搜索结果：Contemporary clinical trials

The Fragility Index (FI) quantifies how small changes in trial outcomes can alter statistical significance, providing a measure of the numerical stability of randomized controlled trial (RCT) results. Despite its growing use, fragility has not been systematically examined in the perioperative evidence supporting anesthesiology guidelines. This study evaluated the FI, Reverse Fragility Index (rFI), and Fragility Quotient (FQ) of RCTs cited in North American and European perioperative clinical practice guidelines and explored trial characteristics associated with fragility. We conducted a methodological survey of RCTs referenced in clinical practice guidelines (CPGs) published between 2012 and 2022. Eligible trials included parallel-group or factorial RCTs with binary outcomes in adult, pediatric, obstetric, cardiovascular, and regional anesthesia populations. Following stratified random sampling, primary analyses were restricted to superiority trials. FI, rFI, and FQ were calculated for the superiority cohort using the binary outcome supporting each guideline recommendation. Trial characteristics associated with FI were explored using a prespecified exploratory negative binomial regression model. Out of 1,868 identified RCTs, 639 met the eligibility criteria, and primary analyses included 161 superiority trials. The median sample size was 120 participants (IQR, 80-310), and the median FI was 4 (IQR, 2-8). Cardiovascular trials had the highest median FI (6 [IQR, 1-13]), whereas pediatric trials had the lowest (1 [IQR, 1-5]). In the exploratory multivariable analysis, obstetric trials were associated with higher FI values than adult trials (incidence rate ratio [IRR], 1.63; 95% CI, 1.02-2.65), whereas single-center trials were associated with lower FI values than multicenter trials (IRR, 0.52; 95% CI, 0.35-0.76). Randomized superiority trials underpinning contemporary perioperative guideline recommendations are generally small and demonstrate modest Fragility Index values, indicating that statistical conclusions often depend on relatively few outcome events. Fragility metrics should complement, rather than replace, established measures of trial quality and evidence certainty when interpreting perioperative evidence.

Until recently, pregnant or lactating women were systematically excluded from drug development. Currently, the ethical consensus is that women who are pregnant or lactating need to be involved in drug development. The rich experience of drug development in HIV/AIDS can be generalized. This article reviews contemporary, integrated, multidisciplinary best practice in the design and conduct of clinical trials that recruit women who are pregnant or lactating and shows how contemporary preclinical methods facilitate clinical studies while minimizing the use of nonhuman animal species. Community engagement is essential for drug development particularly with the rise of multiple sources of misinformation.

To review how response to neoadjuvant therapy (NAT) is assessed in clinical trials of muscle-invasive bladder cancer (MIBC), and to determine whether trial-derived evidence can inform response evaluation in contemporary practice. We searched PubMed, Embase and ClinicalTrials.gov through August 2025 for randomised controlled trials (RCTs) of neoadjuvant chemotherapy, chemo-immunotherapy or immunotherapy in non-metastatic MIBC (cT2-T4a N0-1 M0), and for prospective single-arm chemo-immunotherapy or immunotherapy trials. We extracted data on imaging modality and coverage, endoscopic and biomarker-based assessment, timing, correlation with final pathology and diagnostic accuracy. Given heterogeneity in definitions and reporting, no meta-analysis was performed. We identified 22 studies, including 14 RCTs. Most incorporated response evaluation, yet methods differed widely. Computed tomography (CT) was the most frequent modality in RCTs, whereas bladder magnetic resonance imaging (MRI) predominated in recent single-arm immunotherapy trials. Timing was inconsistent and usually post-treatment; only two trials performed interim assessment. Endoscopic evaluation was concentrated in bladder-preservation trials, and circulating tumour DNA (ctDNA) was used selectively. Only five studies correlated restaging with final pathology; multiparametric MRI scored with nacVI-RADS predicted pathological complete response with 72%-83% accuracy. No trial reported imaging accuracy for distant metastases after NAT. Response assessment after NAT in MIBC remains insufficiently standardised. Trial-derived evidence supports cross-sectional imaging before radical local treatment, with CT the most established modality, largely reflecting trial-design conventions and availability rather than demonstrated diagnostic superiority; bladder MRI is more accurate for local restaging. Emerging biomarkers such as ctDNA require validation. Harmonising timing, modalities and response definitions is needed to enable evidence-based treatment adaptation.

