Citations

Background: The management of acute and chronic pain for individuals living with sickle cell disease (SCD) is a clinical challenge. This reflects the paucity of clinical SCD pain research and limited understanding of the complex biological differences between acute and chronic pain. These issues collectively create barriers to effective, targeted interventions. Optimal pain management requires interdisciplinary care. Objective: These evidence-based guidelines developed by the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in pain management decisions for children and adults with SCD. Methods: ASH formed a multidisciplinary panel, including 2 patient representatives, that was thoroughly vetted to minimize bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic reviews. Clinical questions and outcomes were prioritized according to importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel reached consensus on 18 recommendations specific to acute and chronic pain. The recommendations reflect a broad pain management approach, encompassing pharmacological and nonpharmacological interventions and analgesic delivery. Conclusions: Because of low-certainty evidence and closely balanced benefits and harms, most recommendations are conditional. Patient preferences should drive clinical decisions. Policymaking, including that by payers, will require substantial debate and input from stakeholders. Randomized controlled trials and comparative-effectiveness studies are needed for chronic opioid therapy, nonopioid therapies, and nonpharmacological interventions.

This essay compares the approaches that scientific societies in the ACCESS meta-organization use to implement and assess travel award programs for URM trainees and presents a set of recommendations, including both short- and long-term outcomes assessment in populations of interest and specialized programmatic activities coupled to travel award programs.

Abstract Aims More evidence is needed to quantify the association between tricuspid regurgitation (TR) and mortality in patients with heart failure (HF). Methods and results Between 2008–2017, using the Optum longitudinal database, a patient-level database that integrates multiple US-based electronic health and claim records from several health care providers, we identified 435 679 patients with new HF diagnosis and both an assessment of the left ventricular ejection fraction and at least 1 year of history. TR was graded as mild, moderate or severe and classified as prevalent (at the time of the initial HF diagnosis) or incident (subsequent new cases thereafter). For prevalent TR, the analysis was performed using a Cox proportional hazards model with adjustment for patient covariates. Incident TR was modelled as a time-updated covariate, as were other non-fatal events during follow-up. Prevalence of mild, moderate and severe TR at baseline was 10.1%, 5.1% and 1.4%, respectively. Over a median follow-up of 1.5 years, 121 273 patients (27.8%) died and prevalent TR was independently associated with survival. Compared to patients with no TR at baseline, the adjusted hazard ratios for mortality were 0.99 [95% confidence interval (CI) 0.97–1.01], 1.17 (95% CI 1.14–1.20) and 1.34 (95% CI 1.28–1.39) for mild, moderate and severe TR, respectively. In the 363 270 patients free from TR at baseline, incident TR (at least mild, at least moderate, or severe) developed during follow-up in 12.1%, 5.1% and 1.1%, respectively. Adjusted mortality hazard ratios for such new cases were 1.48 (95% CI 1.44–1.52), 1.92 (95% CI 1.86–1.99) and 2.44 (95% CI 2.32–2.57), respectively. Findings were consistent across all patient subgroups based on age, gender, rhythm, associated comorbidities, prior cardiac surgery, B-type natriuretic peptide/N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction. Conclusions In this large contemporary patient-level database of almost half-million US patients with HF, TR was associated with a marked increases in mortality risk overall and in all subgroups. Future randomized controlled trials will evaluate the impact of TR correction on clinical outcomes and the causal relationship between TR and mortality.

Abstract Background There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19). There is a need for frequently updated practice guidelines on their use, based on critical evaluation of rapidly emerging literature. The objective was to develop evidence-based rapid guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. Methods The Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. Process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and gray literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Results The IDSA guideline panel agreed on 7 treatment recommendations and provided narrative summaries of other treatments undergoing evaluations. Conclusions The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much-needed evidence on the efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

Objective To assess real‐world effectiveness of initial treatment with newer compared to injectable disease‐modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). Methods This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon‐β, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS‐quintile. Time to new/enlarging T2‐hyperintense and gadolinium‐enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS‐quintile. Results A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS‐quintile–adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29–0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14–0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person‐years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36–0.72, p < 0.001) and gadolinium‐enhancing lesions (HR = 0.38, 95% CI = 0.23–0.63, p < 0.001) than those on injectables. Interpretation Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long‐term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42–55

