Phenotype of BTK-lacking myeloid cells during prolonged COVID-19 and upon convalescent plasma.

XLA patient with 7-month course of COVID-19 with persistent plasma SARS-CoV-2 load revealed a sustained non-inflammatory profile of myeloid cells in association with contained severity of disease, arguing in favor of the use of BTK inhibitors in SARS-COV-2 infection.

Coarse Particulate Air Pollution and Daily Mortality: A Global Study in 205 Cities.

Rationale: The associations between ambient coarse particulate matter (PM2.5-10) and daily mortality are not fully understood on a global scale. Objectives: To evaluate the short-term associations between PM2.5-10 and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide. Methods: We collected daily mortality (total, cardiovascular, and respiratory) and air pollution data from 205 cities in 20 countries/regions. Concentrations of PM2.5-10 were computed as the difference between inhalable and fine PM. A two-stage time-series analytic approach was applied, with overdispersed generalized linear models and multilevel meta-analysis. We fitted two-pollutant models to test the independent effect of PM2.5-10 from copollutants (fine PM, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide). Exposure-response relationship curves were pooled, and regional analyses were conducted. Measurements and Main Results: A 10 µg/m3 increase in PM2.5-10 concentration on lag 0-1 day was associated with increments of 0.51% (95% confidence interval [CI], 0.18%-0.84%), 0.43% (95% CI, 0.15%-0.71%), and 0.41% (95% CI, 0.06%-0.77%) in total, cardiovascular, and respiratory mortality, respectively. The associations varied by country and region. These associations were robust to adjustment by all copollutants in two-pollutant models, especially for PM2.5. The exposure-response curves for total, cardiovascular, and respiratory mortality were positive, with steeper slopes at lower exposure ranges and without discernible thresholds. Conclusions: This study provides novel global evidence on the robust and independent associations between short-term exposure to ambient PM2.5-10 and total, cardiovascular, and respiratory mortality, suggesting the need to establish a unique guideline or regulatory limit for daily concentrations of PM2.5-10.

Real-time monitoring shows substantial excess all-cause mortality during second wave of COVID-19 in Europe, October to December 2020.

The European monitoring of excess mortality for public health action (EuroMOMO) network monitors weekly excess all-cause mortality in 27 European countries or subnational areas. During the first wave of the coronavirus disease (COVID-19) pandemic in Europe in spring 2020, several countries experienced extraordinarily high levels of excess mortality. Europe is currently seeing another upsurge in COVID-19 cases, and EuroMOMO is again witnessing a substantial excess all-cause mortality attributable to COVID-19.

Excess all-cause mortality during the COVID-19 pandemic in Europe - preliminary pooled estimates from the EuroMOMO network, March to April 2020.

A remarkable excess mortality has coincided with the COVID-19 pandemic in Europe. We present preliminary pooled estimates of all-cause mortality for 24 European countries/federal states participating in the European monitoring of excess mortality for public health action (EuroMOMO) network, for the period March-April 2020. Excess mortality particularly affected ≥ 65 year olds (91% of all excess deaths), but also 45-64 (8%) and 15-44 year olds (1%). No excess mortality was observed in 0-14 year olds.

Estimates of global seasonal influenza-associated respiratory mortality: a modelling study.

