Citations

Abstractα-synucleinopathies are a complex group of progressive neurodegenerative disorders with an increasingly recognized long prodromal period, during which sleep dysfunction is a hallmark. Sleep disorders during the prodromal synucleinopathy period, primarily isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and daytime hypersomnolence correlate best with the recently proposed “body-first” Lewy body disease progression. iRBD is the most widely recognized form of prodromal α-synucleinopathy, and patients with iRBD show abnormal α-synuclein in tissues and biofluids even in the absence of cognitive or motor symptoms. More importantly, individuals with iRBD have an elevated risk for near-term development of a clinically diagnosable symptomatic synucleinopathy. Other sleep disorders such as hypersomnia and circadian rhythm dysfunction also occur across the synucleinopathy spectrum, although their prognostic significance is less well understood than iRBD. Finally, isolated REM sleep without atonia may represent an even earlier stage of prodromal synucleinopathy, but further studies are needed.

Background: Nonoperative and operative management techniques after anterior cruciate ligament (ACL) injury are both appropriate treatment options for selected patients. However, the subsequent development of posttraumatic knee osteoarthritis (PTOA) remains an area of active study. Purpose: To compare the risk of PTOA between patients treated without surgery and with ACL reconstruction (ACLR) after primary ACL disruption using a machine learning causal inference model. Study Design: Cohort study; Level of evidence, 3. Methods: A geographic database identified patients undergoing ACLR between 1990 and 2016 with minimum 7.5-year follow-up. Variables collected include age, sex, body mass index, activity level, occupation, relevant comorbid diagnoses, radiographic findings, injury characteristics, and clinical course. Treatment effects of ACLR on the development of PTOA and progression to total knee arthroplasty (TKA) were analyzed with machine learning models (MLMs) in a causal inference estimator (targeted maximum likelihood estimation, TMLE), while controlling for confounders. Results: The study included 1194 patients with a minimum follow-up of 7.5 years, among whom 974 underwent primary reconstruction and 220 underwent nonoperative treatment. A total of 215 (22%) patients developed symptomatic PTOA in the ACLR group compared with 140 (64%) in the nonoperative treatment group ( P < .001), whereas 25 (3%) patients underwent TKA in the ACLR group compared with 50 (23%) in the nonoperative treatment group ( P < .001). Patients in the ACLR group had delayed TKA compared with patients in the nonoperative treatment group (193.4 vs 166.0 months, respectively; P = .02). TMLE evaluation revealed that reconstruction decreased the risk of PTOA by 11% (95% CI, 8%-13%; P < .001) compared with nonoperative treatment but did not demonstrate a significant effect on the rate of progression to TKA. Survival analysis with random forest algorithm demonstrated significant delay to the onset of PTOA as well as time to progression of TKA in patients undergoing ACLR. Additional risk factors for the development of PTOA, irrespective of treatment, included older age at injury, greater body mass index, total number of arthroscopic knee surgeries, and residual laxity at follow-up. Conclusion: MLMs in a causal inference estimator found ACLR to exert a significant treatment effect in reducing the rate of development of PTOA by 11% compared with nonoperative treatment. ACLR also delayed the onset of PTOA and progression to TKA.

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of microscopic disease in epithelial ovarian cancer is controversial, it may harbor chemoresistant cells and explain the high recurrence rates. Fluorescence-guided surgery (FGS) is an emerging approach. However, the potential in ovarian cancer remains underexplored; the majority of the existing evidence pertains to gastrointestinal tumors and a limited group of ovarian cancer patients. Their comparative effectiveness is still uncertain. Objective: To systematically review and evaluate the role of fluorescence-guided surgical techniques in detecting microscopic disease in ovarian cancer and compare their efficacy to total peritonectomy. Data Sources: A systematic search was made in three databases (PubMed, Web of Science, and Embase). The search was conducted from 1975 to 2024, including randomized controlled trials, observational studies, and conference abstracts in the last 25 years. Study Selection: Clinical studies published in English involving ovarian cancer patients undergoing FGS or total peritonectomy were included. Case reports, reviews, animal studies, and studies involving mixed cancer populations without ovarian cancer-specific data were excluded. Two independent reviewers screened 631 studies, yielding 12 eligible studies for final analysis. Data Extraction and Synthesis: Data were extracted and synthesized in accordance with PRISMA and MOOSE guidelines, using random-effects models for independent analysis. Sensitivity, specificity, positive predictive value (PPV), and odds ratios (ORs) were grouped, accompanied by subgroup analyses based on the fluorescence agent employed. For quality assessment, we utilized the NIH quality tool. Main Outcome(s) and Measure(s): The primary outcome was the rate of change in surgical management due to fluorescence guidance or total peritonectomy. Secondary outcomes comprised lesion-level sensitivity, specificity, and PPV. Safety outcomes included adverse events associated with fluorescence agents. Results: There were 12 studies involving 429 ovarian cancer patients. FGS improved the detection of microscopic disease compared to standard visualization methods, with a pooled sensitivity of 0.77. Folate receptor-targeted agents had high sensitivity (84%) but low specificity (26%). Aminolevulinic acid (5-ALA) showed superior diagnostic accuracy with a sensitivity of 84% and a specificity of 96%. Total peritonectomy showed no significant advantage over FGS for detecting microscopic disease. The adverse events were mild, with no serious events reported. We observed a high heterogeneity across studies and methodologies. Conclusions and Relevance: Fluorescence-guided surgery utilizing fluorescence tracers demonstrates potential in improving the detection of microscopic disease and may change surgical management in epithelial ovarian cancer, particularly with 5-ALA. Variability in performance and limited data on survival outcomes necessitates additional research. Total peritonectomy does not offer further advantage in the detection of microscopic disease. Future trials should focus on standardizing methodology and evaluating the effects of microscopic disease removal on survival outcomes. Registration: The study was registered to PROSPERO as CRD42024578274.

