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Objective: To externally validate by revision and update the study on the efficacy of nosocomial infection control (SENIC) model of surgical site infection (SSI) using logistic regression (LR) and machine learning (ML) approaches., Methods: A retrospective analysis of hospital database-derived data from patients that had undergone gastrointestinal, colorectal and hernia surgeries (identified by ICD-9-CM). The SENIC index was calculated and fitted in an LR. MLs were developed using decision-tree (DT), random forest (RF), extreme-gradient-boosting (XGBoost) and Naïve Bayes (NB)., Results: The prevalence of an SSI was 3.21% (404 of 12 596 surgeries; 95% confidence interval [CI] 2.91%, 3.53%). The C-statistic for the original SENIC model was 0.668 (95% CI 0.648, 0.688) with an observed/expected (O/E) ratio of 0.998 (interquartile range [IQR] 0.750, 1.047). An updated-SENIC-LR model with six predictors had a C-statistic of 0.768 (95% CI 0.745, 0.790) and O/E ratio of 0.999 (IQR 0.976, 1.004). The performance of MLs considering 14 predictors was poorer than the updated-SENIC-LR with C-statistics of 0.679, 0.675, 0.656 and 0.651 for NB, XGBoost, RF and DT, respectively. Overfitting was detected for ML approaches, particularly for DT, RF and XGBoost., Conclusion: The updated-SENIC-LR model and NB may be useful for monitoring SSI risk following abdominal surgery., Competing Interests: Declaration of conflicting interestThe authors declare that there are no conflicts of interest.

Students with intellectual and developmental disabilities (IDD) are likely to experience psychiatric symptoms, like depression, anxiety, and distress, throughout their lifetime. Due to communication differences and minimal use of specialized diagnostic assessments for anxiety and depression, emotional pain can often be overlooked or underestimated in students with IDD. This is often complicated by atypical presentations of anxiety and depression, such as externalized aggression, self-injurious behaviors, or other behavioral dysregulation, that can indicate emotional distress, physical pain, or other medical complications. School nurses play an important role in assessing for emotional and physical pain in students with IDD using assessment tools currently available and clinical judgment. Tools that have been created for use in this population may account for the diversity of communication, sensory, and developmental differences in students with IDD. Through leading education and advocacy for the interprofessional school team, school nurses can increase the access that students with IDD have to equitable emotional health evaluations and services. School nurses can also promote emotional wellness for students with IDD through the incorporation of mindful and community activities in the care plan.

Objective: To identify the risk factors for and short-term prognosis of intrauterine infection (IUI) in preterm infants., Methods: We retrospectively collected clinical data regarding preterm infants (28 +0 -36 +6 weeks of gestational age) with IUI from the neonatal intensive care unit of our hospital between June 2017 and June 2022. The pathologic characteristics of the infants were classified using the Redline criteria, and the resulting groups were compared with respect to their clinical characteristics, indicators of infection, complications, and mortality rates., Results: Three hundred thirty (78.1%) of the 422 enrolled neonates showed signs of histologic IUI; 51.8% showed histologic chorioamnionitis alone, and 48.2% showed both histologic chorioamnionitis and funisitis. The independent risk factors identified for IUI were maternal prenatal invasive manipulation, premature rupture of membranes (>18 hours before labor), and prenatal C-reactive protein concentration. The infants with IUI showed higher incidences of respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity, and prolonged mechanical ventilation. Low gestational age and low birth weight of preterm infants were significantly associated with a higher incidence of histologic IUI, more severe inflammation, and a higher incidence of complications., Conclusions: Histologic IUI is associated with high complication and mortality rates in preterm infants, as is an increasing severity of inflammation., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

This comprehensive case study aimed to highlight the condition of pulmonary embolism (PE), which despite its relative obscurity, may be more common than initially assumed. PE frequently occurs in the Emergency Department. PE along with deep vein thrombosis are the two most prevalent forms of venous thromboembolism (VTE). VTE ranks as the third most common cardiovascular condition encountered in the Emergency Department, following heart attacks and strokes. Acknowledging the symptoms of VTE and acting on them early are important to prevent chronic manifestations and heart failure in some cases owing to persisting pulmonary hypertension. One of the most frequent causes of VTE is surgery, which often occurs owing to immobilization. However, in some cases, VTE is due to the procedure itself or due to what is used in the procedure or injected in the patient. We report the case of a patient who complained of dyspnea for some time before diagnostic steps were taken, such as computed tomography and echocardiography. This case report describes the complication of PE due to vertebroplasty, which is well described but underdiagnosed because it may not be considered. More focus on this complication during follow-up could help diagnose and treat patients more rapidly., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Background: Both high body mass index (BMI) and anterior cruciate ligament reconstruction (ACLR) independently influence knee osteoarthritis risk. Preliminary evidence shows the combination of these risk factors leads to poorer recovery and altered biomechanical outcomes after ACLR, but few studies have directly evaluated early changes in cartilage health between normal-BMI and high-BMI groups in this population., Purpose: To evaluate ultrasound-based measures of cartilage strain and compositional changes (via echo-intensity [EI]) in response to an incline walking stress test between normal-BMI and high-BMI individuals with ACLR. A secondary evaluation was conducted of associations between habitual walking biomechanics (ie, ground-reaction forces, sagittal knee kinetics and kinematics) and cartilage strain and EI outcomes., Study Design: Controlled laboratory study., Methods: Gait biomechanics and femoral trochlear ultrasound analyses were evaluated in 64 participants with ACLR who had normal BMI (BMI < 27.0; n = 40) and high BMI (BMI ≥ 27.0; n = 24). Ultrasound images were collected bilaterally before and after an incline treadmill walk, and medial and lateral trochlear strain and EI changes pre-post exercise were used to compare BMI groups and limbs. Gait outcomes included ground-reaction forces, peak sagittal plane knee moments, angles, and excursions and were used to determine associations with cartilage outcomes in the entire cohort., Results: High-BMI individuals with ACLR exhibited greater medial trochlear cartilage strain in the ACLR limb compared with normal-BMI individuals (approximately 6%; P < .01). In those with high BMI, the ACLR limb exhibited greater medial trochlear strain relative to non-ACLR limbs (approximately 4%; P < .05), but between-limb differences were not observed in the normal-BMI group ( P > .05). Medial trochlear EI changes were greater bilaterally in those with high BMI compared with normal-BMI ACLR counterparts (approximately 10%; P < .01). Last, individuals who walked with greater peak knee flexion angles exhibited less medial cartilage strain (Δ R 2 = 0.06; P = .025)., Conclusion: The data suggested that high BMI affects cartilage functional properties after ACLR, whereas smaller knee flexion angles were associated with larger medial cartilage strain., Clinical Relevance: High-BMI individuals with ACLR may represent a subset of patients exhibiting earlier declines in cartilage functional integrity in response to loading, necessitating additional or more targeted interventions to mitigate disease development., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. This study was approved by the Medical Institutional Review Board (IRBMED) at the University of Michigan (HUM00169174), and data were collected at the University of Michigan Orthopedic Rehabilitation Biomechanics (ORB) Laboratory.

Objective: To evaluate the relationship between nutritional scoring systems, nutritional support methods, and the prognosis of severe and critically ill patients infected with the Omicron variant of coronavirus disease 2019 (COVID-19)., Methods: Patients with confirmed Omicron variant severe and critical COVID-19, who were admitted to Chongqing Medical University First Hospital between December 2022 and January 2023, were enrolled into this retrospective study. Clinical data of patients who survived for 28 days were compared with those who died during the same period. Nutritional status was assessed using the 2002 Nutrition Risk Screening (NRS) tool and Prognostic Nutritional Index (PNI). Factors influencing patient mortality were identified by multivariate logistic regression, and the relationship between patient nutrition and mortality as the disease progressed was illustrated using Kaplan-Meier curves. The study was registered on the ChiCTR platform (No. ChiCTR2300067595)., Results: A total of 508 patients were included (349 survivors and 159 non-survivors). Significant differences were found in sex, age, NRS score, PNI score, albumin level, lymphocyte count, chronic comorbidities, mechanical ventilation, neutrophil count, procalcitonin, and platelet count between survivors and non-survivors. Multivariate analysis revealed that high NRS score (OR 3.87, 95% CI, 1.97, 7.63), fourth-level nutritional support (combined enteral and parenteral nutrition; OR 7.89, 95% CI, 1.32, 47.28), chronic comorbidities (OR 4.03, 95% CI, 1.91, 8.51), and mechanical ventilation (OR 6.03, 95% CI, 3, 12.13) were risk factors for mortality (OR > 1). The malnutrition rate among patients with NRS ≥ 3 was 41.93%. The median (interquartile range) PNI score was 38.20 (35.65, 41.25) for survivors versus 32.65 (29.65, 36.58) for non-survivors. The mortality rate was higher in patients with high nutritional risk within 28 days of hospitalization. The descending order for mortality rate in patients receiving different nutritional support was: dual parenteral and enteral nutrition, no nutritional intervention, single enteral nutrition, and single parenteral nutrition., Conclusion: A high proportion of severe and critically ill patients with COVID-19 experience malnutrition, and various factors are associated with their prognosis. High nutritional risk is significantly related to patient mortality. Early assessment using NRS or PNI is crucial for these patients, and personalized interventions should be implemented to improve overall nutritional status, maintain organ function, and enhance the body's antiviral defence., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Brain abscesses caused by Mycobacterium tuberculosis are rarely reported and are typically found in immunocompromised patients. The challenges in identifying the pathogen and the frequent delays in initiating appropriate therapy often result in a poor prognosis for patients. We herein report a rare case of a brain abscess caused by M. tuberculosis in a 63-year-old patient with a history of hypertension but no history of pulmonary tuberculosis. The patient was hospitalized twice because of worsening right upper limb weakness and speech difficulties. Both a pus culture and cerebrospinal fluid culture were negative. Ultimately, the diagnosis of M. tuberculosis infection was confirmed through next-generation sequencing and the tuberculosis-specific T-cell test (T-SPOT). The patient's symptoms improved following anti-tuberculosis treatment. This case highlights the importance of considering M. tuberculosis as a potential cause of brain abscesses, even in immunocompetent individuals, and underscores the need for early diagnosis for effective treatment., Competing Interests: Declaration of conflicting interestsThe authors declare that they have no conflicts of interest.

