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Abstract Background Previous research on the association between physical activity (PA) and kidney function is inconsistent. The association between muscle mass and serum creatinine (SCr) may have implications for interpreting the effect of PA on estimated glomerular filtration rate (eGFR). Few studies have reported changes in physical activity and changes in kidney function. Methods A cohort study was constructed using the UK Biobank. Changes in physical activity were self‐reported as metabolic equivalent task (MET) minutes/week. eGFR was calculated using SCr and cystatin C (CysC). Cox and nonlinear regressions with restricted cubic splines were applied to explore the association between changes in physical activity and rapid decline of kidney function (RDKF, eGFR annual decrease ≥3 mL/min/1.73 m2), and the annual change of eGFR. An exploratory analysis of cardiorespiratory fitness as the exposure was conducted. Results Among 11 757 participants, the median follow‐up time was 4.4 years. Participants whose PA decreased by 1000 MET minutes/week at the follow‐up assessment had a 2% reduction in risk of developing RDKFSCr (HR = 0.98, 95% CI: 0.96, 1.00). In contrast, a 1000 MET minutes/week increase in PA was associated with a 4% reduction in risk of developing RDKFCysC (HR = 0.96, 95% CI: 0.93, 0.99). A PA increase of 1000 MET minutes/week was associated with eGFRCysC annual increase of 0.04 mL/min/1.73 m2 (95% CI: 0.03, 0.06) but no significant changes in eGFRSCr. Conclusions In this general population study, there are differing associations between changes in PA and changes in kidney function depending on the kidney biomarker used. Increasing PA is modestly associated with improving annual eGFRCysC and reduced risk of RDKF.

Abstract Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Abstract Background Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, PFDR

Abstract Aims Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium‐glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. Methods and results EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS‐MI) is a randomized, double‐blind, placebo‐controlled, multi‐centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF

Abstract Neuromodulation using high frequency (>1 kHz) electric stimulation (HFS) enables preferential activation or inhibition of individual neural types, offering the possibility of more effective treatments across a broad spectrum of neurological diseases. To improve effectiveness, it is important to better understand the mechanisms governing activation and inhibition with HFS so that selectivity can be optimized. In this study, we measure the membrane potential (Vm) and spiking responses of ON and OFF α-sustained retinal ganglion cells (RGCs) to a wide range of stimulus frequencies (100–2500 Hz) and amplitudes (10–100 µA). Our findings indicate that HFS induces shifts in Vm, with both the strength and polarity of the shifts dependent on the stimulus conditions. Spiking responses in each cell directly correlate with the shifts in Vm, where strong depolarization leads to spiking suppression. Comparisons between the two cell types reveal that ON cells are more depolarized by a given amplitude of HFS than OFF cells—this sensitivity difference enables the selective targeting. Computational modeling indicates that ion-channel dynamics largely account for the shifts in Vm, suggesting that a better understanding of the differences in ion-channel properties across cell types may improve the selectivity and ultimately, enhance HFS-based neurostimulation strategies.

Background: Discharge summaries (DSs) are an important communication tool between hospital and community clinicians however errors in these documents are common. To improve the accuracy of DS information, our health network implemented a suite of quality improvement projects that promoted “More Efficient Documentation (of patient information) for Improved Care” (MEDIC). Objective: The aim of this study was to determine if DSs post-implementation of the MEDIC program of work were associated with lower rates of medication errors. Design: A retrospective pre- (March 2021) post- (March 2022) medical record audit was conducted at five public hospitals. Patients were included chronologically based on discharge date until the target sample size was reached (100 per group). For each patient, the DS medication list was compared to the pharmacy generated patient friendly medication list or interim medication administration chart and any discrepancies were considered errors. Utilisation of electronic Clinical Decision Support (CDS) was evaluated via review of the EMR. Main Outcome Measure: Medication errors Results: The mean number of DS medication errors was lower in the post-intervention group (3.0 vs 1.4, p

