Optimal Treatment Regimen Research Articles

Enzymatic TherapyversusVATS for pleural infections: a systematic review and meta-analysis

QuestionParapneumonic pleural infections are frequently encountered, but the optimal treatment regimen remains controversial. The aim of this systematic review was to investigate whether immediate video-assisted thoracoscopic surgery (VATS) has advantages over intrapleural enzymatic therapy (IET).MethodsWe searched MEDLINE, Embase, and Web of Science Core Collection till November 2023 and included studies comparing IET and VATS in adult patients with parapneumonic pleural infections. Primary outcome was length of hospital stay (LOS), secondary outcomes included mortality and morbidity. Study quality was assessed using ROBINS-I and RoB 2. Inverse variance random-effects meta-analysis was performed.ResultsWe screened 2263 articles, eight were included in the final analysis, covering 1023 patients (n=465 IET (mostly single agent IET); n=558 VATS). Six were non-randomized studies (n=5 with serious risk of bias) comprising 964 patients, and two were small, randomized feasibility studies (n=1 with high risk of bias), comprising 59 patients. In the meta-analysis, LOS in non-randomized studies was shorter for patients treated by VATS (mean difference 4.2 days; 95%CI 1.5 to 7.0). However, no significant difference was reported in the randomized feasibility studies. Mortality and morbidity rates showed no significant difference.InterpretationIn this meta-analysis of non-randomized studies with a high risk of selection bias, VATS appears superior to IET regarding LOS in the treatment of parapneumonic pleural infections, without increased mortality and morbidity rate. Two recently published randomized feasibility studies failed to confirm this finding, but were not designed to detect a difference in LOS. This meta-analysis highlights the need for high quality studies.

Novel Targeted Agents in Advanced and Recurrent Low-Grade Serous Ovarian Cancer: A Silver Lining in the Therapy of a Chemoresistant Disease?

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents.

Various Approaches and Future Prospective for Therapies for Diabetes: A Review

The global prevalence of diabetes mellitus disease marked by increased blood glucose levels, has reached epidemic proportions. This review provides a comprehensive assessment of the current landscape of diabetes therapies and outlines future prospects for improving the management and treatment of this condition. The current scenario highlights a multifaceted approach to diabetes management, with a focus on lifestyle interventions, oral antidiabetic drugs, insulin therapy, and emerging technologies like continuous glucose monitoring and closed-loop systems. While these approaches have significantly improved the lives of people with diabetes, several challenges persist. These include medication adherence, hypoglycemia risk, and the financial burden of diabetes care. Innovative treatments that improve glucose regulation, improve cardiovascular health, and help patients lose weight—like SGLT-2 inhibitors and GLP-1 receptor agonists—have showed promise in treating these issues. The future prospects for diabetes therapies are exciting, with ongoing research into cell-based therapies, including pancreatic islet transplantation and stem cell-derived beta cells. Personalized medicine approaches, driven by genetics and artificial intelligence, hold the potential to optimize treatment regimens and predict individual responses to various therapies. Furthermore, advancements in telemedicine and digital health technologies will enhance patient self-management and remote monitoring.

Перспективы применения технологий искусственного интеллекта для цифровой трансформации здравоохранения.

Introduction. Currently, the digital transformation of healthcare is one of the priority areas of industry development. In Russia, there is a high readiness and interest of both managers and doctors in the practical application of various digital products, including decision support systems using AI technologies. Materials and methods. The authors analyzed the scientific research and practical developments available in Russia in order to systematize and identify the most popular scenarios for the use of artificial intelligence systems. Results. The most promising areas for the development of artificial intelligence systems for healthcare in Russia are: Improved diagnostics. AI systems can analyze medical images, laboratory test data and clinical histories, identify patholo- gies and offer accurate diagnoses, which helps doctors make more informed decisions. Personalized treatment. The use of AI allows taking into account the individual characteristics of patients and offering optimal treatment regimens based on the analysis of numerous factors, such as genetic data, medical history and response to therapy. Disease prediction. AI can help determine the likelihood of developing certain diseases in a particular patient based on their individual risk factors, allowing for preventive measures or early treatment. Automation and optimization of processes. AI can reduce the workload of medical personnel, automate routine tasks, improve medical data management, and ensure more efficient resource allocation. Conclusions. The proposed scenarios and areas of AI application are most likely to impact the achievement of targets and objectives set out in the national project "Healthcare" – which is a priority for the implementation of AI.