Resistant or poorly controlled hypertension is a major contributor to cardiovascular morbidity and mortality despite contemporary multidrug regimens. This study aimed to evaluate the efficacy and safety of SGLT-2 inhibitors as adjunctive agents to standard antihypertensive therapy in this high-risk population. We systematically searched PubMed, Embase, Google Scholar, the Cochrane Library, ScienceDirect, and ClinicalTrials.gov for randomized controlled trials (RCTs) assessing SGLT-2 inhibitors in adults with poorly controlled hypertension (on ≥2 antihypertensive agents) or resistant hypertension. Primary outcome was the mean change in office systolic blood pressure (SBP). Mean differences (MDs) were pooled for continuous outcomes, and risk ratios (RRs) were pooled for dichotomous outcomes using random-effects models. Four RCTs (n=3,718) were included in the meta-analysis. SGLT-2 inhibitors significantly reduced office SBP in both the short term (MD -3.29 mmHg, 95% CI -3.96 to -2.62) and long term (MD -2.96 mmHg, 95% CI -3.58 to -2.35). The overall incidence of adverse events (pooled RR: 0.99, 95% CI 0.95 to 1.02), serious adverse events (pooled RR: 0.92, 95% CI 0.84 to 1.00), AKI (pooled RR: 0.98, 95% CI 0.80 to 1.21), and UTI (pooled RR: 0.88, 95% CI 0.36 to 2.17) were comparable between groups. However, SGLT-2 inhibitors were associated with a significantly increased risk of volume depletion, hypotension, and genital infections. SGLT-2 inhibitors provide a modest incremental benefit in lowering office SBP for patients with uncontrolled or resistant hypertension on multidrug regimens with an overall acceptable safety profile. Future dedicated RCTs are warranted.

Glucagon-like peptide-1 (GLP-1)-based therapies have been observed to produce cardiovascular benefits in cardiometabolic diseases; however, their impact on heart failure-specific outcomes is only becoming known through dedicated randomized controlled trials (RCTs). This scoping review consolidates the most recent randomized data that examine how GLP-1-based therapies affect heart failure-specific symptoms, functional capacity, and the occurrence of clinical events. Literature searches were conducted in PubMed, Google Scholar, and CINAHL for RCTs and prespecified analyses between 2021 and 2026 evaluating GLP-1-based therapies and reporting heart failure-specific outcomes. Five RCT-based studies met inclusion criteria, including randomized trials and prespecified RCT-derived analyses evaluating semaglutide and tirzepatide. Among patients with heart failure with preserved ejection fraction (HFpEF) and obesity, semaglutide significantly improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance compared to placebo. Tirzepatide exhibited improvements across symptoms and functional and event-based outcomes, with prespecified trajectory analyses confirming favorable shifts in New York Heart Association functional class, Patient Global Impression of Severity, health-related quality of life, and background heart failure medication use. Among patients with type 2 diabetes mellitus and chronic kidney disease, semaglutide was associated with a significantly reduced rate of cardiovascular death or worsening heart failure events. Although the available evidence comes from a small number of recent randomized and prespecified RCT-based studies, current findings suggest that GLP-1-based therapies are associated with improvements in symptoms and functional capacity and reductions in heart failure events in certain patient populations, especially those with HFpEF and obesity. These beneficial effects support a potential role for the integration of GLP-1-based therapies in population-specific heart failure management.

To describe how optical coherence tomography (OCT) is used in retinal disease management to aid in decision-making, including whether to treat or observe, extend or shorten dosing intervals, switch therapy, and plan or assess surgical care. Pivotal randomized clinical trials and designs in neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO) were reviewed to characterize how OCT is used within evidence-based retreatment and monitoring strategies, including newer faricimab and aflibercept 8 mg trial programs. These decision strategies were translated into scenario-based clinical guidance for real-world decision-point use. Where randomized evidence is limited, particularly for selected surgical retina decision points, guidance reflects the authors' expert opinion as informed by available literature and common retina practice. OCT is used in trial protocols as an anatomic biomarker for nAMD, DME, and RVO to assess disease activity, treatment response and recurrence, and to determine individualized follow-up and retreatment intervals. OCT was often obtained at protocol visits during active therapy phases and at key reassessment points. When new symptoms, suspected recurrence, incomplete response, diagnostic uncertainty, or high-risk features are present, shorter assessment intervals may be appropriate. OCT-guided, decision-linked monitoring is supported by contemporary randomized clinical trials as integral to the management of nAMD, DME, and RVO, while recognizing that OCT frequency is generally not randomized as an isolated variable. The risk of avoidable vision loss can be reduced with scenario-based retina clinical guidance that emphasizes OCT at clinical decision points, improving patient safety and enhancing individualized care.

