Multicenter registry of United States emergency department patients tested for SARS-CoV-2

This paper summarizes the methodology for the registry of suspected COVID‐19 in emergency care (RECOVER), a large clinical registry of patients from 155 United States (US) emergency departments (EDs) in 27 states tested for SARS‐CoV‐2 from March–September 2020. The initial goals are to derive and test: (1) a pretest probability instrument for prediction of SARS‐CoV‐2 test results, and from this instrument, a set of simple criteria to exclude COVID‐19 (the COVID‐19 Rule‐Out Criteria—the CORC rule), and (2) a prognostic instrument for those with COVID‐19. Patient eligibility included any ED patient tested for SARS‐CoV‐2 with a nasal or oropharyngeal swab. Abstracted clinical data included 204 variables representing the earliest manifestation of infection, including week of testing, demographics, symptoms, exposure risk, past medical history, test results, admission status, and outcomes 30 days later. In addition to the primary goals, the registry will provide a vital platform for characterizing the course, epidemiology, clinical features, and prognosis of patients tested for COVID‐19 in the ED setting

Efficacy and safety of avapritinib in advanced systemic mastocytosis:interim analysis of the phase 2 PATHFINDER trial

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10(-9)), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM

Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19: A Phase 2 Randomized Clinical Trial

IMPORTANCE: The morbidity and mortality associated with COVID-19 remain high despite advances in standard of care therapy, and the role of anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being elucidated. OBJECTIVE: To evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in the treatment of adults with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled, randomized clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up per patient. Data analysis was performed from September 2021 to July 2022. INTERVENTIONS: Patients were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by 200 mg twice daily on days 2-14) vs placebo, for 14 days. MAIN OUTCOMES AND MEASURES: The primary end point was death or need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause mortality and safety were also assessed. RESULTS: A total of 200 patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 [19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) in the placebo group (odds ratio, 0.62; 95% CI, 0.28-1.35; P = .23). Among patients with elevated interleukin 6, the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% [20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 patients]). CONCLUSIONS AND RELEVANCE: The study did not meet its primary end point in patients with severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation that could benefit from pacritinib, although further clinical trials would be needed to confirm these effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04404361

Class II Transactivator (CIITA) Enhances Cytoplasmic Processing of HIV-1 Pr55Gag

The Pr55(gag) (Gag) polyprotein of HIV serves as a scaffold for virion assembly and is thus essential for progeny virion budding and maturation. Gag localizes to the plasma membrane (PM) and membranes of late endosomes, allowing for release of infectious virus directly from the cell membrane and/or upon exocytosis. The host factors involved in Gag trafficking to these sites are largely unknown. Upon activation, CD4+ T cells, the primary target of HIV infection, express the class II transcriptional activator (CIITA) and therefore the MHC class II isotype, HLA-DR. Similar to Gag, HLA-DR localizes to the PM and at the membranes of endosomes and specialized vesicular MHC class II compartments (MIICs). In HIV producer cells, transient HLA-DR expression induces intracellular Gag accumulation and impairs virus release.Here we demonstrate that both stable and transient expression of CIITA in HIV producer cells does not induce HLA-DR-associated intracellular retention of Gag, but does increase the infectivity of virions. However, neither of these phenomena is due to recapitulation of the class II antigen presentation pathway or CIITA-mediated transcriptional activation of virus genes. Interestingly, we demonstrate that CIITA, apart from its transcriptional effects, acts cytoplasmically to enhance Pr160(gag-pol) (Gag-Pol) levels and thereby the viral protease and Gag processing, accounting for the increased infectivity of virions from CIITA-expressing cells.This study demonstrates that CIITA enhances HIV Gag processing, and provides the first evidence of a novel, post-transcriptional, cytoplasmic function for a well-known transactivator

Exploring the Molecular Landscape of Myelofibrosis, with a Focus on Ras and Mitogen-Activated Protein (MAP) Kinase Signaling

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized clinically by cytopenias, fatigue, and splenomegaly stemming from extramedullary hematopoiesis. MF commonly arises from mutations in JAK2, MPL, and CALR, which manifests as hyperactive Jak/Stat signaling. Triple-negative MF is diagnosed in the absence of JAK2, MPL, and CALR but when clinical, morphologic criteria are met and other mutation(s) is/are present, including ASXL1, EZH2, and SRSF2. While the clinical and classic molecular features of MF are well-established, emerging evidence indicates that additional mutations, specifically within the Ras/MAP Kinase signaling pathway, are present and may play important role in disease pathogenesis and treatment response. KRAS and NRAS mutations alone are reportedly present in up to 15 and 14% of patients with MF (respectively), and other mutations predicted to activate Ras signaling, such as CBL, NF1, BRAF, and PTPN11, collectively exist in as much as 21% of patients. Investigations into the prevalence of RAS and related pathway mutations in MF and the mechanisms by which they contribute to its pathogenesis are critical in better understanding this condition and ultimately in the identification of novel therapeutic targets

Mini‐HCVD plus inotuzumab plus or minus blinatumomab: Hype or hope?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151845/1/cncr32381_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151845/2/cncr32381.pd

Multi-Center Study of Outcomes Among Persons with HIV who Presented to US Emergency Departments with suspected SARS-CoV-2

Background: There is a need to characterize patients with HIV with suspected severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2). Setting: Multicenter registry of patients from 116 emergency departments in 27 US states. Methods: Planned secondary analysis of patients with suspected SARS-CoV-2, with (n=415) and without (n=25,306) HIV. Descriptive statistics were used to compare patient information and clinical characteristics by SARS-CoV-2 and HIV status. Unadjusted and multivariable models were used to explore factors associated with death, intubation, and hospital length of stay. Kaplan-Meier curves were used to estimate survival by SARS-CoV-2 and HIV infection status. Results: Patients with both SARS-CoV-2 and HIV and patients with SARS-CoV-2 but without HIV had similar admission rates (62.7% versus 58.6%, p=0.24), hospitalization characteristics (e.g. rates of admission to the intensive care unit from the ED [5.0% versus 6.3%, p=0.45] and intubation [10% versus 13.3%, p=0.17]), and rates of death (13.9% versus 15.1%, p=0.65). They also had a similar cumulative risk of death (log-rank p=0.72). However, patients with both HIV and SARS-CoV-2 infections compared to patients with HIV but without SAR-CoV-2 had worsened outcomes, including increased mortality (13.9% versus 5.1%, p<0.01, log rank p<0.0001) and their deaths occurred sooner (median 11.5 days versus 34 days, p<0.01). Conclusion: Among ED patients with HIV, clinical outcomes associated with SARS-CoV-2 infection are not worse when compared to patients without HIV, but SARS-CoV-2 infection increased risk of death in patients with HIV