European Journal of Clinical Investigation最新文献

Background: The WHO issued recommendations about the ideal amount of physical activity, sedentary behaviour and sleep in infants, toddlers and preschool children. To facilitate their interpretation and translation into public health policies, we analysed the quantity and quality of the evidence that supported the development of each WHO recommendation.

Methods: All data for each exposure-outcome pair analysed in the studies informing WHO guidelines were extracted, and predefined criteria, based upon GRADE methodology, were used to classify each outcome and study result.

Results: Among the 237 studies that could be included, 37 were experimental and 200 were observational, yielding 920 analyses of exposure-outcome associations. Sixty-two analyses used a relevant outcome, with or without significant results. Five of the 10 WHO recommendations were based upon zero analyses with significant results on relevant health outcomes. The remaining recommendations were mostly based upon analyses evaluating obesity-related outcomes. Eight of the 10 GLs thresholds were not supported by any significant analysis on clinically relevant outcomes.

Conclusion: While these findings should not be interpreted as an attempt to disprove the benefits of healthy lifestyle habits in early childhood, neither to minimize the work of the experts in this complex research field, very limited evidence currently supports the adoption of recommended thresholds as behavioural surveillance and public health interventions targets. Therefore, until further data are available, public health interventions should be developed balancing whether to focus on the achievement of specific targets that are still not supported by high-quality evidence or on the general promotion of healthy behaviours.

Background: Mean platelet volume (MPV) is a widely available laboratory index, however its prognostic significance in patients with coronary artery disease (CAD) is still unclear. We intended to investigate and pool the evidence on the prognostic utility of admission MPV in predicting clinical outcomes in patients with CAD.

Methods: PubMed, Web of Science, and Scopus were the major databases used for literature search. The risk of bias was assessed using the quality in prognostic factor studies. We used random-effects pairwise analysis with the Knapp and Hartung approach supported further with permutation tests and prediction intervals (PIs).

Results: We identified 52 studies with 47,066 patients. A meta-analysis of nine studies with 14,864 patients demonstrated that one femtoliter increase in MPV values was associated with a rise of 29% in the risk of long-term mortality (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.22-1.37) in CAD as a whole. The results were further supported with PIs, permutation tests and leave-one-out sensitivity analyses. MPV also demonstrated its stable and significant prognostic utility in predicting long-term mortality as a linear variable in patients treated with percutaneous coronary intervention (PCI) and presented with acute coronary syndrome (ACS) (HR 1.29, 95% CI 1.20-1.39, and 1.29, 95% CI 1.19-1.39, respectively).

Conclusion: The meta-analysis found robust evidence on the link between admission MPV and the increased risk of long-term mortality in patients with CAD patients, as well as in patients who underwent PCI and patients presented with ACS.

Annual vaccination is widely recommended for influenza and SARS-CoV-2. In this essay, we analyse and question the prevailing policymaking approach to these respiratory virus vaccines, especially in the United States. Every year, licensed influenza vaccines are reformulated to include specific strains expected to dominate in the season ahead. Updated vaccines are rapidly manufactured and approved without further regulatory requirement of clinical data. Novel vaccines (i.e. new products) typically undergo clinical trials, though generally powered for clinically unimportant outcomes (e.g. lab-confirmed infections, regardless of symptomatology or antibody levels). Eventually, the current and future efficacy of influenza and COVID-19 vaccines against hospitalization or death carries considerable uncertainty. The emergence of highly transmissible SARS-CoV-2 variants and waning vaccine-induced immunity led to plummeting vaccine effectiveness, at least against symptomatic infection, and booster doses have since been widely recommended. No further randomized trials were performed for clinically important outcomes for licensed updated boosters. In both cases, annual vaccine effectiveness estimates are generated by observational research, but observational studies are particularly susceptible to confounding and bias. Well-conducted experimental studies, particularly randomized trials, are necessary to address persistent uncertainties about influenza and COVID-19 vaccines. We propose a new research framework which would render results relevant to the current or future respiratory viral seasons. We demonstrate that experimental studies are feasible by adopting a more pragmatic approach and provide strategies on how to do so. When it comes to implementing policies that seriously impact people's lives, require substantial public resources and/or rely on widespread public acceptance, high evidence standards are desirable.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are new anti-hyperglycaemic drugs with proven cardiovascular (CV) benefit in diabetic and non-diabetic patients at high CV risk. Despite a neutral class effect on arrhythmia risk, data on semaglutide suggest a possible drug-specific benefit in reducing atrial fibrillation (AF) occurrence.

Objective: To perform a meta-analysis of randomized clinical trials (RCTs) to assess the risk of incident AF in patients treated with semaglutide compared to placebo.

Methods and results: Ten RCTs were included in the analysis. Study population encompassed 12,651 patients (7285 in semaglutide and 5366 in placebo arms), with median follow-up of 68 months. A random effect meta-analytic model was adopted to pool relative risk (RR) of incident AF. Semaglutide reduces the risk of AF by 42% (RR .58, 95% CI .40-.85), with low heterogeneity across the studies (I² 0%). At subgroup analysis, no differences emerged between oral and subcutaneous administration (oral: RR .53, 95% CI .23-1.24, I² 0%; subcutaneous: RR .59, 95% CI .39-.91, I² 0%; p-value .83). In addition, meta-regression analyses did not show any potential influence of baseline study covariates, in particular the proportion of diabetic patients (p-value .14) and body mass index (BMI) (p-value .60).

Conclusions: Semaglutide significantly reduces the occurrence of incident AF by 42% as compared to placebo in individuals at high CV risk, mainly affected by type 2 diabetes mellitus. This effect appears to be consistent independently of the route of administration of the drug (oral or subcutaneous), the presence of underlying diabetes and BMI.

