Citations

Abstract Prolonged infections in immunocompromised individuals may be a source for novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants, particularly when both the immune system and antiviral therapy fail to clear the infection and enable within-host evolution. Here we describe a 486-day case of SARS-CoV-2 infection in an immunocompromised individual. Following monotherapy with the monoclonal antibody Bamlanivimab, the individual’s virus acquired resistance, likely via the earliest known occurrence of Spike amino acid variant E484T. Recently, E484T has arisen again as a derivative of E484A in the Omicron Variant of Concern, supporting the hypothesis that prolonged infections can give rise to novel variants long before they become prevalent in the human population.

Abstract Objective To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A 1c (HbA 1c ). Design Observational study. Setting OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants Adults with type 2 diabetes and HbA 1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures The primary outcome was time to HbA 1c ≥7.0%. Secondary outcomes were time to HbA 1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA 1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA 1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA 1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

Background This study aimed to compare percutaneous left atrial appendage occlusion (LAAO) with non‐vitamin K antagonist oral anticoagulants among patients with atrial fibrillation. Methods and Results Using a US administrative database, 562 850 patients with atrial fibrillation were identified, among whom 8397 were treated with LAAO and 554 453 were treated with non‐vitamin K antagonist oral anticoagulants between March 13, 2015 and December 31, 2018. Propensity score overlap weighting was used to balance baseline characteristics. The primary outcome was a composite end point of ischemic stroke or systemic embolism, major bleeding, and all‐cause mortality. The mean age was 76.4±7.6 years; 280 097 (49.8%) were female. Mean follow‐up was 1.5±1.0 years. LAAO was associated with no significant difference in the risk of the primary composite end point (hazard ratio [HR], 0.93 [0.84–1.03]), or the secondary outcomes including ischemic stroke/systemic embolism (HR, 1.07 [0.81–1.41]), and intracranial bleeding (HR, 1.08 [0.72–1.61]). LAAO was associated with a higher risk of major bleeding (HR, 1.22 [1.05–1.42], P =0.01) and a lower risk of mortality (HR, 0.73 [0.64–0.84], P <0.001). The lower risk of mortality associated with LAAO was most pronounced in patients with a prior history of intracranial bleeding. Conclusions In comparison to non‐vitamin K antagonist oral anticoagulants, LAAO was associated with no significant difference in the risk of the composite outcome and a lower risk of mortality, which suggests LAAO might be a reasonable option in select patients with atrial fibrillation. The observation of higher bleeding risk associated with LAAO highlights the need to optimize postprocedural antithrombotic regimens as well as systematic efforts to assess and address bleeding predispositions.

Abstract We present the case of a 46-year-old male with medically complicated class III obesity who presented with new-onset and persistent dysphagia after undergoing a successful laparoscopic Roux-en-Y gastric bypass surgery. An esophagogastroduodenoscopy was unrevealing, however, further workup with the endoluminal functional lumen imaging probe (EndoFLIP) device was suggestive of esophageal dysmotility with decreased distensibility index of the GE junction and absent/disorganized secondary esophageal peristalsis. Thorough chart review was performed to elicit details of the case presentation. Further, a literature review was performed to supplement background knowledge and discussion. We present a case of symptomatic esophageal dysphagia in a post-procedural bariatric surgery patient with normal EGD yet positive findings on functional lumen imaging, consistent with the newly described entity termed Post Obesity Surgery Esophageal Dysfunction (POSED). POSED is defined by aperistalsis and increased intragastric pressure seen after bariatric surgery. It is thought to occur due to a high-pressure gastric zone created in the noncompliant postoperative stomach after Roux-en-Y gastric bypass, or an increased esophageal afterload by a restrictive laparoscopic sleeve gastrectomy. No treatment guidelines exist, though options include botulinum toxin, dilation, and per-oral esophageal myotomy. This case provides further insight into the role that functional lumen imaging has in the bariatric patient, as it may be able to more accurately detect patients who will develop esophageal dysmotility following bariatric surgery, or perhaps even those who may be predisposed prior to undergoing intervention for weight loss.