Phase II study of carboplatin plus weekly paclitaxel with bevacizumab for non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia (Hanshin Cancer Group IP002)

Abstract Background There is an increased risk of acute exacerbation of idiopathic interstitial pneumonia when treating patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. There is no standard optimal treatment regimen for patients with lung cancer complicated with idiopathic interstitial pneumonia. We aimed to evaluate the efficacy and safety of carboplatin (CBDCA), bevacizumab (Bmab) and weekly paclitaxel (PXT) in patients with idiopathic interstitial pneumonia. Methods This phase 2 study involved chemotherapy-naïve patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. Patients received CBDCA (area under the curve: 5 on day 1), PXT (70 mg/m2 on days 1, 8 and 15) and Bmab (15 mg/kg on day 1) every 4 weeks. The primary endpoint was the overall response rate. Results Twenty-one patients were enrolled between January 2013 and October 2018 and received at least one course of the protocol treatment. The study was terminated before enrolling the planned number of patients because of poor accrual. The median patient age was 69 (range: 62–79) years, and 19 (90.5%) patients were men. The overall response rate was 61.9% (95% confidence interval [CI], 38.4–81.9), meeting the primary endpoint. The median progression-free survival, time to treatment failure, and overall survival were 9.69 (95% CI, 5.78–11.63), 8.21 (95% CI, 3.75–11.63) and 20.93 (95% CI, 13.17–29.83) months, respectively. There was no acute exacerbation or treatment-related death during protocol treatment. Conclusion The results indicate that patients with advanced non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia could be effectively and safely treated using a combination of CBDCA, PXT and Bmab.

Advances in the Insulin-Heart Axis: Current Therapies and Future Directions.

The insulin-heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin-heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor-neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin-heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.

FACT inhibitor CBL0137, administered in an optimized schedule, potentiates radiation therapy for glioblastoma by suppressing DNA damage repair.

Standard-of-care for glioblastoma remains surgical debulking followed by temozolomide and radiation. However, many tumors become radio-resistant while radiation damages surrounding brain tissue. Novel therapies are needed to increase the effectiveness of radiation and reduce the required radiation dose. Drug candidate CBL0137 is efficacious against glioblastoma by inhibiting histone chaperone FACT, known to be involved in DNA damage repair. We investigated the combination of CBL0137 and radiation on glioblastoma. In vitro, we combined CBL0137 with radiation on U87MG and A1207 glioblastoma cells using the clonogenic assay to evaluate the response to several treatment regimens, and the Fast Halo Assay to examine DNA repair. In vivo, we used the optimum combination treatment regimen to evaluate the response of orthotopic tumors in nude mice. In vitro, the combination of CBL0137 and radiation is superior to either alone and administering CBL0137 two hours prior to radiation, having the drug present during and for a prolonged period post-radiation, is an optimal schedule. CBL0137 inhibits DNA damage repair following radiation and affects the subcellular distribution of histone chaperone ATRX, a molecule involved in DNA repair. In vivo, one dose of CBL0137 is efficacious and the combination of CBL0137 with radiation increases median survival over either monotherapy. CBL0137 is most effective with radiation for glioblastoma when present at the time of radiation, immediately after and for a prolonged period post-radiation, by inhibiting DNA repair caused by radiation. The combination leads to increased survival making it attractive as a dual therapy.

FACT inhibitor CBL0137, administered in an optimized schedule, potentiates radiation therapy for glioblastoma by suppressing DNA damage repair.

