Citations

ABSTRACT The complications and symptoms of hypoparathyroidism remain incompletely defined. Measuring serum parathyroid hormone (PTH) and calcium levels early after total thyroidectomy may predict the development of chronic hypoparathyroidism. The study aimed (i) to identify symptoms and complications associated with chronic hypoparathyroidism and determine the prevalence of those symptoms and complications (Part I), and (ii) to examine the utility of early postoperative measurements of PTH and calcium in predicting chronic hypoparathyroidism (Part II). We searched Medline, Medline In-Process, EMBASE, and Cochrane CENTRAL to identify complications and symptoms associated with chronic hypoparathyroidism. We used two predefined criteria (at least three studies reported the complication and symptom and had statistically significantly greater pooled relative estimates). To estimate prevalence, we used the median and interquartile range (IQR) of the studies reporting complications and symptoms. For testing the predictive values of early postoperative measurements of PTH and calcium, we used a bivariate model to perform diagnostic test meta-analysis. In Part I, the 93 eligible studies enrolled a total of 18,973 patients and reported on 170 complications and symptoms. We identified nine most common complications or symptoms probably associated with chronic hypoparathyroidism. The complications or symptoms and the prevalence are as follows: nephrocalcinosis/nephrolithiasis (median prevalence among all studies 15%), renal insufficiency (12%), cataract (17%), seizures (11%), arrhythmia (7%), ischemic heart disease (7%), depression (9%), infection (11%), and all-cause mortality (6%). In Part II, 18 studies with 4325 patients proved eligible. For PTH measurement, regarding the posttest probability, PTH values above 10 pg/mL 12–24 hours postsurgery virtually exclude chronic hypoparathyroidism irrespective of pretest probability (100%). When PTH values are below 10 pg/mL, posttest probabilities range from 3% to 64%. Nine complications and symptoms are probably associated with chronic hypoparathyroidism. A PTH value above a threshold of 10 pg/mL 12–24 hours after total thyroidectomy is a strong predictor that the patients will not develop chronic hypoparathyroidism. Patients with PTH values below the threshold need careful monitoring as some will develop chronic hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Abstract Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by young serum in a transgenic AD mouse model. We found that young serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Neutrophil depletion via Ly6G neutralizing antibodies mimicked the benefits of young serum on AD brain functions. Serum proteomic analysis of young serum revealed significant enrichment of the factors VEGF-A and CXCL1, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Intravenously injected VEGF-A reversed Aβ-induced decreases in Cdk5 and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration and thereby restored memory in APP/PS1 mice. Our data uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and provide a rationale for targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.

AbstractObjectivesWe provide a contemporary consideration of long‐term outcomes and trends of induction therapy use following lung transplantation in the United States. Methods: We reviewed the United Network for Organ Sharing registry from 2006 to 2018 for first‐time, adult, lung‐only transplant recipients. Long‐term survival was compared between induction classes (Interleukin‐2 inhibitors, monoclonal or polyclonal cell‐depleting agents, and no induction therapy). A 1:1 propensity score match was performed, pairing patients who received basiliximab with similar risk recipients who did not receive induction therapy. Outcomes in matched populations were compared using Cox, Kaplan‐Meier and Logistic regression modeling.Measurements and main results22 025 recipients were identified; 8003 (36.34%) were treated with no induction therapy, 11 045 (50.15%) with basiliximab, 1556 (7.06%) with alemtuzumab and 1421 (6.45%) with anti‐thymocyte globulin. Compared with those who received no induction, patients receiving basiliximab, alemtuzumab or anti‐thymocyte globulin were found on multivariable Cox‐regression analyses to have lower long‐term mortality (all p < .05). Following propensity score matching of basiliximab and no induction populations, analyses demonstrated a statistically significant association between basiliximab use and long‐ term survival (p < .001). Basiliximab was also associated with a lower risk of acute rejection (p < .001) and renal failure (p = .002).ConclusionInduction therapy for lung transplant recipients—specifically basiliximab—is associated with improved long‐term survival and a lower risk of renal failure or acute rejection.

