, including inhibition. Although inhibition deficits may contribute to the behavioral deficits commonly observed in alcohol use disorder (AUD), many questions about potentially modulating factors have remained unanswered. We examined the effects of experimentally induced high-dose alcohol intoxication (~ 1.1 ‰) on the interplay between controlled vs. automatic response selection and inhibition in healthy young men. A holistic EEG-based theta activity analysis that considered both reactive control during task performance and preceding proactive control processes was run. It revealed a previously unknown seesaw relationship, with decreased reactive control, but paradoxically increased proactive control. Most importantly, alcohol-induced increases in proactive occipital theta band power were associated with reductions in negative alcohol effects on reactive control processes associated with decreased activity in the SMA and medial frontal cortex. Our findings demonstrate that research should not solely focus on immediate effects during task performance. Aside from differential neurobiochemical and neuroanatomical effects of alcohol, it is also conceivable that proactive control may have been recruited in a (secondary) response to compensate for alcohol-induced impairments in reactive control. Against this background, it could be promising to investigate changes in such compensatory mechanisms in pronounced alcohol-associated inhibition deficits, like in AUD patients.

Background: The multisystem associations between baseline mental health status and coronavirus disease-19 (COVID)-19 illness trajectory are uncertain. Objectives: This article will investigate the associations between baseline mental health status and disease trajectory following COVID-19 hospitalization, which may have implications for practice and future research. Methods: The Chief Scientist Office Cardiovascular and Pulmonary Imaging in severe acute respiratory syndrome (SARS) COVID-19 study is a prospective, observational, multicenter, longitudinal, secondary care cohort study that assessed the time-course of multi-organ injury in posthospital survivors of COVID-19. Patients were assessed in-hospital, at 28–60 days after discharge and in the longer term using electronic health record linkage. Results: One hundred and fifty-two patients (mean ± standard deviation [SD] age 54.3 ± 11.8 years, 43% female, 40% most socio-economically deprived quintile, 33% history of mental health history) were enrolled and had mental health serially assessed using the Patient Health Questionnaire-4 (PHQ-4) questionnaire. Fifty-three (35%) had PHQ-4 score of 6–12 consistent with moderate-severe symptoms of anxiety or depression and this was associated with diagnostic criteria for myocarditis (P = 0.0498). Moderate-severe symptoms of anxiety or depression were positively associated with higher perception of illness, lower health-related quality of life (HRQoL), and poorer physical function. The mean (SD) duration of follow-up after hospital discharge was 428 (86) days (range, 290–627 days). PHQ-4 score was not associated with clinical outcomes at follow-up. Conclusions: In patients who have been hospitalized with COVID-19, moderate-severe symptoms of anxiety or depression were associated with myocarditis, worse HRQoL, higher perception of illness, and lower levels of physical function. Public Registration: ClinicalTrials.gov identifier is NCT04403607.

Summary: Background: Studies from Guinea-Bissau and Bangladesh have shown that campaigns with oral polio vaccine (C-OPV) may be associated with 25–31% lower child mortality. Between 1996 and 2015, Ghana had 50 national C-OPVs and numerous campaigns with vitamin A supplementation (VAS), and measles vaccine (MV). We investigated whether C-OPVs had beneficial non-specific effects (NSEs) on child survival in northern Ghana. Methods: We used data from a health and demographic surveillance system in the Navrongo Health Research Centre in rural northern Ghana to examine mortality from day 1–5 years of age. We used Cox models with age as underlying time scale to calculate hazard ratios (HR) for the time-varying covariate “after-campaign” mortality versus “before-campaign” mortality, adjusted for temporal change in mortality, other campaign interventions and stratified for season at risk. Findings: From 1996 to 2015, 75,610 children were followed for 280,156 person-years between day 1 and 5 years of age. In initial analysis, assuming a common effect across all ages, we did not find that OPV-only campaigns significantly reduced all-cause mortality, the HR being 0.96 (95% CI: 0.88–1.05). However, we subsequently found the HR differed strongly by age group, being 0.92 (0.75–1.13), 1.29 (1.10–1.51), 0.79 (0.66–0.94), 0.67 (0.53–0.86) and 1.03 (0.78–1.36) respectively for children aged 0–2, 3–5, 6–8, 9–11 and above 12 months of age (p

In this photo-theoretical article I interrogate portraits generated by NIVIDIA’s StyleGAN2. Even though these portraits are completely artificial and the pictured persons have never existed, they are surprisingly realistic and could even be read as photographs. I therefore ask the question: How do these pictures relate to the photographic and can we consider them as a new aspect of the medium? I will also present an attempt to locate these images on the Internet and discuss how they are used today. The result of this experiential localization shows that the pictures are mostly used in dubious and even criminal ways.

