Citations

AbstractObjectiveSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) emerged as a global pandemic in early 2020 with rapidly evolving approaches to diagnosing the clinical illness called coronavirus disease (COVID‐19). The primary objective of this scoping review is to synthesize current research of the diagnostic accuracy of history, physical examination, routine laboratory tests, real‐time reverse transcription–polymerase chain reaction (rRT‐PCR), immunology tests, and computed tomography (CT) for the emergency department (ED) diagnosis of COVID‐19. Secondary objectives included a synopsis of diagnostic biases likely with current COVID‐19 research as well as corresponding implications of false‐negative and false‐positive results for clinicians and investigators.MethodsA Preferred Reporting Items for Systematic Reviews and Meta‐Analyses–Scoping Review (PRISMA‐ScR)–adherent synthesis of COVID‐19 diagnostic accuracy through May 5, 2020, was conducted. The search strategy was designed by a medical librarian and included studies indexed by PubMed and Embase since January 2020.ResultsA total of 1,907 citations were screened for relevance. Patients without COVID‐19 are rarely reported, so specificity and likelihood ratios were generally unavailable. Fever is the most common finding, while hyposmia and hypogeusia appear useful to rule in COVID‐19. Cough is not consistently present. Lymphopenia is the mostly commonly reported laboratory abnormality and occurs in over 50% of COVID‐19 patients. rRT‐PCR is currently considered the COVID‐19 criterion standard for most diagnostic studies, but a single test sensitivity ranges from 60% to 78%. Multiple reasons for false‐negatives rRT‐PCR exist, including sample site tested and disease stage during which sample was obtained. CT may increase COVID‐19 sensitivity in conjunction with rRT‐PCR, but guidelines for imaging patients most likely to benefit are emerging. IgM and IgG serology levels are undetectable in the first week of COVID‐19, but sensitivity (range = 82% to 100%) and specificity (range = 87% to 100%) are promising. Whether detectable COVID‐19 antibodies correspond to immunity remains unanswered. Current studies do not adhere to accepted diagnostic accuracy reporting standards and likely report significantly biased results if the same tests were to be applied to general ED populations with suspected COVID‐19.ConclusionsWith the exception of fever and disorders of smell/taste, history and physical examination findings are unhelpful to distinguish COVID‐19 from other infectious conditions that mimic SARS‐CoV‐2 like influenza. Routine laboratory tests are also nondiagnostic, although lymphopenia is a common finding and other abnormalities may predict severe disease. Although rRT‐PCR is the current criterion standard, more inclusive consensus‐based criteria will likely emerge because of the high false‐negative rate of PCR tests. The role of serology and CT in ED assessments remains undefined.

Purpose To explore the relationship between residents’ perceptions of residency program leadership team behaviors and resident burnout and satisfaction. Method In February 2019, the authors surveyed all residents across the 77 graduate medical education training programs at Mayo Clinic’s multiple sites. Survey items measured residents’ perceptions of program director and associate program director behaviors (using a composite residency program leadership team score), resident burnout, and resident satisfaction with the program and organization. Multivariable logistic regression was performed to evaluate relationships between these variables at the individual resident (adjusting for age, sex, postgraduate training year, program location, and specialty) and program (including only programs with at least 5 respondents) levels. Results Of the 1,146 residents surveyed, 762 (66.5%) responded. At the individual resident level, higher composite leadership team scores were associated with lower emotional exhaustion and depersonalization and higher overall satisfaction with the residency program and organization (all P < .001). In adjusted logistic regression models, each 1-point gain in composite leadership team score was associated with 9% lower odds of burnout, 20% higher odds of program satisfaction, and 19% higher odds of satisfaction with the organization (all P < .001). At the residency program level, higher mean composite leadership team scores were associated with a lower rate of burnout (r = −0.35, P = .03) and higher program and organization satisfaction (r = 0.67 and 0.74, respectively, both P < .001). Conclusions The behaviors of residency program leadership teams influence residents’ burnout and satisfaction. Additional studies are needed to determine if leadership training results in improved resident well-being and satisfaction.