Advances in Therapy最新文献

Isthmocele, also known as cesarean scar defect, is an increasingly recognized complication of cesarean delivery, often associated with abnormal uterine bleeding, pelvic pain, and secondary infertility. This narrative review aims to provide a comprehensive overview of the condition, including its pathogenesis, risk factors, diagnostic methods, and current treatment options. The most significant risk factor for isthmocele formation is the number of previous cesarean sections, although other contributing elements include surgical technique, uterine position, and individual wound-healing capacity. Transvaginal ultrasound is the first-line imaging modality, while magnetic resonance imaging may provide enhanced visualization in selected cases. Management depends on the severity of symptoms, residual myometrial thickness, and reproductive goals. Treatment options range from conservative medical therapy to surgical interventions via hysteroscopic, vaginal, or laparoscopic approaches. Surgical correction is particularly indicated in symptomatic women with reproductive desire and thin residual myometrium. The choice of technique should be individualized on the basis of the characteristics of the defect, the presence of coexisting pathologies, and surgical expertise. Preventive strategies focus on optimal cesarean technique, with emerging evidence supporting the importance of suture method and postoperative ultrasound monitoring. Despite increasing awareness, standardized guidelines for diagnosis and treatment are lacking. A tailored approach remains essential, considering both clinical and anatomical variables. This review summarizes the current knowledge on isthmocele and highlights the need for further research to establish evidence-based protocols for diagnosis, prevention, and treatment.

Introduction: The global burden of type 2 diabetes mellitus (T2DM) is rising, with physical inactivity being a key modifiable risk factor. While structured exercise is known to improve glycemic control, the role of integrated moderate-to-vigorous recreational and sports activities in managing T2DM remains underexplored.

Methods: This systematic review examined the therapeutic and preventive effects of moderate-to-vigorous recreational activity programs on individuals with T2DM and prediabetes. A comprehensive search of eight databases was conducted for interventional studies published in English between November 2023 and March 2024. Eligible studies involved adult participants (≥ 18 years) undergoing structured sports or recreational activity interventions, with outcomes including glycemic control, cardiovascular risk factors, physical fitness, and adverse events.

Results: Nine randomized controlled trials from diverse global settings were included. Interventions included high-intensity interval training, recreational soccer, cycling, and pedometer-guided walking, among others. Significant improvements were observed in glycated hemoglobin (HbA1c), with pooled analysis indicating a moderate standardized reduction (Hedges' g = 0.54, 95% confidence interval (CI) 0.16-0.92), equivalent to decreases of up to - 1.8% in individual trials. Body mass index also decreased modestly (pooled mean difference - 0.34 kg/m², 95% CI - 0.53 to - 0.15). Additional benefits were observed in fasting plasma glucose, lipid profiles, blood pressure, body composition, and muscular endurance. Adherence rates across trials were high, and adverse events were minimal, typically limited to transient dizziness or breathlessness.

Conclusion: Moderate-to-vigorous recreational activity programs are effective, safe, and scalable adjuncts to standard diabetes care. While smaller trials often reported larger effects and larger multimodal studies showed more modest outcomes, sensitivity analyses confirmed the robustness of the overall findings. Future research should address these sources of bias by standardizing outcome reporting, ensuring adequate sample sizes, and testing long-term sustainability and integration into health systems, particularly for individuals with comorbidities or limited mobility.

Trial registration: Registration number CRD42024499785.

Introduction: Type 2 diabetes (T2D) is a major public health concern in Australia, associated with substantial clinical, humanistic, and economic burden. The condition is linked to high rates of cardiovascular and microvascular complications, premature mortality, and reduced quality of life. Effective glycemic management is central to reducing these adverse outcomes. Real-time continuous glucose monitoring (RT-CGM) has been shown to improve glycemic control in insulin-treated T2D compared with self-monitoring of blood glucose (SMBG). However, evidence of its cost-effectiveness in the Australian setting is limited. This study aimed to evaluate the cost-effectiveness of Dexcom ONE+ RT-CGM versus SMBG in adults with insulin-treated T2D in Australia.

