Showing papers by "Medical University of South Carolina published in 2020"

European Position Paper on Rhinosinusitis and Nasal Polyps 2020

Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017.

Abstract: Background Low back pain (LBP) is a common musculoskeletal problem globally. Updating the prevalence and burden of LBP is important for researchers and policy makers. This paper presents, compares and contextualizes the global prevalence and years lived with disability (YLDs) of LBP by age, sex and region, from 1990 to 2017. Methods Data were extracted from the GBD (the Global Burden of Disease, Injuries, and Risk Factors Study) 2017 Study. Age, sex and region-specific analyses were conducted to estimate the global prevalence and YLDs of LBP, with the uncertainty intervals (UIs). Results The age-standardized point prevalence of LBP was 8.20% (95% UI: 7.31-9.10%) in 1990 and decreased slightly to 7.50% (95% UI: 6.75-8.27%) in 2017. The prevalent numbers of people with LBP at any one point in time in 1990 was 377.5 million, and this increased to 577.0 million in 2017. Age-standardized prevalence of LBP was higher in females than males. LBP prevalence increased with age, and peaked around the ages of 80 to 89 years, and then decreased slightly. Global YLDs were 42.5 million (95% UI: 30.2 million-57.2 million) in 1990 and increased by 52.7% to 64.9 million (95% UI: 46.5 million-87.4 million) in 2017. YLDs were also higher in females than males and increased initially with age; they peaked at 35-39 years of age in 1990, before decreasing, whereas in 2017, they peaked at 45-49 years of age, before decreasing. Western Europe had the highest number of LBP YLDs. Conclusions Globally, LBP is the leading global cause of YLDs. Greater attention is urgently needed to mitigate this increasing burden and the impact it is having on health and social systems.

Virology, transmission, and pathogenesis of SARS-CoV-2.

Abstract: ### What you need to know Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterise the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail).1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the …

Diagnosis and Detection of Sarcoidosis An Official American Thoracic Society Clinical Practice Guideline

Abstract: Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or mo...

Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure

Abstract: Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF...

Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design.

Abstract: Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.

The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries.

Abstract: Background Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations. Objective To characterize the diversity of cutaneous manifestations of COVID-19 and facilitate understanding of the underlying pathophysiology. Methods Case series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies. Results The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, whereas retiform purpura presented exclusively in ill, hospitalized patients. Limitations We cannot estimate incidence or prevalence. Confirmation bias is possible. Conclusions This study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were nonspecific, whereas others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology.

Promoting Optimal Development: Identifying Infants and Young Children With Developmental Disorders Through Developmental Surveillance and Screening

Abstract: Early identification and intervention for developmental disorders are critical to the well-being of children and are the responsibility of pediatric professionals as an integral function of the medical home. This report models a universal system of developmental surveillance and screening for the early identification of conditions that affect children's early and long-term development and achievement, followed by ongoing care. These conditions include autism, deafness/hard-of-hearing, intellectual and motor disabilities, behavioral conditions, and those seen in other medical conditions. Developmental surveillance is supported at every health supervision visit, as is as the administration of standardized screening tests at the 9-, 18-, and 30-month visits. Developmental concerns elicited on surveillance at any visit should be followed by standardized developmental screening testing or direct referral to intervention and specialty medical care. Special attention to surveillance is recommended at the 4- to 5-year well-child visit, prior to entry into elementary education, with screening completed if there are any concerns. Developmental surveillance includes bidirectional communication with early childhood professionals in child care, preschools, Head Start, and other programs, including home visitation and parenting, particularly around developmental screening. The identification of problems should lead to developmental and medical evaluations, diagnosis, counseling, and treatment, in addition to early developmental intervention. Children with diagnosed developmental disorders are identified as having special health care needs, with initiation of chronic condition management in the pediatric medical home.

Arrhythmogenic right ventricular cardiomyopathy: Evaluation of the current diagnostic criteria and differential diagnosis

Abstract: Domenico Corrado *, Peter J. van Tintelen, William J. McKenna, Richard N.W. Hauer, Aris Anastastakis, Angeliki Asimaki, Cristina Basso, Barbara Bauce, Corinna Brunckhorst, Chiara Bucciarelli-Ducci, Firat Duru, Perry Elliott, Robert M. Hamilton, Kristina H. Haugaa, Cynthia A. James, Daniel Judge, Mark S. Link, Francis E. Marchlinski, Andrea Mazzanti, Luisa Mestroni, Antonis Pantazis, Antonio Pelliccia, Martina Perazzolo Marra, Kalliopi Pilichou, Pyotr G.A. Platonov, Alexandros Protonotarios,

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Abstract: Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, th...

Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth.

