Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10−5 to 1.08×10−6; Bonferroni P = 0.057 to 3.1×10−3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10−4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr−/− and Cftr−/−Msra−/− mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function

Post-artemisinin delayed hemolysis after oral therapy for P. falciparum infection

A documented side-effect of artemisinin therapy is post-artemisinin delayed hemolysis (PADH), primarily occurring after parenteral treatment for severe P. falciparum infections. PADH has been infrequently reported after oral therapy and is rarely severe enough to require hospitalization and blood transfusions. A 24 year old man was diagnosed with P. falciparum, prompting initiation of oral artemether-lumefantrine (AL). Further work-up demonstrated that he met WHO criteria for severe malaria infection on the basis of high parasitemia and his regimen was switched to intravenous quinidine and oral doxycycline. He was transitioned back to AL after 4 days and was discharged on hospital day six. Five days later, he was readmitted for hemolytic anemia. His peripheral blood was absent of malaria parasites and he was diagnosed with PADH, ultimately requiring multiple blood transfusions. Severe hemolytic anemia requiring blood transfusions after oral artemisinin therapy is rare and may be associated with higher parasite loads. This case demonstrates the importance of close reassessment and consideration of PADH in patients treated with oral therapies, particularly in the setting of severe malarial infections

Severe and Progressive Cellulitis Caused by Following a Dog Scratch

Soft tissue infections occur in over 30% of patients with chemotherapy-induced neutropenia. Gram-positive bacterial infections predominate early in neutropenia, and likelihood of infection by resistant bacteria and fungi increases with prolonged neutropenia. Prior infections and exposures influence the risk of rare pathogens. A 55-year-old woman with chemotherapy-induced neutropenia was scratched on her forearm by a dog. She cleaned the wound with isopropanol and was treated empirically with amoxicillin-clavulanate. Over the next 4 days, she developed fever along with erythema, edema, and mild tenderness of the forearm without purulence or crepitus. She was hospitalized and received empiric treatment with intravenous vancomycin, piperacillin-tazobactam, tobramycin, and voriconazole. Despite therapy, her fevers persisted and the cellulitis progressed for over a week. After 10 days of hospitalization, her neutrophil count began to recover and a bulla developed at the wound site. Culture of the bullous fluid grew Serratia marcescens , and antibiotics were switched to cefepime based on susceptibility. She defervesced and showed substantial improvement of cellulitis within 48 hours and was discharged on oral ciprofloxacin. Serratia marcescens skin infections are rare, and this may be the first report of Serratia cellulitis associated with trauma from dog contact. This case highlights the need to consider unusual pathogens based on exposure history and immune status and to obtain cultures from fluid collections or tissue in cases of treatment-resistant soft tissue infections

Performance Analysis of the National Early Warning Score and Modified Early Warning Score in the Adaptive COVID-19 Treatment Trial Cohort.

We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics.DesignWe analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours.SettingA multisite international inpatient trial.PatientsA total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia.InterventionsAdaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment.Measurements and main resultsFor mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60-0.68), and improved with addition of age (c-index, 0.66-0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65-0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68-0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59-0.69) and improved with addition of age (c-index, 0.63-0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05).ConclusionsIn the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions

Indoleamine 2,3 dioxygenase, age, and immune activation in people living with HIV

Immune activation complicates HIV despite antiretroviral therapy (ART). Indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan (T) to kynurenine (K), regulating immune activity, and IDO activity increases with age. This study examines the relationship of IDO activity, bacterial translocation, and aging in people living with HIV (PLWH) on ART. Samples and data from PLWH on ART from the Centers for AIDS Research Network of Integrated Clinical Systems and from matched HIV-uninfected patients (controls) from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study were analyzed. The ratio of K to T (K:T) and neopterin were indicators of inflammation; 16S ribosomal DNA (16S rDNA) and lipopolysaccharide (LPS) were markers of bacterial translocation. Samples and data from 205 PLWH and 99 controls were analyzed. PLWH had higher K:T values across all ages, with a significant relationship between age and K:T for both groups. CD4 count or CD4 nadir had no association with K:T. There was no positive association between level of 16S rDNA or LPS detection and K:T. K:T and neopterin were associated. PLWH had elevated IDO activity, at younger ages, despite ART. This study suggests K:T ratio increases with age in both groups and is elevated in PLWH at all ages compared with age-matched controls

