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BACKGROUND & AIMS: The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, additional strategies to mitigate the spread/severity of COVID-19 continue to be needed. Emerging evidence suggests susceptibility to respiratory tract infections in healthy subjects can be reduced by probiotic interventions; thus, probiotics may be a low-risk, low-cost, and easily implementable modality to reduce risk of COVID-19. METHODS: In this initial study, we conducted a randomized, double-blind, placebo-controlled trial across the United States testing probiotic Lacticaseibacillus rhamnosus GG (LGG) as postexposure prophylaxis for COVID-19 in 182 participants who had household exposure to someone with confirmed COVID-19 diagnosed within ≤7 days. Participants were randomized to receive oral LGG or placebo for 28 days. The primary outcome was development of illness symptoms within 28 days of COVID-19 exposure. Stool was collected to evaluate microbiome changes. RESULTS: Intention-to-treat analysis showed LGG treatment led to a lower likelihood of developing illness symptoms versus placebo (26.4 % vs. 42.9 %, p = 0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank, p = 0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8 % vs. 15.4 %, p = 0.17). CONCLUSIONS: This data suggests LGG is associated with prolonged time to COVID-19 infection, reduced incidence of illness symptoms, and gut microbiome changes when used as prophylaxis ≤7 days post-COVID-19 exposure, but not overall incidence. This initial work may inform future COVID-19 prevention studies worldwide, particularly in developing nations where Lacticaseibacillus probiotics have previously been utilized to reduce other non-COVID infectious-morbidity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04399252, Date: 22/05/2020. https://clinicaltrials.gov/ct2/show/NCT04399252.
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COVID-19 , Probióticos , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Profilaxis Posexposición , Pandemias/prevención & control , Prueba de COVID-19 , Método Doble Ciego , Probióticos/uso terapéuticoRESUMEN
Introduction: Rural Appalachia is endemic to issues such as substance abuse, poverty, and lack of community support, all of which negatively influence health outcomes. The incidence of pediatric trauma as it relates to substance abuse is of concern in the region, where the rate of positive drug screens in pediatric trauma cases is higher than national average. Methods: The West Virginia statewide pediatric trauma database was analyzed in a retrospective cohort study for the years 2009-2019. Variables of interest included injury severity (assessed using Abbreviated Injury Scale (AIS)), drug screening results, and various measures of patient outcome. Results: The sample was divided into 2009-2016 presentations (n = 3,356) and 2017-2019 presentations (n = 1,182). Incidence of critical (AIS 5) head injuries (p = 0.007) and serious (AIS 3) neck injuries (p = 0.001) increased as time progressed. Days requiring ventilation increased from 3.1 in 2009-2016 to 6.3 in 2017-2019 (p < 0.001). Drug screens were obtained at a rate of 6.9% in 2009-2016 versus 23.3% in 2017-2019 (p < 0.001). Benzodiazepine use increased from 0.8% to 1.8% (p < 0.001), and opioid use increased from 1% to 4.9% (p < 0.001). Conclusion: The increasing severity of pediatric trauma and substance abuse in Appalachia is of significant concern. The use of respiratory drive-depressing drugs has risen, just as the severity of head and neck traumas has increased. These results emphasize the importance of targeted interventions in the rural pediatric population.
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Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Anciano , Quimiocina CCL26 , Humanos , Inmunidad , Leucemia Mieloide Aguda/terapia , Recurrencia , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
INTRODUCTION: In order to study the role of the microbiome in hematopoietic stem cell transplantation (HCT), researchers collect stool samples from patients at various time points throughout HCT. However, stool collection requires active subject participation and may be limited by patient reluctance to handling stool. METHODS: We performed a prospective study on the impact of financial incentives on stool collection rates. The intervention group consisted of allogeneic HCT patients from 05/2017-05/2018 who were compensated with a $10 gas gift card for each stool sample. The intervention group was compared to a historical control group of allogeneic HCT patients from 11/2016-05/2017 who provided stool samples before the incentive was implemented. To control for possible changes in collections over time, we also compared a contemporaneous control group of autologous HCT patients from 05/2017-05/2018 with a historical control group of autologous HCT patients from 11/2016-05/2017; neither autologous HCT group was compensated. The collection rate was defined as the number of samples provided divided by the number of time points we attempted to obtain stool. RESULTS: There were 35 allogeneic HCT patients in the intervention group, 19 allogeneic HCT patients in the historical control group, 142 autologous HCT patients in the contemporaneous control group (that did not receive a financial incentive), and 75 autologous HCT patients in the historical control group. Allogeneic HCT patients in the intervention group had significantly higher average overall collection rates when compared to the historical control group allogeneic HCT patients (80% vs 37%, p<0.0001). There were no significant differences in overall average collection rates between the autologous HCT patients in the contemporaneous control and historical control groups (36% vs 32%, p = 0.2760). CONCLUSION: Our results demonstrate that a modest incentive can significantly increase collection rates. These results may help to inform the design of future studies involving stool collection.