Abstract: The microbiota has been shown to promote intestinal tumourigenesis, but a possible anti-tumourigenic effect has also been postulated. Here, we demonstrate that changes in the microbiota and mucus composition are concomitant with tumourigenesis. We identified two anti-tumourigenic strains of the microbiota-Faecalibaculum rodentium and its human homologue, Holdemanella biformis-that are strongly under-represented during tumourigenesis. Reconstitution of ApcMin/+ or azoxymethane- and dextran sulfate sodium-treated mice with an isolate of F. rodentium (F. PB1) or its metabolic products reduced tumour growth. Both F. PB1 and H. biformis produced short-chain fatty acids that contributed to control protein acetylation and tumour cell proliferation by inhibiting calcineurin and NFATc3 activation in mouse and human settings. We have thus identified endogenous anti-tumourigenic bacterial strains with strong diagnostic, therapeutic and translational potential.

Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity

Abstract: Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.

Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials.

Abstract: Objective To examine the dose-response relation between reduction in dietary sodium and blood pressure change and to explore the impact of intervention duration. Design Systematic review and meta-analysis following PRISMA guidelines. Data sources Ovid MEDLINE(R), EMBASE, and Cochrane Central Register of Controlled Trials (Wiley) and reference lists of relevant articles up to 21 January 2019. Inclusion criteria Randomised trials comparing different levels of sodium intake undertaken among adult populations with estimates of intake made using 24 hour urinary sodium excretion. Data extraction and analysis Two of three reviewers screened the records independently for eligibility. One reviewer extracted all data and the other two reviewed the data for accuracy. Reviewers performed random effects meta-analyses, subgroup analyses, and meta-regression. Results 133 studies with 12 197 participants were included. The mean reductions (reduced sodium v usual sodium) of 24 hour urinary sodium, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were 130 mmol (95% confidence interval 115 to 145, P Conclusions The magnitude of blood pressure lowering achieved with sodium reduction showed a dose-response relation and was greater for older populations, non-white populations, and those with higher blood pressure. Short term studies underestimate the effect of sodium reduction on blood pressure. Systematic review registration PROSPERO CRD42019140812.

Update 2020: Management of Non-Small Cell Lung Cancer.

Abstract: The past decade has seen a revolution of new advances in the management of non-small cell lung cancer (NSCLC) with remarkable progresses in screening, diagnosis, and treatment. The advances in systemic treatment have been driven primarily by the development of molecularly targeted therapeutics, immune checkpoint inhibitors, and anti-angiogenic agents, all of which have transformed this field with significantly improved patient outcomes. This review will address updates in lung cancer screening, liquid biopsy, and immunotherapy in the front-line setting. We discuss recent advances and highlight the plethora of new approvals of molecular-targeted therapy for subgroups of NSCLC patients with sensitizing EGFR, ALK, ROS1, RET, BRAF V600E, MET, and NTRK alterations.

Epigenetic therapy inhibits metastases by disrupting premetastatic niches

Abstract: Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy. In mouse models of pulmonary metastasis, adjuvant epigenetic therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Abstract: Vitamin D deficiency co-exists in patients with COVID-19. At this time, dark skin color, increased age, the presence of pre-existing illnesses and vitamin D deficiency are features of severe COVID disease. Of these, only vitamin D deficiency is modifiable. Through its interactions with a multitude of cells, vitamin D may have several ways to reduce the risk of acute respiratory tract infections and COVID-19: reducing the survival and replication of viruses, reducing risk of inflammatory cytokine production, increasing angiotensin-converting enzyme 2 concentrations, and maintaining endothelial integrity. Fourteen observational studies offer evidence that serum 25-hydroxyvitamin D concentrations are inversely correlated with the incidence or severity of COVID-19. The evidence to date generally satisfies Hill's criteria for causality in a biological system, namely, strength of association, consistency, temporality, biological gradient, plausibility (e.g., mechanisms), and coherence, although experimental verification is lacking. Thus, the evidence seems strong enough that people and physicians can use or recommend vitamin D supplements to prevent or treat COVID-19 in light of their safety and wide therapeutic window. In view of public health policy, however, results of large-scale vitamin D randomized controlled trials are required and are currently in progress.

Population-Level Interest and Telehealth Capacity of US Hospitals in Response to COVID-19: Cross-Sectional Analysis of Google Search and National Hospital Survey Data.

