TGF-ß-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.

The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-ß-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-ß-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study.

BACKGROUND: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated. RESULTS: In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; P=0.00043; femorals: 0.60 [0.47-0.78]; P=9.96×10-5; coronaries: 0.53 [0.39-0.74]; P=0.00013; and increased PESA score: 0.58 [0.48-0.71]; P=3.16×10-8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; P=4.70×10-9 versus 0.90 [0.57-1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. CONCLUSIONS: This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION: URL: https://www.clinicaltrials.gov: NCT01410318.

Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

National health examination surveys; a source of critical data.

The aim of this paper is to contribute technical arguments to the debate about the importance of health examination surveys and their continued use during the post-pandemic health financing crisis, and in the context of a technological innovation boom that offers new ways of collecting and analysing individual health data (e.g. artificial intelligence). Technical considerations demonstrate that health examination surveys make an irreplaceable contribution to the local availability of primary health data that can be used in a range of further studies (e.g. normative, burden-of-disease, care cascade, cost and policy impact studies) essential for informing several phases of the health planning cycle (e.g. surveillance, prioritization, resource mobilization and policy development). Examples of the use of health examination survey data in the World Health Organization (WHO) European Region (i.e. Finland, Italy, Malta and the United Kingdom of Great Britain and Northern Ireland) and the WHO Region of the Americas (i.e. Chile, Mexico, Peru and the United States of America) are presented, and reasons why health provider-led data cannot replace health examination survey data are discussed (e.g. underestimation of morbidity and susceptibility to bias). In addition, the importance of having nationally representative random samples of the general population is highlighted and we argue that health examination surveys make a critical contribution to external quality control for a country's health system by increasing the transparency and accountability of health spending. Finally, we consider future technological advances that can improve survey fieldwork and suggest ways of ensuring health examination surveys are sustainable in low-resource settings.

Cet article a pour objet d'apporter des arguments techniques au débat sur l'importance des enquêtes de santé par examen et sur leur utilisation continue pendant la crise post-pandémique du financement de la santé et dans le contexte d'un essor de l'innovation technologique qui offre de nouvelles façons de collecter et d'analyser les données individuelles sur la santé (comme l'intelligence artificielle). Les considérations techniques démontrent que les enquêtes de santé par examen apportent une contribution irremplaçable à la disponibilité locale de données de santé primaires qui peuvent servir dans une série d'études complémentaires (telles que des études normatives, sur la charge de morbidité, la cascade des soins, les coûts et l'impact des politiques). Ces études sont essentielles pour renseigner plusieurs phases du cycle de planification sanitaire (par exemple: surveillance, priorisation, mobilisation de ressources et élaboration de politiques). Cet article présente des exemples d'utilisation des données d'enquêtes de santé par examen dans la Région OMS de l'Europe (Finlande, Italie, Malte et Royaume-Uni de Grande-Bretagne et d'Irlande du Nord) et dans la Région OMS des Amériques (Chili, États-Unis d'Amérique, Mexique et Pérou) et aborde les raisons pour lesquelles les données fournies par les prestataires de soins de santé ne peuvent pas remplacer les données d'enquêtes de santé par examen (par exemple la sous-estimation de la morbidité et la vulnérabilité aux biais). En outre, il soulignet l'importance de disposer d'échantillons aléatoires représentatifs de la population générale au niveau national, et nous soutenons que les enquêtes de santé par examen apportent une contribution essentielle au contrôle externe de la qualité du système de santé d'un pays en renforçant la transparence des dépenses de santé et l'obligation de rendre des comptes à leur sujet. Enfin, nous envisageons les futures avancées technologiques susceptibles d'améliorer le travail d'enquête sur le terrain et suggérons des moyens d'assurer la viabilité des enquêtes de santé par examen dans les environnements à faibles ressources.

