medRxiv : serveur de preprint pour les sciences médicales

Purpose: A subset of patients with post-COVID-19 condition (PCC) fulfill the clinical criteria of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). To establish the diagnosis of ME/CFS for clinical and research purposes, comprehensive scores have to be evaluated. Methods: We developed the Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs) to allow for a rapid evaluation of common ME/CFS case definitions. The MBSQs were applied to young patients with chronic fatigue and post-exertional malaise (PEM) who presented to the MRI Chronic Fatigue Center for Young People (MCFC). Trials were retrospectively registered (NCT05778006, NCT05638724). Results: Using the MBSQs and SSSs, we report on ten patients aged 11 to 25 years diagnosed with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19. Results from their MBSQs and from well-established patient-reported outcome measures indicated severe impairments of daily activities and health-related quality of life. Conclusions: ME/CFS can follow SARS-CoV-2 infection in patients younger than 18 years, rendering structured diagnostic approaches most relevant for pediatric PCC clinics. The MBSQs and SSSs represent novel diagnostic tools that can facilitate the diagnosis of ME/CFS in children, adolescents, and adults with PCC and other post-viral syndromes.

In a pivotal trial, a 5-day course of oral ritonavir-boosted nirmatrelvir decreased hospitalization and death by 89.1% and reduced nasal viral load by 0.87 log relative to placebo when given early during symptomatic infection to high-risk individuals. Yet, more frequent viral and symptomatic rebound has been observed in community cohorts relative to the clinical trial, and ritonavir-boosted nirmatrelvir failed to achieve efficacy in a post-exposure prophylaxis trial. We developed a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulated viral loads from the clinical trial. Our results demonstrate that nirmatrelvir IC50 (50% inhibitory concentrations) estimates from in vitro assays are approximately 60-fold lower than the plasma concentration required to reduce viral infection by 50% in humans and that a maximally potent agent would reduce the viral load by approximately 2.5 logs relative to placebo at 5 days. The model produces frequent viral rebound trajectories and identifies that earlier treatment initiation and shorter treatment duration are key predictors of rebound. Extension of early symptomatic treatment duration to 10 days and post-exposure prophylaxis to 15 days, rather than increasing dose or dosing frequency, is predicted to significantly lower the incidence of viral rebound.

Background The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with Intellectual Disability, Autosomal Dominant 57 (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. Methods A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a novel, heterozygous variant in TLK1 (c.1435C>G, p.Q479E) by genome sequencing (GS). Single cell gel electrophoresis, western blot, flow cytometry and RNA-seq were performed in patient-derived lymphoblast cell lines. In silico, biochemical and proteomic analysis were used to determine the functional impact of the p.Q479E variant and previously reported NDD-associated TLK1 variant, p.M566T. Results Transcriptome sequencing in patient-derived cells confirmed expression of TLK1 transcripts carrying the p.Q479E variant and revealed alterations in genes involved in class switch recombination and cytokine signaling. Cells expressing the p.Q479E variant exhibited reduced cytokine responses and higher levels of spontaneous DNA damage but not increased sensitivity to radiation or DNA repair defects. The p.Q479E and p.M566T variants impaired kinase activity but did not strongly alter localization or proximal protein interactions. Conclusion Our study provides the first functional characterization of TLK1 variants associated with NDDs and suggests potential involvement in central nervous system and immune system development. Our results indicate that, like TLK2 variants, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.

Background: Skeletal muscle atrophy and low physical performance are associated with disease progression and higher mortality rates in multiple pathological conditions. Here, we determined whether body composition and physical performance would predict mortality in metastatic non-small cell lung cancer (NSCLC) patients. In addition, we defined whether plasma samples from NSCLC patients would directly affect the homeostasis of skeletal muscle cells. Methods: The prospective cohort included 55 metastatic NSCLC patients and seven age-matched control subjects. We assessed clinical characteristics, body composition, cancer cachexia, and quality of life (QoL). We determined physical performance with a series of functional tests. We analyzed skeletal muscle and adipose tissue areas. Finally, we evaluated the overall survival rate, and additional blood samples were collected from a subcohort of eighteen patients for further studies in cell culture and metabolomic analysis. Results: We found that physical performance, not body composition, was associated with overall survival in this cohort. Moreover, incubation with plasma derived from NSCLC patients with low physical performance impaired the metabolism and proliferation of primary human myotubes. Unbiased metabolomics revealed several metabolites differentially expressed in the plasma of NSCLC patients with low physical performance compared to healthy control subjects, with serine and N2,N2-dimethylguanosine (M22G) being the most reduced and increased metabolites, respectively. Conclusion: These novel findings confirm physical performance as a significant predictor of overall survival in metastatic NSCLC patients and provide insights into cancer-induced circulating factors that can directly affect skeletal muscle homeostasis and prognosis.

