Search Results (591)

Background: Programmed death-1 (PD-1) inhibitors have significantly improved survival outcomes in melanoma; however, questions persist regarding comparative efficacy across regimens and the predictive value of PD-L1 expression as a biomarker. We therefore performed a meta-analysis evaluating outcomes according to PD-L1 expression status using the most recent follow-up data from each study. Methods: A systematic search was conducted in PubMed, Cochrane and ClinicalTrials.gov from 1 January 2010 to 1 April 2025 for phase II and III randomized clinical trials (RCTs) investigating PD-1 inhibitors as monotherapy or combined with other immune checkpoint inhibitors (ICIs) or targeted therapy in the adjuvant/metastatic setting. Pooled estimates were calculated with random-effects models, and risk of bias was assessed using the Cochrane RoB 2 tool. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251090090). Results: Fifteen RCTs including 9979 patients were included. In the overall analysis, PD-1 inhibitors were associated with significantly improved overall survival (OS, HR = 0.75, 95% CI: 0.66–0.86) compared with control treatments. In the unresectable or metastatic setting, progression-free survival (PFS) was also significantly improved (HR = 0.61, 95% CI: 0.49–0.76). Survival benefits were observed in both PD-L1-positive and PD-L1-negative tumors, with improved PFS in PD-L1-positive (HR = 0.63, 95% CI: 0.48–0.83) and PD-L1-negative patients (HR = 0.58, 95% CI: 0.44–0.77), as well as improved OS in PD-L1-positive (HR = 0.69, 95% CI: 0.59–0.80) and PD-L1-negative patients (HR = 0.79, 95% CI: 0.67–0.93), without evidence of effect modification by PD-L1 expression. PD-1 inhibitor-based regimens were not associated with a statistically significant increase in grade 3–4 treatment-related adverse events (RR = 1.13, 95% CI: 0.71–1.79); however, heterogeneity was substantial (I² = 96.0%). Conclusions: PD-1 inhibitor-based therapies significantly improve survival outcomes in advanced melanoma across PD-L1 subgroups. No clear evidence of differential treatment benefit according to PD-L1 expression was observed, suggesting limited utility as a standalone predictive biomarker. Further studies integrating molecular and immune profiling are warranted to optimize individualized treatment selection. Full article

Background: 5q spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder characterized by progressive muscle weakness. Nusinersen, the first disease-modifying therapy for SMA, has demonstrated efficacy in both clinical trials and real-world studies. However, the precise timing of therapeutic onset following Nusinersen administration remains unclear. Methods: This retrospective study analyzed clinical data from patients with genetically confirmed 5q SMA who received Nusinersen treatment for at least six months at Peking University First Hospital. Motor function was assessed using standardized scales prior to each dose. Results: In total, 74 patients were screened, of whom 62 were enrolled, including 14 with type 1, 29 with type 2, and 19 with type 3 SMA. Thirty-two patients completed motor function assessments. After six months of treatment, 62.5% achieved a primary clinically meaningful response (an increase of ≥4 points in CHOP-INTEND or ≥3 points in HFMSE). Seven patients (21.9%) attained or regained motor milestones. Median improvements were 6 points in CHOP-INTEND (p = 0.001), 4 points in HFMSE (p = 0.003), and 1.5 points in RULM (p = 0.045). Further analysis indicated that the available median time to treatment response was approximately 2 months. In patients with severe scoliosis or prior spinal surgery, ultrasound-guided lumbar puncture demonstrated a high success rate (94.9%). Regarding safety, intrathecal injection-related adverse events occurred in eight patients (12.9%), and no adverse events led to treatment discontinuation. Conclusions: During the loading phase, Nusinersen provides clinical benefit for the majority of patients, with a median time to therapeutic response for monitoring of approximately 2 months. Ultrasound-guided intrathecal administration is the preferred approach for individuals with complicated spinal conditions. These findings may help guide clinical expectations for physicians, patients, and caregivers. Full article

Introduction: Chemotherapy-induced thrombocytopenia (CIT) is a common dose-limiting toxicity that disrupts on-time, full-dose chemotherapy, yet no pharmacologic therapy is formally approved. Growing evidence from randomized and late-phase studies with thrombopoietin receptor agonists (TPO-RAs) has renewed interest in targeted supportive care. We evaluated the effectiveness and safety of eltrombopag for CIT in routine clinical practice. Methods: We conducted a small, retrospective, single-arm multicenter cohort study of 31 adults with solid tumors (74.2% stage IV). Given the descriptive, hypothesis-generating nature of this study, no causal inference regarding efficacy can be drawn. Platelet counts and chemotherapy continuity were tracked from baseline through week 12 after eltrombopag initiation. Bleeding, thrombosis, and laboratory safety signals were recorded. Results: The median platelet count increased from 33 × 10⁹/L at baseline to 71 × 10⁹/L at week 1 and 99.5 × 10⁹/L by week 12. Overall, 18/31 patients (58.1%) resumed chemotherapy within 3 weeks, and 15/31 (48.4%) completed planned regimens by week 6. Adverse events were limited to mild, transient elevations in transaminases (n = 3); no major bleeding or thrombotic events occurred. Conclusions: In this real-world multicenter cohort, eltrombopag was associated with rapid platelet recovery and improved chemotherapy deliverability with an acceptable safety profile. The retrospective, single-arm design and the hypothesis-generating nature of these findings preclude definitive conclusions regarding causal efficacy. These observational data highlight the need for prospective controlled trials to characterize the clinical role, optimal dosing, and long-term safety of oral TPO-RAs in CIT. Full article

Tirzepatide and semaglutide are among the most effective incretin-based therapies currently used in type 2 diabetes and obesity. To review direct comparative clinical evidence on tirzepatide versus semaglutide, with emphasis on glycemic efficacy, body-weight reduction, metabolic and mechanistic parameters, and tolerability. PubMed was searched from inception to March 14, 2026, without language or date restrictions, for original human studies directly comparing these agents and secondary pooled, mechanistic, exploratory, or post hoc analyses derived from direct comparative trials. Eleven eligible publications were identified, largely representing three parent comparative settings: SURPASS-2, a 28-week mechanistic phase 1 study, and SURMOUNT-5. Across the available direct comparative literature, tirzepatide generally demonstrated greater metabolic efficacy within the studied dosing and trial frameworks. In type 2 diabetes, it produced larger reductions in HbA1c and body weight, whereas in obesity without diabetes it was associated with greater weight loss and waist-circumference reduction. Mechanistic analyses also favored tirzepatide across several measures of insulin sensitivity, glucose control, and body composition. Secondary and pooled analyses further suggested more frequent achievement of combined glycemic and weight targets and more durable metabolic benefit. Both agents showed the expected incretin-related tolerability profile, with gastrointestinal adverse events predominating. The currently available direct comparative evidence suggests greater metabolic efficacy of tirzepatide, particularly with respect to HbA1c reduction and body-weight loss. However, this conclusion should be interpreted cautiously because the evidence base remains limited, includes multiple overlapping secondary analyses, and is influenced by comparator-dose selection and trial design. Full article

Autism spectrum disorder (ASD) is frequently associated with gastrointestinal symptoms, immune dysregulation, and altered microbiota-related signaling, supporting interest in microbiota-targeted interventions. This study evaluated adaptive functioning for over 180 days in children with ASD in a previously randomized controlled trial (RCT). After the initial 90-day blinded phase, the study continued as an open-label extension (OLE) in which all participants received K11 TMAX, a kefir-derived probiotic consortium combined with a microencapsulated micronutrient blend. The study included 130 children (3–11 years of age) who continued from the RCT were followed-up in three different trajectories: (1) placebo → K11-TMAX; (2) K11 → K11-TMAX; and (3) continued K11-TMAX supplementation. Children’s adaptive functioning was assessed by the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), Adaptive Behavior Composite (ABC) as well as by four core domains: (1) communication; (2) daily living skills; (3) socialization; and (4) motor skills. All three groups of children improved significantly on all of the parameters that were assessed with the effect sizes ranging from 0.13 to 0.43. The greatest improvement in the communication domain was seen in the transition group (1) and the greatest decrease in the externalizing behavior scores were seen in the continuous group (3) of children. Children’s adaptive functioning improved in clinically meaningful ways. Children’s improvement, however, was within the disability range and did not reach the level of typical development of children of the same age. These findings suggest supplementary therapeutic use of K11-TMAX, modulating the gut–brain axis, in children with autism spectrum disorder (ASD). Full article

