IGF1 promotes human myotube differentiation toward a mature metabolic and contractile phenotype.

Skeletal muscle mediates the beneficial effects of exercise, thereby improving insulin sensitivity and reducing the risk for type 2 diabetes. Current human skeletal muscle models in vitro are incapable of fully recapitulating its physiological functions especially muscle contractility. By supplementation of insulin-like growth factor 1 (IGF1), a growth factor secreted by myofibers in vivo, we aimed to overcome these limitations. We monitored the differentiation process starting from primary human CD56-positive myoblasts in the presence/absence of IGF1 in serum-free medium in daily collected samples for 10 days. IGF1-supported differentiation formed thicker multinucleated myotubes showing physiological contraction upon electrical pulse stimulation (EPS) following day 6. Myotubes without IGF1 were almost incapable of contraction. IGF1 treatment shifted the proteome toward skeletal muscle-specific proteins that contribute to myofibril and sarcomere assembly, striated muscle contraction, and ATP production. Elevated PPARGC1A, MYH7, and reduced MYH1/2 suggest a more oxidative phenotype further demonstrated by higher abundance of proteins of the respiratory chain and elevated mitochondrial respiration. IGF1-treatment also upregulated glucose transporter (GLUT)4 and increased insulin-dependent glucose uptake compared with myotubes differentiated without IGF1. To conclude, addition of IGF1 to serum-free medium significantly improves the differentiation of human myotubes that showed enhanced myofibril formation, response to electrical pulse stimulation, oxidative respiratory capacity, and glucose metabolism overcoming limitations of previous standards. This novel protocol enables investigation of muscular exercise on a molecular level.NEW & NOTEWORTHY Human skeletal muscle models are highly valuable to study how exercise prevents type 2 diabetes without invasive biopsies. Current models did not fully recapitulate the function of skeletal muscle especially during exercise. By supplementing insulin-like growth factor 1 (IGF1), the authors developed a functional human skeletal muscle model characterized by inducible contractility and increased oxidative and insulin-sensitive metabolism. The novel protocol overcomes the limitations of previous standards and enables investigation of exercise on a molecular level.

A burden of proof study on alcohol consumption and ischemic heart disease.

Cohort and case-control data have suggested an association between low to moderate alcohol consumption and decreased risk of ischemic heart disease (IHD), yet results from Mendelian randomization (MR) studies designed to reduce bias have shown either no or a harmful association. Here we conducted an updated systematic review and re-evaluated existing cohort, case-control, and MR data using the burden of proof meta-analytical framework. Cohort and case-control data show low to moderate alcohol consumption is associated with decreased IHD risk - specifically, intake is inversely related to IHD and myocardial infarction morbidity in both sexes and IHD mortality in males - while pooled MR data show no association, confirming that self-reported versus genetically predicted alcohol use data yield conflicting findings about the alcohol-IHD relationship. Our results highlight the need to advance MR methodologies and emulate randomized trials using large observational databases to obtain more definitive answers to this critical public health question.

Mesenchymal stromal cell chondrogenesis under ALK1/2/3-specific BMP inhibition: a revision of the prohypertrophic signalling network concept.

