Citations

ObjectiveTo estimate the risk of magnetic resonance imaging (MRI)–based structural changes in knee osteoarthritis (OA) among individuals with meniscal tear and knee OA, using MRIs obtained at baseline and 18 and 60 months after randomization in a randomized controlled trial of arthroscopic partial meniscectomy (APM) versus physical therapy (PT).MethodsWe used data from the Meniscal Tear in Osteoarthritis Research (METEOR) trial. MRIs were read using the MRI OA Knee Score (MOAKS). We used linear mixed‐effects models to examine the association between treatment group and continuous MOAKS summary scores, and Poisson regression to assess categorical changes in knee joint structure. Analyses assessed changes in OA between baseline and month 18 and between months 18 and 60. We performed both intention‐to‐treat and as‐treated analyses.ResultsThe analytic sample included 302 participants. For both treatment groups, more OA changes were seen during the early interval than during the later interval. ITT analysis revealed that, between baseline and month 18, APM was significantly associated with an increased risk of having a worsening cartilage surface area score, involving both any worsening across all knee joint subregions (risk ratio [RR] 1.35 [95% confidence interval (95% CI) 1.14, 1.61]) and the number of subregions damaged (RR 1.44 [95% CI 1.13, 1.85]) having a worsening effusion‐synovitis score (RR 2.62 [95% CI 1.32, 5.21]), and having ≥1 additional subregion with osteophytes (RR 1.24 [95% CI 1.02, 1.50]). Significant associations were detected between months 18 and 60 only for having any subregion with a worsening osteophyte score (RR 1.28 [95% CI 1.04, 1.58]).ConclusionThese findings suggest that the association between APM and MRI‐based structural changes in knee OA is most apparent during the initial 18 months after surgery. The reason for attenuation of this association over longer follow‐up merits further investigation.

Objectives: Signet-ring cells (SRCs) in effusion specimens represent a diagnostic challenge. In this study, a consecutive series of pleural and peritoneal effusions with benign SRCs are examined and compared with malignant SRCs. Material and Methods: We reviewed consecutive Wright-stained serous effusion slides and searched for cases with SRCs. Corresponding ThinPrep slides and clinical histories were reviewed. Cytology cases with known signet-ring adenocarcinoma were retrieved and reviewed. Results: Four hundred Wright-stained serous effusions were reviewed. Eighteen cases were identified with SRC-like cells. Thirteen patients had liver cirrhosis, three patients had end-stage renal disease, one patient had a history of pancreatic adenocarcinoma, and one patient had endometrioid carcinoma. For the latter two patients, the primary tumor showed no histologic findings of signet-ring features. In all cases, no SRCs were found on the corresponding ThinPrep slides. Five cytology cases with malignant SRCs were reviewed. Benign SRCs have a uniformly pale and markedly distended cytoplasm, and the nuclei are thin and curved. The malignant SRCs showed larger non-curved nuclei and bubbly mucin-containing cytoplasm. Conclusion: Mesothelial cells and histiocytes can mimic signet-ring adenocarcinoma cells on Wright-stained slides. Correlation with ThinPrep specimens is necessary before reporting, as the SRCs typically are not present in ThinPrep preparations.

There is a growing appreciation for differences in epidemiology, treatment, and outcomes of cardiovascular conditions by sex. Historically, cardiovascular clinical trials have under-represented females, but findings have nonetheless been applied to clinical care in a sex-agnostic manner. Thus, much of the collective knowledge about sex-specific cardiovascular outcomes result from post hoc and secondary analyses. In some cases, these investigations have revealed important sex-based differences with implications for optimizing care for female patients with arrhythmias. This review explores the available evidence related to cardiac arrhythmia care among females, with emphasis on areas in which important sex differences are known or suggested. Considerations related to improving female enrollment in clinical trials as a way to establish more robust clinical evidence for the treatment of females are discussed. Areas of remaining evidence gaps are provided, and recommendations for areas of future research and specific action items are suggested. The overarching goal is to improve appreciation for sex-based differences in cardiac arrhythmia care as 1 component of a comprehensive plan to optimize arrhythmia care for all patients.

Abstract Purpose:The incidence of severe combined immunodeficiency (SCID) in the United States was reported as 1 in 58,000 live births. In Arizona, it was anticipated that newborn screening would identify two to four cases of SCID per year. This estimate did not consider ethnic nuances in Arizona, with higher percentages of American Indian and Hispanic populations compared to national percentages. The true incidence of SCID and non SCID T-cell lymphopenia have not previously been reported in Arizona. Methods:A retrospective chart review was performed of abnormal SCID Newborn Screening (NBS) tests from January 1, 2018 to December 31, 2019, using data from the Arizona Department of Health Service and the Phoenix Children’s Hospital’s electronic medical record [IRB# 20-025]. Results: Seven infants were diagnosed with SCID, yielding an incidence of 1 in 22,819 live births. Four of these infants had Artemis type SCID. Eighteen infants were identified with an abnormal initial NBS which ultimately did not lead to a diagnosis of SCID. Four of these infants were diagnosed with congenital syndromes associated with T-cell lymphopenia. Infants of Hispanic ethnicity were over-represented in this cohort. Conclusion: NBS in Arizona confirmed an incidence more than 2.5 times that reported nationally. This increased incidence is likely reflective of Arizona’s unique population profile, with a higher percentage of American Indian population. The findings in our non-SCID cohort are in alignment with previously published data, except for a higher than anticipated number of infants of Hispanic/Latino ethnicity, likely related to Arizona’s higher percentage of Hispanic/Latino population.

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co‐exposures on the mediator, (2) the co‐exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure‐mediator and exposure‐mediator‐outcome relationships are complex, BKMR‐Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co‐exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.

AbstractBackgroundTau hyperphosphorylation at Threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer disease (AD). However, it remains unclear whether pT217 could be modified in other tauopathies. Using immunoprecipitation and mass spectrometry, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid beta (Aβ) 42/40 ratio in cognitively normal controls, and individuals with AD, Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), and sporadic and familial Frontotemporal Dementia (FTD).MethodCSF Aβ, tau and phosphorylated tau (p‐tau) were measured using immunoprecipitation and quantitative mass spectrometry methods. Amyloid and tau Positron Emission Topography (PET) imaging were measured in a subset of participants and analyzed for correlation. Quadrant analyses were performed to assess amyloid and p‐tau positivity.ResultWe confirmed the strong association between CSF Aβ 42/40 and pT217 measures in most samples. Individuals with AD had high CSF pT217/T217 and low Aβ 42/40. In contrast, controls and the majority of patients with other tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio relative to controls. Most of these individuals were identified as MAPT R406W mutation carriers, a tau mutation leading to 3R+4R tauopathy similar to AD but without amyloid pathology. Diagnostic accuracies of CSF Aβ 42/40 alone, CSF pT217/T217 alone, and combination of both biomarkers were examined. We show that combination of both biomarkers can separate MAPT R406W carriers from control (AUC=0.960) and other tauopathies that are primarily 4R tauopathies (AUC=0.934).ConclusionWe demonstrate the importance of measuring both CSF Aβ 42/40 and pT217/T217 to improve AD diagnosis and differentiate MAPT R406W mutation carriers. This supports that changes in CSF pT217/T217 ratio is not a specific biomarker for AD but reflects common downstream tau pathology in these two 3R+4R tauopathies.

Abstract Aims Patients with diabetes (DM) and metabolic syndrome (MS) have elevated risks for atherosclerotic cardiovascular disease (ASCVD). Aggressive LDL-C lowering reduces risks. Inclisiran, a new siRNA, lowers LDL-C and was evaluated in patients with Type 2 diabetes (DM), metabolic syndrome (MS) without DM or neither (N) in the ORION-10 trial. Methods ORION-10 was a double-blind, randomized, placebo controlled trial evaluating inclisiran in 1561 patients with ASCVD on maximally tolerated therapy for lowering LDL-C. 781 inclisiran (INC) participants and 780 placebo (P) patients received 1.5 mL SQ tx at Days 1, 90, then every 6 months until Day 540. We evaluated the time adjusted change in LDL-C from baseline after Days 90–540 in DM (n = 702), MS (n = 455) and N participants (n = 404). Results There were no differences in baseline demographics and background therapies between INC and P. Statins were utilized in 89.8% INC and 88.7% of P. High intensity statins were utilized in 67.2% of INC and 68.8% of P; ezetimibe in 10.2% of NC and 9.5% of P participants. INC reduced LDL-C by − 54.4% (−58.3, −50.6 95% CI) in DM, (P < 0.001), −58.6% (−62.3, −54.8), P < 0.001 in-MS and −56.0% (−60.2, −51.7), in N subjects P < 0.001 (see Figure). Conclusions Inclisiran potently and durably reduces LDL-C across patients with DM, MS and those with neither, demonstrating potent efficacy and durability across glycaemic categories. Inclisiran may also represent a potent LDL-C lowering treatment for those with DM and MS.

Background In kidney transplantation, a contrast CT scan is obtained in the donor candidate to detect subclinical pathology in the kidney. Recent work from the Aging Kidney Anatomy study has characterized kidney, cortex, and medulla volumes using a manual image-processing tool. However, this technique is time consuming and impractical for clinical care, and thus, these measurements are not obtained during donor evaluations. This study proposes a fully automated segmentation approach for measuring kidney, cortex, and medulla volumes. Methods A total of 1930 contrast-enhanced CT exams with reference standard manual segmentations from one institution were used to develop the algorithm. A convolutional neural network model was trained ( n =1238) and validated ( n =306), and then evaluated in a hold-out test set of reference standard segmentations ( n =386). After the initial evaluation, the algorithm was further tested on datasets originating from two external sites ( n =1226). Results The automated model was found to perform on par with manual segmentation, with errors similar to interobserver variability with manual segmentation. Compared with the reference standard, the automated approach achieved a Dice similarity metric of 0.94 (right cortex), 0.90 (right medulla), 0.94 (left cortex), and 0.90 (left medulla) in the test set. Similar performance was observed when the algorithm was applied on the two external datasets. Conclusions A fully automated approach for measuring cortex and medullary volumes in CT images of the kidneys has been established. This method may prove useful for a wide range of clinical applications.