Background: Nonoperative management of posterior shoulder instability is common. However, limited data are available to assess the pathomorphologic factors associated with its failure., Purpose/hypothesis: The purpose of this study was 2-fold: (1) to determine glenohumeral pathomorphologic features predictive of nonoperative management failure of posterior instability; and (2) to determine the relationship between nonoperative management failure and posterior glenoid bone loss (pGBL) progression. It was hypothesized that greater posterior acromial height (PAH) would adversely affect nonoperative survivorship and that shoulders treated nonoperatively would have pGBL progression compared with those undergoing surgical stabilization., Study Design: Case-control study; Level of evidence, 3., Methods: This was a retrospective review of a consecutive series of patients with isolated posterior shoulder instability, defined as isolated posterior labral tear on magnetic resonance imaging (MRI) with corresponding physical examination findings, who underwent nonoperative management for 6 months and had no previous related surgical history. The primary outcome of interest was the failure of nonoperative management, defined as the inability to return to full military duty or requiring surgical intervention. The morphologic features assessed for association with nonoperative management failure included pGBL, glenoid version, acromial morphology, and posterior humeral head subluxation. We secondarily sought to determine the progression of pGBL on serial MRI scans. Cox proportional hazard analysis was used to evaluate risk factors for failure., Results: In this study, 42 of 90 (46.7%) patients had failed nonoperative management and went on to receive an arthroscopic stabilization procedure. The group with failed treatment demonstrated a greater humeral head subluxation ratio than those with successful nonoperative management (0.65 ± 0.2 vs 0.62 ± 0.2; P = .038). Cox proportional hazard analysis identified pGBL, greater PAH, less posterior acromial coverage, and posterior humeral subluxation as significant risk factors for failure. Of those with failed nonoperative management, 17 had repeat MRI scans at a mean of 488.2 ± 87 days after index MRI for comparison, demonstrating a statistically significant progression of pGBL (index MRI, 2.68% ± 1.71%) versus after nonoperative treatment failure (6.54% ± 1.59%; P = .003)., Conclusion: Failure occurred 47% of the time in patients who underwent nonoperative management for isolated posterior glenohumeral instability for a minimum of 6 months, and it was associated with a greater posterior humeral head subluxation, less posterior acromial coverage, greater PAH, and greater amounts of glenoid retroversion on index MRI. Additionally, those who had repeat MRI approximately 1 year after the index MRI demonstrated greater pGBL compared with the index MRI., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: P.K.M. has received support for education from Supreme Orthopedic Systems. M.D.B. has received support for education from Supreme Orthopedic Systems and Stryker Corporation. B.G.Y. has received support for education from Supreme Orthopedic Systems, Southtech Orthopedics, and Stryker Corporation. T.J.D. has received a grant from DJO; support for education from Gemini Mountain Medical, CGG Medical Inc, Evolution Surgical, and Smith & Nephew; and hospitality payments from Arthrex. L.E.L. has received a grant from DJO and support for education from Alpha Orthopedic Systems, Arthrex, and Supreme Orthopedic Systems. K.G.K. has received support for education from Supreme Orthopedic Systems and compensation for services other than consulting from Arthrex. J.F.D. has received support for education from SouthTech Orthopedics and Supreme Orthopedic Systems; compensation for services other than consulting from Arthrex; and fellowship support from Arthrex and Smith & Nephew. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. The views expressed in this manuscript reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown., Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient's outcome at 6-year follow-up., Study Design: Cohort study; Level of evidence, 2., Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) subjective form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity rating score. Patients were followed up for 6 years and asked to complete the identical set of outcome instruments. Regression analysis was used to control for baseline patient characteristics and surgical variables to assess the surgical risk factors for clinical outcomes 6 years after surgery., Results: A total of 1234 patients were enrolled (716 men, 58%; median age, 26 years), and 6-year follow-up was obtained on 79% of patients (980/1234). Using an interference screw for femoral fixation compared with a cross-pin resulted in significantly better outcomes in 6-year IKDC scores (odds ratio [OR], 2.2; 95% CI, 1.2-3.9; P = .008) and KOOS sports/recreation and quality of life subscale scores (OR range, 2.2-2.7; 95% CI, 1.2-4.8; P < .01). Use of an interference screw compared with a cross-pin resulted in a 2.6 times less likely chance of having a subsequent surgery within 6 years. Use of an interference screw for tibial fixation compared with any combination of tibial fixation techniques resulted in significantly improved scores for IKDC (OR, 1.96; 95% CI, 1.3-2.9; P = .001); KOOS pain, activities of daily living, and sports/recreation subscales (OR range, 1.5-1.6; 95% CI, 1.0-2.4; P < .05); and WOMAC pain and activities of daily living subscales (OR range, 1.5-1.8; 95% CI, 1.0-2.7; P < .05). Use of a transtibial surgical approach compared with an anteromedial portal approach resulted in significantly improved KOOS pain and quality of life subscale scores at 6 years (OR, 1.5; 95% CI, 1.02-2.2; P ≤ .04)., Conclusion: There are surgical variables at the time of ACL revision that can modify clinical outcomes at 6 years. Opting for a transtibial surgical approach and choosing an interference screw for femoral and tibial fixation improved patients' odds of having a significantly better 6-year clinical outcome in this cohort., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This project was funded by grant No. 5R01-AR060846 from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases. All author disclosures are listed in the Appendix (available in the online version of this article). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: Clinical diagnosis in primary progressive aphasia (PPA) is challenging. Recently, emphasis has been placed on the importance of screening evaluation. Three different screening tests that use different strategies based on the assessment of language (Mini-Linguistic State Examination, MLSE) or different cognitive domains (Addenbrooke's Cognitive Examination, ACE-III and Dépistage Cognitif de Québec, DCQ) have been proposed and independently validated. These tests aim to detect PPA and classify into the three main variants (non-fluent (nfvPPA), semantic (svPPA) and logopenic (lvPPA))., Objective: This study aims to evaluate and compare the diagnostic capacity of these three instruments in PPA., Methods: A cross-sectional study including 43 patients with PPA (nfvPPA ( n  = 19), svPPA ( n  = 8), and lvPPA ( n  = 16)) and 21 cognitively unimpaired controls was conducted. Clinical diagnoses were established based on an extensive multidisciplinary assessment including neuropsychological assessment, fluorodeoxyglucose-positron emission tomography, MRI, and cerebrospinal fluid biomarkers. Both PPA patients and controls completed the three tests (MLSE, ACE-III, and DCQ)., Results: Internal consistency was excellent for the three tests. The area under the curve for the diagnosis of PPA was 0.950 for MLSE, 0.953 for ACE-III, and 0.933 for DCQ. Correlations between the three tests were high. The MLSE, ACE-III, and DCQ tests obtained adequate levels of discrimination between the variants of PPA, with accuracies between 76-79%., Conclusions: This study confirms the validity of ACE-III, MLSE, and DCQ for the diagnosis of PPA and its variants. This suggests that detailed assessment of linguistic characteristics (MLSE) and non-linguistic features (DCQ, ACE-III) are relevant for the diagnosis and classification of PPA., Competing Interests: Declaration of conflicting interestsJordi A Matias-Guiu is an Associate Editor of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review. The other authors have no conflict of interest to report. Data availabilityThe dataset is available from the corresponding author upon reasonable request.

Background: The impact of social isolation on social cognition is not entirely clear., Objective: The aim of the study is to investigate the association between social isolation and social cognition., Methods: In a population-based sample of 83 individuals aged 50+ years without dementia, we assessed the relationship between social isolation (measured by the Lubben Social Network Scale - LSNS-6) and performance on emotional recognition (measured by the Emotion Recognition Task (ERT)) and on Theory of Mind (ToM) abilities (measured by the Reading the Mind in the Eyes Test (RMET)), two core aspects of social cognition., Results: No significant association was found between social isolation and ToM abilities for both the unadjusted and adjusted models. Similarly, no significant association was observed between social isolation and emotion recognition., Conclusions: Further research is needed to understand the complex correlation between social relationships and cognitive health, particularly in different cognitive domains, adopting a life course perspective., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified., Objective: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype., Methods: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients., Results: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p  = 0.027 and +32.7%, p  = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = -0.444, p  = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = -0.786, p  = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p  = 0.004), driven by APOE4 carriers (r = 0.544, p  = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p  = 0.039) in AD. None of these results were found in MCI-AD patients., Conclusions: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The author FB has been granted by Amgen Inc. (Amgen's PSCK9 Competitive Grant Program 2018, grant number 9406917) with a project entitled: EXplorIng the paThophysological role of PCSK9 in Alzheimer's Disease: focus on inflammation and lipid metabolism (EXIT-AD).

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood., Objective: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis., Methods: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted., Results: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions., Conclusions: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions., Competing Interests: Declaration of conflicting interestsKazunari Ishii received lecture fees from Nihon Medi-physics Co., Ltd.

Background: Evidence on associations of remnant cholesterol (RC) and its variability with cognitive function is still lacking., Objective: To explore the association of RC and its variability with cognitive function., Methods: Participants were recruited from a population-based cohort, the China Health and Retirement Longitudinal Study (CHARLS). Cognitive function was assessed by a standardized questionnaire from CHARLS, with domains of episodic memory and mental intactness. A linear mixed effects model was used to analyze the association of RC with cognitive function, along with its variability (calculated as standard deviation [SD], coefficient of variation [CV], variability independent of the mean [VIM]), with results expressed as β (95%CI). Potential subgroup differences in the association of RC and its variability with cognitive function were also explored., Results: 4234 participants were eventually included, with mean (SD) age of 57.4 (8.0) years. Each 10 mg/dL increase in RC was associated with 0.053 (95%CI: 0.096, 0.009) points, 0.021 (95%CI: 0.042, 0.000) points, 0.032 (95%CI: 0.064, 0.001) points decrease in global cognitive function, episodic memory, and mental intactness scores, respectively. Compared with the first tertile (T1) group of RC variability (calculated as SD, VIM), T3 showed a lower level in global cognition and episodic memory after multivariate adjustment. The potential modification effects of educational level on RC and its variability in relation to cognitive function were also identified., Conclusions: Among Chinese middle-aged and older adults, higher RC level were associated with worse cognitive function. Greater RC variability was also associated with worse cognitive performance, especially in memory function.

Background: No large-scale characterizations of neurofilament light chain (NfL) and cognitive outcomes have been conducted in community-dwelling non-Hispanic Blacks., Objective: This study aims to enhance the application of blood biomarkers, in particular NfL, to ethno-racially diverse communities. We assess the association of NfL with cognitive outcomes, hypothesizing that NfL can identify cognitive changes regardless of diagnostic category., Methods: Baseline data were analyzed among n  = 283 non-Hispanic Blacks (NHB) from the multi-ethnic Health and Aging Brain Study- Health Disparities (HABS-HD). Plasma NfL was measured on the Simoa platform. Linear regression models were conducted, covarying for age, gender, and education., Results: The majority of study participants (72%) were cognitively unimpaired (CU), with 21% having mild cognitive impairment (MCI), and 6.7% with Alzheimer's disease (AD). In adjusted models among the entire sample, significant associations existed between NfL and Trails A ( p  < 0.0001), Trails B ( p  < 0.0001), phonemic (FAS) and semantic (Animals) fluency ( p  = 0.03), and Symbol Digit Substitution ( p  < 0.001). When separated by diagnostic classification, significant associations were removed for functions involving executive functions for all diagnostic groups. Higher levels of NfL were positively associated with cognitive diagnosis, older age, and less education., Conclusions: Plasma NfL levels are significantly associated with measures of executive functioning, which elucidate NfL as a non-specific marker of neurodegeneration associated with efficiency of brain functions involving attention, processing, and generativity. NfL may be a sensitive measure for the detection of alterations in cognitive processing before the onset of phenotypic functional changes of neurodegeneration., Competing Interests: Declaration of conflicting interestsSid O'Bryant is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review. All other authors have no conflict of interest to report.