El objetivo de este artículo es aportar argumentos técnicos al debate sobre la importancia de las encuestas de salud y su uso continuado durante la crisis de financiación sanitaria pospandémica y en el contexto de un auge de la innovación tecnológica que ofrece nuevas formas de recopilar y analizar datos sanitarios individuales (por ejemplo, la inteligencia artificial). Las consideraciones técnicas demuestran que las encuestas de salud contribuyen de manera insustituible a la disponibilidad local de datos sanitarios primarios que pueden utilizarse en toda una serie de estudios posteriores (por ejemplo, estudios normativos, de carga de morbilidad, de cascada asistencial, de costes y de impacto de las políticas) esenciales para fundamentar varias fases del ciclo de planificación sanitaria (por ejemplo, vigilancia, establecimiento de prioridades, movilización de recursos y elaboración de políticas). Se presentan ejemplos del uso de los datos de las encuestas de salud en la Región Europea de la Organización Mundial de la Salud (Finlandia, Italia, Malta y el Reino Unido de Gran Bretaña e Irlanda del Norte) y en la Región de las Américas de la OMS (Chile, Estados Unidos de América, México y Perú) y se analizan las razones por las que los datos obtenidos por los proveedores sanitarios no pueden sustituir a los de las encuestas de salud (por ejemplo, la subestimación de la morbilidad y la posibilidad de sesgo). Además, se destaca la importancia de contar con muestras aleatorias representativas de la población general a escala nacional y se argumenta que las encuestas de salud contribuyen de forma decisiva al control de calidad externo del sistema sanitario de un país, al aumentar la transparencia y la rendición de cuentas del gasto sanitario. Por último, se examinan los futuros avances tecnológicos que pueden mejorar el trabajo de campo de las encuestas y se sugieren métodos para garantizar que las encuestas de salud sean sostenibles en entornos con pocos recursos.

Mean age and body mass index at type 2 diabetes diagnosis: Pooled analysis of 56 health surveys across income groups and world regions.

BACKGROUND: Screening for type 2 diabetes mellitus (T2DM) targets people aged 35+ years and those with overweight/obesity. With mounting evidence on young-onset T2DM and T2DM patients with lean phenotypes, it is worth revising the screening criteria to include younger and leaner adults. We quantified the mean age and body mass index (BMI; kg/m2 ) at T2DM diagnosis in 56 countries. METHODS: Descriptive cross-sectional analysis of WHO STEPS surveys. We analysed adults (25-69 years) with new T2DM diagnosis (not necessarily T2DM onset) as per fasting plasma glucose ≥126 mg/dL measured during the survey. For people with new T2DM diagnosis, we summarized the mean age and the proportion of each five-year age group; also, we summarized the mean BMI and the proportion of mutually exclusive BMI categories. RESULTS: There were 8695 new T2DM patients. Overall, the mean age at T2DM diagnosis was 45.1 years in men and 45.0 years in women; and the mean BMI at T2DM diagnosis was 25.2 in men and 26.9 in women. Overall, in men, 10.3% were 25-29 years and 8.5% were 30-34 years old; in women, 8.6% and 12.5% were 25-29 years and 30-34 years old, respectively. 48.5% of men and 37.3% of women were in the normal BMI category. CONCLUSIONS: A non-negligible proportion of new T2DM patients were younger than 35 years. Many new T2DM patients were in the normal weight range. Guidelines for T2DM screening may consider revising the age and BMI criteria to incorporate young and lean adults.

Outcomes measured in studies assessing health systems interventions for type 1 diabetes management: A scoping review.

AIMS: Describe the outcomes reported in research on health systems interventions for type 1 diabetes management in comparison to the outcomes proposed by a core outcome set (COS) for this condition, an essential list of outcomes that studies should measure. METHODS: Systematic search of studies published between 2010 and 2021 reporting health systems interventions directed to improve the management of type 1 diabetes using PubMed, EMBASE and CENTRAL. Information on the outcomes was extracted and classified according to a COS: self-management, level of clinical engagement, perceived control over diabetes, diabetes-related quality of life, diabetes burden, diabetes ketoacidosis, severe hypoglycemia, and glycated hemoglobin (HbA1C). RESULTS: 187 studies were included. Most of the studies included either children (n = 82/187) or adults (n = 82/187) living with type 1 diabetes. The most common outcome measured was HbA1C (n = 149/187), followed by self-management (n = 105/187). While the least measured ones were diabetes ketoacidosis (n = 15/187), and clinical engagement (n = 0/187). None of the studies measured all the outcomes recommended in the COS. Additionally, different tools were found to be used in measuring the same outcome. CONCLUSIONS: This study provides a description of what researchers are measuring when assessing health systems interventions to improve type 1 diabetes management. In contrast to a COS, it was found that there is a predominance of clinical-based outcomes over patient-reported outcome measures.

