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Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Purpose To evaluate return‐to‐sport (RTS) rates and patient‐reported outcome measures (PROMs) following hip arthroscopic labral repair for femoroacetabular impingement in active basketball players with a minimum of 2‐year follow‐up. Methods All patients who were active basketball players and underwent hip arthroscopy with labral repair for femoroacetabular impingement from 2009 to 2022 were identified. Patients were evaluated for postoperative RTS and revision surgery at a minimum 2‐year follow‐up. RTS was defined as resuming basketball participation, at any level. Modified Harris Hip Score (mHHS), Hip Outcome Score‐Activities of Daily Living (HOS‐ADL) and Sport (HOS‐Sport), and surgery satisfaction were also collected. Results Sixty‐seven hips in 54 athletes (29 male, 25 female) with a mean age of 22.2 years (range 13‐39 years) were included. Eighty‐six (86%) were recreational or high school basketball players. There was significant improvement in all PROMs from baseline to a minimum 2‐year follow‐up (all P < .001). After excluding for athletes who did not RTS for nonmedical reasons, 78% of athletes returned to basketball following hip arthroscopy. Including patients who cited nonmedical reasons for not returning, the overall RTS rate was 65%. Athletes who RTS had significantly higher mHHS ( P = .012), HOS‐ADL ( P = .006), and HOS‐Sport ( P = .002), as well as lower visual analog scale pain (2.2 vs 3.4, P = .037) than those who did not RTS. Calculated minimal clinically important difference values were 8.3 for mHHS, 7.2 for HOS‐ADL, and 13.4 for HOS‐Sport. Anchor‐based patient acceptable symptom state calculations yielded thresholds of 83.5 for mHHS, 92.6 for HOS‐ADL, and 79.2 for HOS‐Sport—with 70%, 63%, and 67% of patients achieving these thresholds, respectively. Conclusions Basketball players who undergo hip arthroscopic labral repair for femoroacetabular impingement show significant improvements in PROMs with 78% RTS rate at a minimum 2‐year follow‐up. Although many athletes discontinued basketball for reasons unrelated to the hip, 18% cited hip issues. Basketball players who successfully return to basketball report higher PROMs than nonreturners, and cohort‐specific minimal clinically important difference analysis indicates that most athletes achieve clinically meaningful improvements. Level of Evidence Level IV, therapeutic retrospective case series.

Background: Despite the growing clinical relevance of obesity in the context of multiligament knee injuries, there remains a paucity of data evaluating patient-reported outcomes in this population. Purpose: To compare clinical and functional outcomes, including postoperative patient-reported outcome measures (PROMs) and complication/revision rates, of multiligament knee reconstruction (MLKR) in individuals with a body mass index (BMI) >30 kg/m 2 versus <30 kg/m 2 at a minimum 2-year follow-up. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review was performed to identify all patients who underwent MLKR between 2001 and 2022 at a single institution. Patients with a BMI >30 kg/m 2 were propensity-matched to patients with a BMI <30 kg/m 2 on a 1:1 basis by age, sex, laterality, and Schenck classification (knee dislocation). Medical records were reviewed for patient characteristics, time to surgery, year of surgery, number and type of ligament interventions, graft choice, single versus staged reconstruction, and concomitant injuries. Postoperative clinical examination findings and PROMs for each cohort, including visual analog scale score, Tegner activity scale score, Lysholm score, and International Knee Documentation Committee (IKDC) subjective score, were analyzed and compared. Postoperative complication and revision rates were evaluated and compared. Results: Of 158 patients, 79 patients with a BMI <30 kg/m 2 (mean age, 31.0 ± 11.5 years; mean BMI, 25.8 ± 3.0 kg/m 2 ) were matched to 79 patients with a BMI >30 kg/m 2 (mean age, 32.8 ± 9.5 years; mean BMI, 37.1 ± 5.8 kg/m 2 ). There were no significant differences between cohorts regarding age, sex, laterality, and Schenck classification ( P ≥ .100); however, patients in the BMI >30 kg/m 2 group had greater numbers of posterior cruciate ligament reconstruction. The mean follow-up was 7.5 ± 4.8 years for the BMI <30 kg/m 2 cohort and 7.2 ± 4.8 years for the BMI >30 kg/m 2 cohort ( P = .229). Patients with a lower BMI (<30 kg/m 2 ) had significantly better postoperative mean IKDC (79.3 ± 18.7 vs 67.9 ± 21.2; P = .004), Lysholm (85.1 ± 17.1 vs 75.7 ± 21.0; P = .007), and Tegner (5.1 ± 2.0 vs 4.4 ± 1.7; P = .041) scores. The BMI >30 kg/m 2 group also had significantly more postoperative complications ( P = .028). However, there was no significant difference between the 2 cohorts in terms of reoperation rate or conversion to total knee arthroplasty ( P ≥ .189). Conclusion: Patients who undergo MLKR and have a BMI >30 kg/m 2 demonstrate significantly decreased postoperative PROMs when compared to patients with a BMI <30 kg/m 2 . Increasing BMI significantly increased the incidence of complication rates after MLKR.