BACKGROUND: In vitro chondrogenesis of mesenchymal stromal cells (MSCs) driven by the essential chondro-inducer transforming growth factor (TGF)-ß is instable and yields undesired hypertrophic cartilage predisposed to bone formation in vivo. TGF-ß can non-canonically activate bone morphogenetic protein-associated ALK1/2/3 receptors. These have been accused of driving hypertrophic MSC misdifferentiation, but data remained conflicting. We here tested the antihypertrophic capacity of two highly specific ALK1/2/3 inhibitors - compound A (CompA) and LDN-212854 (LDN21) - in order to reveal potential prohypertrophic contributions of these BMP/non-canonical TGF-ß receptors during MSC in vitro chondrogenesis. METHODS: Standard chondrogenic pellet cultures of human bone marrow-derived MSCs were treated with TGF-ß and CompA (500 nM) or LDN21 (500 nM). Daily 6-hour pulses of parathyroid hormone-related peptide (PTHrP[1-34], 2.5 nM, from day 7) served as potent antihypertrophic control treatment. Day 28 samples were subcutaneously implanted into immunodeficient mice. RESULTS: All groups underwent strong chondrogenesis, but GAG/DNA deposition and ACAN expression were slightly but significantly reduced by ALK inhibition compared to solvent controls along with a mild decrease of the hypertrophy markers IHH-, SPP1-mRNA, and Alkaline phosphatase (ALP) activity. When corrected for the degree of chondrogenesis (COL2A1 expression), only pulsed PTHrP but not ALK1/2/3 inhibition qualified as antihypertrophic treatment. In vivo, all subcutaneous cartilaginous implants mineralized within 8 weeks, but PTHrP pretreated samples formed less bone and attracted significantly less haematopoietic marrow than ALK1/2/3 inhibitor groups. CONCLUSIONS: Overall, our data show that BMP-ALK1/2/3 inhibition cannot program mesenchymal stromal cells toward stable chondrogenesis. BMP-ALK1/2/3 signalling is no driver of hypertrophic MSC misdifferentiation and BMP receptor induction is not an adverse prohypertrophic side effect of TGF-ß that leads to endochondral MSC misdifferentiation. Instead, the prohypertrophic network comprises misregulated PTHrP/hedgehog signalling and WNT activity, and a potential contribution of TGF-ß-ALK4/5-mediated SMAD1/5/9 signalling should be further investigated to decide about its postulated prohypertrophic activity. This will help to successfully engineer cartilage replacement tissues from MSCs in vitro and translate these into clinical cartilage regenerative therapies.

The global distribution and the risk prediction of relapsing fever group Borrelia: a data review with modelling analysis.

BACKGROUND: The recent discovery of emerging relapsing fever group Borrelia (RFGB) species, such as Borrelia miyamotoi, poses a growing threat to public health. However, the global distribution and associated risk burden of these species remain uncertain. We aimed to map the diversity, distribution, and potential infection risk of RFGB. METHODS: We searched PubMed, Web of Science, GenBank, CNKI, and eLibrary from Jan 1, 1874, to Dec 31, 2022, for published articles without language restriction to extract distribution data for RFGB detection in vectors, animals, and humans, and clinical information about human patients. Only articles documenting RFGB infection events were included in this study, and data for RFGB detection in vectors, animals, or humans were composed into a dataset. We used three machine learning algorithms (boosted regression trees, random forest, and least absolute shrinkage and selection operator logistic regression) to assess the environmental, ecoclimatic, biological, and socioeconomic factors associated with the occurrence of four major RFGB species: Borrelia miyamotoi, Borrelia lonestari, Borrelia crocidurae, and Borrelia hermsii; and mapped their worldwide risk level. FINDINGS: We retrieved 13 959 unique studies, among which 697 met the selection criteria and were used for data extraction. 29 RFGB species have been recorded worldwide, of which 27 have been identified from 63 tick species, 12 from 61 wild animals, and ten from domestic animals. 16 RFGB species caused human infection, with a cumulative count of 26 583 cases reported from Jan 1, 1874, to Dec 31, 2022. Borrelia recurrentis (17 084 cases) and Borrelia persica (2045 cases) accounted for the highest proportion of human infection. B miyamotoi showed the widest distribution among all RFGB, with a predicted environmentally suitable area of 6·92 million km2, followed by B lonestari (1·69 million km2), B crocidurae (1·67 million km2), and B hermsii (1·48 million km2). The habitat suitability index of vector ticks and climatic factors, such as the annual mean temperature, have the most significant effect among all predictive models for the geographical distribution of the four major RFGB species. INTERPRETATION: The predicted high-risk regions are considerably larger than in previous reports. Identification, surveillance, and diagnosis of RFGB infections should be prioritised in high-risk areas, especially within low-income regions. FUNDING: National Key Research and Development Program of China.

