Citations

Abstract Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p < 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.

Background: Non-vitamin K antagonist oral anticoagulants (NOAC) have replaced vitamin K antagonist (VKA) oral anticoagulants as the first-line treatment option for stroke prevention in high-risk patients with atrial fibrillation. With VKA therapy, disease and treatment-related knowledge is associated with improved adherence and outcomes. There is concern that due to the lack of need for ongoing visits for laboratory monitoring in patients on NOACs, there is less opportunity for education, leading to poor disease- and treatment-related knowledge in this patient group. Methods: One hundred ninety-nine (199) patients presenting to 2 primary care clinics on NOAC therapy were surveyed regarding atrial fibrillation and their knowledge regarding NOACs. Chart review was completed to determine patient characteristics and data obtained was compared with survey results to determine the accuracy of the survey responses. Results: Patients with a lower degree of NOAC knowledge tended to be older ( P < .001), have higher Charlson Comorbidity Index scores ( P = .001), use apixaban more often ( P = .008), and have been on NOACs for a shorter time period ( P = .007). Conclusions: There is an opportunity to improve NOAC-related knowledge in patients with atrial fibrillation. When developing educational interventions, patient characteristics associated with poor knowledge should be considered. Based on our results, these are patients who are older, more medically complex, are on apixaban, and have been on NOAC therapy for a shorter duration.

Background: 5-aminolevulinic acid (5-ALA; GleolanTM, NX Development Corps., Lexington, USA) is approved for fluorescence-guided resections of suspected malignant gliomas. Experience has demonstrated that meningiomas also show fluorescence, which may be a useful surgical adjunct. We present an innovative design for a multi-center, prospective study to determine the clinical safety and potential benefit of fluorescence-guided resection of meningiomas with utmost bias reduction. Methods: All patients with suspected meningioma (all grades) receive GleolanTM 20 mg/kg 2–4 h prior to surgery supported by fluorescence excitation from a blue light source (Blue400, Zeiss Meditech, Oberkochen, Germany; FL400, Leica Microsystems, Heerbrugg, Switzerland). Surgeons are asked whether a residual tumor can be observed to fluoresce under blue light (BL) after the tumor is no longer recognizable using conventional illumination at the end of surgery. In addition, when faced with tissues of uncertain tissue type (so-called “indeterminate” tissue), this study records how often surgeons make a correct decision based on fluorescence and how this influences surgical strategy. The primary endpoint is the percentage of patients in whom one of these two benefits are observed. Other endpoints include the diagnostic accuracy of fluorescence compared to white light (WL) versus correlative histology. For bias reduction, pertinent data are derived from surgical videos reviewed by independent reviewers blinded to surgeons’ assessments of tissue type and fluorescence status. Data will be included from approximately 100 study participants completing the study at approximately 15 centers in the United States, Germany, and Austria. Results: As of May 2022, 88 patients have completed the study. No adverse safety signal has been detected. Conclusions: Preliminary data confirm the feasibility of our study design. Accrual is targeted for completion in the third quarter of 2022.

Abstract Introduction Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized. Methods We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non‐AD neuropathologies and tauopathies. Thioflavin‐S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases. Results Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin‐S. Hippocampal burden generally increased with each Braak stage. Discussion These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset. Highlights Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline‐rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi‐quantitative frequency to calculate tangle maturity frequency.

Background: Diagnosis and treatment of posterior shoulder instability (PSI) has improved with advances in imaging and surgical technique. However, the relationship between PSI and osteoarthritis (OA) remains unclear. Purpose: To evaluate a population-based cohort to (1) determine the rate of symptomatic OA, (2) identify patient characteristic risk factors for OA, and (3) evaluate the effect of posterior capsulolabral repair on OA progression. Study Design: Case-control study; Level of evidence, 3. Methods: After review of 324 patient records, we included 115 patients (14 female, 101 male) diagnosed with PSI between January 1994 and July 2012 with an average follow-up of 12.5 years (range, 5-23 years). Medical records were reviewed for patient characteristics, injury characteristics, surgical details (if any), and radiographic progression of OA. Kaplan-Meier survival was used to estimate survival free of OA; characteristics associated with OA progression were determined via univariate Cox regression models, and associated 95% CIs and hazard ratios (HRs) are presented. Results: Overall, 14% (16/115) of patients had radiographic progression of symptomatic glenohumeral arthritis, with 5-year survival of 88.3% (95% CI, 79.7%-97.3%). Older age at the time of instability diagnosis was associated with arthritis progression (10-year unit HR, 1.95; 95% CI, 1.26-3.03). Patients who underwent surgery demonstrated increased radiographic progression of OA (HR, 4.03; 95% CI, 1.23-13.23). There was a trend of increased OA in patients treated with labral debridement compared with repair despite lower baseline levels of OA; however, this difference was not statistically significant ( P = .09). Conclusion: Symptomatic glenohumeral arthritis is not seen routinely in patients with PSI. Although uncommon, an age of at least 30 years at the time of diagnosis and surgical intervention were identified as risk factors for developing symptomatic arthritis at long-term follow-up.