Background: Reserves' mechanisms explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves., Objective: This study evaluates whether cognitive, social, and physical leisure activities performed over life-span predict current cognitive functioning in normal aging and Alzheimer's disease (AD) continuum., Methods: 35 AD, 24 amnestic-Mild Cognitive Impairment (a-MCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities' scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses., Results: Current level of cognition was predicted by (i) social and physical activities performed in middle age and current cognitive activity in AD; (ii) cognitive and social activities performed in middle age, current age and cortical thickness in a-MCI; (iii) recreational activities the set of lifetime, current age, and brain features in SCD; (iv) education and the set of lifetime leisure activities over lifespan in controls., Conclusions: This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging., Competing Interests: Declaration of conflicting interestsL.S. and M.B. are Editorial Board Members of this journal but were not involved in the peer-review process of this article nor had access to any information regarding its peer-review. The remaining authors have no conflict of interest to report.

Background: Effect of education attainment and nutritional status on the development of cognitive impairment in Chinese elderly has not been reported., Objective: To investigate the role of education and nutrition in preventing cognitive impairment in the hospitalized Chinese elderly., Methods: Cognitive function was examined using the scoring system of Mini-Mental State Examination (MMSE) domains performed under instruction of Physicians of Geriatrics. Generalized linear mixed-effect regression was used for analyzing the association of demographic factors (age and gender), socioeconomic factors (education attainment and monthly income), as well as health-related factors (nutritional status, comorbidity, anxiety, and depression) and MMSE scores., Results: Total 246 hospitalized Chinese elders were enrolled into this study. Of them, 96 participants were 60-70 years old, 65 participants were 71-80 years old, and 85 of them were 81 years or older. Of the examined factors, we found that age, education attainment, and nutritional status were significantly associated with the outcome of MMSE scores, while monthly income and health condition (comorbidity, anxiety, and depression) were not significantly associated with MMSE score. Furthermore, education attainment was significantly associated with majority of the MMSE domains, including orientation, registration, attention and calculation, recall, and most of language sub-domains., Conclusion: Education attainment and nutritional status were significantly associated with MMSE scores in the hospitalized Chinese elderly. Higher education and better nutritional status are protective factors for the development of cognitive impairment in the hospitalized elderly Chinese population., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Blood metabolites have emerged as promising candidates in the search for biomarkers for Alzheimer's disease (AD), as evidence shows that various metabolic derangements contribute to neurodegeneration in AD., Objective: We aim to identify metabolic biomarkers for AD diagnosis., Methods: We conducted an in-depth analysis of the serum metabolome of AD patients and age, sex-matched cognitively unimpaired older adults using ultra-high-performance liquid chromatography-high resolution mass spectrometry. The biomarkers associated with AD were identified using machine learning algorithms., Results: Using the discovery dataset and support vector machine (SVM) algorithm, we identified a panel of 14 metabolites predicting AD with a 1.00 area under the curve (AUC) of receiver operating characteristic (ROC). The SVM model was tested against the verification dataset using an independent cohort and retained high predictive accuracy with a 0.97 AUC. Using the random forest (RF) algorithm, we identified a panel of 13 metabolites that predicted AD with a 0.96 AUC when tested against the verification dataset., Conclusions: These findings pave the way for an efficient, blood-based diagnostic test for AD, holding promise for clinical screenings and diagnostic procedures., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Clinical and preclinical studies have shown that extra virgin olive oil (EVOO), a major component of the Mediterranean diet, has beneficial effects on brain aging and cognition. Individuals with Down syndrome develop age-dependent cognitive decline and synaptic dysfunction. However, whether EVOO intake is beneficial in Down syndrome is not known., Objective: In this study, by implementing a mouse model of Down syndrome, we aimed to investigate the effect that chronic administration of EVOO has on memory, synaptic function, and neuroinflammation., Methods: Starting at 4 months of age Ts65dn mice were randomized to receive EVOO for 5 months in their diet, after which they were tested for learning and memory impairment. After euthanasia, synaptic function was measured in freshly obtained hippocampal slices, whereas brain tissues were assessed for inflammatory biomarkers., Results: Compared with controls, mice receiving EVOO had a significant improvement in learning and spatial memory. Additionally, field potential recordings showed that treated mice had an improvement in synaptic function. Finally, array analysis showed that EVOO modulated the expression levels of several inflammatory biomarkers., Conclusions: Chronic administration of EVOO to a mouse model of Down syndrome has beneficial effects on memory impairments, synaptic function deficits and neuroinflammation. Our findings provide additional support for the potential therapeutic effects of EVOO also in individuals with Down syndrome., Competing Interests: Declaration of conflicting interestsDomenico Pratico is an Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding the peer-review.The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The aging global population is increasing the attention to cognitive decline in older individuals., Objective: This study sought to examine the potential link between the neutrophil percentage-to-albumin ratio (NPAR) and cognitive function., Methods: We analyzed data from the National Health and Nutrition Examination Survey 2011-2014 using multivariate logistic regression and smooth curve fitting, to investigate the correlation between NPAR and cognitive performance. Restricted cubic spline analysis assessed the linear relationship with high-risk cognitive dysfunction, while piecewise linear regression identified thresholds. Subgroup analyses confirmed the consistency and reliability of our findings., Results: Our study included data from 2759 individuals aged >60 years. NPAR showed a significant correlation with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning score, CERAD delayed recall score, total z-score and a high risk of cognitive dysfunction. Furthermore, there were statistically significant trends in the changes in CERAD word learning, digit symbol substitution test, and CERAD delayed recall scores as the NPAR quartile increased, these trends were inverted U-shaped. When the NPAR exceeded 14.57, there was a positive association with the likelihood of a high risk of cognitive impairment. The link between NPAR and cognitive performance was notably stronger in individuals with moderate body mass index and those aged 73-80 years., Conclusions: A strong link was observed between the NPAR and cognitive function. NPAR may serve as a tool to identify individuals at increased risk of cognitive decline., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The correlation between Alzheimer's disease (AD) and the glucose-triglyceride (TyG) index remains undetermined., Objective: This study aimed to investigate the relationship between the TyG index and AD, as well as the relationship between the TyG index and cerebrospinal fluid (CSF) AD biomarkers and cognition., Methods: Six hundred twenty-eight non-dementia participants were included. The TyG index, pathological markers, and cognitive measures were studied using multiple linear regression. Also calculated using a multivariate Cox regression model were the hazard ratio (HR) and its 95% confidence interval (CI). Ten thousand bootstrap iterative causal mediation analyses were performed to investigate the potential mediating effect of AD pathology on cognition., Results: The TyG index was linked to CSF AD biomarkers (β Aβ42  = 0.880; β Tau  = -0.674; β pTau  = -0.884; β Aβ42/pTau  = 1.764; β Aβ42/Tau  = 1.554; β pTau/Tau  = -0.210) and cognitive measurements (β MEM  = 0.570; β EF  = 0.535; β ADAS11  = -0.789). Mediation analysis revealed that the TyG index may influence cognition via CSF AD biomarkers, including Aβ 42 , tau, and pTau. Furthermore, each 1-unit increase in TyG index was associated with a 29.5% reduction in the risk of incident AD., Conclusions: A delayed rate of cognitive decline and a reduced risk of AD were found to be correlated with higher levels of the TyG index, but this does not mean increasing TyG index levels is beneficial for health. Through AD pathology, the TyG index may influence AD and cognitive changes., Competing Interests: Declaration of conflicting interestsLan Tan is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

Background: Women comprise approximately two-thirds of Alzheimer's disease cases., Objective: This is the first known study to investigate the role of intersectionality between gender and other social determinants of health (SDOH) in the presentation of cognitive symptoms (i.e., being asymptomatic or symptomatic) among those with pathologically confirmed Alzheimer's disease., Methods: We studied 3107 individuals with Alzheimer's disease neuropathology (ADNP) confirmed at autopsy. Asymptomatic ADNP was defined as the absence of a clinical diagnosis of mild cognitive impairment (MCI) or dementia before death (versus symptomatic: diagnosis of MCI/dementia). SDOH included gender, education, ethnoracial group, living alone, and primary language. Multivariable logistic regression tested associations between SDOH and asymptomatic ADNP (versus symptomatic); models were also stratified by gender., Results: Women, Hispanics, those living alone, and more educated individuals were found to have higher odds of asymptomatic ADNP. Non-English speakers had lower odds of asymptomatic ADNP. Both women and men had higher odds of asymptomatic ADNP if Hispanic or living alone. In only women, non-English speakers had lower odds while in only men, more education was associated with higher odds of asymptomatic ADNP., Conclusions: Gender, education, ethnicity, primary language, and living alone, and intersectionality of gender with primary language, may differentially influence MCI and dementia diagnosis prior to death among those with underlying ADNP. These findings emphasize the need for future Alzheimer's disease research to prioritize social determinants of brain health including their intersectionality with gender and how to inform targeted interventions., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Besser, Dr O’Shea, and Dr Galvin are Editorial Board Member of this journal but were not involved in the peer-review process of this article nor had access to any information regarding its peer-review. The remaining authors have no conflict of interest to report.