Abstract Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimer’s and Huntington’s diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1α, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

Background: Femoroacetabular impingement (FAI) is a common injury experienced by basketball players. Surgical management with arthroscopic labral repair and femoral osteochondroplasty can lead to successful outcomes for athletes whose nonoperative management fails. Recent studies have demonstrated that athletes undergoing hip arthroscopy in the setting of FAI had favorable return-to-sport (RTS) and sport continuation outcomes. Purpose: To evaluate patient-reported outcome measures (PROMs) and RTS rates at minimum 5-year follow-up in basketball players after hip arthroscopy for FAI. Study Design: Case series; Level of evidence, 4. Methods: All active basketball players at the recreational, high school, and collegiate levels who underwent primary hip arthroscopy with labral repair for FAI between August 2009 and December 2019 were identified. Postoperative RTS, revision rates, and surgery satisfaction at final follow-up were evaluated. PROMs were also analyzed as follows: visual analog scale, Tegner Activity Scale, modified Harris Hip Score, Hip Outcome Score–Activities of Daily Living, and Hip Outcome Score–Sport. Results: Fifty-three patients (64 hips) were included with a mean ± SD age of 21.2 ± 6.0 years. Most athletes played recreational or high school basketball (85%), while 15% played college basketball. Forty-three patients attempted to return to basketball. Of these patients, 35 (81%) returned to basketball after surgery, with 32 (91%) returning to the same level of play. Patients who returned to basketball had significantly improved outcomes on the modified Harris Hip Score ( P = .006), Hip Outcome Score–Activities of Daily Living ( P = .007), Hip Outcome Score–Sport ( P = .004), Tegner Activity Scale ( P = .010), and visual analog scale with use ( P = .041) as compared with those who did not return. High school athletes had decreased odds of RTS when compared with recreational athletes ( P = .01). There was significant improvement in all PROMs from baseline to minimum 5-year follow-up ( P < .05). Conclusion: At minimum 5-year follow-up, basketball players demonstrated durable improvements in PROMs and an RTS rate of 81% after hip arthroscopy for FAI. The majority of athletes returned to the same level of competition. There were significantly improved PROMs in patients who returned to sport versus those who did not. High school athletes had decreased odds of RTS when compared with recreational athletes. However, body mass index, sex, age, alpha angle, and basketball position did not significantly correlate with RTS outcomes.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract Background The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. Purpose This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across all LVEF categories. Methods Patients with severe isolated TR from the TRIGISTRY, a multicenter international registry, were categorized based on LVEF (preserved EF-pEF:≥50%, mildly reduced EF-mrEF:41–49%, and reduced EF-rEF:≤40%). We assessed the impact of treatment modality and procedural success, defined as residual TR ≤mild-to-moderate, on two-year survival within each LVEF category. Results Among 2,384 patients, 1,383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (P&lt;0.0005) and TTVI (P&lt;0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (P=0.28 for both), nor in those with rEF (P=0.76 and P=0.22 respectively). Similar results were obtained when surgical and transcatheter interventions were grouped together (P&lt;0.0001, P=0.17 and P=0.29 in patients with pEF, mrEF and rEF respectively). Patients with significant residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (P=0.47, P=0.33, and P=0.008 respectively)(Figure 1). Conclusion Tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with preserved LVEF but not in those with mildly reduced or reduced LVEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering tricuspid interventions in individuals with reduced LVEF.Figure 1

