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Background: Hip arthroscopy continues to advance and become increasingly commonly performed. With the evolution of techniques and instrumentation, labral repair rather than debridement has emerged as the treatment of choice for labral pathology. There remains a lack of data on long-term outcomes after labral repair. Purpose: To (1) evaluate long-term patient-reported outcomes of primary hip arthroscopy with labral repair for femoroacetabular impingement, (2) report achievement rates of Patient Acceptable Symptom State (PASS) and minimal clinically important difference (MCID), and (3) investigate rates of reoperation and progression to total hip arthroplasty (THA). Study Design: Case series; Level of evidence, 4. Methods: Prospectively collected data were reviewed for patients who underwent primary hip arthroscopy with labral repair between 2010 and 2013. Patients’ medical records were reviewed for demographic characteristics, intraoperative findings, reoperation, and progression to THA. Patients were assessed pre- and postoperatively using the following scales: visual analog scale (VAS) for pain; Tegner activity scale; modified Harris Hip Score (mHHS); 12-item International Hip Outcome Tool (iHOT-12); Hip Outcome Score–Activities of Daily Living (HOS-ADL); HOS–Sport-Specific Subscale (HOS-SSS); and Non-Arthritic Hip Score. Patients were also surveyed for satisfaction, subjective improvement, and level of function. Results: A total of 32 patients (n = 24 women; n = 8 men) with a mean age of 27.7 years (range, 13.6-51 years) were evaluated for a mean of 9.4 years (range, 9-12.1 years). Patients achieved significant mean improvements in VAS pain at rest of 2 points, VAS pain with use of 1.9, mHHS of 19.9 points, iHOT-12 of 33.5 points, HOS-ADL of 17.4 points, and HOS-SSS of 29.5 points ( P≤ .015 for all). Eleven patients (34.4%) underwent reoperation and 4 (12.5%) progressed to THA during the study period. At the final follow-up, the MCID achievement rate was ≥68%, the PASS achievement rates ranged from 39% to 65%, and the mean patient satisfaction was 8.1 on a 1 to 10 scale, with 10 denoting most satisfied. Conclusion: Patients demonstrated significant postoperative improvements in pain, mHHS, iHOT-12, HOS-ADL, and HOS-SSS scores at 9 years postoperatively. The all-cause reoperation rate was 34.4%, and 12.5% of patients progressed to THA.

AbstractIntroductionOne goal of the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40–64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.MethodsLEADS amyloid‐positive early‐onset Alzheimer's disease (EOAD) or negative early‐onset non‐AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar‐age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.ResultsPreviously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DiscussionResults suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.Highlights Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) is a key resource for early‐onset Alzheimer's genetic research

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5′-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 −7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Background: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. Design: A prospective, observational cohort study. Methods: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. Results: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml (P = 0.003) and -55.6 ng/ml (P = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 (r = 0.64, P = 0.002; r = 0.58, P = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. Conclusion: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

Background: Arthrofibrosis (AF) after anterior cruciate ligament reconstruction (ACLR) remains a challenge. There is a paucity of data on arthroscopic interventions for AF after ACLR. Purpose: To (1) describe the patient, injury, and surgical characteristics and patient-reported outcomes (PROs) of those requiring an arthroscopic intervention for loss of motion after ACLR and (2) compare outcomes between patients undergoing an early intervention (within 3 months) versus those undergoing a late intervention (after 3 months). Study Design: Case series; Level of evidence, 4. Methods: Patients with a history of ACLR and a subsequent operative procedure for postoperative AF at a single institution between 2000 and 2018 were retrospectively identified. Arthroscopic interventions included lysis of adhesions, capsular release with or without manipulation under anesthesia, and excision of cyclops lesions. Patients were excluded if they had a knee dislocation or multiple-ligament injury, a periarticular fracture, or less than 2-year follow-up from the arthroscopic intervention. PROs including the Tegner activity score, visual analog scale pain score, and International Knee Documentation Committee score as well as knee range of motion (ROM) were recorded. Results: A total of 40 patients were included with a mean age of 27.2 years (range, 11.0-63.8 years) at surgery and a mean follow-up of 10.0 years (range, 2.9-20.7 years). The mean preoperative flexion and extension were 102° (range, 40°-150°) and 8° (range, 0°-25°), respectively. The mean postoperative flexion and extension were 131° (range, 110° to 150°) and 0° (range, –10° to 5°), respectively. After the arthroscopic intervention, the mean ROM improved from 94° (range, 40°-140°) preoperatively to 131° (range, 107°-152°) at final follow-up ( P < .001), and the visual analog scale pain score improved from 3.0 preoperatively to 1.2 postoperatively ( P = .001). Overall, 13 patients (32.5%) underwent an intervention within 3 months and 27 (67.5%) after 3 months. The early intervention group had a higher postoperative International Knee Documentation Committee score compared with the late intervention group (86.8 vs 71.7, respectively; P = .035). Conclusion: An arthroscopic intervention for AF after ACLR successfully improved knee ROM and pain. Patients who underwent either early or late surgery obtained satisfactory motion and function, although improved PROs were observed when the intervention occurred within 3 months of the primary procedure.

