Search Results (1,586)

Background: Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in intensive care units (ICUs), particularly in low- and middle-income countries (LMICs). Evidence-based practice (EBP) bundles have shown effectiveness in reducing VAP; however, the implementation in Bangladesh remains limited. This study aimed to evaluate the effectiveness of EBP to reduce the incidence rate of VAP among adult ICU patients in Bangladesh. Methods: A quasi-experimental study with a historical control group was conducted among 347 eligible ICU patients from October 2024 to April 2025. The intervention included nurse training on VAP bundle practices with advanced equipment support. Data on VAP incidence as a primary endpoint and VAP-related patients’ outcomes were analyzed. Results: The clinically suspected VAP incidence was 30.1 and 51.1 per 1000 ventilator-days, and the prevalence decreased significantly in the intervention group compared to the control group (26.9% vs. 46.1%; p < 0.001), respectively. Logistic regression indicated VAP bundle implementation was associated with reduced VAP (Exp(B) = 0.417, 95% CI: 0.262–0.666), while ventilation ≥96 h was a significant risk factor (Exp(B) = 2.6, 95% CI: 1.385–4.881). Early-onset VAP was reduced (25.0% vs. 10.2%), though late-onset predominated in the intervention group (75.0% vs. 89.8%). Conclusion: Implementation of an EBP-based VAP bundle by trained nurses significantly reduced VAP incidence. However, increased overall ICU mortality highlights the need for broader critical care improvements, including advanced comorbidity management and comprehensive ICU services. This study underscores the feasibility and effectiveness of VAP bundle implementation in the ICU of an LMIC. Full article

Background: Neonatal sepsis (NS) is a life-threatening condition in newborns, which is an infectious process with a systemic inflammatory reaction to bacterial, viral, or fungal infection acquired in the first 28 days of life. Methods: This study examines the major pathogens causing neonatal sepsis in the Gulf Cooperation Council (GCC) and their resistance patterns to antimicrobial agents. We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to develop this systematic review to follow a systematic and transparent process. The comprehensive literature review was done in several national and global databases, which include PubMed, Scopus, Google Scholar, Embase, and Cochrane Library. The key words inserted in the search strategy were “neonatal sepsis,” “late-onset sepsis,” “early-onset sepsis,” and “Gulf Cooperation Council (GCC),” and the keywords of antimicrobial resistance and pathogens were used: “antimicrobial drug resistance” and “pathogens.” Only articles published from January 1983 to January 2025 were included for screening. Results: The final count of the articles that fit the inclusion criteria is 54, and 5177 neonatal sepsis cases’ data have been identified. The most common pathogens were coagulase-negative staphylococci (CoNS) and Klebsiella spp., which caused 17.4 percent (901 cases) and 15.9 percent (825 cases) of neonatal sepsis, respectively. Coagulase-negative staphylococci (CoNS) were the most resistant, especially to oxacillin and erythromycin. The most isolated pathogens among Gram-negative spp. were Klebsiella spp., which showed a resistance to ampicillin, amoxicillin, and ceftriaxone. Conclusions: The bacterial isolates had a diversity of antimicrobial resistance, stressing the necessity of continuous hospital surveillance. Sophisticated diagnostic methods and well-designed research are necessary, especially in areas characterized by high rates of neonatal mortality, to determine the prevalence of neonatal sepsis, risk factors, and clinical outcomes. Full article

