Severe asthma affects a minority of patients with asthma; however, it substantially impacts morbidity, health-care use, and systemic corticosteroid-related harm. Despite the increasing use of biological treatments, achievement of severe asthma remission remains elusive. Notably, real-world data on the disease burden and remission potential of severe asthma in Europe remain limited. We aimed to close this knowledge gap, offering insights with global relevance. Using data from 13 455 adults with severe asthma enrolled in the European Severe Heterogeneous Asthma Registry, Patient-centred Clinical Research Collaboration (SHARP CRC), this cross-sectional observational study evaluated the burden of severe asthma and remission-related clinical domains (exacerbations, asthma control, airflow limitation, and maintenance oral corticosteroid use) across Europe and examined their relationship with disease duration, biological therapy, and type 2 biomarkers (blood eosinophils, fractional exhaled nitric oxide [FeNO], and total IgE). Patients with severe asthma had been enrolled in national registries according to local principles and guidelines and in accordance with the European Respiratory Society/American Thoracic Society guidelines; 3% (430 of 13 885) of patients were excluded due to no consent for the international study and/or missing medication data. Patients were predominantly female (59%; 7999 of 13 453), with adult-onset asthma (82%; 8751 of 10 711), and a median disease duration of 23 years (95% CI 20-26 years). 59% (4148 of 7006) of patients had FEV1/FVC of 0·7 or less, 62% (4680 of 7568) had FEV1 lower than 80% predicted, and 89% (3519 of 3968) had at least one active disease domain. Despite 79% (10 632 of 13 453) receiving biological therapy, more than 66% (2621 of 3968) still had at least two active domains. Elevation of type 2 biomarkers persisted (89% [2806 of 3153] with at least one elevated biomarker) despite widespread biological and maintenance oral corticosteroid treatment. A subset of biologic-naive patients (35%; 1069 of 3018) exhibited a rapid accumulation of disease burden within less than 10 years, suggesting a potentially accelerated progression trajectory. This pan-European analysis of severe asthma revealed significant clinical heterogeneity and a substantial disease burden despite advanced therapies, highlighting the enduring nature of type 2 inflammation, the potential inadequacy of current remission strategies with available therapeutic approaches, and the necessity for early identification of high-risk patients. SHARP Clinical Research Collaboration and consortium partners: European Respiratory Society, GlaxoSmithKline Research and Development, Chiesi Farmaceutici Società per Azioni, Novartis Pharma Aktiengesellschaft, Sanofi-Genzyme Corporation, and Teva Branded Pharmaceutical Products R&D.
Emerging research suggests those with food allergy may have a higher risk of eating and feeding disorders; however, data on the prevalence of Avoidant/Restrictive Food Intake Disorder (ARFID) among individuals with food allergy is limited. We examined whether possible ARFID in 10-year-old children was more common in children with or without food allergy. The HealthNuts study recruited 5276 one-year-olds across Melbourne, Australia who were followed-up at ages 4, 6, and 10 years. Food allergy was assessed at each age with skin prick tests, clinical history, and/or oral food challenges. The Food Allergy Quality of Life Parent Form (FAQLQ-PF) capturing food allergy anxiety was completed for those with suspected food allergy. The ARFID assessment tool 'Eating Disorders in Youth Questionnaire (EDY-Q)' was completed by children participating in their age 10 assessment after 10 April 2019. A total of 951 children completed the EDY-Q, of whom 102 had a current food allergy. The prevalence of possible ARFID was similar among children with current food allergy, 23% (95% CI 15-32) compared to without, 21% (95% CI 18-24). When considering food allergy anxiety (reported on FAQLQ-PF) as a symptom of possible ARFID (a variant not captured by EDY-Q), an additional 10 children (of 102) with food allergy may meet the criteria for possible ARFID but were missed by the EDY-Q. A similar proportion of children with and without food allergy were identified by the EDY-Q of being at risk of ARFID. The EDY-Q may lack sensitivity to detect ARFID in individuals with food allergy as it does not capture fear of allergic reactions. Newer ARFID tools incorporating fear of allergic reactions have since become available. Future research using these tools may provide more precise prevalence estimates among individuals with food allergy.
