Cabotegravir (CAB) is an integrase strand transfer inhibitor and the first long-acting injectable antiretroviral agent for human immunodeficiency virus (HIV), administered with rilpivirine. Because approval in Japan relied largely on overseas and international collaborative trials, domestic real-world evidence remains limited. This study evaluated the real-world safety and effectiveness of CAB in people living with HIV (PLHIV) in Japan. This interim analysis (June 27, 2022 and June 17, 2025) was part of an ongoing post-marketing surveillance of Japanese PLHIV treated with CAB at institutions participating in the HIV-related Drugs Cooperative Survey. Safety was assessed by the incidence of adverse drug reactions (ADRs). Associations between ADR incidence and background characteristics were examined using Fisher's exact and χ2 tests without multiplicity adjustment. Effectiveness was evaluated using virologic suppression assessed by log-transformed HIV RNA copies/mL and peripheral CD4+ cell counts. A total of 121 and 117 participants were included in the safety and efficacy analysis sets, respectively; most were aged over 20 years, and over 96% were male participants. Overall, 76 ADRs were reported in 45 participants (37.19%). The most frequent ADRs were injection site pain and musculoskeletal pain (12.40% each). Four serious ADRs that were not explicitly deemed unrelated to CAB by the reporting physicians occurred in 4 participants: hepatitis B reactivation, monkeypox, syphilis, and type 2 diabetes mellitus. Stratification analyses by participant characteristics revealed high ADR incidences among participants aged ≥ 30 to < 40 years (p = 0.038), without allergy (p = 0.016), and with comorbidities (p = 0.045). HIV RNA copies remained suppressed and CD4+ cell counts were maintained at levels comparable to treatment initiation throughout follow-up. This interim analysis indicates that CAB therapy is safe, with no new safety signals, and effective, as demonstrated by sustained virological suppression and stable CD4+ cell counts. These findings are consistent with outcomes reported in overseas and international collaborative clinical studies. Taking multiple oral medications every day can be challenging for people living with human immunodeficiency virus (PLHIV). Cabotegravir, co-administered with rilpivirine, is the first long-acting injectable HIV treatment that can be given once monthly or every 2 months. Its approval in Japan was primarily based on overseas and international collaborative studies, and real-world clinical evidence in Japan has been limited. To address this gap, a post-marketing surveillance has been conducted to confirm the safety and effectiveness of cabotegravir in Japanese PLHIV. This was a 3-year interim analysis of post-marketing surveillance including 121 participants at 10 institutions in Japan who were virologically suppressed for over 6 months before switching to cabotegravir. During follow-up, 45 participants experienced 76 adverse drug reactions (37.19%) that included injection site pain and musculoskeletal pain (12.40% each), and oral herpes, high cholesterol, thickened or hardened injection site, fever, and decreased white blood cell counts (2.48% each). These findings were consistent with those reported in previous clinical studies. Higher adverse drug reaction rates were observed among participants aged ≥ 30 to < 40 years, those without allergy, and those with other medical conditions. Most adverse drug reactions considered related to cabotegravir occurred within 180 days after treatment initiation. Throughout the follow-up period, HIV RNA copies remained suppressed and CD4+ cell counts were maintained at levels similar to those at treatment initiation. Overall, these results confirm the real-world safety and effectiveness of cabotegravir in Japan.
China's rapidly aging population and high burden of frailty make proactive preparation for future care increasingly urgent, yet few older adults engage in such preparation. Existing interventions often overlook the heterogeneity between prefrail and frail populations and lack precision-oriented digital strategies. Building on a series of prior empirical studies, this study aimed to develop and pilot-test a digital intervention to support preparation for future care among community-dwelling older adults with prefrailty and frailty. The "Yi Yang Plan," a WeChat mini-program, was developed through a rigorous multiphase process, including a scoping review, a convergent mixed methods study, and a structural equation model. These findings informed the design of a tailored, stage-specific intervention targeting the distinct needs of prefrail and frail older adults. An interdisciplinary team subsequently refined the intervention using an iterative design approach. The intervention modules comprised 4 processes: Awareness Enhancement, Care Resources, Care Decision-Making, and Care Planning. Pilot testing involved expert panel consultations and think-aloud tests. Expert characteristics, engagement, and authority coefficients were assessed, and feedback was synthesized using content analysis. Feasibility and acceptability among older adults and their family members were evaluated through task completion metrics, satisfaction surveys, think-aloud protocols, and semistructured interviews. Seven experts participated in the consultation, with an engagement coefficient of 100% and an authority coefficient of 0.88. Recommendations were synthesized into four key themes: (1) establishing mechanisms for care plan updating and review, (2) strengthening user-centered design, (3) implementing dynamic resource management and robust data security measures, and (4) enhancing integration with community care systems and policy frameworks. A total of 20 older adults and 20 family members were recruited. All participants successfully completed the assigned tasks, with a mean completion time of 20.7 (SD 5.2) minutes. Satisfaction ratings were generally favorable. The qualitative findings indicated that the intervention was perceived as useful and professionally designed, while also identifying several challenges, including variability in preparation for future care readiness and educational levels, limited interactivity, insufficient practical content, and reliance on support from adult children. Suggested improvements included enhanced personalization, additional supportive tools, improved usability, greater involvement of adult children, and stronger integration with offline services. The "Yi Yang Plan" demonstrated preliminary scientific validity, feasibility, and acceptability as a multidisciplinary, collaboratively developed digital intervention to support preparation for future care among older adults with prefrailty and frailty. By translating prior empirical and theoretical findings into a differentiated, precision-oriented digital strategy, this study advances interventions beyond conventional one-size-fits-all approaches. Future iterations should focus on optimizing system architecture, user interface design, platform functionality, and implementation strategies. Further research should conduct higher-quality randomized controlled trials to evaluate the platform's effectiveness.