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Purpose To explore the interaction between practice setting (academic practice [AP], private practice [PP]) and gender in relation to physician burnout and satisfaction with work–life integration (WLI). Method In 2017, the authors administered a cross-sectional survey of U.S. physicians and characterized rates of burnout and satisfaction with WLI using previously validated and/or standardized tools. They conducted multivariable logistic regression to determine the interaction between the included variables. Results Of the 3,603 participants in the final analysis, female physicians reported a higher prevalence of burnout than male physicians in both AP (50.7% vs 38.2%, P < .0001) and PP (48.1% vs 40.7%, P = .001). However, the multivariable analysis found no statistically significant gender-based differences in burnout (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.76–1.17, P = .60). Women and men in AP were less likely to report burnout than men in PP (OR 0.70, 95% CI 0.52–0.94, P = .01 and OR 0.69, 95% CI 0.53–0.90, P < .01, respectively); women in PP did not report different burnout rates from men in PP (OR 0.89, 95% CI 0.68–1.16, P = .38). Women in both AP and PP were less likely to be satisfied with WLI than men in PP (OR 0.62, 95% CI 0.47–0.83, P < .01 and OR 0.75, 95% CI 0.58–0.97, P = .03, respectively); men in AP did not report different satisfaction with WLI than men in PP (OR 1.05, 95% CI 0.82–1.33, P = .71). Conclusions Gender differences in rates of burnout are related to practice setting and other differences in physicians’ personal and professional lives. These results highlight the complex relationships among gender, practice setting, and other personal and professional factors in their influence on burnout and satisfaction with WLI.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a common pre-malignant plasma cell disorder associated with a 1% per year risk of progression to multiple myeloma or related malignancy. Since the risk factors for MGUS are poorly defined, the goal of the present study was to determine if the risk of MGUS is increased in first degree relatives of patients with known multiple myeloma (MM) or MGUS. Methods: MGUS probands (index cases) were recruited from a population-based prevalence study of MGUS in Olmsted County, MN while MM probands were recruited through the Mayo Clinic practice. Consenting probands were asked to provide contact information on all first-degree relatives ages 40 years and older. Serum samples were then collected from first-degree relatives with informed consent and subjected to agaraose-gel electrophoresis and immunofixation. The prevalence of MGUS in first-degree relatives of MM and MGUS probands was compared to population-based rates from Olmsted County using risk ratios (RR). For comparisons to the reference population, only cases detected by protein electrophoresis and confirmed by immunofixation were included so that the diagnostic strategy was identical in the two groups being compared. Results: Serum samples were obtained from 911 relatives of 329 unique families, including 493 siblings, 324 children and 94 parents of patients with MGUS or MM. Using protein electrophoresis, monoclonal protein was detected in the serum of 55 (6%) while immunofixation identified 28 additional relatives (3%), for an age- and sex-adjusted prevalence rate of 8.1% (95%CI: 6.3, 9.8). The age-specific prevalence of MGUS in first-degree relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, and 21.0% for ages 40–49, 50–59, 60–69, 70–79 and ≥80, respectively; P&lt;0.001). Based on similar MGUS detection methodology as the reference population, there was a significantly higher risk of MGUS in first-degree relatives (age-adjusted RR, 2.6, 95%CI: 1.9, 3.4) compared to the reference population. The increased risk (P&lt;0.001) was seen both in relatives of MM probands (RR, 2.0, 95%CI: 1.4, 2.8), as well as MGUS probands (RR, 3.3, 95%CI: 2.1, 4.8). This association was similar across age of proband, age and gender of relative, and relationship of the first-degree relative. When examining whether the increased risk of MGUS in relatives was specific to probands with a large monoclonal protein concentration or specific monoclonal immunoglobulin isotype (i.e. high-risk MGUS phenotype), there was suggestion of a greater risk for relatives of probands with a high (3 1.5 g/dL) M-protein (RR, 2.8, 95%CI: 2.0,3.8) compared to lower M-protein levels (RR, 1.8, 95%CI: 1.1,2.8) although the difference did not reach statistical significance (P=0.12). The risk of MGUS in relatives did not differ by proband’s isotype (IgG vs. other). Conclusions: First-degree relatives of patients with MM or MGUS have a greater than two-fold risk of MGUS compared to the general population, implying underlying genetic predisposition for these diseases and providing rationale for identifying genetic determinants of MGUS. This study also provides important baseline rates of MGUS in first-degree relatives that impact the clinical care of these patients.