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression, which blocks proliferation, was associated with increased rather than decreased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and also increased autophagic flux. We speculated that the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. Addressing a mechanism for ERK suppression-increased autophagy, we describe three mechanisms: 1) ERK inhibition-mediated increased transcription of autophagy and lysosomal genes, 2) ERK inhibitor-induced AMPK activation and suppression of mTOR signaling, and 3) ERK inhibition-facilitated decreased glycolytic flux. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine (CQ) synergistically enhanced ERK inhibitor-mediated antiproliferative activity. Similarly, genetic or pharmacologic inhibition of specific regulators of autophagy also enhanced ERK inhibitor activity. Encouraged by the synergistic relationship between ERK and autophagy inhibition, we performed a CRISPR/Cas-9 mediated genetic loss of function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple mediators of the DNA damage response. One such sensitizing gene was CHEK1, which encodes the CHK1 serine/threonine kinase, required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to DNA damage. Accordingly, we showed that treatment with prexasertib, a clinical candidate CHK1 inhibitor, increased autophagic flux in PDAC cells and synergized with CQ to decrease PDAC cell proliferation and increase apoptosis. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment. This abstract is also being presented as Poster B07. Citation Format: Kirsten L. Bryant, Jennifer E. Klomp, Ye S. Lee, Clint A. Stalnecker, Kajal R. Grover, A. Cole Edwards, Sen Peng, Mariaelena Pierobon, Emanuel F. Petricoin III, Nhan Tran, Alec C. Kimmelman, Adrienne D. Cox, Channing J. Der. Enhancing the effect of autophagy inhibition for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR10.

Background: Patients with bicuspid aortic valve (AV) stenosis were excluded from the pivotal evaluations of transcatheter AV replacement (TAVR) devices. We sought to evaluate the outcomes of TAVR in patients with bicuspid AV stenosis in comparison with those with tricuspid AV stenosis. Methods: We used data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry (November 2011 through November 2018) to determine device success, procedural outcomes, post-TAVR valve performance, and in-hospital clinical outcomes (mortality, stroke, and major bleeding) according to valve morphology (bicuspid versus tricuspid). Results were stratified by older and current (Sapien 3 and Evolut R) generation valve prostheses. Medicare administrative claims were used to evaluate mortality and stroke to 1 year among eligible individuals (≥65 years). Results: After exclusions, there were 170 959 eligible procedures at 593 sites during the specified interval. Of these, 5412 TAVR procedures (3.2%) were performed in patients with bicuspid AV, including 3705 with current-generation devices. In comparison with patients with tricuspid valves, patients with bicuspid AV were younger and had a lower Society of Thoracic Surgeons Predicted Risk of Operative Mortality score. When current-generation devices were used to treat patients with bicuspid AV, device success increased (93.5 versus 96.3; P =0.001) and the incidence of 2+ aortic insufficiency declined (14.0% versus 2.7%; P <0.001) in comparison with older-generation devices. With current-generation devices, device success was slightly lower in the bicuspid (versus tricuspid) AV group (96.3% in bicuspid versus 97.4% in tricuspid, P =0.07), with a slightly higher incidence of residual moderate or severe aortic insufficiency among patients with bicuspid AV (2.7% versus 2.1%; P <0.001). A lower 1-year adjusted risk of mortality (hazard ratio, 0.88 [95% CI, 0.78–0.99]) was observed for patients with bicuspid AV versus patients with tricuspid AV in the Medicare-linked cohort, whereas no difference was observed in the 1-year adjusted risk of stroke (hazard ratio, 1.14 [95% CI, 0.94–1.39]). Conclusions: Using current-generation devices, procedural, postprocedural, and 1-year outcomes were comparable following TAVR for bicuspid AV versus tricuspid AV disease. With newer-generation devices, TAVR is a viable treatment option for patients with bicuspid AV disease.

Introduction Population-level screening has been shown to reduce the incidence and mortality of colorectal cancer (CRC). Unfortunately, adherence to screening recommendations among eligible US adults remains below national goals. A relatively new non-invasive screening modality, the Food and Drug Administration–approved multi-target stool DNA (mt-sDNA) assay (commercialised as Cologuard), which combines the detection of haemoglobin and DNA abnormalities, has been completed by more than 3 million individuals. Given mt-sDNA’s recent availability, the effectiveness of mt-sDNA screening with respect to CRC incidence and mortality reduction has not yet been established. Methods and analysis Through an academic–industry collaboration, a prospective cohort study (Voyage) was designed with an initial enrolment target of 150 000 individuals with mt-sDNA ordered by their healthcare provider for CRC screening. Consented participants will be asked to complete a baseline questionnaire to collect sociodemographic and health information. Additional questionnaires will be provided after 1 year, and every 3 years thereafter, to collect data regarding CRC screening follow-up in order to estimate rates of CRC incidence and other health outcomes. Linkage to the National Death Index will be used to estimate mortality rates. Ethics and dissemination The Voyage study will be conducted in accordance with international guidelines and local regulatory requirements and laws. Data will be stored and retained at Mayo Clinic. Only limited data elements required for research purposes will be transmitted between Mayo Clinic and Exact Sciences Laboratories. Results of the Voyage study will be disseminated through scientific presentations and publications. Trial registration number NCT04124406.