Atherectomy has become an established tool for lesion preparation in the endovascular treatment of peripheral artery disease (PAD), particularly for complex and heavily calcified lesions. Despite the widespread clinical use of atherectomy, the long-term benefits of this tool remain controversial, and the available evidence is heterogeneous. This review aimed to provide a clinically oriented, expert-driven narrative evaluation of peripheral atherectomy, including the historical evolution, currently available technologies, and the contemporary clinical role of the procedure, while integrating randomized and real-world evidence to support rational patient and lesion selection. A narrative literature review was conducted based on continuous expert monitoring since 2021 and targeted PubMed searches using combinations of the terms "peripheral artery disease", "atherectomy", "critical limb ischemia", and "intermittent claudication". Randomized controlled trials, meta-analyses, major registries, and high-quality observational studies were identified, selected based on clinical relevance and methodological quality, and synthesized accordingly. Randomized trials have consistently shown that atherectomy does not provide superior long-term patency or limb salvage compared with balloon angioplasty, stenting, or drug-coated balloons (DCB). However, atherectomy has demonstrated reproducible procedural advantages across multiple studies, including greater luminal gain, fewer dissections, and less need for bailout stenting. Observational and registry data further suggest potential benefits in selected scenarios, particularly for heavily calcified lesions, long-segment occlusions, in-stent restenosis (ISR), and anatomically challenging mobile segments. Current evidence does not support the routine use of atherectomy in PAD. Nevertheless, when applied selectively in appropriately chosen patients and lesions, atherectomy represents a valuable strategy for vessel preparation. The responsible use of atherectomy requires careful integration of the available evidence with operator expertise, awareness of alternative technologies, and consideration of procedural risks and reimbursement issues.

Endovascular thrombectomy transformed acute ischemic stroke care while exposing ethical tensions in emergency research. As landmark trials rapidly shifted standards, investigators faced complex questions regarding equipoise, early stopping, and respecting autonomy when patients lack capacity and time is critical. We conducted a focused literature analysis from 2003 to 2024 spanning practice-changing thrombectomy trials and contemporary ethics literature. We synthesized three domains: (1) equipoise dynamics during evidence accumulation; (2) balancing non-maleficence against the social value of continuing trials; and (3) consent models for incapacitated patients in time-sensitive settings. Initial uncertainty regarding endovascular efficacy justified early randomized controls. However, post-2015 data precipitated a rapid loss of equipoise, necessitating the early termination of trials to uphold the duty of care for control arm participants. While early stopping rules successfully minimized harm, they raised tensions regarding the precision of treatment effect estimates. Furthermore, the requirement for standard informed or surrogate consent was found to introduce selection bias against severe stroke patients lacking capacity. The literature supports shifting toward deferred or presumed consent models in these emergencies, arguing that rigid adherence to autonomy can paradoxically violate the principles of justice and beneficence by systematically excluding the most vulnerable patient populations from life-altering interventions. Ethical conduct of emergency stroke trials requires continuous reassessment of equipoise, pre-specified stopping rules that prioritize participant welfare, and consent pathways tailored to incapacity and time sensitivity. We explore principles integrating beneficence, non-maleficence, autonomy, and justice to maximize lives saved and prevent disability while preserving rights. These principles generalize to future trials as indications, technologies, and timelines evolve.