Introduction Recurrent infarcts to the internal carotid artery territory in the setting of a corresponding occlusion raises concern for carotid stump syndrome. Over time, robust anastomoses may develop between the patent ipsilateral external carotid artery and the anterior circulation distal to the site of occlusion. A carotid stump’s disturbance of flow uncommonly can form emboli that travel via retrograde flow from the occluded internal carotid artery to the ipsilateral external carotid artery and its collaterals. Stenosis of the external carotid artery in such patients can be a source of atheroembolism or hypoperfusion. We describe a case of external carotid stenting with carotid stump coil occlusion. Methods We present a case report. Verbal consent to share this information was obtained directly from the patient. Results A 75‐year‐old man with aortic stenosis, atrial arrhythmia, multiple prior bi‐hemispheric strokes, on aspirin and clopidogrel, presented with left facial droop, arm weakness, and slurred speech. Magnetic resonance imaging revealed embolic appearing strokes in the right middle cerebral artery territory (Figure 1A). Cerebral angiography revealed complete occlusion of the right internal carotid artery with perfusion of the right middle cerebral artery by external carotid artery anastomoses, and the external carotid was found to be stenosed proximally. Digital subtraction angiography revealed right external carotid – middle cerebral artery anastomoses via the right sphenopalatine artery, middle meningeal artery, internal maxillary artery, and ophthalmic collaterals (Figure 1B). The patient underwent coiling of the right internal carotid artery stump (Figure 1C) followed by stenting of the right external carotid using a 9 mm x 40 mm Cordis precise Pro stent. Post‐stenting angiogram demonstrated good apposition of the stent to the parent vessel walls and improvement of flow into the right external carotid and intracranial circulation (Figure 1D). The patient was treated with aspirin and ticagrelor for 3 months. Repeat imaging at follow up did not show further embolic episodes, with improvement in the patient’s deficits. After three months, he was continued on aspirin alone. Conclusion In patients with an occluded internal carotid artery and recurrent embolic infarcts ipsilateral to the side of the occlusion, carotid stump syndrome may be considered. In this case, we believe the patient’s carotid occlusion served as a nidus for emboli formation, or that there was atheroembolism from the stenosed external carotid artery despite adherence to dual antiplatelet therapy. By coiling the stump, we addressed a possible source of emboli, and stenting of the proximal external carotid optimized anterograde flow and prevented further atheroembolism. Our case showcases an interventional neuroradiology approach to carotid stump emboli and external carotid artery stenosis.

Objective: To describe a rare congenital deformity of the phalanges and the surgical details and outcome in a dog with ectrodactyly combined with polydactyly. Study design: Single case report. Animal: A 3.5-month-old male intact mixed breed dog with forelimb lameness and paw malformations. Methods: Surgery was performed on a dog with a congenital limb deformity consisting of resection of the extra bone and soft tissue structure to prevent further subluxation of the remaining metacarpals. Stabilisation consisted of a cortical screw in compression and a K wire across the proximal metacarpals. Results: Postoperative radiographs showed adequate implant positioning and good reduction of the proximal metacarpal row. At six weeks, the dog showed improvement in limb function and weight bearing. Major complications occurred at twelve weeks, and revision surgery with implant removal was required. At six months, the dog showed near normal range of motion and no lameness. Conclusions and Clinical Relevance: The decision to perform surgery on a dog with limb deformity resulted in an almost physiological gait, and the dog showed no abnormalities in daily life. This report adds to the literature on congenital limb deformities by describing the combination of ectrodactyly and polydactylism in a canine species, including the surgical approach and outcome. However, the optimal management of this heterogeneous condition is currently unclear.

A sleeper, or more generally a “bearer”, moves vertically under a passing train load. The extent of this motion depends on the static and dynamic load of the train, the train speed, and the support conditions at the bearer and its neighbours. Excessive motion, typically from voiding see-sawing, low support stiffness or possibly excessive stiffness, or even too little stiffness, are all of interest to maintainers. Typically, problems arise around transition zones, switches and crossings, but plain track with poor support can also be a problem. Within the last decade, low-cost micro-electro-mechanical system (MEMS) accelerometers have been used to capture the time history of vertical motion for use in condition monitoring. Existing condition monitoring systems often overlook or sometimes even ignore the possibility of problematic data, which seem to be common in monitored locations. It is essential to understand whether such “bad” data require further attention. Three problematic sites are presented, focussing on examples where the acceleration was higher than expected or the computed displacement was not as expected. Potential causes include wheel defects, hammering of the ballast by a hanging bearer, or high acceleration at some structural resonant frequency. The present paper aims to show the challenges of using MEMS accelerometers to collect data for condition monitoring and offers insights into the sort of problematic data that may be collected from real sites.

