Bioscientia Medicina - Journal of Biomedicine and Translational Research
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The Dual Role of Hypoxia-Inducible Factor-1α in Sepsis-Induced Immunomodulation and Organ Dysfunction: A Systematic Review and Meta-Analysis
Get PDFBackground: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of global mortality. Hypoxia-inducible factor-1α (HIF-1α) is a master transcriptional regulator of the cellular adaptive response to hypoxia but plays a complex, paradoxical role in sepsis. While essential for innate immune function, its sustained activation may amplify inflammation and drive organ damage. This meta-analysis was conducted to synthesize the evidence on the association of HIF-1α with key markers of immunomodulation and organ dysfunction in sepsis.
Methods: We performed a systematic review and meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, Scopus, and Web of Science was conducted for studies published between January 2014 and December 2024. We included observational studies that measured HIF-1α levels in adult sepsis patients and reported outcomes related to organ dysfunction (Sequential Organ Failure Assessment [SOFA] score) or mortality, and immunomodulation (Interleukin-6 [IL-6] levels). Seven studies meeting the inclusion criteria were included in the final analysis. Data were pooled using a random-effects model. Standardized Mean Difference (SMD) and Odds Ratios (OR) with 95% confidence intervals (CI) were calculated.
Results: The seven included studies comprised 1,288 patients. The overall quality of the included studies was moderate to high as per the Newcastle-Ottawa Scale. The pooled analysis revealed that HIF-1α levels were significantly elevated in sepsis patients who died compared to those who survived (OR = 2.68, 95% CI: 1.55–4.64, p < 0.001), with moderate heterogeneity (I² = 45%). Furthermore, HIF-1α levels were strongly associated with greater organ dysfunction, as measured by the SOFA score (5 studies; SMD = 0.92, 95% CI: 0.51–1.33, p < 0.0001), with substantial heterogeneity (I² = 78%). HIF-1α levels also showed a significant positive correlation with the pro-inflammatory cytokine IL-6 (4 studies; SMD = 1.15, 95% CI: 0.65–1.65, p < 0.00001), with high heterogeneity (I² = 82%).
Conclusion: This meta-analysis provides robust evidence that elevated HIF-1α levels are significantly associated with increased sepsis severity, characterized by greater organ dysfunction, a heightened pro-inflammatory state, and a higher risk of mortality. These findings underscore the maladaptive consequences of sustained HIF-1α activation in sepsis, positioning it as a critical prognostic biomarker and a complex, high-value target for future therapeutic modulation
Enhancing the Early Inflammatory Response: The Role of Ozonated Aloe Vera Oil on IL-6 and TNF-α in Cutaneous Wound Repair
Get PDFBackground: Dysregulation of the initial inflammatory phase is a primary driver of impaired healing and the formation of chronic wounds, creating a critical need for therapies that can optimize this early response. This study tested the hypothesis that a novel formulation of ozonated aloe vera oil functions as a sophisticated bioregulator, promoting a beneficial, pro-regenerative inflammatory phenotype by transiently enhancing the host's innate repair signals.
Methods: This was a preclinical, randomized, controlled study using fifty male Sprague-Dawley rats with 1 cm full-thickness excisional wounds. The therapeutic agent, ozonated aloe vera oil, was chemically characterized by its peroxide value (PV). Animals were randomized to receive topical treatment with either a positive control (aloe vera oil), a negative control (gentamicin ointment), or one of three graded doses of ozonated oil (Low PV, Medium PV, High PV). The primary outcomes, systemic (serum) and local (wound tissue homogenate) concentrations of Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were quantified by ELISA on days 3 and 7.
Results: On day 3, all ozonated oil formulations induced a profound and significant upregulation of both local and systemic TNF-α and IL-6 compared to controls (p < 0.001). The topical treatment increased systemic TNF-α levels by over 40% and local tissue concentrations by over 60%. Critically, this pro-inflammatory surge was transient; by day 7, both local and systemic cytokine levels in all groups had returned to statistically indistinguishable baseline levels.