Comprehensive cost measurement is essential for an effective policy response to societal dementia costs. Using dynamic microsimulation, the Health and Retirement Study, and other national data, we quantified the 2026 cost of dementia in the United States. In 2026, 5.7 million (95% confidence interval [CI] [5.6, 6.0]) US adults aged 51 and older are living with dementia, supported by 5.2 million (95% CI [4.9, 5.5]) care partners. Total costs are $818 billion (B, 95% CI [759, 866]), driven by quality-of-life losses for persons with dementia ($320B, 95% CI [269, 363]) and care partners ($15B 95% CI [6, 25]). Unpaid care ($237B, 95% CI [220, 253]), earnings losses ($23B), and out-of-pocket costs combined with quality-of-life losses account for 80% of costs and are borne by families. Governments cover 70% of healthcare costs ($222B, 95% CI [209, 237]). The costs of dementia fall on families, highlighting limited policy and work supports. Treatment innovation may increase medical costs but reduce caregiver burden and improve quality of life. The costs of dementia in the United States in 2026 are $818 billion. Quality-of-life losses are the largest driver of dementia's total burden. Individuals and families bear over three times the cost versus health systems. Methods enable analysis of treatment, care, and policy innovations on future costs.
Foetal cholesterol is primarily carried by high-density lipoprotein (HDL) enriched with apolipoprotein E (apoE) and the foetus depends on a maternal-placental supply in early gestation until foetal de novo synthesis is established. We aimed to examine HDL cholesterol (HDL-C), apoE, and apolipoprotein AI (apoAI) concentrations in early life and the association with foetal growth and placental insufficiency. We used data from the Copenhagen Baby Heart and COMPARE study cohorts, including cord- (n = 13 353) and parallel child and maternal venous blood samples at birth (n = 444), 2- (n = 364), and 14-16 months (n = 156) after birth. HDL-C, apoAI, and apoE concentrations were higher in female vs. male newborns (P < 0.001). During the first 14-16 months of life, concentrations of HDL-C and apoAI increased (P < 0.02), apoE decreased (P < 0.001), and the HDL-C-apoAI correlation increased (Spearman's rho: 0.71, 0.87, 0.90), while the HDL-C-apoE correlation decreased (Spearman's rho: 0.58, 0.18). Small (SGA), appropriate (AGA), and large (LGA) for gestational age showed a stepwise increase in cord blood concentrations of HDL-C and apoE, but not apoA1, from SGA to LGA (P < 0.001). We found higher risk of low cord blood concentrations (<20th percentile) of HDL-C and apoE associated with placental insufficiency [odds ratio 1.39 (95% confidence interval 1.16-1.65) and 1.46 (1.22-1.75)], low pregnancy-associated plasma protein A (PAPP-A) [1.82 (1.47-2.25) and 1.50 (1.19-1.88)), preeclampsia (1.62 (1.28-2.04) and 1.39 (1.09-1.78)], hypertension (1.35 (1.05-1.73) and 1.28 (0.99-1.67)), body mass index (BMI) ≥ 25 kg/m2 [1.29 (1.17-1.43) and 1.13 (1.02-1.25)], and smoking [1.79 (1.43-2.23) and 1.38 (1.09-1.76)]. Only placental insufficiency [1.23 (1.03-1.48)], low PAPP-A [1.48 (1.18-1.85)], and smoking[(1.35 (1.06-1.72)] were associated with low cord blood apoAI. During the first 14-16 months of life, the apolipoprotein profile of HDL approaches that of adults. Offspring concentrations of HDL-C and apoE at birth were positively associated with foetal growth and placental insufficiency was associated with increased risk of low HDL-C and apoE, suggesting these traits as markers of placental function.
Disclosure of conflict of interest (COI) is important for surgical societies to minimize bias. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) requires committee members to disclose potential COI to promote full transparency. This study investigates compliance with this requirement and quantifies the actual dollar amounts that ineligible companies, collectively "industry", give to committee members. All SAGES committee members were queried in the Centers for Medicare & Medicaid Services Open Payments database (OPD). The query results for 2023 and 2024 were compared to the actual self-reported disclosure statements submitted to SAGES in the spring of 2025. Due to the nature of the database, only US-based physicians were included. Only payments of $500 or more were recorded. Only committees whose rosters were available online were utilized. Incorrect disclosure was defined as a mismatch between the OPD and the member's disclosure. There were 930 individual committee members and 185 were excluded by OPD. Only 51% (382/745) of OPD queries matched disclosures. Correct disclosure occurred in 104/467 who had disclosable COI. Industry paid over $18,000,000 to committee members; one-third came from Intuitive Surgical. Members who received payments received an average of $38,992. The largest total amount to one individual was over $2,500,000. There was no difference in average payments received or appropriate disclosure rate by committee members on one committee versus those on multiple committees. Chair/co-chairs (n = 114) did not differ from other members (n = 631) in percent of appropriate disclosures (59 vs. 50%). However, chairs/co-chairs did receive larger payments ($37,501 vs. $22,021; p < 0.0035). SAGES has set policies for disclosing COI. Enforcement of these policies is challenging. Many committee members receive large payments from industry; thus the actual dollar amount should also be reported. Full and accurate reporting will allow for full transparency and reduce perception of bias.