Health effects associated with chewing tobacco: a Burden of Proof study.

Chewing tobacco use poses serious health risks; yet it has not received as much attention as other tobacco-related products. This study synthesizes existing evidence regarding the health impacts of chewing tobacco while accounting for various sources of uncertainty. We conducted a systematic review and meta-analysis of chewing tobacco and seven health outcomes, drawing on 103 studies published from 1970 to 2023. We use a Burden of Proof meta-analysis to generate conservative risk estimates and find weak-to-moderate evidence that tobacco chewers have an increased risk of stroke, lip and oral cavity cancer, esophageal cancer, nasopharynx cancer, other pharynx cancer, and laryngeal cancer. We additionally find insufficient evidence of an association between chewing tobacco and ischemic heart disease. Our findings highlight a need for policy makers, researchers, and communities at risk to devote greater attention to chewing tobacco by both advancing tobacco control efforts and investing in strengthening the existing evidence base.

Regulatory role of miRNAs in nasopharyngeal cancer involving PTEN/PI3K/AKT, TGFß/SMAD, RAS/MAPK, Wnt/ß-catenin and pRB-E2F signaling pathways: A review.

MicroRNAs (miRNA) are small and conserved noncoding RNA molecules that regulate gene expression at the posttranscriptional level. These groups of RNAs are crucial in various cellular processes, especially in mediating disease pathogenesis, particularly cancer. The dysregulation of miRNAs was reported in many cancer types, including nasopharyngeal cancer (NPC), which is a malignant tumor of the nasopharynx. In this review, miRNAs involvement in crucial signaling pathways associated with NPC such as PTEN/PI3K/AKT, TGFß/SMAD, RAS/MAPK, Wnt/ß-catenin and pRB-E2F was investigated. miRNAs could function as tumor suppressor-miR or onco-miR in NPC profoundly influenced cell cycle, apoptosis, proliferation, migration, and metastasis. This comprehensive review of current literature provided a thorough profile of miRNAs and their interplay with the aforementioned signaling pathways in NPC. Understanding these molecular interactions could remarkably impact the diagnosis, prognosis, and therapeutic strategies for NPC.

Mapping the incidence rate of typhoid fever in sub-Saharan Africa.

BACKGROUND: With more than 1.2 million illnesses and 29,000 deaths in sub-Saharan Africa in 2017, typhoid fever continues to be a major public health problem. Effective control of the disease would benefit from an understanding of the subnational geospatial distribution of the disease incidence. METHOD: We collated records of the incidence rate of typhoid fever confirmed by culture of blood in Africa from 2000 to 2022. We estimated the typhoid incidence rate for sub-Saharan Africa on 20 km × 20 km grids by exploring the association with geospatial covariates representing access to improved water and sanitation, health conditions of the population, and environmental conditions. RESULTS: We identified six published articles and one pre-print representing incidence rate estimates in 22 sites in 2000-2022. Estimated incidence rates showed geospatial variation at sub-national, national, and regional levels. The incidence rate was high in Western and Eastern African subregions followed by Southern and Middle African subregions. By age, the incidence rate was highest among 5-14 yo followed by 2-4 yo, > 14 yo, and 0-1 yo. When aggregated across all age classes and grids that comprise each country, predicted incidence rates ranged from 43.7 (95% confidence interval: 0.6 to 591.2) in Zimbabwe to 2,957.8 (95% CI: 20.8 to 4,245.2) in South Sudan per 100,000 person-years. Sub-national heterogeneity was evident with the coefficient of variation at the 20 km × 20 km grid-level ranging from 0.7 to 3.3 and was generally lower in high-incidence countries and widely varying in low-incidence countries. CONCLUSION: Our study provides estimates of 20 km × 20 km incidence rate of typhoid fever across sub-Saharan Africa based on data collected from 2000 through 2020. Increased understanding of the subnational geospatial variation of typhoid fever in Africa may inform more effective intervention programs by better targeting resources to heterogeneously disturbed disease risk.