Abstract Multiple Myeloma (MM) is a hematologic malignancy marked by uncontrolled clonal expansion of plasma cells. Previous research has examined single-cell transcriptome profiles of Monoclonal gammopathy of undetermined significance (MGUS) and MM tumor microenvironment (TME) and found that natural killer (NK) cell abundance is elevated in the early stages and correlated with altered chemokine receptor expression. This study suggested the critical role of immune cells on myeloma progression from asymptomatic MGUS to symptomatic MM. Up to date, however, there are no published studies comprehensively comparing tumor and immune populations differences between MM NON-progressors (NPs) and FAST-progressors (FPs) and investigating how clonal plasma cells affect disease progression in a large cohort. Therefore, understanding how tumor and immune cells influence disease progression within symptomatic MM is of great interest.Here, we subjected CD138-negative Bone Marrow Mononuclear cells (BMMC) samples from 418 MM patients to scRNA-seq. From MMRF CoMMpass study (NCT01454297), we also have whole exome sequencing (WES) and bulk RNA-seq from CD138-positive fraction of BMMC samples. Based on time to progressive disease (TTPD), we classified patients into 2 categories. Patients with TTPD less than 18 months were classified as FAST-progressors (FPs), whereas patients with TTPD more than 5 years were classified as NON-progressors (NPs). By analyzing patient genomic alterations and its association with progression, we found that there was a significant association of slow MM progression with t(11;14) (p = 0.048), consistent with previous study. In our preliminary analysis, we profiled 83 CD138-sorted MM bone marrow samples using scRNA-seq. Interestingly, we found plasma cells from samples with the same genetic alterations tend to cluster together, highlighting the important role of genetic drivers in transcriptome profiles of plasma cells. Moreover, integrated analysis of bone marrow samples from 83 MM patients and 4 healthy donors revealed an atypical naïve-B cell subset with enrichment of cells from fast-progressors and partial expression of MS4A1. Differentially expressed genes for this naïve-B cell subset includes KLF9, BCL2L11, JOSD1, and IRS2, etc. Overall, as part of MMRF immune profiling research, this study will help to interrogate how genetic alterations and disease progression interplay MM tumor and TME and provide a sufficiently broad and valuable dataset for systematically characterizing MM at single-cell resolution. Hopefully, this study could identify novel targets for MM immunotherapies, and ultimately identify patients with high risk of fast progression for early intervention in the clinic. Citation Format: Lijun Yao, Tianjiao Wang, Kazuhiro Sato, Reyka Jayasinghe, I-Ling Chiang, Darwin D'souza, William Pilcher, Edgar Gonzalez-Kozlova, Yered Pita-Juarez, Taxiarchis Kourelis, Deon Bryant Doxie, Beena Thomas, Brian Lee, Swati Sharma Bhasin, Upadhyaya Bhaskar, Mark Fiala, Julie Fortier, Travis Dawson, John Leech, Shaji Kumar, Hearn Cho, Seunghee Kim-Schulze, Bee Raj, Stephen Oh, the MMRF Immune Profiling Research Team, John Dipersio, Ravi Vij, Adeeb Rahman, Ionnis Vlachos, Shaadi Mehr, Mark Hamilton, Daniel Auclair, Surendra Dasari, David Avigan, Madhav Dhodapkar, Sacha Gnjatic, Manoj Bhasin, Li Ding. Single-cell transcriptome profiling of multiple myeloma bone marrow samples suggests that disease progression interplays with tumor and tumor microenvironment in The MMRF CoMMpass Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1729.

Abstract Tixagevimab-cilgavimab is authorized for preexposure prophylaxis against coronavirus disease 2019 (COVID-19) in immunocompromised hosts. Herein, we report the clinical characteristics of 8 patients who developed COVID-19 soon after receiving tixagevimab-cilgavimab. This study emphasizes the need to maintain additional measures to prevent COVID-19 during periods of high severe acute respiratory syndrome coronavirus 2 transmission.

6589 Background: Real-world utilization and comparative effectiveness of direct oral anticoagulants (DOACs), low molecular weight heparin (LMWH) and warfarin for cancer-associated venous thromboembolism (VTE) treatment remains largely unexplored. Methods: De-identified administrative claims data (OptumLabs - Data Warehouse) for adult active cancer patients with acute VTE (1/1/2012-9/30/2019) were assessed for utilization patterns, recurrent VTE, and major bleeding differences between DOACs, LMWH, and warfarin. Patients were followed up till the end of treatment. Patients who crossed over to other anti-coagulants within the follow up period were excluded. Multinomial logistic regression was used to assess predictors of anticoagulant administration. Kaplan-Meier curves were used to evaluate the differences in time to medication discontinuation among the three groups. Propensity score (PS) and inverse probability of treatment weighting were used to balance baseline differences between groups. Standardized difference (SD) was used to assess the balance of covariates after weighting and SD < 10% was considered acceptable. Weighted Cox proportional hazards regression with a robust variance estimator was then used to assess outcomes in PS weighted groups. Results: A total of 5100 patients met the inclusion criteria; 49.3% filled DOACs (n = 2512), 29.2% LMWH (n = 1488), and 28.6% warfarin (n = 1460). Median treatment duration was around 3.2 months for DOACs and warfarin, and 1.8 months for LWMH ( P-value < 0.01). Multinomial regression analysis showed that younger patients were more likely to be prescribed LMWH (OR 0.97 95% CI: 0.97-0.98) as compared to DOACs. Patients with lung (OR 2.07 95% CI: 1.12-3.65; OR 1.87 95% CI: 1.04-3.37), urological (OR: 1.94 95% CI:1.08-3.49; OR: 2.04 95% CI: 1.12-3.73), gynecological (OR 4.25, 95% CI: 2.31-7.82; OR 2.31 95% CI: 1.22-4.39) and colorectal cancer (OR 2.26 95% CI: 1.20-4.32; OR 2.51; 95% CI: 1.32-4.79) were more likely to be prescribed LMWH or warfarin respectively, compared to DOACs. VTE recurrences were more frequent for patients receiving LMWH (HR: 1.47; 95% CI: 1.14-1.90) or warfarin (HR: 1.46; 95% CI: 1.13-1.87) compared to DOACs. LMWH, but not warfarin, was associated with greater major bleeding rates compared to DOACs (HR: 2.27; 95% CI: 1.62-3.20). All-cause mortality rates were also significantly higher for patients receiving LMWH, but not warfarin compared to DOACs (HR: 1.61; 95% CI: 1.15-2.25). Conclusions: Patients with cancer associated VTE remain on anti-coagulation for a remarkably short duration in real-world clinical practice. DOACs and warfarin may offer better compliance than LMWH. Patients receiving DOACs have a lower risk of VTE recurrence, less major bleeding, and improved mortality. Warfarin may still be considered for patients with contraindications to DOACs and non-compliant to LMWH.

Background EAST‐AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) demonstrated clinical benefit of early rhythm‐control therapy (ERC) in patients with new‐onset atrial fibrillation (AF) and concomitant cardiovascular conditions compared with current guideline‐based practice. This study aimed to evaluate the generalizability of EAST‐AFNET 4 in routine practice. Methods and Results Using a US administrative database, we identified 109 739 patients with newly diagnosed AF during the enrollment period of EAST‐AFNET 4. Patients were classified as either receiving ERC, using AF ablation or antiarrhythmic drug therapy, within the first year after AF diagnosis (n=27 106) or not receiving ERC (control group, n=82 633). After propensity score overlap weighting, Cox proportional hazards regression was used to compare groups for the primary composite outcome of all‐cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction. Most patients (79 948 of 109 739; 72.9%) met the inclusion criteria for EAST‐AFNET 4. ERC was associated with a reduced risk for the primary composite outcome (hazard ratio [HR], 0.85; 95% CI, 0.75–0.97 [ P =0.02]) with largely consistent results between eligible (HR, 0.89; 95% CI, 0.76–1.04 [ P =0.14]) or ineligible (HR, 0.77; 95% CI, 0.60–0.98 [ P =0.04]) patients for EAST‐AFNET 4 trial inclusion. ERC was associated with lower risk of stroke in the overall cohort and in trial‐eligible patients. Conclusions This analysis replicates the clinical benefit of ERC seen in EAST‐AFNET 4. The results support adoption of ERC as part of the management of recently diagnosed AF in the United States.

Abstract Aims Artificial intelligence (AI) enabled electrocardiography (ECG) can detect latent atrial fibrillation (AF) in patients with sinus rhythm (SR). However, the change of AI-ECG probability before and after the first AF episode is not well characterized. We sought to characterize the temporal trend of AI-ECG AF probability around the first episode of AF. Methods and results We retrospectively studied adults who had at least one ECG in SR prior to an ECG that documented AF. An AI network calculated the AF probability from ECGs during SR (positive defined &gt;8.7%, based on optimal sensitivity and specificity). The AI-ECG probability was reported prior to and after the first episode of AF and stratified by age and CHA2DS2-VASc score. Mixed effect models were used to assess the rate of change between time points. A total of 59 212 patients with 544 330 ECGs prior to AF and 413 486 ECGs after AF were included. The mean time between the first positive AI-ECG and first AF was 5.4 ± 5.7 years. The mean AI-ECG probability was 19.8% 2–5 years prior to AF, 23.6% 1–2 years prior to AF, 34.0% 0–3 months prior to AF, 40.9% 0–3 months after AF, 35.2% 1–2 years after AF, and 42.2% 2–5 years after AF (P &lt; 0.001). The rate of increase prior to AF was higher for age &gt;50 years CHA2DS2-VASc score ≥4. Conclusion The AI-ECG probability progressively increases with time prior to the first AF episode, transiently decreases 1–2 years following AF and continues to increase thereafter.