Citations

Importance The Implantable Neurostimulator for the Treatment of Parkinson’s Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). Objective To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. Design, Setting, and Participants This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson’s Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. Intervention Bilateral STN-DBS for moderate to advanced PD. Main Outcomes and Measures Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. Results A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-II improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. Conclusions and Relevance Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

Background: Adductor avulsions are complex injuries often involving multiple structures, as indicated by several magnetic resonance imaging (MRI) studies. However, no studies have compared MRI assessments using a dedicated groin protocol with surgical findings. Hypothesis: It was hypothesized that MRI assessments using a dedicated groin protocol would correlate closely with surgical findings, applicable to both experienced and novice users of the pyramidalis–anterior pubic ligament–adductor longus complex (PLAC) classification. Study Design: Case series; Level of evidence, 4. Methods: This retrospective study analyzed 161 athletes who underwent MRI using a dedicated groin protocol, followed by surgical repair of the PLAC. Two musculoskeletal radiologists—1 experienced (rater A) and 1 inexperienced (rater B) in the use of the PLAC classification—independently assessed the MRI scans twice, 6 weeks apart, using a structured 3-step protocol to evaluate (1) adductor longus fibrocartilage (intact, partially avulsed, or completely avulsed), (2) pyramidalis separation from adductor longus (intact, partially separated, or completely separated), and (3) pectineus status (intact or partially avulsed). Agreement between MRI and surgical findings was evaluated using a PLAC injury classification (types 1-5), with intra- and interobserver reliability measured by Cohen kappa. Results: Among the 161 athletes, 93 played soccer, of whom 69 were professional. All athletes exhibited complete fibrocartilage avulsion, with 83 athletes (52%) showing adductor longus separation from the pyramidalis. Isolated adductor longus avulsions (PLAC type 1) were observed in only 36 athletes (22%). The interobserver kappa score between MRI assessments and surgical findings was 0.942 for rater A and 0.858 for rater B. Intraobserver ratings were 0.967 for rater A and 0.875 for rater B. Both inter- and intraobserver scores indicated almost perfect agreement. In combination, these statistical findings support the validity, reliability, and applicability of the MRI protocol using the PLAC classification system for 2 users with varying levels of experience. Conclusion: Adductor avulsions were rarely isolated, typically involving multiple muscles. The PLAC classification effectively captured the complexity of these injuries. When used in conjunction with a dedicated MRI protocol, the PLAC classification demonstrated almost perfect agreement and concordance with surgical findings. Together, the PLAC classification and MRI protocol offered a more comprehensive and accurate representation of patients’ clinical and radiological features and provided valuable guidance for surgical planning.

Bone health is a key determinant of success in spine surgery, making preoperative assessment of bone quality essential to optimal surgical risk stratification. Magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score offers a novel approach to assess bone health in spine surgery candidates. The ability of MRI to assess bone quality without exposure to ionizing radiation makes it a potentially advantageous alternative to other traditional measures of bone density. VBQ has additionally shown potential to predict adverse outcomes, such as fragility fractures, instrumentation failure, subsidence and proximal junctional kyphosis. Variations of VBQ, such as endplate bone quality, S1 VBQ, and cervical VBQ, provide targeted insights at specific anatomical regions and potentially enhance the predictive accuracy of VBQ. However, clinical application of VBQ is limited by variability in MRI systems, patient-specific factors, and lack of standardized threshold values. This review aims to critically evaluate VBQ scores as an opportunistic, MRI-based assessment of bone health and its potential role in predicting surgical outcomes. While VBQ may provide some valuable insights into bone health, its role in preoperative risk assessment likely remains supplementary and requires further research to establish clinical validity and optimal cutoffs.

