Citations

In this emulated comparative effectiveness target trial of glucagon-like peptide 1 (GLP-1) receptor agonist, sodium–glucose cotransporter 2 (SGLT2) inhibitor, dipeptidyl peptidase 4 (DPP-4) inhibitor, and sulfonylurea therapy among adults with type 2 diabetes at moderate cardiovascular disease risk, sulfonylurea use was associated with a significantly higher risk of hypoglycemia requiring emergency department or hospital care than treatment with DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors. This consideration can guide the choice of glucose-lowering therapy in this highly prevalent patient population, in whom avoidance of hypoglycemia is important, yet among whom the risk of severe hypoglycemia has not been examined previously.

AbstractBackgroundThe psychological and cardiovascular health impacts on family members of patients who have been diagnosed with cancer have not been well characterized. The purpose of this study is to determine whether a family member’s cancer diagnosis influences the risk of psychological illness and cardiovascular disease in first‐degree relatives and spouses of patients affected by cancer.MethodsThis retrospective cohort analysis evaluated the risk of psychological illness and cardiovascular disease in first‐degree relatives and spouses of patients diagnosed with a genitourinary cancer between 1990 and 2015 compared to relatives of those not diagnosed with a genitourinary cancer. The Utah Population Database was used and familial linkage was determined. Follow‐up included 1‐, 3‐, and 5‐year intervals. Patients residing outside of Utah and first‐degree relatives and spouses with psychological or cardiovascular disease diagnosed before a family member’s cancer diagnosis were excluded.ResultsA total of 49,284 patients with a genitourinary cancer were identified with 77,938 first‐degree relatives and spouses. A matched control group included 246,775 patients with 81,022 first‐degree relatives and spouses. Via Cox proportional hazards models, a 10% increased risk of developing a psychological illness (hazard ratio [HR], 1.10; 95% CI, 1.00–1.20) and a 28% increased risk of developing cardiovascular disease (HR, 1.28; 95% CI, 1.17–1.41) at 1 year after a family member’s cancer diagnosis were found.ConclusionsThis study provides population‐level evidence to support the hypothesis that cancer diagnoses will lead to adverse health outcomes for family members of patients with cancer. Increased clinical attention and support are needed to reduce the harm to families caused by cancer.

Purpose To evaluate the effectiveness of microfragmented adipose tissue (MFAT) for pain relief and improved joint functionality in osteoarthritis (OA) of the knee in a randomized controlled clinical trial with 1‐year follow‐up. Methods Seventy‐five patients were stratified by baseline pain level and randomized to 1 of 3 treatment groups: MFAT, corticosteroid (CS), or saline control (C) injection. Patients 18 years of age or older, diagnosed with symptomatic OA of the knee, with radiographic evidence of OA of the knee and a visual analog pain scale score of 3 of 10 or greater were included. Patients were excluded if they had any previous intra‐articular knee injection, current knee ligamentous instability, or an allergy to lidocaine/corticosteroid. The visual analog pain scale, Western Ontario and McMaster Universities Osteoarthritis Index, and the Knee Injury and Osteoarthritis Outcome score (KOOS) were recorded preprocedure and at 2 weeks, 6 weeks, 3 and 6 months, and 1‐year follow‐up. Results MFAT demonstrated consistent and statistically significant improvements across all primary outcome measures for joint pain and functionality compared with C. For MFAT, there was a significant improvement over baseline at each follow‐up, with median (95% confidence interval) KOOS Pain score changes of 18.1 (11.1‐26.4) at week 2 to 27.8 (19.4‐37.5) at 1 year. For CS, the median KOOS pain score reached a maximum of 22.2 (15.3‐30.6) at week 2, only to level off to 13.9 (–2.8 to 29.2), a level not statistically different from baseline, at 1 year. The median changes for C hovered around 6 to 11 points, with statistically significant improvements over baseline indicating a placebo effect. Similar trends were seen for the Western Ontario and McMaster Universities Osteoarthritis Index Pain score and VAS Pain score. Conclusions In this study, MFAT demonstrated a clinically significant improvement in primary outcome scores compared with the C group, whereas the CS group only showed statistically significant improvement compared with the C group at 2 and 6 weeks. This finding indicates that MFAT may be a viable alternative treatment for patients with OA of the knee who fall into the orthopaedic treatment gap. Level of Evidence Level II, partially blinded, randomized controlled clinical trial.