Purpose To evaluate long‐term patient‐reported outcomes and achievement rates of patient acceptable symptomatic state (PASS) in young athletes undergoing hip arthroscopy, and to report long‐term sports continuance and reoperation. Methods Inclusion criteria consisted of age <24 years at surgery, femoroacetabular impingement undergoing primary hip arthroscopy with labral repair, and participation in sport with intent to return to sport after surgery. The enrollment period was from April 2009 to June 2014. Modified Harris Hip Scores (mHHS), Hip Outcome Score (HOS), HOS Activities of Daily Living (HOS‐ADL), and HOS Sport (HOS‐Sport) were collected preoperatively, 2 years’ postoperatively, and final follow‐up. Patients were evaluated for PASS achievement, reoperation, and sports participation. Results Forty‐two hips in 37 patients (11 male, 26 female, age: 17.7 ± 2.1 years, range 13.6‐23.0, body mass index 22.8 ± 2.9, range 17.6‐33.7) met inclusion criteria and were followed for 10.0 ± 1.3 years (range 8.5‐13.0) postoperatively. Mean mHHS, HOS‐ADL and HOS‐Sports outcome scores at minimum 8.5 years were 82.2 ± 12.9, 89.6 ± 10.9, and 81.8 ± 16.4, respectively, with significant ( P < .001) postoperative improvements. Thirty survey respondents (83%) met PASS for mHHS, 27 (75%) for HOS‐ADL, and 24 (67%) for HOS‐Sports. At minimum 8.5‐year follow‐up, only 9 of 37 (24%) cited their hip as the reason for stopping sport. Of the remaining patients, 17 of 28 (61%), continued playing their initial sport. There was no difference in patient‐reported outcomes between patients who endorsed sports continuance and patients who did not report sports continuance and did not cite their hip as a reason ( P ≥ .229). At final follow‐up, 4 hips (10%) had undergone subsequent surgical intervention at a mean of 4.8 ± 3.3 years (range 1.0‐8.4) postoperatively. Conclusions Durable mid‐term outcomes and satisfactory PASS achievement rates are observed in young amateur athletes undergoing primary hip arthroscopy. At minimum 8.5‐year follow up, approximately 1 in 4 patients discontinue their sports due to hip related reasons. Level of Evidence Level IV, case‐series.

Abstract Objectives To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. Methods Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron’s papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). Results In total 1054 patients were included (DM, n = 405; ASyS, n = 649). In the ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic’s hands, Raynaud’s phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P &lt; 0.001), whereas higher frequency of any of four DM-type rashes—heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V-sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%)—differentiated DM from ASyS-DMskin (all P &lt; 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both P &lt; 0.001). Conclusion DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

Abstract INTRODUCTION We aimed to describe baseline amyloid‐beta (Aβ) and tau‐positron emission tomograrphy (PET) from Longitudinal Early‐onset Alzheimer's Disease Study (LEADS), a prospective multi‐site observational study of sporadic early‐onset Alzheimer's disease (EOAD). METHODS We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)‐PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ−) based on the combination of visual read by expert reader and image quantification. RESULTS 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid‐PET; 231 (95.1%) of them were tau‐PET positive (A+T+). Tau‐PET signal was elevated across cortical regions with a parietal‐predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau‐PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS 72% of patients with clinical EOAD were positive on both amyloid‐ and tau‐PET. Amyloid‐positive patients with EOAD had high tau‐PET signal across cortical regions. In EOAD, tau‐PET mediated the relationship between amyloid‐PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau‐PET.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.