Plain English summary Making your own decisions is important. There are disabled people who need support to make some decisions. Supporting disabled people to make decisions is needed so that they are not excluded from society. However, the evidence is limited on disabled people’s experiences of how best to support decision-making. This article will explore the experiences of four researchers with mental health problems or an intellectual disability who worked with other researchers to conduct a project on how people have, or have not been, supported to make their own decisions. These researchers are called peer researchers. The peer researchers interviewed 21 people with mental health problems and 20 people with an intellectual disability. These interviews were conducted in order to gain a detailed understanding of the experiences and preferences for how decision-making should be supported. Blogs written by the peer researchers, discussions in team meetings and a workshop at the end of the study enabled the peer researchers to reflect on their experiences. The peer researchers reported a number of positive effects of being involved in the research project which included improvements in skills and self-confidence. The peer researchers’ involvement challenged assumptions about the inability of people with an intellectual disability and/or mental health problems to participate in a research project whilst also highlighting the importance of training for all team members.

Abstract Background Whether women’s physical function in mid-life is related to their reproductive age is not known. The objectives of this study were to examine and compare changes in physical function in women by reproductive age, measured as time since final menstrual period (FMP), and chronological age, and to explore associations with repeatedly assessed levels of reproductive hormones. Methods We used data from 2319 UK women with up to three repeated measurements of physical function (median length of follow up: 2 years), focusing on changes occurring in women experiencing a natural menopausal transition. The main outcome was a composite physical function score that incorporated assessments of strength (grip strength), balance (one-leg stand) and cardiorespiratory fitness (timed chair rises). Associations with time since FMP, age, and time-updated measures of anti-Müllerian hormone, follicle-stimulating hormone and luteinizing hormone were assessed by multilevel models and generalised estimating equations models adjusted for the underlying effects of chronological age and confounding by education, age at first birth and smoking. Results The results showed that, adjusted for these confounders, time since FMP (− 0.21 SD per 10 years, 95% CI − 0.37, − 0.06) and chronological age (− 0.31 SD per 10 years, 95% CI − 0.46, − 0.15) were inversely associated with the physical function composite score. Grip strength seemed to be the main contributor to the decline in the composite score by time since FMP. There was no strong evidence of associations between any of the three reproductive hormones and the composite score. Conclusions Physical function in women in mid-life declined with both chronological and reproductive age. The decline with reproductive age was independent of chronological age but did not seem to be driven by changes in reproductive hormones.

Plain English summary Since the 1970’s, there has been a shift from research on disabled people to research with disabled people. This is often referred to as co-produced research. Co-production has a wide definition but includes disabled people working with academics to produce research and outcomes which neither group could achieve by working in isolation. This paper presents the co-production methodology used to conduct a research project called ‘Getting our Voices Heard’. This project, sought to find the best way to get the voices of people with a learning disability heard inpolicy development in the UK. We explain how this research was carried out, using a co-produced participatory design. We established a research team with professional researchers from a university, who worked with peer researchers. Peer researchers are people who have lived experience of the issue being studied. In this project, we worked with six peer researchers who all had a learning disability. The experiences of the peer researchers, and ways in which the peer researchers were involved at each stage of the project are discussed. The peer researchers described feeling positive about their role and felt involved. We show that working together is important and recommend that additional time and resources are essential for this joint working.