AbstractObjectivesTo report lessons from integrating the methods and perspectives of clinical informatics (CI) and implementation science (IS) in the context of Improving the Management of symPtoms during and following Cancer Treatment (IMPACT) Consortium pragmatic trials.Materials and MethodsIMPACT informaticists, trialists, and implementation scientists met to identify challenges and solutions by examining robust case examples from 3 Research Centers that are deploying systematic symptom assessment and management interventions via electronic health records (EHRs). Investigators discussed data collection and CI challenges, implementation strategies, and lessons learned.ResultsCI implementation strategies and EHRs systems were utilized to collect and act upon symptoms and impairments in functioning via electronic patient-reported outcomes (ePRO) captured in ambulatory oncology settings. Limited EHR functionality and data collection capabilities constrained the ability to address IS questions. Collecting ePRO data required significant planning and organizational champions adept at navigating ambiguity.DiscussionBringing together CI and IS perspectives offers critical opportunities for monitoring and managing cancer symptoms via ePROs. Discussions between CI and IS researchers identified and addressed gaps between applied informatics implementation and theory-based IS trial and evaluation methods. The use of common terminology may foster shared mental models between CI and IS communities to enhance EHR design to more effectively facilitate ePRO implementation and clinical responses.ConclusionImplementation of ePROs in ambulatory oncology clinics benefits from common understanding of the concepts, lexicon, and incentives between CI implementers and IS researchers to facilitate and measure the results of implementation efforts.

Abstract Background A dual filtration-based method for determination of serum labile bound copper (LBC) and LBC fraction (LBC/total copper) was developed. Reduced total copper, elevated LBC, and elevated LBC fraction have been reported in Wilson disease (WD). Methods To evaluate the diagnostic performance of these markers, samples were obtained from 21 WD treatment-naïve (WD-TN, no WD treatment or <28 days of treatment) patients, 46 WD standard-of-care–treated (WD-SOC) patients, along with 246 patients representing other potential disorders of copper status. These were then compared to 213 reference interval population patients. Results Receiver operating characteristic curves for the reference population vs WD-TN yielded areas under the curve for total copper, LBC, and LBC fraction, of 0.99, 0.81, and 0.98, respectively. Using Youden cutoffs, sensitivity/specificity for WD-TN was 95%/97% for total copper, 71%/85% for LBC, and 95%/94% for LBC fraction. LBC values, but not total copper and LBC fraction, differed substantially between WD-TN and WD-SOC cohorts. We propose a dual model wherein total copper and LBC fraction results must agree to be classified as a “positive” or “negative” result for WD. This correctly classified 19/21 WD-TN patients as positive, and 194/213 reference interval patients as negative. The remaining “indeterminate” patients (representing approximately 9% of the reference and the WD-TN populations) exhibited conflicting total copper and LBC fraction results. When indeterminate results are excluded, this model exhibited apparent 100% sensitivity/specificity. Conclusions Agreement of total serum copper and LBC fraction classification may constitute an effective “rule-in” and “rule-out” assessment for WD-TN patients.

Abstract Introduction: Current guidelines state the effectiveness of desmopressin to reduce hematoma expansion in antiplatelet-related intracerebral hemorrhage (ICH) is uncertain. This study sought to determine if desmopressin decreased hematoma expansion in ICH patients on antiplatelet agents. Methods: We conducted a multi-center, retrospective propensity-matched cohort study at 11 US emergency departments (ED) that participate in EMPHARM-NET. Adult patients ≥18 years with a primary diagnosis of spontaneous ICH on antiplatelets prior to admission from January 1, 2017 through May 1, 2021 were included. The primary endpoint was good or excellent hemostatic efficacy within the first 24 hours following ICH between patients that did and did not receive desmopressin. Brain imaging was reviewed using 3D-Slicer by blinded expert physicians. Results: Overall, 1408 patients were evaluated for inclusion. A total of 324 patients were included, of which 13.8% (n=45) received desmopressin and 86.1% (n=279) did not. After propensity matching, 35 patients receive desmopressin compared to 140 controls. Baseline hematoma volume (27.6 mL vs. 2.1 mL) and was significantly higher in the desmopressin group. The primary endpoint of good or excellent hemostatic efficacy was similar between groups (74.3% desmopressin group vs. 85% control group, -10.7% [-28.1% to 6.7%]). There was no difference in secondary outcomes. Conclusion: In this multicenter cohort, patients receiving desmopressin had higher baseline intraparenchymal hematoma volume, and did not appear to result in improved hemostatic efficacy relative to the control group. These results suggest against routine administration of desmopressin for antiplatelet-related ICH, though future study in a randomized trial design is necessary.