Introduction Post-COVID-19 condition (post COVID, also known as long COVID) is a global public health issue estimated to affect over 100 million people. Common symptoms include fatigue, dyspnoea and cognitive dysfunction (‘brain fog’). Over time, these symptoms have an adverse effect on mental health, physical activity and quality of life (QoL). The condition requires innovative and feasible treatment approaches that can be effective and self-managed. Physical activity is essential for good health; however, aerobic exercise or weightlifting may not be suitable for post COVID patients who experience fatigue or breathlessness. The benefits of yoga include improved flexibility, mobility, body strength and balance. It is also shown to reduce symptoms of fatigue and improve breathing efficiency, mental health and QoL. This study protocol describes the rationale and methods for a randomised controlled trial (RCT) of a yoga-based intervention designed for adults with post COVID.Methods and analysis A two-group, parallel, RCT with blinded follow-up assessments. Participants will be randomised with a 1:1 allocation to either a 12-week yoga-based intervention or a 12-week health promotion (active comparison) intervention. In total, 88 participants aged 30–65 years will be recruited and randomised. The primary outcome is health-related QoL (36-item Short-Form). Secondary outcomes are dyspnoea, fatigue, sleep quality, cognitive functions, mental fatigue, depression, anxiety, physical activity, demographic data and physical health measures. Data will be analysed as intention-to-treat basis, using linear mixed modelling. All assessments are conducted at Karolinska Institutet in Stockholm, Sweden. The yoga-based intervention will take place at a yoga studio centrally located in Stockholm city.Ethics and dissemination The study is approved by the Swedish Ethical Review Authority, reference number 2023/06518-01. All participants must sign written informed consent before enrolment and are free to withdraw from the study at any point. Key results will be available through research articles and seminars.Trial registration number German Clinical Trials Register, DRKS00032837.

Objective Amid a drug poisoning epidemic, UCalgary adapted its comprehensive wastewater monitoring program to track illicit drug use. The joint initiative between the academic community and Alberta municipalities aims to provide early warning information on changes in the drug supply to healthcare workers, policymakers, and people with substance use disorders (pwSUD). Approach The logistic network, first used for SARS-CoV-2 monitoring, has evolved to track 48 substances linked to substance use. These include the parent drugs (e.g., cocaine, methamphetamines, various opiates) and their metabolites. The comprehensive nature of this tracking provides a nuanced understanding of trends. Collected up to 3X-weekly across various locations in Alberta including municipal wastewater treatment plants, entire neighbourhoods, and shelters, the data reveals geographical and temporal patterns in substance use. Findings were cross validated with Alberta’s substance use surveillance system to predict trends in wastewater, correlating with emergency and inpatient admissions and overdose deaths. Results The research uncovered noteworthy trends. Intermittent, alarming, spikes in carfentanyl, benzodiazepines, and xylazine in wastewater were observed during periods of elevated Emergency Medical Services (EMS) responses to opioid-related incidents in the year 2023. This correlation underscores the real-world impact of the identified substance trends, emphasizing the urgency for targeted interventions to address the escalating opioid crisis. Further work to create a dashboard with additional data sources has begun. Conclusions Timely data on the dynamic drug supply is crucial in addressing the ongoing drug poisoning crisis. The team is exploring ways to share information with emergency responders, healthcare providers, government officials, and pwSUD.

Introduction Hypertension is a major cause of premature death worldwide as it is an important risk factor for coronary artery disease, myocardial infarction, heart failure and stroke. Although an estimated 1.3 billion adults suffer from hypertension, less than half of them are diagnosed correctly and therefore receive sufficient treatment. Furthermore, only one fifth of those treated reach the therapy target of normotension. This significant deficit underlines the need for new therapy concepts to improve long-term health outcomes. Several studies have shown positive effects of digital health programmes in the disease management of ambulatory, long-term hypertension treatment. More research is needed to explore the abilities of digital health programmes as an innovative pathway in ambulatory healthcare.The eXPLORE study aims to evaluate the feasibility of a clinical trial on the impact of a supplementary digital therapy programme for the treatment of primary arterial hypertension.Methods and analyses The eXPLORE study collects data in the setting of a prospective randomised controlled trial to evaluate methodological feasibility for larger-scaled follow-up research. The study compares a digital therapy programme using a smartphone application that is based on functions and algorithms creating tasks and recommendations based on individual health data to standard care for the treatment of primary arterial hypertension. The study period is 180 days, with a 90-day in-life phase followed by a 90-day follow-up phase. Baseline and follow-up data (3 months, 6 months follow-up) of all participants included is collected via questionnaire surveys as well as self-administered blood pressure monitoring. Patient inclusion, initial data acquisition and follow-up were carried out in an innovative remote setting. The study was initiated in November 2022 and is currently ongoing. Study outcome measures are changes in mean blood pressure, health literacy and self-sufficient health behaviour.Ethics and dissemination The eXPLORE study is carried out in accordance with all applicable legal regulations. Cost-effectiveness is assured by continuous evaluation and documentation over the course of the study. All health-relevant data from the eXPLORE study will be provided for analyses and publication to the investigators of LMU Hospital. The study was approved by the local ethics committee of LMU Munich (project nr.: 22–0115).Trial registration NCT05580068. Protocol Version: 1.5, 28.08.2023.