Co-creation process of an intervention to implement a multiparameter point-of-care testing device in a primary healthcare setting for non-communicable diseases in Peru.

BACKGROUND: Point-of-care testing (POCT) devices are diagnostic tools that can provide quick and accurate results within minutes, making them suitable for diagnosing non-communicable diseases (NCDs). However, these devices are not widely implemented in healthcare systems and for this reason is relevant to understand the implementation process. AIM: To describe the process and define a strategy to implement a multiparameter POCT device for diagnosing and managing NCDs in one region of Peru. METHODS: A descriptive and non-experimental study, using the participatory methodologies of co-creation process. It was conducted in one region of Peru (Tumbes) to design an intervention for implementing a multiparameter POCT device. Two co-creation sessions were conducted involving five groups: community members, primary healthcare workers, these groups in both rural and urban settings, and regional decision-makers. These sessions included activities to understand patient journeys in receiving care for NCDs, identify facilitators and barriers to POCT devices usage, and define an implementation strategy for POCT devices in both rural and urban settings of Tumbes. The research team analysed the data and summarized key topics for discussion after each session. RESULTS: A total of 78 participants were enrolled across the five groups. Among community members: 22.2% had only diabetes, 24.1% had only hypertension, and 18.5% had both diagnoses. In the patient journey, community members mentioned that it took at least three days to receive a diagnosis and treatment for an NCD. Most of the participants agreed that the POCT devices would be beneficial for their communities, but they also identified some concerns. The strategy for POCT devices implementation included healthcare workers training, POCT devices must be placed in the laboratory area and must be able to perform tests for glucose, glycated haemoglobin, cholesterol, and creatinine. Advertising about POCT devices should be displayed at the healthcare centres and the municipality using billboards and flyers. CONCLUSIONS: The co-creation process was useful to develop strategies for the implementation of multiparameter POCT devices for NCDs, involving the participation of different groups of stakeholders guided by moderators in both, rural and urban, settings in Peru.

Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study.

AIMS: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. METHODS AND RESULTS: Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. CONCLUSION: The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.

Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 

The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.

Fraunhofer diffraction at the two-dimensional quadratically distorted (QD) grating.

A two-dimensional (2D) mathematical model of quadratically distorted (QD) grating is established with the principles of Fraunhofer diffraction and Fourier optics. A discrete sampling method is applied for finding a numerical solution of the diffraction pattern of QD grating. An optimized working phase term, which determines the balanced energies and high efficiency of multi-plane images, can be obtained by the bisection algorithm. To confirm the analytical approach described above, the results have been compared with those obtained using a classical numerical model based on Fraunhofer diffraction theory and a fast Fourier transform (FFT) algorithm. The results show that our analytical approach allows the precise design of QD grating and improves the optical performance of simultaneous multi-plane imaging system. An optical setup based on our well-designed QD grating has been appended to the camera port of a commercial microscope, and some preliminary microscopy images have been successfully obtained. Further upgrade of our analytical model is in progress to improve the image quality and promote the applications.

Early insulin resistance in normoglycemic low-risk individuals is associated with subclinical atherosclerosis.