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Trasplante de Células Madre Hematopoyéticas , Microbiota , Adulto , Trasplante de Médula Ósea/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Motivación , Estudios Prospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Trasplante HomólogoRESUMEN
Microbial diversity is associated with improved outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanism underlying this observation is unclear. In a cohort of 174 patients who underwent allo-HCT, we demonstrate that a diverse intestinal microbiome early after allo-HCT is associated with an increased number of innate-like mucosal-associated invariant T (MAIT) cells, which are in turn associated with improved overall survival and less acute graft-versus-host disease (aGVHD). Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vδ2 cells, the major circulating subpopulation of γδ T cells, closely correlated with the frequency of MAIT cells and was associated with less aGVHD. Analysis of these populations using both single-cell transcriptomics and flow cytometry suggested a shift toward activated phenotypes and a gain of cytotoxic and effector functions after transplantation. A diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vδ2 cells appeared to be necessary for the maintenance of these populations after allo-HCT. These data suggest an immunological link between intestinal microbial diversity, microbe-derived ligands, and maintenance of unconventional T cells.
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Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Células T Invariantes Asociadas a Mucosa , Humanos , LigandosRESUMEN
Patients undergoing allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) require extensive hospitalizations or daily clinic visits for the duration of their transplantation. Home HCT, wherein patients live at home and providers make daily trips to the patient's residence to perform assessments and deliver any necessary interventions, may enhance patient quality of life and improve outcomes. We conducted the first study of home HCT in the United States to evaluate this model in the US healthcare setting and to determine the effect on clinical outcomes and quality of life. This case-control study evaluated patients who received home HCT at Duke University in Durham, North Carolina, from November 2012 to March 2018. Each home HCT patient was matched with 2 controls from the same institution who had received standard treatment based on age, disease, and type of transplant for outcomes comparison. Clinical outcomes were abstracted from electronic health records, and quality of life was assessed via Functional Assessment of Cancer Therapy-Bone Marrow Transplant. Clinical outcomes were compared with Student's t-test or Fisher's exact test (continuous variables) or chi-square test (categorical variables). Quality of life scores were compared using the Student t-test. All analyses used a significance threshold of 0.05. Twenty-five patients received home HCT, including 8 allos and 17 autos. Clinical outcomes were not significantly different between the home HCT patients and their matched controls; home HCT patients had decreased incidence of relapse within 1 year of transplantation. Pre-HCT quality of life was well preserved for autologous home HCT patients. This Phase I study demonstrated that home HCT can be successfully implemented in the United States. There was no evidence that home HCT outcomes were inferior to standard-of-care treatment, and patients undergoing autologous home HCT were able to maintain their quality of life. A Phase II randomized trial of home versus standard HCT is currently underway to better compare outcomes and costs.