Background: Although early mobilization has been shown to improve clinical outcomes after intensive care unit (ICU)-acquired weakness, its implementation remains limited in routine clinical practice. This study aimed to evaluate the feasibility, safety, and preliminary clinical outcomes of a mobile application-based rehabilitation program in non-ambulatory patients during the early ward phase following ICU discharge. Methods: This prospective single-arm pilot trial included adult patients (≥19 years) who had received ICU care and demonstrated limited ambulatory function, defined as Functional Ambulatory Category (FAC) ≤3. Participants received an individualized, application-guided exercise program comprising two daily sessions over two weeks. Primary outcomes were programmatic feasibility, safety, and patient satisfaction. Rehabilitation compliance was quantified using application usage logs and categorized as high (≥50%) or low (<50%). Secondary functional outcomes, such as Medical Research Council Sum Score (MRC-SS), ICU Mobility Scale, FAC, muscle strength measures, health-related quality of life, and pain scores, were assessed at baseline, week 1, and week 2. Results: Of the 25 initially enrolled patients, 5 dropped out due to clinical status changes or transfers, yielding a retention rate of 80.0%. For the 20 analyzed patients (mean age 52.7 ± 13.9 years; 45% male), the overall mean rehabilitation compliance was 40.6%. No serious adverse events related to the intervention were reported, and overall patient satisfaction and application usability were high. Progressive increases in exercise intensity and training levels were observed throughout the intervention period. Significant improvements over time were found in MRC-SS, ICU Mobility Scale, FAC, grip strength, health-related quality of life, and pain scores (all p < 0.05). Although compliance-based recovery trajectories were confounded by small subgroup sizes and baseline clinical imbalance, exploratory analyses nonetheless identified statistically significant time × compliance interaction effects for MRC-SS and straight leg raise performance. Conclusions: This pilot study demonstrates that a mobile application-based rehabilitation program is a feasible and safe approach to implement in deconditioned patients after ICU discharge. These preliminary functional recovery trajectories provide encouraging signals, suggesting that this digital platform may serve as a potential adjunct to conventional care. Rigorous, randomized controlled trials are required to confirm its definitive clinical efficacy and scalability. Full article

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3–targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease. Full article

Background/Objectives: HXP-GPOVac is a locally produced, inactivated Newcastle disease virus-based (NDV-HXP-S) COVID-19 vaccine manufactured in Thailand. This phase II trial compared its safety and immunogenicity with the mRNA vaccine BNT162b2 in adults aged 18–75 years. Methods: In this randomized, double-blind, active-controlled trial registered with the Thai Clinical Trials Registry (TCTR20220819003), 300 participants were assigned 3:1 to receive HXP-GPOVac or BNT162b2 on Days 1 and 29. Solicited adverse events (AEs) were recorded for 7 days after each dose, AEs were summarized through 28 days after each dose, and serious adverse events (SAEs), medically attended AEs (MAAEs), and adverse events of special interest (AESIs) were collected through Day 197. Humoral immunogenicity was assessed by pseudovirus 50% neutralization titers (NT₅₀) and anti-spike IgG concentrations at baseline, Day 29, Day 43, and Day 197. Seroconversion was defined as a ≥4-fold increase from baseline. A predefined subset underwent interferon-γ (IFN-γ) and interleukin-5 (IL-5) ELISpot assays to assess cell-mediated immune responses. The primary immunogenicity analysis assessed non-inferiority of HXP-GPOVac compared with BNT162b2 based on the NT₅₀ geometric mean titer ratio, with a prespecified non-inferiority margin of 0.5. Results: Solicited AEs were predominantly mild and occurred more frequently after the first dose in both groups; one or more solicited local or systemic AEs were reported by 23.7% (95% CI: 18.3–29.8) of HXP-GPOVac recipients and 44.7% (95% CI: 33.3–56.6) of BNT162b2 recipients after the first dose. AEs through 28 days after vaccination and SAEs were uncommon; MAAEs occurred in 17.0% of HXP-GPOVac recipients and 22.4% of BNT162b2 recipients, and none were considered related to vaccination. In the HXP-GPOVac group, NT₅₀ geometric mean titers increased from 5.6 at baseline to 65.5 at Day 29 and 505 at Day 43, declining to 63.6 at Day 197. Anti-spike IgG geometric mean concentrations rose from 7.5 BAU/mL at baseline to 102.7 BAU/mL at Day 29 and 514.6 BAU/mL at Day 43, decreasing to 61.0 BAU/mL at Day 197. BNT162b2 induced higher antibody levels at all time points. The NT₅₀ GMT ratio (HXP-GPOVac/BNT162b2) at Day 43 was 0.51 (95% CI: 0.39–0.67); the lower bound did not exceed the prespecified non-inferiority margin of 0.5, and non-inferiority was not established. Seroconversion rates at Day 43 were 97.6% for HXP-GPOVac and 97.1% for BNT162b2 (neutralizing antibody) and 98.6% and 97.1%, respectively (anti-spike IgG). ELISpot analyses demonstrated increased IFN-γ responses after the second dose without evidence of Th2-dominant skewing. Conclusions: HXP-GPOVac was well tolerated and induced substantial humoral and cellular immune responses, with high seroconversion rates and balanced T-cell polarization. Although absolute antibody levels were lower than those induced by BNT162b2 and the prespecified non-inferiority criterion was not met, these findings support continued evaluation of the inactivated NDV-HXP-S vaccine platform. Full article