BACKGROUND: Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015. METHODS: We estimated country-specific influenza-associated respiratory excess mortality rates (EMR) for 33 countries using time series log-linear regression models with vital death records and influenza surveillance data. To extrapolate estimates to countries without data, we divided countries into three analytic divisions for three age groups (<65 years, 65-74 years, and ≥75 years) using WHO Global Health Estimate (GHE) respiratory infection mortality rates. We calculated mortality rate ratios (MRR) to account for differences in risk of influenza death across countries by comparing GHE respiratory infection mortality rates from countries without EMR estimates with those with estimates. To calculate death estimates for individual countries within each age-specific analytic division, we multiplied randomly selected mean annual EMRs by the country's MRR and population. Global 95% credible interval (CrI) estimates were obtained from the posterior distribution of the sum of country-specific estimates to represent the range of possible influenza-associated deaths in a season or year. We calculated influenza-associated deaths for children younger than 5 years for 92 countries with high rates of mortality due to respiratory infection using the same methods. FINDINGS: EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0·1 to 6·4 per 100 000 individuals for people younger than 65 years, 2·9 to 44·0 per 100 000 individuals for people aged between 65 and 74 years, and 17·9 to 223·5 per 100 000 for people older than 75 years. We estimated that 291 243-645 832 seasonal influenza-associated respiratory deaths (4·0-8·8 per 100 000 individuals) occur annually. The highest mortality rates were estimated in sub-Saharan Africa (2·8-16·5 per 100 000 individuals), southeast Asia (3·5-9·2 per 100 000 individuals), and among people aged 75 years or older (51·3-99·4 per 100 000 individuals). For 92 countries, we estimated that among children younger than 5 years, 9243-105 690 influenza-associated respiratory deaths occur annually. INTERPRETATION: These global influenza-associated respiratory mortality estimates are higher than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated. FUNDING: None.

Investigating the predictors of happiness, life satisfaction and success in schizophrenia.

BACKGROUND: Previous studies have suggested that, despite marked functional impairments, remitted first episode patients with schizophrenia report levels of well-being that are comparable to healthy controls. The aim of the current study was to specifically evaluate self-reported happiness, life satisfaction and success in individuals with schizophrenia beyond their first-episode of psychosis, and to investigate the impact of symptoms and functioning on these subjective experiences. METHODS: Fifty-one schizophrenia patients and 56 matched healthy controls participated in the study. Factor scores were computed to compare happiness and life satisfaction and success (LSS) between groups. Hierarchical multiple regression analyses were conducted to investigate the predictive value of symptoms and functional impairments on patients' subjective reports of happiness and LSS. RESULTS: Schizophrenia participants endorsed lower levels of LSS compared to healthy controls, with no significant group differences in self-reported happiness. For patients with schizophrenia, motivation deficits and depressive symptoms predicted reductions in both happiness and LSS. CONCLUSIONS: Patients with schizophrenia do not report significant reductions in their subjective experience of happiness, but do endorse lower levels of life satisfaction and success. Further, the absence of a robust link between poor functioning and lower happiness or LSS serves to reaffirm the notion that functional status does not dictate whether an individual with schizophrenia experiences a sense of happiness, satisfaction or success in life.

Efficacy and Safety of Prucalopride in Chronic Constipation: An Integrated Analysis of Six Randomized, Controlled Clinical Trials.

BACKGROUND: Prucalopride, a selective, high-affinity 5-hydroxytryptamine 4 receptor agonist, stimulates gastrointestinal and colonic motility and alleviates common symptoms of chronic constipation (CC) in adults. The relative efficacy by gender has not been evaluated. AIM: To evaluate the global efficacy and safety of prucalopride 2 mg daily in men and women with CC using data from six large, randomized, controlled clinical trials. METHODS: Data were combined from six phase 3 and 4, double-blind, randomized, placebo-controlled, parallel-group trials. The primary efficacy endpoint was the percentage of patients with a mean of ≥3 spontaneous complete bowel movements (SCBMs) per week over 12 weeks of treatment. Safety was assessed throughout all the trials. RESULTS: Overall, 2484 patients (597 men; 1887 women; prucalopride, 1237; placebo, 1247) were included in the integrated efficacy analysis and 2552 patients were included in the integrated safety analysis. Significantly more patients achieved a mean of ≥3 SCBMs/week over the 12 weeks of treatment in the prucalopride group (27.8 %) than in the placebo group [13.2 %, OR 2.68 (95 % CI 2.16, 3.33), p < 0.001]. Prucalopride had a favorable safety and tolerability profile. Efficacy and safety outcomes were not significantly different between men and women. CONCLUSION: The integrated analysis demonstrates the efficacy and safety of prucalopride in the treatment of CC in men and women.

Proper formation of whisker barrelettes requires periphery-derived Smad4-dependent TGF-beta signaling.