Little is known about the implementation of guideline recommendations and healthcare provider decision-making when managing hyperkalemia. We aimed to address these knowledge gaps and better understand hyperkalemia management in routine clinical care and the baseline characteristics and longitudinal (12-month) clinical variables of participants with hyperkalemia. This was an observational, prospective, longitudinal, cohort study including adults with recent (≤ 21 days of enrollment) hyperkalemia (serum potassium [K+] > 5.0 mmol/L) during standard of care, across Germany, Italy, Spain, the UK, and the USA from July 2022 to December 2024. Primary and secondary data were collected from participants' medical records and their respective healthcare providers. Healthcare providers' hyperkalemia management decisions, treatment rationale, and expectations were measured overall, by incident versus recurrent cases, and by hyperkalemia severity. In total, 1330 participants with hyperkalemia were included (458 incident, 870 recurrent). The most common treatment rationale for index hyperkalemia was ease of treatment (41.4%). Overall, 80.9% of participants received conservative treatment (no hyperkalemia treatment, monitoring K+ levels, or a low K+ diet; incident hyperkalemia 76.9%, recurrent hyperkalemia 83.2%). K+ binder use was low (10.8%) but increased with hyperkalemia severity (mild, 6.6%; moderate, 17.0%; severe 20.0%). Renin-angiotensin-aldosterone system inhibitors were stopped/reduced in < 5% of participants. Over 12 months, 71.7% of participants achieved normokalemia at any timepoint (incident 65.7%, recurrent 74.8%). Among participants with normokalemia at 9 months (incident, n = 125; recurrent, n = 294), the probability of hyperkalemia recurrence at 12 months was lower in the incident than in the recurrent group (14.5% vs 39.3%; crude odds ratio 0.26 [95% confidence interval 0.13-0.53]). Guideline recommendations for incident and recurrent hyperkalemia were inconsistently implemented in clinical practice, as demonstrated by a conservative approach to treatment. Unmet hyperkalemia treatment goals and recurrent hyperkalemia were common. Individuals with chronic kidney disease and/or heart failure have an increased risk of hyperkalemia, a condition caused by elevated blood potassium levels that can impair cardiac function. Additionally, some medications used to treat chronic kidney disease and heart failure conditions can further increase potassium levels. The TRACK study assessed how healthcare providers (HCPs) in five countries treated adults who had a recent first-time episode (incident) or recurring episodes (recurrent) of hyperkalemia in routine clinical practice. Researchers reviewed the medical records of participants with incident or recurrent hyperkalemia and collected data from HCPs over 12 months to document treatment decisions, reasons for those choices, and outcomes. Data were analyzed to identify patterns over time. The researchers found that HCPs did not consistently follow guidelines when treating patients with hyperkalemia. HCPs tended to use conservative treatment approaches, including monitoring blood potassium levels and advising a low-potassium diet, and few patients were given specialized treatments such as potassium binder medication, which helps lower potassium levels. ‘Ease of treatment’ was the most common reason HCPs gave for their treatment choice. Many patients returned to normal potassium levels, but it was common for them to have recurrences of hyperkalemia. The findings show inconsistent use of clinical guidelines by HCPs in everyday clinical practice and a conservative approach to treating hyperkalemia. A more proactive care approach and closer adherence to clinical guidelines could reduce hyperkalemia recurrence and improve patient outcomes.
A phase 2 trial (NCT04818346) of the oral Janus kinase 1 inhibitor povorcitinib demonstrated substantial total body and facial repigmentation over 52 weeks in adults with extensive nonsegmental vitiligo (NSV). Here, post hoc analyses evaluated povorcitinib efficacy in patients based on demographic and clinical characteristic subgroups, as well as affected body regions. Data were pooled for 103 patients in the extension-evaluable population who received povorcitinib (15, 45, or 75 mg once daily) throughout the 52-week study. Efficacy among subgroups was evaluated using achievement of ≥ 50% reduction from baseline in total Vitiligo Area Scoring Index (T-VASI50) and ≥ 50%/≥ 75% reduction from baseline in facial VASI (F-VASI50/F-VASI75). Efficacy in the affected body regions was evaluated using VASI50 responses. Data were analyzed using descriptive statistics, and missing values were imputed as nonresponders. At Week 52, 34.0% (35/103) of patients achieved T-VASI50, 61.2% (63/103) achieved F-VASI50, and 45.6% (47/103) achieved F-VASI75. Repigmentation occurred across subgroups regardless of patient age, sex, race, Fitzpatrick skin type, affected body surface area, other autoimmune comorbidities, disease duration, or prior NSV treatment. In addition, VASI50 response rates increased consistently and, in most cases, without plateauing for each body region, ranging from 25.8% for the feet to 57.3% for the head and neck (excluding the face). Decreased rates of disease activity were also evident across body regions. In this exploratory post hoc analysis of adults with extensive NSV, oral povorcitinib produced clinically meaningful repigmentation (as measured by achievement of T-VASI50 and F-VASI75) across patient characteristic subgroups and body regions through 1 year of treatment. Response rates varied by body region, reinforcing the lengthy repigmentation process, especially in nonfacial areas, and highlighting the need to manage patient expectations and encourage adherence to long-term therapy. ClinicalTrials.gov identifier, NCT04818346. Vitiligo is a condition that causes the skin to form white patches. These patches can develop anywhere on the body. In a recent study, people with widespread vitiligo took povorcitinib tablets daily for 1 year. Many saw color return to the white patches of skin on their face and body. The analysis described here examined data from this study and assessed how well the treatment worked in different groups of people based on factors such as age, skin tone, duration of vitiligo, prior treatments, and affected body parts. The analysis included 103 patients who took povorcitinib for 1 year. After a year of treatment, one in three patients had at least half of the lost color return across their body. The face responded even better—nearly half the patients had at least three-quarters of their color return. Importantly, povorcitinib improved skin coloring across different groups of people, regardless of their age, sex (men/women), race, skin tone (fairer/darker), or how much of the body was affected with vitiligo. It also helped people whether they had other autoimmune health problems or not, had vitiligo for a short or long time, or had tried other medicines before. Povorcitinib also worked on different parts of the body, although results were best on the face and the head and neck. Since treatment takes many months and results may appear slowly in some body areas (e.g., the hands and feet), patients should be encouraged to continue treatment long term for the best outcomes.
Respiratory tract infections (RTIs) are the leading causes of paediatric morbidity worldwide, particularly in regions with high antimicrobial resistance (AMR). High-dose amoxycillin-clavulanate formulations, which increase amoxycillin exposure while maintaining standard clavulanate levels, offer enhanced antibacterial coverage with acceptable tolerability. This phase IV study evaluated the safety and observed clinical outcomes of a high-dose oral suspension of amoxycillin (600 mg/5 mL) and potassium clavulanate (42.9 mg/5 mL) in Indian children with upper RTIs or non-severe lower RTIs. This prospective, multicentre, open-label study enrolled children aged ≥ 3 months to < 18 years with tonsillopharyngitis, acute bacterial sinusitis, acute otitis media, or lobar and/or bronchopneumonia across 12 Indian centres. Participants received amoxycillin-clavulanate at 90/6.4 mg/kg/day in two divided doses for 5-10 days. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included serious adverse events (SAEs), diarrhoea incidence, clinical cure, clinical improvement, clinical failure, clinical relapse and time to symptom resolution. Safety analyses used the safety population, while clinical outcomes were analysed using the modified intention-to-treat population. All 174 enrolled children completed the study. Overall, 21 patients (12.1%) experienced 23 TEAEs (all mild and self-limiting). No SAEs, discontinuations or clinically significant laboratory or vital sign changes were reported. Diarrhoea occurred in 6.3% of patients. Overall clinical cure rate was 82.8% (95% CI 76.3-88.1), highest in acute bacterial sinusitis (95.8%), tonsillopharyngitis (83.7%), acute otitis media (76.9%) and pneumonia (76.5%). An additional 17.2% demonstrated clinical improvement without the need for alternative therapy. No clinical failures or relapses were observed. Overall median time to symptom resolution was 6 days. High-dose amoxycillin-clavulanate demonstrated a favourable safety profile. Observed clinical outcomes were favourable, with a clinical cure or improvement rate of 100% across all patients. These findings provide post-marketing safety and tolerability data to support clinical decision-making in settings with rising AMR. Prospectively registered on Clinical Trials Registry-India [CTRI/2023/08/056267] on 08th August 2023; URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODY5MzI=&Enc=&userName= .
Timely initiation of disease-modifying antirheumatic drugs (DMARDs) is critical for achieving disease control, preventing irreversible joint damage, and improving the long-term outcomes of rheumatoid arthritis (RA). Despite guideline recommendations, real-world delays remain common and may be influenced by demographics, clinical, and geographical factors. Therefore, this study aimed to evaluate initiation patterns and identify demographic, clinical, and regional predictors associated with time to first DMARD initiation and assess differences in timing by drug class and age group among adults with RA in a large US electronic health record (EHR) cohort. A retrospective cohort study was conducted using EHR data of adults with incident RA diagnosed between November 2012 and August 2024. The primary outcome was the time from confirmed RA diagnosis to the first DMARD prescription. Covariates included age, sex, race and ethnicity, marital status, geographic location, and comorbidity. Descriptive analyses of initiation patterns were performed using Kaplan-Meier curves. Furthermore, multivariable Cox proportional hazards ratio (HR) regression models along with 95% confidence intervals (CI) were used to evaluate factors associated with time to DMARD initiation. Among 197,107 patients with incident RA, 57.53% initiated DMARD within the first 3 months of diagnosis, with a mean delay of 18.18 months (SD 41.8); 28.6% initiated treatment after 12 months of diagnosis. Compared with the age group 18-29 years, initiation rates increased across older age groups, reaching an HR of 1.390 (95% CI 1.340-1.442) among patients aged ≥ 80 years. Furthermore, higher comorbidity burden was associated with a faster initiation (HR 1.045, 95% CI 1.042-1.047). Female sex was associated with slower initiation than male patients (HR 0.945, 95% CI 0.934-0.955). American Indian/Alaska Native patients showed 22% faster initiation compared with white patients (HR 1.292, 95% CI 1.219-1.369; p < 0.001). Moreover, longer delays were observed among patients in the Northeast and South than in the West (19% and 4% lower, respectively). Patients who were initiated on biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) experienced a delay compared to conventional synthetic DMARDs (csDMARDs) initiation (bDMARD: HR 0.807, 95% CI 0.798-0.817; tsDMARD: HR 0.732, 95% CI 0.711-0.754). In this real-world study, patients with RA experienced a substantial delay in DMARD initiation, despite the availability of effective therapies and compelling evidence supporting early treatment. Furthermore, demographic, clinical, geographic, and treatment class characteristics were independently associated with the timing of DMARD initiation. These findings emphasize the need for targeted interventions to address treatment delays and ensure equitable access to early and effective RA therapy.
Prospective, randomized evidence for clinical remission, an ambitious treatment goal relevant for all patients with asthma, with single-inhaler triple therapy (SITT) in routine care is lacking. Significant improvement in lung function and asthma control with SITT versus inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) was demonstrated in PERFORM at week 24. PERFORM (GSK 219912/NCT06372496), a randomized, open-label, active-controlled, global pragmatic trial, evaluated the effectiveness and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus usual care ICS/LABA in adults (18-75 years) with uncontrolled, infrequently exacerbating asthma. Secondary outcomes related to clinical remission (no oral corticosteroid use, no severe exacerbations, optimized lung function [change from baseline (CFB) in forced expiratory volume in 1 second (FEV1) ≥ 100 mL], asthma control [Asthma Control Questionnaire total score < 1.50]) were assessed at week 52, following prespecified analysis plans. Alternative clinical remission definitions using stabilized lung function (CFB FEV1 ≥ 0 mL) and those within Japanese guidelines were also assessed. Clinical remission responder analyses are presented as multiplicity-adjusted odds ratios. Safety was assessed throughout. Overall, 1236 participants (mean age 48.9 years; 68.6% [n = 848/1236] female) were included (FF/UMEC/VI: N = 619/1236; ICS/LABA: N = 617/1236). Participants receiving FF/UMEC/VI had statistically significantly greater odds of achieving clinical remission (including optimized lung function) at week 52 versus usual care ICS/LABA (adjusted odds ratio [95% confidence interval] 2.13 [1.54, 2.94], P < 0.0001). Similar results were observed for alternative definitions. Week 52 safety profile aligned with previous studies. In a broad patient population with uncontrolled asthma, treatment with FF/UMEC/VI resulted in statistically significantly greater odds of achieving clinical remission versus usual care ICS/LABA in a setting reflecting routine practice, a secondary outcome of PERFORM. These findings were consistent irrespective of clinical remission definitions and provide evidence informing the use of FF/UMEC/VI in an underserved group of symptomatic patients with infrequent exacerbations and minimal lung function impairment. GSK 219912/NCT06372496.
Daratumumab-based triplet and quadruplet regimens have significantly improved patient outcomes as first-line (1L) treatment in newly diagnosed multiple myeloma (MM). However, with the evolution of available 1L combination regimens, the proportion of patients with exposure and refractoriness to multiple treatment classes at first relapse is increasing. Patients experience worsening prognosis with each successive relapse, and attrition rates increase with each line of therapy (LOT). Therefore, in the second-line setting and beyond (2L+), it is critical to use the most effective treatment available up front to optimize patient outcomes. Treatments that target the B-cell maturation antigen (BCMA), particularly chimeric antigen receptor T-cell therapy, are rapidly becoming a new 2L+ standard of care (SOC). Other BCMA-targeted options, including combinations of belantamab mafodotin plus dexamethasone with bortezomib or pomalidomide, have shown promising efficacy in the 2L+ setting. BCMA-targeted bispecific antibodies are a new treatment option being explored in earlier LOTs and offer patients a steroid-sparing approach with the potential for use across all practice settings. Teclistamab combined with daratumumab is approved in the United States for patients with ≥ 1 prior LOT based on results of the phase 3 MajesTEC-3 trial, in which teclistamab-daratumumab significantly improved progression-free and overall survival versus SOC in patients with 1 to 3 prior LOTs. Several other clinical trials of BCMA-targeted bispecific antibodies in earlier LOTs are ongoing, including teclistamab monotherapy (MajesTEC-9), teclistamab combined with the G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted bispecific antibody talquetamab (MonumenTAL-6), elranatamab (MagnetisMM-5), and linvoseltamab (LINKER-MM3), paving the way for the next evolution of treatment options for patients following first relapse. In this podcast, 2 leading hematologists discuss the unmet needs in 2L+ MM, considerations for treatment decisions, and the evolving treatment landscape with a focus on BCMA-targeted bispecific antibodies, a rapidly advancing class of treatments in this setting. Podcast (MP4 179036 KB).
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with a poor survival rate despite advances in therapy. Metabolic reprogramming, particularly involving lactate transport, plays a critical role in HCC progression. Monocarboxylate transporter 4 (MCT4) is a key lactate exporter often overexpressed in cancers, yet its precise role in HCC pathogenesis and immune modulation remains incompletely defined. We integrated bioinformatic analyses of multiple datasets (TCGA-LIHC, GSE46408, GSE36411) with experimental validation in HCC cell lines (Huh7, MHCC97-H) and a murine xenograft model. Functional assays including wound healing, Transwell invasion, Western blot, and flow cytometry were employed. Immune cell infiltration and polarization were analyzed via CIBERSORT and single-cell RNA sequencing data (GSE282701). MCT4 was identified as a prognostic hub gene among lactate metabolism-related genes (LMRGs) and was significantly upregulated in HCC tissues, correlating with advanced tumor stage and poor survival. Gene Set Enrichment Analysis (GSEA) revealed a strong association between MCT4 expression and matrix metalloproteinase (MMP) pathways. In vitro, MCT4 knockdown downregulated MMP1, MMP2, and MMP9 expression and suppressed HCC cell migration and invasion. Furthermore, high MCT4 expression was linked to an immunosuppressive tumor microenvironment characterized by M2 macrophage polarization. In vivo, MCT4 knockdown inhibited tumor growth and reduced infiltration of CD206+ M2 macrophages. Our findings demonstrate that MCT4 drives HCC progression through two complementary mechanisms: enhancing MMP-mediated invasion and metastasis, and promoting immunosuppressive M2 macrophage polarization. These results nominate MCT4 as a promising therapeutic target for restoring antitumor immunity and inhibiting metastasis in HCC.
Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) exert complementary metabolic effects and have independently demonstrated cardiovascular benefits in individuals with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD). However, despite growing evidence suggesting potential additive benefits in high-risk populations, real-world data on dual therapy remain limited. This study aimed to identify clinical factors associated with the use of combined GLP-1RA/SGLT2i therapy in routine practice. This retrospective observational study included 202 adults with T2DM and established ASCVD admitted to a tertiary care hospital between November and December 2025. Patients were categorized according to their pre-admission outpatient regimen into four groups: neither therapy, GLP-1RA only, SGLT2i only, and combined therapy. Clinical characteristics and comorbidities were recorded at admission. Multinomial logistic regression analysis was performed to identify factors associated with treatment allocation. Among 202 patients, 54.5% were not receiving either class, 10.9% were treated with GLP-1RA only, 21.3% with SGLT2i only, and 13.4% with both. In adjusted analyses, combined therapy was independently associated with younger age [odds ratio (OR) 0.89 per year, 95% confidence interval (CI) 0.84-0.95, p < 0.001], presence of heart failure (OR 9.64, 95% CI 2.65-35.04, p < 0.001), and insulin use (OR 10.99, 95% CI 3.12-38.72, p < 0.001). Chronic kidney disease and polyvascular disease were not associated with dual therapy use. In this real-world cohort of patients with T2DM and ASCVD, more than half were not receiving a cardioprotective glucose-lowering therapy. Combined GLP-1RA/SGLT2i therapy was infrequently prescribed and was associated with selected clinical characteristics rather than overall cardiorenal risk burden. These findings highlight an opportunity to better align treatment strategies with a comprehensive risk-based approach.
Hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer represents the most prevalent subtype of early-stage breast cancer. Adjuvant endocrine therapy (ET) substantially reduces recurrence and breast cancer mortality; however, late relapse remains a major challenge, with a considerable proportion of recurrences occurring beyond 5 years after diagnosis. Although extended ET can modestly reduce late recurrence, it is associated with cumulative toxicities and impaired quality of life, highlighting the urgent need for biomarkers to identify patients who truly benefit from treatment escalation or extension, while sparing low-risk individuals from overtreatment. Tissue-based multigene expression assays, including the Breast Cancer Index (BCI), EndoPredict, Prosigna, Oncotype DX, and MammaPrint, have improved risk stratification and informed treatment decisions, with BCI demonstrating the strongest evidence for predicting benefit from extended endocrine therapy. Among currently available assays, BCI has the strongest level of evidence supporting its use in guiding extended endocrine therapy decisions. In parallel, liquid biopsy approaches, particularly circulating tumor DNA (ctDNA)/minimal residual disease (MRD) detection, have emerged as promising tools for dynamic monitoring and early detection of molecular relapse. This review summarizes current evidence supporting biomarker-guided decision-making in early-stage HR+/HER2- breast cancer, focusing on three clinically relevant questions: who requires treatment escalation, who benefits from extended endocrine therapy, and who may safely de-escalate. We further discuss challenges and future directions toward integrated models combining genomic assays with longitudinal ctDNA monitoring to refine personalized adjuvant endocrine strategies. However, current evidence remains limited, and prospective validation is required.
This study aimed to evaluate the effectiveness and safety of vosoritide in Chinese children with achondroplasia (ACH) in a real-world setting. A total of 26 children diagnosed with ACH and treated with vosoritide were enrolled in the study. Clinical indicators such as height, sitting height, and body mass index (BMI), as well as laboratory indicators including bone age and insulin-like growth factor level, were collected and analyzed before and after treatment. Improvements in height standard deviation score (SDS), sitting height/height ratio, and BMI were evaluated. Statistical differences were analyzed across different age and sex groups. Adverse reactions during the treatment were also monitored. Among the 17 patients assessed at 12 months, height SDS (based on general population growth charts) improved from - 4.7 ± 0.1 at baseline to - 4.3 ± 0.2 at 12 months (P < 0.001). With continued treatment, annual growth velocity (AGV) significantly increased, reaching 8.7 ± 1.4 cm/year in 12 patients who remained under follow-up after 18 months of treatment. Furthermore, BMI SDS exhibited a continuous decline. The sitting height/height ratio decreased during the treatment, indicating an optimization of body proportions. Additionally, growth improvement was found in both age (below five years old and above five years old) and sex (male and female) groups. Except for the total procollagen I intact N-terminal (TP1NP), which significantly increased at 12 months of treatment compared to baseline, other biochemical indicators (including insulin-like growth factor, alkaline phosphatase, and osteocalcin) showed no significant differences after the treatment. Vosoritide exerts significant growth-promoting effects and favorable safety in Chinese children with ACH. It improves height SDS and body proportions, demonstrating consistent effectiveness across various age groups and sex groups. Early diagnosis and timely initiation of vosoritide treatment can significantly alter the growth trajectory of these children.
