Rates, Outcomes, and Resource Burden of Extracorporeal Membrane Oxygenation Use in Hospitalizations in the United States During the Pandemic.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a lifesaving medical intervention for patients with severe refractory cardiopulmonary dysfunction. This study aims to characterize hospitalizations and resource use burdens associated with ECMO use during the onset of the pandemic. METHODS: We performed a retrospective analysis of ECMO use in United States (US) hospitals between 2019 and 2020, utilizing data from the National Inpatient Sample database. Patient demographics, comorbidities, admission characteristics, inpatient mortality, length of hospital stay (LOS), healthcare costs, and ECMO utilization trends were assessed. RESULTS: Of the 17,520 hospitalizations analyzed, the most common reasons for admission were diseases and disorders of the circulatory system (40.5%) and diseases and disorders of the respiratory system (31.2%). The average patient age was 52.5 years, with a male predominance (64.2%). Hospitalizations were predominantly for White Americans (59.5%), followed by Blacks (16.3%) and Hispanics (14.8%). Nearly 88.2% of cases were at an extremely high risk of mortality without intervention. Inpatient mortality was significantly associated with Hispanic descent, a higher Charlson Comorbidity Index (CCI) score, age >60 years, and a higher All Patients Refined Diagnosis Related Groups (APRDRG) risk of mortality. Hospitalizations involving ECMO had a significantly higher inpatient mortality rate compared to non-ECMO hospitalizations (43.1% vs. 2.1%, p<0.0001). The mean LOS was 26 days for ECMO hospitalizations, with ECMO initiation occurring approximately five days from admission. ECMO-related hospitalizations often involve over 10 unique procedures, resulting in an average healthcare cost of US$967,647 per hospitalization, totaling US$16.7 billion. Comparatively, non-ECMO hospitalizations had shorter LOS and lower mean costs (mean LOS, 4.7 days, and US$52,659, respectively). ECMO utilization increased significantly from 2019 to 2020, reflecting rising demand for this life-saving therapy. CONCLUSION: Compared to non-ECMO hospitalizations, ECMO patients had higher inpatient mortality, associated with Hispanic descent, higher CCI scores, an age >60 years, and a higher APRDRG risk. ECMO hospitalizations had longer stays (26 days) and higher costs (US$967,647 per case, US$16.7 billion total) compared to pre-pandemic levels. ECMO use increased significantly from 2019 to 2020, reflecting rising demand.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Risk factors and patterns of household clusters of respiratory viruses in rural Nepal.

Viral pneumonia is an important cause of death and morbidity among infants worldwide. Transmission of non-influenza respiratory viruses in households can inform preventative interventions and has not been well-characterised in South Asia. From April 2011 to April 2012, household members of pregnant women enrolled in a randomised trial of influenza vaccine in rural Nepal were surveyed weekly for respiratory illness until 180 days after birth. Nasal swabs were tested by polymerase chain reaction for respiratory viruses in symptomatic individuals. A transmission event was defined as a secondary case of the same virus within 14 days of initial infection within a household. From 555 households, 825 initial viral illness episodes occurred, resulting in 79 transmission events. The overall incidence of transmission was 1.14 events per 100 person-weeks. Risk of transmission incidence was associated with an index case age 1-4 years (incidence rate ratio (IRR) 2.35; 95% confidence interval (CI) 1.40-3.96), coinfection as initial infection (IRR 1.94; 95% CI 1.05-3.61) and no electricity in household (IRR 2.70; 95% CI 1.41-5.00). Preventive interventions targeting preschool-age children in households in resource-limited settings may decrease the risk of transmission to vulnerable household members, such as young infants.

Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract.

Local mucosal cellular immunity is critical in providing protection from HSV-2. To characterize and quantify HSV-2-reactive mucosal T cells, lymphocytes were isolated from endocervical cytobrush and biopsy specimens from 17 HSV-2-infected women and examined ex vivo for the expression of markers associated with maturation and tissue residency and for functional T-cell responses to HSV-2. Compared with their circulating counterparts, cervix-derived CD4+ and CD8+ T cells were predominantly effector memory T cells (CCR7-/CD45RA-) and the majority expressed CD69, a marker of tissue residency. Co-expression of CD103, another marker of tissue residency, was highest on cervix-derived CD8+ T cells. Functional HSV-2 reactive CD4+ and CD8+ T-cell responses were detected in cervical samples and a median of 17% co-expressed CD103. HSV-2-reactive CD4+ T cells co-expressed IL-2 and were significantly enriched in the cervix compared with blood. This first direct ex vivo documentation of local enrichment of HSV-2-reactive T cells in the human female genital mucosa is consistent with the presence of antigen-specific tissue-resident memory T cells. Ex vivo analysis of these T cells may uncover tissue-specific mechanisms of local control of HSV-2 to assist the development of vaccine strategies that target protective T cells to sites of HSV-2 infection.