BACKGROUND: Elevated glycated hemoglobin (HbA1c) is associated with a higher burden of subclinical atherosclerosis (SA). However, the association with SA of earlier insulin resistance markers is poorly understood. The study assessed the association between the homeostatic model assessment of insulin resistance index (HOMA-IR) and SA in addition to the effect of cardiovascular risk factors (CVRFs) in individuals with normal HbA1c. METHODS: A cohort of 3,741 middle-aged individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study with basal HbA1c < 6.0% (< 42 mmol/mol) and no known CV disease underwent extensive imaging (multiterritorial vascular ultrasound and coronary artery calcium score, CACS) to assess the presence, burden, and extent of SA. RESULTS: Individuals with higher HOMA-IR values had higher rates of CVRFs. HOMA-IR showed a direct association with the multiterritorial extent of SA and CACS (p < 0.001) and with global plaque volume measured by 3-dimensional vascular ultrasound (p < 0.001). After adjusting for key CVRFs and HbA1c, HOMA-IR values ≥ 3 were associated with both the multiterritorial extent of SA (odds ratio 1.41; 95%CI: 1.01 to 1.95, p = 0.041) and CACS > 0 (odds ratio 1.74; 95%CI: 1.20 to 2.54, p = 0.004), as compared with the HOMA-IR < 2 (the reference HOMA-IR category). In a stratified analysis, this association remained significant in individuals with a low-to-moderate SCORE2 risk estimate (75.6% of the cohort) but not in high-risk individuals. CONCLUSIONS: The use of HOMA-IR identified low-risk individuals with a higher burden of SA, after adjusting for the effects of key traditional CVRFs and HbA1c. HOMA-IR is a simple measure that could facilitate earlier implementation of primary CV prevention strategies in clinical practice.

Use of continuous glucose monitors in low- and middle-income countries: A scoping review.

AIMS: The use of continuous glucose monitors (CGMs) has been shown to have positive impact on diabetes management for people with type 1 diabetes (T1DM), type 2 diabetes (T2DM) and gestational diabetes (GDM) in high-income countries. However, as useful as CGMs are, the experience in low- and middle-income countries (LMICs) is limited and has not been summarized. METHODS: A scoping review of the scientific literature was conducted. Medline, Embase, Global Health and Scopus were used to seek original research conducted in LMICs. The search results were screened by two reviewers independently. We included studies assessing health outcomes following the use of CGMs at the individual level (e.g. glycaemic control or complications) and at the health system level (e.g. barriers, facilitators and cost-effectiveness) in English, Portuguese, Spanish and French. Results were summarized narratively. RESULTS: From 4772 records found in database search, 27 reports were included; most of them from China (n = 7), Colombia (n = 5) and India (n = 4). Thirteen reports studied T1DM, five T2DM, seven both T1DM and T2DM and two GDM. Seven reports presented results of experimental studies (five randomized trials and two quasi-experimental); two on cost-effective analysis and the remaining 18 were observational. Studies showed that CGMs improved surrogate glycaemic outcomes (HbA1c reduction), hard endpoints (lower hospitalization rates and diabetes complications) and patient-oriented outcomes (quality of life). However, several caveats were identified: mostly observational studies, few participants in trials, short follow-up and focused on surrogate outcomes. CONCLUSIONS: The scoping review identified that studies about CGMs in LMICs have several limitations. Stronger study designs, appropriate sample sizes and the inclusion of patient-important outcomes should be considered to inform the evidence about CGMs for the management of people with diabetes in LMICs.

Skeletal muscle mass and all-cause mortality: Findings from the CRONICAS cohort study.

OBJECTIVE: We aimed (1) to evaluate the agreement between two methods (equation and bio-impedance analysis [BIA]) to estimate skeletal muscle mass (SMM), and (2) to assess if SMM was associated with all-cause mortality risk in individuals across different geographical sites in Peru. METHODS: We used data from the CRONICAS Cohort Study (2010-2018), a population-based longitudinal study in Peru to assess cardiopulmonary risk factors from different geographical settings. SMM was computed as a function of weight, height, sex and age (Lee equation) and by BIA. All-cause mortality was retrieved from national vital records. Cox proportional-hazard models were developed and results presented as hazard ratios (HRs) with 95% confidence intervals (95% CIs). RESULTS: At baseline, 3216 subjects, 51.5% women, mean age 55.7 years, were analysed. The mean SMM was 23.1 kg (standard deviation [SD]: 6.0) by Lee equation, and 22.7 (SD: 5.6) by BIA. Correlation between SMM estimations was strong (Pearson's ρ coefficient = 0.89, p < 0.001); whereas Bland-Altman analysis showed a small mean difference. Mean follow-up was 7.0 (SD: 1.0) years, and there were 172 deaths. In the multivariable model, each additional kg in SMM was associated with a 19% reduction in mortality risk (HR = 0.81; 95% CI: 0.75-0.88) using the Lee equation, but such estimate was not significant when using BIA (HR = 0.98; 95% CI: 0.94-1.03). Compared to the lowest tertile, subjects at the highest SMM tertile had a 56% reduction in risk of mortality using the Lee equation, but there was no such association when using BIA estimations. CONCLUSION: There is a strong correlation and agreement between SMM estimates obtained by the Lee equation and BIA. However, an association between SMM and all-cause mortality exists only when the Lee equation is used. Our findings call for appropriate use of approaches to estimate SMM, and there should be a focus on muscle mass in promoting healthier ageing.

