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Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

Background: Patellofemoral instability (PFI) is a condition that leads to recurrent dislocation events and is typically secondary to extensor mechanism malalignment and rotational deformities. To correct malalignment, a tibial tubercle osteotomy (TTO) can be performed; however, an understanding of the associated complications, recurrence rates, and potential for reoperation is necessary. Purpose: To systematically review the literature to determine the incidence of postoperative complications, rate of recurrent instability, and all-cause reoperation rate after TTO for PFI. Study Design: Systematic review; Level of evidence 4. Methods: The Cochrane Database of Systematic Reviews, PubMed, Embase, MEDLINE, and CINAHL were queried for studies that reported complications after TTO. No date limits were applied. A total of 1050 studies were identified. Complications were categorized into “minor” and “major” groups using a modified Clavien-Dindo Classification. A meta-analysis was conducted to examine complication rates, recurrent instability, and all-cause reoperation, utilizing a DerSimonian and Laird random-effects model. A meta-analysis for recurrent instability was subgrouped according to follow-up periods of ≤2 years and >2 years. Results: A total of 38 studies were included, comprising 1546 patients, representing 1733 knees. The study dates ranged from 1989 to 2024, and the level of evidence ranged from 2 to 4. The weighted mean age at surgery was 24.1 years (range, 20-54 years), and 67% of patients were women. The weighted mean follow-up of all studies was 4.2 years. Overall, 197 minor complications, 39 major complications, 90 recurrent instability events, and 275 reoperations were identified. The minor complication rate was 9% (range, 0%-65% [95% CI, 6%-13%]). The major complication rate was 3% (range, 0%-10% [95% CI, 3%-4%]). Seven studies had a ≤2-year follow-up, and the remaining 31 studies had a >2-year follow-up. The recurrent instability rate was 3% in studies with ≤2 years of follow-ups (range, 0%-26% [95% CI, 1%-13%]). In studies with >2 years of follow-up, the recurrent instability rate was 8% (range, 0%-31% [95% CI, 6%-12%]). The all-cause reoperation rate was 16% (range, 0%-54% [95% CI, 11%-21%]). Conclusion: This systematic review and meta-analysis identified the incidence of complications (17%), the rate of recurrent instability (3%-8%), and the all-cause reoperation rate (16%) after TTO. TTO, performed alone or in combination with medial patellofemoral ligament reconstruction for the treatment of PFI, reliably improved clinical outcome scores in the setting of variable complication rates. Interestingly, rates of recurrent instability increased over time, and most reoperations were undertaken for hardware removal rather than revision patellar stabilization surgery.

Abstract Background Mitotane monotherapy is the standard adjuvant treatment for adrenocortical carcinoma (ACC), yet reliable predictors of treatment response remain lacking. Given the well-recognized interplay between inflammation and cancer progression, serum inflammation-based scores have shown prognostic significance in various malignancies, including ACC in palliative settings. However, their relevance during adjuvant mitotane therapy remains uncertain. This study aimed to assess the prognostic value of inflammation-scores in patients with ACC receiving adjuvant mitotane. Methods Multicenter ENSAT retrospective study including patients with ACC treated with adjuvant mitotane as first-line therapy. Clinical data including age, sex, ENSAT tumor stage, Ki67 index, resection status, and hormone secretion were collected at diagnosis. Inflammation-scores - neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), systemic immune inflammation index (SII), and pan-immune-inflammation value (PIV) - were calculated at diagnosis (pre-surgery) and at mitotane start. Median values of inflammation-scores at diagnosis defined low and high levels. Overall survival (OS) and time to progression (TTP) from mitotane start were the primary endpoints. Results The study included 395 patients (66% female; median age: 51 years). Median time to mitotane start was 54 days (IQR: 32–90). At diagnosis, patients with glucocorticoid excess (n=84) had significantly higher inflammation-scores than those without (n=104): NLR (3.61 vs 2.53), dNLR (2.31 vs 1.72), SII (864.1 vs 679.3), and PIV (531.6 vs 343.1); all p≤0.005. All scores significantly declined after surgery (p<0.05). Higher inflammatory scores at diagnosis were associated with worse OS (NLR: HR=3.85, 95%CI=1.95–7.59, p<0.001; dNLR: HR=3.19, 95%CI=1.67- 6.08, p<0.001; SII: HR=1.97, 95%CI = 1.07–3.61, p=0.03; PIV: HR=2.11, 95%CI=1.13-3.95, p=0.02). However, only the NLR and dNLR remained independently associated with OS at multivariate analysis adjusted for ENSAT stage, Ki67 index, and resection status (p<0.05). At mitotane start (n=372), high SII and PIV were associated with shorter TTP (SII: HR=1.36, 95%CI=1.02-1.82, p=0.03; PIV: HR=1.40, 95%CI=1.04-1-87, p=0.02), with only SII remaining significant at multivariate regression (p=0.04). Conclusions Inflammation-based scores are higher in patients with glucocorticoid excess and decrease postoperatively. NLR and dNLR at diagnosis, and SII at mitotane start, are associated with clinical outcomes in patients with ACC receiving mitotane adjuvant monotherapy. These readily available markers may help improve prognostic stratification in clinical practice.

ABSTRACT Objective Autosomal dominant progranulin ( GRN ) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN ‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Methods Utilizing T1 and task‐free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole‐brain degree, and GRN ‐relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive‐compulsive disorder symptom severity, and gray matter volume. Results Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive‐compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN ‐frontotemporal dementia. Interpretation In asymptomatic carriers, the co‐occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P < 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Abstract We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.