Background: Inherited retinal dystrophies (IRDs) include a clinically and genetically diverse array of conditions resulting in progressive visual impairment. The PROM1 gene is crucial for the development and maintenance of photoreceptors. Variants in PROM1 are linked to a wide phenotypic spectra of IRDs; however, the correlation between genotype and phenotype is not fully elucidated. Comprehending these relationships is essential for enhanced diagnostic precision, patient guidance, and formulation of focused treatments. Objective: This study aims to examine the genotype–phenotype associations in patients with PROM1-associated IRDs. Clinical variability and inheritance patterns linked to different pathogenic variants are examined, aiming to clarify their different behaviors. Methods: We performed a retrospective investigation of patients identified as affected by PROM1-related IRDs. Thorough ophthalmologic assessments, including retinography, fundus autofluorescence, optical coherence tomography (OCT), and electrodiagnostic testing (EDT), were conducted. Genetic testing was performed via targeted gene panels or whole-exome sequencing. Variants were categorized based on ACMG criteria, and inheritance patterns were determined by familial segregation analysis. Clinical characteristics were analyzed among genotypic groups to ascertain potential phenotype–genotype relationships. Results: All patients had pathogenic or likely pathogenic PROM1 mutations. Both autosomal dominant and autosomal recessive inheritance patterns were identified. Dominant pathogenic variants were predominantly linked to late-onset cone-rod dystrophy or macular dystrophy, whereas biallelic variants frequently resulted in early-onset severe rod–cone dystrophy characterized by fast vision deterioration. A group of patients with the same genotypes displayed significant phenotypic variability, indicating the potential impact of modifier genes or environmental influences. Truncating mutations in the N-terminal region were significantly associated with earlier illness onset and greater functional impairment. Conclusions: PROM1-related IRDs demonstrated significant clinical and genetic heterogeneity, with the route of inheritance and type of variant affecting disease severity and progression. Our findings underscore the significance of thorough genotypic and phenotypic characterization in afflicted individuals. A deeper comprehension of PROM1-related IRD disease pathways can enhance prognosis, direct clinical care, and facilitate the advancement of genotype-based therapy strategies. Full article

This narrative review of Alzheimer’s disease (AD) history, therapy and prevention shows that its conceptualization has changed three times over 100 years. First, AD was a normative creation by Kraepelin in 1910 of a rare presenile dementia characterized by specific histological features. Second, during the 1970s, American neurologists, driven by sociological changes, merged presenile and senile dementias into an Alzheimer-type dementia with the universally accepted clinicopathological diagnostic criteria of McKhann. By the end of the 20th century, AD was divided into early-onset genetic (1%) and late-onset sporadic (99%) forms. In the 21st century, AD was redefined as a biological entity, using biological and neuroimaging markers of amyloid, tau and neurodegeneration, to better address research and clinical trials. This new nosology has been widely criticized, given the absence of curative therapy, the evidence of mixed pathology in most cases and the decline in the dementia/AD incidence in high-income countries. However, there are currently many drugs against AD in the pipeline; prevention appears as medical and social therapy. In summary, the ancient concept of age-related dementia has evolved into AD normative disorders over 100 years. Nowadays, AD requires a conceptual reassessment, although its medical paradigm remains. Awaiting pharmacological breakthroughs, dementia prevention seems the best practical approach. Full article

Background/Objectives: Pacemaker-associated heart failure (PaHF) is a recognized complication of chronic ventricular pacing, yet its long-term incidence and prognostic impact remain incompletely defined. Previous studies on PaHF have been largely limited by small sample sizes, single-center designs, and insufficient long-term or time-dependent analyses. We aimed to evaluate the incidence, clinical predictors, and mortality risk of PaHF in a nationwide real-world cohort. Methods: Using the Korean National Health Insurance Service database, we identified 32,216 patients who underwent de novo pacemaker implantation between 2008 and 2019 without prior heart failure. Results: During a median follow-up of 3.8 years, 4170 patients (12.9%) developed new-onset PaHF and 6184 (19.2%) died. PaHF was independently associated with increased all-cause mortality (adjusted hazard ratio [HR]: 3.11, 95% confidence interval [CI]: 2.93–3.32, p < 0.001), even after accounting for immortal-time bias and relevant covariates. The incidence of PaHF and its associated mortality risk both peaked within the first six months post implantation and remained persistently elevated throughout follow-up; notably, PaHF-associated mortality showed a late resurgence. Sensitivity and subgroup analyses consistently demonstrated higher mortality among patients with PaHF across a wide range of clinical characteristics. Conclusions: In this large, nationwide cohort, the development of PaHF was associated with a substantial and sustained increase in mortality risk following pacemaker implantation. Given the persistent and dynamic nature of this risk, longitudinal monitoring of cardiac function and individualized pacing strategies may be warranted to mitigate long-term adverse outcomes. Additionally, these findings provide real-world benchmarks to guide future pacing strategies and surveillance efforts. Full article