Propofol is widely used for deep sedation during endoscopic retrograde cholangiopancreatography (ERCP) due to its rapid onset and favorable recovery profile; however, it is associated with dose-dependent cardiopulmonary adverse effects, particularly hypoxia and hypotension. Significant heterogeneity persists in the definition, severity classification, and reporting of these adverse events, limiting comparability across studies and hindering reliable risk stratification. Therefore, the aim of this systematic review was to evaluate the incidence and clinical characteristics of propofol-associated hypoxia and hypotension in adult patients undergoing ERCP, and to assess variability in reporting practices across studies. A systematic review was conducted and reported in accordance with PRISMA guidelines. PubMed was searched for English-language studies published between 1995 and 2025 involving adult patients undergoing ERCP under propofol-based sedation. Across studies reporting extractable data, oxygen desaturation occurred in 16.9% of aggregated cases (1194/7049), whereas hypotension occurred in 13.0% (187/1440). These values represent descriptive estimates and should not be interpreted as meta-analytic pooled incidences. Both events were predominantly mild and transient, responding to standard supportive measures, whereas severe complications, including cardiopulmonary arrest, were exceptionally rare. Considerable variability in definitions, outcome reporting, and study design was observed across studies. Propofol sedation during ERCP is associated with frequent but generally manageable hypoxia and hypotension. Continuous respiratory and hemodynamic monitoring facilitates early recognition and prompt intervention. Standardization of outcome definitions and reporting, along with the development of structured risk stratification tools, may improve patient selection and enhance procedural safety.
Gonorrhea is a preventable and treatable infection caused by Neisseria gonorrhoeae , remaining a major public health concern because of antibiotic-resistant strains. A milestone was reached with zoliflodacin, the first therapeutic in its class in nearly 2 decades. Zoliflodacin is a first-in-class spiropyrimidinetrione antibacterial agent that targets type II topoisomerases DNA gyrase and topoisomerase IV enzymes essential for DNA synthesis. Its primary target is the GyrB subunit of DNA gyrase, rather than the GyrA or ParC subunits affected by fluoroquinolones. The area under the concentration-time curve/minimum inhibitory concentration is the primary pharmacokinetics and pharmacodynamics index associated with bacterial killing. Zoliflodacin binds approximately 83% to plasma proteins, undergoes extensive metabolism through cytochrome P450-mediated and non-P450-mediated pathways, has a low urinary excretion with a major fecal route elimination pathway, and an elimination half-life of around 5-6 hours. Zoliflodacin demonstrated positive results for the treatment of uncomplicated urogenital gonorrhea in phase 2 and subsequently phase 3 trials. In a phase 2, multicenter, open-label RCT, the efficacy and safety of zoliflodacin was compared with ceftriaxone. Cure rates for urogenital infections were 96% (55/57) (2 g), 96% (54/56) (3 g), and 100% (28/28) (ceftriaxone). In a phase 3, multinational, open-label, noninferiority RCT, participants were randomly assigned (2:1) to receive a single 3 g oral dose of zoliflodacin or a single dose of 500 mg intramuscular injection of ceftriaxone plus 1 g oral azithromycin. The primary end point for microbiological cure was achieved in 90.9% (460/506) of patients on zoliflodacin compared with 96.2% (229/238) of the comparator, demonstrating noninferiority and good tolerability. Oral zoliflodacin represents a novel option for the treatment of uncomplicated urogenital gonorrhea, including antibiotic-resistant strains, providing an important alternative therapy.