Re-emergent tremor (RET) during stable posture in Parkinson's disease (PD) is characterized as a continuation of resting tremor (RT) and is often highly therapy refractory. The pathophysiology of both RT and RET is linked to deficits in cerebello-cortical circuits and dopaminergic depletion. However, it remains unclear how these two types of tremors differ functionally. The aim of this study is to examine the differences in brain activity between RT and RET in PD, as well as to investigate the relationship between neuronal oscillatory activity, in PD tremor phenotype patients. Forty PD patients (25 males, mean age 66.78 plus/minus 5.03 years) and 40 age- and sex-matched healthy controls were assessed. 256 channel HD-EEG and EMG signals were recorded while the participants extended their hands against gravity. Tremor was recorded in both L-dopa ON and OFF for PD patients and mimicked by healthy controls. Coherent sources of EEG-EMG were located using beamforming technique, and information flow between different sources was estimated using time-resolved partial-directed coherence. Cross-frequency coupling (CFC) was then used to analyze the association between tremor frequency and neuronal oscillatory activity. Under L-dopa administration, coherent sources referenced to the tremor frequency revealed differences in brain activity between RT and RET in the premotor cortex and cerebellum of PD patients, which were similar to those observed in healthy controls. However, PD patients exhibited an additional source location in the primary sensorimotor cortex. Withdrawal of L-dopa led to coherent sources being observed in the supplementary motor area and subthalamic nucleus. Furthermore, L-dopa was found to suppress the strength of connections between these coherent sources and modulate the tremor-associated beta and gamma frequency, leading to a decrease in beta power and an increase in gamma power. The findings of this study reveal discernible neural activity patterns during resting and re-emergent tremors. In patients with PD, the primary sensorimotor cortex plays a primordial role as the exclusive source of activity involved in the generation of RET. It shows a significant amount of co-activation within the network involving the premotor areas and cerebellum, and its activation accounts for the discrepancy in tremor phenotypes. Moreover, the oscillatory neuronal responses involve pathological beta and prokinetic gamma activity alterations that are highly specific to tremor phenotypes. These peculiarities play an essential role in our understanding of tremor phenomena and its therapeutic modulation by dopamine medication or deep brain stimulation, which could specifically target the tremor- and motor-control-related pathological beta and prokinetic gamma oscillations.

Background In the general population, advanced cancer stage at presentation is associated with poorer health outcomes. People with chronic kidney disease (CKD) have increased incidence and mortality from most cancer types. We sought to determine whether people with CKD were more likely to present with advanced stage cancer, whether this was associated with survival, and whether these associations varied by sex. Methods Data were from Secure Anonymised Information Linkage Databank (SAIL), a Welsh primary care database with linkage to cancer and death registries. We included patients with a de-novo cancer diagnosis (2011 to 2017), and at least two kidney function tests in the two years prior to diagnosis. Estimated glomerular filtration rate based on serum creatinine (eGFRcr) was calculated using the CKD-EPI 2009 equation (mL/min/1.73m2). Logistic regression models determined odds of presenting with advanced cancer (stage 3 or 4 at diagnosis) by different values of eGFRcr at baseline. Cox proportional hazards models tested associations between eGFRcr at baseline and all-cause mortality risk (reference eGFR 75 to <90). Findings There were 66,128 patients: 30,857 (46.7%) were female, mean age was 69.1 (standard deviation [SD] 13.8) years in females and 70.6 (SD 11.1) years in males; median eGFRcr at baseline was 78 (interquartile range [IQR] 63-90) mL/min/1.73m2 in both females and males. Over a median follow-up time of 3.1 (IQR 0.5-5.7) years in females and 2.9 (IQR 0.5-5.5) years in males, there were 17,303 deaths in females and 20,855 in males. An eGFRcr <30 was associated with higher odds of presenting with advanced cancer in males (OR 1.33 95% CI 1.09-1.62), but not in females (OR 1.17 95% CI 0.92-1.50); positive associations were primarily driven by prostate and breast cancers. With lower eGFRcr, hazards of cancer death increased in both sexes, but lower eGFRcr was associated with greater hazards of cancer death in females (eGFRcr <30: HR 1.71, 95% CI 1.56-1.88, p<0.001; male versus female comparison HR 0.88, 95% CI 0.78-0.90; p=0.037). Interpretation CKD was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites (except prostate and breast), but was associated with reduced survival. Despite an initial survival advantage compared to males, females with CKD had disproportionately higher hazards of death. Though potential explanations for reduced survival after a cancer diagnosis are manifold, scrutiny of access to, efficacy, and safety of cancer treatments in people with CKD, particularly females with CKD, are warranted. Funding Chief Scientist Office (Scotland) Postdoctoral Lectureship (PCL/20/10) and University of Sydney/University of Glasgow Office of Global Engagement Collaboration Partnership (9241562498).