Background/Objectives: Breast cancer incidence is increasing in younger Ghanaian women. However, few epidemiological studies have evaluated the modifiable risk factors in this population. Additionally, these studies have classified breast cancer in Ghanaian women based on the global menopausal case classification. This study reclassified premenopausal and postmenopausal breast cancer in a Ghanaian cohort, assessing the risk factors using the observed menopausal age in Ghanaian women of 48 years, rather than the global standard of 50 years. Methods: Women diagnosed with breast cancer and scheduled for surgery from December 2018 to March 2023 were recruited across four hospitals in Ghana for the Ghana Breast Cancer Omics Project (BCOPGh), and data were collected using a questionnaire. Cross-tabulation and linear regression were used to evaluate the relationships between categorical variables and age at diagnosis. Results: Out of a total of 262 women recruited, 34.4% were classified as having premenopausal breast cancer, while early-onset breast cancer (EOBC) accounted for 14.9% of all cases. The molecular subtypes were predominantly hormone receptor (HR)-positive (61%) while triple-negative breast cancer (TNBC) accounted for 16%. The tumours were predominantly at stage II (62%) and grade 2 (51%), with invasive carcinoma NST (56%) being the most common subtype. Within this cohort, nulliparity increased the odds of EOBC by 13.5-fold, while having a first birth after the age of 23 doubled the odds of premenopausal breast cancer. Reproductive factors (menarche and menopause) and lifestyle (alcohol intake, smoking, contraceptive use, and breastfeeding duration) were not associated with premenopausal breast cancer in this cohort. About 13% of participants reported a family history of breast cancer, and 79% had prior knowledge of the disease. Conclusion: This study supports previous reports of the relatively higher incidence of aggressive disease in young Ghanaian women and the protective effect of early age at first birth. It further underscores the need to investigate its genetic underpinnings, whilst highlighting the importance of public education on self-examination techniques to reduce advanced disease presentation in Ghanaian women. Full article

Autonomic nervous system (ANS) dysfunction has emerged as a central feature of post-infectious syndromes, including post-COVID syndrome (PCS), chronic fatigue syndrome (CFS), and late-stage Lyme disease. This cross-sectional study included 1036 patients evaluated in the Neurocardiological Laboratory of the Institute for Cardiovascular Diseases “Dedinje,” divided into four groups: PCS, CFS after COVID-19, CFS of insidious onset, and Lyme disease. All patients underwent head-up tilt testing (HUTT), and serological testing was performed in accredited institutions. The Lyme disease group demonstrated the highest prevalence of positive HUTT responses and a significantly greater frequency of orthostatic hypotension and syncope. Approximately 50–65% of patients in the PCS and Lyme groups were positive for IgM antibodies against at least one microorganism, with more than 10% showing positivity for three or more pathogens. Logistic regression analysis revealed that, beyond classical hemodynamic parameters, antibody status served as a significant predictor of HUTT outcomes, with specific associations identified for HSV-1, HHV-6, Coxiella burnetii, Toxoplasma gondii, and Borrelia spp. Multinomial regression further indicated that negative IgG antibodies, particularly to HSV-1 and VZV, predicted Lyme disease group membership. These findings support the hypothesis that ANS dysfunction in post-infectious syndromes may be driven by persistent or prior infections, highlighting the need for integrative diagnostic approaches. Full article

