The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the ...mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.
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•SARS-CoV-2 infection leads to macrophage infiltrates in the lung of infected macaques•SARS-CoV-2 upregulates proinflammatory cytokines and ISGs in macaques•SARS-CoV-2 upregulates complement and coagulation cascade in macaques•SARS-CoV-2 infection leads to endothelial damage and thrombosis in macaques
Aid et al. show that SARS-CoV-2 causes endothelial disruption and vascular thrombosis in both human and rhesus macaques lungs by inducing an upregulation of proinflammatory cytokines. Using an approach that combines histopathology and multiomics in macaques, they show the progression to vascular disease over time, which involves complement, macrophage, cytokine, and thrombosis cascades.
The coronavirus disease 2019 (COVID-19) presents critical diagnostic challenges for managing the pandemic. We investigated the 30-month changes in COVID-19 testing modalities and functional testing ...sites from the early period of the pandemic to the most recent Omicron surge in 2022 in Kyoto City, Japan.
This is a retrospective-observational study using a local anonymized population database that included patients' demographic and clinical information, testing methods and facilities from January 2020 to June 2022, a total of 30 months. We computed the distribution of symptomatic presentation, testing methods, and testing facilities among cases. Differences over time were tested using chi-square tests of independence.
During the study period, 133,115 confirmed COVID-19 cases were reported, of which 90.9% were symptomatic. Although nucleic acid amplification testing occupied 68.9% of all testing, the ratio of lateral flow devices (LFDs) rapidly increased in 2022. As the pandemic continued, the testing capability was shifted from COVID-19 designated facilities to general practitioners, who became the leading testing providers (57.3% of 99,945 tests in 2022).
There was a dynamic shift in testing modality during the first 30 months of the pandemic in Kyoto City. General practitioners increased their role substantially as the use of LFDs spread dramatically in 2022. By comprehending and documenting the evolution of testing methods and testing locations, it is anticipated that this will contribute to the establishment of an even more efficient testing infrastructure for the next pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prurigo nodularis (PN) is a poorly understood, understudied pruritic dermatosis that reduces quality of life.
To characterize the demographics and comorbidities associated with PN.
Cross-sectional ...study of patients 18 years and older who were seen at the Johns Hopkins Health System between December 6, 2012, and December 6, 2017.
Over the past 5 years, 909 patients with PN were seen at Johns Hopkins Health System. African American patients were 3.4 times more likely to have PN than white patients were (odds ratio OR, 3.4; 95% confidence interval CI, 2.9-3.9; P < .001). A comparison of the study patients and race-matched controls revealed that PN was significantly associated with a variety of systemic, cardiovascular, and psychiatric comorbidities, including chronic kidney disease, chronic hepatitis C, chronic obstructive pulmonary disease, congestive heart failure, depression, and atopic dermatitis. Black patients with PN were 10.5 times more likely (OR, 10.5; 95% CI, 7.9-13.9; P < .001) to have HIV than were race-matched controls with atopic dermatitis, and 8 times more likely (OR, 8.0; 95% CI, 5.7-11.1; P < .001) to have HIV than were African American patients with psoriasis.
Our data describe patients seen by 1 hospital system. Our data identify associated conditions and comorbidities but are unable to support a causal relationship.
PN disproportionately affects African Americans and is associated with several systemic conditions, including HIV, chronic kidney disease, and diabetes.
Abstract
Entrainment, the unconscious process leading to coordination between communication partners, is an important dynamic human behavior that helps us connect with one another. Difficulty ...developing and sustaining social connections is a hallmark of autism spectrum disorder (ASD). Subtle differences in social behaviors have also been noted in first-degree relatives of autistic individuals and may express underlying genetic liability to ASD. In-depth examination of verbal entrainment was conducted to examine disruptions to entrainment as a contributing factor to the language phenotype in ASD. Results revealed distinct patterns of prosodic and lexical entrainment in individuals with ASD. Notably, subtler entrainment differences in prosodic and syntactic entrainment were identified in parents of autistic individuals. Findings point towards entrainment, particularly prosodic entrainment, as a key process linked to social communication difficulties in ASD and reflective of genetic liability to ASD.
We comparatively assessed the performance of six simple obesity indices to identify adults with cardiovascular disease (CVD) risk factors in a diverse and contemporary South Asian population.
8,892 ...participants aged 20-60 years in 2010-2011 were analyzed. Six obesity indices were examined: body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), waist-hip ratio (WHR), log of the sum of triceps and subscapular skin fold thickness (LTS), and percent body fat derived from bioelectric impedance analysis (BIA). We estimated models with obesity indices specified as deciles and as continuous linear variables to predict prevalent hypertension, diabetes, and high cholesterol and report associations (prevalence ratios, PRs), discrimination (area-under-the-curve, AUCs), and calibration (index χ2). We also examined a composite unhealthy cardiovascular profile score summarizing glucose, lipids, and blood pressure.
No single obesity index consistently performed statistically significantly better than the others across the outcome models. Based on point estimates, WHtR trended towards best performance in classifying diabetes (PR = 1.58 1.45-1.72, AUC = 0.77, men; PR = 1.59 1.47-1.71, AUC = 0.80, women) and hypertension (PR = 1.34 1.26,1.42, AUC = 0.70, men; PR = 1.41 1.33,1.50, AUC = 0.78, women). WC (mean difference = 0.24 SD 0.21-0.27) and WHtR (mean difference = 0.24 SD 0.21,0.28) had the strongest associations with the composite unhealthy cardiovascular profile score in women but not in men.