Background: Biomarkers of neuronal and axonal damage (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) may provide insight into the aetiology of natalizumab wearing-off symptoms (WoSs)., Objectives: We investigated the longitudinal association between and predictive value of sNfL and sGFAP and the occurrence of WoS in MS patients treated with natalizumab., Methods: We performed longitudinal measurements of sNfL and sGFAP in NEXT-MS trial participants who completed a questionnaire about WoS., Results: A total of 364 participants were included. In total, 55.5% presented with WoS and 44.5% without WoS during natalizumab treatment. Longitudinal analyses showed no association between sNfL and sGFAP levels and WoS at any timepoint. Biomarker levels at baseline did not predict first-time WoS occurrence., Conclusion: Acute and chronic neuronal and axonal damage are most likely not the underlying cause of WoS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: A.A.T. has nothing to disclose. M.H.J.W. has nothing to disclose. L.B. has nothing to disclose. L.M.Y.G. has nothing to disclose. E.H. has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche and Sanofi Genzyme. E.M.P.E.Z. reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. L.C.v.R. has nothing to disclose. C.E.P.v.M. has nothing to disclose. A.V. has nothing to disclose. J.P.M. has nothing to disclose. B.H.A.W. has nothing to disclose. N.F.K. has nothing to disclose. E.L.J.H. has nothing to disclose. J.J.J.v.E. reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. C.M.R. has nothing to disclose. J.J.K. has nothing to disclose. M.E. has nothing to disclose. J.N. has nothing to disclose. J.v.G. has nothing to disclose. L.G.F.S. has nothing to disclose. M.E.K. has nothing to disclose. E.P.J.A. has nothing to disclose. G.W.v.D. has nothing to disclose. W.H.B. has nothing to disclose. E.M.M.S. has nothing to disclose. B.W.v.O. has nothing to disclose. B.A.d.J. has nothing to disclose. B.M.J.U. reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche and Immunic Therapeutics. T.R. received funding for research from Genmab and consultancy fees from Novartis. J.K. received research grants for multicentre investigator-initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds) (ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution) and adjudication committee of MS clinical trial of Immunic (payments to institution only). Z.L.E.v.K. has nothing to disclose. C.E.T. reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434); has a research contract with Celgene; serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book Springer.

Background: Genetic variations in a common single nucleotide polymorphism in the ninth intron of the KIBRA gene have been linked to memory performance and risk of Alzheimer's disease (AD)., Objective: We examined the risk of AD related to presence of KIBRA T allele (versus CC homozygote) and to memory performance. The role of established genetic risk factors APOE ε4 and BDNF Met was also considered., Methods: Participants were cognitively healthy individuals (n = 19), participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 99) and AD dementia (n = 37) from the Czech Brain Aging Study. Binary and multinomial logistic regressions compared odds of belonging to a certain diagnostic category and multivariate linear regressions assessed associations with memory., Results: KIBRA T allele was associated with increased AD dementia risk (odds ratio [OR] = 5.98, p  = 0.012) compared to KIBRA CC genotype. In APOE ε4 negative individuals, KIBRA T allele was associated with a greater risk of both aMCI due to AD (OR = 6.68, p  = 0.038) and AD dementia (OR = 15.75, p  = 0.009). In BDNF Met positive individuals, the KIBRA T allele was associated with a greater risk of AD dementia (OR = 10.98, p  = 0.050). In AD dementia, the association between KIBRA T allele and better memory performance approached significance (β = 0.42; p  = 0.062). The link between possessing the KIBRA T allele and better memory reached statistical significance only among BDNF Met carriers (β = 1.21, p  = 0.027)., Conclusions: Findings suggest that KIBRA T allele may not fully protect against AD dementia but could potentially delay progression of post-diagnosis cognitive deficits., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Recent research suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce mortality in COVID-19 patients; however, research into their benefits for elderly Alzheimer's disease (AD) patients remains limited., Objective: To investigate the relationship between SSRIs therapy and the mortality risk after COVID-19 infection in elderly patients with and without AD., Methods: This retrospective cohort study leveraged a large database containing over 100 million electronic health records in the US from the TriNetX platform to compare the hazard rates of mortality after COVID-19 infection in elderly AD patients prescribed SSRIs versus propensity-score matched individuals prescribed other antidepressants. This study was also conducted in separate cohorts of patients without AD to compare the findings., Results: When compared with non-SSRI antidepressants, SSRIs were associated with lower risk for mortality after COVID-19 infection in elderly patients without AD over early, middle, and later stages of the pandemic with HRs of 0.84 (95% CI: 0.75-0.93), 0.86 (95% CI: 0.79-0.93), and 0.77 (95% CI: 0.71-0.33), respectively. When comparing SSRIs with non-SSRI antidepressants for mortality risk following COVID-19 among patients with AD, HRs of 0.95 (95% CI: 0.71-1.27), 0.80 (95% CI: 0.61-1.06), and 0.99 (95% CI: 0.75-1.32), were found respectively., Conclusions: Our findings suggest that the use of SSRIs is significantly associated with reduced mortality risk following COVID-19 in elderly patients without AD compared to other antidepressants. While a lower mortality risk was also observed among AD patients, the association was not statistically significant., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-β (Aβ) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population., Objective: Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein ( APOE ) ɛ4 status) risk factors in detecting preclinical AD., Methods: 125 cognitively unimpaired older adults (mean age = 66 years) who completed Aβ PET and plasma draw were analyzed using multiple regression with Aβ PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors APOE ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aβ 42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aβ PET status, and these markers were added in Model 4., Results: The best model for predicting Aβ PET status included age, years of education, APOE ɛ4 status, Aβ 42/40 ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model., Conclusions: Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JA receives funding from R21AG074153, R01AG079241, and the Warren Alpert Foundation. AL receives funding from R01AG068990, U24AG057437, U01AG057195 and the Alzheimer's Association.

Background: Degradation of magnetic resonance imaging (MRI) remains a challenging issue, with noise being a key damaging component introduced due to a variety of environmental and mechanical factors., Objective: The aim of this research work is to addresses the issue of noise reduction and to predict Alzheimer's disease detection efficiently., Methods: First, we present a genetic programming (GP) technique for reducing Rician noise in MRI images to pre-process the dataset. To effectively reduce Rician noise, this GP approach combines a Feature Extraction component, GP Optimal Expression, and an Optimum Removal Estimation component. In the second phase, we design and develop an explainable Deep Learning framework. This framework uses a local data-driven interpretation technique based on SHAP values to investigate the relationship between the neural network's estimated AD diagnosis and the input MRI images. In addition, we handle class distribution by combining an oversampling strategy with a minority approach. Several assessment metrics are used to analyze the performance of our proposed model., Results: The proposed method is tested on a variety of medical samples, and the results are compared to those obtained using other comparable approaches. We also test and compare our model to three cutting-edge models: DenseNet169, VGGNet15, and Inceptionv3., Conclusions: The empirical results show that our proposed model outperforms others, particularly in handling basic structures with limited spectral features, lower computational complexity, and less overfitting. This research worked addressed Rician noise issue in MRI images and predict AD severity prediction using explainable deep learning framework., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The neurodegenerative diseases like Alzheimer's disease (AD) can result in progressive decline in both cognitive functions and motor skills, which have critical need for accurate early diagnosis. However, current diagnosis approaches primarily rely on timely clinical magnetic resonance imaging (MRI) scans, which impede widely application for potential patients. Leveraging handwriting as a diagnostic tool offers significant potential for identifying AD in its early stages., Objective: This study aims to develop an efficient, rapid, and accurate method for early diagnosis of AD by utilizing handwriting analysis, a promising avenue due to its association with compromised motor skills in neurodegenerative diseases., Methods: We propose a novel methodology that leverages self-attention mechanisms for the early diagnosis of AD. Our approach integrates data from 25 distinct handwriting tasks available in the DARWIN (Diagnosis AlzheimeR WIth haNdwriting) dataset., Results: The Self-Attention model achieved an accuracy of 94.3% and an F1-score of 94.5%, outperforming other state-of-the-art models, including traditional machine learning and deep learning approaches. Specially, the Self-Attention model surpassed the previous best model, the convolutional neural networks, by approximately 4% in both accuracy and F1-score. Additionally, the model demonstrated superior precision (94.7%), sensitivity (94.5%), and specificity (94.1%), indicating high reliability and excellent identification of true positive and true negative cases, which is crucial in medical diagnostics., Conclusions: Handwriting analysis, powered by self-attention mechanisms, offers significant potential as a diagnostic tool for identifying AD in its early stages, providing an effective alternative to traditional MRI-based diagnosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Data availabilityThe data and codes used for the analysis are available from the corresponding authors upon request.

Background: The MSIS-29 measures the physical and psychological impact of MS., Objective: The associations between MSIS-29 domains and demographic/clinical aspects were examined and trajectories analysed over time., Methods: Data were collected in the Trajectories of Outcome in Neurological Conditions study for a diverse population of people with MS, with follow-up for up to 5 years. Following Rasch analysis, minimal important change (MIC) was computed for ensuing total, physical and psychological domains., Results: Fit to the Rasch model using data from 5921 participants validated physical, psychological and total domains, and the conversion table transforms raw scores to interval-level metric equivalents. These domains showed significant differences across demographic (age, gender, employment, education, and marital status) and clinical (subtype, treatment, and duration) factors with large effect sizes. The MIC scores were physical: 9.1, total: 14.1, which were both above measurement error, and psychological: 5.5 which was not, so 1.6% of participants reported psychological change which was clinically important but not statistically significant. Trajectory analysis showed three groups, one stable and two with significant slopes, improving and deteriorating., Conclusion: The MSIS-29 has shown adequate fit to the Rasch model after accommodating problems with local item dependency, through a bi-factor solution. The domains showed good discrimination across key factors., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Total talus replacement (TTR) implants are designed to replace the diseased talar anatomy, reduce pain, maintain ankle range of motion, and restore ankle function after conservative treatments have failed. Currently TTR implants are produced by 3D printing a patient-specific implant designed from the patient's preoperative anatomy. TTR surgery using patient-specific implants is a relatively new technique that remains understudied in the literature. Therefore, the purpose of this investigation was to determine the early safety and potential benefit of the TTR implant in patients with talar avascular necrosis., Methods: This retrospective, multicenter, cohort study evaluates the safety and potential benefits of TTR using 3D-printed patient-specific implants across 4 US centers. The primary outcome was the occurrence of early adverse events after TTR surgery. Secondary outcomes including, pain, and physical function were assessed using the pain visual analog scale (VAS), and Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF), respectively., Results: The study team analyzed 15 patients with more than 1 year of follow-up. The mean duration of follow-up was 25.9 months (range: 18.3-41 months). Although 33.3% (5 of 15) of patients experienced adverse events, primarily occurring within the initial 6 months postoperatively, 93% (14 of 15) of patients reported implant survivorship. Of the 5 cases (33.3%) resulting in an adverse event, 3 (60.0%) were determined to be unrelated to the subject device, 2 (40.0%) were determined to be possibly procedure-related, and none (0%) were determined to be device-related., Conclusion: Although further studies are needed to compare TTR with the standard of care, the results of this study demonstrate the relative early safety of TTR surgery using a 3D-printed implant for the treatment of challenging talar pathologies. A larger and longer clinical study is required to see if the efficacy of this approach will be statistically and clinically meaningful., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Bijan Abar, PhD, reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Restor3d. Michael Kim reports stock or stock options from Restor3d. Samuel B. Adams, MD, reports support for the present manuscript and royalties or licenses from Restor3d. William R. Adams, DPM, reports consulting fees and stock or stock options from Restor3d. John Kent Ellington, MD, reports royalties or licenses, consulting fees, and stock or stock options from Restor3d. Samuel E. Ford, MD, reports royalties or licenses and stock or stock options from Restor3d. Peter D. Highlander, DPM, MS, reports consulting fees and stock holder from Restor3d Inc, no fees or shares accepted for this manuscript/project. John Y. Kwon, MD, reports royalties or licenses and consulting fees from Restor3D, unrelated to this work. Christopher P. Miller, MD, MHS, reports support for the present manuscript from Restor3D. Selene G. Parekh, MD, MBA, reports grants or contracts, consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and stock or stock options from Restor3d. Karl M. Schweitzer, MD, reports stock or stock options from Restor3D, Inc. Scott B. Shawen, MD, reports royalties or licenses, consulting fees, and stock or stock options from Restor3d. Tara Mann, PhD, reports stock or stock options, full-time employee of Restor3d, Inc. with equity in the form of stock and stock options and full-time salary from Restor3d, Inc. Cambre Kelly, PhD, reports leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid and stock or stock options from Restor3d. Disclosure forms for all authors are available online.