Background: Treatment decisions in patients with anterior cruciate ligament (ACL) injuries are influenced by multiple factors, such as the desire to return to sports or symptomatic instability. Identifying the differential treatment effect of ACL reconstruction (ACLR) compared with nonoperative management on a patient-specific level can inform surgical decision-making. Hypothesis: Unsupervised machine learning can identify distinct patient subgroups based on outcome achievement after ACL injury, and ACLR will exert a protective effect on the development of posttraumatic osteoarthritis (PTOA) over nonoperative management. Study Design: Cohort study; Level of evidence, 3. Methods: A longitudinal populational registry identified patients with ACL injuries from 1990 to 2016 with a minimum 7.5-year follow-up. An unsupervised random forest algorithm was utilized to develop and validate patient subgroups. Treatment effects of ACLR on outcomes were analyzed using a machine learning causal inference estimator. Patient subgroup membership was incorporated into a multivariable logistic regression to identify factors predictive of optimal outcomes. Results: A total of 923 patients (785 primary ACLR, 138 nonoperative) were included. The random forest algorithm arrived at an optimal partition of 2 subgroups, with 653 patients in the optimal outcome subgroup (368 male [56.4%]; mean age, 26.0 ± 10.2 years; mean body mass index [BMI], 26.5 ± 4.30) and 270 patients in the suboptimal outcome subgroup (152 male [56.3%]; mean age, 35.0 ± 10.1 years; mean BMI, 30.5 ± 5.54). The latter group demonstrated significantly increased rates of secondary meniscal injury, development of symptomatic PTOA, and progression to total knee arthroplasty (TKA) at the final follow-up (all P < .01). In the optimal outcome subgroup, ACLR had significantly protective treatment effects on the risk of secondary meniscal injury (average treatment effect [ATE], 61%), contralateral ACL injury (ATE, 8%), symptomatic PTOA (ATE, 16%), and progression to TKA (ATE, 6%) (all P < .01). Conversely, in the suboptimal outcome subgroup, ACLR only protected against symptomatic PTOA (ATE, 11%) and progression to TKA (ATE, 8%) (both P < .01). Conclusion: Two clinically meaningful subgroups were identified from retrospectively collected data and found to experience differential treatment responses after ACL injuries. ACLR decreased the rate of development of PTOA and TKA in both subgroups but was not as effective in preventing secondary meniscal injuries or contralateral ACL injuries in patients who were older, heavier, or had concomitant medial meniscus injuries.

Abstract Anterior cruciate ligament reconstruction (ACLR) using bone–patellar tendon–bone autograft remains one of the most common autografts used, and there is significant evidence to support its title as the “gold standard.” There are nuances and technical challenges associated with every step of an ACLR, which always leave room for improvement. The purpose of this Technical Note is to provide reproducible, technical pearls where errors are commonly encountered during ACLR. In this article, we detail 10 technical pearls that surgeons should consider to enhance operative workflow and optimize success during ACLR with a bone–patellar tendon–bone autograft. Technique Video video See video under supplementary data.

ImportanceIdentifying factors associated with resilience during the COVID-19 pandemic can inform targeted interventions and resource allocation for groups disproportionately affected by systemic inequities.ObjectiveTo examine factors associated with self-reported resilience during the COVID-19 pandemic in racially and ethnically diverse, community-dwelling US adults.Design, Setting, and ParticipantsThis cross-sectional study was conducted as part of the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) study, which assessed the associations of the pandemic with self-reported resilience of participants from 14 established US prospective cohorts since January 2021. This report includes participants who responded to the self-reported resilience question on C4R questionnaires. Data was initially analyzed from October 2023 to May 2024, with updated analyses performed from August 2024 to April 2025.ExposureRace and ethnicity, behavior factors, health conditions, and social determinants of health measurements accessed before and during the COVID-19 pandemic through cohort visits and C4R questionnaires.Main Outcomes and MeasuresSelf-reported resilience was collected via 1 question (from the Brief Resilience Scale) in C4R questionnaires, “I tend to bounce back quickly after hard times.” Participants who answered agree or strongly agree were classified as resilient, and those who reported neutral, disagree, or strongly disagree were classified as not resilient. Modified Poisson regression was performed to estimate prevalence ratios (PRs) and access multivariable-adjusted associations with resilience.ResultsOf 31 045 participants (18 672 [60%] women; 10 746 [34.6%] aged &amp;lt;65 years), 1185 (3.8%) identified as American Indian, 6728 (21.7%) as Black, 293 (0.9%) as East Asian, 6311 (20.3%) as Hispanic, 565 (1.8%) as South Asian, and 15 961 (51.3%) as White; a total of 23 103 participants (74.4%) self-identified as resilient. Compared with White participants, Black and Hispanic participants had higher prevalence of self-reported resilience (adjusted PR [aPR], 1.04; 95% CI, 1.02-1.06; aPR, 1.08; 95% CI, 1.06-1.11; respectively) and American Indian and East Asian participants had lower prevalence (aPR, 0.90; 95% CI, 0.86-0.94; aPR, 0.76; 95% CI, 0.68-0.84; respectively). Higher education, being married or living as married, higher income, and overweight were also associated with higher prevalence of resilience. Being female, having diabetes, and being unemployed were associated with lower prevalence of self-reported resilience. Compared with participants with public insurance only, participants with private insurance had higher prevalence of resilience (aPR, 1.07; 95% CI, 1.03-1.10). COVID-19 vaccination and infection statuses were not significantly associated with resilience. Modification analyses showed important racial and ethnic differences in how factors such as hypertension, marital status, and insurance status were associated with resilience.Conclusions and RelevanceIn this cross-sectional study of 31 045 adults, self-reported resilience varied by race, ethnicity, and sociodemographic factors. These findings highlight the complex interplay of individual and social factors in shaping the perception of resilience.

Abstract INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.