Stillbirths are a known outcome of untreated sexually transmitted infections (STIs). Sub-Saharan Africa (SSA) shares a disproportionate burden of both stillbirths (2015: 29/1000 births vs 3/1000 births in high income countries globally) and STIs. Nationally representative survey data can inform stillbirth prevention measures in multiple countries in the SSA region, with greater generalizability than clinic-based studies. We assessed the association between any self-reported STI symptoms (STI diagnosis, abnormal genital discharge, genital sore or ulcer) in the last 12 months and stillbirth in the prior five years, among women aged 15-49 years participating in nationally representative Demographic and Health Surveys (DHS) in 19 countries in SSA between 2015-2021 and reporting a pregnancy in the five years prior to interview. We used multivariable logistic regression models adjusting for maternal age, wealth index, education level of mother, cigarette smoking behaviors, health care utilization and country of residence. Among 160,995 SSA women who reported being pregnant at least once between 2011-2021, 18.0% (25,596) reported any STI symptom in the prior year and 1.9% (3,205) reported a stillbirth in the past five years. Women who self-reported STI symptoms in the past year had 1.30 (95% CI 1.16-1.47) times the odds of stillbirth in the prior five years compared to women who did not report STI symptoms. Women 35-49 years old had 1.17 (95% CI 1.04-1.33) times the odds of stillbirth compared to those 15-24 years old. The association found between self-reported STI symptoms and stillbirth highlights the need for increased screening for STI symptoms and subsequent treatment among pregnant women in SSA.

Purpose: As large analyses merge data across sites, a deeper understanding of variance in statistical assessment across the sources of data becomes critical for valid analyses. Diffusion tensor imaging (DTI) exhibits spatially varying and correlated noise, so care must be taken with distributional assumptions. Here we characterize the role of physiology, subject compliance, and the interaction of subject with the scanner in the understanding of variance. Approach: We analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging (BLSA), with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. In each session, a scan and a rescan of DTI were performed. We assess variance of DTI scalars within regions of interest (ROIs) defined by four segmentation methods and investigate the relationships between the variance and covariates, including baseline age, time from the baseline (referred to as "interval"), motion, sex, and scan-rescan pairs. Results: Covariate effects are heterogeneous and bilaterally symmetric across ROIs. The interval is positively related to FA variance in the cuneus and occipital gyrus, but negatively in the caudate nucleus. Males show higher FA variance in the right putamen, thalamus, body of the corpus callosum, and cingulate gyrus. In certain ROIs, an increase in motion is associated with a decrease in FA variance. Head motion increases during the rescan of DTI. Conclusions: The effects of each covariate on DTI variance, and their relationships across ROIs are complex. Ultimately, we encourage researchers to include estimates of variance when sharing data and consider models of heteroscedasticity in analysis.

Background: Multiple spinal dural arteriovenous fistulas (SDAVFs) are rare and account for only 1?2% of all SDAVF cases. The treatment for SDAVFs typically involves either direct surgy or endovascular treatment. Identifying the precise location of all fistulas is paramount for successful treatment procedures when multiple SDAVFs are present. They can be classified as synchronous (occurring simultaneously) or metachronous (occurring at different times), with each type differing with respect to etiology, diagnosis, and treatment. This study systematically reviewed the literature on multiple synchronous SDAVFs. Methods: A comprehensive search was performed to identify all published multiple synchronous SDAVF cases. Overall, 23 patients with multiple SDAVFs were identified, including 21 from 19 articles and 2 from this study. Clinical presentation, lesion location, radiographic features, surgical treatment, and outcome were analyzed in each patient. Results: All patients in this study were male individuals, and the duration from symptom onset to diagnosis in many of these patients was longer than that previously reported. Previous studies suggested that multiple SDAVFs typically occurred within three of fewer vertebral levels. However, >50% of examined patients had remote lesions separated by more than three vertebral levels. Patients with remote lesions had a significantly worse outcome (1/7 vs. 8/11, P=0.049). Therefore, accurate localization of fistulas before spinal angiography is critical for managing multiple remote SDAVFs. Conclusions: Considering the possibility of multiple remote SDAVFs, careful interpretation of imaging findings is essential for accurate diagnosis and appropriate treatment planning.

Over the pandemic, health has become increasingly important, and our idea of what it means to be healthy has changed. Previously we viewed health disparities as an issue that affected those who were less fortunate, but the pandemic has shown us that the health of all of us is interconnected. Reducing health disparities is important for everyone, as it would improve health not just for those who are directly impacted, but for society as a whole. This study contributes towards reducing health disparities by analyzing what factors have the largest impact on health disparities, and discussing policy changes that are relevant to these factors. This study uses a random forest algorithm to identify important predictors of health from a large variety of factors in Chicagoland and the Bay Area. The analysis finds that race is an important factor in both Chicagoland and the Bay Area, and that lack of internet access and computing devices is an especially important predictor of neighborhoods with poor health.

Background: In light of the increasing population of late reproductive-aged women (aged 35 and above) within the broader demographic of reproductive-aged females, the concern surrounding their contraceptive considerations has escalated to a point of critical importance. This study aims to examine the trends and determinants of modern contraceptive practices among late reproductive-aged women in Bangladesh. Methods: A total of 17,736 women aged 35 and more were included in the analysis, utilizing data from three consecutives Bangladesh Demographic and Health Surveys conducted in 2011, 2014, and 2017-18. The outcome variable was the use of modern contraceptive methods (yes or no). The explanatory variables encompassed survey years, individual characteristics of the women, as well as characteristics of their partners and the community. To examine the association of the outcome variable with the explanatory variables, a multilevel logistic regression model was used. Results: Approximately 54% of women aged 35 and older do not utilize modern contraceptive methods, and there have been no significant shifts in their usage observed over the survey years. The probability of using modern contraceptive methods exhibited a notable decline in relation to increasing age, the educational level of women's partners, and their categorization within the richer or richest wealth quintile. Conversely, women with higher education, increased exposure to mass media, and residing in the Dhaka or Rajshahi division displayed an elevated likelihood of embracing modern contraceptive methods. Conclusion: The study highlights the relatively stable adoption of modern contraceptive methods among women aged 35 or older in Bangladesh, despite their increasing representation within the population. This raises concerns about the elevated risk of unintended pregnancies and shorter birth intervals, emphasizing the need for targeted interventions to address the specific needs and preferences of this demographic

The study aimed to investigate the impact of demographic, socio-economic, health, and lifestyle variables on the development of PTSD symptoms in COVID survivors. The study used a cross-sectional design, and data were collected via a standard set of questionnaires from 228 COVID survivors, who required oxygen support and were admitted to Damak COVID hospital from April to October 2021. Descriptive statistics such as frequency and percentage were used to summarize the data and inferential statistics such as chi-square test, Fisher's exact test, and Binary logistic regression were used to analyze the data and to infer the overall result from the taken sample. The study found that only three variables, i.e., gender, diabetes, and chronic obstructive pulmonary disorder (COPD), were significant factors that posed a higher threat of PTSD in COVID survivors. Additionally, the study uses model adequacy tests such as Pseudo R2 test, Reliability test and Hosmer and Lemeshow test to validate the model fitted. The study found that only three variables had significant impact PTSD symptoms in COVID survivors. Male patients were more likely to have PTSD symptoms than female patients. The presence of diabetes before or after the infection increased the risk of PTSD. The patients with high blood pressure before COVID and those who developed chronic obstructive pulmonary disorder (COPD) after COVID were more likely to experience PTSD symptoms. The study provides valuable information on the risk factors for developing PTSD symptoms in COVID survivors. This study can contribute to the understanding and growing body of research on the psychological impact of COVID and help healthcare professionals identify patients who are at risk of developing PTSD and provide them with appropriate interventions to prevent or treat PTSD.