Conclusion: Ozonated aloe vera oil acts as a potent, transient modulator of the wound microenvironment, enhancing the expression of key initiatory cytokines. This mechanism, likely mediated by the activation of redox-sensitive transcription factors, optimizes the crucial first phase of healing without inducing pathological chronic inflammation. This study supports a novel therapeutic paradigm aimed at enhancing, rather than suppressing, the body's innate capacity for repair
Redefining the Therapeutic Ladder in Refractory Chronic Constipation: A Systematic Review and Meta-Analysis of the Role of Ileal Bile Acid Transporter (IBAT) Inhibitors
Get PDFBackground: Chronic constipation (CC) refractory to conventional laxatives is a prevalent clinical challenge that significantly impairs quality of life. Ileal bile acid transporter (IBAT) inhibitors, a novel class of drugs, modulate colonic function by increasing the delivery of bile acids to the colon. This study aimed to quantitatively synthesize the evidence for the efficacy and safety of IBAT inhibitors in this difficult-to-treat population to clarify their position in the therapeutic algorithm.
Methods: Following PRISMA guidelines, we systematically searched PubMed, Scopus, Embase, and Cochrane CENTRAL, along with clinical trial registries, from inception to June 1st, 2025. We included parallel-group, randomized controlled trials (RCTs) comparing the IBAT inhibitor elobixibat with placebo in adults with CC refractory to at least two prior laxative classes. The primary efficacy outcome was the overall responder rate. Key secondary outcomes included change in spontaneous bowel movements (SBMs) per week, quality of life (QoL) scores, and incidence of adverse events. Data were pooled using a random-effects model. Number needed to treat (NNT) and to harm (NNH) were calculated.
Results: Our search identified six eligible RCTs enrolling 2,155 patients. Patients treated with elobixibat were significantly more likely to be responders compared to placebo (Risk Ratio [RR] = 2.58; 95% CI: 1.87–3.56; p < 0.00001), with moderate heterogeneity (I² = 59%). The NNT to achieve one additional responder was 5 (95% CI: 4–7). Elobixibat significantly increased the mean number of SBMs per week (Mean Difference [MD] = 1.65; 95% CI: 1.19–2.11; p < 0.00001; I² = 64%). The most common adverse events were gastrointestinal; elobixibat significantly increased the risk of diarrhea (RR = 4.21; 95% CI: 3.01–5.89; NNH = 6) and abdominal pain (RR = 2.35; 95% CI: 1.63–3.38; NNH = 11). Most events were mild to moderate.
Conclusion: This meta-analysis provides robust evidence that the IBAT inhibitor elobixibat is a highly effective therapy for refractory CC, offering a significant improvement in symptoms for a substantial portion of patients. This benefit must be carefully balanced against the high incidence of mechanism-based gastrointestinal side effects. These findings establish elobixibat as a potent, mechanistically distinct option, thereby informing its strategic placement on the therapeutic ladder for patients failed by conventional laxatives
Beyond Cholesterol: The Independent Roles of Inflammation and Renal Dysfunction in Carotid Atherosclerosis Among Indonesian Elders
Get PDFBackground: Atherosclerosis remains a leading cause of mortality in aging populations, driven by a complex interplay of metabolic and inflammatory factors. While dyslipidemia is a cornerstone of risk, the contributions of systemic inflammation, marked by high-sensitivity C-reactive protein (hsCRP), and declining renal function are increasingly recognized. This study aimed to elucidate the independent associations of hsCRP, dyslipidemia, and renal function with the presence of carotid atherosclerosis in an understudied elderly Indonesian population.
Methods: We conducted a single-center, case-control study at a tertiary hospital in Palembang, Indonesia, from January to June 2024. One hundred participants aged ≥60 years were enrolled from the geriatric outpatient clinic. Cases were defined by the presence of carotid plaque, identified via B-mode Doppler ultrasound, and defined according to international consensus criteria. Controls had no evidence of plaque. We performed multivariate logistic regression to identify independent predictors of atherosclerosis, including hsCRP, lipid parameters, and estimated glomerular filtration rate (eGFR).