Background: Short-term results after arthroscopic/endoscopic lateral ligament repair for chronic lateral ankle instability have been satisfactory, although medium- to longer-term results are lacking., Purpose/hypothesis: The purpose of this study was to report the medium-term results of an all-inside endoscopic classic Bröstrom-Gould procedure where both the both lateral ligaments and the inferior extensor retinaculum can be approached directly, interchanging between arthroscopy for intracapsular structures and endoscopy for extracapsular structures. It was hypothesized that the all-inside endoscopic classic Bröstrom-Gould procedure would produce sustainable good outcomes at a medium term of 5 years., Study Design: Case series; Level of evidence, 4., Methods: A prospective database for 43 patients who underwent an all-inside endoscopic classic Bröstrom-Gould repair of the anterior talofibular ligament and calcaneofibular ligament with inferior extensor retinaculum augmentation was reviewed. Patient details, American Orthopaedic Foot & Ankle Society score, Karlsson score, ankle activity score (AAS), and patient satisfaction were collected and analyzed., Results: The study cohort of 43 patients with a mean age of 29.4 years (SD, 11.9 years) were reviewed at a mean follow-up of 63.1 months (SD, 8.5 months). The American Orthopaedic Foot & Ankle Society scores showed significant improvement from a mean of 69.6 (SD, 13.9) to 93.7 (SD, 10.7), while the Karlsson score improved from 59.7 (SD, 14.5) to 91.5 (SD, 14.5) at the final follow-up. The AAS showed that 32 (74.4%) patients maintained or had improvement in the AAS, from a mean of 5.38 (SD, 2.8) to 5.41 (SD, 2.8), with a mean satisfaction rate of 9.1 (SD, 1.3). Although the remaining 11 patients had a reduced AAS, at a mean of 4.6 (SD, 2.6), they reported a mean satisfaction rate of 7.4 (SD, 2.9). There were no surgical complications or reoperations reported in this cohort, although there were 3 patients with recurrent instability at their last follow-up, resulting in a failure rate of 7%., Conclusion: The current study is the first to report the medium-term outcomes of an all-inside endoscopic classic Bröstrom-Gould procedure. Overall, 93% of the patients had good functional outcomes, but approximately 25% of patients had decreased ankle activity levels at a mean of 5 years postoperatively, albeit with good satisfaction rates., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: Machine learning (ML) methods can identify complex patterns of treatment effect heterogeneity. However, before ML can help to personalize decision making, transparent approaches must be developed that draw on clinical judgment. We develop an approach that combines clinical judgment with ML to generate appropriate comparative effectiveness evidence for informing decision making., Methods: We motivate this approach in evaluating the effectiveness of nonemergency surgery (NES) strategies, such as antibiotic therapy, for people with acute appendicitis who have multiple long-term conditions (MLTCs) compared with emergency surgery (ES). Our 4-stage approach 1) draws on clinical judgment about which patient characteristics and morbidities modify the relative effectiveness of NES; 2) selects additional covariates from a high-dimensional covariate space ( P  > 500) by applying an ML approach, least absolute shrinkage and selection operator (LASSO), to large-scale administrative data ( N  = 24,312); 3) generates estimates of comparative effectiveness for relevant subgroups; and 4) presents evidence in a suitable form for decision making., Results: This approach provides useful evidence for clinically relevant subgroups. We found that overall NES strategies led to increases in the mean number of days alive and out-of-hospital compared with ES, but estimates differed across subgroups, ranging from 21.2 (95% confidence interval: 1.8 to 40.5) for patients with chronic heart failure and chronic kidney disease to -10.4 (-29.8 to 9.1) for patients with cancer and hypertension. Our interactive tool for visualizing ML output allows for findings to be customized according to the specific needs of the clinical decision maker., Conclusions: This principled approach of combining clinical judgment with an ML approach can improve trust, relevance, and usefulness of the evidence generated for clinical decision making., Highlights: Machine learning (ML) methods have many potential applications in medical decision making, but the lack of model interpretability and usability constitutes an important barrier for the wider adoption of ML evidence in practice.We develop a 4-stage approach for integrating clinical judgment into the way an ML approach is used to estimate and report comparative effectiveness.We illustrate the approach in undertaking an evaluation of nonemergency surgery (NES) strategies for acute appendicitis in patients with multiple long-term conditions and find that NES strategies lead to better outcomes compared with emergency surgery and that the effects differ across subgroups.We develop an interactive tool for visualizing the results of this study that allows findings to be customized according to the user's preferences., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for this study was provided partly by a grant from the National Institute for Health Research and a grant from the Medical Research Council/National Institute for Health Research: Better Methods Better Health (award No. 19091). The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.