AbstractBackgroundPost‐infectious disorders of gut‐brain interaction (PI‐DGBI) have significant impact on children and adolescents. The effect of COVID‐19 on PI‐DGBI‐associated symptoms in this population, however, is unknown.MethodsWe performed electronic medical record searches to identify patients 8–17 years old with a SARS‐CoV2 PCR test at Lurie Children's Hospital between November 2020 and March 2021 (cohort 1) and April–October 2021 (cohort 2). Questionnaires were administered to assess symptoms prior to and 3 months following the test. This included the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS), questionnaire of pediatric gastrointestinal symptoms—Rome IV, Nausea Profile (NP), dyspepsia symptom survey (DSS), nausea severity profile (NSP), and Pediatric Quality of Life Inventory (PedsQL). We grouped patients based on the presence of symptoms prior to COVID‐19 test or the test result.ResultsOne hundred and ninety‐six parent(s) or guardian(s) in cohort 1 and 274 in cohort 2 completed surveys and self‐reported their child's COVID‐19 result. Cohort 1 had increased PEESS and DSS scores, lower PedsQL scores, and increased frequency of abdominal pain disorders among patients with symptoms prior to COVID‐19 testing. Both cohorts had increased NP and NSP scores among patients with symptoms prior to COVID‐19 testing that was highest among patients with a positive COVID‐19 test. Abdominal pain and diarrhea prior to COVID‐19 testing predicted higher NP scores.ConclusionsAmong symptomatic COVID‐19 tested children, we found increased severity of nausea‐associated somatic, emotional, and gastrointestinal symptoms in the 3 months following the test that was most increased among patients with a positive COVID‐19 test.

AbstractBackgroundBolus materials have been used for decades in radiotherapy. Most frequently, these materials are utilized to bring dose closer to the skin surface to cover superficial targets optimally. While cavity filling, such as nasal cavities, is desirable, traditional commercial bolus is lacking, requiring other solutions. Recently, investigators have worked on utilizing 3D printing technology, including commercially available solutions, which can overcome some challenges with traditional bolus.PurposeTo utilize failure modes and effects analysis (FMEA) to successfully implement a comprehensive 3D printed bolus solution to replace commercial bolus in our clinic using a series of open‐source (or free) software products.Methods3D printed molds for bespoke bolus were created by exporting the DICOM structures of the bolus designed in the treatment planning system and manipulated to create a multipart mold for 3D printing. A silicone (Ecoflex 00–30) mixture is poured into the mold and cured to form the bolus. Molds for sheet bolus of five thicknesses were also created. A comprehensive FMEA was performed to guide workflow adjustments and QA steps.ResultsThe process map identified 39 and 30 distinct steps for the bespoke and flat sheet bolus workflows, respectively. The corresponding FMEA highlighted 119 and 86 failure modes, with 69 shared between the processes. Misunderstanding of plan intent was a potential cause for most of the highest‐scoring failure modes, indicating that physics and dosimetry involvement early in the process is paramount.ConclusionFMEA informed the design and implementation of QA steps to guarantee a safe and high‐quality comprehensive implementation of silicone bolus from 3D printed molds. This approach allows for greater adaptability not afforded by traditional bolus, as well as potential dissemination to other clinics due to the open‐source nature of the workflow.

Abstract TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis. These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of these inflammatory circuits is unknown. To address this, we performed scRNA-seq and scATAC-seq in patients with COVID-19 with and without TET2-mutated clonal hematopoiesis reasoning that inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified metastasis-associated lung adenoma transcript 1 (MALAT1), a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic proinflammatory features of mTET2 in vivo. We also elucidate the mechanism by which mTET2 upregulate MALAT1 and describe an interaction between MALAT1 and p65, which leads to RNA “shielding” from protein phosphatase 2A dephosphorylation, thus preventing resolution of inflammatory signaling. Significance: This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 “shields” p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

AbstractWith an annual cumulative occurrence of approximately 15,000 in North America, all childhood cancers are rare. Very rare cancers as defined by both the European Cooperative Study Group for Rare Pediatric Cancers and the Children's Oncology Group fall into two principal categories: those so uncommon (fewer than 2 cases/million) that their study is challenging even through cooperative group efforts (e.g., pleuropulmonary blastoma and desmoplastic small round cell tumor) and those that are far more common in adults and therefore rarely studied in children (e.g., thyroid, melanoma, and gastrointestinal stromal tumor). Treatment strategies for these latter tumors are typically based on adult guidelines, although the pediatric variants of these tumors may harbor different genetic signatures and demonstrate different behavior. If melanoma and differentiated thyroid cancer are excluded, other rare cancer types account for only 2% of the cancers in children aged 0 to 14. This article highlights several of the most common rare tumor types.