Results: After multivariable adjustment, three factors emerged as significant, independent predictors of carotid atherosclerosis. High total cholesterol (≥200 mg/dL) was the most powerful predictor, associated with a more than seven-fold increased odds of plaque (Adjusted Odds Ratio [aOR]: 7.38; 95% Confidence Interval [CI]: 2.87–18.94; p<0.001). Elevated hsCRP (≥2 mg/L) (aOR: 3.38; 95% CI: 1.33–8.59; p=0.005) and abnormal eGFR (≤90 mL/min/1.73m²) (aOR: 3.36; 95% CI: 1.10–10.22; p<0.001) were also robustly associated with atherosclerosis, each conferring over a three-fold increase in odds.
Conclusion: In this elderly Indonesian study, dyslipidemia remains a dominant risk factor for carotid atherosclerosis. However, systemic inflammation (high hsCRP) and mild renal dysfunction (abnormal eGFR) are also powerful, independent contributors. These findings highlight the multifactorial nature of atherosclerosis and underscore the importance of a comprehensive risk assessment that extends beyond traditional lipid profiling to include markers of inflammation and renal health
Modernizing a Classic Test: Validation and Clinical Utility of Infrared-Barrier and Near-Infrared Photometry for Erythrocyte Sedimentation Rate Determination
Get PDFBackground: The erythrocyte sedimentation rate (ESR) is a cornerstone laboratory test for monitoring inflammation. The manual Westergren method, while the established gold standard, is slow and hazardous, prompting a shift towards automation. This study provides a rigorous, head-to-head validation of two mechanistically distinct automated technologies—infrared-barrier photometry (IBP) and near-infrared photometry (NIP)—to assess their analytical performance and operational utility in a tertiary care setting.
Methods: A cross-sectional method comparison study was conducted on 59 outpatient samples at Adam Malik General Hospital, Indonesia. Each sample was analyzed for ESR using the manual Westergren method, the Caretium XC-A30 analyzer (IBP), and the Mindray BC-760 hematology analyzer (NIP). Method agreement was assessed using Passing-Bablok regression and Bland-Altman analysis. Clinical concordance was evaluated using categorized results.
Results: Both automated methods demonstrated excellent agreement with the Westergren reference. Passing-Bablok regression showed no significant proportional or constant bias for either method. The NIP method exhibited a near-perfect regression equation (y = 1.01x - 0.58), while the IBP method also performed well (y = 0.98x + 1.25). Bland-Altman analysis revealed a clinically insignificant mean bias of +0.44 mm/hr for NIP and -4.47 mm/hr for IBP. Clinical concordance was high, with 96.6% of NIP results and 91.5% of IBP results falling within the same clinical category as the Westergren method.
Conclusion: Both automated methods are valid and reliable alternatives to the Westergren method. The NIP technology, in particular, offers a substantial leap in laboratory efficiency by providing results in under two minutes from a standard EDTA sample. Its superior workflow integration and strong analytical performance support its adoption to drastically reduce turnaround times and enhance modern patient care pathways
The Prognostic Utility of Immature Platelet Fraction (IPF) in Adult Sepsis: A Correlation Analysis with SOFA Score and Conventional Platelet Indices
Get PDFBackground: Sepsis is a leading cause of mortality, driving the search for biomarkers that can accurately reflect its severity. The immature platelet fraction (IPF) measures real-time thrombopoiesis, which is profoundly stressed during sepsis. Its clinical utility relative to conventional platelet indices (MPV, PDW) in predicting organ dysfunction remains to be fully elucidated. This study aimed to explore the relationship between these platelet parameters and the Sequential Organ Failure Assessment (SOFA) score in adult sepsis patients.
Methods: An observational, cross-sectional study was conducted on 32 adult patients diagnosed with sepsis at a tertiary hospital in Medan, Indonesia. Upon admission, platelet indices and IPF were measured using a Sysmex XN-1000 hematology analyzer. The SOFA score was calculated to quantify organ dysfunction. The relationships between variables were assessed using Pearson or Spearman correlation analysis.