Background There is an increased risk for tuberculosis (TB) infection and disease progression in prison settings. TB prevalence in prisons of high and middle/low income countries have been measured to be between 5 and 50 -times higher than in the general population. Methods We performed TB active case finding in five central prisons, Keko, Segerea, Ukonga, Butimba and Ruanda prison in Tanzania, using the Xpert MTB/RIF(R) assay on early morning or spot sputum sample from inmates and new entries between April 2014 and July 2015. Results Out of 13,868 prisoners tested, 13,763 had valid results. TB prevalence was 1.55% (214/13,763); new admissions contributed to the majority (61.68%) of TB cases, but prevalence was higher among inmates (1.75%) compared to new admissions (1.45%). Ukonga, an urban prison which incarcerates long-term convicted inmates had the highest prevalence of 4.02%. Male gender (OR=2.51, p<0.001), repeated incarcerations (OR=2.85, p<0.001), history of TB treatment (OR=1.78, p =0.002), TB symptoms (OR=2.78, p=0.006) and HIV infection (OR=2.86, p=0.002) were associated with positive TB results. Conclusion New admissions could be the driving force of the TB epidemic in the penitentiary system. However, prison environments remain a major risk factor for developing active TB disease.

Introduction The widespread use of antigen-detection rapid diagnostic tests (Ag-RDTs) has revolutionized SARS-CoV-2 (COVID-19) testing, particularly through the option of self-testing. The full extent of Ag-RDT utilization for self-testing, however, remains largely unexplored. To inform the development of WHO guidance on COVID-19 self-testing, we conducted a cross-sectional survey to gather the views and experiences of policy makers, researchers, and implementers worldwide. Methods The survey was shared through professional networks via email and social media, encouraging onward sharing. We used closed and open-ended questions related to policy and program information concerning the regulation, availability, target population, indications, implementation, benefits, and challenges of COVID-19 self-testing (C19ST). We defined self-testing as tests performed and interpreted by an untrained individual, often at home. Descriptive summaries, cross-tabulations, and proportions were used to calculate outcomes at the global level and by WHO region and World Bank income classifications. Results Between 01 and 11 February 2022, 844 individuals from 139 countries responded to the survey, with 45% reporting affiliation with governments and 47% operating at the national level. 504 respondents from 101 countries reported policies supporting C19ST for a range of use cases, including symptomatic and asymptomatic populations. More respondents from low-and-middle-income countries (LMICs) than high-income countries (HICs) reported a lack of an C19ST policy (61 vs 11 countries) and low population-level reach of C19ST. Respondents with C19ST experience perceived that the tests were mostly acceptable to target populations, provided significant benefits, and highlighted several key challenges to be addressed for increased success. Reported costs varied widely, ranging from specific programmes enabling free access to certain users and others with high costs via the private sector. Conclusion Based on the survey responses, systems for the regulatory review, policy development and implementation of C19STappeared to be much more common in HIC when compared to LIC in early 2022, though most respondents indicated self-testing was available to some extent (101 out of 139 countries) in their country. Addressing such global inequities is critical for ensuring access to innovative and impactful interventions in the context of a public health emergency of international concern. The challenges and opportunities highlighted by survey respondents could be valuable to consider as future testing strategies are being set for outbreak-prone diseases.