A new generation of cancer screening tests, Multi-Cancer Detection (MCD) tests, aims to advance cancer early detection. MCD tests combine blood-based assays of biological components and bioinformatics algorithms to simultaneously detect multiple types of cancer. If shown to improve health outcomes, these new technologies would be simple to implement, improving accessibility and uptake. Importantly, MCD tests offer early detection opportunities for cancers with no established screening modalities. Despite their promise, evidence supporting public health benefits of MCD tests for early detection benefits is lacking. No consensus yet exists for determining the level of screening performance or the effects on cancer outcomes needed to recommend adoption. Further, the potential harms of screening (e.g., unnecessary procedures, increased anxiety and cancer worry) are often overlooked. To address the need for objective evaluation of novel screening methods, the National Cancer Institute created the Cancer Screening Research Network (CSRN). The CSRN mission is to implement rigorous clinical trials to evaluate a broad range of technologies and approaches for cancer screening. The CSRN Vanguard Study is the first US randomized trial of MCDs. The study will develop and determine the feasibility of critical protocol components of a subsequent full-scale trial to evaluate MCD tests. The study will enroll 18,000-24,000 participants aged 45-75 years without known cancer and randomize them into one of 3 arms: two separate intervention arms each evaluating one MCD test, or a control arm. Information gained will inform full-scale trial design and implementation features. ClinicalTrials.gov Identifier: NCT06995898; https://clinicaltrials.gov/study/NCT06995898; registered May 29, 2025.

This scoping review aims to systematically map how outcomes are defined and operationalised in contemporary radiological randomised clinical trials (RCTs). The findings will inform a subsequent Delphi process to develop a core outcome set for clinical studies in radiology, including adaptive platform trials (APTs), conventional RCTs, and observational studies. The scoping review will be conducted in accordance with PRISMA-P and PRISMA-ScR guidelines and will encompass articles published from 1 January 2023 in select high-impact general medical and radiological journals, using a search strategy developed and vetted by an independent information specialist. The search strategy yielded 4,202 hits on 7 April 2026. All steps, from screening through data extraction, will be done in duplicate by two independent authors. Extracted trial data will include number of trial sites, number of participants, sub-speciality, intervention type, and interventions under study. For each outcome in each trial, we will extract the name and type of the outcome, operationalisation/definition/tool used, assessment of temporality (e.g. truncation, censoring, repeated sampling), missingness proportion, missingness handling, effect quantification, and statistical analyses of effects (e.g. unadjusted or regression-model based). Data extraction will start with a 10-trial pilot phase for maximised data quality. Data synthesis will be descriptive without risk of bias evaluation. This scoping review will map how outcomes are defined and operationalised in contemporary radiological RCTs and inform a Delphi process to identify core outcomes for APTs and RCTs, supporting the advancement of value-based radiology.

Real-world safety and outcome data from Phase 1 trial populations-including screen failures-remain limited. We conducted a retrospective audit to evaluate the predictive utility of established Phase 1 prognostic scores for screen failure and post-enrollment outcomes, and to describe safety and clinical outcomes in a contemporary cohort. A single-center retrospective audit was conducted of patients screened for Phase 1 trials between January 2020 and December 2024. Data were collected from electronic medical records, including demographics, comorbidities, enrollment outcomes, treatment regimens, toxicity, trial discontinuation, and survival. Of 165 patients screened, 34 (20.6%) did not enroll. All 131 enrolled patients commenced treatment. Median age was 61 (range: 27-83) years, with predominantly good performance status (ECOG ≤ 1 = 99.2%). Most received immunotherapy-based regimens (74.0%), with combination regimens slightly more common than monotherapy. The overall objective response rate for patients who had an assessable response was 21.1% (27/128). For the 15 patients who received an antibody drug conjugate, the objective response rate was 46.7%. Unplanned admissions within 90 days of treatment occurred in 43 patients (32.8%), though only 8.3% were treatment-related. Unplanned admissions within 30 days occurred in 26/131 patients (19.8%). Disease progression was the main reason for trial discontinuation (79.8%), with toxicity accounting for 10.0%. Subsequent therapy was received by 45%. Median overall survival was 12.6 months (95% CI 9.5, 16.7), with 13.0% of patients dying within 90 days of treatment initiation and no deaths were attributed to treatment toxicity. Age was not associated with 90-day mortality, early admissions, or screen failure. Established prognostic scores in the Phase 1 trial setting (Royal Marsden, MD Anderson-ICI, and Gustave Roussy immune score) predicted screen failure but not post-enrollment outcomes. Treatment-related toxicity and mortality were uncommon in this real-world Phase 1 cohort, and outcomes were driven by disease progression. Prognostic scores predicted screen failures but not clinical outcomes suggesting their utility lies in screening rather than stratification. These findings support the safety and feasibility of Phase 1 trials in appropriately selected patients.