Background: Several studies have demonstrated suture repair of ramp lesions of the medial meniscus via a posteromedial approach was associated with a significantly lower rate of secondary meniscectomy. However, these studies are not long-term and highlight the need for extended follow-up research to better understand the outcomes over a more extended period., Purpose: To evaluate the long-term results and reoperation rate for the failure of arthroscopic all-inside suture repair of ramp lesions of the medial meniscus via a posteromedial approach during anterior cruciate ligament (ACL) reconstruction., Study Design: Case series; Level of evidence, 4., Methods: All patients who underwent all-inside suture repair of the posterior segment of the medial meniscus (ramp lesion) via a posteromedial approach during ACL reconstruction at a minimum follow-up of 10 years were included in the study. Side-to-side anterior laxity was assessed preoperatively and postoperatively. Pre- and postoperative functional assessment was based on the subjective International Knee Documentation Committee score for activities of daily living and the Tegner activity scale for sporting ability. Reinterventions for meniscal repair failure and other complications were also recorded at the last follow-up., Results: A total of 81 patients met the inclusion criteria for this study. Two patients had an ACL graft rupture with a new ramp lesion and were excluded from the analysis. Additionally, 15 patients were lost to follow-up, leaving a total of 64 patients in the final analysis. The mean follow-up was 124.8 months (range, 122.4-128.4 months). Mean side-to-side difference in anterior laxity significantly improved from 7.4 ± 1.5 mm (range, 5-12 mm) to 0.4 ± 1.3 mm (range, -3 to 4 mm) ( P = .01). The mean subjective International Knee Documentation Committee score increased from 64.3 ± 13.4 (range, 34-92) before the operation to 91.1 ± 10.1 (range, 49-100) at the last follow-up ( P = .001). The Tegner activity scale score at the last follow-up (6.3 ± 1.6) was lower than that before the trauma (7.1 ± 1.6) ( P = .02). Fourteen patients (21.9%) had a failed meniscal repair and were reoperated. The mean time from initial repair to reoperation was 64.5 months (range, 13-126 months), and the median was 60.6 months. The multivariate analysis, including parameters such as lateral tenodesis (hazard ratio [HR], 1.62; P = .50), preoperative Tegner score (HR, 1.66; P = .41), preoperative laxity (HR, 1.75; P = .35), age at surgery (HR, 1.02; P = .97), and number of sutures (HR, 2.38; P = .19), did not reveal any factors associated with suture failure., Conclusion: The results show that arthroscopic repair of ramp lesions of the medial meniscus during ACL reconstruction using a posteromedial approach has a high failure rate at the 10-year follow-up, with half of these suture failures occurring within 5 years after the initial repair., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.-M.F. is a consultant for Arthrex and New Clip Technics, M.T. is a consultant for Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: The long-term prognosis of jumper's knee and whether structural changes in the patellar tendon persist is unknown., Purpose: To investigate whether limitations in knee function and structural changes persisted beyond the athletic career of young elite volleyball players., Study Design: Cohort study; Level of evidence, 2., Methods: Volleyball players (mean ± SD age, 18 ± 0.8 years) enrolled in 2006-2011 in a prospective cohort study were invited in 2020-2022 to a follow-up study. Participants rated their knee function with the Victorian Institute of Sport Assessment-Patellar Tendon (VISA-P) score (baseline and follow-up) and the International Knee Documentation Committee (IKDC) score (follow-up) and reported if jumper's knee had influenced their decision to retire from sport. Tendon thickness and structural changes were assessed with ultrasound (baseline) and magnetic resonance imaging (MRI) (follow-up) of both patellar tendons., Results: We included 138 of 143 former athletes (97%) 11.4 ± 1.6 years after their baseline examination. At baseline, 37 persons (52 knees) had developed jumper's knee. At follow-up, participants reported lower knee function scores in knees diagnosed with jumper's knee at baseline than healthy knees (VISA-P scores: jumper's knee, 81 [95% CI, 70-92]; healthy, 90 [95% CI, 86-94]; P < .001; IKDC scores: jumper's knee, 82 [95% CI, 75-89]; healthy, 92 [95% CI, 91-95]; P < .001). Jumper's knee problems directly caused 7 of the 37 athletes (19%) with jumper's knee at baseline to retire from competitive volleyball. Of the 138 players included, 97 (70%) completed a bilateral MRI examination (194 knees). At follow-up, 38 of the 54 abnormal tendons (70%) had no structural changes ( P < .001 vs baseline) while 22 of the 140 normal tendons (16%) had developed structural changes. Clinical symptoms were not correlated with tendon structure at follow-up (VISA-P scores for normal tendons: 85 [95% CI, 73-87]; abnormal: 89 [95% CI, 85-92]; P = .48)., Conclusion: Jumper's knee is not a self-limiting condition; volleyball players who had developed jumper's knee during adolescence reported persistent reductions in knee function 11 years later, leading one-fifth to retire from competitive volleyball. Although approximately 70% of tendons with structural changes at baseline were normal at follow-up, there was no clear relationship between structure and function., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was made possible through a grant from the International Olympic Committee Medical Research Fund. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: The critical shoulder angle (CSA) has become an important topic of study in patients with rotator cuff tears (RCTs). However, there are conflicting data on whether the CSA can differentiate between patients with normal shoulder pathology and full-thickness RCTs on shoulder radiographs., Purpose/hypothesis: The purpose of this study was to define the relationship between full-thickness RCTs and the CSA. It was hypothesized that patients with full-thickness RCTs would have an increased CSA compared with matched controls., Study Design: Cross-sectional study; Level of evidence, 3., Methods: This retrospective case-control study identified patients with magnetic resonance imaging scans showing full-thickness RCTs between 2009 and 2019. A 1 to 1 propensity score match was performed to identify a control group with normal rotator cuffs while controlling for baseline participant characteristics-including age, sex, body mass index, and tobacco use. A total cohort of 532 was identified, with 266 cases and 266 controls. Two independent observers measured CSAs on true anteroposterior shoulder radiographs., Results: There was no difference in baseline participant characteristics between the RCT and the non-RCT groups ( P > .05). The mean CSA for the entire cohort was 33.6°± 4.2°. The CSA did not significantly vary by sex ( P = .088) or tobacco usage ( P = .16). The mean CSA for the RCT case group, 36.2°± 3.3°, was significantly different from the mean CSA for the control group, 30.9°± 3.3° ( P < .0001). The receiver operating characteristic curve analysis produced an area under the curve of 0.88 ( P < .0001). At CSAs ≥35°, there was a 67.7% sensitivity and 89.4% specificity for having a full-thickness RCT. Last, each degree of increase in the CSA increased the risk of having an associated RCT by 1.7 times (OR, 1.7 [95% CI, 1.551-1.852]; P < .0001)., Conclusion: Patients with RCTs had significantly higher CSAs compared with matched controls. Increased CSA was an independent risk factor for RCTs, with an odds ratio of 1.7 per degree. The CSA is an accurate test (area under the curve, 0.88) with good sensitivity (67.7%) and specificity (89.4%) at values ≥35°. The CSA is a simple, reproducible measurement that can assist in clinical decision-making regarding full-thickness RCTs., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: E.G. has received hospitality payments from Stryker. R.W.N. has received support for education from Arthrex, Gotham Surgical Solutions & Devices, and Smith & Nephew; and hospitality payments from Stryker. C.L.W. has received hospitality payments from Stryker. D.J.J. has received support for education from Active Medical, Arthrex, Rock Medical Orthopedics, and Smith & Nephew; grant funding from Arthrex; and hospitality payments from Stryker. G.M. has received consulting fees and royalties from Zimmer Biomet Holdings. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: Arthroscopic meniscectomy is one of the most performed surgical procedures in orthopaedics. Different approaches have been proposed to improve patient recovery but with unsatisfactory results. Platelet-rich plasma (PRP) augmentation has been proposed as a strategy to improve the recovery after meniscectomy., Purpose: To investigate the clinical benefits of an intra-articular PRP injection after meniscectomy, in terms of faster and better patient recovery., Study Design: Randomized controlled trial; Level of evidence, 1., Methods: Ninety patients were randomized into a treatment group, with arthroscopic partial meniscectomy immediately followed by a 5-mL injection of autologous conditioned plasma, and a control group with partial meniscectomy alone. Patients were evaluated at baseline and at 15, 30, 60, and 180 days of follow-up with the visual analog scale (VAS) score for pain (primary outcome), as well as with International Knee Documentation Committee subjective score, Knee injury and Osteoarthritis Outcome Score subscales, Tegner score, and EuroQol-Visual Analog Scale score. Objective evaluation was performed analyzing knee range of motion and circumference and the International Knee Documentation Committee objective score. Complications, patient judgment, and satisfaction were documented as well., Results: No major complications and an overall significant improvement in the clinical scores were observed in both groups. Overall, the comparative analysis did not demonstrate significant between-group differences in absolute values or improvements of both subjective and objective scores, as well as activity level. The improvement in terms of VAS pain score for the treatment group was significant already at 15 days (from 4.3 ± 2.5 to 2.5 ± 2.5; P = .014), while in the control group it became significant at 30 days (from 3.7 ± 2.3 to 2.0 ± 2.4; P = .004). No significant differences were observed between the 2 groups in terms of judgment of treatment results and satisfaction., Conclusion: A single postoperative injection of PRP was not able to significantly improve patient recovery after arthroscopic partial meniscectomy. PRP augmentation did not provide overall benefits at a short-term follow-up (6 months) in terms of pain relief, function, objective parameters, and return-to-sport activities., Registration: NCT02872753 (ClinicalTrials.gov identifier)., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: Arthrex provided kits for this study. S.Z. has received institutional support from Fidia Farmaceutici, Cartiheal, IGEA Clinical Biophysics, Biomet, and Kensey Nash; grant support from I+; and royalties from Springer outside the submitted work. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: People with multiple sclerosis (PwMS) have an increased cardiovascular and cerebrovascular disease burden, but this could be mitigated by vascular risk factor management., Objectives: We compared the trajectories of vascular risk factors, vascular comorbidities and clinical management in PwMS against the general population post-MS diagnosis while controlling for frailty., Methods: Retrospective longitudinal analysis using English data from the Clinical Practice Research Datalink between 1987 and 2018 comprising PwMS matched with up to six controls without MS by age, sex and general practice., Results: We compared 12,251 PwMS with 72,572 matched controls; 3.8% of PwMS had mild-moderate frailty, 1.2% more than matched controls. Compared to controls, PwMS had an elevated incidence of Type 2 diabetes (HR 1.18, 95% CI (1.04, 1.34)), and starting antihypertensive medications (HR 1.40, 95% CI (1.33, 1.47)). Among those with hypertension at baseline, blood pressure trajectories did not differ between PwMS and controls. PwMS had increased rates of meeting targets for hypertension management (HR 1.25, 95% CI (1.12, 1.41))., Conclusion: The observation that PwMS with hypertension are more likely to meet treatment targets than matched controls is encouraging, but the elevated rates of vascular comorbidities suggest that tighter vascular management may be needed in this population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: In the last 3 years, R.P. has received support from the UK MS Society and has taken part in advisory boards/consultancy for MSD and Sanofi. In the last 3 years, J.C. has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society, and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by Ionis, Novartis and Roche, and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. R.A.M. receives research funding from the Canadian Institutes of Health Research (CIHR), Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Research Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defence, and is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada.

Background and Objectives: Serum neurofilament light (sNfL) is a biomarker for neuro-axonal damage in multiple sclerosis (MS). Clinical implementation remains limited. We investigated the impact of implementation on clinical decisions using questionnaires at the MS Center Amsterdam, a tertiary outpatient clinic., Methods: sNfL assessments were added to routine clinical practice (August 2021-December 2022). Before and after the results, clinicians filled in questionnaires on context of testing, clinical decisions, certainty herein, expectation of magnetic resonance imaging (MRI) activity, urgency, and motivation to receive the sNfL result and perceived value of sNfL., Results: sNfL was assessed in 166 cases (age 41 ± 12 years, 68% female, 64% disease-modifying therapy (DMT) use) for the following contexts: "DMT monitoring" (55%), "new symptoms" (18%), "differential diagnosis" (17%), and "DMT baseline" (11%). Clinical decisions changed in 19.3% of cases post-disclosure, particularly in context "new symptoms" (38%) and with higher sNfL levels (β = 0.03, p = 0.04). Certainty increased ( p = 0.004), while expectation of MRI activity decreased with disclosure of low sNfL levels ( p = 0.01). Motivation was highest in context "differential diagnosis" ( p < 0.001); perceived value and urgency were highest in context "new symptoms" ( p = 0.02)., Conclusion: In this study, sNfL implementation had considerable impact on clinical decision-making and certainty herein. Standard implementation may complement patient care but warrants caution and more exploration in diverse clinical settings., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Z.Y.G.J.v.L., M.H.J.W., W.M.L.L., B.M., S.N.H., and L.H. report no disclosures. B.A.d.J. receives research support from Dutch MS Research Foundation, National MS Foundation, Dutch MS Association, and Zorgverzekeraars Nederland (i.e. umbrella organization of health insurers in the Netherlands). N.M., L.A.M., B.W.v.O., N.S., Z.L.E.v.K., L.V., M.J.W., and E.M.M.S. report no disclosures. B.M.J.U. reports consultancy fees from Immunic Therapeutics. J.K. received research grants for multicentre investigator-initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW), and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161; received consulting fees for F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis, and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd, Biogen, Immunic, Teva, Merck, Novartis, and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only). C.E.T. reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434); has a research contract with Celgene; serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology and Neuroinflammation, and is an editor of a Neuromethods book Springer.

