Background: Endothelial and microvascular dysfunction play a central role in the pathogenesis of both cardiovascular and neurodegenerative disorders. However, whether impaired peripheral endothelial function independently predicts cognitive decline, cerebral small-vessel disease (SVD) progression, or stroke remains uncertain. Methods: We conducted a systematic review and meta-analysis of prospective cohort studies assessing the prognostic value of non-invasive peripheral endothelial tests—flow-mediated dilation (FMD), peripheral arterial tonometry (PAT/EndoPAT), and sublingual microcirculatory imaging—for cognitive or cerebrovascular outcomes. Databases (PubMed, Embase, Scopus, Web of Science) were searched from inception through 30 September 2025. Study quality was appraised using the Newcastle–Ottawa Scale (NOS), and evidence certainty was graded via GRADE. Random-effects models (DerSimonian–Laird or REML) pooled hazard ratios (HRs) using inverse-variance weighting. PROSPERO-registered (CRD42025211876). Results: Fifteen prospective cohorts (n = 13,972 participants; median follow-up 4.3 years) met inclusion criteria. Across all modalities, impaired endothelial or microvascular function predicted cognitive decline, SVD progression, or cerebrovascular events (pooled HR = 1.72, 95% CI 1.38–2.14, p < 0.001; I² = 57%). Subgroup analyses confirmed consistent associations for FMD (HR = 1.59, 95% CI 1.27–1.98) and PAT/EndoPAT (HR = 1.84, 95% CI 1.40–2.41). Evidence certainty was rated moderate-to-high according to GRADE. Conclusions: Peripheral endothelial dysfunction, measured by validated non-invasive techniques, independently predicts future cognitive and cerebrovascular events. These findings support the concept of a vascular–neural continuum, suggesting that endothelial health represents a modifiable biomarker for early neurovascular risk stratification. Routine assessment of endothelial function may help identify high-risk individuals and guide preventive interventions aimed at preserving brain and vascular health.

Background/Objectives: Antibiotic exposure is highly prevalent in patients hospitalized with COVID-19, yet the relationship between specific prescribing patterns, microbiologically confirmed secondary infections, and clinical outcomes remains incompletely understood, particularly in settings with high antimicrobial resistance. Methods: This single-center retrospective observational cohort included 395 consecutive adults hospitalized with RT-PCR-confirmed COVID-19 in a tertiary infectious diseases hospital. Data on demographics, comorbidities, baseline disease severity, antimicrobial prescribing (timing, WHO AWaRe class, duration, monotherapy/combination, escalation/de-escalation), microbiological results, and outcomes were extracted from electronic records and the microbiology information system. The primary outcome was microbiologically confirmed secondary infection; secondary outcomes were ICU admission, invasive mechanical ventilation, length of stay, and in-hospital mortality. Multivariable logistic regression and survival analyses assessed associations between antibiotic exposure and outcomes. Results: Overall, 88.4% of patients received systemic antibiotics, predominantly initiated within 24 h of admission and mostly empirical; 58.7% received combination regimens, with frequent use of Watch/Reserve agents. Secondary infections occurred in 28.4% of patients, were hospital-acquired in 82.1%, and involved multidrug-resistant organisms in 41.1% of cases. Any antibiotic exposure was independently associated with secondary infection (adjusted odds ratio, aOR 2.15; 95% CI 1.42–3.27), while prolonged therapy (≥7 days), Watch/Reserve use, and early initiation showed additional risk gradients. Antibiotic exposure was also associated with higher odds of ICU admission, invasive mechanical ventilation, prolonged hospitalization, and in-hospital mortality after adjustment. Conclusions: In this real-world COVID-19 cohort, broad and largely empirical antibiotic use was common and strongly associated with hospital-acquired, often multidrug-resistant secondary infections and worse clinical outcomes. These findings highlight the need for reinforced antimicrobial stewardship focusing on restrictive early broad-spectrum use, AWaRe-guided agent selection, systematic 48–72 h reassessment with de-escalation, and minimization of treatment duration.