Mammalian somatosensory topographic maps contain specialized neuronal structures that precisely recapitulate the spatial pattern of peripheral sensory organs. In the mouse, whiskers are orderly mapped onto several brainstem nuclei as a set of modular structures termed barrelettes. Using a dual-color iontophoretic labeling strategy, we found that the precise topography of barrelettes is not a result of ordered positions of sensory neurons within the ganglion. We next explored another possibility that formation of the whisker map is influenced by periphery-derived mechanisms. During the period of peripheral sensory innervation, several TGF-ß ligands are exclusively expressed in whisker follicles in a dynamic spatiotemporal pattern. Disrupting TGF-ß signaling, specifically in sensory neurons by conditional deletion of Smad4 at the late embryonic stage, results in the formation of abnormal barrelettes in the principalis and interpolaris brainstem nuclei and a complete absence of barrelettes in the caudalis nucleus. We further show that this phenotype is not derived from defective peripheral innervation or central axon outgrowth but is attributable to the misprojection and deficient segregation of trigeminal axonal collaterals into proper barrelettes. Furthermore, Smad4-deficient neurons develop simpler terminal arbors and form fewer synapses. Together, our findings substantiate the involvement of whisker-derived TGF-ß/Smad4 signaling in the formation of the whisker somatotopic maps.

Deep learning based characterization of human organoids using optical coherence tomography.

Organoids, derived from human induced pluripotent stem cells (hiPSCs), are intricate three-dimensional in vitro structures that mimic many key aspects of the complex morphology and functions of in vivo organs such as the retina and heart. Traditional histological methods, while crucial, often fall short in analyzing these dynamic structures due to their inherently static and destructive nature. In this study, we leveraged the capabilities of optical coherence tomography (OCT) for rapid, non-invasive imaging of both retinal, cerebral, and cardiac organoids. Complementing this, we developed a sophisticated deep learning approach to automatically segment the organoid tissues and their internal structures, such as hollows and chambers. Utilizing this advanced imaging and analysis platform, we quantitatively assessed critical parameters, including size, area, volume, and cardiac beating, offering a comprehensive live characterization and classification of the organoids. These findings provide profound insights into the differentiation and developmental processes of organoids, positioning quantitative OCT imaging as a potentially transformative tool for future organoid research.

Fluctuating risk of acute kidney injury-related mortality for four weeks after exposure to air pollution: A multi-country time-series study in 6 countries.

BACKGROUND: Recent studies have reported that air pollution is related to kidney diseases. However, the global evidence on the risk of death from acute kidney injury (AKI) owing to air pollution is limited. Therefore, we investigated the association between short-term exposure to air pollution-particulate matter ≤ 2.5 µm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)-and AKI-related mortality using a multi-country dataset. METHODS: This study included 41,379 AKI-related deaths in 136 locations in six countries during 1987-2018. A novel case time-series design was applied to each air pollutant during 0-28 lag days to estimate the association between air pollution and AKI-related deaths. Moreover, we calculated AKI deaths attributable to non-compliance with the World Health Organization (WHO) air quality guidelines. RESULTS: The relative risks (95% confidence interval) of AKI-related deaths are 1.052 (1.003, 1.103), 1.022 (0.994, 1.050), and 1.022 (0.982, 1.063) for 5, 10, and 10 µg/m3 increase in lag 0-28 days of PM2.5, warm-season O3, and NO2, respectively. The lag-distributed association showed that the risk appeared immediately on the day of exposure to air pollution, gradually decreased, and then increased again reaching the peak approximately 20 days after exposure to PM2.5 and O3. We also found that 1.9%, 6.3%, and 5.2% of AKI deaths were attributed to PM2.5, warm-season O3, and NO2 concentrations above the WHO guidelines. CONCLUSIONS: This study provides evidence that public health policies to reduce air pollution may alleviate the burden of death from AKI and suggests the need to investigate the several pathways between air pollution and AKI death.

Seasonality of mortality under climate change: a multicountry projection study.