Background: While standard clinical assessments provide great value for people with multiple sclerosis (PwMS), they are limited in their ability to characterize patient perspectives and individual-level symptom heterogeneity., Objectives: To identify PwMS subgroups based on patient-reported outcomes (PROs) of physical, cognitive, and emotional symptoms. We also sought to connect PRO-based subgroups with demographic variables, functional impairment, hypertension and smoking status, traditional qualitative multiple sclerosis (MS) symptom groupings, and neuroperformance measurements., Methods: Using a cross-sectional design, we applied latent profile analysis (LPA) to a large database of PROs; analytic sample N = 6619)., Results: We identified nine distinct MS subtypes based on PRO patterns. The subtypes were primarily categorized into low, moderate, and high mobility impairment clusters. Approximately 70% of participants were classified in a low mobility impairment group, 10% in a moderate mobility impairment group, and 20% in a high mobility impairment group. Within these subgroups, several unexpected patterns were observed, such as high mobility impairment clusters reporting low non-mobility impairment., Conclusions: The present study highlights an opportunity to advance precision medicine approaches in MS. Combining PROs with data-driven methodology allows for a cost-effective and personalized characterization of symptom presentations. that can inform clinical practice and future research designs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: High tibial osteotomy (HTO) modifies the mechanics of the affected knee but can also affect the nonoperated knee. However, no research has reported on the prognosis and risk factors related to the nonoperated knee after unilateral HTO., Purpose: To assess the radiological parameters associated with osteoarthritis (OA) progression and the need for surgery in the nonoperated knee after unilateral HTO, with concurrent assessment of the operated knee., Study Design: Case series; Level of evidence, 4., Methods: The medical charts of 197 patients with knee OA who underwent unilateral HTO between March 2007 and December 2020 were retrospectively investigated. Radiological parameters such as the Kellgren-Lawrence grade, weightbearing line ratio, joint line convergence angle (JLCA), and joint line obliquity angle were assessed preoperatively and 1 year postoperatively., Results: The mean follow-up length for the 197 patients was 5.9 ± 3.2 years for the operated knee and 5.5 ± 3.2 years for the nonoperated knee. A smaller postoperative JLCA in the operated knee was a significant risk factor for OA progression ( P = .027) and undergoing surgery ( P = .006) in the nonoperated knee. Conversely, a larger postoperative JLCA in the operated knee was a significant risk factor for OA progression ( P = .014) and conversion to arthroplasty ( P = .027) in the operated knee. A postoperative JLCA >1.5° ( P < .001) and <3.9° ( P < .001) was needed to reduce the risk of undergoing surgery in the nonoperated knee and OA progression in the operated knee, respectively. Additionally, a pre- to postoperative change in the JLCA (ΔJLCA) between -5.6° and -1.7° ( P = .021 and P = .004, respectively) was needed to reduce the risk of OA progression in both knees., Conclusion: A large medial joint opening (a small postoperative JLCA) in the operated knee after unilateral HTO was associated with a higher risk of OA progression and surgery in the nonoperated knee. Conversely, a small medial joint opening (a large postoperative JLCA) was associated with a higher risk of OA progression and conversion to arthroplasty in the operated knee. For a balanced medial joint opening, if the postoperative JLCA was between 1.5° and 3.9° or the ΔJLCA was between -5.6° and -1.7°, a favorable prognosis in both knees could be anticipated., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This research was supported by a grant of the Korea Health Technology R&D Project through the Patient-Doctor Shared Decision Making Research Center (PDSDM), funded by the Ministry of Health & Welfare, Republic of Korea (grant No. RS-2023-KH142246). D.H.R. is a CEO of CONNECTEVE Co, Ltd. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: Participation in recreational and competitive sports can predispose people to musculoskeletal injuries. Chronic overuse with insufficient recovery, overloading, and direct contact can result in acute primary tendon ruptures. There is scarce literature regarding the epidemiology of sports-related acute primary tendon ruptures in the United States (US)., Purpose: To identify the incidence rate (IR) of sports-related acute primary tendon ruptures presenting to US emergency departments using the National Electronic Injury Surveillance System (NEISS) database and describe the trends in the IR from 2001 to 2020., Study Design: Descriptive epidemiology study., Methods: The NEISS database was queried using injury case narratives; cases with a clear diagnosis of an acute primary tendon rupture were included in the final analysis. National estimates, estimated IRs (reported as per 1,000,000 person-years at risk), and temporal trends in the annual IR (reported as average annual percent change) of acute primary tendon ruptures were calculated using NEISS sample estimates and US Census Bureau population estimates., Results: An estimated total of 141,382 patients (95% confidence interval [CI], 107,478-175,286) presented to US emergency departments with a sports-related tendon rupture over the study period (IR, 22.9 person-years at risk [95% CI, 17.4-28.3]). The mean age was 37.7 years (95% CI, 37.0-38.5). Of all cases of a tendon rupture identified from 2001 to 2020, 60.1% were secondary to exercise/sports-related injury mechanisms. An Achilles tendon rupture was the most common injury, representing 55.9% of cases. Basketball was the most common sports-related injury mechanism, accounting for 36.6% of cases. The overall injury rate in male patients was 7.7 times that of female patients (IR ratio, 7.7 [95% CI, 4.4-13.5]; P < .05). The annual incidence of all sports-related tendon ruptures in the US increased significantly from 2001 to 2020 (average annual percent change, 1.9 [95% CI, 1.0-2.8]; P < .01)., Conclusion: Recreational/competitive sports participation accounted for a large proportion of acute primary tendon ruptures in the US during the study period., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Laparoscopic robot-assisted colorectal surgery can pose significant haemodynamic challenges for patients with severe aortic regurgitation. The increased afterload caused by pneumoperitoneum and aortic compression, along with concurrent factors like hypercarbia, Trendelenburg positioning and ventilatory impairment, can worsen aortic regurgitation, leading to myocardial ischaemia and heart failure. Transoesophageal echocardiography (TOE) assists haemodynamic management intraoperatively but requires subspecialist skills and enables limited inferences to be drawn regarding the impact of afterload on myocardial performance. Minimally invasive haemodynamic monitoring enabling real-time visualisation of a patient's 'pressure field' has been suggested as a potential adjunct or alternative to TOE, with the added advantage of providing continuous quantitative information about both stroke volume and the afterload to ventricular ejection in a single visualisation. We describe an example of successful concurrent use of pressure field haemodynamic monitoring and TOE in a patient with severe aortic regurgitation having a prolonged laparoscopic robot-assisted pelvic exenteration., Competing Interests: Declaration of conflicting interestsS Woodford has received honoraria from Edwards Lifesciences. This author holds patents related to the pressure field.

Background: Osteochondral allograft transplantation (OCAT) has become a standard-of-care treatment option for patients with large symptomatic articular defects. Recent advances in allograft science and OCAT protocols have been reported to result in consistently robust outcomes after OCAT in the knee. However, only short-term comparisons have been reported, and analyses are lacking for treatment failure risk factors that account for confounding variables., Hypothesis: Midterm functional graft survival rate would exceed 80% for all OCATs combined, with consideration of risk factors for lower survivorship including older patient age, higher body mass index (BMI), tibiofemoral bipolar OCAT, and nonadherence to prescribed postoperative rehabilitation protocols., Study Design: Case series; Level of evidence, 4., Methods: Patients with outcome data available at ≥5 years after primary OCAT using high chondrocyte-viability (HCV) osteochondral allografts were analyzed according to 2 clinically relevant definitions: (1) initial treatment failure, defined by revision or arthroplasty surgery performed for the primary OCAT at any time point during the study period; and (2) functional graft failure, defined by documented conversion to arthroplasty after primary or revision OCAT at any time point during the study period. Analyses were used to assess outcomes for each definition, separately for age group, sex, obesity status, tobacco use, type of OCAT surgery, osteotomy status, concurrent ligament surgery status, and adherence to postoperative protocols. Kaplan-Meier analyses were used to assess differences in survival rates, and Cox proportional hazards models were used to assess risk factors and multivariable relationships with survival. Patient-reported outcome measures for pain, function, mobility, and satisfaction were also analyzed., Results: Analysis included 137 primary knee OCATs performed in 134 patients with a mean follow-up of 66 months (59 female, 75 male; mean age, 37.8 years; mean BMI, 28.5). The midterm (5- to 8-year) functional graft survival rate for patients undergoing primary OCAT in the knee using HCV grafts was 82% for all cases combined, ranging from 69% for tibiofemoral bipolar HCV OCATs to 89% for patellofemoral bipolar, 94% for multisurface unipolar, and 97% for single-surface unipolar. Initial treatment failure rates (revision or arthroplasty after primary OCAT) and OCAT nonsurvival rates (arthroplasty after primary or revision OCAT) were greater for older patient age, concurrent ligament reconstruction, tibiofemoral bipolar OCAT, and nonadherence to the prescribed postoperative rehabilitation protocols. When adjusted for patients' age, BMI, and tobacco use status, different surgery types did not demonstrate an increased risk for failure, while concurrent ligament reconstruction and nonadherence did. Patients who experienced functional graft survival after primary OCAT reported significantly greater improvements in PROMIS Physical Function and Mobility (Patient-Reported Outcomes Measurement Information System), International Knee Documentation Committee questionnaire, and Single Assessment Numeric Evaluation scores such that they were significantly higher at final follow-up as compared with patients who required arthroplasty. Patient-reported improvements in pain, function, and mobility exceeded minimal clinically important differences for ≥5 years after primary OCAT. When asked if they were satisfied with primary OCAT surgery, 76.2% of patients were very satisfied or satisfied with their results, while 8.5% were neutral and 15.4% were unsatisfied or very unsatisfied., Conclusion: With use of HCV osteochondral allografts, midterm (5- to 8-year) functional graft survival rates for patients undergoing primary OCAT in the knee were notably higher than previously reported midterm rates for traditional OCATs. When adjusted for patient characteristics, risk factors for nonsurvival included concurrent ligament reconstruction for knee instability and nonadherence to the prescribed postoperative rehabilitation protocols. Patients who experienced functional graft survival for ≥5 years after primary OCAT reported statistically significant and clinically meaningful improvements in pain, function, and mobility., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.L.C. has received intellectual property royalties, consulting fees, and research support from Arthrex; consulting fees from Bioventus, Boehringer Ingelheim, Collagen Matrix Inc, and Trupanion; research support from GE Healthcare, Collagen Matrix, Musculoskeletal Transplant Foundation, PCORI, Regenosine, and SITES Medical; and royalties from Musculoskeletal Transplant Foundation and Thieme. C.W.N. has received other financial or material support from AO Foundation; speaking fees from Arthrex, Synthes GmbH, and Vericel; consulting fees from Arthrex and Guidepoint Consulting; and support for education from Elite Orthopedics. J.P.S. had received consulting fees and research support from Arthrex; consulting fees from DePuy, Orthopedic Designs North America, Medical Device Business Services, and Smith & Nephew; speaking fees from Synthes GmbH; support for education from Elite Orthopedics; and publishing royalties from Thieme. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Occupationally acquired COVID-19 is a hazard for healthcare workers (HCWs). In four hospitals of the Metro North Hospitals and Health Service in Queensland, Australia, we invited HCWs to report the nature of any anaesthesia interactions with COVID-19-positive and COVID-19-suspect patients. This was to assist workforce planning in future pandemics. Data collection consisted of three phases; 1) participating HCWs recorded details of episodes of care (EOCs) with COVID-19-positive or COVID-19-suspect patients; 2) these HCWs were invited to complete a follow-up survey about their own health status regarding COVID-19 infections; 3) electronic health records were used to assess patient demographics, infectious status and outcomes. Between 21 March 2020 and 17 May 2022, 63 anaesthesia HCWs reported 90 EOCs with 67 unique patients. The median (interquartile range (IQR)) age of the HCWs was 40.5 years (34-46); 55% (34/62) were male, 62% (39/63) were consultants and 21% (13/63) were registrars. The median (IQR) age of patients was 39 (28-63) years. Personal protective equipment (PPE) was deemed to be appropriate by the HCWs in (86/88) 98% of the EOCs. Twenty-four HCWs (38%) responded to a follow-up survey. Of 12 HCWs who subsequently tested positive to COVID-19, only four had cared for a COVID-19-positive patient in the two weeks prior to their diagnosis. Most responding HCWs perceived they contracted COVID-19 in the community, experiencing mild illness. We found relatively low COVID-19 case numbers, high PPE use and low transmission of COVID-19 within the hospital setting., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Etiology of osteochondral lesions of the talus (OLT) is multifactorial and may develop from trauma, genetics, or hypovascularity. The talar dome is supplied by the posterior tibial artery (PTA) and, to a lesser degree, the sinus tarsi artery (STA). The role of talar dome hypovascularity on OLT remains poorly studied. We aimed to determine any relationship between the diameter of PTA (dPTA) and STA (dSTA) and the incidence and characteristics of talus OLT., Methods: This retrospective study included 77 patients with OLT and 77 subjects as a matched control group (age range: 30-40 years). Using magnetic resonance imaging, the dPTA was measured 1 cm above the tibial plafond, at the plafond, and at the level of medial malleolar tip. Likewise, dSTA was measured at the level of the talar neck. The area, volume, depth, localization, and surgical intervention for OLT were recorded as well., Results: The study group had significantly smaller dPTA at all 3 levels (1.05 ± 0.22 mm, 0.99 ± 0.18 mm, 0.98 ± 0.31 mm, proximal to distal, respectively) compared with controls (1.25 ± 0.23 mm, 1.20 ± 0.22 mm, 1.14 ± 0.18 mm, respectively) ( P  < .001). The dSTA was also significantly smaller in the study group compared with the control group (0.5 ± 0.11 mm vs 0.57 ± 0.08 mm, respectively; P  = .001). The mean dPTA (of all 3 levels) cutoff value for predicting the occurrence of OLT was 1.1 mm with 74% sensitivity and 75% specificity. A significant inverse correlation was observed between OLT area and arterial diameters ( P  < .001)., Conclusion: Smaller luminal dPTA and dSTA appear to be associated with higher incidence of OLT, with defect size inversely correlated to arterial diameter., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure forms for all authors are available online.