Effects of intravenous lysine acetylsalicylate versus oral aspirin on platelet responsiveness in patients with ST-segment elevation myocardial infarction: the ECCLIPSE-STEMI trial.

Prasugrel and ticagrelor, new P2Y12-ADP receptor antagonists, are associated with greater pharmacodynamic inhibition and reduction of cardiovascular events in patients with an acute coronary syndrome. However, evidence is lacked about the effects of achieving faster and stronger cyclooxygenase inhibition with intravenous lysine acetylsalicylate (LA) compared to oral aspirin. Recently, we demonstrated in healthy volunteers that the administration of intravenous LA resulted in a significantly reduction of platelet reactivity compared to oral aspirin. Loading dose of LA achieves platelet inhibition faster, and with less variability than aspirin. However, there are no data of this issue in patients with an ST-segment elevation myocardial infarction (STEMI). This is a prospective, randomized, multicenter, open platelet function study conducted in STEMI patients. Subjects were randomly assigned to receive a loading dose (LD) of intravenous LA 450 mg plus oral ticagrelor 180 mg, or LD of aspirin 300 mg plus ticagrelor 180 mg orally. Platelet function was evaluated at baseline, 30 min, 1 h, 4 h and 24 h using multiple electrode aggregometry and vasodilator-stimulated phosphoprotein phosphorylation (VASP). The primary endpoint of the study is the inhibition of platelet aggregation (IPA) after arachidonic acid (AA) 0.5 mM at 30 min. Secondary endpoints were the IPA at 1, 4, and 24 h after AA, and non-AA pathways through the sequence (ADP and TRAP). A total of 32 STEMI patients were randomized (16 LA, 16 aspirin). The inhibition of platelet aggregation after AA 0.5 mM at 30 min was greater in subjects treated with LA compared with aspirin: 166 vs. 412 respectively (p = 0.001). This differential effect was observed at 1 h (p = 0.01), but not at 4 and 24 h. Subjects treated with LA presented less variability and faster inhibition of platelet aggregation wit AA compared with aspirin. The administration of intravenous LA resulted in a significantly reduction of platelet reactivity compared to oral aspirin on ticagrelor inhibited platelets in patients with STEMI. Loading dose of LA achieves an earlier platelet inhibition, and with less variability than aspirin.Trial Registration: Unique identifier: NCT02929888; URL: http://www.clinicaltrials.gov.

Surgical correction of corneal opacity and aniridia with penetrating keratoplasty and a new iris prosthesis implant.

PURPOSE: This study is to describe the clinical outcome of penetrating keratoplasty combined with implantation of a novel intraocular lens with an artificial iris, aided by continuous vitreous chamber infusion, in patients with severe aniridia and corneal alterations. METHODS: This was a prospective single-center case series study involving five patients with corneal alterations and aniridia. All subjects underwent simultaneous penetrating keratoplasty and implantation of a new intraocular lens with an artificial iris with the assistance of infusion into the vitreous chamber to regulate intraocular pressure during the surgical procedure. Visual acuity, corneal endothelial cell density, and intraocular pressure assessments were performed in the postoperative period. The final cosmetic outcome of the iris prosthesis placement was also evaluated. RESULTS: In all cases, increased visual acuity and a good aesthetic result were observed in all affected eyes except one in which, despite the excellent aesthetic outcome, the eye was very hypotonic as it had high myopia and had undergone several previous surgeries. CONCLUSION: The single surgical procedure combining implantation of an intraocular lens-iris prosthesis with penetrating keratoplasty is an effective technique for the simultaneous treatment of aphakia and aniridia. However, larger series with longer-term follow-up are needed to definitively establish the benefits of this technique.