Background: Early-onset colorectal cancer (EOCRC), defined as diagnosis before the age of 50, is rising rapidly and disproportionately affects high-risk populations, particularly Hispanic/Latino (H/L) individuals, who experience the steepest increases in incidence and mortality. While prevention and screening strategies have curbed late-onset CRC rates, EOCRC remains outside standard screening guidelines and is projected to become the leading cause of cancer-related death in individuals aged 20–49 by 2030. FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is a standard first-line therapy for microsatellite stable (MSS) CRC lacking actionable driver mutations; however, its efficacy and genomic impact in EOCRC, particularly in underrepresented groups, remain poorly understood. The phosphatidylinositol 3-kinase (PI3K) pathway regulates cell growth, survival, and metabolism, and its alterations have been implicated in therapeutic resistance and adverse outcomes. Yet, the prevalence, clinical relevance, and treatment-specific associations of PI3K pathway alterations in EOCRC remain underexplored. Methods: We analyzed somatic mutation and clinical data from 2515 CRC patients (266 H/L and 2249 Non-Hispanic White [NHW]) across publicly available genomic datasets. Patients were stratified by age at diagnosis (EOCRC < 50 vs. LOCRC ≥ 50), ancestry (H/L vs. NHW), and FOLFOX treatment status. PI3K pathway alterations—including mutations in PIK3CA, PTEN, AKT isoforms, and regulatory genes—were identified using curated pathway definitions. Mutation prevalence was compared across groups using Fisher’s exact or chi-squared tests. AI-HOPE-PI3K, a conversational AI platform, was deployed to automate cohort construction, stratify subgroups, and perform post hoc survival analysis. Results: PI3K pathway alterations were observed across all demographic groups. In EO NHW patients treated with FOLFOX, Kaplan–Meier analysis revealed significantly reduced overall survival among those with PI3K pathway alterations (n = 124) compared with their unaltered counterparts (n = 251; p = 0.0008), identifying alterations as a candidate prognostic biomarker in this subgroup. AI-guided subgroup interrogation further highlighted mutation-specific signals: INPP4B and RPTOR emerged as exploratory candidates in EO H/L patients but did not show significant treatment- or ancestry-specific enrichment upon confirmatory testing. Similarly, ancestry-stratified analysis of PIK3R2 mutations revealed comparable rates in EO H/L (1.37%) and EO NHW (1.6%) FOLFOX-treated patients (p = 1.0). Across ancestry and age groups, mutational landscape analysis revealed diverse molecular events—including missense, nonsense, splice-site, frameshift, and in-frame deletions—underscoring the heterogeneity of PI3K pathway dysregulation. Conclusions: This study identifies PI3K pathway alterations as a potential prognostic marker of poor survival in EO NHW patients receiving FOLFOX and uncovers ancestry- and treatment-specific mutational differences in high-risk CRC populations. By integrating clinical, molecular, and treatment variables, the AI-HOPE and AI-HOPE-PI3K platforms enabled rapid, reproducible, and fine-grained analysis of complex datasets. These findings underscore the need for ancestry-informed molecular profiling to optimize therapeutic strategies and highlight AI-guided interrogation as a powerful tool for advancing precision oncology in underrepresented and disproportionately affected CRC populations. Full article

Genetic background is a critical determinant of disease expression, arrhythmic vulnerability, and therapeutic response in inherited cardiomyopathies. Implantable cardioverter-defibrillators (ICD) remain the cornerstone for primary prevention of sudden cardiac death, yet conventional selection based on left ventricular ejection fraction does not adequately reflect the heterogeneity of genetic substrates. Increasing evidence demonstrates that pathogenic variants differ not only in prevalence across cardiomyopathy subtypes but also in prognostic impact. Truncating variants, particularly in genes encoding structural proteins, are often associated with severe remodeling, progressive dysfunction, and high arrhythmic risk, whereas missense variants may confer variable expressivity, ranging from aggressive arrhythmogenic phenotypes to milder or late-onset disease. This variability underscores the importance of distinguishing variant classes in clinical decision-making. Integrating genetic information with advanced imaging markers, such as late gadolinium enhancement, allows refinement of arrhythmic risk stratification beyond static thresholds and supports more tailored ICD allocation. Nevertheless, translation into routine practice is limited by challenges in variant interpretation, phenotypic overlap between cardiomyopathy subtypes, and the lack of prospective validation of genotype-based models. In the precision medicine era, evolving strategies should move toward dynamic, multimodal approaches that combine genotype, phenotype, and imaging biomarkers, enabling more accurate prediction of arrhythmic risk and more cost-effective use of ICD therapy. Full article