Background: Post-COVID-19 syndrome is associated with endothelial dysfunction (ED) and various sequelae, particularly in individuals who experienced critical illness during the acute phase, affecting lung function and the musculoskeletal system. L-citrulline, a nonessential amino acid, has been shown to improve endothelial function, systemic inflammation, blood pressure, and physical performance. This study aimed to assess the effects of L-citrulline supplementation on ED and body composition in patients with post-COVID-19 syndrome. Methods: We conducted an open-label randomized controlled clinical trial at the Instituto Nacional de Enfermedades Respiratorias in Mexico City, Mexico, from February 2021 to May 2022. Eligible subjects were adults aged ≥18 years who recovered from COVID-19 and required hospitalization during acute COVID-19. Participants were randomized 1:1 into two groups: (1) the L-citrulline group (4 g/day) and (2) the control group. The intervention lasted three months. Endothelial-related biomarkers, including endothelin-1, sE-selectin, ICAM-1, and VCAM-1, were investigated. Body composition was measured using electrical bioimpedance, and aerobic capacity was assessed with the 6 min walk test (6MWT). Treatment effects were analyzed using two-way repeated-measures ANOVA (group × time). Results: In total, 43 subjects participated in the study. After three months of follow-up, the intervention group showed a decrease in ICAM-1 (−32.59 ng/mg of protein; 95% CI −52.85 to −12.33 vs. −2.31 ng/mg of protein, CI 95%: −21.59 to 16.95, p = 0.034) and an increase in 6MWT (141.2 m; 95% CI: 98.40 to 184 vs. 67.70 m, CI 95%: 30.62 to 104.78, p = 0.011) compared with the control group. No differences in body composition were observed between the groups at follow-up. Conclusions: L-citrulline supplementation for three months decreased ICAM-1 and increased 6MWT. Full article

Background/Objectives: CDK4/6i and ET improve outcomes in HR-positive, HER2-negative breast cancer, but their benefits differ between early-stage (EBC) and metastatic disease (MBC). We aimed to compare the efficacy and toxicity of CDK4/6i plus ET versus ET alone across these disease settings. Methods: We conducted a meta-analysis of phase III randomized trials identified through MEDLINE, EMBASE, and Web of Science up to 1 October 2025. Twenty-two trials (18 MBC, n = 6364; 4 EBC, n = 17,741) met the inclusion criteria. Two reviewers extracted data and assessed risk of bias. The study followed PRISMA 2020 guidelines (PROSPERO: CRD420251132302). Outcomes included overall survival (OS), progression-free survival (PFS), invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), response rates, treatment discontinuation (TDR), dose reductions (DRR), and grade 3–4 adverse events. Results: In MBC, CDK4/6i improved OS (HR: 0.78, 95% CI: 0.72–0.85) and PFS (HR: 0.53, 95% CI: 0.50–0.56) and increased objective response, clinical benefit, and disease control rates along with TDR, DRR, and grade 3–4 adverse events. In EBC, iDFS improved, whereas OS (HR: 0.92, 95% CI: 0.75–1.12; p = 0.40) and DRFS did not. TDR, DRR, and grade 3–4 adverse events were increased. Conclusions: CDK4/6i confer significant OS and PFS benefits in MBC, supporting first-line use. In EBC, no OS benefit was observed, and toxicity was increased, underscoring the need for individualized risk–benefit assessment. Longer follow-up is warranted to clarify survival outcomes. Full article

This scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. It summarizes advances in fibroblast activation protein inhibitor (FAPI) positron emission tomography (PET) for oncologic and fibroinflammatory diseases. FAP is expressed broadly on activated mesenchymal cells—including cancer-associated fibroblasts (CAFs) and myofibroblasts within desmoplastic tumor stroma, FAP-positive tumor cells in selected sarcomas, and activated fibroblasts in chronic fibroinflammatory disorders such as rheumatoid arthritis, Crohn’s disease, and organ fibrosis. By targeting these activated fibroblasts, [⁶⁸Ga]- and [¹⁸F]-labeled FAPI tracers provide high tumor-to-background contrast, particularly in desmoplastic and stromal-rich cancers. Compared with [¹⁸F]FDG, FAPI PET demonstrates superior lesion conspicuity in selected malignancies and enables a streamlined, non-fasting imaging workflow. Beyond oncology, FAPI PET is emerging as a promising tool for assessing cardiac fibrosis, pulmonary inflammation, and autoimmune conditions characterized by fibroblast activation. A systematic literature search of PubMed and Scopus was performed for peer-reviewed publications from 1 January 2018 to 28 February 2026. Inclusion criteria encompassed original studies, systematic reviews, meta-analyses, clinical guidelines, case series, and case reports reporting on FAPI-targeted PET in human subjects or translational models, published in English. After screening, 256 sources met the eligibility criteria and are included. The development of standardized SNMMI/EANM imaging protocols, along with ongoing multicenter trials and the first prospective phase 2 clinical trial of ⁶⁸Ga-FAPI-46 PET with histopathological confirmation, now supports the reproducible implementation of FAPI PET across institutions. FAPI PET demonstrates strong translational potential, largely due to its favorable biodistribution, safety profile, and theranostic flexibility. However, its widespread use in routine clinical practice is contingent upon large-scale clinical validation, structured reader training, and formal regulatory approval. In conclusion, FAPI PET represents a maturing molecular imaging platform targeting activated fibroblasts across oncologic and fibroinflammatory diseases. Its widespread adoption into clinical practice requires large-scale prospective trials, reader training, standardized reporting, and regulatory approval—all of which are now actively underway. Full article

Background: For almost two decades now, chimeric antigen receptor-natural killer cells (CAR-NK) have been investigated in pre-clinical breast cancer models, yet clinical evidence on efficacy remains scarce. This meta-analysis provides pooled evidence of pre-clinical CAR-NK effectiveness and safety in breast cancer and an overview of current clinical trials to support clinical translation. Methods: Following PRISMA guidelines and a registered protocol (PROSPERO, CRD420251131530), PubMed, Web of Science, and Scopus were searched up to 30 June 2025 for pre-clinical CAR-NK studies in breast cancer. Clinical studies were retrieved from clinicaltrials.gov and the International Clinical Trial Registry Platform (ICTRP) up to 1 March 2026. Pre-clinical studies without in vivo data or non-human CAR-NK cells were excluded. Primary outcomes were tumor burden (ratio of means, ROMs) and survival (median survival ratio, MSR). Data were analyzed in JASP™ and risk of bias (RoB) was assessed using SYRCLE’s tool. Results: Fourteen pre-clinical studies (38 CAR-NK treatment groups targeting EGFR, HER2, tissue factor, CD70, mesothelin, or folate receptor, with peripheral blood as the primary NK source, and a 5–10 million cell dose) and 11 early-phase clinical studies (targeting HER2, TROP2, PD-L1, MUC1, or NKG2D ligands under ongoing investigation) were included. In pooled pre-clinical analysis, CAR-NK significantly reduced tumor burden against untreated and unmodified/mock controls (ROM 0.311 [0.22–0.44] and 0.42 [0.33–0.53], p < 0.001, respectively). Survival was also prolonged significantly (MSR 1.47 [1.15–1.87], p = 0.010 vs. untreated; 1.30 [1.09–1.60], p = 0.007 vs. unmodified/mock NK cells). Subgroup analyses indicated improved efficacy with peripheral blood source and 5–10 M dosing. No treatment-related toxicities were reported. CAR-NK persistence was generally higher than unmodified/mock NK cells. Discussion and Conclusions: Significant heterogeneity was observed in ROM analysis which the multi-level meta-analysis configured as intra-study interventional variability. There was moderate RoB in pre-clinical studies. Published results from clinical trials remain limited, highlighting early stages of investigation. Overall, CAR-NK therapy demonstrated consistent pre-clinical efficacy and safety, supporting further translational and clinical evaluation in breast cancer. Full article