Detection of hematopoietic stem cells by flow cytometry.

Various studies have been conducted to identify hematopoietic stem cells (HSCs) using flow cytometry. The technique is primarily based on fluorochrome-conjugated antibodies against cell surface markers of HSCs and the physiological properties of HSCs such as high-efflux activity of certain fluorescent dyes. The surface marker schemes are based on using c-Kit, Sca-1, and Lineage markers, resulting in "KSL" population. Markers in KLS scheme can be used to further subfractionate this KLS population to distinguish HSCs from differentiating progenitors. The "signaling lymphocyte activation molecule" (SLAM) family of proteins can also be used to enhance the KLS enrichment scheme. The other strategy is to identify HSCs based on their high efflux ability of fluorescent dyes. This chapter describes the method used for identifying the side population (SP) in combination with surface markers to isolate HSCs from murine bone marrow and to discuss the advantages and pitfalls of this method.

Sensitivity and specificity of herpes simplex virus-2 serological assays among HIV-infected and uninfected urban Ugandans.

Herpes simplex virus type 2 (HSV-2) is a risk factor for HIV-1 infection. We characterized HSV-2 serology assay performance in HIV-positive and HIV-negative Africans. Serostatus for HSV-2 and HIV-1 was determined in 493 serum specimens stored from a community HSV-2 prevalence survey in Kampala, Uganda. HSV-2 serology by Focus HerpeSelect ELISA, Biokit HSV-2 rapid assay and Kalon HSV-2 was compared with HSV-2 Western blot (WB) according to HIV-1 serostatus. Sensitivity/specificity was: 99.5%/70.2% for Focus, 97.0%/86.4% for Biokit and 97.5%/96.2% for Kalon. Focus with Biokit confirmation improved sensitivity/specificity (99.4%/96.8%, respectively). Use of a higher Focus index value cut-off of 2.2 instead of 1.1 increased specificity from 70.2% to 92.4%. Kalon had higher specificity than Focus (P < 0.001). Of commercially available HSV-2 serological assays, Kalon alone, or Focus ELISA followed by Biokit confirmation perform best. Improved HSV-2 assays are needed for HSV-2 and HIV-1 public health activities in Africa.

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Use of the designation "shedder" in mucosal detection of herpes simplex virus DNA involving repeated sampling.

OBJECTIVES: We evaluated two methods to describe detection of herpes simplex virus (HSV) from the genital mucosa. METHODS: We assessed genital swabs from HSV-2 seropositive people participating in longitudinal studies of HSV DNA detection at the University of Washington Virology Research Clinic. We determined the length of observation period necessary to ensure some HSV detection for most individuals. We compared two measures to assess differences in shedding according to HIV status, the shedding rate ratio, defined as the proportion of total samples with detectable HSV in HIV-1 seropositive versus HIV-1 seronegative participant, and the ratio of "shedders", defined as the proportion of people with any shedding over the interval in HIV-1 seropositive versus HIV-1 seronegative people. RESULTS: While only 17% (51/308) of HSV-2 seropositive people shed on their first day on study, 77% (238/308) had some genital shedding over 30 days (any HSV DNA detected on genital swabs). Shedding rate ratios (SRR) for HIV-seropositive versus HIV-seronegative people varied from SRR = 1.42 using 10 samples to SRR = 1.35 using 50 samples. The ratio of "shedders" (RS) approached 1 as the observation period increased (RS = 1.13 using 10 samples to RS = 1.01 using 50 samples). In a hypothetical case, the ratio of "shedders" was shown to exceed 1 when shedding rates were equal. CONCLUSIONS: Most HSV-2 seropositive people shed HSV from the genital mucosa. Dichotomisation of people into "shedders" and "non-shedders" or "high" and "low" shedders yields inferences that depend upon sampling interval length. Overall shedding rates provide consistent measures regardless of the number of swabs collected.

Placebo found equivalent to amoxicillin for treatment of acute bronchitis in Nairobi, Kenya: a triple blind, randomised, equivalence trial.

BACKGROUND: Antibiotic treatment is not recommended for acute bronchitis in immunocompetent patients in industrialised countries. Whether these recommendations are relevant to the developing world and to immunocompromised patients is unknown. DESIGN, SETTING AND PARTICIPANTS: Randomised, triple blind, placebo controlled equivalence trial of amoxicillin compared with placebo in 660 adults presenting to two outpatient clinics in Nairobi, Kenya, with acute bronchitis but without evidence of chronic lung disease. MAIN OUTCOME MEASURE: The primary study end point was clinical cure, as defined by a >or=75% reduction in a validated Acute Bronchitis Severity Score by 14 days; analysis was by intention to treat with equivalence defined as