Mechanisms of SARS-CoV-2 Inactivation Using UVC Laser Radiation.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has had a tremendous impact on humanity. Prevention of transmission by disinfection of surfaces and aerosols through a chemical-free method is highly desirable. Ultraviolet C (UVC) light is uniquely positioned to achieve inactivation of pathogens. We report the inactivation of SARS-CoV-2 virus by UVC radiation and explore its mechanisms. A dose of 50 mJ/cm2 using a UVC laser at 266 nm achieved an inactivation efficiency of 99.89%, while infectious virions were undetectable at 75 mJ/cm2 indicating >99.99% inactivation. Infection by SARS-CoV-2 involves viral entry mediated by the spike glycoprotein (S), and viral reproduction, reliant on translation of its genome. We demonstrate that UVC radiation damages ribonucleic acid (RNA) and provide in-depth characterization of UVC-induced damage of the S protein. We find that UVC severely impacts SARS-CoV- 2 spike protein's ability to bind human angiotensin-converting enzyme 2 (hACE2) and this correlates with loss of native protein conformation and aromatic amino acid integrity. This report has important implications for the design and development of rapid and effective disinfection systems against the SARS-CoV-2 virus and other pathogens.

Health effects associated with exposure to secondhand smoke: a Burden of Proof study.

Despite a gradual decline in smoking rates over time, exposure to secondhand smoke (SHS) continues to cause harm to nonsmokers, who are disproportionately children and women living in low- and middle-income countries. We comprehensively reviewed the literature published by July 2022 concerning the adverse impacts of SHS exposure on nine health outcomes. Following, we quantified each exposure-response association accounting for various sources of uncertainty and evaluated the strength of the evidence supporting our analyses using the Burden of Proof Risk Function methodology. We found all nine health outcomes to be associated with SHS exposure. We conservatively estimated that SHS increases the risk of ischemic heart disease, stroke, type 2 diabetes and lung cancer by at least around 8%, 5%, 1% and 1%, respectively, with the evidence supporting these harmful associations rated as weak (two stars). The evidence supporting the harmful associations between SHS and otitis media, asthma, lower respiratory infections, breast cancer and chronic obstructive pulmonary disease was weaker (one star). Despite the weak underlying evidence for these associations, our results reinforce the harmful effects of SHS on health and the need to prioritize advancing efforts to reduce active and passive smoking through a combination of public health policies and education initiatives.

Hearing Loss Prevalence, Years Lived With Disability, and Hearing Aid Use in the United States From 1990 to 2019: Findings From the Global Burden of Disease Study.