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by GLA mutations, leading to deficient α-galactosidase A (α-Gal A) activity and progressive glycosphingolipid accumulation. While α-Gal A activity is the diagnostic gold standard, its sensitivity is reduced in late-onset or heterozygous patients. Conventional biomarkers such as lyso-Gb3 provide only limited insight into disease progression and therapeutic response. Exosomes, as stable carriers of disease-specific proteins, may offer complementary biomarkers for early detection and longitudinal monitoring. Methods: Twenty-one pediatric FD patients with confirmed GLA mutations were enrolled. Clinical, enzymatic, renal, and cardiac parameters were assessed. Plasma-derived exosomes were characterized by transmission electron microscopy and proteomic profiling. Differentially expressed proteins were identified using mass spectrometry, analyzed using GO/KEGG enrichment, and validated using RT-PCR, ELISA, and immunofluorescence in patient samples and Gla^−/− mice. Results: Male patients showed markedly reduced α-Gal A activity and elevated lyso-Gb3 compared with females. Although overt renal and cardiac dysfunction was uncommon, several patients exhibited early abnormalities such as proteinuria, an elevated LVMI, or increased cTnI levels. Proteomic analysis identified 2553 proteins, of which 188 were differentially expressed. Fibrosis- and inflammation-related proteins, including THBS1 and CFHR5, were upregulated, while protective factors such as APM1, SERPINA10, and CAB39 were downregulated. IGFBP3 was also elevated and closely linked to tissue remodeling. Enriched pathways were involved in PPAR/AMPK signaling, lipid metabolism, and complement activation. Conclusions: Exosomal proteomic profiling revealed early molecular signatures of cardiorenal involvement in pediatric FD. Key proteins such as THBS1, CFHR5, IGFBP3, APM1, and CAB39 show strong potential as biomarkers for risk stratification, disease monitoring, and therapeutic evaluation. Full article

Transcription factor EB (TFEB) is expressed at high levels in the trophoblast cells of the placenta, where it plays a critical role in regulating normal vascularization. Preeclampsia (PE) is a severe complication of pregnancy with a high incidence of maternal and fetal morbidity and mortality. Gestational diabetes (GD) is a metabolic disease that can affect placental villous maturation and villous vascularity. We analyzed the expression of three different antibodies: TFEB from Invitrogen (TFEB-INV), which detects endogenous levels of TFEB only when phosphorylated at Ser211; TFEB from Bethyl Labs (TFEB-B), which recognizes and binds E-box sequences; and TFEB from Santa Cruz (C-6) (TFEB-SC), which is specifically used for epitope mapping between 440 and 470. We evaluated the presence/absence of TFEB in six placental districts: syncytiotrophoblast (STB), cytotrophoblast (CTB), extravillous trophoblast (EVT), syncytial knots, stem villi vessels, and villous capillaries. TFEB-B was significantly expressed in the stem villi vessels, STB, and villi vessels of GD cases. The lack of TFEB expression in late-onset PE appears to corroborate the role of TFEB in vascular remodeling during placental development. The positive results in STB and vessels in GD cases, regardless of the histological diagnosis, may suggest that the expression of TFEB mitigates hypoxic injury via the Akt/mTOR pathway. Full article

Aging is a multifactorial process that progressively disrupts cellular and tissue homeostasis, affecting all organ systems at distinct rates and predisposing individuals to chronic diseases such as cancer, type II diabetes, and sarcopenia. Among these systems, skeletal muscle plays a central role in healthspan decline, yet the precise onset of its deterioration remains unclear. Most studies emphasize late-life models, overlooking the transitional phase of middle age, when initial alterations emerge. Evidence indicates that middle-aged muscle exhibits aberrant metabolism, impaired insulin sensitivity, and an early, gradual reduction in mass, suggesting that decline begins long before overt sarcopenia. This narrative review synthesizes current findings on linear and non-linear molecular biomarkers associated with the onset of skeletal muscle aging, aiming to improve early detection of muscular alterations and support the development of interventions that delay or prevent functional decline. Full article