Results: The analysis revealed a statistically significant but weak positive correlation between IPF and the SOFA score (r=0.354, p=0.047). In contrast, conventional indices like MPV (r=0.219, p=0.228) and PDW (r=0.190, p=0.297) showed no significant association with the SOFA score. Mechanistically, strong positive correlations were confirmed between IPF and both MPV (r=0.768, p<0.001) and PDW (r=0.775, p<0.001), reflecting a coordinated bone marrow response.
Conclusion: This study reveals a critical paradox in sepsis: while the bone marrow mounts a robust thrombopoietic response, evidenced by the tight correlation between markers of platelet production, this response is poorly coupled with clinical outcomes. The weak association between IPF and organ dysfunction severity suggests that IPF's primary utility may not be as a standalone prognostic tool, but rather as a biomarker of a high-turnover, "futile thrombopoiesis." This highlights the complexity of platelet kinetics in sepsis and warrants further investigation into its role within a multi-marker prognostic strategy
Genetic and Epigenetic Alterations in Exhaled Breath Condensate for Early Detection of Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
Get PDFBackground: Early detection of non-small cell lung cancer (NSCLC) is critical for improving patient survival, yet current methods face challenges of invasiveness and limited accuracy. Exhaled breath condensate (EBC) offers a non-invasive window into the deep airways. This study aimed to synthesize and critically evaluate the diagnostic accuracy of genetic and epigenetic alterations in EBC for NSCLC detection.
Methods: We conducted a systematic review and meta-analysis of studies published between January 2015 and August 2025, sourced from PubMed, Scopus, Web of Science, and Embase. We included diagnostic accuracy studies evaluating genetic (KRAS, EGFR, p53) or epigenetic (gene methylation) markers in EBC against a histopathological reference standard. Data were used to construct 2x2 contingency tables. Methodological quality was assessed using the QUADAS-2 tool. A bivariate random-effects model was used to derive pooled accuracy estimates.
Results: Seven case-control studies, comprising 812 NSCLC patients and 995 controls, met the inclusion criteria. The analysis yielded a pooled sensitivity of 0.81 (95% Confidence Interval [CI]: 0.74–0.87) and a pooled specificity of 0.96 (95% CI: 0.93–0.98). The pooled diagnostic odds ratio was 112 (95% CI: 65–194), and the area under the SROC curve was 0.95 (95% CI: 0.93–0.97). However, extreme statistical heterogeneity (I² > 80%) was observed, and all included studies were rated at high risk of bias due to their case-control design, suggesting the pooled estimates must be interpreted with significant caution.
Conclusion: Analysis of DNA alterations in EBC shows promising diagnostic potential for NSCLC, particularly with high specificity. However, the current evidence is limited by significant methodological heterogeneity and study design flaws that likely overestimate performance. The primary contribution of this analysis is not a definitive accuracy value, but a critical appraisal of the monumental challenges in pre-analytical and analytical standardization that must be overcome for this technology to achieve clinical translation
Clinical Characteristics and Progression of Osteogenesis Imperfecta Type III: A Case Series
Get PDFBackground: Osteogenesis imperfecta (OI) is a rare genetic disorder primarily affecting bone formation, leading to increased bone fragility and fractures. OI Type III is characterized by severe clinical manifestations, including multiple fractures, skeletal deformities, and short stature. This case series describes the clinical characteristics and progression of three patients diagnosed with OI Type III, highlighting the impact of early intervention with zoledronic acid on their outcomes.
Case presentation: This study presents three cases of OI Type III in female patients. Two patients (Patient A and Patient R) were diagnosed at birth with multiple fractures and received zoledronic acid treatment starting at three months of age. The third patient (Patient D) presented with fractures later in infancy and began treatment at one year of age. All patients demonstrated hallmark features of OI Type III, including blue sclerae, short stature, and progressive skeletal deformities. However, the two patients who received earlier treatment with zoledronic acid showed better mobility and fewer fractures compared to the patients who started treatment later.
