CONTEXT:Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare yet severe multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Classical APS-1 arises from biallelic recessive AIRE mutations, whereas dominant negative mutations cause a milder, nonclassical phenotype with variable clinical presentation. Due to its rarity, long-term, population-based data are limited, underscoring the need for extended follow-up to guide lifelong care and research. OBJECTIVE:To characterize the clinical profiles of APS-1 and explore associations between disease manifestations, autoantibody profiles, and AIRE mutations over an extended follow-up (1996-2025). PATIENTS:All known Norwegian patients with APS-1. METHODS:We analyzed longitudinal clinical and laboratory data of 71 APS-1 patients (49 classical, 22 nonclassical) from the Norwegian Registry of Organ-specific Autoimmune Diseases. Data included clinical progression, autoantibody and cytokine profiles, and AIRE genotypes. Additionally, we compared age at diagnosis of primary adrenal insufficiency (PAI) in patients with and without (n = 999) APS-1. RESULTS:In classical APS-1, the most frequent clinical manifestations were chronic mucocutaneous candidiasis, enamel hypoplasia, and PAI, while for nonclassical APS-1 vitiligo, hypothyroidism, and PAI were most common. A broad proinflammatory cytokine signature was observed in classical APS-1, along with increased levels of the soluble form of the interferon (IFN)-α/β receptor. CONCLUSION:APS-1 should be considered in patients diagnosed with PAI before age 20, and AIRE sequencing is recommended for diagnostic confirmation. The presence of IFN-ω autoantibodies, a proinflammatory cytokine profile, and increased soluble IFN receptor levels further support the role of dysregulated interferon responses in APS-1 pathogenesis.
Background Chronic migraine is frequently refractory to available preventive therapies. Image-guided cryoneurolysis of the greater occipital nerve (CryoGON) may provide longer-lasting relief than conventional greater occipital nerve (GON) blocks. This Stage 1 Registered Report describes a prospective, exploratory study evaluating whether response to a conventional GON block predicts subsequent response to CryoGON, and assesses open-label safety, tolerability, feasibility and efficacy of CryoGON. Methods The study is planned as a single-site, investigator-initiated, open-label clinical investigation. Adults with chronic migraine will complete a ≥28-day electronic baseline diary before receiving bilateral conventional GON blocks, followed by a ≥28-day observation. Eligible participants then undergo navigation-guided CryoGON with 12-week follow-up. The primary endpoint is the association between change in moderate-to-severe headache days after GON block (weeks 1–4) and after CryoGON (weeks 9–12). Key secondary endpoints estimate the diagnostic performance of GON-block response applying a ≥30% reduction threshold for treatment effect to identify CryoGON responders, including sensitivity, specificity and predictive values. Additional endpoints include change in migraine days, patient-reported global impression of change, Migraine-Specific Quality of Life Questionnaire v2.1, procedure tolerability, technical success, and safety (treatment-emergent adverse events and adverse device effects). Women of childbearing potential, including pregnant and breastfeeding participants, are eligible for participation. Discussion This study will provide the first systematic evaluation of whether a simple, widely available GON block can guide patient selection for CryoGON and will generate foundational open-label data on its clinical performance and safety. Findings will inform the design and justification of a subsequent sham-controlled trial. Trial registration and approvals The study will preregister at ClinicalTrials.gov. and obtain all necessary ethical approvals before study initiation. Sponsor: St. Olav’s University Hospital, Trondheim, Norway. Funding: Stiftelsen Dam (grant SDAM_FOR701626).