Abstract Background Progress in clinical trials and drug development for paediatric perianal fistulising CD (pfCD) depends upon accurate, reproducible imaging to assess disease activity and measure treatment response. We evaluated the inter- and intra-rater reliability of existing radiologic disease activity indices and anatomical classification systems previously identified as appropriate for assessment of paediatric pfCD.1 Methods A retrospective cohort (N=50) of magnetic resonance imaging (MRI) exams representing a full spectrum of paediatric (&lt;18 years) perianal CD severity was selected by a single expert paediatric radiologist. Methods described by Zou2 were used to estimate sample size. Three separate radiologists (2 paediatric) blinded to clinical information assessed pfCD in the exams using the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD), Van Assche Index (VAI), modified VAI (mVAI), Paediatric MRI based Perianal Crohn’s disease (PEMPAC) index, a visual analogue scale (VAS) of overall pfCD disease severity (range, 0-100 mm), as well as with the Park’s and St. James University Hospital anatomic classification systems. Two radiologists read all exams twice, separated by 2 weeks, and 1 radiologist read the exams once (250 total reads). Intra- and inter-rater reliability was evaluated using intraclass correlation coefficients (ICC; equivalent to weighted kappa). Precision of the ICC estimates was quantified with 95% confidence intervals (CIs) obtained using clustered bootstrapping. Degree of reliability was interpreted with benchmarks proposed by Landis and Koch3. Results Median age of children was 13.5 years (IQR 11.4-16.1), and 64% were male. Median Paediatric Crohn’s Disease Activity Index score at time of imaging was 17.5 (IQR 10-32.5). Substantial (ICC&gt;0.61) inter-rater reliability was observed for MAGNIFI-CD, VAI, and mVAI (Table 1), with the highest ICCs observed for the mVAI (0.72 [0.6 to 0.79]). Moderate (ICC&gt;0.41) inter-rater reliability was observed for PEMPAC, St. James University Hospital classification, and the VAS, and fair (ICC&gt;0.21) inter-rater reliability was observed for Parks classification. Intra-rater reliability was nearly perfect (ICC&gt;0.81) for the VAS, and substantial for all indices except for Parks classification, which had moderate (0.60 [0.44 to 0.75]) intra-rater reliability (Table 1). Conclusion Most existing multi-item MRI-based disease activity indices and the St. James Hospital classification were reliable for the assessment of paediatric pfCD in our cohort. Our preliminary results suggest that the disease activity indices may have utility to measure treatment effect in paediatric pfCD clinical trials. References 1.Crowley E, Ma C, Guizzetti L, Zou G, Lewindon PJ, Gee MS, et al. Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials. Inflamm Bowel Dis. 2024;30(3):357-69. 2.Zou GY. Sample size formulas for estimating intraclass correlation coefficients with precision and assurance. Statistics in Medicine. 2012;31(29):3972-398 3.Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159-74.

AbstractBackgroundEvidence for abnormal amyloid‐β (Aβ) plaque accumulation is necessary prior to initiating anti‐amyloid therapy in early symptomatic Alzheimer’s disease (AD). While the clinical trials for lecanemab and related drugs utilized positron emission tomography (PET) to demonstrate brain amyloidosis, current appropriate use recommendations for clinical practice consider PET or cerebrospinal fluid (CSF) biomarkers as satisfactory for this purpose. Here, we present four clinical cases where CSF biomarker results were discordant from amyloid PET, with the potential to result in erroneous treatment targeting.MethodPatients were seen at a tertiary care subspecialty clinic in consideration for lecanemab therapy. All patients had office examination, neuropsychological assessment, structural magnetic resonance imaging (MRI), amyloid PET (with either 11C‐Pittsburgh compound B or 18F‐florbetapir), CSF AD biomarkers (Roche Elecsys p‐tau181/Aβ42 and Fujirebio Lumipulse Aβ42/Aβ40 ratios), and apolipoprotein E (APOE) allele testing. Amyloid PET interpretations were made by consensus visual review from experienced readers.ResultAll four patients had clinical diagnoses of mild cognitive impairment or mild dementia (Table 1). Two patients had positive CSF p‐tau181/Aβ42 and Aβ42/40 ratios with negative amyloid PET (indicating sparse to no neuritic plaques). Case 1 displayed aphasia (characterized by anomia and deep dysgraphia) and imaging findings possibly compatible with semantic dementia. Case 2 displayed a gait abnormality and imaging signs of abnormal CSF dynamics. Two other patients had negative CSF p‐tau181/Aβ42 measures with positive amyloid PET (indicating moderate to frequent neuritic plaques). In those instances, the clinical syndrome and imaging studies were strongly supportive of AD and the CSF Aβ42/40 ratio was “likely positive” (Table 1). For one patient (Case 4), tau PET and Lumipulse plasma p‐tau217 concentration were both positive.ConclusionClinicians prescribing anti‐amyloid therapies should be aware of the possibility for CSF biomarkers to be discordant from amyloid PET status in select scenarios. These cases highlight the value of considering PET imaging in the presence of clinically atypical features, concern for mixed etiology, or strong clinical suspicion for AD despite negative CSF biomarkers. Larger series are needed to identify broader patterns contributing to biomarker discordance by assay, modality (PET versus CSF/plasma measures), and medical/neurologic comorbidities.