To date, no head-to-head comparisons of apalutamide versus darolutamide have been reported for metastatic castration-sensitive prostate cancer (mCSPC). This study compared prostate-specific antigen decline ≥ 90% (PSA90) and overall survival (OS) between apalutamide and darolutamide, both without docetaxel, among patients with mCSPC in real-world clinical practice in the USA. Men diagnosed with mCSPC who initiated apalutamide or darolutamide between 2022 and 2025 were identified from linked electronic medical records and insurance claims. The apalutamide and darolutamide cohorts were balanced using inverse probability of treatment weighting. PSA90 response was assessed on-treatment. The proportions of patients achieving a PSA90 response and OS through a maximum of 6 months and 24 months post-treatment initiation, respectively, were compared between the two cohorts using weighted Kaplan-Meier and weighted Cox proportional hazards models. For PSA90 analyses, weighted characteristics were well balanced between the apalutamide (n = 714; mean age 73.9 years, 59.6% White, 21.2% Black, 13.7% other, 5.5% unknown race) and darolutamide cohorts (n = 145; mean age 74.3 years, 58.8% White, 21.6% Black, 15.0% other, 4.7% unknown race). PSA90 response rates through 6 months were 49% higher for apalutamide than for darolutamide (weighted hazard ratio [HR]: 1.49 [95% confidence interval (CI) 1.07, 2.07]; p = 0.017). For OS analyses, weighted characteristics were also well balanced between apalutamide (n = 1460; mean age 73.5 years, 59.6% White, 21.5% Black, 13.5% other, 5.4% unknown race) and darolutamide (n = 287; mean age 73.7 years, 60.0% White, 22.4% Black, 12.4% other, 5.2% unknown race). Apalutamide was associated with a 51% lower rate of mortality relative to darolutamide through 24 months (weighted HR: 0.49 [95% CI 0.30, 0.83]; p = 0.007). Among patients with mCSPC treated without docetaxel, apalutamide was associated with higher PSA90 response rates and lower mortality than darolutamide. These findings indicate a potential difference in disease control and survival between the two androgen receptor-targeted agents in routine clinical practice. Apalutamide and darolutamide are medications that block hormone activity that fuels prostate cancer growth. They are currently approved to treat metastatic castration-sensitive prostate cancer (mCSPC) with standard hormone-lowering combination therapy (androgen-deprivation therapy, ADT).This study used medical and insurance data from US community urology practices to compare outcomes between patients with mCSPC who started apalutamide (1460 patients) or darolutamide (287 patients), both without docetaxel. Apalutamide was FDA approved for this use throughout the study period. Darolutamide without docetaxel was FDA approved only near the end of the study period (June 2025) but was still widely used in US urology practices during this time. Statistical methods were used to standardize patient features between the two groups by weighting them for specific measured differences in patient and disease characteristics.Overall, 74.6% of patients treated with apalutamide and 56.1% of patients receiving darolutamide achieved ≥ 90% drop in prostate-specific antigen (PSA, a prostate cancer marker) levels among those tested within 6 months of starting treatment, a 49% increase in the rate of PSA response for apalutamide.Additionally, 24 months after starting treatment, 92.1% of patients who received apalutamide and 85.8% of patients who received darolutamide remained alive, a 51% lower rate of death with apalutamide.While these findings are subject to limitations, discussed in the full manuscript, they suggest that in clinical practice and without chemotherapy intensification, apalutamide may provide better disease control and longer overall survival than darolutamide in patients with mCSPC. Notably, no prior studies have directly compared these two treatments for these outcomes.
Titanium fastener technology is increasingly adopted for use in minimally invasive valve surgery and open procedures to facilitate faster operative times and reproducible fastening of sutures. The objective of this study was to evaluate the technical feasibility and short-term safety of automated titanium fastener technology for securing sutures in heart valve repair and/or heart valve replacement procedures. The CRIMP study is a multicenter, prospective study that enrolled patients undergoing heart valve repair or replacement via open or minimally invasive approaches at three centers (n = 120). The primary endpoints were device success and prosthesis implantation time. Mean age was 62.5 (SD 11.1) years, 33.3% of patients was female and the cohort was characterized as low surgical risk (EuroSCORE II 1.6%; SD 2.3%). Predominant valve disease was mitral regurgitation. Median procedure time was 178 (IQR 145-210) min. Median aortic cross-clamp time was 82 (IQR 59-107) min. The majority of procedures was minimally invasive (76.7%). In aortic valve procedures, median prosthesis implantation time (first stitch until last COR-KNOT placement) was 25 (IQR 18-46) min and in mitral valve procedures median implantation time was 50 (IQR 48-52) min. Device success was 100%, since no automated titanium fastener failed to grip or crimp appropriately. Median number of COR-KNOTS used was 14 (IQR 12-16) per valve. In-hospital mortality was 0.8%. All observed adverse events were considered unrelated to the device and there was no valve prosthesis dehiscence at 30-days of follow-up. The use of automated titanium fastener technology for suture fixation in heart valve surgery was technically feasible and showed short-term safety in all patients, with no obvious device-related adverse events observed. Graphical abstract available for this article.  Clinical trial registration number: DRKS00038956. Heart valve surgery often requires surgeons to tie many small sutures to secure repaired or replaced valves. Automated titanium fastener devices can replace manual knot tying and may help surgeons work faster and more consistently. This study evaluated whether this technology is safe during short-term observation and technically feasible when used in heart valve repair or replacement surgery. The CRIMP study was a prospective study conducted at three hospitals and included 120 patients undergoing heart valve surgery. Procedures included mitral, tricuspid, and aortic valve repair or replacement. The average patient age was about 63 years, one-third were women, and overall surgical risk was low. Researchers measured if the fastener device worked and how long it took to implant the valve prostheses. The automated titanium fasteners functioned successfully in all cases, meaning every fastener properly secured the sutures. In aortic valve procedures, placing and fastening the sutures took about 25 min, while in mitral valve procedures it took about 50 min. Around 14 fasteners were used per valve. In-hospital mortality was low (0.8%), and no complications were related to the fastener device. At 30 days after surgery, no patients experienced loosening of the implanted valve. However, the study only had one group, which was observed without a comparative group of patients undergoing manual knot tying, and the follow-up period was relatively short, which are important limitations. Overall, the results suggest that automated titanium fastener technology show short-term safety and are technically feasible for securing sutures in heart valve surgery.