Abstract Background While tricuspid regurgitation (TR) is predominantly functional, it can arise from various cardiac conditions. This study aimed to evaluate whether the benefits of tricuspid valve intervention, compared to conservative management, differ based on the underlying etiology. Methods In the TRIGISTRY international cohort, which includes consecutive patients with severe isolated functional TR across 33 centers in 10 countries, we compared mortality rates at 2 years between patients who underwent a tricuspid valve intervention (surgical or transcatheter) versus conservative management according to TR etiology. Patients were classified into three groups: (1) Isolated TR (ITR), defined as left ventricular ejection fraction (LVEF) &gt;60%, systolic pulmonary artery pressure (sPAP) &lt;50 mmHg, and no prior left-heart intervention (LHI); (2) LHI-TR, comprising patients with a history of LHI; and (3) Undetermined TR (UTR), which included those who did not meet the criteria for ITR or LHI, as well as those with missing sPAP data. Given previous findings indicating that intervention provided no survival benefit for patients with a high TRI-SCORE, the present analysis was restricted to individuals with low to intermediate TRI-SCORE (≤5). Survival outcomes between groups were compared using restricted mean survival time (RMST). Results A total of 1,552 patients (72±13 years; 56% female) with severe functional TR and a low (48%) or intermediate (52%) TRI-SCORE were included. Of these, 772 (50%) underwent an intervention, while 780 (50%) were conservatively managed. TR was classified as ITR in 201 patients (13%), LHI in 395 (25%), and UTR in 956 (62%). Overall, patients with ITR exhibited the lowest comorbidity burden, whereas those with UTR had the highest. After adjusting for comorbidities and TRI-SCORE, a survival benefit of a tricuspid valve intervention was observed in patients with ITR (survival estimate: 0.17, 95% CI [0.009, 0.32], P=0.039) and, to a lesser extent, in patients with UTR (survival estimate: 0.09, 95% CI [0.0, 0.184], P=0.048), but not in those with prior LHI (survival estimate: 0.06, 95% CI [-0.08, 0.2], P=0.4). Similar results were found when excluding patients with moderate or greater residual TR after intervention. Conclusion In TRIGISTRY, patients with ITR appeared to derive the greatest benefit from tricuspid valve intervention, followed to a lesser extent by those with UTR, while no benefit was observed in patients with prior LHI. However, the potential influence of unaccounted confounders cannot be excluded, and further studies are needed to better identify patients’ subsets that may derive the most benefit from a tricuspid valve intervention.

Abstract Background Valve-sparing aortic root replacement has increasingly been performed in Marfan patients. However, there is ongoing debate on whether the non-aneurysmal sized aortic arch should be prophylactically replaced during the index operation. The aim of our retrospective single-centre study was to investigate the long-term status of the aortic arch in these patients. Methods Between 1993 and 2021, a total of 723 patients underwent valve-sparing aortic root replacement with a straight tube graft (David I reimplantation) at our institution; 119 patients had confirmed Marfan disease. Of these 119 Marfan patients, 67 patients had isolated aortic root aneurysm with no aortic arch pathology. These 67 patients underwent isolated David I procedure in an elective setting (only aortic root and ascending aortic replacement) without any concomitant procedures and were included in the present study. Results This study includes 67 patients with Marfan syndrome who underwent isolated elective valve-sparing aortic root replacement. The median age of patients was 30 years (20-41), and 47 were male (70%). The cardiopulmonary time was 157.5 (145.8-178.3) min, and aortic clamp time was 117.0 ± 19.8 min. The in-hospital mortality and stroke rates were both 0%. Follow-up was 100% complete. Survival at 1, 5, 10, 15, and 20 years were 100%, 100%, 93%, 89%, and 85%, respectively. Freedom from aortic arch reoperation due to aneurysm at 1, 5, 10, 15, and 20 years was 100%, 100%, 100%, 100%, and 95%, respectively. In follow-up, no patient required aortic arch replacement due to aortic arch aneurysm. A total of 3 patients underwent aortic arch replacement for type B aortic dissection. Of these 3 patients, 1 had chronic type B dissection with aortic aneurysm, and 2 had acute type B dissection. Conclusions The long-term results after valve-sparing aortic root replacement with a straight tube graft (David I procedure) in Marfan patients are excellent. Our study shows that the risk for future aortic arch intervention after elective valve sparing aortic root replacement in Marfan patients is extremely low. Hence, our study supports the idea that concomitant prophylactic aortic arch replacement during elective valve sparing aortic root replacement in Marfan patients with non-aneurysmal aortic arch is not necessary.