Citations

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

This practice recommendation serves as an update to the 2023 AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction–associated steatotic liver disease (MASLD), and provides implementable guidance on patient selection for treatment, consideration of comorbidities, and monitoring of treatment safety and efficacy of semaglutide. FDA-indication and Practice Recommendation: The Wegovy formulation, whose main ingredient is semaglutide, received accelerated FDA approval in August 2025 for treating MASH with moderate-to-advanced fibrosis (consistent with stages F2–F3 fibrosis), based on interim results of the phase 3 ESSENCE trial where 72 weeks of 2.4 mg/week subcutaneous injection resulted in achievement of both primary histologic endpoints: (1) resolution of MASH without worsening of fibrosis (62.9% vs. 34.3% placebo, p <0.001) and (2) ≥1 stage reduction in liver fibrosis without worsening of MASH (36.8% vs. 22.4% placebo, p <0.001); final approval awaits long-term outcomes. Patient Selection: Candidates should have MASH with stage 2–3 fibrosis, identified using non-invasive tests (NITs) such as VCTE (8–15 kPa), MRE (3.1–4.4 kPa), or ELF (9.2–10.5), rather than liver biopsy, which is impractical and unnecessary for most patients. In those with VCTE (15–20 kPa), MRE (4.4–5 kPa), or ELF (10.5–11.3), an individualized decision to treat should be based on exclusion of cirrhosis with another confirmatory NIT, or cross-sectional imaging excluding nodular-appearing liver contour and signs of portal hypertension, or a platelet count of <150,000/mm 3 . While semaglutide is not approved to treat patients with MASH cirrhosis (VCTE >20 kPa, MRE>5.0 kPa, ELF>11.3, and/or evidence of portal hypertension), those with compensated cirrhosis who are receiving semaglutide for another FDA-approved indication should be monitored carefully. Monitoring and Safety: Semaglutide showed a favorable hepatic safety profile in the ESSENCE trial, with no discontinuations due to liver enzyme elevations. Routine hepatic panels are recommended only as clinically indicated. The most common adverse events were gastrointestinal (nausea, diarrhea, constipation, vomiting), generally mild and transient; patient education and dose titration help improve tolerance. Clinicians should monitor for rare but serious risks, including acute kidney injury (from dehydration), symptomatic gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, and lean mass loss. Treatment Response and Concomitant Therapy: Lifestyle modification remains the cornerstone of MASLD/MASH management alongside semaglutide. Combination use of resmetirom with semaglutide 2.4mg/week has not been studied. While no NITs reliably predict histologic response at the individual patient level, reductions from baseline to 72 weeks of treatment suggest significant improvement in MASH resolution (ALT ≥17 U/L or ≥20%) and fibrosis improvement (VCTE LSM ≥30%; MRE LSM ≥20%; ELF ≥0.5). Non-response may be suspected if ALT or NITs worsen. The benefit is uncertain if a suboptimal response occurs, and may require an individualized approach and further follow-up.

Background: Internalized HIV stigma (IHS) is associated with reductions in antiretroviral therapy (ART) adherence and HIV viremia mediated through depression. However, there is still a need to quantify the direct impact of IHS on ART adherence to inform interventions to improve medication adherence. Methods: The Center for AIDS Research Network of Integrated Clinical Systems is a longitudinal, US-based, multisite cohort of people with HIV who complete patient-reported outcome assessments as part of HIV-care visits. Patient-reported outcome data include IHS items, ART adherence, depression assessments, substance use, and other outcomes. We examined associations between IHS and ART adherence using generalized linear latent and mixed models with a nonparametric random effects intercept to accommodate repeated measures. Results were compared with analyses using generalized estimating equations and marginal structural models. Results: Among 13,119 people with HIV, the mean age was 47.4 years, 17.6% were women, and 59.3% were non-White. Across 33,139 observations, controlled for repeated measures on individuals, HIV medication adherence was reduced by 1.07% for every point increase in IHS after controlling for age, sex, ethnicity, geographic location, and substance use, and 0.58% when additionally adjusted for depression score. Marginal structural models and generalized estimating equations provided similar results. Conclusions: Our study demonstrates that IHS has a direct association with reductions in ART adherence, which could affect other comorbid health outcomes that are influenced by unsuppressed viremia over time. Developing a thorough understanding of the mechanisms through which IHS affects ART adherence is critical for developing interventions to mitigate IHS and improve health outcomes across the lifespan.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

Background: Age is the strongest factor determining disease expression in multiple sclerosis (MS). We previously demonstrated biological age acceleration in pediatric-onset MS (POMS) compared to controls with both epigenetic clocks (DNAm) and telomere length (TL). It is unknown whether these markers report overlapping or distinct aging-related processes. Objectives: To determine the correlation between DNAm and TL aging markers. Methods: We conducted a cross-sectional case–control study within the US Network of Pediatric MS Centers. We calculated age acceleration residuals for the Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks and measured TL from whole blood samples to estimate telomere to somatic DNA ratios (T/S ratio). We employed multivariable analysis of covariance to assess the correlation between DNAm estimates and TL. Results: We analyzed biological ages in 270 participants (125 POMS, mean 15.7 years; 145 controls, mean 15.3 years). There were moderate correlations among the different DNAm clocks, but no correlations between DNAm clocks and TL in pooled analyses. In a stratified analysis, only the control group showed a modest correlation between TL and PhenoAge clock ( r = 0.2, p = 0.06). Conclusions: DNAm did not correlate with TL in this sample of POMS and controls, suggesting that these biomarkers may capture complementary and non-overlapping elements of aging-related biology.