OBJECTIVES: This article describes key data sources and methods used to estimate hearing loss in the United States, in the Global Burden of Disease study. Then, trends in hearing loss are described for 2019, including temporal trends from 1990 to 2019, changing prevalence over age, severity patterns, and utilization of hearing aids. DESIGN: We utilized population-representative surveys from the United States to estimate hearing loss prevalence for the Global Burden of Disease study. A key input data source in modeled estimates are the National Health and Nutrition Examination Surveys (NHANES), years 1988 to 2010. We ran hierarchical severity-specific models to estimate hearing loss prevalence. We then scaled severity-specific models to sum to total hearing impairment prevalence, adjusted estimates for hearing aid coverage, and split estimates by etiology and tinnitus status. We computed years lived with disability (YLDs), which quantifies the amount of health loss associated with a condition depending on severity and creates a common metric to compare the burden of disparate diseases. This was done by multiplying the prevalence of severity-specific hearing loss by corresponding disability weights, with additional weighting for tinnitus comorbidity. RESULTS: An estimated 72.88 million (95% uncertainty interval (UI) 68.53 to 77.30) people in the United States had hearing loss in 2019, accounting for 22.2% (20.9 to 23.6) of the total population. Hearing loss was responsible for 2.24 million (1.56 to 3.11) YLDs (3.6% (2.8 to 4.7) of total US YLDs). Age-standardized prevalence was higher in males (17.7% [16.7 to 18.8]) compared with females (11.9%, [11.2 to 12.5]). While most cases of hearing loss were mild (64.3%, 95% UI 61.0 to 67.6), disability was concentrated in cases that were moderate or more severe. The all-age prevalence of hearing loss in the United States was 28.1% (25.7 to 30.8) higher in 2019 than in 1990, despite stable age-standardized prevalence. An estimated 9.7% (8.6 to 11.0) of individuals with mild to profound hearing loss utilized a hearing aid, while 32.5% (31.9 to 33.2) of individuals with hearing loss experienced tinnitus. Occupational noise exposure was responsible for 11.2% (10.2 to 12.4) of hearing loss YLDs. CONCLUSIONS: Results indicate large burden of hearing loss in the United States, with an estimated 1 in 5 people experiencing this condition. While many cases of hearing loss in the United States were mild, growing prevalence, low usage of hearing aids, and aging populations indicate the rising impact of this condition in future years and the increasing importance of domestic access to hearing healthcare services. Large-scale audiometric surveys such as NHANES are needed to regularly assess hearing loss burden and access to healthcare, improving our understanding of who is impacted by hearing loss and what groups are most amenable to intervention.

Health effects associated with exposure to intimate partner violence against women and childhood sexual abuse: a burden of proof study.

The health impacts of intimate partner violence against women and childhood sexual abuse are not fully understood. Here we conducted a systematic review by comprehensively searching seven electronic databases for literature on intimate partner violence-associated and childhood sexual abuse-associated health effects. Following the burden of proof methodology, we evaluated the evidence strength linking intimate partner violence and/or childhood sexual abuse to health outcomes supported by at least three studies. Results indicated a moderate association of intimate partner violence with major depressive disorder and with maternal abortion and miscarriage (63% and 35% increased risk, respectively). HIV/AIDS, anxiety disorders and self-harm exhibited weak associations with intimate partner violence. Fifteen outcomes were evaluated for their relationship to childhood sexual abuse, which was shown to be moderately associated with alcohol use disorders and with self-harm (45% and 35% increased risk, respectively). Associations between childhood sexual abuse and 11 additional health outcomes, such as asthma and type 2 diabetes mellitus, were found to be weak. Although our understanding remains limited by data scarcity, these health impacts are larger in magnitude and more extensive than previously reported. Renewed efforts on violence prevention and evidence-based approaches that promote healing and ensure access to care are necessary.

Dispersed DNA variants underlie hearing loss in South Florida's minority population.

BACKGROUND: We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. RESULTS: The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. CONCLUSION: This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses.

Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS).

BACKGROUND: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. METHODS: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. FINDINGS: Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. INTERPRETATION: By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. FUNDING: German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.

Catastrophic health expenditure during the COVID-19 pandemic in five countries: a time-series analysis.