BACKGROUND: Climate change can directly impact temperature-related excess deaths and might subsequently change the seasonal variation in mortality. In this study, we aimed to provide a systematic and comprehensive assessment of potential future changes in the seasonal variation, or seasonality, of mortality across different climate zones. METHODS: In this modelling study, we collected daily time series of mean temperature and mortality (all causes or non-external causes only) via the Multi-Country Multi-City Collaborative (MCC) Research Network. These data were collected during overlapping periods, spanning from Jan 1, 1969 to Dec 31, 2020. We projected daily mortality from Jan 1, 2000 to Dec 31, 2099, under four climate change scenarios corresponding to increasing emissions (Shared Socioeconomic Pathways [SSP] scenarios SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5). We compared the seasonality in projected mortality between decades by its shape, timings (the day-of-year) of minimum (trough) and maximum (peak) mortality, and sizes (peak-to-trough ratio and attributable fraction). Attributable fraction was used to measure the burden of seasonality of mortality. The results were summarised by climate zones. FINDINGS: The MCC dataset included 126 809 537 deaths from 707 locations within 43 countries or areas. After excluding the only two polar locations (both high-altitude locations in Peru) from climatic zone assessments, we analysed 126 766 164 deaths in 705 locations aggregated in four climate zones (tropical, arid, temperate, and continental). From the 2000s to the 2090s, our projections showed an increase in mortality during the warm seasons and a decrease in mortality during the cold seasons, albeit with mortality remaining high during the cold seasons, under all four SSP scenarios in the arid, temperate, and continental zones. The magnitude of this changing pattern was more pronounced under the high-emission scenarios (SSP3-7.0 and SSP5-8.5), substantially altering the shape of seasonality of mortality and, under the highest emission scenario (SSP5-8.5), shifting the mortality peak from cold seasons to warm seasons in arid, temperate, and continental zones, and increasing the size of seasonality in all zones except the arid zone by the end of the century. In the 2090s compared with the 2000s, the change in peak-to-trough ratio (relative scale) ranged from 0·96 to 1·11, and the change in attributable fraction ranged from 0·002% to 0·06% under the SSP5-8.5 (highest emission) scenario. INTERPRETATION: A warming climate can substantially change the seasonality of mortality in the future. Our projections suggest that health-care systems should consider preparing for a potentially increased demand during warm seasons and sustained high demand during cold seasons, particularly in regions characterised by arid, temperate, and continental climates. FUNDING: The Environment Research and Technology Development Fund of the Environmental Restoration and Conservation Agency, provided by the Ministry of the Environment of Japan.

[Eating Habits of People with Type 2 Diabetes Mellitus in Portugal: A Cross-Sectional Study]. / Hábitos Alimentares das Pessoas com Diabetes Mellitus Tipo 2 em Portugal: Um Estudo Transversal.

INTRODUCTION: Nutrition is a cornerstone of diabetes mellitus prevention and management; therefore, it is essential to enable patients to adopt healthy eating habits. Previous studies have not yet documented the main errors in the eating habits of Portuguese people with type 2 diabetes mellitus. This study aims to identify the main errors in the eating habits of people living with type 2 diabetes mellitus in Portugal and to evaluate its associations with sociodemographic variables. METHODS: Cross-sectional multicentric study in a convenience sample of people with type 2 diabetes mellitus in Primary Health Care Units. The UK Diabetes and Diet Questionnaire (UKDDQ) - translated and adapted, was applied from July to October 2022. Descriptive and inferential statistical analyses were conducted. RESULTS: Of the 550 participants, 52.2% were female, 68.3% were 65 years or over, 55.8 % had an education level up to the fourth grade, 24.7% had economic deprivation, and the mean time since diagnosis was 10.60 ± 8.13 years. Only 36.2% of the sample had a healthy UKDDQ score. Less than 50% of the sample had healthy scores for the items "high-fiber rice or pasta", "high-fiber bread", "butter, margarine and vegetable oils" and "vegetables and pulses". Only 8.9% of the sample had a healthy consumption of fiber. About 70.4% reported healthy scores for the consumption of "high-added-sugar foods" and 54.7% for "high-saturated fat". A statistically significant weak positive correlation was found between the UKDDQ score and age (ρ = 0.201, p < 0.001) with a more frequent choice of healthy foods with increasing age. Female respondents reported healthier habits, particularly in the consumption of "high-saturated fat" and "high-fiber foods". CONCLUSION: The majority of our sample did not take advantage of the potential benefits of healthy eating habits. The main food groups whose consumption should be emphasized or discouraged were individualized, particularly the need to encourage the consumption of high-fiber foods. Targeted educational actions must focus especially on younger and/or male patients.