Abstract Introduction This is a follow-up study on a recent systematic review by Storeboe et al. [1]. It aims to investigate research waste and publication bias in randomized clinical studies investigating the use of methylphenidate for children and adolescent with ADHD. Method The method used includes an initial cohort selection from searching Clinicaltrials.gov and the EUCTR with the following inclusion criteria: Use of methylphenidate either as stand-alone or part of psychological treatment for ADHD, randomised clinical trials, any dosage, any delivery method and at least 75% children and adolescents with ages less than 18. Results The primary objective is to assess how many randomised clinical trials of methylphenidate on children and adolescents with ADHD are registered in protocol databases, but never published in academic literature or as tabular summary results. The number of participants included in these trials is a secondary objective. The tertiary objective is to assess the time from registry to publication of randomised clinical trials of methylphenidate on children and adolescents with ADHD in either a journal or as summary results, and the number of participants in these trials. The cutoff time for a publication to be considered timely published will be 12 months, as per FDAA guidelines [3]

Introduction Nottingham histological grade (NHG) is a well established prognostic factor in breast cancer histopathology. However, manual NHG assessment of biopsies is challenging and has a large inter-assessor variability with a large proportion being classified as NHG2 (intermediate grade). Here, we evaluate whether DeepGrade, a previously developed model for the risk stratification of resected tumour specimens, could be applied to risk-stratify biopsy specimens. Methods A total of 11,943,905 tiles from 1171 whole slide images (WSIs) of preoperative biopsies from 897 patients diagnosed with breast cancer in Stockholm, Sweden, were included in this retrospective observational study. DeepGrade, a deep convolutional neural network model, was applied for classification of low and high risk tumours and evaluated against clinically assigned grades 1 and 3 using area under the operating curve (AUC). The prognostic value of the DeepGrade model in the biopsy setting was evaluated using time-to-event analysis. Results The DeepGrade model classified resected tumour cases with grades NHG1 and NHG3 using only biopsy specimens with an AUC of 0.903 (95% CI: 0.88;0.93). The model could also classify the biopsy NHG (1 and 3) assessed on the biopsy of 186 patients with an AUC of 0.959 (95% CI: 0.93; 0.99). Furthermore, out of the 434 NHG2 tumours, 255 (59%) were classified as DeepGrade2-low, and 179 (41%) were classified as DeepGrade2-high. Using a multivariable Cox proportional hazards model the hazard ratio between low- and high-risk groups was estimated as 2.01 (p-value = 0.036). Conclusions DeepGrade could predict the resected tumour grades NHG1 and NHG3 using only the biopsy specimen and sub-classify grade 2 tumours into low and high risks. The results demonstrate that the DeepGrade model can provide decision support for biopsy grading, and potentially provide decision support in the clinical setting to identifying high-risk tumours based on preoperative breast biopsies, thus improving information available for clinical treatment decisions.

Wastewater monitoring for infectious disease targets is increasingly used to better understand circulation of diseases. The present study validated hydrolysis-probe digital droplet (reverse-transcriptase (RT))-PCR assays for important enteric viruses (rotavirus, adenovirus group F, norovirus GI and GII, and enteroviruses), outbreak or emerging viruses (hepatitis A and West Nile virus), and an emerging drug resistant fungal pathogen (Candida auris). We used the assays to retrospectively measure concentrations of the targets in wastewater solids. Viral and fungal nucleic-acid concentrations were measured in two wastewater solids samples per week at two wastewater treatment plants in the San Francisco Bay Area of California, USA for 26 months. We detected all targets in wastewater solids with the exception of West Nile virus. At both wastewater treatment plants, human adenovirus group F was detected at the highest concentrations, followed by norovirus GII, enteroviruses, norovirus GI, and rotavirus at the lowest concentrations. Hepatitis A and C. auris were detected less consistently than the aforementioned viruses. Enterovirus D68 was detected in a limited time frame during fall 2022 at both sites. The measurements reported herein, and in some cases their seasonal trends, are consistent with previous reports of these targets in wastewater. These measurements represent some of the first quantitative measurements of these infectious disease targets in the solid fraction of wastewater. This study lays a foundation for the use of wastewater solids for the detection of specific infectious disease targets in wastewater monitoring programs aimed to better understand the spread of these diseases.