BACKGROUND: The COVID-19 pandemic disrupted health systems in 2020, but it is unclear how financial hardship due to out-of-pocket (OOP) health-care costs was affected. We analysed catastrophic health expenditure (CHE) in 2020 in five countries with available household expenditure data: Belarus, Mexico, Peru, Russia, and Viet Nam. In Mexico and Peru, we also conducted an analysis of drivers of change in CHE in 2020 using publicly available data. METHODS: In this time-series analysis, we defined CHE as when OOP health-care spending exceeds 10% of consumption expenditure. Data for 2004-20 were obtained from individual and household level survey microdata (available for Mexico and Peru only), and tabulated data from the National Statistical Committee of Belarus and the World Bank Health Equity and Financial Protection Indicator database (for Viet Nam and Russia). We compared 2020 CHE with the CHE predicted from historical trends using an ensemble model. This method was also used to assess drivers of CHE: insurance coverage, OOP expenditure, and consumption expenditure. Interrupted time-series analysis was used to investigate the role of stay-at-home orders in March, 2020 in changes in health-care use and sector (ie, private vs public). FINDINGS: In Mexico, CHE increased to 5·6% (95% uncertainty interval [UI] 5·1-6·2) in 2020, higher than predicted (3·2%, 2·5-4·0). In Belarus, CHE was 13·5% (11·8-15·2) in 2020, also higher than predicted (9·7%, 7·7-11·3). CHE was not different than predicted by past trends in Russia, Peru, and Viet Nam. Between March and April, 2020, health-care visits dropped by 4·6 (2·6-6·5) percentage points in Mexico and by 48·3 (40·6-56·0) percentage points in Peru, and the private share of health-care visits increased by 7·3 (4·3-10·3) percentage points in Mexico and by 20·7 (17·3-24·0) percentage points in Peru. INTERPRETATION: In three of the five countries studied, health systems either did not protect people from the financial risks of health care or did not maintain health-care access in 2020, an indication of health systems failing to maintain basic functions. If the 2020 response to the COVID-19 pandemic accelerated shifts to private health-care use, policies to cover costs in that sector or motivate patients to return to the public sector are needed to maintain financial risk protection. FUNDING: The Bill & Melinda Gates Foundation.

Room-Temperature Monitoring of CH4 and CO2 Using a Metal-Organic Framework-Based QCM Sensor Showing Inherent Analyte Discrimination.

The detection of methane and carbon dioxide is of growing importance due to their negative impact on global warming. This is true for both environmental monitoring and leak detection in industrial processes. Although solid-state sensors are technologically mature, they have limitations that prohibit their use in certain situations, e.g., explosive atmospheres. Thus, there is a need to develop new types of sensor materials. Herein, we demonstrate a simple, low-cost, metal-organic framework (MOF)-based gas leak detection sensor. The system is based on gravimetric sensing by using a quartz crystal microbalance. The quartz crystal is functionalized by layer-by-layer growth of a thin metal-organic framework film. This film shows selective uptake of methane or carbon dioxide under atmospheric conditions. The hardware has low cost, simple operation, and theoretically high sensitivity. Overall, the sensor is characterized by simplicity and high robustness. Furthermore, by exploiting the different adsorption kinetics as measured by multiple harmonic analyses, it is possible to discriminate whether the response is due to methane or carbon dioxide. In summary, we demonstrate data relevant toward new applications of metal-organic frameworks and microporous hybrid materials in sensing.

Development of a Core Outcome Set for the research and assessment of inoperable malignant bowel obstruction.

BACKGROUND: Malignant bowel obstruction is experienced by 15% of people with advanced cancer, preventing them from eating and drinking and causing pain, nausea and vomiting. Surgery is not always appropriate. Management options include tube or stent drainage of intestinal contents and symptom control using medication. Published literature describing palliative interventions uses a broad range of outcome measures, few of which are patient-relevant. This hinders evidence synthesis, and fails to consider the perspectives of people undergoing treatment. AIMS: To develop a Core Outcome Set for the assessment of inoperable malignant bowel obstruction with clinician, patient and caregiver involvement, using COMET methodology (Core Outcome Measures in Effectiveness Trials). METHODS: A systematic review of clinical trials and observational studies, a rapid review of the qualitative literature and in-depth patient and clinician interviews were conducted to identify a comprehensive list of outcomes. Outcomes were compared and consolidated by the study Steering Group and Patient and Public Involvement contributors, and presented to an international clinical Expert Panel for review. Outcomes from the finalised list were rated for importance in a three-round international Delphi process: results of two survey rounds were circulated to respondents, and two separate consensus meetings were conducted with clinicians and with patients and caregivers via virtual conferencing, using live polling to reach agreement on a Core Outcome Set. RESULTS: 130 unique outcomes were identified. Following the independent Expert Panel review, 82 outcomes were taken into round 1 of the Delphi survey; 24 outcomes reached criteria for critical importance across all stakeholder groups and none reached criteria for dropping. All outcomes rated critically important were taken forward for re-rating in round 2 and all other outcomes dropped. In round 2, all outcomes were voted critically important by at least one stakeholder group. Round 2 outcomes were presented again at online consensus meetings, categorised as high ranking (n = 9), middle ranking (n = 7) or low ranking (n = 8). Stakeholders reached agreement on 16 core outcomes across four key domains: Symptom control, Life impact, Treatment outcomes, and Communication and patient preferences. CONCLUSION: Use of this Core Outcome Set can help to address current challenges in making sense of the evidence around treatment for inoperable malignant bowel obstruction to date, and underpin a more robust future approach. Clearer communication and an honest understanding between all stakeholders will help to provide a basis for responsible decision-making in this distressing situation in clinical practice.