Introdução: A nutrição é uma área de intervenção na prevenção e gestão da diabetes mellitus; por isso, é fulcral promover a capacitação da população para a adoção de hábitos alimentares saudáveis. Ainda que existam alguns estudos nesta área, não se conhecem os principais erros nos hábitos alimentares das pessoas com diabetes em Portugal. Os objetivos deste estudo foram identificar os principais erros nos hábitos alimentares das pessoas com diabetes mellitus tipo 2 em Portugal e avaliar a sua relação com variáveis sociodemográficas. Métodos: Estudo transversal multicêntrico, em amostra de conveniência de pessoas com diabetes mellitus tipo 2 seguidas em Unidades de Cuidados de Saúde Primários. Aplicação do UK Diabetes and Diet Questionnaire (UKDDQ) ­ traduzido e adaptado, de julho a outubro de 2022. Análise estatística descritiva e inferencial. Resultados: Amostra de 550 participantes, 52,2% do sexo feminino, 68,3% com 65 anos ou mais, 55,8% com nível de escolaridade igual ou inferior ao 1.º ciclo do ensino básico, 24,7% com insuficiência económica e tempo desde o diagnóstico médio de 10,60 ± 8,13 anos. Apenas 36,2% da amostra obteve um score UKDDQ considerado saudável. Menos de 50% obteve scores saudáveis para os itens "arroz ou massa ricos em fibras", "pão integral", "manteiga, margarina e óleos vegetais" e "vegetais e leguminosas". Somente 8,9% da amostra obteve score saudável para o consumo de fibras. Cerca de 70,4% obteve score saudável para o consumo de açúcares livres e 54,7% para o consumo de ácidos gordos saturados. Verificou-se a existência de uma correlação com significado estatístico positiva fraca entre o score UKDDQ e a idade (ρ = 0,201, p < 0,001), com escolha mais frequente de alimentos saudáveis com o aumentar da idade. As pessoas do sexo feminino reportaram hábitos alimentares mais saudáveis, particularmente no consumo de fibras e ácidos gordos saturados. Conclusão: A maior parte da nossa amostra não usufruiu do potencial efeito positivo de uma alimentação saudável. Individualizam-se grupos de alimentos cujos consumos devem ser enfatizados ou desencorajados, particularmente, a necessidade de incentivar o consumo de alimentos ricos em fibra. Ações educacionais dirigidas devem ter especial foco em pessoas mais jovens e/ou do sexo masculino.

Seroprevalence of Protective Antibodies Against Influenza and the Reduction of the Influenza Incidence Rate: An Annual Repeated Cross-Sectional Study From 2014 to 2019.

BACKGROUND: Seroepidemiological studies provide estimates of population-level immunity, prevalence/incidence of infections, and evaluation of vaccination programs. We assessed the seroprevalence of protective antibodies against influenza and evaluated the correlation of seroprevalence with the cumulative annual influenza incidence rate. METHODS: We conducted an annual repeated cross-sectional seroepidemiological survey, during June-August, from 2014 to 2019, in Portugal. A total of 4326 sera from all age groups, sex, and regions was tested by hemagglutination inhibition assay. Seroprevalence and geometric mean titers (GMT) of protective antibodies against influenza were assessed by age group, sex, and vaccine status (65+ years old). The association between summer annual seroprevalence and the difference of influenza incidence rates between one season and the previous one was measured by Pearson correlation coefficient (r). RESULTS: Significant differences in seroprevalence of protective antibodies against influenza were observed in the population. Higher seroprevalence and GMT for A(H1N1)pdm09 and A(H3N2) were observed in children (5-14); influenza B seroprevalence in adults 65+ was 1.6-4.4 times than in children (0-4). Vaccinated participants (65+) showed significant higher seroprevalence/GMT for influenza. A strong negative and significant correlation was found between seroprevalence and ILI incidence rate for A(H1N1)pdm09 in children between 5 and 14 (r = -0.84; 95% CI, -0.98 to -0.07); a weak negative correlation was observed for A(H3N2) and B/Yamagata (r ≤ -0.1). CONCLUSIONS: The study provides new insight into the anti-influenza antibodies seroprevalence measured in summer on the ILI incidence rate in the next season and the need for adjusted preventive health care measures to prevent influenza infection and transmission.