Spinal muscular atrophy (SMA) is a neuromuscular disorder historically associated with high morbidity, mortality, and healthcare costs. Disease-modifying therapies have improved outcomes, but their long-term economic burden remains uncertain. Nusinersen and risdiplam, both chronic therapies, differ from onasemnogene abeparvovec, a one-time gene therapy. Understanding real-world treatment costs of chronic SMA therapies is critical to inform therapeutic choice. This retrospective cohort study used the Komodo Health Research Database (2016-2024). Patients with SMA aged ≥ 2 years who initiated nusinersen or risdiplam were followed up to 5 years. Dosing patterns and drug acquisition and administration costs (2024 USD) were assessed annually, overall and by age group and scoliosis status. Among 3864 eligible patients, 2743 initiated nusinersen and 1121 initiated risdiplam (mean age 21.4 vs. 25.3 years, respectively; 51.5% vs. 46.1% male). Median follow-up was 5.5 years for nusinersen and 1.1 years for risdiplam. Persistence declined over time, with 39.5% of patients treated with nusinersen and 63.7% of patients treated with risdiplam remaining on their index therapy at years 5 and 4. Patients treated with nusinersen received 3.6 injections on average in year 1 and 2.8-3.1 annually thereafter. Median annualized nusinersen treatment costs were $504,173 in year 1 and $438,788-548,608 in years 2-5. Patients treated with risdiplam had a median of 96 days of supply in year 1 (51.5% with > 90 days); median annualized drug costs were $143,331 overall in year 1 and $259,419 among those with > 90 days of supply, increasing to $264,701-289,340 in years 2-4. Costs were similar across subgroups. Nusinersen and risdiplam persistence declined over time. Among patients remaining on their index therapy, both treatments had high long-term costs, highlighting the substantial and ongoing financial burden of chronic SMA therapies and the need for real-world evidence to inform healthcare planning. ClinicalTrials.gov identifier, NCT07378943.
Heart failure with reduced ejection fraction (HFrEF) represents a major clinical and economic burden in Italy, driven by an aging population. Mineralocorticoid receptor antagonists (MRAs) are a cornerstone of guideline-recommended therapy. Eplerenone has demonstrated efficacy in reducing mortality and hospitalizations but remains underutilized. This study assessed the budget impact of increasing eplerenone use in eligible patients with HFrEF from national and regional perspectives. A budget impact analysis (BIA) was conducted over a 3-year horizon from the perspective of the Italian National Health Service (INHS). Two scenarios were compared: Current (observed MRA use) and Projected (increased eplerenone uptake). Model inputs included eligible population, treatment distribution, drug acquisition costs, and clinical outcomes (all-cause mortality, hospitalizations, renal impairment, hyperkalemia, and gynecomastia) with associated costs. Clinical inputs were derived from a network meta-analysis (NMA); cost inputs from Italian literature and national tariffs. Total expenditure increased from €598.6 million (M) to €600.6 M over 3 years, corresponding to a net budget impact of + €2.01 M (+ 0.34%), with annual increments of €880,000 (year 1), €885,000 (year 2), and €245,000 (year 3). Increased eplerenone use resulted in higher costs (+ €35.07 M), driven by drug acquisition and hospitalization costs, partially offset by mortality-related savings (-€3.62 M). These were partially counterbalanced by reductions in other MRAs (spironolactone - €6.37 M, potassium canrenoate - €8.32 M, canrenone - €18.37 M), mainly due to fewer hospitalizations, renal events, and a lower drug volume. Results were primarily driven by clinical parameters for eplerenone, particularly NMA-derived hazard ratios for hospitalization and all-cause mortality. The net budget impact was modest in relative terms (< 0.4% of total MRA-related expenditure), indicating substantial budget neutrality. Greater adoption of eplerenone was associated with a modest net increase in healthcare expenditure for the INHS, corresponding to approximately €3.20 per treated patient per year and consistent with substantial budget neutrality. The budget impact reflects both treatment redistribution and differences in clinical outcomes across MRAs. Expanding eplerenone use in line with guideline-recommended therapy may be achieved at a limited additional cost, while offering a more favorable renal and selectivity profile relative to other MRAs.
Dextroamphetamine transdermal system (d-ATS) is the first and only amphetamine-based transdermal system FDA-approved for attention-deficit/hyperactivity disorder (ADHD) in adults and children aged ≥ 6 years, providing an alternative to oral stimulants. Although transdermal systems can cause local skin reactions, in the d-ATS pivotal study, no discontinuations due to patch application site reactions occurred, and discomfort/pain typically resolved within 2-4 h post-application. d-ATS is approved for five bilateral application sites (10 unique locations). This paper evaluates the pharmacokinetic (PK) bioequivalence between different application sites and summarizes dermal safety and irritation findings from four d-ATS clinical studies (studies 1-4). The application site PK bioequivalence study was a single-dose, open-label, 5-way crossover study assessing amphetamine bioavailability, discomfort, and irritation in healthy adults after a 9 h application of 20 mg/19.05 cm2 d-ATS to five distinct sites. Other studies, studies 1-4, conducted in healthy adults or patients with ADHD, evaluated dermal irritation from d-ATS alone or vs placebo under intended-use or exaggerated-use conditions. The application site PK study population included 50 patients. All 90% CIs for key exposure parameters fell within the FDA-specified bioequivalence limit of 80-125%, demonstrating bioequivalence across five application sites, with no discontinuations related to irritation or discomfort. Under intended-use conditions (site rotation consistent with approved d-ATS use; studies 1 and 2), instances of skin irritation were not clinically meaningful (≥ 3 point Bowman and Berger scale combination score). Under exaggerated-use conditions consistent with FDA guidance (studies 3 and 4), clinically meaningful irritation occurred in 55-61% of patients; 3/249 discontinued because of d-ATS-associated skin irritation, which generally resolved within 15-27 h after patch removal. d-ATS's benefits as an additional treatment option for ADHD in children, adolescents, and adults likely outweigh any minor irritation concerns. Transdermal delivery confers practical advantages, and the range of bioequivalent application sites can help minimize dermal irritation. d-ATS's efficacy has been established in prior clinical studies and published elsewhere. Overall, d-ATS represents a valuable, flexible treatment option for children and adolescents with ADHD.