Methods: A lifetime economic evaluation was conducted using version 10 of the IQVIA CORE Diabetes Model. The analysis simulated clinical and economic outcomes for two subgroups: those on intensive insulin therapy (IIT) and non-intensive insulin therapy (NIIT). Treatment effects were sourced from clinical trials and real-world evidence. Outcomes included life years, quality-adjusted life years (QALYs), and direct healthcare costs. Incremental cost-effectiveness ratios (ICERs) were calculated as cost per QALY gained. Scenario and sensitivity analyses tested robustness.

Results: RT-CGM was dominant compared to SMBG in both IIT and NIIT subgroups. In IIT, RT-CGM yielded 0.567 additional QALYs and cost savings of AUD 9869. In NIIT, it yielded 0.319 additional QALYs and savings of AUD 5253. Results were robust across sensitivity analyses. Health equity considerations were also identified, particularly for Indigenous populations and those with youth-onset T2D.

Conclusions: RT-CGM was dominant in both insulin-treated subgroups, improving patient outcomes while reducing healthcare costs. These findings highlight the potential value of RT-CGM for broad reimbursement in Australia and the importance of addressing inequities in glycemic management, particularly among Indigenous Australians and younger individuals with T2D.

One of the major mechanisms in the pathogenesis of pulmonary arterial hypertension (PAH) is mediated by elevated levels of endothelin (ET)-1, which activates both ET_A and ET_B receptors in the pulmonary vasculature. Endothelin receptor antagonists (ERAs) are established treatments for PAH, and three agents-bosentan, ambrisentan, and macitentan-are approved for use in adults in the USA. All are orthosteric antagonists of ET-1 and bind with high affinity to the ET_A receptor, which is found largely on vascular smooth muscle cells (SMCs) and involved in vasoconstriction. Bosentan and macitentan also bind to the ET_B receptor, which is upregulated on SMCs and downregulated on endothelial cells in PAH, resulting in vasoconstriction, cell proliferation, and vascular remodeling. Studies show all three ERAs are efficacious in treating PAH as monotherapy or in combination with other PAH drugs and are generally well tolerated, but all can cause fetal harm and are contraindicated in pregnancy. However, there are no head-to-head clinical trials providing a comprehensive comparison of the overall efficacy and safety of ERAs in PAH. Consequently, we examined the literature on ERAs in PAH through a targeted search of the PubMed/MEDLINE database. This narrative review explores the role of ET-1 in PAH underlying the rationale for ET receptor antagonism. It also discusses the differing physicochemical and pharmacokinetic properties of each ERA and how these unique characteristics influence their receptor binding and kinetics, mechanisms of action, therapeutic effects, dosing frequency, and safety in PAH. In the absence of head-to-head clinical trials assessing their comparative efficacy and safety, it is important to understand both the similarities and the distinguishing characteristics of the three ERAs approved in PAH, to inform individualized treatment selection.

Introduction: Oral methotrexate is the standard first-line treatment for rheumatoid arthritis (RA), but subcutaneous methotrexate may offer improved efficacy and tolerability and, as a second-line treatment, delay escalation to biologics. This study evaluates the cost-utility of treatment pathways including subcutaneous methotrexate versus current practice for moderate-to-severe RA in the UK.

Methods: A hybrid decision tree-Markov model simulating RA treatment pathways was developed. The decision tree classified patients as (non-)responders based on American College of Rheumatology criteria. Responders continued first-line therapy; non-responders transitioned to second-line treatment. In the Markov model, states were defined by treatment line, with patient entry determined by decision tree outcomes. Transitions represented discontinuation due to inefficacy or toxicity. Health Assessment Questionnaire scores changed over time by Markov state, affecting quality of life, mortality, and hospitalisation costs. Resource use, adverse events, and treatment costs were included. Inputs were sourced from peer-reviewed literature, national costing databases, and health technology appraisals.

Results: Over 30 years, the pathway including second-line subcutaneous methotrexate was projected as less costly and more effective than current practice with £5217 in total cost savings and 0.23 quality-adjusted life years gained per patient, for a net monetary benefit of £9789. One-way and probabilistic sensitivity and scenario analyses supported the robustness of results. Dominance was maintained across all variations and iterations, including a scenario with first-line subcutaneous methotrexate.

Conclusion: Including subcutaneous methotrexate as second-line RA treatment after oral methotrexate represents effective healthcare resource use in the UK, improving patient outcomes while reducing total costs.

Atopic dermatitis (AD) is a chronic, relapsing, and heterogeneous skin disease characterized by eczematous morphology and intense pruritus, significantly impacting the quality of life of affected individuals. A primary cytokine implicated in AD is interleukin-13 (IL-13), which directly drives pruritus skin sensitization, contributing to pruritus. Lebrikizumab, a high-affinity IgG4 monoclonal antibody, targets IL-13 to block inflammatory and neuronal sensitization processes. This review aims to provide a comprehensive summary of lebrikizumab's efficacy in managing pruritus in patients with AD, focusing on data from the ADvocate 1&2, ADjoin, ADmirable, and ADhere studies. Clinical trials have demonstrated rapid and sustained improvements in pruritus outcomes, with significant relief observed within days of treatment initiation and maintained over long periods. Lebrikizumab has shown efficacy across diverse populations, including adolescents, the elderly, and skin of color. By effectively targeting IL-13, lebrikizumab offers a valuable treatment option for moderate-to-severe AD, providing significant and sustained pruritus relief, skin clearance, and quality of life improvements.

Introduction: Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of all esophageal cancer cases and is associated with poor prognosis. However, recent advancements have transformed the treatment landscape. Tislelizumab, a humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal antibody, was developed to overcome resistance mechanisms by minimizing binding to FcγR on macrophages. The RATIONALE-302 clinical trial showed statistically significant survival benefits of tislelizumab over chemotherapy in second-line ESCC highlighting the necessity of evaluating comparative efficacy with existing treatments. This study aimed to identify trials evaluating anti-PD-1 therapies for second-line ESCC and indirectly estimate the relative efficacy of tislelizumab versus existing anti-PD-1 therapies.

Methods: A systematic literature review (SLR) was originally conducted in 2021 then updated in 2022 and 2023. A feasibility assessment (FA) was undertaken to evaluate required assumptions for indirect treatment comparisons (ITCs) and determined that anchored simulated treatment comparisons (STCs) were the most appropriate methodology. Assessed outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAEs). Analyses were conducted in the hazard ratio scale for OS and PFS and in the odds ratio scale for TRAEs, whilst uncertainty was expressed in 95% confidence intervals.

Results: The SLR identified 13 studies, six of which evaluated immunotherapies and were included in the FA. All studies were deemed similar and considered in the ITC, except for RAMONA, which differed substantially in study design, inclusion criteria, and patient characteristics. Indirect estimates obtained from the STCs were not statistically significant, except for the comparison of TRAEs with tislelizumab versus camrelizumab, where tislelizumab was more favorable.

Conclusions: Tislelizumab appears comparable to existing anti-PD-1 therapies (nivolumab, pembrolizumab, camrelizumab, and sintilimab) in OS, PFS, and TRAEs of grade ≥ 3 for patients receiving second-line treatment for ESCC with a potentially more favorable TRAE grade ≥ 3 profile than camrelizumab that requires confirmation.

Trial registration: NCT03430843.

Current clinical recommendations for asthma management are based on a symptom-driven, stepwise approach; however, the effects of patient characteristics and patient preference should be considered as they can influence adherence and, in turn, treatment effectiveness. In this Practical Approach article, an international group of asthma specialists reviews the current evidence to be considered when prescribing (as initial or secondary therapy) conventional maintenance inhaled corticosteroid (ICS)/long-acting β₂-agonist (LABA), plus as-needed short-acting β₂-agonist (SABA), or maintenance and reliever therapy (MART) with ICS, and the LABA formoterol (FOR), to patients on the 2025 Global Initiative for Asthma (GINA) treatment steps 3 and 4 with moderate-to-severe asthma. Many of the trials evaluating MART performed during the last 2 decades have explored MART, and the results have influenced the current recommendations proposed by 2025 GINA and others; however, the 'conventional' strategy relying on maintenance ICS/LABA therapy plus as-needed SABA may be more suitable to some patients and easier to manage for some healthcare professionals (HCPs). The purpose of this article is to provide a practical approach to help HCPs choose the best management regimen for each patient, to facilitate a personalised strategy tailored to the individual patient characteristics rather than a uniform approach. A special focus is placed on circumstances where a conventional ICS (± LABA) + SABA strategy should be followed. The focus of asthma management should not be on asthma control alone, but should also consider the risk of long-term outcomes, particularly future exacerbation risk. In addition to real-world effectiveness, baseline characteristics and behavioural patterns, such as patient preferences and adherence patterns, need to be considered when choosing between conventional dosing with maintenance ICS/LABA plus as-needed SABA or MART.