Adoptive tumor-infiltrating lymphocyte (TIL) therapy is an established personalized cellular immunotherapy with demonstrated activity in selected solid tumors, particularly metastatic melanoma. However, clinical outcomes, safety, and manufacturing feasibility vary across tumor types and treatment strategies. This systematic review evaluates the efficacy, safety, and operational characteristics of TIL therapy across solid malignancies. This systematic review was conducted in accordance with PRISMA guidelines. PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and the WHO International Clinical Trials Registry Platform were searched from inception to 31 December 2025. Eligible studies included clinical trials and observational studies evaluating autologous TIL therapy in solid tumors. Due to substantial clinical and methodological heterogeneity, quantitative synthesis was restricted to clinically comparable cohorts, predominantly melanoma studies reporting objective response rates (ORR). A single-arm random-effects meta-analysis using the Freeman-Tukey transformation was performed. All other outcomes, including survival, safety, manufacturing success, and resection-to-infusion time, were synthesized narratively. Thirty-eight studies were included: 5 randomized controlled trials (RCTs), 22 prospective non-randomized studies, and 11 retrospective analyses, spanning melanoma and 8 other solid tumour types. Meta-analysis of 18 melanoma single-arm cohorts demonstrated a pooled objective response rate (ORR) of 42% (95% CI 37%-47%; I² = 33.1%; prediction interval 29%-56%) under a random-effects model. In the phase III RCT (Rohaan et al.), TIL therapy produced superior ORR (49% vs. 21%) and progression-free survival (median 7.2 vs. 3.1 months; HR 0.50, 95% CI 0.35-0.72) compared with ipilimumab. Subgroup analysis by TIL product type revealed a statistically significant difference (χ² = 7.25, p = 0.0266): tumor-reactive TIL products pre-screened ex vivo for antigen-specific reactivity showed the highest pooled ORR at 50% (95% CI 35%-64%), followed by young TIL at 43% (95% CI 29%-58%) and bulk TIL at 36% (95% CI 31%-42%); this observation is based on only 4 cohorts with a limited aggregate patient number and should be regarded as hypothesis-generating. No significant difference in ORR was observed by lymphodepletion status (p = 0.9544). Evidence in non-melanoma solid tumours was limited and heterogeneous, with generally lower response rates. Safety profiles were consistent across studies and primarily attributable to lymphodepleting chemotherapy and interleukin-2 administration, including haematologic and cytokine-related toxicities; treatment-related mortality was uncommon. Manufacturing success rates were high across contemporary cohorts, with a resection-to-infusion time typically spanning 4-6 weeks. TIL therapy demonstrates consistent and clinically meaningful antitumor activity in melanoma, while evidence in non-melanoma tumors remains limited and heterogeneous. Future studies should prioritize biomarker-driven patient selection, optimization of manufacturing and conditioning strategies, and rational combination approaches to expand its applicability. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261291389.

Racial and ethnic disparities in percutaneous coronary intervention (PCI) persist despite major advances in contemporary acute coronary syndrome (ACS) care and represent an important challenge in achieving equitable cardiovascular outcomes. In this State-of-the-Art Review, we propose a PCI care-continuum framework demonstrating how inequities emerge sequentially across multiple stages of care; including baseline cardiovascular risk, prehospital triage, invasive coronary angiography, PCI decision-making, procedural optimization, and post-procedural outcomes. Contemporary evidence from randomized trials, large PCI registries, administrative datasets, and systems-of-care analyses demonstrate that Black, Hispanic, and certain Asian populations experience higher cardiometabolic burden, delayed presentation, reduced access to invasive management, and persistent disparities in clinical outcomes compared with White populations. These inequities are further amplified by structural determinants including residential segregation, unequal distribution of PCI-capable facilities, insurance-related barriers, and variation in healthcare delivery processes. Addressing these disparities requires coordinated multi-level interventions focused on standardized prehospital pathways, equitable access to invasive care, reduction of structural barriers, and implementation of equity-focused quality metrics. Improving PCI equity will require health systems to move beyond procedural excellence alone and address disparities across the entire cardiovascular care pathway.