Conclusion: This case series emphasizes the importance of early diagnosis and intervention in OI Type III. Zoledronic acid appears to be effective in reducing fracture rates and improving mobility in these patients. Further studies with larger sample sizes are needed to confirm these findings and optimize treatment strategies for OI Type III
Platelet-to-Lymphocyte Ratio in Pediatric Dengue Patients: A Key Indicator of Disease Severity
Get PDFBackground: Dengue infection remains a significant health concern in Indonesia, with a high mortality rate. Early identification and prediction of severe dengue are crucial for effective management and mortality reduction. The platelet-to-lymphocyte ratio (PLR) has emerged as a potential biomarker for assessing dengue severity due to its association with inflammatory responses.
Methods: This descriptive study included 48 pediatric patients diagnosed with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) at Dr. M. Djamil General Hospital Padang between March and August 2024. Patients were included if they were aged 0-18 years, had a confirmed diagnosis of DHF or DSS, and underwent complete blood count and serological testing for dengue. Patients with chronic diseases or other comorbidities were excluded. Complete blood counts were performed using flow cytometry, and PLR was calculated by dividing the platelet count by the absolute lymphocyte count. Clinical data were obtained from medical records.
Results: The majority of patients were aged 6-18 years (68.8%), with 20 (41.7%) presenting with DHF and 28 (58.3%) with DSS. The median platelet count was lower in DSS patients (26,000/mm3) compared to DHF patients (35,500/mm3). The median PLR was also significantly lower in DSS patients (8.95) compared to DHF patients (15.61). A PLR value <20 was more frequently observed in DSS patients (89.3%) than in DHF patients (75%).
Conclusion: A lower PLR value was associated with more severe clinical manifestations of dengue infection, particularly DSS. PLR can serve as a valuable biomarker for assessing dengue severity, utilizing readily available and cost-effective complete blood count results
Hyperthyroidism-Induced Myocardial Ischemia: Quantification and Correlation with fT4 via 99mTc-Sestamibi Scintigraphy
Get PDFBackground: Hyperthyroidism exerts significant detrimental effects on the cardiovascular system, increasing the risk of major adverse cardiac events (MACE). While associations with atrial fibrillation and cardiomyopathy are well-documented, the incidence and characteristics of myocardial ischemia, particularly assessed by functional imaging, remain less explored. This study aimed to investigate the incidence of myocardial ischemia in hyperthyroid patients using Technetium-99m Sestamibi (⁹⁹ᵐTc-Sestamibi) myocardial perfusion scintigraphy (MPS) and correlate findings with thyroid hormone levels.
Methods: This prospective preliminary study enrolled fifteen consecutive patients with confirmed hyperthyroidism and no prior history of ischemic heart disease between January and April 2024. All subjects underwent thyroid function tests (TSH, fT4, T3) and a one-day rest/adenosine-stress ⁹⁹ᵐTc-Sestamibi MPS protocol. Myocardial ischemia presence, reversibility, severity (Summed Stress Score, SSS), and extent (total ischemic segments) were assessed using the AHA 17-segment model. Spearman correlation was used to analyze the relationship between hormone levels and MPS parameters.
Results: Fifteen subjects (93.3% female, mean age 34 ± 11 years) were included. Myocardial ischemia was detected in 14/15 subjects (93.3%). Among those with ischemia, 12 (80% of total subjects, 85.7% of ischemic subjects) exhibited reversible defects. Free thyroxine (fT4) levels showed a strong positive correlation with SSS (rs = 0.64, p = 0.01) and the total number of ischemic segments (rs = 0.65, p = 0.01).
Conclusion: This preliminary study revealed a high incidence of myocardial ischemia, predominantly reversible, in patients with hyperthyroidism detected by ⁹⁹ᵐTc-Sestamibi MPS. The severity and extent of ischemia demonstrated a significant positive correlation with fT4 levels. These findings underscore the potential utility of MPS in cardiovascular risk assessment and suggest the need for comprehensive cardiac evaluation in hyperthyroid patients, particularly those with higher fT4 levels