While the United States of America (USA) faces a substantial substance use disorder (SUD) burden on a global scale, relatively little is known about the current trends and future trajectories at both national and state levels. Using the Global Burden of Disease Study 2023, we examined estimates of prevalence and disability-adjusted life years (DALYs) for SUDs in the USA, including alcohol use disorders (AUDs) and drug use disorders (DUDs), across all 50 states and Washington, DC, from 1990 to 2023 and forecasted trends to 2050. In 2023, the USA had the highest age-standardized prevalence of SUDs across the globe. Overall, age-standardized SUD prevalence increased from 4,664.6 (95% uncertainty interval, 4,076.4-5,333.3) estimated rates per 100,000 people in 1990 to 6,430.1 (5,871.7-7,056.3) per 100,000 people in 2023, representing an increase of 37.9%. At the state level in 2023, broader geographical variations were observed in terms of estimated age-standardized DALYs for SUDs. At both the national and state levels, the age-standardized prevalence and burden of DUDs have outpaced and surpassed the increase in AUDs over time. By 2050, if existing trends continue, the age-standardized prevalence of SUDs is projected to rise to 8,956.0 (7,478.8-10,118.4) per 100,000 people, driven primarily by increasing age-standardized prevalence of DUDs, while age-standardized prevalence of AUDs is predicted to increase slightly. These findings suggest that current interventions have been insufficient to curb the SUD crisis. Without urgent, evidence-based reforms, the SUD burden will continue to increase and deepen health disparities across the USA. This work was funded by the Gates Foundation.
Risankizumab (RZB) is an anti-interleukin 23 (anti-IL-23) approved for the treatment of Crohn disease (CD). We aimed to evaluate the effectiveness and safety of RZB in the treatment of CD in real-world settings. We performed a retrospective review of a multicentre consortium of patients with CD treated with RZB. Coprimary outcomes were clinical remission at week 12, 24, and 52 (Harvey-Bradshaw Index score of ≤4), and safety. Secondary outcomes included steroid-free clinical remission, clinical response, and endoscopic remission at 52 weeks. A total of 487 patients were included. The median follow-up was 24 (interquartile range: 16-38) weeks. A total of 372 (76.4%) patients achieved clinical remission at maximal follow-up. According to the treatment line in which RZB was administered, clinical remission occurred in 115/134 (85.8%) patients on second-line therapy, 112/153 (73.2%) on third-line therapy, and 145/200 (72.5%) on fourth-line therapy, with a significant difference (P = 0.010). Adverse events occurred in 60 patients (12.6%) during follow-up; most of them were mild (50/60, 83.3%). Regarding the secondary outcomes: steroid-free clinical remission was achieved in 342 (71.8%) patients, and clinical response was observed in 443 (91.0%) patients. Six (1.2%) patients underwent surgery during follow-up. Mucosal healing was achieved in 34/67 (50.7%) patients. In this extensive, real-world study, RZB was effective and well tolerated in an advanced-therapy-exposed population of patients with CD and associated with favorable clinical and endoscopic outcomes.
Among high-bleeding risk (HBR) patients undergoing coronary stenting, abbreviated dual antiplatelet therapy (DAPT) reduces bleeding without ischemic risk trade-off; whether these benefits persist across the entire spectrum of bleeding risk has not been investigated. The aim of this study is to explore the value of the novel PRECISE-HBR score as a risk stratification tool to guide DAPT duration in patients at high bleeding risk. The XIENCE Short DAPT program combined 3 international single-arm studies of HBR patients treated with cobalt-chromium everolimus-eluting stents who discontinued DAPT at 1 month (XIENCE 28 USA/Global) or 3 months (XIENCE 90), if event free and treatment adherent. Bleeding risk was classified as nonhigh (PRECISE-HBR score ≤22), high (score 23-26), or very high (score ≥27). Clinical outcomes were assessed between 1 and 12 months using propensity score stratification. Among 3,364 patients, the PRECISE-HBR score was ≤22, 23-26, and ≥27 in 359 (10.7%), 744 (22.1%), and 2,261 (67.2%), respectively. Rates of BARC (Bleeding Academic Research Consortium) type 3-5 bleeding (0.3%, 2.5%, 5.6%) and death or myocardial infarction (2.9%, 4.6%, 9.8%) increased progressively across risk categories. One- versus 3-month DAPT was associated with a significant reduction in BARC type 3-5 bleeding in patients with a score ≥27 (HR: 0.59, 95% CI: 0.39-0.88) but not in those <27 (HR: 2.31, 95% CI: 0.89-5.99; P-interaction = 0.012). Ischemic risk was similar between 1- and 3-month DAPT, irrespective of the PRECISE-HBR score (P-interaction = 0.40). The PRECISE-HBR score identified patients at increased risk for both bleeding and ischemic events who seemed to derive greater benefit from 1-month DAPT after stent implantation.