Importance Nicotinamide riboside, a nicotinamide adenine dinucleotide precursor, has been proposed as a potential disease-modifying therapy for Parkinson disease based on preclinical and early studies. Whether prolonged oral nicotinamide riboside improves clinical outcomes in Parkinson disease is unknown. Objective To determine whether nicotinamide riboside improves clinical outcomes in Parkinson disease compared with placebo. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 11 centers in Norway. Eligible participants were patients aged 35 years or older with Parkinson disease diagnosed within 2 years before enrollment, Hoehn and Yahr disease stage less than 3, abnormal dopamine transporter scintigraphy findings confirming dopaminergic nigrostriatal denervation, and stable dopaminergic treatment before enrollment. Of 537 screened individuals, 410 were randomized from May 6, 2020, to June 20, 2024, and 393 were included in the primary analysis. Final follow-up was completed on June 19, 2025. Interventions Patients were randomized to receive oral nicotinamide riboside, 500 mg twice daily (n = 206), or matching placebo (n = 204) for 52 weeks. Main Outcomes and Measures The primary outcome was change from baseline to week 52 in the Movement Disorder Society Unified Parkinson Disease Rating Scale total score (MDS-UPDRS parts I-III; range, 0-236, with higher scores indicating more severe disease; clinically important differences for improvement and worsening, 6.7 and 5.2 points, respectively), analyzed using a mixed model for repeated measures. The 5 key secondary outcomes were the individual parts I, II, and III of the MDS-UPDRS; dopamine transporter single-photon emission computed tomography brain imaging findings; and the Non-Motor Symptoms Scale score (NMSS; range, 0-360, with higher scores indicating greater nonmotor symptom burden). Results Among the 393 participants in the primary analysis, the mean age was 65.6 (SD, 9.4) years and 133 (34%) were female. At week 52, the total MDS-UPDRS score increased by 2.45 (95% CI, 0.80-4.10) points with nicotinamide riboside and decreased by 0.27 (95% CI, −1.95 to 1.40) points with placebo, yielding an adjusted mean difference of 2.72 points (95% CI, 0.47-4.98 points; P = .02), favoring placebo. Of the 5 prespecified key secondary outcomes, 4 showed no significant difference, but nonmotor symptom burden worsened more with nicotinamide riboside (NMSS score adjusted mean difference, 4.22 [95% CI, 1.07-7.37] points; P = .009). Serious adverse events occurred in 17 (8.3%) of 205 participants receiving nicotinamide riboside and 29 (14.1%) of 205 receiving placebo in the safety population. Conclusions and Relevance Among patients with early Parkinson disease, nicotinamide riboside treatment for 52 weeks did not improve clinical outcomes and was associated with worse clinical outcomes than placebo. These findings do not support nicotinamide riboside as a disease-modifying treatment for Parkinson disease. Trial Registration ClinicalTrials.gov Identifier: NCT03568968
Background Chronic migraine is frequently refractory to available preventive therapies. Image-guided cryoneurolysis of the greater occipital nerve (CryoGON) may provide longer-lasting relief than conventional greater occipital nerve (GON) blocks. This Stage 1 Registered Report describes a prospective, exploratory study evaluating whether response to a conventional GON block predicts subsequent response to CryoGON, and assesses open-label safety, tolerability, feasibility and efficacy of CryoGON. Methods The study is planned as a single-site, investigator-initiated, open-label clinical investigation. Adults with chronic migraine will complete a ≥28-day electronic baseline diary before receiving bilateral conventional GON blocks, followed by a ≥28-day observation. Eligible participants then undergo navigation-guided CryoGON with 12-week follow-up. The primary endpoint is the association between change in moderate-to-severe headache days after GON block (weeks 1–4) and after CryoGON (weeks 9–12). Key secondary endpoints estimate the diagnostic performance of GON-block response applying a ≥30% reduction threshold for treatment effect to identify CryoGON responders, including sensitivity, specificity and predictive values. Additional endpoints include change in migraine days, patient-reported global impression of change, Migraine-Specific Quality of Life Questionnaire v2.1, procedure tolerability, technical success, and safety (treatment-emergent adverse events and adverse device effects). Women of childbearing potential, including pregnant and breastfeeding participants, are eligible for participation. Discussion This study will provide the first systematic evaluation of whether a simple, widely available GON block can guide patient selection for CryoGON and will generate foundational open-label data on its clinical performance and safety. Findings will inform the design and justification of a subsequent sham-controlled trial. Trial registration and approvals The study will preregister at ClinicalTrials.gov. and obtain all necessary ethical approvals before study initiation. Sponsor: St. Olav’s University Hospital, Trondheim, Norway. Funding: Stiftelsen Dam (grant SDAM_FOR701626).
Subsequent fracture rates and associated mortality were compared before and after the introduction of fracture liaison service (FLS). In 100,198 women and men, FLS was associated with 13
