Citations

Abstract Graves’ disease (GD) is an autoimmune entity that had an unchanged treatment paradigm for more than half a century with radioactive iodine, antithyroid drugs (ATDs), and surgery representing the mainstay of therapy, with variation in their use over time and geographic location. Hypothyroidism has been an accepted tradeoff in many cases, though recently there are increased concerns about altered quality of life in these patients. Fortunately, the last decade has seen an intense pursuit of GD's immunological mechanisms and a recalibration of classic treatment modalities focusing on thyroid preservation, as reflected in the preference for ATD as primary therapy, including its use in long-term protocols. The immune targets currently explored aim to address this gap by intervening in the TRAb lifecycle: minimizing production (eg, B-cell targeting), enhancing clearance (eg, neonatal Fc receptor inhibitors), or neutralizing its target—the TSH receptor (eg, receptor blockade). While these approaches are going through the necessary clinical trials evaluation, we are starting to see the potential for technology and artificial intelligence to make an impact on how we identify, treat, and monitor patients with GD. The combination of these approaches will likely lead to a significant individualization of GD management that will take us from the goal of normalization of thyroid levels to that of inducing long-term remission and prevention of the associated autoimmune phenomena that GD is associated with. While time is needed for these aspects to mature, the future looks bright for our GD patients and maybe soon these lessons will open new doors for our patients with Hashimoto's thyroiditis as well.

Purpose of review Indoor water parks, with over 1100 facilities in the United States, are popular recreational venues with an estimated 1.5 million visitors per year in North America. While generally well tolerated, they can be associated with significant respiratory and nonrespiratory health risks. This review focuses exclusively on the infectious and noninfectious respiratory health issues associated with indoor water park usage and is timely due to increasing popularity, evolving water-treatment practices, and the unique vulnerability of specific populations. Recent findings This review synthesizes peer-reviewed studies and institutional data from 2014 to 2024, detailing exposure mechanisms, health effects, mitigation strategies, and impacts on vulnerable populations such as children, asthmatic individuals, cystic fibrosis patients, immunocompromised individuals, and workers. Topics covered include disinfection by-products (DBPs), chloramine inhalation effects, asthma risks, hypersensitivity pneumonitis from nontuberculous mycobacteria, and occupational exposures. Emerging technologies in air and water quality management, alongside recent policy and facility-design developments, are also examined. Summary While indoor water parks remain a valued recreational resource, they pose significant and often under-recognized respiratory risks. Through better facility ventilation, hygiene education, disinfection innovation, and regulatory reform, these risks can be mitigated to protect both patrons and staff, particularly in vulnerable subpopulations.

Background: Arthroscopic treatment of excessive acetabular coverage with pincer morphology or coxa profunda can be challenging. In patients with excessive acetabular coverage with nondistractible hips, an outside-in capsuolotomy can be considered to gain safe and efficient intra-articular access to the hip. Indications: The indications for an outside-in capsulotomy include patients with acetabular retroversion, a lateral center-edge angle >40°, coxa profunda or protrusio, or stiff, older male patients who remain hip preservation candidates. Technique Description: The outside-in capsulotomy is performed once it is recognized that traction on the operative extremity will not provide adequate working space for safe intra-articular access. Traction is taken off the operative extremity, and an anterolateral portal is localized to the 12:00 position on the hip joint with the use of fluoroscopy. The camera is then placed in a juxta-capsular location, and a modified anterior portal is created under direct arthroscopic visualization. We then proceed with extracapsular dissection to identify the indirect head of the rectus. An outside-in capsulotomy is then performed parallel to the indirect head of the rectus, approximately 5 mm distal to its insertion on the acetabular rim. Prior to deep completion of the capsulotomy, the hip joint is flexed to 30° to protect the articular cartilage of the femoral head. Once intra-articular access is obtained, traction can be reapplied, and one can proceed with hip arthroscopy in a standard fashion. Results: This technique decreases the traction time needed, given that the capsulotomy is performed without traction applied. Additionally, the amount of force required for hip distraction is decreased once the capsuolotomy has been completed, through usual sectioning of the iliofemoral ligament. The presented technique is both safe and efficacious, with no published difference in complications as compared to standard inside-out access. A published series of patients with severe pincer morphology and lateral overcoverage who undergo hip arthroscopy with outside-in access demonstrates satisfactory postoperative improvements in patient-reported outcome measures. Discussion/Conclusion: The outside-in capsulotomy provides a means for safe access to the hip joint in otherwise limited or nondistractible hips.

Abstract Background Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer’s disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood–brain barrier—a major site of insulin receptor signaling and transport into the brain—remains unclear. Methods We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models. Results Aβ40 reduced insulin-stimulated Akt activation and converted insulin’s normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Conclusions These findings suggest that Aβ40 acutely impairs insulin signal transduction in BBB endothelial cells, supporting a model in which vascular Aβ exposure contributes directly to the early development of brain insulin resistance in AD.