Background: There is little data available in infants on the extent to which inhalational anesthetics prolong the effects of neuromuscular blocking agents compared with intravenous agents. Here, we assessed the differences between the neuromuscular blocking effects (duration and recovery time) of a single dose of rocuronium during propofol vs. sevoflurane anesthesia. Methods: The prospective study enrolled 20 infants (4–12 months of age) scheduled for craniosynostosis surgery, randomly assigned to receive general anesthesia maintenance with sevoflurane or propofol. All patients received 0.6 mg/kg rocuronium as a single bolus dose to facilitate tracheal intubation and surgery. Primary study endpoint was the clinical duration of rocuronium, from administration until spontaneous recovery to a train-of-four ratio (TOFR) > 0.90. Secondary endpoints were times for reappearance of the first, second, third, and fourth twitches of the TOF (T1, T2, T3 and T4, respectively) in the two patient groups. Results: There were no differences in the infants’ age (sevoflurane maintenance: 5.8 ± 2.4 months; propofol maintenance: 6.7 ± 3.1 months, p = 0.47) or weight (sevoflurane: 7722 ± 1644 g; propofol: 7433 ± 1782 g, p = 0.71). Rocuronium onset time was 101.0 ± 55.0 s in the sevoflurane group and 83.4 ± 47.9 s in the propofol group (p = 0.46). Total duration of anesthesia was comparable in the sevoflurane (122.0 ± 23.8 min) and propofol (107.7 ± 25.2 min, p = 0.18) groups. Rocuronium recovery to TOFR > 0.9 required 136 min (CI: 123.7–149.5 min) in the sevoflurane group and 61.5 min (CI: 58.0–101.0 min) in the propofol group (p < 0.001). Conclusions: In infants, sevoflurane maintenance enhances the neuromuscular blocking effect of a single, 0.6 mg/kg BW dose of rocuronium as compared to propofol maintenance. After discontinuation of sevoflurane, additional time is necessary to reach the acceptable TOFR >0.9 needed before tracheal extubation. The present study further underscores the importance of objective (quantitative) neuromuscular monitoring in infants to guide intraoperative management and prevent residual neuromuscular block.

Abstract Background and Aims Intestinal ultrasound (IUS) is increasingly used to monitor treatment efficacy in inflammatory bowel disease (IBD) trials. However, standardized definitions for response, remission, and optimal assessment timing remain undefined. An international expert consensus meeting was held to establish IUS endpoints for clinical trials. Methods A panel of 35 international gastroenterologists and radiologists participated in a modified Delphi process, reviewing the literature and developing consensus statements. Agreement was defined as at least 75% consensus. Results Consensus was reached on 150 statements across four domains: general IBD (30 statements), luminal Crohn’s disease (CD) (43), perianal CD (51), and ulcerative colitis (UC) (26). For luminal CD and UC, ultrasound response was defined by: (1) a ≥25% reduction in bowel wall thickness (BWT) from baseline, or (2) multifactorial improvement, combining BWT reduction with ≥1 grade decrease in color Doppler signal (CDS) or another IUS parameter. Assessments were set at weeks 4-8 for the colon and week 12 for the terminal ileum. Ultrasound remission in luminal CD was defined as: (1) BWT normalization (≤3 mm) or (2) normalization of multiple parameters, including BWT, CDS, and all other IUS parameters. Similar remission criteria were proposed for UC, but the sigmoid BWT normal range (3-4 mm) remained uncertain. The bowel ultrasound score (BUSS) for CD and the Milan ultrasound criteria (MUC) for UC were supported as standardized scoring systems for trials. Conclusion This consensus provides standardized IUS definitions to enhance consistency in IBD trials, supporting the integration of IUS in future research.

Abstract Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells—a highly dynamic lymphocyte subtype—undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes—FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258—with strong evidence for a causal role in CRC development (FDR-P &lt; 0.05; colocalisation H4 &gt; 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.

The prognosis of high-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is highly variable and reported median overall survival remains low. There is no established standard of care for patients with higher grade 2 (G2) (Ki-67 ≥ 10% and ≤ 20%) and grade 3 (G3) (Ki-67 ≥ 20% and ≤ 55%) GEP-NETs and most of the current treatment regimens, particularly for G3 NETs, are extrapolated from lower-grade GEP-NET treatments or based on data from small retrospective studies. Robust evidence to support treatment recommendations for high-grade NETs, especially in the first-line (1L) setting, is limited and the optimal treatment sequence has not been clearly defined. This review summarizes the latest literature on sequencing of therapies, identifies patient selection considerations for utilizing peptide receptor radionuclide therapy (PRRT), and offers data-driven expert opinions and clinical practice recommendations in high-grade GEP-NETs. As authors, we recommend that all patients with well-differentiated, higher G2 and G3 NETs are evaluated with [68Ga]Ga-DOTA-peptide positron emission tomography (PET) for baseline somatostatin receptor expression and if positive, a 1L treatment option of PRRT should be considered, especially in clinically stable patients. Somatostatin analog therapy may benefit patients with low-volume, indolent disease, and chemotherapy is usually a better fit for patients in visceral crisis, in need of urgent treatment, or with no access to [68Ga]Ga-DOTA-peptide PET. In complex cases, a robust discussion at a multidisciplinary NET tumor board can be beneficial.