Abstract Diabetic kidney disease is the leading cause of end-stage kidney disease worldwide; however, the integration of high-dimensional trans-omics data to predict this diabetic complication is rare. We develop artificial intelligence (AI)-assisted models using machine learning algorithms to identify a biomarker signature that predisposes high risk patients with diabetes mellitus (DM) to diabetic kidney disease based on clinical information, untargeted metabolomics, targeted lipidomics and genome-wide single nucleotide polymorphism (SNP) datasets. This involves 618 individuals who are split into training and testing cohorts of 557 and 61 subjects, respectively. Three models are developed. In model 1, the top 20 features selected by AI give an accuracy rate of 0.83 and an area under curve (AUC) of 0.89 when differentiating DM and non-DM individuals. In model 2, among DM patients, a biomarker signature of 10 AI-selected features gives an accuracy rate of 0.70 and an AUC of 0.76 when identifying subjects at high risk of renal impairment. In model 3, among non-DM patients, a biomarker signature of 25 AI-selected features gives an accuracy rate of 0.82 and an AUC of 0.76 when pinpointing subjects at high risk of chronic kidney disease. In addition, the performance of the three models is rigorously verified using an independent validation cohort. Intriguingly, analysis of the protein–protein interaction network of the genes containing the identified SNPs (RPTOR, CLPTM1L, ALDH1L1, LY6D, PCDH9, B3GNTL1, CDS1, ADCYAP and FAM53A) reveals that, at the molecular level, there seems to be interconnected factors that have an effect on the progression of renal impairment among DM patients. In conclusion, our findings reveal the potential of employing machine learning algorithms to augment traditional methods and our findings suggest what molecular mechanisms may underlie the complex interaction between DM and chronic kidney disease. Moreover, the development of our AI-assisted models will improve precision when diagnosing renal impairment in predisposed patients, both DM and non-DM. Finally, a large prospective cohort study is needed to validate the clinical utility and mechanistic implications of these biomarker signatures.

There is large potential to increase cycling participation worldwide. Participation in cycling is associated with lower risk of mortality from any cause, and incidence of cardiovascular disease and type 2 diabetes, as well as positive mental health and well-being. The largest potential for health gains likely to come from increasing participation amongst those who do not currently cycle regularly, rather than encouraging those who already cycle regularly to cycle more. Replacing car journeys with cycling can lead to reductions in air pollution emissions and lower pollutant exposure to the general population. Important gaps and uncertainties in the existing evidence base include: the extent to which the health benefits associated with cycling participation are fully causal due to the observational nature of much of the existing evidence base; the real-world economic cost-benefits of pragmatic interventions to increase cycling participation; and the most effective (combination of) approaches to increase cycling participation. To address these uncertainties, large-scale, long-term randomised controlled trials are needed to: evaluate the effectiveness, and cost-effectiveness, of (combinations of) intervention approaches to induce sustained long-term increases in cycling participation in terms of increases in numbers of people cycling regularly and number of cycling journeys undertaken, across a range of population demographic groups; establish the effects of such interventions on relevant outcomes related to health and wellbeing, economic productivity and wider societal impacts; and provide more robust quantification of potential harms of increasing cycling participation, such as collision risks.

Objectives The aim of this study is to look at spatial and temporal trends in undernutrition in children under 5 years age in Burkina Faso.Setting We used data from annual National Nutrition Surveys using Standardised Monitoring and Assessment of Relief and Transitions methodology (anthropometry, morbidity) over 7 years (2012–2018) in Burkina Faso.Participants Children of under 5 years from households selected through systemic sampling at countrywide level.Main outcome measures Prevalence of stunting (height-for-age z-score,

No presente artigo busca-se introduzir uma discussão sobre a unidade da obra musical a partir dos sentidos primordiais propostos pelo filósofo na Metafísica. O problema é: Em que sentido a obra musical pode ser una, considerando os significados primordiais de uno discutidos por Aristóteles? A discussão se inicia em torno da noção de obra musical. A seguir, são introduzidos alguns aspectos do pensamento musical aristotélico para abordar, mais tarde, a continuidade como sentido primordial de unidade e posteriormente desdobrar a contemplação do problema da unidade musical em apontamentos distintos concentrados na noção de variedade e no problema do belo. Por fim, sobre essas bases, também são introduzidas algumas questões relativas ao problema da unidade enquanto valor representado. Espera-se que este trabalho estimule reflexões filosóficas sobre problemas composicionais e contribua na discussão sobre a unidade da obra musical.