Road crashes continue to be a major cause of death and serious injury for low- and middle-income countries (LMICs). At the global level, 90% of traffic fatalities occur in these countries with a dramatic daily amount of 3 260 road deaths, many of whom are children. The first UN Decade of Action for Road Safety 2011–2020 was designed to develop a massive movement towards a decrease of these numbers. This resulted in many initiatives to introduce the safe system approach in LMICs, i.e. to implement road safety management, make roads, road users, and vehicles safer, and improve post-crash health care. International organisations together with NGOs and universities prepared road safety guides and manuals, gave courses and webinars, introduced auditing and inspection systems, with the overall intention to build capacity in LMICs. Together these actions contributed to a variety of road safety developments in LMICs but the overall results were still modest. At the third Global Ministerial Conference on Road Safety in Stockholm, 2020, and in the Global Status report by the World Health Organization, 2023, the results of all efforts were presented and evaluated. Many countries made progress through road safety management and better legislation addressing risk factors such as speeding, drinking and driving, failing to use seatbelts, and poor infrastructure design. However, the reduction in road deaths strongly lagged behind the original goals. Continued implementation of programs and development of new approaches are needed to make a breakthrough, and to reach the goals of the 2nd Decade of Action, i.e. a 50% reduction in fatalities by 2030, and the same percentage reduction in injuries. The present position paper argues that despite the enormous amount of road safety information, which has been and is ‘sent’ to LMICs, and despite the quality and robustness of international organisations behind these programs, there is a shortfall in the scale of the knowledge and research infrastructure currently existing in LMICs, which is needed to ‘receive and transfer’ this knowledge. In order to develop evidence-based policy, LMICs need research programs that are able to transfer safe system principles to the local context and culture. Several literature overviews illustrate the lack of such research in LMICs, i.e. the limited number of programs at local universities and research institutes. Although recently initiatives have been taken in some countries, the implementation of such programs is urgently needed. Based on this observation we call on international organisations to establish a special program for the development of a sustainable road safety knowledge and research infrastructure in LMICs. Such structural local capacity is a prerequisite to translate international road safety knowledge into local guidelines and to develop an evidence-based road safety policy. Most importantly, this local infrastructure will give countries a national knowledge bank, thus providing them with an urgently needed sustainable road safety memory.

Abstract Background Hazardous alcohol use is a leading risk factor for disability and death, yet observational studies have also reported reduced cardiovascular disease mortality among regular, low-level drinkers. Such findings are refuted by more recent research, yet have received significant media coverage. We aimed to explore: (1) how patients with cardiovascular diseases access health information about moderate drinking and cardiovascular health; (2) the perceived messages these sources convey, and (3) associations with own level of alcohol use. Methods We conducted a cross-sectional survey of patients in cardiology services at three hospitals in Sweden. The study outcome was hazardous alcohol use, assessed using the AUDIT-C questionnaire and defined as ≥ 3 in women and ≥ 4 in men. The exposure was accessing information sources suggesting that moderate alcohol consumption can be good for the heart, as opposed to accessing information that alcohol is bad for the heart. Health information sources were described using descriptive statistics. Gender, age and education were adjusted for in multiple logistic regression analyses. Results A total of 330 (66.3%) of 498 patients (mean age 70.5 years, 65% males) who had heard that drinking moderately can affect the heart described being exposed to reports that moderate alcohol use can be good for the heart, and 108 (21.7%) met criteria for hazardous alcohol use. Health information sources included newspapers (32.9%), television (29.2%), healthcare staff (13.4%), friends/family (11.8%), social media (8.9%) and websites (3.7%). Participants indicated that most reports (77.9%) conveyed mixed messages about the cardiovascular effects of moderate drinking. Exposure to reports of healthy heart effects, or mixed messages about the cardiovascular effects of alcohol, was associated with increased odds of hazardous alcohol use (OR = 1.67, 95%CI = 1.02–2.74). Conclusions This study suggests that many patients in cardiology care access health information about alcohol from media sources, which convey mixed messages about the cardiovascular effects of alcohol. Exposure to reports that moderate drinking has protective cardiovascular effects, or mixed messages about the cardiovascular effects of alcohol, was associated with increased odds of hazardous alcohol use. Findings highlight a need for clear and consistent messages about the health effects of alcohol.