As part of the Multiple Myeloma Research Foundation (MMRF) immune atlas pilot project, we compared immune cells of multiple myeloma bone marrow samples from 18 patients assessed by single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to understand the concordance of measurements among single-cell techniques. Cell type abundances are relatively consistent across the three approaches, while variations are observed in T cells, macrophages, and monocytes. Concordance and correlation analysis of cell type marker gene expression across different modalities highlighted the importance of choosing cell type marker genes best suited to particular modalities. By integrating data from these three assays, we found International Staging System stage 3 patients exhibited decreased CD4+ T/CD8+ T cells ratio. Moreover, we observed upregulation of RAC2 and PSMB9, in natural killer cells of fast progressors compared with those of nonprogressors, as revealed by both scRNA-seq and CITE-seq RNA measurement. This detailed examination of the immune microenvironment in multiple myeloma using multiple single-cell technologies revealed markers associated with multiple myeloma rapid progression which will be further characterized by the full-scale immune atlas project. Significance: scRNA-seq, CyTOF, and CITE-seq are increasingly used for evaluating cellular heterogeneity. Understanding their concordances is of great interest. To date, this study is the most comprehensive examination of the measurement of the immune microenvironment in multiple myeloma using the three techniques. Moreover, we identified markers predicted to be significantly associated with multiple myeloma rapid progression.

Objective Heart failure (HF) imposes a substantial burden and the prevalence of HF is high in patients with chronic kidney disease (CKD). HF results in multiple hospital admissions, but whether HF subtypes worsen long-term outcomes and renal function in patients with CKD remains inconclusive. Methods The study comprised 10 904 patients with CKD aged ≥20 years who underwent echocardiography between 1 January 2011 and 31 December 2018. The patients were stratified into four groups: non-HF, HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF). The primary end points were all-cause mortality, major adverse cardiovascular events (MACEs) and adverse renal outcomes. Results In inverse probability of treatment weighting-adjusted method, the risk of all-cause mortality and MACEs relative to the non-HF group was greatest in the HFrEF group (HR 3.18 (95% CI 2.57 to 3.93) and HR 3.83 (95% CI 3.20 to 4.59)), followed by the HFmrEF (HR 2.75 (95% CI 2.22 to 3.42) and HR 3.08 (95% CI 2.57 to 3.69)) and HFpEF (HR 1.85 (95% CI 1.59 to 2.15) and HR 2.43 (95% CI 2.16 to 2.73) groups. In addition, the HFrEF group had the greatest risks of end-stage renal disease (HR 2.58 (95% CI 1.94 to 3.44)) compared with other groups. Conclusions HF is associated with subsequent worse clinical outcomes, which may be more pronounced in patients with HFrEF, followed by those with HFmrEF and those with HFpEF relative to non-HF group.

ABSTRACT To develop guidelines for hypoparathyroidism and primary hyperparathyroidism, the panel assembled a panel of experts in parathyroid disorders, general endocrinologists, representatives of the Hypoparathyroidism Association, and systematic review and guideline methodologists. The guideline panel referred to a formal process following the Recommendations, Assessment, Development, and Evaluation Working Group (GRADE) methodology to issue GRADEd recommendations. In this approach, panelists and methodologists formatted the questions, conducted systematic reviews, evaluated risk of bias, assessed certainty of evidence, and presented a summary of findings in a transparent fashion. For most recommendations, the task forces used a less structured approach largely based on narrative reviews to issue non-GRADEd recommendations. The panel issued Eight GRADEd recommendations (seven for hypoparathyroidism and one for hyperparathyroidism). Each GRADEd recommendation is linked to the underlying body of evidence and judgments regarding the certainty of evidence and strength of recommendations, values and preferences, and costs, feasibility, acceptability and equity. This article summarizes the methodology for issuing GRADEd and non-GRADEd recommendations for patients with hypoparathyroidism or hyperparathyroidism. © 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 The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a systematic review and meta-analysis of currently available randomized controlled trials to investigate the benefits and harms of PTH therapy and conventional therapy in the management of patients with chronic hypoparathyroidism. To identify eligible studies, published in English, we searched Embase, PubMed, and Cochrane CENTRAL from inception to May 2022. Two reviewers independently extracted data and assessed the risk of bias. We defined patients' important outcomes and used grading of recommendations, assessment, development, and evaluation (GRADE) to provide the structure for quantifying absolute effects and rating the quality of evidence. Seven randomized trials of 12 publications that enrolled a total of 386 patients proved eligible. The follow-up duration ranged from 1 to 36 months. Compared with conventional therapy, PTH therapy probably achieves a small improvement in physical health-related quality of life (mean difference [MD] 3.4, 95% confidence interval [CI] 1.5–5.3, minimally important difference 3.0, moderate certainty). PTH therapy results in more patients reaching 50% or greater reduction in the dose of active vitamin D and calcium (relative risk [RR] = 6.5, 95% CI 2.5–16.4, 385 more per 1000 patients, high certainty). PTH therapy may increase hypercalcemia (RR =2.4, 95% CI 1.2–5.04, low certainty). The findings may support the use of PTH therapy in patients with chronic hypoparathyroidism. Because of limitations of short duration and small sample size, evidence from randomized trials is limited regarding important benefits of PTH therapy compared with conventional therapy. Establishing such benefits will require further studies. © 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).