Introduction: This study evaluated the implications of intravenous acetaminophen (Ofirmev) on perioperative outcomes in patients undergoing robotic-assisted laparoscopic prostatectomy (RALP) for prostate cancer. The primary objective was to determine whether adding IV acetaminophen to standard analgesia could reduce hospital length of stay (LOS), pain intensity, and opioid use compared with placebo. Methods: This study was conducted as a secondary descriptive analysis of publicly available aggregate results from a previously completed randomized, double-blind, placebo-controlled Phase IV trial (NCT02369211). No individual patient-level data were accessed, and no new independent statistical analyses were performed. Eighty-six male patients were randomly assigned to receive either 1 g IV acetaminophen or saline placebo every six hours for four doses during the perioperative period. Primary endpoints were hospital and post-anesthesia care unit (PACU) LOS; secondary endpoints included postoperative pain scores and opioid consumption (morphine milligram equivalents). Results: Baseline characteristics were similar between groups (n = 43 each). Mean PACU stay was slightly shorter with IV acetaminophen (124 ± 58 min) than placebo (132 ± 63 min; not significant). Median hospital LOS was 0.81 days versus 0.82 days (p = 0.006), a statistically significant difference reported in the original trial dataset, although the absolute difference was clinically minimal. Pain scores and opioid requirements were lower with IV acetaminophen but not significantly different. No adverse events occurred in either group. Conclusions: IV acetaminophen was safe and well tolerated as part of multimodal analgesia for RALP. Although pain scores and opioid use numerically favored IV acetaminophen, these differences were not statistically significant. The reported difference in hospital LOS was statistically significant in the original trial record but clinically minimal; therefore, the findings should be interpreted as exploratory and hypothesis-generating regarding potential operational and economic implications. Full article

A decade has elapsed since the first recognized cluster of congenital anomalies associated with Zika virus (ZIKV) was reported in Brazil in 2015, culminating in the formal delineation of Congenital Zika Syndrome (CZS) as a specific pattern of birth defects. This narrative review examines the ten-year trajectory of CZS as a tropical infectious disease, from its initial emergence and public health emergency declaration by the World Health Organization (WHO) in February 2016, through evolving epidemiological, clinical, and scientific understanding. CZS is characterized by a spectrum of severe neurological manifestations—including microcephaly, subcortical calcifications, malformations of cortical development, ventriculomegaly, and corpus callosum abnormalities—alongside ophthalmic, auditory, and musculoskeletal complications. Transmitted primarily by Aedes aegypti mosquitoes in tropical and subtropical regions, ZIKV disproportionately affects low- and middle-income countries in Latin America, Africa, and Southeast Asia, underscoring its nature as a quintessential tropical disease linked to poverty, inadequate vector control, and health inequity. Over ten years, substantial advances have been made in understanding ZIKV pathogenesis, neurodevelopmental outcomes, diagnostic criteria, and multidisciplinary clinical management of affected children. In the therapeutic and preventive domain, over 45 vaccine candidates have been identified, with 16 reaching Phase 1 or 2 clinical trials by late 2025, though no licensed vaccine or specific antiviral therapy yet exists. This review contextualizes CZS within the broader framework of neglected tropical diseases, evaluates its global and family-level burden, and critically appraises progress and remaining gaps in clinical care, vaccination, and vector control over the past ten years. Full article

Recent Phase 3 clinical trials of selective kappa-opioid (KOP) receptor antagonists aticaprant and navacaprant failed to demonstrate sufficient clinical efficacy in treatment-resistant depression (TRD). This highlights a critical gap in current strategies that target opioid-mediated hedonic suppression. We propose two hypotheses to explain these setbacks: (1) neutral antagonists are inherently ineffective in blocking constitutively active KOP receptor hyperactivation and (2) the nociceptin opioid (NOP) receptor provides functional redundancy that compensates for KOP receptor blockade. Gaining insights from paralogous compensation in drug-resistant tumors, we argue for shifting from selective opioid antagonists to dual KOP/NOP receptor blockers to meaningfully improve reward function. This concept provides a theoretical framework for overcoming clinical resistance where selective KOP targeting with neutral antagonists has failed. Thus, we advocate for the development of opioid inverse agonists (such as nor-BNI, CAS: 105618-26-6), pan-antagonists (such as AT-076, CAS: 1657028-64-2), and combinations of selective blockers. Full article