Emerging epidemiologic, clinical, and real-world data establish GPP as a distinct disease entity associated with high rates of hospitalization, multisystem involvement, and increased mortality. Accurate diagnosis requires recognition of characteristic cutaneous findings together with laboratory and clinical evidence of systemic involvement, and exclusion of key mimickers such as acute generalized exanthematous pustulosis, as well as recognition of patient-reported systemic symptoms such as fever, malaise, and joint pain. Advances in pathophysiologic understanding have identified dysregulated innate immune signaling centered on the interleukin-36 (IL-36) pathway as the primary driver of neutrophilic inflammation and pustule formation. Randomized clinical trials, real-world evidence, and meta-analyses consistently demonstrate that IL-36 receptor blockade achieves rapid and reliable control of acute GPP flares and provides a rational strategy for flare prevention. In contrast, off-label biologic therapies targeting IL-17, IL-23, or tumor necrosis factor-α show more variable and often delayed efficacy, particularly for acute disease control. Contemporary evidence supports a paradigm shift toward disease-specific, pathway-directed management of GPP, with IL-36 pathway inhibition positioned as the cornerstone of modern therapy. &nbsp.

Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM. Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%. Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.

To evaluate contemporary global treatment of diffuse cutaneous systemic sclerosis (dcSSc) skin by SSc specialists. An anonymous survey was distributed via the Scleroderma Clinical Trials Consortium, European Scleroderma Trials and Research Group (EUSTAR), and Collaborative National Quality and Efficacy Registry (CONQUER) distribution lists between June and September 2025. The survey comprised four sections: Demographics, Treatment of dcSSc Skin, Impact of Recent Guidelines, and Clinical Trials. Responses included 103 physicians (93 completed): 43% North America, 31% Europe, 15% South America and 12% elsewhere. The majority practice within an SSc centre (80%) and participate in clinical trials (84%). Mycophenolate mofetil (MMF) was preferred first-line treatment (71%) for dcSSc without ILD, rising to 92% for dcSSc with mild/non-progressive ILD. For active skin involvement despite MMF, trial referral was preferred as next step irrespective of ILD (59% without ILD and 58% with ILD). Treatment preferences have evolved, with 40% increasing MMF use and 47% decreasing methotrexate use, over the previous 2-3 years. Biologic use has increased, with 56% and 37% reporting increasing rituximab and tocilizumab use, respectively. For dcSSc without ILD, 85% have prescribed rituximab, and 65% have prescribed tocilizumab. Biologic availability has impacted trial enrolment (73% agreement). Treatment decision-making for dcSSc skin involvement has been materially influenced by recent BSR and/or EULAR guidelines (43% agreement). MMF is preferred first-line for dcSSc. In the absence of compelling scientific justification for combination or step-up immunomodulatory approaches, trial referral is currently the preferred next treatment option. Biologic use is increasing, which impacts trial enrolment.

Treatment for heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) has evolved significantly in recent years. This period of therapeutic progress follows a span of over two decades during which randomized controlled trials (RCTs) of neurohormonal blockade and other therapies failed to definitively demonstrate clinical benefits. As such, traditionally, management guidelines for HFmrEF and HFpEF were limited to recommendations focused on optimization of volume status with diuretics, management of comorbidities, and consideration of certain medications such as angiotensin receptor-neprilysin inhibitor (ARNi) or steroidal mineralocorticoid receptor antagonists (MRA) to subsets of patients. After definitive results from multiple RCTs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently a main pillar in treating HFmrEF and HFpEF in European and American guidelines. However, other therapies, including non-steroidal mineralocorticoid receptor antagonists (nsMRA) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), are proving to be additional effective treatments for HFmrEF and HFpEF and preventing the progression of cardiovascular-kidney-metabolic (CKM) syndrome. There is now increasing justification for combining multiple proven treatments for HFmrEF and HFpEF to maximize potential benefits. Treatment for different types of heart failure has improved significantly in recent years. For many years, there were few treatments that clearly helped people with heart failure whose heart still pumps normally or nearly normally. Care mainly focused on treating symptoms, helping the body remove excess fluid, and managing related health conditions such as high blood pressure, diabetes, and obesity. Today, research has expanded the available treatment options. One important group of medicines helps the body remove excess sugar and salt through the urine, which also reduces excess fluid and lowers the strain on the heart. Newer studies have shown that medicines that block the effects of a hormone called mineralocorticoid can improve outcomes while causing fewer side effects than older steroid-based treatments. For people who also have obesity, another newer group of medicines that acts on natural gut hormones has been shown to improve symptoms, physical activity, and quality of life. Overall, using a combination of these newer treatments may help people with heart failure whose heart still pumps normally or nearly normally feel better, improve their quality of life, and achieve better long-term health outcomes.