Standard-of-care for glioblastoma remains surgical debulking followed by temozolomide and radiation. However, many tumors become radio-resistant while radiation damages surrounding brain tissue. Novel therapies are needed to increase the effectiveness of radiation and reduce the required radiation dose. Drug candidate CBL0137 is efficacious against glioblastoma by inhibiting histone chaperone FACT, known to be involved in DNA damage repair. We investigated the combination of CBL0137 and radiation on glioblastoma. In vitro, we combined CBL0137 with radiation on U87MG and A1207 glioblastoma cells using the clonogenic assay to evaluate the response to several treatment regimens, and the Fast Halo Assay to examine DNA repair. In vivo, we used the optimum combination treatment regimen to evaluate the response of orthotopic tumors in nude mice. In vitro, the combination of CBL0137 and radiation is superior to either alone and administering CBL0137 two hours prior to radiation, having the drug present during and for a prolonged period post-radiation, is an optimal schedule. CBL0137 inhibits DNA damage repair following radiation and affects the subcellular distribution of histone chaperone ATRX, a molecule involved in DNA repair. In vivo, one dose of CBL0137 is efficacious and the combination of CBL0137 with radiation increases median survival over either monotherapy. CBL0137 is most effective with radiation for glioblastoma when present at the time of radiation, immediately after and for a prolonged period post-radiation, by inhibiting DNA repair caused by radiation. The combination leads to increased survival making it attractive as a dual therapy.

Efficacy and Safety of Mebendazole in the Treatment of Intestinal Helminth Infections

Mebendazole was introduced in 1971 and is not soluble in water or other organic solvents, it is also not absorbed from the intestinal tract in a high-fat context. Both albendazole and mebendazole have a low rate of absorption in the human intestine. These drugs primarily target parasites in the stomach's lumen, and their metabolites are effective against parasites in the stomach's muscles and tissues. For instance, albendazole sulfoxide is the primary metabolite that possesses anthelmintic properties. Metabolites of mebendazole are expelled in the urine. Both drugs negatively affect the function of microtubules in parasites and mammalian cells, this results in the depletion of the parasites' glycogen stores. Current helminth control strategies involve periodic deworming with albendazole or mebendazole. However, concerns about drug resistance and the persistence of high prevalence rates suggest the need for additional strategies, such as improved water, sanitation, and hygiene, and optimized treatment regimens. Albendazole and mebendazole are highly effective against Ascaris lumbricoides, with a single dose of albendazole showing a cure rate of 96% and mebendazole showing a cure rate of 92.3%. Mebendazole's efficacy against hookworms varies, but a recommended dosing regimen improves effectiveness. Mebendazole's effectiveness against Trichuris trichiura depends on the dosing regimen. It is less effective against hymenolepiasis, where praziquantel is preferred. Mebendazole has also been used to treat Giardia lamblia infections. In summary, STH infections are a significant health issue, and albendazole and mebendazole are commonly used drugs for treatment. However, there is a need for additional strategies to address drug resistance and improve treatment efficacy. Mebendazole has potential side effects and should be used with caution, especially during pregnancy.

Treatment Patterns and Clinical Outcomes in Patients With EGFR-Mutated Non–Small-Cell Lung Cancer After Progression on Osimertinib

IntroductionFor patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) who progress on first-line osimertinib, the optimal second-line treatment regimen after progression is not known. We sought to assess practice patterns and evaluate the association between different therapies and survival in patients with EGFR-mutated NSCLC following progression on first-line osimertinib. MethodsRetrospective cohort study of patients who received first-line treatment with osimertinib using a population-based, multicenter nationwide electronic health record-derived deidentified database. ResultsWe identified 2373 patients who received first-line osimertinib. The majority (n = 2279) received osimertinib monotherapy. A total of 538 patients received first-line osimertinib and had second-line treatment data available. Second-line treatment regimens were varied: 65% (n = 348) included chemotherapy, 37% (n = 197) included an immune checkpoint inhibitor (ICI), and 44% (n = 234) included an EGFR tyrosine kinase inhibitor (TKI).We then analyzed the 333 patients with PS 0-2 who received chemotherapy with osimertinib (n = 107, 32%) versus chemotherapy without osimertinib (n = 226, 68%). The continuation of osimertinib with chemotherapy was associated with superior PFS (median: 10.1 versus 5.9 months, Hazard Ratio [HR]: 0.48, 95% Confidence Interval [CI]: [0.34, 0.68], P < .001) and overall survival (OS) (median: 17.0 versus 12.8 months, HR: 0.64, 95% CI: [0.44, 0.93], P = .018) compared to other chemotherapy approaches without osimertinib. This effect was most pronounced in patients with an EGFR exon 19 deletion. ConclusionsFollowing progression on osimertinib, a wide variety of treatment regimens were used. The continuation of osimertinib with chemotherapy in the second line was associated with increased PFS and OS.