Continuous renal replacement therapy (CRRT) in critically ill patients often requires anticoagulation to maintain circuit patency, but systemic anticoagulation may increase bleeding risk. Regional citrate anticoagulation (RCA) has been proposed as an alternative. This meta-analysis evaluated the efficacy and safety of RCA versus no anticoagulation (NA) during CRRT in critically ill patients at high risk of bleeding. PubMed, Embase, Web of Science, Cochrane Library, Wanfang, and China National Knowledge Infrastructure were searched for randomized controlled trials comparing RCA with NA during CRRT in adult critically ill patients with high bleeding risk. Mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models accounting for potential heterogeneity. Seventeen RCTs involving 893 patients were included. Compared with NA, RCA significantly prolonged filter lifespan (MD: 13.82 h; 95% CI 10.83-16.81) and reduced the incidence of circuit clotting (RR: 0.20; 95% CI 0.12-0.35). RCA was associated with higher risks of citrate accumulation (RR: 4.67; 95% CI 1.30-16.77) and hypocalcemia (RR: 1.78; 95% CI 1.12-2.83), while acid-base disturbances were not significantly different between groups (RR: 1.34; 95% CI 0.60-3.03). In addition, RCA significantly reduced major bleeding (RR: 0.37; 95% CI 0.16-0.87), but did not significantly affect the in-hospital mortality (RR: 0.82; 95% CI 0.65-1.04). RCA improves circuit patency during CRRT in critically ill patients with a high risk of bleeding, although it increases the risk of certain metabolic complications but does not affect mortality. While RCA was associated with fewer reported major bleeding events than no anticoagulation, the certainty of evidence for this outcome was low and the finding should be interpreted with caution.
Systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD) represents a heterogeneous group of pulmonary disorders with substantial effects on morbidity and mortality. The clinical course varies according to the underlying rheumatic disease, radiological phenotype, extent of lung involvement and risk of progression. Although interstitial lung disease is particularly frequent in systemic sclerosis and idiopathic inflammatory myopathies, it also significantly contributes to outcomes in rheumatoid arthritis, Sjögren's disease and mixed connective tissue disease. Early recognition is essential, as clinically silent disease may progress to irreversible fibrosis, whereas some patients may present with rapidly progressive or progressive fibrosing phenotypes requiring urgent or intensified treatment. Recent American College of Rheumatology/American College of Chest Physicians (ACR/CHEST) and European Respiratory Society/European Alliance of Associations for Rheumatology (ERS/EULAR) guidelines provide an important framework for screening, monitoring and management of SARD-ILD, but differ in several clinically relevant aspects. ACR/CHEST adopts a largely risk-based and pragmatic approach, whereas ERS/EULAR places greater emphasis on disease-specific assessment, the central role of high-resolution computed tomography in screening and structured monitoring according to progression risk. In treatment, both guidelines support immunosuppression as the main therapeutic strategy, while recognizing the growing role of antifibrotic therapy in selected patients with fibrotic or progressive disease. The available evidence remains strongest for systemic sclerosis-associated interstitial lung disease, with important uncertainties persisting across other SARD subtypes. This narrative review summarizes the epidemiology, clinical and radiological phenotypes, and pathobiological basis of SARD-ILD, and critically discusses recent guideline recommendations from a pulmonary perspective. Particular emphasis is placed on translating the differences between the current guidelines into practical multidisciplinary decisions regarding screening, longitudinal assessment, treatment selection and future research priorities.
The clinical and economic burden among patients with non-thermal full-thickness wounds (NFTW) resulting from trauma or surgery and undergoing autologous skin grafts is not well characterized. Assessing burden of care can inform treatment choice, evaluation of emerging wound therapies, and payer coverage decisions. Clarivate's Real-world Data Repository® national claims database between 01/01/2019 and 08/31/2024 was used to select patients aged ≥ 15 years with a primary NFTW diagnosis who underwent an autologous skin graft procedure (index). Separate cohorts were analyzed according to the site of care where the index procedure was performed (inpatient, outpatient hospital, office/clinic). Kaplan-Meier estimates of the 90-day post-index adverse outcome rates, select adjunct procedures, and select medication use were generated. All-cause 12-month healthcare resource utilization (HRU) and costs [in 2024 United States (US) dollars] were also estimated. Of the 26,117 patients with a NFTW, the mean age was 59.3 years and 43.3% were female. During the 12-month pre-index period 41.2% were smokers, 32.0% were obese, 31.8% had diabetes or diabetes-related comorbidities, and 21.5% were malnourished. Drug or alcohol abuse (15.6%), frailty (13.6%), and autoimmune diseases/immunodeficiency (10.4%) were also common. Traumatic wounds accounted for 56.1% and surgical wounds for 29.7% of all cases. Within 90 days, regrafting and graft failure occurred in 7.6% and 4.9% of the inpatient cohort, 3.4% and 3.1% of the outpatient hospital cohort, and 3.5% and 0.1% of the office/clinic cohort, respectively. Total mean annual costs were $266,231 (standard deviation (SD) = $458,484] per patient in the inpatient, $62,619 (SD = $132,510) in the outpatient hospital, and $14,261 (SD = $36,894) in the office/clinic cohorts with an average all-cohort cost of $128,959 (SD = $306,485). Patients receiving autologous skin grafts for NFTW are medically complex with high rates of complications and significant costs, highlighting the need for novel interventions or adjunct therapies to reduce the associated clinical and economic burden. Nonthermal full-thickness wounds are severe injuries that damage the skin and often require autologous skin grafts to heal. This study looked at over 26,000 people in the United States who received autologous skin grafts for non-thermal full-thickness wounds between 2019 and 2024. Many of these patients had other health problems including diabetes, obesity, or poor nutrition, which made their care more complicated. The study found that patients with non-thermal full-thickness wounds undergoing skin grafting need intense care and their average healthcare costs exceeded $128,000 over 12 months. This study suggests that new treatment approaches are needed to help reduce complications and costs.