Hemophilia has traditionally been viewed as an X-linked disorder affecting men and boys, with women and girls labeled as "carriers", presumed to be clinically unaffected. This paradigm has contributed to under-recognition, delayed diagnosis, and undertreatment of females with hemophilia-associated genotypes despite an increasingly recognized burden of bleeding. To propose a conceptual framework for understanding and addressing persistent gaps in the diagnosis, management, and research of women and girls with hemophilia-associated genotypes. Drawing on contemporary literature, emerging evidence, and clinical experience, the authors developed a framework to identify factors contributing to inequities in hemophilia care and opportunities for improvement. The framework identifies four key domains contributing to the "XX gap" in hemophilia care: biological complexity, diagnostic challenges, therapeutic inequities, and research gaps. Biological factors, including variable X-chromosome inactivation, contribute to heterogeneous factor levels and bleeding phenotypes. Diagnostic challenges include under-recognition of bleeding symptoms, reliance on factor levels alone, and gender bias in clinical assessment. Therapeutic inequities persist despite advances in hemophilia care, with limited evidence to guide management across the lifespan. Research gaps are reinforced by underrepresentation in clinical trials, restrictive eligibility criteria, and limited real-world data. Collectively, these domains contribute to delayed diagnosis, unmet clinical needs, and inequitable access to evidence-based care. Women and girls with hemophilia-associated genotypes remain underserved within traditional care models. This framework highlights priorities for improving recognition, diagnosis, treatment, and research inclusion. Addressing these interconnected gaps is essential to advancing equitable, patient-centered, and evidence-based care for all individuals affected by hemophilia.

Cystinuria is a hereditary aminoaciduria causing recurrent cystine nephrolithiasis, impaired quality of life and potential renal function decline. Despite established treatment guidelines, real-world data reveal a persistent gap between recommended targets and clinical outcomes. Preliminary data from the EUROCYS 2024 prospective European registry (269 patients, 29 centers, 8 countries) showed that only 16.3% of patients achieved the target urinary pH range, 55.2% remained above the conventional urinary cystine threshold of 250 mg/L, and approximately 39% experienced a new stone event within the preceding 12 months, despite follow-up in specialist centers. Discontinuation rates for available thiol drugs have been reported to reach 30-50%. This narrative review, based on a structured non-systematic search of major databases and guideline repositories (2009-2026), synthesizes current evidence on cystinuria diagnosis and management and appraises emerging adjunctive interventions. Next-generation sequencing-based genetic testing and the cystine capacity assay represent key recent advances in monitoring. Thulium fiber laser lithotripsy and miniaturized percutaneous approaches offer less traumatic surgical options in this high-burden population. Oral N-acetylcysteine has mechanistic plausibility and a favorable, well-characterized safety profile in other clinical settings, making it a rational candidate for formal prospective evaluation; however, robust clinical trial evidence in cystinuria using contemporary monitoring parameters is lacking. Current standard treatment remains insufficient for a substantial proportion of patients, underscoring the need to evaluate accessible adjunctive therapies with defined mechanisms and measurable outcomes. Cystinuria is a rare inherited condition in which the kidneys cannot properly reabsorb certain amino acids, leading to the formation of kidney stones made of cystine. These stones recur frequently, often require surgery, and can cause long-term kidney damage over time. Diagnosis relies on urine and blood tests, genetic testing, and a newer urine test called the cystine capacity assay, which more accurately reflects how close a patient is to forming stones. Treatment begins with drinking large amounts of fluid, alkalinizing the urine with potassium citrate, and reducing salt and protein in the diet. When these measures are insufficient, a drug called tiopronin is added to help prevent stone formation. Despite specialist care, real-world data show that most patients still do not meet recommended treatment targets and continue to form stones. For stone removal, ureteroscopy with laser lithotripsy and percutaneous nephrolithotomy are the main surgical options; newer thulium fiber lasers show promising results for this stone type. Oral N-acetylcysteine has a plausible mechanism and known safety from other conditions, but clinical evidence in cystinuria is lacking and it cannot yet be considered a standard treatment. This review highlights a persistent gap between treatment targets and real-world outcomes, underscoring the urgent need for accessible adjunctive therapies supported by well-designed clinical trials.