604. REAL-WORLD MANAGEMENT AND OUTCOMES OF PATIENTS WITH NON METASTATIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA IN THE FREGAT DATABASE

Abstract Background International guidelines for locally advanced esophageal squamous cell carcinoma (ESCC) recommend both neoadjuvant chemoradiotherapy (nCRT) followed by planned surgery (P-surg) or definitive chemoradiotherapy (dCRT) with salvage surgery (S-surg). However, the optimal treatment remains unknown, and the ongoing pragmatic NEEDS randomized trial is assessing the efficacy of an organ-preserving strategy after dCRT (Nilsson, Front Oncol 2022). Real-world data on the management of non-metastatic ESCC is limited. This study aims to describe the treatment strategies and prognosis of patients with non-metastatic ESCC in a real-world setting. Methods We conducted a retrospective cohort study of patient treated for non-metastatic ESCC between 2014 and 2022. Data were extracted from the FREGAT database. For the entire population, different treatment strategies were described. We compared patients who received nCRT with those who received dCRT under real-life conditions (“Real-life” population) and according to the NEEDS randomized trial criteria (“NEEDS-like” population). Five-year overall survival (OS) and relapse-free survival (RFS) were compared between nCRT and dCRT patients using a Cox proportional hazard model adjusting for major confounders. In operated patients, the impact of surgery on OS and RFS was assessed using a time-dependent Cox proportional hazard model. Postoperative outcomes were compared between P-surg and S-surg using Fisher’s exact test. Results From 971 patients diagnosed with non-metastatic ESCC, 867 (89.3%) received a curative treatment including dCRT (41.0%), nCRT (28.0%), primary esophagectomy (9.8%), neoadjuvant chemotherapy (3.4%), or endoscopic resection (1.0%). Fifty-nine patients (6,1%) received supportive care or chemotherapy alone. Forty-five patients (4.6%) died during or before treatment. In the “real-life” population (n=659), 269 patients received nCRT and 390 patients received dCRT. A total of 229 patients (93.5%) in nCRT group underwent P-surg and S-surg was performed in 44 patients (11.3%) in dCRT group. After adjustment, dCRT was associated with a significantly poorer 5-year OS and RFS (respectively HR=1.83, 95%CI 1.44-2.33; HR=1.98, 95%CI 1.57-2.49). A complete clinical response (cCR) was observed in 21.6% and 29.5% of the nCRT and dCRT groups, respectively. Among cCR undergoing resection, 35.8% had residual disease on pathological specimen. Time between CRT and surgery was 58 days (IQR44-72) vs. 109 days (IQR71-278) for P-surge and S-Surg respectively. The 90-day mortality, major morbidity (Clavien-Dindo III/IV) and pulmonary complication rates were similar in both groups, except for a higher risk of anastomotic leakage after S-surg (p=0.05). In the “NEEDS-like” population (n=598), findings were consistent and comparable to those observed in the “real-life” population. Conclusion Among non-mestastatic ESCC included in the FREGAT database, 10.6% had a non-curative approach or died prematurely. Most patients underwent dCRT, with S-surg rate of only 11.3%. Neoadjuvant CRT followed by P-surg was associated with the best outcome in terms of OS and RFS in both “rela life” and “Needs-like” populations. In operated patients, postoperative outcomes were similar after nCRT and dCRT, except for a higher incidence of anastomotic leakage after S-surg. This study highlighted the therapeutic strategies used and their results in real-life conditions for non-metastatic ESCC inside the FREGAT database. The treatment option of nCRT followed by P-surg appears to remain the optimal curative treatment regimen.

Drug sensitivity tumor cell clusters in malignant peritoneal mesothelioma.

To explore the most effective adjuvant chemotherapy regimen for malignant peritoneal mesothelioma (MPM) through patient derived tumor-like cell clusters (PTC) drug sensitivity test. PTC were cultured in vitro with intraoperative specimens, and drug sensitivity test was performed to calculate the most effective chemotherapy regimen for MPM. The patients were divided into conventional and individualized chemotherapy group according to whether they received PTC drug testing. Univariate and multivariate analyses were conducted to identify independent prognostic factors. Among 186 MPM patients included, 63 underwent PTC culture and drug sensitivity test. The results showed that the most effective chemotherapy regimen was oxaliplatin + gemcitabine. After propensity score matching, a total of 64 patients were enrolled in the following study, including 32 patients receiving individualized chemotherapy guided by PTC drug results as group 1 and 32 patients receiving conventional chemotherapy as group 2. Survival analysis showed that the median OS of group 1 was not reached, significantly longer than that of group 2 (23.5 months) (p < 0.05). Compared with conventional chemotherapy, individualized chemotherapy guided by PTC drug sensitivity tests can prolong patient survival, and oxaliplatin + gemcitabine + apatinib could be the optimal adjuvant treatment regimen for MPM.