Ozone-related acute excess mortality projected to increase in the absence of climate and air quality controls consistent with the Paris Agreement.

Short-term exposure to ground-level ozone in cities is associated with increased mortality and is expected to worsen with climate and emission changes. However, no study has yet comprehensively assessed future ozone-related acute mortality across diverse geographic areas, various climate scenarios, and using CMIP6 multi-model ensembles, limiting our knowledge on future changes in global ozone-related acute mortality and our ability to design targeted health policies. Here, we combine CMIP6 simulations and epidemiological data from 406 cities in 20 countries or regions. We find that ozone-related deaths in 406 cities will increase by 45 to 6,200 deaths/year between 2010 and 2014 and between 2050 and 2054, with attributable fractions increasing in all climate scenarios (from 0.17% to 0.22% total deaths), except the single scenario consistent with the Paris Climate Agreement (declines from 0.17% to 0.15% total deaths). These findings stress the need for more stringent air quality regulations, as current standards in many countries are inadequate.

BMP signaling in the development of the mouse esophagus and forestomach.

The stratification and differentiation of the epidermis are known to involve the precise control of multiple signaling pathways. By contrast, little is known about the development of the mouse esophagus and forestomach, which are composed of a stratified squamous epithelium. Based on prior work in the skin, we hypothesized that bone morphogenetic protein (BMP) signaling is a central player. To test this hypothesis, we first used a BMP reporter mouse line harboring a BRE-lacZ allele, along with in situ hybridization to localize transcripts for BMP signaling components, including various antagonists. We then exploited a Shh-Cre allele that drives recombination in the embryonic foregut epithelium to generate gain- or loss-of-function models for the Bmpr1a (Alk3) receptor. In gain-of-function (Shh-Cre;Rosa26(CAG-loxpstoploxp-caBmprIa)) embryos, high levels of ectopic BMP signaling stall the transition from simple columnar to multilayered undifferentiated epithelium in the esophagus and forestomach. In loss-of-function experiments, conditional deletion of the BMP receptor in Shh-Cre;Bmpr1a(flox/flox) embryos allows the formation of a multilayered squamous epithelium but this fails to differentiate, as shown by the absence of expression of the suprabasal markers loricrin and involucrin. Together, these findings suggest multiple roles for BMP signaling in the developing esophagus and forestomach.

Modeling Effort-Based Decision Making: Individual Differences in Schizophrenia and Major Depressive Disorder.

BACKGROUND: A critical facet of motivation is effort-based decision making, which refers to the mental processes involved in deciding whether a potential reward is worth the effort. To advance understanding of how individuals with schizophrenia and major depressive disorder utilize cost-benefit information to guide choice behavior, this study aimed to characterize individual differences in the computations associated with effort-based decision making. METHODS: One hundred forty-five participants (51 with schizophrenia, 43 with depression, and 51 healthy control participants) completed the Effort Expenditure for Rewards Task, with mixed effects modeling conducted to estimate the predictors of decision making. These model-derived, subject-specific coefficients were then clustered using k-means to test for the presence of discrete transdiagnostic subgroups with different profiles of reward, probability, and cost information utilization during effort-based decision making. RESULTS: An optimal 2-cluster solution was identified, with no significant differences in the distribution of diagnostic groups between clusters. Cluster 1 (n = 76) was characterized by overall lower information utilization during decision making than cluster 2 (n = 61). Participants in this low information utilization cluster were also significantly older and more cognitively impaired, and their utilization of reward, probability, and cost was significantly correlated with clinical amotivation, depressive symptoms, and cognitive functioning. CONCLUSIONS: Our findings revealed meaningful individual differences among participants with schizophrenia, depression, and healthy control participants in their utilization of cost-benefit information in the context of effortful decision making. These findings may provide insight into different processes associated with aberrant choice behavior and may potentially guide the identification of more individualized treatment targets for effort-based motivation deficits across disorders.