Background: Apolipoprotein E (APOE) is the strongest genetic risk determinant for late-onset Alzheimer’s disease (AD). The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains from a mouse model homozygous for each of these humanized APOE alleles to study gene expression profiles between mice aged 12 months of age (MO) and 18 MO, independent of β-amyloid and tau pathology. Results: More than half of the differentially expressed genes (DEGs) within each genotype were shared with at least one other APOE allele, including 1610 DEGs that were shared across the three genotypes. These DEGs represent changes driven by aging rather than APOE genotype. Aging induced DEGs and biological pathways involving metabolism, synaptic function, and protein synthesis, among others. Alterations in these pathways were also identified by DEGs unique to APOE4, suggesting that the APOE4 allele drives the aging phenotype. In contrast, fewer pathways were identified from DEGs unique to APOE2 or APOE3. Conclusions: Transcriptomic results suggest that the most significant impact on brain-level expression changes in humanized APOE mice is aging and that APOE4 exacerbates this process. These in vivo findings within an established model system are consistent with brain aging being the greatest risk factor for AD and suggest that APOE4 expression promotes an aging phenotype in the brain that interacts with, and contributes to, aging-driven AD risk. Results reinforce the impact age and APOE allele contribute to AD and age-related neurodegeneration, and foster greater mechanistic understanding as well as inform therapeutic intervention. Full article

Background: Colorectal cancer (CRC) represents one of the leading causes of cancer-related morbidity and mortality globally. Although national screening programs in Europe and the United States have demonstrated success in reducing incidence and death rates among populations aged 50 and above, a concerning increase in early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, has emerged. Methods: This paper is a narrative literature review comparing American and European CRC screening guidelines. A comprehensive search was conducted using the PubMed database with emphasis on publications from the past ten years. Results: The United States has adapted more swiftly to EOCRC trends by lowering the recommended screening age to 45, supported by modeling studies showing life-years gained and improved cost-effectiveness. In contrast, European programs remain largely organized and cost-efficient but predominantly initiate screening at age 50, potentially missing high-risk younger adults. EOCRC appears to demonstrate unique molecular and pathological features compared to late-onset CRC. Participation and adherence to screening also vary significantly between regions and modalities, with colonoscopy remaining the gold standard but less scalable than fecal immunochemical tests. Conclusions: The rising incidence of EOCRC calls for a reassessment of CRC screening policies. While the European model emphasizes equity and structure, its slower responsiveness to epidemiological changes may lead to late detection in younger cohorts. The American model’s earlier screening age addresses emerging trends but faces challenges in implementation equity. A hybrid approach may provide the optimal management, balancing public health benefit with system sustainability. Full article

Objectives: The incidence of Fuchs endothelial corneal dystrophy (FECD) is growing, and with it, the unmet need for a corneal transplant. Among alternative treatment modalities, only genetic therapy represents a causal therapy. Methods: Following the SNARA protocol, the PubMed and ClinicalTrials databases were searched using the keywords Fuchs endothelial corneal dystrophy, FECD, genetic therapy, and CRISPR-Cas9. Results: FECD is polyfactorial disease and mutations or polymorphisms in at least 15 different genes were connected to the disease. For the early-onset form of the disease, exclusive connection to mutations in COL8A2 was confirmed, while for the late-onset form, the most characteristic mutation is the expansion of the CTG18.1 triplet in the TCF4 gene, making these two possible targets. While the CRISPR-Cas9 approach represents the mainstay of genetic therapy development recently, the application of this method to FECD contains several obstacles, studied in preclinical settings. DT-168 and the Ad-Cas9-Col8a2gRNA molecules were developed for FECD treatment and preclinically tested, and phase I and II clinical studies for DT-168 are also already being performed. Conclusions: The review of the literature proved that genetic therapy for FECD is at the level of preclinical research and that there are several specific challenges connected to the target genetic mutation as well as the delivery of possible treatment and duration of the effect. Further studies in the field might bring solutions in the future for alternative treatments for this common corneal disease. Full article