Abstract Background Out-of-pocket payment (OOPP) is reported to be a major barrier to seeking maternal health care especially among the poor and can expose households to a risk of catastrophic expenditure and impoverishment.This study examined the OOPPs women made during childbirth in the Upper West region of Ghana. Methods We carried out a cross-sectional study and interviewed women who gave birth between January 2013 and December 2017. Data on socio-demographic characteristics, place of childbirth, as well as direct cost (medical and non-medical) were collected from respondents. The costs of childbirth were estimated from the patient perspective. Logistics regression was used to assess the factors associated with catastrophic payments cost. All analyses were done using STATA 16.0. Results Out of the 574 women interviewed, about 71% (406/574) reported OOPPs on their childbirth. The overall average direct medical and non-medical expenditure women made on childbirth was USD 7.5. Cost of drugs (USD 8.0) and informal payments (UDD 5.7) were the main cost drivers for medical and non-medical costs respectively. Women who were enrolled into the National Health Insurance Scheme (NHIS) spent a little less (USD 7.5) than the uninsured women (USD 7.9). Also, household childbirth expenditure increased from primary health facilities level (community-based health planning and services compound = USD7.2; health centre = USD 6.0) to secondary health facilities level (hospital = USD11.0); while home childbirth was USD 4.8. Overall, at a 10% threshold, 21% of the respondents incurred catastrophic health expenditure. Regression analysis showed that place of childbirth and household wealth were statistically significant factors associated with catastrophic payment. Conclusions The costs of childbirth were considerably high with a fifth of households spending more than one-tenth of their monthly income on childbirth and therefore faced the risk of catastrophic payments and impoverishment. Given the positive effect of NHIS on cost of childbirth, there is a need to intensify efforts to improve enrolment to reduce direct medical costs as well as sensitization and monitoring to reduce informal payment. Also, the identified factors that influence cost of childbirth should be considered in strategies to reduce cost of childbirth.

Abstract Background Women experience adverse changes in cardiovascular health in mid-life; whether the menopausal transition influences these remains strongly debated. The aim of this study was to examine associations of reproductive age (time since final menstrual period (FMP)) with change in carotid intima media thickness (CIMT) and cardiovascular risk factors and determine the role of chronological and reproductive age. Methods We used data from 1702 women from a pregnancy-based UK cohort who had up to four repeat cardiovascular health measures between mean age 51 (SD = 4.0) and 56 (SD = 3.6) years and experienced a natural menopause. Multilevel models were used to assess the relationship between cardiovascular measures and time since FMP (reproductive age), whilst adjusting for the underlying effects of chronological age and confounders (socioeconomic factors, body mass index, smoking, alcohol, parity, age at menarche). In addition, we looked at the relationship between cardiovascular measures by chronological age according to menopausal stages (pre-menopause, peri-menopause and post-menopause) using information from women who had and had not experienced menopause (N = 3892). Results There was no strong evidence that reproductive age was associated with CIMT (difference in mean 0.8 μm/year, 95% CI − 0.4, 2.1), whereas there was a strong positive association of chronological age (7.6 μm/year, 95% CI 6.3, 8.9). Consistent with this, we found weaker linear associations of reproductive compared with chronological age for atherosclerotic risk factors, such as with systolic blood pressure (− 0.1 mmHg/year, 95% CI − 0.3, 0.1, and 0.4 mmHg/year, 95% CI 0.2, 0.5, respectively) and non-HDL-cholesterol (0.02 mmol/l/year, 95% CI 0.005, 0.03, and 0.06, 95% CI 0.04, 0.07, respectively). In contrast, associations with fat mass (0.06 kg/m2/year, 95% CI 0.03, 0.10, and 0 kg/m2/year, 95% CI − 0.04, 0.04, respectively) and C-reactive protein (0.01, 95% CI 0.001, 0.02, and 0.01, 95% CI − 0.001, 0.02 natural logged mg/l/year, respectively) were stronger for reproductive compared with chronological age. Both reproductive and chronological age were (weakly) positively associated with glucose (0.002, 95% CI 0.0001, 0.003, and 0.002, 95% CI 0.0001, 0.003 natural logged mmol/l/year, respectively). Conclusions Our results suggest that going through the menopausal transition does not further increase women’s risk of atherosclerosis (measured by CIMT) beyond effects of ageing. Menopausal transition may, in additional to ageing, modestly increase adiposity and glucose levels and therefore a possible associated diabetes risk.

Abstract Background Canine relationship is a key reference identifying anterior malocclusion and an important implication for evaluating preimplantation bone morphology at maxillary esthetic zone. This study aimed to compare the differences of maxillary central incisor-related measurements (alveolar bone thickness and tooth sagittal angulation) between Class I and Class III canine relationship and further explore the risk factors for immediate implant placement in the anterior maxilla based on cone beam computed tomography (CBCT) data. Methods CBCT digital imaging and communications in medicine (DICOM) files of 107 patients (54 with Class I canine relationship and 53 with Class III canine relationship) were collected and the alveolar bone thickness at mid-root (mid-root buccal thickness/MBT; palatal/MPT), apical regions (apical buccal thickness/ABT; palatal/APT) and sagittal angulation (SA) of the maxillary central incisor at the examined side were measured on the mid-sagittal observation plane. Descriptive statistical analysis and frequency distributions of the measurements based on Class I or Class III canine relationship were established. Statistical analyses were performed using Fisher’s exact test, independent samples t test and Pearson correlation test with the significance level set at p