Abstract Background: Traditionally response to therapy in multiple myeloma (MM) is based on changes in the serum and urine monoclonal protein by immunoelectrophoresis. Immunofixation allows for detection of small amounts of monoclonal protein that cannot be quantitated on immunoelectrophoresis. Serum immunoglobulin free light chain (FLC) assay allows for detection of unbound kappa and lambda free light chain and has allowed disease measurement in patients with oligosecretory myelomas and can potentially allow detection of low levels of tumor burden, below the threshold of the standard tests. We examined this hypothesis in patients who had obtained a negative immunofixation in serum and urine following treatment of their MM. Methods: For the purposes of the study, we included selected patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as &gt;1 gm/dL in the serum or &gt;200 mg/24 hour in the urine or involved free light chain &gt; 10 mg/dL) on protein electrophoresis; patients with non-secretory and oligo-secretory myeloma were excluded. We then identified patients who since 1995 had a negative immunofixation in the serum and urine, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine immunofixation, and serum free light chain (FLC) ratio within 30 days of the immunofixation were all collected from the existing databases. Results: Eighty-four patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative immunofixation in serum and urine. Among these, 46 patients (55%) also had a normal FLC ratio (K/L ratio; 0.26–1.65). Th median time from diagnosis to the documented immunofixation was 7.5 months (range, 1–157). The median overall survival from diagnosis among those with a normal FLC ratio along with negative immunofixation was not reached compared to 76 months for those with abnormal FLC ratio, P = 0.02. The median overall survival from the documentation of negative immunofixation was not reached for the group with normal FLC ratio compared to 46.5 months for those with an abnormal FLC, P = 0.03. Conclusion: Attainment of a normal FLC ratio at the time of serum and urine immunofixation negative status identifies a group of patients with better outcome. The presence of an abnormal FLC ratio likely represents persistence of the clonal population that is secreting none or very small amounts of monoclonal protein. The data presented here supports the inclusion of FLC measurements as part of response criteria for MM as has been done for the definition of stringent CR in the IMWG response criteria. Figure: Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation. Figure:. Overall survival from diagnosis in patients with or with out a normal FLC ratio at the time of serum and urine immunofixation.

Abstract Background: Immunoglobulin free light chains (FLC) form the substrate for synthesis of amyloid fibrils in patients with AL amyloidosis. Development of FLC assay (Freelite) has allowed us to better assess the clonal cell burden in patients with AL amyloid. The relationship of the light chain types and their levels in serum to the clinical feature at presentation and the eventual outcome has not been systematically studied. Methods: We identified 730 patients with biopsy proven AL amyloidosis, who were seen at Mayo Clinic between January 1980 and July 2006, who were seen within 90 days of their diagnosis and in whom FLC levels were performed or had stored serum available for analysis. Cardiac biomarkers (cTnT, NT ProBNP) were also performed on stored serum for some of the patients as part of previous studies. Clinical data and follow up status are prospectively collected into the Dysproteinemia database, which was used for the study. Results: The median age of the study population was 63 years (range; 32–90) and 463 patients (63%) were male. The median estimated survival for the entire group was 37 months from diagnosis and the median follow up for the 263 patients (37%) alive at the time of the analysis was 27.8 months (range; 1–177 months). The plasma cell clone was lambda in 528 patients (72%) and kappa in 202 (28%) patients. The median absolute difference between the FLCs was 19.6 mg/dL for the entire group (range; 0.01–2478); for the kappa patients was 29.4 mg/dL (range; 0.01–1359) and for the lambda patients was 18.2 mg/dL (range; 0.03–2478). Kappa AL was associated with more involvement of the GI tract and liver as indicated by higher alkaline phosphatase (1.8 vs. 1.3 fold; P=0.03), higher total bilirubin (0.95 vs. 0.78 mg/dL, P = 0.04) and lower serum carotene (119 vs. 155 ug/dL; P = 0.0002). On the contrary, renal involvement was more in the lambda AL with the 24 hour urinary albumin higher in the lambda AL (2.4 gm vs. 1.4 gm; P = 0.0002) and lower serum albumin (2.77 vs. 2.97 mg/dL; P = 0.001). While there was no difference in the overall survival (OS) between the kappa and