Background/Objectives: BPC-157 (body protection compound 157) is a synthetic pentadecapeptide derived from a gastric protein fragment with reported cytoprotective and regenerative properties across multiple organ systems. Despite over three decades of preclinical research demonstrating consistent biological activity, its pharmaceutical development remains rudimentary, with no approved formulation, no validated dosing regimen, and no completed Phase II clinical trial. This review critically evaluates BPC-157 from a biopharmaceutical and drug development perspective, examining its physicochemical and pharmacokinetic properties, formulation challenges across routes of administration, the pharmacokinetic–pharmacodynamic disconnect that characterizes its preclinical profile, and the regulatory and translational barriers that currently preclude clinical advancement. Methods: A narrative review of the literature was conducted using PubMed/MEDLINE, Embase, and Cochrane Library from database inception to April 2026. Search terms included “BPC-157”, “BPC157”, “body protection compound 157”, “pentadecapeptide”, and “GEPPPGKPADDAGLV”, each combined with “pharmacokinetics”, “formulation”, “biopharmaceutics”, “drug delivery”, “clinical trial”, “toxicology”, and “regulatory”. Patent databases (Espacenet, Google Patents) and regulatory agency websites (FDA, EMA, WADA) were searched independently. Searches were supplemented by forward and backward citation tracking of key references. Articles were selected based on relevance to biopharmaceutical characterization, pharmacokinetics, formulation science, clinical evidence, and regulatory status; pharmacodynamic studies were included insofar as they inform translational development. Evidence was synthesized with emphasis on pharmaceutical characterization, formulation science, and translational feasibility; no formal quality assessment instrument was applied, consistent with the narrative review design. Results: BPC-157 exhibits unusual stability in gastric juice and demonstrates activity via oral, parenteral, and topical routes, yet its human pharmacokinetic profile remains critically undercharacterized despite a recently published formal preclinical ADME study in two species confirming a sub-30-min plasma half-life, linear dose-proportional kinetics, and intramuscular bioavailability of 14–51% depending on species. A plasma half-life of under 30 min—confirmed preclinically and in a preliminary two-subject human pilot—contrasts with prolonged biological effects lasting hours to days—a disconnect with significant implications for dosing strategy and formulation design. No pharmaceutical-grade formulation has been developed or validated. The peptide lacks bcs classification data, permeability characterization, and formal excipient compatibility studies. Available clinical data derive from fewer than 30 subjects across three uncontrolled pilot studies, none of which employed standardized pharmaceutical preparations. Conclusions: BPC-157 presents a compelling but pharmaceutically underdeveloped profile. The primary barrier to clinical translation is not the absence of biological activity, but the absence of fundamental pharmaceutical science: characterized formulations, validated pharmacokinetics, and a coherent drug development strategy. Addressing these biopharmaceutical gaps is a prerequisite for any meaningful clinical program.

Background and Objectives: Dysglycemia is a major determinant of adverse outcomes in COVID-19, yet the separate contributions of poor glycemic control and glycemic variability (GV) remain incompletely defined. We conducted a systematic review and meta-analysis of observational cohort studies (both prospective and retrospective) to quantify the impact of chronic hyperglycemia and glucose instability on disease severity, intensive care requirements, and mortality in patients with COVID-19. Materials and Methods: We searched PubMed, Scopus, and Web of Science from January 2020 to October 2024 for observational cohort studies reporting clinically relevant COVID-19 outcomes stratified by glycemic control or GV. Dysglycemia definitions varied across studies (HbA1c-based chronic hyperglycemia, fasting glucose, or admission/in-hospital hyperglycemia). GV was assessed using metrics including mean amplitude of glycemic excursions (MAGE), standard deviation (SD), coefficient of variation (CV), or maximum daily glucose difference. Twelve studies met inclusion criteria and were included in qualitative synthesis; five studies were eligible for quantitative synthesis of clinical outcomes. Random-effects DerSimonian–Laird models were applied due to anticipated clinical heterogeneity. Heterogeneity was evaluated using Cochran’s Q, τ², and I² statistics. Results: Overall, 12 observational studies (9 prospective and 3 retrospective cohorts; n = 1,008,310 patients) were included. In quantitative analyses of five eligible cohorts, poor glycemic control was associated with a significantly increased risk of severe or critical COVID-19 (pooled RR = 1.75, 95% CI: 1.45–2.11; I² = 29%), ICU admission (RR = 1.54, 95% CI: 1.18–2.01), and mechanical ventilation (RR = 1.72, 95% CI: 1.31–2.26). Three studies evaluating GV demonstrated a strong association with adverse outcomes (pooled RR = 2.07, 95% CI: 1.71–2.50; I² = 0%); this low heterogeneity should be interpreted cautiously given the limited number of studies. GV remained associated with mortality in multivariable models, indicating that glycemic variability is separately associated with mortality as a clinically relevant prognostic risk marker in hospitalized COVID-19 patients. Conclusions: Both chronic hyperglycemia and elevated glycemic variability are each associated with increased risk of severe COVID-19 outcomes. Glycemic variability appeared to be a consistent, low-heterogeneity prognostic marker of mortality, being separately associated with higher death risk in hospitalized COVID-19 patients, highlighting its potential utility as a dynamic metabolic biomarker. Early identification and targeted management of dysglycemia—especially glucose instability—may improve prognosis in hospitalized COVID-19 patients. PROSPERO: CRD420251250718.

Background/Objectives: Acute pulmonary edema (APE) has emerged as an overlooked but life-threatening manifestation of COVID-19, reflecting the intersection of inflammatory, endothelial, and cardiac injury pathways. This study aimed to determine the incidence, independent predictors, and long-term pulmonary sequelae of APE in hospitalized COVID-19 patients. Materials and Methods: We conducted a retrospective cohort study including 127 consecutively admitted adults with confirmed SARS-CoV-2 infection at a tertiary-care center in Romania. Demographic, clinical, biochemical, and imaging data were analyzed. Multivariate logistic regression identified independent predictors of APE and in-hospital mortality, while three-month follow-up assessed pulmonary recovery and biomarker dynamics. Results: APE occurred in 36.2% of patients and was associated with a four-fold increase in in-hospital mortality (43.5% vs. 12.3%, p < 0.001). Elevated NT-proBNP, troponin I, and IL-6 levels independently predicted both APE occurrence and mortality. APE patients required more frequent ICU admission (52.2% vs. 18.5%, p < 0.001) and had longer hospital stays. At three months, 39% of APE survivors exhibited fibrotic CT changes, and 37% had restrictive ventilatory defects, correlating with persistently increased NT-proBNP and IL-6 concentrations. Conclusions: Acute pulmonary edema delineates a distinct cardio-inflammatory phenotype of COVID-19, driven by endothelial dysfunction and biomarker-elevated cardiac stress. Early biomarker-guided fluid management and structured multidisciplinary follow-up may mitigate both acute mortality and chronic pulmonary sequelae in post-COVID populations.

Background: Cardiovascular comorbidities are major determinants of poor outcomes among patients admitted with COVID-19. However, the prognostic role of arterial hypertension alone remains uncertain. Little is known about the cumulative impact of concomitant hypertension and heart failure. This study assessed whether the combined burden of arterial hypertension and pre-existing heart failure identifies a high-risk phenotype for adverse in-hospital outcomes among COVID-19 patients. Methods: In this retrospective, real-world cohort study, 395 consecutive adults hospitalized with confirmed COVID-19 at a single infectious diseases center between March 2020 and December 2024 were included. We categorized patients into three cardiovascular phenotype groups: no hypertension or heart failure (n = 23), hypertension without heart failure (n = 193), and concomitant hypertension and heart failure (n = 178). The primary outcome was in-hospital all-cause mortality, while ICU admission served as a secondary outcome, invasive mechanical ventilation, and length of hospital stay. Multivariable logistic regression included age, sex, BMI, diabetes mellitus, and vaccination status to evaluate independent associations between the cardiovascular risk group and outcomes. Results: Overall in-hospital mortality was 7.3% (29/395). Mortality increased stepwise across the cardiovascular risk groups: 8.7% in patients without hypertension or heart failure, 3.1% in those with hypertension only, and 11.8% in patients with concomitant hypertension and heart failure (p = 0.004). In adjusted analyses, concomitant hypertension and heart failure were linked to higher adjusted odds of in-hospital death than no cardiovascular disease (odds ratio, 3.49; 95% confidence interval, 1.46–8.35). Isolated hypertension was not significantly associated with mortality. ICU admission and length of hospital stay also increased with cumulative cardiovascular burden. Patients with combined hypertension and heart failure showed more pronounced inflammatory and renal abnormalities at admission. Conclusions: Among hospitalized COVID-19 patients, the coexistence of arterial hypertension and heart failure identifies a vulnerable cardiovascular phenotype associated with higher in-hospital mortality and resource use than either no cardiovascular disease or hypertension alone. These findings support evaluating cardiovascular comorbidities cumulatively rather than in isolation. These findings are exploratory and require external validation in independent, larger multicentre cohorts. Findings may support careful use for short-term risk stratification and closer monitoring strategies during COVID-19 hospitalization.