Citations

Background: Particulated juvenile articular cartilage (PJAC) implantation has demonstrated promising early results in the treatment of symptomatic articular cartilage defects of the patella. However, some uncertainty exists regarding the stability of this cell-based technique in lesions that are not well contained or shouldered. Purpose: To compare clinical and magnetic resonance imaging (MRI) outcomes of PJAC treatment in shouldered versus unshouldered full-thickness cartilage defects of the patella. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of prospectively collected data from an institutional knee registry was conducted to identify patients treated with PJAC for full-thickness symptomatic patellar cartilage lesion between January 2009 and August 2017. Cartilage defects were graded arthroscopically according to the Outerbridge classification and characterized as shouldered or unshouldered. For the primary outcome, postoperative MRI studies were read by a musculoskeletal fellowship-trained radiologist who characterized the percentage of fill based on both coronal and sagittal images. Patient-reported outcome measures (PROMs) were obtained at baseline and 2-year follow-up. MRI and PROM results were compared between the shouldered and unshouldered cohorts. Results: A total of 64 knees in 60 patients (mean age, 26.3 ± 7.6 years) were identified, of which 62 (97%) knees underwent a concomitant patellar stabilization or offloading procedure. There were 32 (50%) shouldered and 32 (50%) unshouldered defects. On postoperative MRI, 68.8% of shouldered lesions demonstrated 67% to 100% fill, compared with 59.4% of unshouldered lesions; 12.5% of shouldered lesions and 15.6% of unshouldered lesions demonstrated 34% to 66% fill; and 18.8% of shouldered lesions and 25.0% of unshouldered lesions demonstrated 0% to 33% fill ( P = .604). At 2 years, significant improvements were observed in Knee Injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) (23.1 to 65.3; P < .001), International Knee Documentation Committee (IKDC) (41.2 to 76.0; P < .001), KOOS Physical Function Shortform (PS) (34.8 to 13.9; P < .001), Kujala (52.0 to 87.5; P < .001), 12-Item Short Form Survey (SF-12) Physical Health (39.5 to 51.5; P < .001), Veterans Rand 12 Item Health Survey (VR-12) Physical Health (40.7 to 52.8; P < .001), Veterans Rand 6D (0.66 to 0.79; P < .001), SF-12 Mental Health (48.9 to 53.4; P = .015), and VR-12 Mental Health (49.4 to 54.0; P = .019) values. No significant change was observed in Pediatric Functional Activity Brief Scale score (9.1 to 10.3; P = .384). All PROMs were equivalent between shouldered and unshouldered defects at the 2-year follow-up ( P = .318-.980). There was a greater improvement in both KOOS PS (27.2 vs 10.7; P = .015) and Kujala (44.3 vs 26.9; P = .039) values from baseline to the 2-year follow-up in the shouldered group. Conclusion: PJAC implantation with concomitant patellar stabilization led to significantly improved PROMs for both shouldered and unshouldered patellar cartilage lesions over time. Additionally, minimal differences were observed between shouldered and unshouldered defects treated with PJAC at the 2-year follow-up.

Background Catatonia in medically ill patients is rare but often unrecognized. This monograph summarizes current knowledge on the diagnosis, epidemiology, etiology, and management of catatonia occurring in the medical setting. Methods PubMed searches were used to identify relevant articles from 1962 to present. Results More than 3,000 articles were obtained and reviewed for relevance, including references of articles identified by the initial search. Several areas were identified as important, including: (1) catatonia and delirium; (2) malignant catatonia; (3) pediatric catatonia; (4) catatonia associated with another medical condition (CAMC); (5) drug exposure and withdrawal syndromes associated with catatonia; and (6) treatment of catatonia in the medical setting. Conclusions Catatonia in the medically ill appears to have numerous etiologies, although etiology does not seem to modify the general treatment approach of prompt administration of lorazepam. Delirium and catatonia are commonly comorbid in the medical setting and should not be viewed as mutually exclusive. Electroconvulsive therapy should be offered to patients who do not respond to benzodiazepines or have malignant features. Removing offending agents and treating the underlying medical condition is paramount when treating CAMC. Memantine or amantadine may be helpful adjunctive agents. There is not enough evidence to support the use of antipsychotics or stimulants in treating CAMC.