Background: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells.

Methods: This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis.

Results: We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance.

Conclusion: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

Background: Infertility is a major health issue, affecting 15% of reproductive-age couples with male factors contributing to 50% of cases. Asthenozoospermia (AS), or low sperm motility, is a common cause of male infertility with complex aetiology, involving genetic and metabolic alterations, inflammation and oxidative stress. However, the molecular mechanisms behind low motility are unclear. In this study, we used a metabolomics approach to identify metabolic biomarkers and pathways involved in sperm motility.

Methods: We compared the metabolome and lipidome of spermatozoa of men with normozoospermia (n = 44) and AS (n = 22) using untargeted LC-MS and the metabolome of seminal fluid using ¹H-NMR. Additionally, we evaluated the seminal fluid redox status to assess the oxidative stress in the ejaculate.

Results: We identified 112 metabolites and 209 lipids in spermatozoa and 27 metabolites in the seminal fluid of normozoospermic and asthenozoospermic men. PCA analysis of the spermatozoa's metabolomics and lipidomics data showed a clear separation between groups. Spermatozoa of asthenozoospermic men presented lower levels of several amino acids, and increased levels of energetic substrates and lysophospholipids. However, the metabolome and redox status of the seminal fluid was not altered inAS.

Conclusions: Our results indicate impaired metabolic pathways associated with redox homeostasis and amino acid, energy and lipid metabolism in AS. Taken together, these findings suggest that the metabolome and lipidome of human spermatozoa are key factors influencing their motility and that oxidative stress exposure during spermatogenesis or sperm maturation may be in the aetiology of decreased motility in AS.

Background: Inflammation and immunity contribute pivotally to diverse acute and chronic diseases. Inflammatory pathways have become increasingly targets for therapy. Yet, despite substantial similarity in mechanisms and pathways, the scientific, medical, pharma and biotechnology sectors have generally focused programs finely on a single disease entity or organ system. This insularity may impede progress in innovation and the harnessing of powerful new insights into inflammation biology ripe for clinical translation.

Methods: A multidisciplinary thinktank reviewed highlights how inflammation contributes to diverse diseases, disturbed homeostasis, ageing and impaired healthspan. We explored how common inflammatory and immune mechanisms that operate in key conditions in their respective domains. This consensus review highlights the high degree of commonality of inflammatory mechanisms in a diverse array of conditions that together contribute a major part of the global burden of morbidity and mortality and present an enormous challenge to public health and drain on resources.

Results: We demonstrate how that shared inflammatory mechanisms unite many seemingly disparate diseases, both acute and chronic. The examples of infection, cardiovascular conditions, pulmonary diseases, rheumatological disorders, dementia, cancer and ageing illustrate the overlapping pathogenesis. We outline opportunities to synergize, reduce duplication and consolidate efforts of the clinical, research and pharmaceutical communities. Enhanced recognition of these commonalties should promote cross-fertilization and hasten progress in this rapidly moving domain.

Conclusions: Greater appreciation of the shared mechanisms should simplify understanding seemingly disparate diseases for clinicians and help them to recognize inflammation as a therapeutic target which the development of novel therapies is rendering actionable.

Background: Growth differentiation factor 15 (GDF15), a stress-responsive cytokine from transforming growth factor superfamily, is highly expressed in mammalian tissues, including pancreas, stomach and intestine under pathological conditions. In particular, elevated levels of GDF15 might play an important role in the development and progression of various gastrointestinal cancers (GCs), suggesting its potential as a promising target for disease prediction and treatment.

Methods: In this review, systematic reviews addressing the role of GDF15 in GCs were updated, along with the latest clinical trials focussing on the GDF15-associated digestive malignancies.

Results: The multiple cellular pathways through which GDF15 is involved in the regulation of physiological and pathological conditions were first summarized. Then, GDF15 was also established as a valuable clinical index, functioning as a predictive marker in diverse GCs. Notably, latest clinical treatments targeting GDF15 were also highlighted, demonstrating its promising potential in mitigating and curing digestive malignancies.

Conclusions: This review unveils the pivotal roles of GDF15 and its potential as a promising target in the pathogenesis of GCs, which may provide insightful directions for future investigations.

Background: Clinical practice guidelines for patients with chronic kidney disease (CKD) recommend regular monitoring and management of kidney function and CKD risk factors. However, the majority of patients with stage 3 CKD lack a diagnosis code, and data on the implementation of these recommendations in the real world are limited.

Aim: To assess the implementation of guideline-directed monitoring and management practices in the real world in patients with stage 3 CKD without a recorded diagnosis code.

Methods: REVEAL-CKD (NCT04847531) is a multinational, observational study of patients with stage 3 CKD. Eligible patients had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements indicative of stage 3 CKD recorded >90 and ≤730 days apart, lacked an International Classification of Diseases 9/10 diagnosis code corresponding to CKD any time before and up to 6 months after the second eGFR measurement. Testing of key measures of care quality were assessed.

Results: The study included 435,971 patients from 9 countries. In all countries, the prevalence of urinary albumin-creatinine ratio and albuminuria testing was low. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker and statin prescriptions were highly variable, and sodium-glucose cotransporter-2 inhibitor prescriptions remained below 21%. Blood pressure measurements were recorded in 20.2%-89.9% of patients.

Conclusions: Overall, a large proportion of patients with evidence of stage 3 CKD did not receive recommended, guideline-directed monitoring and management. The variability in standard of care among countries demonstrates a clear opportunity to improve monitoring and management of these patients, most likely improving long-term outcomes.