Evaluating the Risk-Benefit Profile of Corticosteroid Therapy for COVID-19 Patients: A Scoping Review.

The 2019 coronavirus (COVID-19) outbreak was declared a global pandemic in March 2020. It quickly spread across all continents, causing significant social, environmental, health, and economic impacts. During the pandemic, there has been consideration of repurposing and repositioning of medications, such as corticosteroids, for the treatment of hospitalised COVID-19 patients. To assess and summarise corticosteroid regimens used for hospitalised COVID-19 patients, focusing on dosage, route of administration, and clinical outcome from clinical trials. PubMed and Embase databases and the grey literature were searched to identify randomised controlled trials (RCTs) that evaluated the efficacy of corticosteroids in hospitalised patients with COVID-19 between January 2020 and January 2023. This scoping review was conducted in line with the PRISMA extension for scoping reviews (PRISMA-ScR) checklist. A total of 24 RCTs were eligible for inclusion. There was variation in the steroid regimens used for treatment across COVID-19 trials. Despite the heterogeneity of included RCTs, the overall results have shown the benefits of improving lung function and a lower all-cause mortality rate in hospitalised COVID-19 patients treated with systematic corticosteroids. Corticosteroids have proven to be an effective treatment for COVID-19 patients in critical condition. However, comparative effectiveness studies should be conducted to assess the efficacy and safety of optimal corticosteroid treatment at the population level. Moreover, the global burden of long COVID is significant, affecting millions with persistent symptoms and long-term health complications. Thus, it is also necessary to evaluate the optimal steroid regimen for long COVID treatment.

Estimating optimal decision trees for treatment assignment: The case of K > 2 treatment alternatives.

For many problems in clinical practice, multiple treatment alternatives are available. Given data from a randomized controlled trial or an observational study, an important challenge is to estimate an optimal decision rule that specifies for each client the most effective treatment alternative, given his or her pattern of pretreatment characteristics. In the present paper we will look for such a rule within the insightful family of classification trees. Unfortunately, however, there is dearth of readily accessible software tools for optimal decision tree estimation in the case of more than two treatment alternatives. Moreover, this primary tree estimation problem is also cursed with two secondary problems: a structural missingness in typical studies on treatment evaluation (because every individual is assigned to a single treatment alternative only), and a major issue of replicability. In this paper we propose solutions for both the primary and the secondary problems at stake. We evaluate the proposed solution in a simulation study, and illustrate with an application on the search for an optimal tree-based treatment regime in a randomized controlled trial on K = 3 different types of aftercare for younger women with early-stage breast cancer. We conclude by arguing that the proposed solutions may have relevance for several other classification problems inside and outside the domain of optimal treatment assignment.

Oral Dissolution Therapy of Uric Acid Stones: A Systematic Review

Background/Objectives: Uric acid stones are the second most common type of kidney stones worldwide. Despite being cost-effective and widely available, pharmacological management for these stones is less utilized compared to surgical approaches. Therefore, we conducted a systematic review of the literature to assess the efficacy and shortcomings of oral dissolution therapy for uric acid stones. Methods: Embase, Scopus, PubMed, and Cochrane library databases were searched for English language studies on adults who were diagnosed with uric acid kidney stones and treated with oral dissolution therapy. Results: Twelve studies met our inclusion criteria. Potassium citrate was the primary agent used for dissolution in 10 of the studies and demonstrated a 50% or higher success rate for complete dissolution of uric acid stones. Treatment time for successful dissolution varied, with an average of 3 months minimum and an average of 2.78 years maximum. Overall, 11 of the studies recommended that oral dissolution therapy should be used for either treatment or prevention of uric acid stones. Conclusions: The available evidence demonstrates benefit of oral dissolution therapy for patients with uric acid stones. However, future rigorous studies are required to determine the optimal treatment regimen.