Cohort study of molecular identification and typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii

Submitted by Sandra Infurna ([email protected]) on 2018-09-25T17:46:16Z No. of bitstreams: 1 elisabeth2_sampaio_etal_IOC_2009.pdf: 1445529 bytes, checksum: 8222b19cc6edf5b2e7fcb87dfd6309bd (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-09-25T18:04:55Z (GMT) No. of bitstreams: 1 elisabeth2_sampaio_etal_IOC_2009.pdf: 1445529 bytes, checksum: 8222b19cc6edf5b2e7fcb87dfd6309bd (MD5)Made available in DSpace on 2018-09-25T18:04:55Z (GMT). No. of bitstreams: 1 elisabeth2_sampaio_etal_IOC_2009.pdf: 1445529 bytes, checksum: 8222b19cc6edf5b2e7fcb87dfd6309bd (MD5) Previous issue date: 2009National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Microbiology Service. Bethesda, Maryland, USA / National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Immunopathogenesis Section. Bethesda, Maryland, USA.National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Immunopathogenesis Section. Bethesda, Maryland, USA.National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Microbiology Service. Bethesda, Maryland, USANational Institutes of Health. Clinical Center. Department of Laboratory Medicine. Immunopathogenesis Section. Bethesda, Maryland, USA.National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Tuberculosis Research Section. Bethesda, Maryland, USA.National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Microbiology Service. Bethesda, Maryland, USANational Institutes of Health. National Human Genome Research Institute. Bethesda, Maryland, USA.The University of Texas Health Science Center. Department of Microbiology. Tyler, Texas, USA.The University of Texas Health Science Center. Department of Microbiology. Tyler, Texas, USA.The University of Texas Health Science Center. Department of Microbiology. Tyler, Texas, USA.National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Immunopathogenesis Section. Bethesda, Maryland, USA.National Institutes of Health. Clinical Center. Department of Laboratory Medicine. Immunopathogenesis Section. Bethesda, Maryland, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Mycobacterium abscessus is the most common cause of rapidly growing mycobacterial chronic lung disease. Recently, two new M. abscessus-related species, M. massiliense and M. bolletii, have been described. Health care-associated outbreaks have recently been investigated by the use of molecular identification and typing tools; however, very little is known about the natural epidemiology and pathogenicity of M. massiliense or M. bolletii outside of outbreak situations. The differentiation of these two species from M. abscessus is difficult and relies on the sequencing of one or more housekeeping genes. We performed extensive molecular identification and typing of 42 clinical isolates of M. abscessus, M. massiliense, and M. bolletii from patients monitored at the NIH between 1999 and 2007. The corresponding clinical data were also examined. Partial sequencing of rpoB, hsp65, and secA led to the unambiguous identification of 26 M. abscessus isolates, 7 M. massiliense isolates, and 2 M. bolletii isolates. The identification results for seven other isolates were ambiguous and warranted further sequencing and an integrated phylogenetic analysis. Strain relatedness was assessed by repetitive-sequence-based PCR (rep-PCR) and pulsed-field gel electrophoresis (PFGE), which showed the characteristic clonal groups for each species. Five isolates with ambiguous species identities as M. abscessus-M. massiliense by rpoB, hsp65, and secA sequencing clustered as a distinct group by rep-PCR and PFGE together with the M. massiliense type strain. Overall, the clinical manifestations of disease caused by each species were similar. In summary, a multilocus sequencing approach (not just rpoB partial sequencing) is required for division of M. abscessus and closely related species. Molecular typing complements sequence-based identification and provides information on prevalent clones with possible relevant clinical aspects

Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial

BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases