Citations

Background and Objectives The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs). Methods Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy. Results One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction. Discussion This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

ABSTRACTThere is a need for objective, continuous and remote assessment of exercise capacity in patients with pulmonary arterial hypertension (PAH). Using data from the TRACE study, in which 108 adult patients with PAH were continuously monitored with a wrist‐worn accelerometer, we evaluated whether actigraphy can facilitate continuous monitoring of exercise capacity. Distributions of step rate, distance and duration of patient's walking bouts were estimated at baseline, Week 16 and Week 24 using 2‐week periods of actigraphy data. Twenty‐one metrics per walking bout characteristic were described (mean, standard deviation, 19 percentiles [5th–95th]). The relationships between these metrics and the 6‐min walk distance (6MWD), Borg dyspnea index (BDI), and the PAH Symptoms and Impact questionnaire (PAH‐SYMPACT) Physical Impact domain score were assessed at the three timepoints. Test‐retest reliability, and discriminant and known‐group validity of each metric were also evaluated. All metrics of step rate and bout distance were significantly correlated with 6MWD (Pearson's correlation coefficients: 0.34–0.67; p < 0.005) and the PAH‐SYMPACT Physical Impact domain score (Pearson's correlation coefficients: −0.51 to −0.32; p < 0.05) at all timepoints. Negative correlations were also observed with the BDI and the actigraphy‐derived metrics, with the majority reaching significance. Strong test‐retest reliability was demonstrated (intra‐class correlation coefficient ≥ 0.70). The metrics differentiated well between patients with varying disease severity levels. In conclusion, actigraphy‐derived metrics of patients' walking bouts correlate significantly with 6MWD, BDI and physical impacts of PAH, indicating the utility of actigraphy in facilitating continuous monitoring of exercise capacity in adult patients with PAH.Trial RegistrationClinicalTrials.gov: NCT03078907; URL: clinicaltrials.gov.

Patient complaints are valuable sources of information for quality improvement and provide an avenue for patient self-advocacy. This paper outlines the development and implementation of a novel training program, termed CODE (Compassion, Operational Support, De-escalation, Empowerment), for patient experience complaint management staff. The program consists of 2 core tracks: procedural training on operational systems and resources, and interpersonal communication training. A dual-track framework ensures practical knowledge to access resources to assist complainants is paired with communication for empathy and human connection. The CODE program's dual-track structure is a key strength, bridging the gap between operational efficiency and compassionate communication. By emphasizing both procedural knowledge and interpersonal skills, it equips healthcare professionals to manage patient complaints successfully. The CODE program represents a novel approach for healthcare institutions seeking to optimize patient experience and complaint-handling performance.

ABSTRACT Erectile dysfunction (ED) is a prevalent condition severely impacting men's quality of life. While micronutrient balance is critical for sexual health, observational studies on micronutrient and ED remain inconclusive. The objective of this study was to evaluate the causal role of circulating levels of copper and other micronutrients in ED risk by Mendelian randomization (MR). We conducted bidirectional two‐sample MR using summary statistics from European‐ancestry cohorts involving thirteen micronutrients. Inverse‐variance weighted (IVW) MR was complemented by sensitivity analyses, including MR‐Egger and MR‐PRESSO, and pooled analysis of two GWAS‐based datasets was performed to substantiate the findings of MR. In this study, circulating copper levels significantly increased ED risk in the discovery (OR = 1.129, 95% CI: 1.004–1.27, p = 0.042) and replication (OR = 1.115, 95% CI: 1.001–1.242, p = 0.0476) stages, as well as pooled analyses (OR = 1.122, 95% CI: 1.036–1.214, p = 0.0046). Sensitivity analyses reinforced the robustness of these findings, with no significant heterogeneity or directional pleiotropy observed. Reverse MR found no causal effect of ED on micronutrients. In summary, this study provides robust genetic evidence that elevated circulating copper levels are a modifiable risk factor for ED. Personalized management of copper intake, guided by genetic predisposition, may mitigate ED risk and improve sexual health outcomes. These findings highlight the clinical relevance of copper homeostasis in ED prevention and underscore the need for targeted nutritional interventions.

Background Adult asthma is a prevalent chronic condition that is suboptimally managed in primary care settings. Local problem Uncontrolled asthma rates were noted in our local clinic where adult patients with asthma receive care. Methods We used a structured intervention to improve adult asthma management, with the primary objective of increasing the percentage of patients at our clinic with an updated Asthma Action Plan (AAP) during a 1-year period. Data were collected through electronic health record audits and patient surveys and were analysed by using run charts. This quality improvement initiative was based on the chronic care model, which emphasises self-management support, clinical decision support and clinic systemic changes. Intervention An approach involving a multidisciplinary team (ie, clinicians, nurses, panel managers and front desk personnel) was used to increase the percentage of adult patients (18–50 years old) at our clinic with an updated AAP (ie, reviewed within the past 12 months). The 1-year intervention period was from February 2023 through January 2024. The nursing team reviewed patients’ problem lists to ensure updated information. In addition, the Asthma Management Questionnaire and Asthma Control Test were pushed through the patient portal for previsit completion or were administered during the rooming process by nursing staff. During the visit, clinicians followed up with patients to complete an AAP. Results Adherence to asthma management guidelines was improved during the intervention period. The percentage of patients with updated AAPs increased from 7.5% (n=120) in February 2023 to 43.4% (n=152) in January 2024. The percentage of patients with optimal asthma control also increased from 40.0% (n=120) in February 2023 to 55.2% (n=165) in August 2023 and 66.4% (n=152) in January 2024. Conclusions This quality improvement project led to measurable improvements in asthma care, highlighting the effectiveness of a structured intervention in the primary care setting.

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of Lewy bodies, leading to motor and nonmotor symptoms. While both genetic and environmental factors contribute to PD, recent studies highlight the crucial role of lipid metabolism disturbances in disease progression. Altered lipid homeostasis promotes protein aggregation and oxidative stress, with significant changes in lipid classes such as sphingolipids and glycerolipids observed in patients with PD. These disturbances are involved in key pathological processes, such as α-synuclein aggregation, organelle dysfunction, lipid-mediated neuroinflammation, and impaired lipid homeostasis. This review examines the relationship between lipid species and PD progression, focusing on the physiological roles of lipids in the central nervous system. It explores the mechanistic links between lipid metabolism and PD pathology, along with lipid-related genetic risk factors. Furthermore, this review discusses lipid-targeting therapeutic strategies to mitigate PD progression, emphasizing the potential of lipid modulation for effective treatment development.

BACKGROUND Cerebral arteriovenous malformations (AVMs) are complex vascular anomalies associated with significant risks of hemorrhage and neurological deficits. Stereotactic radiosurgery (SRS) has emerged as a viable treatment option, particularly for small, deep-seated, or eloquent lesions, offering a less invasive alternative to microsurgical resection. However, SRS carries risks, including radiation-induced complications such as radiation necrosis. OBSERVATIONS This report describes the case of a 24-year-old male with a left temporal AVM, classified as Spetzler-Martin grade II, who underwent SRS with a marginal dose of 18 Gy. Over a 36-month follow-up period, complete obliteration of the AVM nidus was achieved. However, significant radiation-induced complications emerged, including vasogenic edema, radiation necrosis, memory deficits, partial seizures, and bilateral visual field defects. These complications peaked around 20 months post-SRS, requiring long-term management with corticosteroids, diuretics, and anticonvulsants. LESSONS This case underscores the importance of balancing the benefits of AVM obliteration with the risks of radiation-induced injury. While SRS is effective for treating AVMs, particularly in high-risk locations, the potential for delayed complications highlights the need for careful patient selection, meticulous treatment planning, and long-term follow-up. The report also discusses the pathophysiology of radiation-induced necrosis, strategies to mitigate its risk, and the role of advanced imaging techniques in optimizing treatment planning. https://thejns.org/doi/10.3171/CASE25201

AbstractBackgroundImmune thrombotic thrombocytopenic purpura (iTTP) is a hematologic disorder characterized by severe acquired deficiency in ADAMTS13, resulting in thrombotic microangiopathy and death if untreated. Plasma exchange (PLEX) is the backbone of iTTP management and has improved survival in this disorder. Guidelines suggest initiation of PLEX within 4–8 h of presentation; however, there is little evidence to guide the precise timing of PLEX, and barriers exist to its timely deployment.Study design and methodsWe examined determinants of time between symptom onset to PLEX initiation (S2P) and hospital presentation to PLEX initiation (door to PLEX, D2P) in a large iTTP research cohort at an academic medical center.ResultsIn 225 cases occurring in 143 unique patients, the median (IQR) S2P time was 4.28 (1.92–7.47) days. In linear mixed effects regression analysis, increased S2P was associated with greater distance from a participating apheresis center (p = .01) and higher presenting platelet count (p = .046), while relapse presentation was associated with shorter S2P (p = .036). The median (IQR) D2P time was 8.4 (5.03–15.63) h. Longer D2P time was associated with a higher presenting platelet count (p = .002) and trended towards association with male sex (p = .057). Increased S2P and D2P times were not associated with hospital length of stay, mortality, or the composite of mortality and ICU stay.ConclusionOur data show that different factors contribute to the interval between symptom onset and presentation versus the time between presentation and initiation of therapy in iTTP.