Aims/Hypothesis. it is important to address our use of cheaper generic therapies for type 2 diabetes (T2DM as the global prevalence of type 2 diabetes (T2DM) will surpass 600 million by 2035. Negative aspects of SU may be avoided by their use at low dose. We have previously shown that 20mg standard release gliclazide reduces plasma glucose through augmentation of the classical incretin effect, increased beta cell glucose sensitivity and late-phase incretin potentiation. We hypothesised that there would be potential synergy between low dose SU when given in combination with a DPP4i, without increased hypoglycaemia risk, and aimed to assess this in a randomised clinical trial. Methods 30 participants with T2DM (HbA1c <64 mmol/mol) treated with diet or metformin monotherapy were recruited to a single-centre, open-label, randomised crossover study. Participants completed four, 14-day study periods in a random order: control, gliclazide 20mg once daily (SU), sitagliptin 100mg (DPP4i), or combination (SUDPP4i). A 2-hour mixed meal tolerance test was conducted at the end of each period. Beta-cell function was assessed by modelling. The primary outcome was the effect of treatment on beta cell glucose sensitivity. Secondary end points included frequency of blood glucose <3mmol/l on continuous glucose monitoring, sub analysis by genotype (KNCJ11 E23K), and analysis by gender and body mass index. Results Linear mixed model estimates showed a potent additive, glucose lowering effect of low dose SU combination with DPP4. Mean glucose AUC (mean 95% CI) (mmol/l) was: Control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (p <0.001). Beta cell glucose sensitivity (pmol min-1 m-2mM-1) mirrored this additive effect: Control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-14.3) (p = 0.04). Glucose time in range <3mmol/l on CGM (%) was unaffected: Control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (p = 0.65). The increase in glucose sensitivity with sulphonylurea treatment was seen in men not women. Conclusions Combination low dose gliclazide with a DPP4i has potent glucose lowering effect through augmentation of beta cell function. Glucose reduction was achieved at gliclazide concentrations far below those achieved with standard therapeutic doses. A double-blind randomised controlled trial is merited to formalise efficacy and safety of this combination, which may avoid negative aspects of SU and provide pharmacoeconomic benefit in diabetes care.

Background: Global longitudinal active strain energy density (GLASED) is an innovative method for assessing myocardial function by quantifying the work performed by the left ventricular muscle. The use of GLASED holds promise for improving the diagnosis and management of cardiac diseases. This study aimed to evaluate the feasibility of measuring GLASED using echocardiography and investigate potential differences in GLASED values among athletes based on age and sex. Methods and Results: An observational echocardiographic study was conducted, involving male controls, male and female young athletes, and male and female veteran athletes. GLASED was calculated from the myocardial stress and strain. The mean age (years) of young athletes was 21.6 for males and 21.4 for females, while the mean age of veteran athletes was 53.5 for males and 54.2 for females. GLASED was found to be highest in young male athletes (2.40 kJ/m3) and lowest in female veterans (1.96 kJ/m3). Veteran males exhibited lower values (1.96 kJ/m3) compared to young male athletes (P<0.001). Young females demonstrated greater GLASED (2.28 kJ/m3) than veteran females (P<0.01). However, no significant difference in GLASED was observed between male and female veterans. Conclusions: Our findings demonstrate the feasibility of measuring GLASED using echocardiography. GLASED values were higher in young male athletes compared to female athletes, and it decreased with age. Importantly, the sex-related differences observed in GLASED values among young athletes were no longer present in veteran athletes. Estimating GLASED may serve as a valuable screening tool for cardiac diseases in athletes, particularly for those with borderline phenotypes of hypertrophic and dilated cardiomyopathies.

Predicting an individual's risk of infectious disease is a critical technology in infectious disease response. During the COVID-19 pandemic, identifying and isolating individuals at high risk of infection was an essential task for epidemic control. We introduce a new machine learning model that predicts the risk of COVID-19 infection using only individuals' mobile cell tower location information. This model distinguishes the cell tower location information of an individual into residential and non-residential areas and calculates whether the cell tower locations overlapped with other individuals. It then generates various variables from the information of overlapping and predicts the possibility of COVID-19 infection using a machine learning algorithm. The predictive model we developed showed performance comparable to models using individual's clinical information. This predictive model, which can be used to predict infections of diseases with asymptomatic infections such as COVID-19, has the advantage of supplementing the limitations of existing infectious disease prediction models that use symptoms and other information.