Background Sex affects the prevalence of atherosclerotic cardiovascular disease (ASCVD) risk factors but whether sex differences exist in the associations between ASCVD risk burden and cognitive function is unclear. Methods This cross‐sectional study included participants from a population‐based cohort study in China that recruited community‐dwelling adults aged 50 to 75 years without baseline cardiovascular disease and stroke. The 10‐year ASCVD risk burden was quantified with 3 multivariate risk prediction equations. Cognitive domains of memory, attention, visuospatial function, executive function, and processing speed were assessed. Multivariable linear regression models were used to examine the interaction terms between sex and ASCVD risk scores on cognition. Results The final analytical sample included 2180 participants. Mean±SD age was 60.14 (6.38) and 52.1% were women. Men showed significantly higher ASCVD risk burden than women at baseline but the effect of ASCVD risk on 2‐year cognition were amplified in women compared with men, for the domains of memory (eg, β=−0.20 [95% CI, –0.26 to −0.13] versus β=−0.11 [95% CI, –0.16 to −0.07]), executive function (eg, β=−0.23 [95% CI, –0.31 to −0.16] versus β=−0.16 [95% CI, –0.21 to −0.10]), and processing speed (eg, β=−0.33 [95% CI, –0.39 to −0.27] versus β=−0.17 [95% CI, –0.21 to −0.13]). Sex‐stratified analyses showed different neuropsychological profiles at moderate ASCVD risk burden levels, suggesting sex‐specific ASCVD‐risk related cognitive phenotypes. Conclusions Sex differences in cognitive health affected by ASCVD risk underscore the importance of sex‐specific cognitive monitoring during ASCVD risk management and better vascular risk control in women to prevent cognitive decline.

Context Adolescence is a critical period for bone development. Due to an elevated risk for low body mass index (BMI) and/or low energy availability, certain adolescent athletes are at increased risk of bone stress injury (BSI) and eating disorders (EDs). Despite this risk, the incidence of EDs in patients with BSI is unclear. Objective To compare the incidence of a premorbid drop in BMI percentile in a sample of adolescent athletes diagnosed with a BSI between 2005 and 2016. We also evaluated the relative risk of developing an ED for this sample, compared with a sex-matched, age-matched (±6 months), and time-matched (±2 years) sample of active adolescents with knee pain. Design Retrospective cohort study. Setting Data collected through the Rochester Epidemiology Project. Patients or Other Participants One hundred eighty-seven adolescent (aged 13–18) athletes with BSI and 187 active adolescents with knee pain. Main Outcome Measure(s) Conditional logistic regression was used to assess whether premorbid weight loss was a risk factor for BSI. A stratified log-rank test was used to evaluate the association between ED diagnosis and case-control status up to 5 years postinjury. Results Patients with a BSI had 1.53 times the odds of premorbid BMI percentile drop compared with controls (95% CI = 0.83, 2.12; P = .17). A total of 14 patients with a BSI had ED diagnoses after injury compared with 8 controls ( P = .13). Patients from weight-based or aesthetic sports had 1.93 times the odds of a BSI compared with controls (95% CI = 1.23, 3.02; P = .0040). The Kaplan-Meier estimates indicate that the case group had a greater risk of ED diagnosis. Conclusions Results suggest a trend toward a greater drop in BMI percentile and increased frequency of ED diagnoses in the BSI group compared with controls. The documented co-occurrence of weight loss, stress fractures, and EDs in adolescent athletes should inform guidelines for screening and treatment of adolescent athletes with BSIs.

ABSTRACT The Clinical and Laboratory Standards Institute Subcommittee on Antimicrobial Susceptibility Testing (AST) publishes annual updates to the M100 Performance Standards for Antimicrobial Susceptibility Testing . This important document contains key information critical to the laboratory’s performance of accurate and current AST. This minireview will highlight and provide supporting data for major changes in the M100 32nd and 33rd editions published in February 2022 and March 2023, respectively. New and revised breakpoints for gram-negative and gram-positive organisms are explained. Proper use of the restructured M100 Table 1 guidance for antimicrobial agents to be considered for testing and reporting is outlined. Reporting guidance for multidrug-resistant gram-negative bacilli is discussed. Other topics within this minireview include additional agents to test and report for direct blood disk diffusion of gram-negative bacilli and quality control range changes and troubleshooting. The minireview concludes with other issues under consideration by the AST Subcommittee.