Introduction: Cluster headache (CH) is a debilitating condition with health-related and economic burden to patients, including reduced quality of life (QoL) and suicidality. Brazilian data on comorbidities, symptoms, or impact on QoL and productivity remain limited. This study aims to assess CH's impact on patients' QoL, overall health, and employment in Brazil from physicians' and patients' perspectives.

Methods: Data were extracted from the Adelphi Real World CH Disease Specific Programme™, a real-world, cross-sectional survey of physicians and their patients with CH in Brazil from November 2021-July 2022. Physicians reported on demographics, clinical characteristics, comorbidities, and suicidality. Patients reported CH's impact on feelings/reactions, suicidality, employment using the Work Productivity and Activity Impairment questionnaire, and QoL using the EuroQol 5 Dimension 5 Level survey. Data analyses were conducted with R Statistical software (v4.1.2).

Results: Patients completed 177 forms, while physicians completed 450 forms. Patients had episodic CH (ECH, n = 355) and chronic CH (CCH, n = 95). Common comorbidities were anxiety, insomnia, hypertension, depression, and dyslipidemia. Stress and lack of sleep were key physician-reported CH triggers, and 10.34% of patients had considered suicide. The presence of CH may have led to absenteeism (11.45%) and presenteeism (30.08% overall work impairment, 29.38% activity impairment, and 29.36% impairment while working).

Conclusions: CH carries a significant disease burden and negative socioeconomic impact, especially among patients with CCH. Stress was the most common trigger for both attacks and bouts with notable rates of suicidality. This indicates a need among physicians and patients for targeted and more efficacious interventions to reduce CH's burden, improving patients' QoL.

Introduction: Lack of or delayed treatment of primary biliary cholangitis (PBC) is associated with worsening outcomes. This study assessed the real-world healthcare resource use (HRU) and costs of PBC in the USA to understand its economic burden by line of therapy.

Methods: This retrospective study analyzed IQVIA PharMetrics^® Plus claims data (2016-2022) for three non-mutually exclusive cohorts of adults diagnosed with PBC from January 1, 2017: untreated; first-line (1L) treatment with ursodeoxycholic acid (UDCA); second-line or more (2L+) treatment after UDCA. Index date for each cohort was: untreated, date of PBC diagnosis; 1L, 1L treatment initiation; 2L+, 2L treatment initiation. All-cause per-patient per-year (PPPY) HRU and costs during baseline and follow-up periods were compared among groups.

Results: Patients in the untreated cohort had higher mean inpatient (IP) admissions (PPPY; 0.93 visits) and longer mean IP length of stay (LOS) (PPPY; 7.45 days) than the 1L (0.16 visits; 1.12 days) and 2L+ (0.19 visits; 1.77 days) cohorts during follow-up. Patients in the untreated cohort had the highest mean IP costs during the follow-up period (untreated: $37,974; 1L: $5854; 2L+: $6898). Compared with baseline, significantly higher HRU during follow-up was observed for the 1L and 2L+ cohorts regarding mean number of outpatient visits (incidence rate ratio [IRR]: 1.07; p = 0.001) and mean IP LOS (IRR: 2.12; p = 0.001), respectively.

Conclusions: These results highlight the importance of initiating timely treatment for PBC to reduce HRU and medical costs. The findings also demonstrate the need for novel, more effective PBC treatments.