Citations

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

Background: Osteochondral autograft transplant (OAT) is often used to treat large osteochondral lesions of the talus and is generally associated with good outcomes. The addition of adjuncts such as cartilage extracellular matrix with bone marrow aspirate concentrate (ECM-BMAC) may further improve the OAT procedure but have not been thoroughly studied. We hypothesized that the placement of ECM-BMAC around the OAT graft would improve radiographic and patient-reported outcomes following OAT. Methods: Patients who received OAT, with ECM-BMAC or BMAC alone, were screened and their charts were reviewed. For patients who did receive ECM-BMAC, the mixture was spread around the edges of the OAT plug and into any surrounding areas of cartilage damage. Survey and radiographic data were collected. Average follow-up in both groups was over 2 years. Magnetic resonance imaging scans were scored using the Magnetic Resonance Observation of Cartilage Tissue (MOCART) system. Outcomes were compared statistically between groups. Results: Patients treated with ECM-BMAC (n = 34) demonstrated significantly greater improvement of scores in the FAOS categories Symptoms (17 vs −3; P = .02) and Sports Activities (40 vs 7; P = .02), and the MOCART category Subchondral Lamina ( P = .008) compared to those treated with BMAC alone (n = 30). They also experienced significantly lower rates of postoperative cysts (53% vs 18%, P = .04) and edema (94% vs 59%, P = .02). Conclusion: The addition of ECM-BMAC to OAT was associated with improved imaging and clinical outcomes compared to OAT with BMAC alone.

Purpose Health systems science (HSS) curricula equip future physicians to improve patient, population, and health systems outcomes (i.e., to become “systems citizens”), but the degree to which medical students internalize this conception of the physician role remains unclear. This study aimed to explore how students envision their future professional identity in relation to the system and identify experiences relevant to this aspect of identity formation. Method Between December 2018 and September 2019, authors interviewed 48 students at 4 U.S. medical schools with HSS curricula. Semistructured interviews were audiorecorded, transcribed, and analyzed iteratively using inductive thematic analysis. Interview questions explored how students understood the health system, systems-related activities they envisioned as future physicians, and experiences and considerations shaping their perspectives. Results Most students anticipated enacting one or more systems-related roles as a future physician, categorized as “bottom-up” efforts enacted at a patient or community level (humanist, connector, steward) or “top-down” efforts enacted at a system or policy level (system improver, system scholar, policy advocate). Corresponding activities included attending to social determinants of health or serving medically underserved populations, connecting patients with team members to address systems-related barriers, stewarding health care resources, conducting quality improvement projects, researching/teaching systems topics, and advocating for policy change. Students attributed systems-related aspirations to experiences beyond HSS curricula (e.g., low-income background; work or volunteer experience; undergraduate studies; exposure to systems challenges affecting patients; supportive classmates, faculty, and institutional culture). Students also described future-oriented considerations promoting or undermining identification with systems-related roles (responsibility, affinity, ability, efficacy, priority, reality, consequences). Conclusions This study illuminates systems-related roles medical students at 4 schools with HSS curricula envisioned as part of their future physician identity and highlights past/present experiences and future-oriented considerations shaping identification with such roles. These findings inform practical strategies to support professional identity formation inclusive of systems engagement.

Background: Modular fluted tapered (MFT) stems have advanced treatment of Vancouver B 2 and B 3 periprosthetic femoral fractures, but series to date have been limited with respect to cohort size and follow-up duration. The purpose of this study was to determine implant survivorship, radiographic results, complications, and clinical outcomes of Vancouver B 2 and B 3 periprosthetic femoral fractures treated with MFT stems in a large series of patients. Methods: We identified 171 Vancouver B 2 (109) and B 3 (62) periprosthetic femoral fractures treated with an MFT stem between 2000 and 2018 using our institutional total joint registry. The mean age was 75 years, 50% were female, and the mean body mass index was 29 kg/m 2 . The median stem diameter was 18 mm and median stem length was 210 mm. The cumulative incidences of revision and reoperation with death as the competing risk were calculated, radiographs were reviewed, and clinical outcomes were evaluated using the Harris hip score (HHS). The mean follow-up was 5 years. Results: The 10-year cumulative incidence of any revision was 10%. There were 17 revisions, of which only 3 were for the distal fluted portion of the MFT stem. Revision indications included periprosthetic joint infection (PJI) (n = 6) and dislocation (n = 11). The 10-year cumulative incidence of any reoperation was 15%. In addition to the above 17 revisions, there were 7 reoperations for superficial wound complications (n = 4), Vancouver B 1 periprosthetic femoral fracture (n = 1), vascular occlusion (n = 1), and acetabular cartilage degeneration requiring an acetabular component (n = 1). Radiographically, there was 1 fracture nonunion. All unrevised MFT stems were radiographically well fixed. Subsidence of ≥5 mm occurred in 11%, but all implants were stable at the most recent follow-up. The mean HHS was 75 at 2 years (n = 71). Conclusions: In this large series of 171 Vancouver B 2 and B 3 periprosthetic femoral fractures treated with MFT stems, we found that such constructs were associated with a high rate of fracture healing and provided extremely reliable and durable implant fixation, with no revisions for aseptic loosening. Dislocation and PJI were the most common complications. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

ABSTRACT Estrogen is known to regulate bone metabolism in both women and men, but substantial gaps remain in our knowledge of estrogen and estrogen receptor alpha (ERα) regulation of adult bone metabolism. Studies using global ERα-knockout mice were confounded by high circulating sex-steroid levels, and osteocyte/osteoblast-specific ERα deletion may be confounded by ERα effects on growth versus the adult skeleton. Thus, we developed mice expressing the tamoxifen-inducible CreERT2 in osteocytes using the 8-kilobase (kb) Dmp1 promoter (Dmp1CreERT2). These mice were crossed with ERαfl//fl mice to create ERαΔOcy mice, permitting inducible osteocyte-specific ERα deletion in adulthood. After intermittent tamoxifen treatment of adult 4-month-old mice for 1 month, female, but not male, ERαΔOcy mice exhibited reduced spine bone volume fraction (BV/TV (−20.1%, p = 0.004) accompanied by decreased trabecular bone formation rate (−18.9%, p = 0.0496) and serum P1NP levels (−38.9%, p = 0.014). Periosteal (+65.6%, p = 0.004) and endocortical (+64.1%, p = 0.003) expansion were higher in ERαΔOcy mice compared to control (Dmp1CreERT2) mice at the tibial diaphysis, reflecting the known effects of estrogen to inhibit periosteal apposition and promote endocortical formation. Increases in Sost (2.1-fold, p = 0.001) messenger RNA (mRNA) levels were observed in trabecular bone at the spine in ERαΔOcy mice, consistent with previous reports that estrogen deficiency is associated with increased circulating sclerostin as well as bone SOST mRNA levels in humans. Further, the biological consequences of increased Sost expression were reflected in significant overall downregulation in panels of osteoblast and Wnt target genes in osteocyte-enriched bones from ERαΔOcy mice. These findings thus establish that osteocytic ERα is critical for estrogen action in female, but not male, adult bone metabolism. Moreover, the reduction in bone formation accompanied by increased Sost, decreased osteoblast, and decreased Wnt target gene expression in ERαΔOcy mice provides a direct link in vivo between ERα and Wnt signaling. © 2022 American Society for Bone and Mineral Research (ASBMR).

Background: The COVID-19 pandemic has led to increased burnout and staff turnover for health care providers (HCPs). The purpose of this pilot study was to evaluate the safety and acceptability of a Stress Resilience Program (SRP) for reducing perceived stress and improving resilience among HCPs during a pandemic. Method: Of the 12 HCPs expressing interest in the study, 10 were enrolled in this study. Participants attended three in-person visits (consent/screen, baseline, and end-of-study). The SRP consisted of education related to resilience enhancement and a breathing device ( BreatherFit®) for combined respiratory muscle training (cRMT). Participants completed 4 weeks of cRMT and applied situational breathing strategies as needed. Outcomes measured were changes in stress (PSS-10), resilience (BRS), depression (PRIME-MD), and sleep (PSQI and Ōura Ring®). Findings: The majority of participants were male (60%) and White (60%) with an average age of 39.7 years. Changes from baseline to end-of-treatment indicated a positive trend with significant stress reduction (−3.2 ± 3.9, p = .028) and nonsignificant depression reduction (−0.5 ± 0.7, p = .05). Resilience was high at baseline and continued to stay high during the study with a nonsignificant increase at end-of-study (+0.07 ± 0.7, p = .77). No changes in overall sleep scores were noted. All participants agreed the study was worthwhile, 80% indicated they would repeat the experience, while 90% indicated they would recommend the study to others. Conclusion/Application to Practice: Because of its size and portability, SRP is an easily applicable and promising option for reducing stress among HCPs during a high-stress period, such as a pandemic. Larger studies are needed.

OBJECTIVES To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C). METHODS Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients <21-years-old, hospitalized May 2020 to May 2021 for acute COVID-19 or MIS-C with follow-up 2 to 4 months after admission. We assessed readmissions, persistent symptoms or activity impairment, and new morbidities. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI). RESULTS Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04–1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06–1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55–6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35–4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C). CONCLUSIONS Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

AbstractWilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi‐institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event‐free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage‐specific treatment regimens.

Abstract We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P &lt; .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.