Facilitators and barriers of the implementation of point-of-care devices for cardiometabolic diseases: a scoping review.

BACKGROUND: Point-of-care testing (POCT) devices may facilitate the delivery of rapid and timely results, providing a clinically important advantage in patient management. The challenges and constraints in the implementation process, considering different levels of actors have not been much explored. This scoping review aimed to assess literature pertaining to implementation facilitators and barriers of POCT devices for the diagnosis or monitoring of cardiometabolic diseases. METHODS: A scoping review of the literature was conducted. The inclusion criteria were studies on the inception, planning, or implementation of interventions with POCT devices for the diagnosis or monitoring of cardiometabolic diseases defined as dyslipidemia, cardiovascular diseases, type 2 diabetes, and chronic kidney disease. We searched MEDLINE, Embase, and Global Health databases using the OVID searching engine until May 2022. The Consolidated Framework of Implementation Research (CFIR) was used to classify implementation barriers and facilitators in five constructs. Also, patient, healthcare professional (HCP), and organization level was used. RESULTS: Twenty studies met the eligibility criteria for data extraction. All studies except two were conducted in high-income countries. Some findings are: 1) Intervention: the most widely recognized facilitator was the quick turnaround time with which results are obtained. 2) Outer setting: at the organizational level, the lack of clear regulatory and accreditation mechanisms has hindered the adoption and sustainability of the use of POCT. 3) Inner setting: for HCP, performing POCT during the consultation was both a facilitator and a barrier in terms of time, personnel, and service delivery. 4) Individuals: the implementation of POCT may generate stress and discomfort in some HCP in terms of training and new responsibilities. 5) Process: for patients, it is highly appreciated that obtaining the sample was simple and more comfortable if venipuncture was not used. CONCLUSION: This scoping review has described the facilitators and barriers of implementing a POCT device for cardiometabolic conditions using the CFIR. The information can be used to design better strategies to implement these devices and benefit more populations that have low access to cardiometabolic tests.

Effects of a comprehensive lifestyle intervention on cardiovascular health: the TANSNIP-PESA trial.

AIMS: To investigate the effectiveness of a 3-year worksite lifestyle intervention on cardiovascular metrics and to study whether outcomes are influenced by baseline subclinical atherosclerosis (SA) by non-invasive imaging. METHODS AND RESULTS: A randomized controlled trial was performed to compare a lifestyle intervention with standard of care in asymptomatic middle-aged subjects, stratified by SA. The intervention consisted of nine motivational interviews during the first year, followed by three further sessions between Years 1 and 3. The primary outcome was the change in a pre-specified adaptation of the Fuster-BEWAT score (Blood pressure, Exercise, Weight, Alimentation, and Tobacco) between baseline and follow-up Years 1-3. A total of 1020 participants (mean age 50 ± 4 years) were enrolled, of whom 510 were randomly assigned to the intervention and 510 to the control group. The baseline adapted Fuster-BEWAT score was 16.2 ± 3.7 points in the intervention group and 16.5 ± 3.5 points in the control group. At Year 1, the score improved significantly in intervention participants compared with controls [estimate 0.83 (95% CI 0.52-1.15) points]. However, intervention effectiveness decreased to non-significant levels at Year 3 [0.24 (95% CI -0.10 to 0.59) points]. Over the 3-year period, the intervention was effective in participants having low baseline SA [0.61 (95% CI 0.30-0.93) points] but not in those with high baseline SA [0.19 (95% CI -0.26 to 0.64) points]. CONCLUSION: In middle-aged asymptomatic adults, a lifestyle intervention was associated with a significant improvement in cardiovascular health and behavioural metrics. The effect attenuated after 1 year as the intensity of the intervention was reduced. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02561065).

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

AIMS: Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. METHODS AND RESULTS: Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). CONCLUSION: In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].