Abstract Introduction This study investigated if acute alcohol exposure produces sex differences in aged rats compared to adult and adolescent rats on ataxia and nonspatial cognition. Materials and Methods Sex- and age-related differences were assessed by using aged, young adult, and adolescent Sprague–Dawley rats. For acute alcohol exposure, animals were administered either 1 or 2 g/kg alcohol via intraperitoneal injection before testing. To examine the effects of acute alcohol exposure on balance and motor control and nonspatial learning, animals underwent behavioral testing in the aerial righting reflex (ARR) and Morris water maze (MWM) tests. Blood alcohol levels were determined 60 min following administration of either 1.0 or 2.0 g/kg alcohol. Results Sex differences were found in the ARR, as aged females were significantly less sensitive to the effect of acute alcohol exposure compared to aged males. Age was also found to significantly affect ARR performance, where aged animals performed worse than younger animals in response to acute alcohol. However, these sex- and age-related differences were not found in the nonspatial MWM test or in blood alcohol concentrations. Conclusions These results indicate that the sex- and age-dependent effects of acute alcohol exposure are task specific. In conclusion, these findings highlight the importance of studying the effects of acute alcohol on the aged population.

ABSTRACTTissue‐specific gene manipulation using Cre/loxP or Flp/frt recombination systems is a cornerstone of genetically engineered mouse models. In this study, we aim to develop a novel hepatocyte‐specific, tamoxifen‐inducible Flp mouse line. BAC (bacterial artificial chromosome)‐Alb(albumin)‐FlpER2(estrogen receptor ligan binding domain) was developed by inserting IRES‐FlpER2 cDNA between the translation stop codon and 3′‐UTR of the mouse albumin gene in a bacterial artificial chromosome. Upon tamoxifen induction in mice crossed with reporter lines, western blotting, immunohistochemistry, immunofluorescence staining, and X‐gal staining (5‐bromo‐4‐chloro‐3‐indolyl‐β‐D‐galactopyranoside Staining) were used to verify the recombination efficiency and specificity of this mouse model. Recombination was highly efficient and specific in hepatocytes, with no recombination detected in intrahepatic cholangiocytes or other organs in this mouse model. We generated a new tamoxifen‐induced hepatocyte‐specific mouse model with highly efficient recombination specifically in hepatocytes, and this model can be used to generate tumor model lines.

ImportanceEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood.ObjectiveTo examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes.Design, Setting, and ParticipantsThis study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024.ExposureMHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use).Main Outcomes and MeasuresBreast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-&amp;lt;25; overweight, 25-&amp;lt;30; or obesity, ≥30).ResultsThis study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P &amp;lt; .04 for heterogeneity) tumors.Conclusions and RelevanceIn this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Spinocerebellar ataxia type 7 (SCA7), a rare form of ataxia, possesses a wide phenotypic spectrum ranging from classic ataxic symptoms to blindness, multiorgan failure, cardiomyopathy, and early death among younger age groups. Biomarkers associated with disease progression and severity could aid in disease prognostication. We evaluated the utility of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in distinguishing patients with SCA7 from healthy controls and estimating patient prognosis. GFAP and NfL levels were measured in 23 plasma and 20 cerebrospinal fluid (CSF) samples from asymptomatic (N = 3) and symptomatic SCA7 participants (N = 10) and from healthy controls (N = 8). GFAP concentrations were elevated in the plasma (82.7 pg/mL) and CSF (9318 pg/mL) of patients with SCA7 compared to controls (plasma: 48.0 pg/mL; CSF: 89,056 pg/mL). Similarly, NfL plasma (21.6 pg/mL) and CSF (2615.0 pg/mL) levels were also significantly upregulated in SCA7 compared to controls (plasma: 8.2 pg/mL; CSF: 414.6 pg/mL). Higher levels of NfL, but not of GFAP, significantly discriminated symptomatic SCA7 patients from controls (area under de curve, AUC: 0.898, p = 0.0059, in plasma, and AUC: 1.0, p = 0.0012, in CSF). The levels of both biomarkers increased overtime, with plasma NfL levels strongly associated with a worse score in the scale for the assessment and rating of ataxia (SARA) (Spearman r: 0.8354, p = 0.0007; regression analysis: β: 0.021, 95% CI: 0.008–0.035, p = 0.0048). These findings suggest that NfL could serve as a valuable biomarker for monitoring disease progression and prognosis in SCA7 patients.