Abstract Recent advancements in membrane-assisted seawater electrolysis powered by renewable energy offer a sustainable path to green hydrogen production. However, its large-scale implementation faces challenges due to slow power-to-hydrogen (P2H) conversion rates. Here we report a modular forward osmosis-water splitting (FOWS) system that integrates a thin-film composite FO membrane for water extraction with alkaline water electrolysis (AWE), denoted as FOWSAWE. This system generates high-purity hydrogen directly from wastewater at a rate of 448 Nm3 day−1 m− 2 of membrane area, over 14 times faster than the state-of-the-art practice, with specific energy consumption as low as 3.96 kWh Nm−3. The rapid hydrogen production rate results from the utilisation of 1 M potassium hydroxide as a draw solution to extract water from wastewater, and as the electrolyte of AWE to split water and produce hydrogen. The current system enables this through the use of a potassium hydroxide-tolerant and hydrophilic FO membrane. The established water-hydrogen balance model can be applied to design modular FO and AWE units to meet demands at various scales, from households to cities, and from different water sources. The FOWSAWE system is a sustainable and an economical approach for producing hydrogen at a record-high rate directly from wastewater, marking a significant leap in P2H practice.

ABSTRACT Objectives The aim of this in vitro study was to investigate whether and to what extent different scenarios of rotational freedom in different IAC designs affect the vertical dimension of a three‐part fixed partial denture (FPD). At the same time, the experimental setup should simulate all clinical and laboratory steps of the implementation of such an FPD as accurately as possible. Material and Methods Twenty identical pairs of jaw models were fabricated from aluminum, each lower‐jaw model holding two implants with conical or flat IACs. Three impressions of each model were taken to fabricate stone casts and three‐unit FPDs. Three assembly scenarios were compared for the vertical position stability they offered for these FPDs, differing by how the sequential implant components (impression posts > laboratory analogs > abutments 1 > abutments 2) were aligned with the positional index of the IAC. In this way, a total of 60 stone casts and FPDs were fabricated and statistically analyzed for changes in vertical dimension (p 0.05), significantly greater mean changes in vertical dimension were consistently (all comparisons p

Background: Revision total knee (TKR) and hip (THR) arthroplasty surgeries are disincentivized due to unfavorable reimbursement rates, surgical times, and complication rates. Our study investigates secondary benefits of performing these surgeries by generating subsequent cases for surgeons and practices. Methods: Patients undergoing TKR and THR between April 1, 2011, and January 1, 2019, at our tertiary academic institution were analyzed. Patients were identified with Current Procedural Terminology codes for TKR and THR. We calculated a subsequent surgery rate on the same or different joint by the initial surgeon or another surgeon within the practice to determine the procedure yield after initial revision arthroplasty. Results: One thousand six hundred twenty-five patients met inclusion criteria. Six hundred forty-nine (39.9%) patients received at least one subsequent procedure on any joint by any orthopaedic surgeon in the practice. Four hundred five patients (24.9%) underwent another procedure on any joint by the same surgeon. Two hundred sixty patients (16.0%) underwent another procedure on the same joint by the same surgeon, with 109 cases (41.9%) being a planned second stage of a 2-stage revision for infection. Two hundred eighty-five patients (17.5%) underwent another procedure on a different joint by the same surgeon, with 122 of these patients (42.8%) undergoing at least one primary total hip or knee arthroplasty. Conclusions: TKRs and THRs can increase surgeon and practice volumes through the generation of future cases, which are primarily the second stage of a 2-stage revision or primary joint arthroplasties on other joints.

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.

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.

Abstract Background The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain. Methods A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28–60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status. Results Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation. Conclusions In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19.

Abstract We demonstrate three-dimensional magnetic resonance tomography with a resolution down to 5.9 ± 0.1 nm. Our measurements use lithographically fabricated microwires as a source of three-dimensional magnetic field gradients, which we use to image NV centers in a densely doped diamond by Fourier-accelerated magnetic resonance tomography. We also demonstrate a compressed sensing scheme, which allows for direct visual interpretation without numerical optimization and implements an effective zoom into a spatially localized volume of interest, such as a localized cluster of NV centers. It is based on aliasing induced by equidistant undersampling of k-space. The resolution achieved in our work is comparable to the best existing schemes of super-resolution microscopy and approaches the positioning accuracy of site-directed spin labeling, paving the way to three-dimensional structure analysis by magnetic-gradient based tomography.

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.

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.

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.

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

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