Association between growth differentiation factor-15 and adverse outcomes among patients with heart failure: A systematic literature review

Growth differentiation factor-15 (GDF-15) is an emerging biomarker in several conditions. This SLR, conducted following PRISMA guidelines, examined the association between GDF-15 concentration and range of adverse outcomes in patients with heart failure (HF). Publications were identified from Embase® and Medline® bibliographic databases between January 1, 2014, and August 23, 2022 (congress abstracts: January 1, 2020, to August 23, 2022). Sixty-three publications met the eligibility criteria (55 manuscripts and 8 abstracts; 45 observational studies and 18 post hoc analyses of randomized controlled trials [RCTs]). Of the 19 outcomes identified, the most frequently reported longitudinal outcomes were mortality (n = 32 studies; all-cause [n = 27] or cardiovascular-related [n = 6]), composite outcomes (n = 28; most commonly mortality ± hospitalization/rehospitalization [n = 19]), and hospitalization/re-hospitalization (n = 11). The most common cross-sectional outcome was renal function (n = 22). Among longitudinal studies assessing independent relationships with outcomes using multivariate analyses (MVA), a significant increase in risk associated with higher baseline GDF-15 concentration was found in 22/24 (92 %) studies assessing all-cause mortality, 4/5 (80 %) assessing cardiovascular-related mortality, 13/19 (68 %) assessing composite outcomes, and 4/8 (50 %) assessing hospitalization/rehospitalization. All (7/7; 100 %) of the cross-sectional studies assessing the relationship with renal function by MVA, and 3/4 (75 %) assessing exercise capacity, found poorer outcomes associated with higher baseline GDF-15 concentrations. This SLR suggests GDF-15 is an independent predictor of mortality and other adverse but nonfatal outcomes in patients with HF. A better understanding of the prognostic role of GDF-15 in HF could improve clinical risk prediction models and potentially help optimize treatment regimens.

Efficacy of Antibiotic Regimens for Meningitis in Young Infants Aged 0-59 Days: A Systematic Review.

Meningitis is associated with high mortality risk in young infants, yet the optimal treatment regimen is unclear. To systematically evaluate the efficacy of antibiotic regimens to treat meningitis in young infants aged 0 to 59 days on critical clinical outcomes. MEDLINE, Embase, CINAHL, WHO Global Index Medicus, and Cochrane Central Registry of Trials. We included randomized controlled trials (RCTs) of young infants with meningitis (population) comparing the efficacy of antibiotic regimens (interventions) with alternate regimens (control) on clinical outcomes. We extracted data on study characteristics and assessed risk of bias in duplicate. Grading of Recommendations Assessment, Development, and Evaluation was used to assess certainty of evidence. Of 1088 studies screened, only 2 RCTs were identified. They included 168 infants from 5 countries and were conducted between 1976 and 2015. Neither study compared current World Health Organization-recommended regimens. One multisite trial from 4 countries compared intrathecal gentamicin plus systemic ampicillin/gentamicin to systemic ampicillin/gentamicin and found no difference in mortality (relative risk, 0.88; 95% confidence interval, 0.41-1.53; 1 trial, n = 98, very low certainty of evidence) or adverse events (no events in either trial arm). Another trial in India compared a 10-day versus 14-day course of antibiotics and found no difference in mortality (relative risk, 0.88; 95% confidence interval, 0.41-1.53; 1 trial, n = 98, very low certainty of evidence) or other outcomes. Trial data on the efficacy of antibiotic regimens in young infant meningitis are scarce. Rigorous RCTs are needed to inform recommendations for optimal antibiotic regimens for meningitis treatment in this vulnerable population, particularly within the context of changing epidemiology and increasing antimicrobial resistance.