INTRODUCTION: Anemia and micronutrient deficiencies are common in newly diagnosed patients with celiac disease (CeD). We aim to determine the prevalence and etiology of anemia in a cohort of patients with CeD in the United States and examine the effect of a gluten-free diet (GFD) on the laboratory parameters related to anemia in CeD. METHODS: We analyzed a prospectively collected cohort of adults with biopsy-proven CeD followed in a specialized CeD center between January 2000 and June 2016. We used the level of hemoglobin (Hb) and micronutrients suggested by the World Health Organization to establish the diagnosis of anemia or deficiencies. Demographic data and laboratory parameters related to anemia and micronutrients were recorded at the time of diagnosis and on a GFD. A celiac expert nutritionist or gastroenterologist evaluated all patients. RESULTS: In 572 patients with laboratory evaluation before starting a GFD, approximately 25% presented with anemia at the time of diagnosis of CeD. Iron deficiency was present in 50.8% of the cohort and in 78.8% of the patients with anemia. Within the anemic population, 84.4% of female patients as compared with 58.3% of male patients ( P = 0.02) showed iron deficiency. Folate deficiency (23.2%), vitamin B12 deficiency (11%), and anemia of chronic diseases (7.8%) were also part of both sexes' anemia etiology. Of the initially anemic patients, 81% and 89% normalized their Hb levels within 1 year and 2 years of beginning a GFD, respectively. All patients received appropriate supplementation when needed. DISCUSSION: Approximately 25% of individuals have anemia at CeD diagnosis. The anemia etiology included iron deficiency, vitamin deficiencies, and anemia of chronic diseases. Most of the patients will normalize their Hb levels and the anemia laboratory parameters 1 year after starting a strict GFD.

Objective Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. Design An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. Results Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. Conclusion This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

TPS4615 Background: While a standard approach to muscle-invasive bladder cancer (MIBC) management involves neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC), up to 50% of pts recur with metastatic disease. Moreover, removal of the bladder has a significant impact on pts’ quality of life. Pathologic downstaging to non-muscle-invasive disease (<pT2) or complete response (pT0) at RC is associated with long-term survival benefit. Somatic DDR gene alterations were shown to be enriched in pts who were pT0 at RC following NAC in multiple retrospective analyses. We hypothesize that MIBC pts with somatic loss-of-function alterations within specific DDR genes and clinical responses to NAC can be uniquely managed with a bladder-sparing approach consisting of close cystoscopic and radiographic surveillance, avoiding the toxicities of definitive local therapy. Methods: A031701 is a multicenter phase II trial that will enroll 271 pts with T2-T4aN0/xM0 MIBC diagnosed within 60 days prior to enrollment. Multifocal MIBC, tumors >5 cm by cystoscopic assessment, and Bacillus Calmette-Guérin (BCG)-refractory disease (beyond standard induction and maintenance) are not allowed. Intravesical chemotherapy is allowed. Pts must be eligible for cisplatin chemotherapy. Eligible pts will receive either standard dose or dose dense gemcitabine and cisplatin chemotherapy (investigator’s choice) with simultaneous genetic sequencing of pre-treatment transurethral resection specimens. Pts whose tumors contain deleterious alterations in any 1 of 9 pre-selected DDR genes ( ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, RAD51C, ATM, ATR, and FANCC) and who exhibit <T1 response on clinical restaging are eligible for organ-sparing management. Pts without deleterious DDR gene alterations or with >T1 disease after NAC will undergo RC or chemoradiation therapy (investigator/patient choice). The primary endpoint is 3-year event-free survival in DDR-altered pts who undergo bladder sparing, defined as the proportion of pts without BCG-unresponsive non-muscle invasive recurrences, any >T2 recurrences, or any metastatic recurrences. Secondary endpoints include clinical response rate (<cT1) in patients with deleterious DDR gene alterations following NAC, bladder-intact survival, overall survival, pT0 rate in DDR-altered pts who elect to undergo RC, pT0 rate in pts without DDR gene alterations, 3-year RC rate in pts with DDR gene alterations, and proportion of pts undergoing intravesical management for in-bladder recurrences. The study opened for enrollment in September 2018. Support: U10CA180821, U10CA180882. Clinical trial information: NCT03609216.