Background: A theoretical interpretation of factors influencing time tradeoff (TTO) scores is lacking. In this conceptual study, we use a sociopsychological theory, terror management theory (TMT), to explain how death thoughts may play a role in the TTO method. TMT describes how respondents suppress death thoughts by invoking psychological defenses, such as self-esteem, and by bolstering cultural values., Research Question: What is the relation between TMT and TTO scores?, Methods: A framework is developed to link TMT to TTO scores. Predictions of the framework pertain to the directionality of relations between characteristics (e.g., being religious) affecting TTO scores. These predictions are then tested against the findings in the literature., Results: The value "prolonging life" can be used as a linking pin between TTO and TMT as it is relevant for both TMT and TTO. It is argued that the value "prolonging life" is related to TTO scores but also to TMT defense strengths. Thus, TMT defense strengths become associated with trading. Directionality predictions of the framework were confirmed in 34 out of 39 retrospective tests ( P  < 0.001)., Conclusion: Directionalities of relations between TTO scores and socioeconomic characteristics, euthanasia, subjective life expectancy, and religion were explained in terms of TMT defense strengths. Our framework offers a theory-based and parsimonious framework to think about characteristics influencing TTO scores., Highlights: Terror management theory (TMT) is a sociopsychological theory about death thoughts.Several factors are known to influence TTO scores.A new framework applies TMT to TTO scores to interpret such factors.Our framework is mostly of importance to health economists studying the TTO., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Bram Roudijk and Peep Stalmeier reported receiving grants from the EuroQol Research Foundation during the conduct of the study. Dr Stalmeier reports receiving research grants from the Dutch Cancer Society during the conduct of the study and reports funding for traveling to and attending meetings and conferences organized by the EuroQol Research Foundation. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Partial financial support for this study was provided by a grant from the EuroQol Research Foundation, EQ Project 115-2020RA. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.

Background: Platelet-rich plasma (PRP) is one of the most frequently used orthobiologic products for the injection treatment of patients affected by knee osteoarthritis (OA). Some preliminary evidence supports the influence of platelet concentration on patients' clinical outcomes., Purpose: To analyze if platelet concentration can influence the safety and clinical efficacy of PRP injections for the treatment of patients with knee OA., Study Design: Cohort study; Level of evidence, 3., Methods: This study consisted of 253 patients with knee OA (142 men, 111 women; mean ± SD age, 54.8 ± 11.4 years; Kellgren-Lawrence grades 1-3) who were treated with 3 intra-articular injections of 5 mL of autologous leukocyte-rich or leukocyte-poor PRP. All patients were prospectively evaluated at baseline and at 2, 6, and 12 months. Patients were clinically assessed thorough the Knee injury and Osteoarthritis Outcome Score (KOOS) subscales and the International Knee Documentation Committee (IKDC) Subjective score. Platelet concentration was correlated with clinical outcome. Further analysis was performed by stratifying patients into 3 groups (homogeneous for OA severity) based on platelet concentration (high, medium, and low). All complications and adverse events were reported, as well as failures., Results: An overall statistically significant improvement in all clinical scores was documented from baseline to each follow-up evaluation. Platelet concentration positively correlated with clinical outcome. KOOS Pain improved more with higher platelet concentration at 2 months ( P = .036; rho = 0.132), 6 months ( P = .009; rho = 0.165), and 12 months ( P = .014; rho = 0.155). The same trend was shown by the other KOOS subscales and by the IKDC Subjective score, as well as by the comparison of the groups of high-, medium-, and low-platelet PRP. The highest failure rate (15.0%) was found in the low-platelet group as compared with the medium-platelet group (3.3%) and the high-platelet group (3.3%). No differences were observed among the 3 groups in terms of adverse events., Conclusion: This study demonstrated that platelet concentration influences the clinical outcome of PRP injections in knee OA treatment. PRP with a higher platelet concentration provides a lower failure rate and higher clinical improvement as compared with PRP with a lower platelet concentration, with overall better results up to 12 months of follow-up in patients with knee OA., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: S.Z. reports nonfinancial support from personal fees from I+ SRL and grants from Fidia Farmaceutici SPA, Cartiheal Ltd, IGEA Clinical Biophysics, Biomet, and Kensey Nash, outside the submitted work. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: The COVID-19 pandemic highlighted the negative impact of moral injury on nurses' well-being. However, there is a lack of research about generational differences among nurses, particularly on newer nurses who have been identified as having a higher rate of intention to leave., Objective: This study examines generational differences among nurses on moral injury, well-being, resilience, and intention to leave their nursing position and profession., Methods: This is a secondary analysis of cross-sectional data from registered nurses in clinical practice in Ohio between July and August 2021. Data on demographics, moral injury, resilience, and well-being were collected using an online survey. Participants were categorized into 4 generational groups based on their age in 2021: Baby Boomers (57-75 years old), Generation X (42-56 years old), Generation Y (27-41 years old), and Generation Z (12-26 years old). Descriptive and inferential statistics, including logistic regression and analysis of variance, were employed for analysis., Results: Significant generational differences were found in years of clinical experience, moral injury, resilience, and well-being. Baby Boomers reported higher well-being and resilience and lower moral injury. Notably, the intention to leave the profession was more strongly associated with well-being and moral injury levels than with the years of experience or generational group., Conclusions: The findings suggest that interventions to improve nurse retention should prioritize enhancing well-being and addressing the root causes of moral injury. Tailored strategies addressing the needs of different generations are necessary for mitigating the adverse effects of current healthcare challenges on nurse attrition., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD's anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress., Method: Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA., Results: CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC ( p  = 0.042), but did not systematically alter amygdala-AI rsFC ( p- values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context., Conclusion: CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The effectiveness and safety of matrix-associated autologous chondrocyte implantation with an autologous periosteal flap (pMACI) remain unclear. The Japanese Ministry of Health, Labor, and Welfare requires postmarketing surveillance of all patients undergoing pMACI using the tissue-engineered product JACC., Purpose: To evaluate the effectiveness and safety of pMACI for large articular cartilage defects (≥4 cm 2 ) in the knee joint using real-world data analysis., Study Design: Case series; Level of evidence, 4., Methods: Data were collected from patients who underwent pMACI between 2012 and 2019, with 2 years of follow-up. The primary outcomes were the Lysholm knee score and Knee injury and Osteoarthritis Outcome Score (KOOS) at 6, 12, and 24 months. Adverse events were assessed by physical examination, magnetic resonance imaging, and/or arthroscopy., Results: Overall, 232 knees in 225 patients who presented with trauma (198 knees) or osteochondritis dissecans (34 knees) in the medial (132 knees) and lateral (44 knees) femoral condyle, patella (25 knees), trochlea (86 knees), and tibial plateau (4 knees) were included. The mean age of the patients was 40.9 ± 15.0 years, with mean cartilage defects of 5.6 ± 2.4 cm 2 in size. Concomitant surgeries, such as osteotomy (50 knees), ligament reconstruction (27 knees), meniscal procedures (28 knees), osteochondral autograft transplantation (24 knees), and microfracture (14 knees), were performed in 113 (48.7%) knees. The minimal clinically important difference in the Lysholm knee score and KOOS Symptoms subscale was achieved in 79.7% and 63.5% of patients, respectively, and the Patient Acceptable Symptom State was achieved in 90.1% and 73.7%, respectively. Substantial clinical benefit was achieved in the KOOS Sports/Recreation and Quality of Life subscales at 39.6% and 37.8%, respectively. Knees that underwent concomitant microfracture had significantly worse KOOS values than the remainder of the cohort. Complications, including effusion (16.8%), graft delamination (14.7%), knee contracture (9.1%), graft hypertrophy (8.2%), and ossification (3.4%), were observed in 86 (37.1%) knees. Osteochondritis dissecans was significantly associated with graft hypertrophy and ossification, whereas concomitant surgery was significantly associated with delamination and contracture. Treatment failure required additional cartilage procedures in 11 (4.7%) knees., Conclusion: Treatment of large cartilage defects (≥4 cm 2 ) with pMACI resulted in improved outcome scores in approximately 75% of patients. However, complications occurred in one-third of patients, and 4.7% required reoperation., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: Y.U. is a consultant who receives institutional support from Japan Tissue Engineering Co., LTD. (Japan). Y.U. has received institutional support from Pfizer Japan, Inc. (Japan), Eli Lilly Japan KK (Japan), Ono Pharmaceutical Co., LTD. (Japan), Daiichi Sankyo Co., LTD. (Japan), Shionogi & Co., LTD. (Japan), Kaken Pharmaceutical Co., LTD. (Japan), Chugai Pharmaceutical Co., LTD. (Japan), Mochida Pharmaceutical Co., LTD. (Japan), Nippon Zoki Pharmaceutical Co., LTD. (Japan), Seikagaku Corporation (Japan), Taisho Pharmaceutical Holdings Co., LTD. (Japan), Hisamitsu Pharmaceutical Co., Inc. (Japan), and Stryker (Japan). R.K. is a consultant who receives institutional support from Medacta International (Japan) and Japan Tissue Engineering Co., LTD. (Japan). R.K. has received institutional support from Zimmer Biomet (Japan), Smith & Nephew (Japan), and Hirosaki Life Science Innovation, Inc. (Japan). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.