Abstract: Background: As the novel coronavirus disease (COVID-19) is widely spreading across the United States, there is a concern about the overloading of the nation’s health care capacity. The expansion of telehealth services is expected to deliver timely care for the initial screening of symptomatic patients while minimizing exposure in health care facilities, to protect health care providers and other patients. However, it is currently unknown whether US hospitals have the telehealth capacity to meet the increasing demand and needs of patients during this pandemic. Objective: We investigated the population-level internet search volume for telehealth (as a proxy of population interest and demand) with the number of new COVID-19 cases and the proportion of hospitals that adopted a telehealth system in all US states. Methods: We used internet search volume data from Google Trends to measure population-level interest in telehealth and telemedicine between January 21, 2020 (when the first COVID-19 case was reported), and March 18, 2020. Data on COVID-19 cases in the United States were obtained from the Johns Hopkins Coronavirus Resources Center. We also used data from the 2018 American Hospital Association Annual Survey to estimate the proportion of hospitals that adopted telehealth (including telemedicine and electronic visits) and those with the capability of telemedicine intensive care unit (tele-ICU). Pearson correlation was used to examine the relations of population search volume for telehealth and telemedicine (composite score) with the cumulative numbers of COVID-19 cases in the United States during the study period and the proportion of hospitals with telehealth and tele-ICU capabilities. Results: We found that US population–level interest in telehealth increased as the number of COVID-19 cases increased, with a strong correlation (r=0.948, P<.001). We observed a higher population-level interest in telehealth in the Northeast and West census region, whereas the proportion of hospitals that adopted telehealth was higher in the Midwest region. There was no significant association between population interest and the proportion of hospitals that adopted telehealth (r=0.055, P=.70) nor hospitals having tele-ICU capability (r=–0.073, P=.61). Conclusions: As the number of COVID-19 cases increases, so does the US population’s interest in telehealth. However, the level of population interest did not correlate with the proportion of hospitals providing telehealth services in the United States, suggesting that increased population demand may not be met with the current telehealth capacity. Telecommunication infrastructures in US hospitals may lack the capability to address the ongoing health care needs of patients with other health conditions. More practical investment is needed to deploy the telehealth system rapidly against the impending patient surge.

Pernio-like skin lesions associated with COVID-19: A case series of 318 patients from 8 countries.

Abstract: Background Increasing evidence suggests pernio-like lesions are cutaneous manifestations of coronavirus infectious disease 2019 (COVID-19). Objective To describe clinical and pathologic findings of pernio-like lesions in patients with confirmed or suspected COVID-19. Methods An international dermatology registry was circulated to health care providers worldwide through the American Academy of Dermatology, International League of Dermatologic Societies, and other organizations. Results We documented 505 patients with dermatologic manifestations associated with COVID-19, including 318 (63%) with pernio-like lesions. Patients with pernio-like lesions were generally young and healthy, with relatively mild COVID-19. Of 318 patients with confirmed or suspected COVID-19 by providers, 23 (7%) were laboratory-confirmed COVID-19 positive, and 20 others (6%) were close contacts of patients with confirmed COVID-19. Given current testing criteria, many patients lacked COVID-19 testing access. For 55% of patients, pernio-like lesions were their only symptom. In patients with other COVID-19 symptoms, pernio-like lesions typically appeared after other symptoms. Pernio-like lesions lasted a median of 14 days (interquartile range, 10-21 days). Limitations A case series cannot estimate population-level incidence or prevalence. In addition, there may be confirmation bias in reporting. We cannot exclude an epiphenomenon. Conclusions Pernio-like skin changes of the feet and hands, without another explanation, may suggest COVID-19 infection and should prompt confirmatory testing.

Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator‐Initiated, Multicenter, Double‐Blind, Randomized, Placebo‐Controlled Trial

Abstract: Objective T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. Results Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P Conclusion In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

Global Retinoblastoma Presentation and Analysis by National Income Level

Abstract: Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders

Abstract: Objective:Disrupted emotional processing is a common feature of many psychiatric disorders. The authors investigated functional disruptions in neural circuitry underlying emotional processing acros...

ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper.

Abstract: An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Endomyocardial Biopsy Characterization of Heart Failure With Preserved Ejection Fraction and Prevalence of Cardiac Amyloidosis

Abstract: Objectives This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics. Background Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking. Methods Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF). Results Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m2 (25th to 75th percentile: 32 to 45 kg/m2), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm2) was greater in patients with HFpEF versus controls (60.4 cells/mm2 [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm2 [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro−B-type natriuretic peptide and troponin I levels. Conclusions In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.

Mental health among otolaryngology resident and attending physicians during the COVID-19 pandemic: National study.

Abstract: BACKGROUND: Otolaryngologists are among the highest risk for COVID-19 exposure. METHODS: This is a cross-sectional, survey-based, national study evaluating academic otolaryngologists. Burnout, anxiety, distress, and depression were assessed by the single-item Mini-Z Burnout Assessment, 7-item Generalized Anxiety Disorder Scale, 15-item Impact of Event Scale, and 2-item Patient Health Questionnaire, respectively. RESULTS: A total of 349 physicians completed the survey. Of them, 165 (47.3%) were residents and 212 (60.7%) were males. Anxiety, distress, burnout, and depression were reported in 167 (47.9%), 210 (60.2%), 76 (21.8%), and 37 (10.6%) physicians, respectively. Attendings had decreased burnout relative to residents (odds ratio [OR] 0.28, confidence interval [CI] [0.11-0.68]; P = .005). Females had increased burnout (OR 1.93, CI [1.12.-3.32]; P = .018), anxiety (OR 2.53, CI [1.59-4.02]; P < .005), and distress (OR 2.68, CI [1.64-4.37]; P < .005). Physicians in states with greater than 20 000 positive cases had increased distress (OR 2.01, CI [1.22-3.31]; P = .006). CONCLUSION: During the COVID-19 pandemic, the prevalence of burnout, anxiety, and distress is high among academic otolaryngologists.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Abstract: BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutieres syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.