lambda AL, the median OS for those without a heavy chain was significantly shorter (12.6 months vs. 29.9 months; P= 0.01) compared to those with a heavy chain identified. There was also a correlation between high FLC difference and degree of organ involvement, especially cardiac. Among the 202 kappa AL patients, the median survival for those with a high FLC difference ( &gt; 29.4 mg/dL) was 13 months vs. 48.8 months for those with low difference (P = 0.001). Similarly among the 528 patients with lambda AL, those with high difference (&gt; 18.2 mg/dL) had a median OS of 9.3 months compared to 33 months for those with low difference (P &lt; 0.0001) (Figure). The FLC difference was independent of the cTnT, NT Pro BNP, uric acid and fold-increase in alkaline phosphatase, all of which were significant in the multivariable analysis. Conclusions: The type of FLC impacts the spectrum of organ involvement, with gastrointestinal involvement observed more frequently with kappa, and renal involvement with lambda FLC. The FLC burden correlates with the degree of organ involvement, and is a significant predictor of overall survival in AL amyloidosis. Lambda FLC exerts similar effect as kappa FLCs, but at lower levels confirming the increased “amyloidogenicity” of lambda FLC. Finally, lack of a chaperone heavy chain is associated with a poorer outcome. Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC) Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC)

Abstract Background: In multiple myeloma (MM), a complete response (CR) is defined by the European Group for Blood and Bone Marrow Transplantation (EBMT) and the International Myeloma Working Group (IMWG) Uniform Response Criteria as absence of monoclonal protein in serum and urine by immunofixation (IFE), and a bone marrow (BM) aspirate/biopsy containing &lt;5% plasma cells (PC). This definition of CR is widely adopted in clinical trials, but there is a high degree of non-compliance with the BM requirement. As a result, differences in CR rates across trials can occur not just as a result of treatment efficacy, but also on how rigorously the BM requirement for CR is implemented. Moreover, requiring BM examinations merely to confirm CR is cumbersome in clinical practice. The goal of this study was to determine the added value of BM examinations in patients who can otherwise be considered to be in CR by virtue of a negative IFE in the serum and urine. Methods: For the purpose of the study, we included only patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as &gt;1 gm/dL in the serum and/or &gt;200 mg/24 hour in the urine) on protein electrophoresis; patients with non-secretory and oligo-secretory MM were excluded. We then identified patients who since 1995 had a negative IFE in the serum and urine and a BM aspirate/biopsy, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine IFE, serum free light chain (FLC) ratio and BM aspirate/biopsy within 30 days of complete response were all collected from the existing databases. Results: Ninety-five patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative IFE in serum and urine (‘IF- CR’). Of these, only 83 patients (87%) met criteria for CR by the EBMT/IMWG criteria with less than 5% PC in the BM; 13% of patients had 5% or more PC despite the apparent IF-CR on serum and urine IFE. In fact, the BM showed 10% or more PC in 5% of IF-CR patients. We then assessed whether a normal serum FLC ratio in addition to negative serum and urine IFE would eliminate the need for a BM biopsy. The additional requirement of the serum FLC ratio to negative IFE was not fully adequate in eliminating false positive CR’s. Among 34 patients who had IF- CR plus a normal serum FLC ratio, only 88% of patients met CR definition with &lt;5% BM PC; 12% had 5% or more PC, and one patient (3%) had 10% or more PC. We studied the survival (from time of diagnosis) of patients who had true CR’s (negative IFE and &lt;5% PC) versus patients who had IF- CR’s but BM had 5% or more PC. Overall survival from diagnosis between the two groups was 10.7 years versus 5.6 years, respectively, P=0.001 (see Figure 1). Conclusions: BM examination is essential to accurately estimate CR. Up to 13% of patients with negative IFE in serum and urine fail to meet the BM requirement. The addition of a normal serum FLC ratio to negative IFE did not significantly reduce the proportion of patients who fail to meet the BM requirement. Based on this study, we recommend that the CR definition in the EBMT and IMWG criteria should not be revised to eliminate the need for BM examination. Moreover, the consistent collection of BM samples is essential for future strategies to evaluate immunophenotypic CR and molecular CR in MM. Figure 1: Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells. Figure 1:. Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells.