Citations

Introduction The Accreditation Council for Graduate Medical Education (ACGME) offers descriptions of competencies and milestones but does not provide standardized assessments to track trainee competency. Entrustable professional activities (EPAs) and special assessments (SAs) are emerging methods to assess the level of competency obtained by regional anesthesiology and acute pain medicine (RAAPM) fellows. Methods A panel of RAAPM physicians with experience in education and competency assessment and one medical student were recruited to participate in a modified Delphi method with iterative rounds to reach consensus on: a list of EPAs, SAs, and procedural skills; detailed definitions for each EPA and SA; a mapping of the EPAs and SAs to the ACGME milestones; and a target level of entrustment for graduating US RAAPM fellows for each EPA and procedural skill. A gap analysis was performed and a heat map was created to cross-check the EPAs and SAs to the ACGME milestones. Results Participants in EPA and SA development included 19 physicians and 1 medical student from 18 different programs. The Delphi rounds yielded a final list of 23 EPAs, a defined entrustment scale, mapping of the EPAs to ACGME milestones, and graduation targets. A list of 73 procedural skills and 7 SAs were similarly developed. Discussion A list of 23 RAAPM EPAs, 73 procedural skills, and 7 SAs were created using a rigorous methodology to reach consensus. This framework can be utilized to help assess RAAPM fellows in the USA for competency and allow for meaningful performance feedback.

Background: Sex as a biological variable and gender as a sociocultural variable influence many health conditions and outcomes. However, they have not been incorporated systematically into education across health professions. Methods: Areas of knowledge and abilities that apply to sex and gender education across health professions were summarized from the 2015 and 2018 Sex and Gender Health Education Summits. Results: Using this summary, draft tenets were developed by facilitated interprofessional discussion groups at the 2020 Summit, and then reviewed, edited, and refined by a writing group who recommended four tenets that health care professionals should be able to do: (1) demonstrate knowledge of sex and gender specific health (SGSH), (2) evaluate literature and the conduct of research for incorporation of sex and gender, (3) incorporate sex and gender considerations into clinical decision making, and (4) demonstrate patient advocacy with respect to sex and gender. Conclusion: These tenets provide the framework for collaborative interprofessional education about SGSH. Individual professions can also use the tenets to develop practice-specific competencies, competency statements, and/or assessment benchmarks within the structures of their respective accrediting bodies to advance the health of women, men, and sex and gender minority persons. Interprofessional collaborations are key for sharing best practices in development, curricular integration, and dissemination.

Background: Lytic or malpositioned tunnels may require bone grafting during revision anterior cruciate ligament reconstruction (rACLR) surgery. Patient characteristics and effects of grafting on outcomes after rACLR are not well described. Purpose: To describe preoperative characteristics, intraoperative findings, and 2-year outcomes for patients with rACLR undergoing bone grafting procedures compared with patients with rACLR without grafting. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 1234 patients who underwent rACLR were prospectively enrolled between 2006 and 2011. Baseline revision and 2-year characteristics, surgical technique, pathology, treatment, and patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index, and Marx Activity Rating Scale [Marx]) were collected, as well as subsequent surgery information, if applicable. The chi-square and analysis of variance tests were used to compare group characteristics. Results: A total of 159 patients (13%) underwent tunnel grafting—64 (5%) patients underwent 1-stage and 95 (8%) underwent 2-stage grafting. Grafting was isolated to the femur in 31 (2.5%) patients, the tibia in 40 (3%) patients, and combined in 88 patients (7%). Baseline KOOS Quality of Life (QoL) and Marx activity scores were significantly lower in the 2-stage group compared with the no bone grafting group ( P≤ .001). Patients who required 2-stage grafting had more previous ACLRs ( P < .001) and were less likely to have received a bone–patellar tendon–bone or a soft tissue autograft at primary ACLR procedure ( P≤ .021) compared with the no bone grafting group. For current rACLR, patients undergoing either 1-stage or 2-stage bone grafting were more likely to receive a bone–patellar tendon–bone allograft ( P≤ .008) and less likely to receive a soft tissue autograft ( P≤ .003) compared with the no bone grafting group. At 2-year follow-up of 1052 (85%) patients, we found inferior outcomes in the 2-stage bone grafting group (IKDC score = 68; KOOS QoL score = 44; KOOS Sport/Recreation score = 65; and Marx activity score = 3) compared with the no bone grafting group (IKDC score = 77; KOOS QoL score = 63; KOOS Sport/Recreation score = 75; and Marx activity score = 7) ( P≤ .01). The 1-stage bone graft group did not significantly differ compared with the no bone grafting group. Conclusion: Tunnel bone grafting was performed in 13% of our rACLR cohort, with 8% undergoing 2-stage surgery. Patients treated with 2-stage grafting had inferior baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting. Patients treated with 1-stage grafting had similar baseline and 2-year patient-reported outcomes and activity levels compared with patients not undergoing bone grafting.

Abstract Background Although multiple clinical studies have found an association between vitamin D (Vit D) deficiency and asthma, a recent clinical study suggested lack of therapeutic effect of Vit D supplementation. Nonetheless, the mechanisms by which Vit D influences airway structure and function in the context of inflammation and asthma remains undefined. In this regard, Vit D effects on airway smooth muscle (ASM) are important, given the role of this cell type in the hypercontractility and remodeling. We assessed the mechanisms by which Vit D modulates the enhancing effects of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-13 on intracellular Ca2+ ([Ca2+]i) levels and remodeling in nonasthmatic versus asthmatic human ASM. Methods Human ASM was enzymatically isolated from surgical lung specimens of patients with clinically defined mild to moderate asthma versus no asthma. Cells were treated with 10 ng/ml TNF-α and 50 ng/ml IL-13 in the presence or absence of 100 nM calcitriol. Measurements and Main Results Interestingly, Vit D receptor (VDR) and retinoic X receptor-α levels were maintained, even increased, in subjects with asthma when treated with TNF-α and IL-13. Compared with untreated cells, calcitriol blunted the heightened effect of TNF-α on [Ca2+]i response to histamine in ASM. Calcitriol particularly blunted TNF-α and IL-13 effects on collagen and fibronectin deposition, especially in asthmatic ASM. Calcitriol stimulated VDR/retinoic X receptor dimerization and VDR activity even in subjects with asthma and with IL-13, highlighting retained functionality. Expression of Class I histone deacetylases 1–3 (HDAC) and overall HDAC activity were lower in IL-13–exposed ASM, but calcitriol enhanced HDAC expression/activity. Conclusions In asthmatic ASM, Vit D functionality is maintained, allowing calcitriol to reduce the procontractile and proremodeling effects of inflammatory cytokines, particularly IL-13, which is relevant to asthma. These findings highlight a potential role for Vit D in asthma pathogenesis, particularly in the context of airway structure and functional changes early in disease.

Purpose To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. Methods Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. Results Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. Conclusion The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

Abstract GATA2 mutation can result in profoundly reduced monocytes, dendritic cells, natural killer cells, and B cells, and is associated with a predisposition for recurrent and disseminated nontuberculous mycobacterial (NTM) infections and myelodysplasias. Herein, we describe a unique case of 3 simultaneous disseminated NTM infections in a patient with GATA2 mutations.

Abstract Background Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. Methods We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity. Results Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78–2.15; P = .32). Conclusions Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.

AbstractCongenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multisystem involvement. Individuals with ALG8‐CDG commonly present with hypotonia, protein‐losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8‐CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8‐CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8‐CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8‐CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.

Abstract Background: We compared the predictive and prognostic value of ctDNA dynamics in high-risk hormone receptor-positive/HER2-negative (HR+/HER2-) and triple negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) enrolled in the I-SPY 2 trial (NCT01042379). To our knowledge, this is the largest ctDNA study in breast cancer in the neoadjuvant setting. Methods: Blood samples were collected at pre-treatment (T0), during treatment (T1 at 3 weeks, and T2 at 12 weeks) and after NAC (T3 at 24 weeks) from 106 HR+/HER2- and 97 TNBC patients. Plasma samples (n=734) were analyzed using a personalized and tumor-informed mPCR NGS-based ctDNA test (SignateraTM). Patients, all high risk for recurrence by MammaPrint, received paclitaxel-based treatment +/- experimental therapy followed by anthracycline. The median follow-up was 3.0 years (0.5 to 6.5). The predictive and prognostic value of ctDNA dynamics and status at different timepoints were examined. Our analysis is exploratory and does not adjust for other biomarkers. Results: Pretreatment ctDNA positivity (Fisher p&lt;0.0001) and levels (mean tumor molecules/mL, MTM/mL, t test p=0.0062) were significantly higher in TNBC (90.7%, 14.7 MTM/mL) than in high risk HR+/HER2- (66.0%, 5.5 MTM/mL). Early and late ctDNA clearance during treatment (3 and 12 weeks of NAC) was predictive of pathologic complete response (pCR) and residual cancer burden (RCB), class 0-III, in TNBC but not HR+/HER2- (Table). In both subtypes: (1) ctDNA was a significant negative prognostic factor for distant recurrence-free survival (DRFS) at all timepoints (p&lt;0.05) except at pretreatment; (2) all patients who achieved pCR were ctDNA-negative after NAC; (3) among non-responding patients, ctDNA-negativity after NAC was associated with improved DRFS (Table). Conclusions: The predictive value of ctDNA for prediction of pCR and RCB differed between subtypes (HR+/HER2- vs. TNBC), while similar prognostic value was observed. In TNBC, early clearance of ctDNA at 3 weeks was a significant predictor of favorable response to NAC. Compared to patients who were ctDNA-positive after NAC, ctDNA-negative status in both subtypes was associated with improved DRFS even in patients with residual cancer (no pCR or RCB-II/III). These findings could inform on the design of future studies that seek to demonstrate the utility of ctDNA in the curative setting. Predictive and prognostic significance of ctDNA in early breast cancer in the neoadjuvant setting HR+HER2- (n=106) TNBC (n=97) Predictive value for prediction of pCR and RCB Fisher p-value Fisher p-value Early ctDNA clearance (between T0 and T1) and pCR 0.4521 &lt;0.0001 Late ctDNA clearance (between T0 and T2) and pCR 0.8071 0.0004 Early ctDNA clearance (between T0 and T1) and RCB (0-III) 0.1360 &lt;0.0001 Late ctDNA clearance (between T0 and T2) and RCB (0-III) 0.4869 0.0004 Early ctDNA clearance at T1 and pCR rates pCR rate pCR rate ctDNA clearance (ctDNA+ at T0/ctDNA- at T1) 21% 67% Late ctDNA clearance (betweeNo early clearance (ctDNA+ at T0/ctDNA+ at T1) 13% 14% Prognostic value for prediction of DRFS Log rank p-value Log rank p-value ctDNA at T3 and pCR vs no PCR 0.0002 &lt;0.0001 ctDNA at T3 and RCB (0-I vs II-III) 0.0110 &lt;0.0001 Timepoints: T0 - pretreatment; T1 - three weeks after treatment initiation; T2 - at 12 weeks, between paclitaxel-based and anthracycline regimens; T3- after neoadjuvant chemotherapy prior to surgery Citation Format: Mark Jesus Mendoza Magbanua, Lamorna Brown Swigart, Derrick Renner, Svetlana Shchegrova, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Hsin-Ta Wu, Ekaterina Kalashnikova, Amy L. Delson, A. Jo Chien, Debu Tripathy, Smita Asare, Raheleh Salari, Angel Rodriguez, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Paul Billings, Rita Nanda, Hope S. Rugo, Laura J. Esserman, Minetta C. Liu, Angela DeMichele, Laura van 't Veer. Comparison of the predictive and prognostic significance of circulating tumor DNA in patients with high risk HER2-negative breast cancer receiving neoadjuvant chemotherapy [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 LB111.