Iron deficiency (ID) is a highly prevalent and clinically significant comorbidity in heart failure with preserved ejection fraction (HFpEF), affecting 40-60% of patients. Independent of anemia, ID is associated with reduced exercise capacity, diminished quality of life (QoL), and increased healthcare utilization. Although intravenous (IV) iron therapy has demonstrated consistent benefits in HF with reduced ejection fraction (HFrEF), including improvements in symptoms, QoL, functional status, and reductions in hospitalizations, its role in HFpEF remains incompletely defined. This review synthesizes the epidemiology, pathophysiologic mechanisms, and diagnostic challenges of ID in HFpEF, with particular attention to emerging data for IV iron supplementation in this clinical setting. It summarizes recent and ongoing clinical trials, highlights limitations of current diagnostic criteria, and outlines innovative strategies, including pragmatic trial designs, patient-reported outcomes, and wearable technologies, to evaluate therapeutic response in this heterogeneous population. Together, these insights provide a roadmap for improving the diagnosis and management of ID in HFpEF and addressing a significant unmet clinical need in this growing patient population.
Cardiovascular disease remains the leading cause of global mortality (19.8 million deaths in 2022; 32% of all deaths worldwide). Drug repurposing-extending approved agents beyond their original indications-has emerged as a high-impact strategy in cardiovascular prevention, offering reduced development timelines, established safety profiles, and faster implementation than de novo molecular development. Which repurposed cardiovascular agents demonstrate the most favorable pharmacoeconomic profiles, and how does the convergence of clinical benefit, patient risk stratification, and economic sustainability define the optimal hierarchy for cardiovascular prevention? Narrative review synthesizing evidence from 19 pivotal cardiovascular outcomes trials and European and American guidelines. No formal meta-analysis was applied. For 13 agents across 8 therapeutic classes, efficacy was quantified as relative and absolute risk reductions, and as the number needed to treat or to harm. Pharmacoeconomic value was assessed via incremental cost-effectiveness ratio in US dollars per quality-adjusted life year, integrating mortality in years of life lost and morbidity in years lived with disability. Primary outcomes included all-cause mortality, cardiovascular mortality, major adverse cardiovascular events, and heart failure hospitalizations. Three Incremental Cost-Effectiveness Ratio (ICER) tiers were identified: Low-cost (< $20,000/ Quality-Adjusted Life Year (QALY)): ramipril (Number Needed to Treat (NNT) 28), carvedilol (NNT 29), metformin ( NNT 9-15, highest Relative Risk Reduction (RRR) 38-42%), and generic statins - robust mortality benefits at negligible cost; Moderate-cost ($3,000-$50,000/QALY): empagliflozin (↓38% cardiovascular mortality, NNT 61), dapagliflozin (NNT 20 in Heart Failure with Reduced Ejection Fraction), liraglutide (NNT 51), semaglutide (NNT 43), colchicine (NNT 36, morbidity benefit only), and branded statins; High-cost ($80,000-$300,000/QALY): Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors (evolocumab NNT 63; alirocumab NNT 64) - proven benefit compromised by unaffordable biologic pricing. Pharmacoeconomic stratification of repurposed cardiovascular agents identifies 3 distinct tiers. Generic agents-ramipril, carvedilol, metformin, and statins-demonstrate the most favorable cost-effectiveness profiles and should form the basis of any prevention protocol. SGLT2 inhibitors and GLP-1 receptor agonists offer clinically meaningful benefits in secondary prevention when applied to populations meeting pivotal trial eligibility criteria. PCSK9 inhibitors remain cost-effective only in patients with very high cardiovascular risk and inadequate LDL control on maximally tolerated statin therapy.
Immune checkpoint inhibitors (ICIs) have transformed the management of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), yet most patients eventually develop resistance. Investigational immunotherapy strategies beyond checkpoint blockade are being explored, but their clinical activity and associated biomarkers remain poorly defined. To evaluate the safety, antitumor activity, and biomarkers associated with novel immunotherapy agents in patients with recurrent or metastatic HNSCC treated in early-phase clinical trials. This retrospective cohort study was conducted at The University of Texas MD Anderson Cancer Center Department of Investigational Cancer Therapeutics and included adult patients (aged ≥18 years) with advanced HNSCC treated with novel immunotherapy agents in early-phase clinical trials between January 1, 2015, and May 31, 2025. Patients were followed up from treatment initiation until disease progression, death, or last clinical contact. Treatment with investigational immunotherapy agents administered in early-phase clinical trials. The primary outcomes included treatment-related adverse events, objective response rate (complete or partial response), clinical benefit rate (complete or partial response or stable disease lasting ≥6 months), progression-free survival, and overall survival. Logistic regression was used to evaluate biomarkers associated with the clinical benefit rate, including clinical, genomic, and treatment-related variables, while survival outcomes were estimated using the Kaplan-Meier method. The sample included 158 patients (median [range] age, 60.7 [25.7-84.6] years; 136 male [86.1%]). The oropharynx was the most common primary site (94 patients [59.6%]). Patients had received a median of 3 prior lines (range, 0-8 prior lines) of systemic therapies, and 126 patients (79.7%) had prior ICI exposure. A total of 91 of 153 patients (59.5%) had human papillomavirus-positive tumors, and PD-L1 combined positive score of at least 1 was observed in 67 of 87 patients (77.0%). Most patients received combination immunotherapy (106 [67.1%]), with a median treatment duration of 2.3 months (range, 0.1-19.7 months). Treatment-related adverse effects occurred in 85 patients (53.8%), including grade 3 or higher events in 23 patients (14.6%). The overall response rate was 7.7% (12 patients), and the clinical benefit rate was 16.1% (25 patients). Bispecific antibodies were associated with improved clinical benefit (odds ratio, 1.95; 95% CI, 1.23-4.15), whereas PIK3CA alterations were associated with reduced benefit (odds ratio, 0.03; 95% CI, 0.00-0.51). Median progression-free survival was 2.3 months (95% CI, 2.0-2.9 months) and median overall survival was 8.3 months (95% CI, 7.2-11.0 months). This retrospective cohort study of heavily pretreated patients with HNSCC treated in early-phase clinical trials found that novel immunotherapy agents may have manageable toxic effects but modest antitumor activity. Bispecific antibodies may have encouraging activity while genomic alterations may help inform treatment stratification.
The thalassaemia syndromes, which primarily include α-thalassaemia and β-thalassaemia, are a complex group of inherited disorders affecting haemoglobin production. They are prevalent throughout the most populated parts of the world and span a wide range of severity from mild to fatal. Advances in the management of these syndromes, including blood transfusion and iron chelation, have led to substantial improvements in the life expectancy and quality of life of many patients worldwide. Nevertheless, major forms of thalassaemia are still associated with chronic comorbidities and remain an important but neglected global health burden. Prevention and advances in the treatment and management of the thalassaemia syndromes rely on the early identification of people affected, either through prenatal or premarital screening or through newborn screening or testing at later stages in life. This depends on the availability of expertise, facilities and treatment options for patients. Fast and groundbreaking developments in disease-modifying and curative gene editing therapies are promising, but not without challenges in terms of costs, accessibility and uncertainties around their long-term benefits and safety. Better awareness, patient-centred approaches and coordinated strategies are needed to reduce current inequalities.
The phase 4 RESOLUTION trial showed that the first 12 weeks of treatment with eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody, reduced migraine frequency, severity, and disease burden, and improved quality of life (QOL) versus placebo in participants with chronic migraine (CM) and medication-overuse headache (MOH) who also received patient education. Here, we present 24-week eptinezumab efficacy and safety in the RESOLUTION trial. RESOLUTION was a randomized, parallel-group, multinational clinical trial that included a 12-week double-blind, placebo-controlled period and a 12-week open-label extension period (OLE). Adults (18-75 years) with CM and MOH (excluding opioid-overuse headache) received a brief educational intervention about MOH at baseline and were randomized (1:1) to IV eptinezumab 100 mg or placebo. At Week 12, all participants received eptinezumab 100 mg. Measures used for primary and key secondary efficacy endpoints were also captured during the OLE: mean changes from baseline in monthly migraine days (primary endpoint: Weeks 1-4), monthly headache days, monthly days with acute medication use, average daily pain, and participants no longer meeting threshold criteria for CM nor MOH. Secondary endpoints (including patient-reported-outcomes [PROs] assessing disease-related burden and health-related QOL) and treatment-emergent adverse events (TEAEs) were also captured during the OLE. Of 608 participants randomized, 593 (97.5%) were treated with eptinezumab in the OLE, and 584/608 (96.1%) completed the trial. Reductions in migraine frequency and active CM/MOH diagnosis, and improvements across multiple PROs observed in post hoc analyses during the placebo-controlled period were sustained during the OLE for participants initially treated with eptinezumab, with similar levels of improvement gained for those initially receiving placebo. The proportion of participants with TEAEs in the OLE was similar between eptinezumab-eptinezumab and placebo-eptinezumab treatment sequence groups (30% vs 34%); no new safety signals were identified. In participants with CM and MOH who received patient education, reductions in disease burden and improvements in QOL during the first 12 weeks with eptinezumab treatment were sustained for up to 24 weeks following a second eptinezumab infusion, with similar improvements observed in participants switched from placebo to eptinezumab. Eptinezumab was generally well tolerated, with no new safety signals. ClinicalTrials.gov Identifier: NCT05452239 (https://clinicaltrials.gov/study/NCT05452239); EudraCT Number: 2021-003049-40 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-003049-40).
Reirradiation can be considered for some patients with recurrent or second primary head and neck squamous cell carcinoma arising within previously irradiated regions, a clinical scenario associated with few therapeutic options. The increasing use of modern conformal radiotherapy techniques, including intensity-modulated radiotherapy, proton therapy, and stereotactic body radiotherapy, has expanded the feasibility of reirradiation in clinical practice. However, evidence remains heterogeneous, and clinical choices are challenged by substantial variability in patient presentation, previous treatments, and toxicity risk. This international expert consensus statement aims to provide pragmatic guidance across key domains, including patient selection, imaging, target delineation, treatment planning, dose accumulation, and toxicity management. Developed through a structured expert consensus process with formal agreement assessment, this document reflects current expert practice. By offering a shared clinical framework, this consensus seeks to promote more consistent practice, facilitate communication across centres, and support future research efforts in this complex and evolving field.
Atrial myopathy is a heterogeneous condition associated with atrial fibrillation (AF). This study aimed to identify atrial myopathy subtypes using unsupervised machine learning and assess their association with incident AF. We analyzed 1414 ARIC participants with atrial myopathy, defined by left atrial reservoir strain, and no prevalent AF. Using LASSO for selection among 52 clinical, demographic, ECG, and echocardiographic candidate variables we identified clusters via mClust. A multivariate Cox regression model was used to evaluate the association between clusters and incident AF. In total, 1414 participants with atrial myopathy were included in the clustering analysis. Three clusters were identified in the clustering analysis based on 26 selected variables. Over a mean follow-up of 6.3 years, 712 incident AF cases occurred. Compared to participants without atrial myopathy (n = 3790), Clusters 1, 2, and 3 showed significantly higher AF risk, with hazard ratios of 2.26, 3.22, and 4.71, respectively. Integrating these clusters into the CHARGE-AF model improved the C-statistic from 0.68 to 0.72. Clusters identified three unique atrial myopathy phenotypes with differential AF risks. These clusters elucidate the heterogeneity of atrial myopathy and enhance AF risk prediction beyond traditional clinical variables.
This analysis describes disease activity, organ damage and health-related quality of life (HRQoL) in patients with active SLE and moderate-to-severe disease activity from the Spanish SLE Prospective Observational Cohort Study (SPOCS) cohort. SPOCS (NCT03189875) is a multicentre, prospective, observational cohort that followed-up adults with SLE every 6 months for up to 3 years. Disease activity was assessed using SLE Disease Activity Index 2000 (SLEDAI-2K) and Physician Global Assessment. Remission and Lupus Low Disease Activity State (LLDAS) definitions were therapeutic objectives; organ damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI); HRQoL by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Patient Health Questionnaire-8 (PHQ-8) and EuroQol 5-Dimension 5-Level (EQ-5D-5L). Patients were recruited from 18 Spanish sites (2017-2019). 99 patients were enrolled. At baseline, median (IQR) SLEDAI-2K was 8 (7-12); 45% of patients had organ damage (mean (SD) SDI 1.1 (1.6)). Remission was achieved by 13% at 6 months and at 24 months; sustained remission occurred in 9%. 24% achieved LLDAS at 6 months and ≤22% thereafter; 8% maintained LLDAS for ≥70% of follow-up. Median SLEDAI-2K declined to 4 at 6 months. New or worsening organ damage occurred in 11%, 8% and 12% of patients at 12, 24 and 36 months, respectively; mean SDI (SD) increased to 1.8 (2.0) by 36 months. Musculoskeletal, cutaneous, neuropsychiatric and renal systems were most frequently involved. HRQoL remained poor: 60%-75% had depressive symptoms (PHQ-8 ≥5), 35%-50% moderate-to-severe depression (PHQ-8 ≥10), mean FACIT-F ≈30 (indicating persistent severe fatigue) and mean EQ-5D-5L index 0.70-0.75. Pain/discomfort affected up to 76% and anxiety/depression up to 66% of participants. In Spanish clinical practice, sustained remission and low disease activity state remain uncommon in moderate-to-severe SLE. Nearly half had organ damage at baseline, with continued accrual and impaired HRQoL. These findings highlight ongoing challenges in achieving lasting disease control and underscore the need for broader adoption of treat-to-target approaches to improve outcomes and prevent irreversible organ damage in this patient population. NCT03189875.