WC and WHtR were the most useful indices for identifying South Asian adults with prevalent diabetes and hypertension. Collection of waist circumference data in South Asian health surveys will be informative for population-based CVD surveillance efforts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this ...paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Up to 15% of individuals with a clinical phenotype of type 1 diabetes (T1D) do not have evidence of seropositivity for pancreatic islet autoantibodies. On this basis, they are classified as nonimmune ...or idiopathic, and remain an understudied population, as they are excluded from T1D immunomodulatory trials. Our limited understanding of the disease aetiopathogenesis in autoantibody-negative T1D hinders our ability to improve diagnostic pathways and discover novel therapeutic agents; particularly as we progress towards an era of precision medicine. This review summarises the current understanding and challenges in studying autoantibody-negative T1D. We review the literature regarding T1D classification, and the role of autoimmunity and defects in the immunogenic pathway that may distinguish autoantibody-positive and -negative T1D.
Autoantibody-negative type 1 diabetes (T1D) has been neglected from our diagnostic and management framework. Subsequently, this cohort has been excluded from novel T1D immunotherapy trials.While studying this subtype has inherent challenges, there has been minimal effort in the literature to recognise and characterise this group, understand underlying disease mechanisms and discover novel and/or adjunct therapies.Elucidating if and how this cohort differs from classic T1D will unravel and emphasise the need to discover alternate immune-based biomarkers (to aid disease prediction, diagnosis, severity, and monitoring of treatment response) as we strive towards precision medicine.
Aims/hypothesis
We aimed to estimate the lifetime risk of diabetes and diabetes-free life expectancy in metropolitan cities in India among the population aged 20 years or more, and their variation by ...sex, age and BMI.
Methods
A Markov simulation model was adopted to estimate age-, sex- and BMI-specific lifetime risk of developing diabetes and diabetes-free life expectancy. The main data inputs used were as follows: age-, sex- and BMI-specific incidence rates of diabetes in urban India taken from the Centre for Cardiometabolic Risk Reduction in South Asia (2010–2018); age-, sex- and urban-specific rates of mortality from period lifetables reported by the Government of India (2014); and prevalence of diabetes from the Indian Council for Medical Research INdia DIABetes study (2008–2015).
Results
Lifetime risk (95% CI) of diabetes in 20-year-old men and women was 55.5 (51.6, 59.7)% and 64.6 (60.0, 69.5)%, respectively. Women generally had a higher lifetime risk across the lifespan. Remaining lifetime risk (95% CI) declined with age to 37.7 (30.1, 46.7)% at age 60 years among women and 27.5 (23.1, 32.4)% in men. Lifetime risk (95% CI) was highest among obese Indians: 86.0 (76.6, 91.5)% among 20-year-old women and 86.9 (75.4, 93.8)% among men. We identified considerably higher diabetes-free life expectancy at lower levels of BMI.
Conclusions/interpretation
Lifetime risk of diabetes in metropolitan cities in India is alarming across the spectrum of weight and rises dramatically with higher BMI. Prevention of diabetes among metropolitan Indians of all ages is an urgent national priority, particularly given the rapid increase in urban obesogenic environments across the country.
Graphical abstract
Tracking changes in socioeconomic disparities in diabetes in the U.S. is important to evaluate progress in health equity and guide prevention efforts. Disparities in diabetes prevalence by ...educational attainment from 2001 to 2020 were investigated.
Using a serial cross-sectional design, data from 33,220 adults aged 30–79 assessed in nine rounds of the National Health and Nutrition Examination Surveys between 2001 and 2020 were analyzed in 2023–2024. Diabetes was defined as self-reported prior diagnosis, elevated glycated hemoglobin (HbA1c≥6.5%), or use of diabetes medications. Marginalized age- and covariate-adjusted prevalence differences (PD) and prevalence ratios (PR) of diabetes by educational attainment (less than high school graduation, high school graduation, some college education or associate degree, or college graduation reference) by calendar period (2001–2004, 2005–2008, 2009–2012, 2013–2016, 2017–2020) were derived from logistic regression models.
From 2001 to 2020, age-adjusted diabetes prevalence was consistently higher among adults without a college degree. Adults without a high school diploma exhibited the largest disparities in both 2001–2004 (PD 8.0%; 95%CI 5.6–10.5 and PR 2.1; 95%CI 1.5–2.6) and 2017-20 (PD 11.0%; 95%CI 6.7–15.2 and PR 2.1; 95%CI 1.5–2.7). Between 2001–2004 and 2017–2020, the absolute disparity in diabetes changed only among adults with a high school diploma (increase from PD 1.7%; 95%CI –0.5- 3.9 to PD 8.8% 95%CI 4.1–13.4, respectively), while the PR did not change in any group. Education-related disparities in diabetes were attenuated after accounting for socio-demographic factors and BMI.
From 2001 to 2020, national education-related disparities in diabetes prevalence have shown no signs of narrowing.
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