Background: The effect of intrauterine exposure to SARS-CoV-2 infection during pregnancy on neurodevelopment and growth trajectories during the first year of life remains under investigation. Methods: We retrospectively reviewed the electronic medical records of all pregnant women who received care at Mayo Health System and tested positive for SARS-CoV-2 (RT-PCR) from March 2020 through October 2021 and examined the effects of fetal sex and trimester of maternal SARS-CoV-2 infection on the risk of neurodevelopmental disorder diagnosis and growth trajectories of head circumference (HC) and body weight (BW) percentiles over the first year of life using linear mixed models. Results: We observed that a higher percentage of male infants (n = 357), compared to females (n = 344), have neurodevelopmental disorders (10.9% vs. 5.2%, p = 0.008), and infants exposed to maternal SARS-CoV-2 infection in the second (n = 183) or third trimester (n = 358) have a higher prevalence of neurological diagnoses compared to those exposed in the first trimester (n = 160) (1st vs. 2nd vs. 3rd trimester: 0% vs. 0.9% vs. 0.7%, respectively, p = 0.037). In addition, female infants, compared to males, had significantly lower BW (B = −0.04, p < 0.0001) and HC (B = −0.06, p < 0.0001) percentile growth trajectories over the first year of life. Moreover, infants exposed to maternal SARS-CoV-2 infection in the second trimester had a significantly lower BW percentile growth trajectory (B = −0.01, p = 0.006), while infants exposed to maternal SARS-CoV-2 infection in the third trimester had a significantly lower HC percentile growth trajectory (B = −0.02, p = 0.02). Conclusions: In utero exposure to maternal SARS-CoV-2 infection could have long-term effects on growth trajectories, depending on the infant’s sex and timing of exposure.

Abstract Background The mechanisms of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) with moderate septal hypertrophy (≤ 18 mm) remain uncertain with therapeutic implications. This study investigated the role of three-dimensional echocardiography (3DE)-derived myocardial mechanics in LVOTO. Methods We retrospectively analyzed 216 HCM patients with moderate septal hypertrophy, stratified into nonobstructive (n = 38), provokable LVOTO (n = 63), and resting LVOTO (n = 115). Transthoracic echocardiography assessed LV geometry, LVOT diameter, anterior mitral leaflet length, and papillary muscle abnormalities (via a composite SubMV score). 3DE-derived strain parameters, including global longitudinal (GLS), circumferential, radial, area (GAS) strain, twist, and torsion, were quantified. Determinants of LVOTO were evaluated using multivariate regression, restricted cubic splines (RCS), and receiver operating characteristic (ROC) analysis. Results Both LVOTO subgroups showed significantly augmented strain mechanics versus nonobstructive patients, greatest in resting LVOTO (p < 0.05); twist and torsion were the strongest discriminators (p < 0.001). Multivariate regression showed that, beyond LVOT diameter and SubMV score, torsion (B = 9.47), twist (B = 1.92), and GAS (B = 1.29) independently predicted provoked LVOT gradients (all p < 0.05); RCS demonstrated nonlinear twist/torsion–LVOTO relationships, with obstruction risk rising sharply above twist = 15° and torsion = 3°/cm, especially under provocation. Torsion discriminated provokable LVOTO achieving 81% specificity (cutoff 2.4°/cm, AUC = 0.72), outperforming all structural parameters. Integrating 3DE-derived mechanics with structural metrics improved diagnostic accuracy, especially in provokable LVOTO (AUC 0.84 vs. 0.76, DeLong p = 0.003). Conclusions In moderate-hypertrophy HCM, 3DE-derived strain mechanics, especially twist and torsion, independently determine LVOTO beyond structural narrowing, particularly under provocation, strengthening mechanistic insight and clinical applicability.

ABSTRACT Objective This study aims to identify both fluid and neuroimaging biomarkers for CSF1R‐RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression. Methods Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers ( N = 14), symptomatic CSF1R pathogenic variant carriers ( N = 17), and healthy controls ( N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1‐weighted MPRAGE scans, providing a highly valuable physiological component to our analyses. Results Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early‐stage CSF1R‐RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms. Interpretation Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R‐RD.

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.

Key Points α Klotho as an antiaging protein can extend the lifespan of healthy animals; serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease. Transgenic α Klotho and recombinant α Klotho delayed cyst growth in Pkd1 mutant mouse kidneys. α Klotho exerted its proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1. Background α -Klotho ( α Klotho) is expressed mainly in the kidney, which is encoded by the KL gene, existing in a membrane-bound form and a soluble circulating form. Soluble serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the role of α Klotho in ADPKD remains unknown. Methods To investigate the roles of α Klotho in ADPKD, we generated transgenic α Klotho and Pkd1 mutant Pkd1-HOMO-KL Tg mice to evaluate cyst growth and investigated underlying mechanisms with single-cell RNA sequencing analysis. Results We showed that α Klotho was lower in diverse kidney cell types in Pkd1 mutant kidneys, which was restored by transgenic α Klotho. We identified differential expression genes and pathways mediated by transgenic α Klotho at single-cell resolution and determined the cytokines and their receptors mediated cell-to-cell communication networks in Pkd1 mutant and Pkd1-HOMO-KL Tg kidneys by CellChat analysis. We further showed that α Klotho exerted a proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1, which disturbed TNF and its receptor mediated prosurvival complex, leading to ( 1 ) the formation of predeath complex to increase cystic cell death and ( 2 ) the decrease of the activation of NF-κB, the expression of cytokines, and the recruitment of macrophages, resulting in a delay of cyst growth. Treatment with recombinant α Klotho also delayed cyst growth in Pkd1 mutant kidneys. Conclusions This study defined an unknown role and mechanism of α Klotho in the regulation of a TNF-dependent cystic cell apoptosis and inflammation in Pkd1 mutant kidneys.