Neurological soft signs (NSS) are frequent in schizophrenia spectrum disorders (SSD) and have been linked to structural alterations in basal ganglia-thalamic (BGT) regions. We hypothesized that SSD patients would show BGT volume differences compared to healthy controls (HC) and that NSS severity would relate to BGT volume and surface morphology in a replicable pattern. Structural 3T T1-weighted MRI scans were obtained from 327 SSD patients and 134 matched HC in Mannheim (Germany) and Bern (Switzerland). NSS were assessed using the Heidelberg Scale and the Neurological Evaluation Scale (NES). BGT volumes were segmented using FSL-FIRST and compared across groups using general linear models adjusted for age, sex, intracranial volume, and daily antipsychotic medication. Associations with NSS scores were tested using regression analyses. High-NSS compared to low-NSS SSD patients showed reduced left accumbens volume in both cohorts, with a significant main effect in the Mannheim cohort (β = -43.73, p = .002 uncorrected, p = .019 corrected) and a partial replication in the Bern cohort (β = -53.06, uncorrected p = .03, p > .05, corrected). In contrast, IF-related effects on left accumbens and bilateral thalamic volumes were cohort specific. Daily antipsychotic medication and illness duration did not mediate or moderate these associations. This bicentric MRI study provides converging evidence that NSS severity in SSD is associated with BGT alterations, particularly reduced left nucleus accumbens volume. However, thalamic and surface-level findings were cohort specific, indicating partial rather than uniform reproducibility. Associations were not explained by daily dosage of antipsychotic medication or illness duration.
Aortic enlargement is a powerful predictor of dissection and rupture, yet it is rarely evaluated during routine myocardial perfusion imaging, despite the widespread availability of computed tomography (CT) attenuation correction scans. The aim of this study was to determine whether fully automated, opportunistically derived, artificial intelligence-based aortic measurements from myocardial perfusion imaging CT attenuation correction scans are associated with adverse outcomes in a large multicenter cohort. CT attenuation correction scans from patients undergoing positron emission tomography/CT and single-photon emission CT/CT myocardial perfusion imaging across 10 centers were included. A deep learning model automatically segmented the thoracic aorta, and a postprocessing algorithm extracted maximum ascending and descending diameters. The aortic size index was calculated by indexing the diameter to body surface area. A total of 29 339 patients (56% men; median age, 66 years [interquartile range, 58-75 years]) were included. Over a median follow-up of 3.5 years (interquartile range, 1.9-5.0 years), 5083 (17.3%) patients died. Median ascending and descending aortic size index values were 1.8 cm/m2 (interquartile range, 1.6-2.0) and 1.5 cm/m2 (interquartile range, 1.4-1.6), respectively, with an increase with age and higher values in females. Elevated aortic size index thresholds (ascending >2.2 cm/m2; descending >1.6 cm/m2) were significantly associated with increased all-cause mortality (ascending: adjusted hazard ratio, 1.16 [95% CI, 1.07-1.26], P<0.001; descending: adjusted hazard ratio, 1.23 [95% CI, 1.14-1.31]; P<0.001). Notably, the prognostic value of an abnormal aortic size index persisted independent of age, sex, and perfusion abnormalities. Artificial intelligence can unlock previously unused information within routine myocardial perfusion imaging CT attenuation correction scans by rapidly and automatically quantifying aortic size at scale. Opportunistic aortic measurements derived from CT attenuation correction may serve as an adjunctive risk biomarker and could add prognostic value to standard myocardial perfusion imaging without additional imaging or radiation.