Estimating vaccine coverage in conflict settings using geospatial methods: a case study in Borno state, Nigeria.

Reliable estimates of subnational vaccination coverage are critical to track progress towards global immunisation targets and ensure equitable health outcomes for all children. However, conflict can limit the reliability of coverage estimates from traditional household-based surveys due to an inability to sample in unsafe and insecure areas and increased uncertainty in underlying population estimates. In these situations, model-based geostatistical (MBG) approaches offer alternative coverage estimates for administrative units affected by conflict. We estimated first- and third-dose diphtheria-tetanus-pertussis vaccine coverage in Borno state, Nigeria, using a spatiotemporal MBG modelling approach, then compared these to estimates from recent conflict-affected, household-based surveys. We compared sampling cluster locations from recent household-based surveys to geolocated data on conflict locations and modelled spatial coverage estimates, while also investigating the importance of reliable population estimates when assessing coverage in conflict settings. These results demonstrate that geospatially-modelled coverage estimates can be a valuable additional tool to understand coverage in locations where conflict prevents representative sampling.

Disease-specific health spending by age, sex, and type of care in Norway: a national health registry study.

BACKGROUND: Norway is a high-income nation with universal tax-financed health care and among the highest per person health spending in the world. This study estimates Norwegian health expenditures by health condition, age, and sex, and compares it with disability-adjusted life-years (DALYs). METHODS: Government budgets, reimbursement databases, patient registries, and prescription databases were combined to estimate spending for 144 health conditions, 38 age and sex groups, and eight types of care (GPs; physiotherapists & chiropractors; specialized outpatient; day patient; inpatient; prescription drugs; home-based care; and nursing homes) totaling 174,157,766 encounters. Diagnoses were in accordance with the Global Burden of Disease study (GBD). The spending estimates were adjusted, by redistributing excess spending associated with each comorbidity. Disease-specific DALYs were gathered from GBD 2019. RESULTS: The top five aggregate causes of Norwegian health spending in 2019 were mental and substance use disorders (20.7%), neurological disorders (15.4%), cardiovascular diseases (10.1%), diabetes, kidney, and urinary diseases (9.0%), and neoplasms (7.2%). Spending increased sharply with age. Among 144 health conditions, dementias had the highest health spending, with 10.2% of total spending, and 78% of this spending was incurred at nursing homes. The second largest was falls estimated at 4.6% of total spending. Spending in those aged 15-49 was dominated by mental and substance use disorders, with 46.0% of total spending. Accounting for longevity, spending per female was greater than spending per male, particularly for musculoskeletal disorders, dementias, and falls. Spending correlated well with DALYs (Correlation r = 0.77, 95% CI 0.67-0.87), and the correlation of spending with non-fatal disease burden (r = 0.83, 0.76-0.90) was more pronounced than with mortality (r = 0.58, 0.43-0.72). CONCLUSIONS: Health spending was high for long-term disabilities in older age groups. Research and development into more effective interventions for the disabling high-cost diseases is urgently needed.