Learning Optimal Dynamic Treatment Regime from Observational Clinical Data through Reinforcement Learning

Learning Optimal Dynamic Treatment Regime from Observational Clinical Data through Reinforcement Learning

Effects of growth hormone and sex steroid therapy on brain structure and pituitary function in turner syndrome

Introduction: Turner syndrome (TS) is a chromosomal disorder affecting approximately 1 in 2,500 live female births, characterized by the partial or complete absence of one X chromosome. This genetic anomaly leads to physical, cognitive, and endocrine abnormalities, including short stature, gonadal dysgenesis, and structural brain anomalies. Cognitive deficits in TS involve visuospatial processing, memory, and executive function, often linked to structural brain changes. Magnetic resonance imaging (MRI) has revealed significant alterations in gray and white matter volumes in various brain regions. Growth hormone (GH) and sex steroid therapies, such as estrogen and progesterone, are used to address growth and developmental delays in TS. However, their impact on brain structure and pituitary function remains an area of active research. Aim of the Review: To systematically review and synthesize findings on the effects of GH and sex steroid therapy on brain structure and pituitary function in patients with Turner syndrome. Methods: A comprehensive literature review was conducted to identify studies examining the effects of GH and sex steroid therapy on brain structure and pituitary function in TS. Data from various sources were compiled, focusing on MRI-based structural brain changes. Key parameters analyzed included sample size, findings from MRI and fMRI studies, and clinical associations. Studies were summarized and presented in a structured table format. Results: Estrogen-progesterone treatment was found to suppress pituitary gonadotropin release more effectively than estrogen alone, indicating a feedback interaction between pituitary gonadotropin release and sex steroids. MRI studies showed that TS patients exhibit smaller volumes in the hippocampus, caudate, lenticular, thalamic nuclei, and parieto-occipital brain matter, correlating with cognitive deficits. GH-IGF axis abnormalities are modulated by body composition and physical fitness, with sex hormone replacement normalizing the GH-IGF axis and improving body composition. Although GH therapy alone did not significantly improve cognitive functions, the combination of GH with oxandrolone improved working memory. Estrogen deficiency and TS are associated with slower growth in parieto-occipital regions and enhanced volume growth in basal ganglia and cerebellar areas during adolescence, underscoring the importance of estrogen replacement in brain development. Discussion: GH and sex steroid therapies significantly impact brain structure, pituitary function, and clinical outcomes in TS. GH therapy, often combined with sex steroids, improves growth and cognitive functions, particularly working memory. However, GH alone does not significantly impact overall cognitive function. The timing and combination of these therapies are crucial for optimizing outcomes. Regular monitoring and individualized treatment plans are essential to address the complex needs of TS patients. Further research is needed to explore the long-term impacts of these therapies and develop optimal treatment regimens. Conclusion: GH and sex steroid therapies are vital in managing TS contributing to improved growth, body composition, and cognitive enhancements. A multifaceted therapeutic approach and regular monitoring are crucial for optimizing treatment outcomes and quality of life for TS patients.

Next-Generation strategies to combat antimicrobial resistance: Integrating genomics, CRISPR, and novel therapeutics for effective treatment

Antimicrobial resistance (AMR) poses a significant threat to global public health, necessitating innovative strategies to combat this escalating issue. This review outlines next-generation approaches integrating genomics, CRISPR technology, and novel therapeutics to effectively address AMR. Genomic techniques enable comprehensive understanding of the genetic mechanisms underpinning resistance, facilitating the development of targeted interventions. By sequencing the genomes of resistant pathogens, researchers can identify resistance genes, track their spread, and predict emerging resistance patterns. CRISPR-Cas systems offer a revolutionary tool for combating AMR through precise genome editing. This technology can disrupt resistance genes, restore antibiotic sensitivity, and develop bacteriophage therapies that selectively target resistant bacteria. Moreover, CRISPR-based diagnostics enable rapid, accurate detection of resistant strains, enhancing infection control measures. The advent of novel therapeutics, such as antimicrobial peptides, bacteriophage therapy, and synthetic biology-derived compounds, provides alternative treatment options. These therapeutics can bypass traditional resistance mechanisms and exhibit efficacy against multi-drug resistant organisms. Additionally, integrating artificial intelligence (AI) and machine learning with genomics and CRISPR can accelerate the discovery of new antibiotics and predict resistance trends, optimizing treatment regimens. Implementing these next-generation strategies requires robust global collaboration, regulatory frameworks, and investment in research and development. By combining genomics, CRISPR, and novel therapeutics, we can create a multifaceted approach to overcome AMR, ensuring effective treatments and safeguarding public health. This integration represents a paradigm shift in antimicrobial strategy, offering hope for a future where resistant infections can be effectively managed and treated. Keywords: Integrating Genomics, Antimicrobial Resistance, CRISPR, Therapeutic