Optimal heat stress metric for modelling heat-related mortality varies from country to country.

Combined heat and humidity is frequently described as the main driver of human heat-related mortality, more so than dry-bulb temperature alone. While based on physiological thinking, this assumption has not been robustly supported by epidemiological evidence. By performing the first systematic comparison of eight heat stress metrics (i.e., temperature combined with humidity and other climate variables) with warm-season mortality, in 604 locations over 39 countries, we find that the optimal metric for modelling mortality varies from country to country. Temperature metrics with no or little humidity modification associates best with mortality in ~40% of the studied countries. Apparent temperature (combined temperature, humidity and wind speed) dominates in another 40% of countries. There is no obvious climate grouping in these results. We recommend, where possible, that researchers use the optimal metric for each country. However, dry-bulb temperature performs similarly to humidity-based heat stress metrics in estimating heat-related mortality in present-day climate.

Effects of Ozone Treatment on Health-Related Quality of Life and Toxicity Induced by Radiotherapy and Chemotherapy in Symptomatic Cancer Survivors.

(1) Background: The continuous improvement in cancer treatment has led to improvement in patients' survival and a subsequent increase in the number of cancer survivors living with adverse side effects of cancer treatments, sometimes with a high and adverse impact on their health-related quality of life (HRQOL). Side effects of cancer treatments are frequently associated with chronic status of oxidative stress, inflammation, and/or ischemia. The potential for ozone treatment to modulate those processes and improve some of those adverse effects has previously been described. The aim of this study was to evaluate the effect of ozone treatment on the HRQOL and grade of toxicity in symptomatic cancer survivors. (2) Methods: Before and after ozone treatment, we assessed (i) the HRQOL (according to the EQ-5D-5L questionnaire) and (ii) the grade of toxicity (according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute of EEUU (CTCAE v.5.0)) in 26 cancer survivors with chronic side effects of radiotherapy and chemotherapy. (3) Results: There was a significant (p < 0.001) improvement in the EQ-5D-5L index as per the self-reported outcome evaluation of patients' health status. All the dimensions of the EQ-5D-5L questionnaire (mobility, self-care, activities, pain/discomfort, and anxiety/depression) and the self-evaluation of the health status using the visual analog scale were significantly improved (p < 0.05). The grade of toxicity was also significantly decreased (p < 0.001). (4) Conclusions: In cancer survivors with chronic side effects of cancer treatment, ozone treatment can improve the grade of toxicity and the HRQOL. These results merit additional research. Further studies are ongoing.

Behavioural phenotypes of intrinsic motivation in schizophrenia determined by cluster analysis of objectively quantified real-world performance.

Intrinsic motivation deficits are a prominent feature of schizophrenia that substantially impacts functional outcome. This study used cluster analysis of innate real-world behaviours captured during two open-field tasks to dimensionally examine heterogeneity in intrinsic motivation in schizophrenia patients (SZ) and healthy controls (HC). Wireless motion capture quantified participants' behaviours aligning with distinct aspects of intrinsic motivation: exploratory behaviour and effortful activity in the absence of external incentive. Cluster analysis of task-derived measures identified behaviourally differentiable subgroups, which were compared across standard clinical measures of general amotivation, cognition, and community functioning. Among 45 SZ and 47 HC participants, three clusters with characteristically different behavioural phenotypes emerged: low exploration (20 SZ, 19 HC), low activity (15 SZ, 8 HC), and high exploration/activity (10 SZ, 20 HC). Low performance in either dimension corresponded with similar increased amotivation. Within-cluster discrepancies emerged for amotivation (SZ > HC) within the low exploration and high performance clusters, and for functioning (SZ < HC) within all clusters, increasing from high performance to low activity to low exploration. Objective multidimensional characterization thus revealed divergent behavioural expression of intrinsic motivation deficits that may be conflated by summary clinical measures of motivation and overlooked by unidimensional evaluation. Deficits in either aspect may hinder general motivation and functioning particularly in SZ. Multidimensional phenotyping may help guide personalized remediation by discriminating between intrinsic motivation impairments that require amelioration versus unimpaired tendencies that may facilitate remediation.

Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation.

Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto's thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5-Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.