Objective To assess real‐world effectiveness of switching disease‐modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. Methods Of 2615 pediatric‐onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. Results A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety‐three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52–1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20–0.57; rate ratio: 0.38, 95% CI = 0.21–0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09–0.37; rate ratio: 0.21, 95% CI = 0.10–0.44) ( p < 0.001). Adjusted number needed to treat in person‐years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03–8.69) and infusion over injectable 1.43 (95% CI = 1.00–3.88). Interpretation Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long‐term safety data are required. ANN NEUROL 2026;99:715–729

Background: Hip decompression effectively treats early-stage osteonecrosis of the femoral head (ONFH) by slowing disease progression and potentially delaying joint replacement. Biological adjuvants like bone marrow aspirate concentrate (BMAC) and platelet-rich plasma (PRP) support bone regeneration and improve outcomes 1–7 . The present video article demonstrates a simple, coreless hip decompression technique with BMAC and PRP injection for early-stage ONFH. Description: The procedure is performed in the same operating room setting as traditional core decompression, with the patient supine on a radiolucent table for fluoroscopic guidance. One or both legs are draped free for access to the iliac crests. Bone marrow is harvested percutaneously from the anterior superior iliac crest with a trocar needle kit, centrifuged, and prepared for injection. We recommend precoating needles and syringes with 1:1,000 heparin to prevent clotting. The BioCUE System (Zimmer Biomet) is typically utilized for centrifugation. Hip decompression is performed with use of a trocar and cannula (PerFuse System; Zimmer Biomet), with subsequent injection through the cannula into the femoral head. A 0.5-cm skin incision is made. The trocar is placed lateral to the femur and advanced percutaneously through the lateral femoral cortex, with a starting point proximal to the lesser trochanter. The trocar is then advanced along the femoral neck into the necrotic region by performing mallet strikes on the instrument’s strike cap. Anteroposterior and frog-leg lateral views assist in positioning the trocar within the necrotic area. Internal leg rotation, which aligns the patella upward, helps position the trocar horizontally parallel to the floor. Positioning is adjusted using repeated imaging as needed. Once the patient is positioned, the trocar is removed, leaving the cannula in place. With the cannula retracted 1 cm, a 30-mL syringe is utilized to inject BMAC and PRP into the necrotic lesion. Because of sclerotic resistance, substantial pressure is needed, but retraction of the cannula helps. Following injection, the cannula is withdrawn another 1 cm, and demineralized bone matrix is injected to prevent escape of the BMAC. Alternatives: Alternative treatments for ONFH include traditional core decompression with a sliding hip screw drill or an X-REAM device (Stryker), both of which carry a higher risk of fracture because of the larger diameter of the tract and require limited weightbearing postoperatively. Bone-cement injection can stabilize the femoral head but lacks regenerative properties. Core decompression with either BMAC or PRP alone, rather than in combination, also serves as an alternative treatment strategy. Open approaches, like osteotomy, are more invasive, have longer recovery times, and may complicate future hip arthroplasty if unsuccessful. Rationale: This technique enables minimally invasive hip decompression and delivery of adjuvant cell therapy or grafting, typically without the use of power instruments. This approach avoids the risk of injuring the bone due to the heat from power tools, protecting the BMAC injection site. Patients are generally discharged the same day and permitted full weight-bearing immediately, even in bilateral surgeries. Expected Outcomes: Hip decompression for ONFH has shown variable rates of success 8,9 , but adding BMAC or PRP may improve outcomes 1–3 . Houdek et al. reported that among 35 hips treated with decompression plus BMAC and PRP for corticosteroid-induced ONFH, 88% avoided THA at 3 years 2 and 70%, at 7 years 3 . Patients with grade-1 or 2 Kerboul angles had a 90% survivorship rate, underscoring the benefits of BMAC and PRP. Important Tips: Insert the trocar into the lateral cortex, positioned distal to the vastus ridge and proximal to the lesser trochanter, to reduce iatrogenic subtrochanteric fracture risk. Avoid advancing closer than 5 mm to the subchondral cortex to prevent joint-surface disruption or collapse, especially with eccentric lesions. If resistance occurs during injection, retract the cannula a few millimeters laterally to increase delivery space and reduce pressure. Acronyms and Abbreviations: BMAC = bone marrow aspirate concentrate ONFH = osteonecrosis of the femoral head PRP = platelet-rich plasma AP = anteroposterior THA = total hip arthroplasty ARCO = Association Research Circulation Osseous classification MRI = magnetic resonance imaging

Introduction Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME. Research design and methods This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis. Results The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02). Conclusions and relevance We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.