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Trasplante de Células Madre Hematopoyéticas , Calidad de Vida , Estudios de Casos y Controles , Humanos , Recurrencia , Trasplante Autólogo , Estados UnidosRESUMEN
BACKGROUND: Enterococcus intestinal domination (EID), a state of dysbiosis wherein enterococci comprise ≥30% abundance within the microbiota, has been associated with Enterococcus bacteremia, graft-versus-host disease, and mortality in the allogeneic hematopoietic stem cell transplant (allo HCT) population. The acute leukemia (AL) chemotherapy population includes patients receiving intensive chemotherapy but do not all go on to have an allo HCT. The impact of EID on outcomes including mortality in the AL chemotherapy population is unknown. METHODS: Microbiota composition from weekly stool samples was analyzed by 16S ribosomal RNA gene sequencing. Patients were analyzed in 2 cohorts: AL chemotherapy cohort and allo HCT cohort. Alpha-diversity and richness were calculated. Kaplan Meier Analysis was used to analyze mortality. RESULTS: 929 stool samples were collected from 139 patients. Both allo HCT and AL cohorts had a decline in α-diversity and richness over the course of treatment that tends not to return to baseline months later. EID was observed in at least one sample in 36% of allo HCT patients and 49% of AL patients. Patients with observed EID had lower alpha-diversity over time. Similar to the HCT cohort, AL patients with EID had reduced overall survival. We identified 4 other genera that were commonly found in ≥30% relative abundance within the microbiota, but none were associated with mortality. In fact, in allo HCT, Bacteroides abundance ≥30% was associated with improved survival. CONCLUSIONS: EID is associated with increased all-cause mortality in HCT and AL cohorts. UnlikeEID, relative abundance ≥30% by other genera is not associated with increased all-cause mortality.
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PURPOSE: In pandemics, centralized healthcare leadership is a critical requirement. The objective of this study was to analyze the early development, operation, and effectiveness of a COVID-19 organizational leadership team and transformation of healthcare services at West Virginia University Hospitals and Health System (WVUHS). The analysis focused on how Kotter's Leading Change eight-stage paradigm could contribute to an understanding of the determinants of successful organizational change in response to the COVID-19 pandemic. METHODS: The fifteen core leaders of WVUHS COVID-19 strategic system were interviewed. A qualitative thematic analysis of the interviews was used to evaluate key aspects of leadership dynamics and system-wide changes in healthcare policies and protocols to contain the pandemic. Outcome measures included the degree to which WVUHS could handle and contain COVID-19 cases as well as COVID-19 death and vaccination rates in West Virginia compared with other states. RESULTS: The leadership team radically and rapidly revamped nearly all healthcare policies, procedures, and protocols for WVUHS hospitals and clinics, and launched a Hospital Incident Command System. As a result of this effective leadership team and strategic plan, WVUHS surge capacity was adequate for COVID-19 cases. In addition, West Virginia was an early frontrunner in COVID-19 vaccination rates as well as lower death rates. CONCLUSION: WVUHS's leadership response to the COVID-19 pandemic followed Kotter's eight-stage paradigm for Leading Change in organizations, including the establishment of a sense of urgency, formation of a powerful guiding coalition, creation of a vision, communication of the vision, empowerment of others to act on the vision, plan for and creation of short-term wins, consolidation of improvements and production of more changes, and institutionalization of new approaches. This approach was effective in limiting the spread and impact of COVID-19 within the hospital network and across the state, with many lessons learned along the way.
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We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.
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Heces/microbiología , Microbioma Gastrointestinal , Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante HomólogoRESUMEN
The gut microbiota influences development1-3 and homeostasis4-7 of the mammalian immune system, and is associated with human inflammatory8 and immune diseases9,10 as well as responses to immunotherapy11-14. Nevertheless, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans, where the difficulty of direct experimentation makes inference challenging. Here we study hundreds of hospitalized-and closely monitored-patients with cancer receiving haematopoietic cell transplantation as they recover from chemotherapy and stem-cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, enabling the relationships between the two to be studied simultaneously. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota-together and over time-on systemic immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.
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Microbioma Gastrointestinal/inmunología , Leucocitos/citología , Leucocitos/inmunología , Factores de Edad , Teorema de Bayes , Trasplante de Microbiota Fecal , Femenino , Humanos , Recuento de Leucocitos , Linfocitos/citología , Linfocitos/inmunología , Monocitos/citología , Monocitos/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Reproducibilidad de los ResultadosRESUMEN
Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.
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Butiratos/sangre , Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped/microbiología , Propionatos/sangre , Adulto , Aloinjertos , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Estudios de Casos y Controles , Enfermedad Crónica , Disbiosis/etiología , Disbiosis/microbiología , Heces/microbiología , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Metaboloma , RibotipificaciónRESUMEN
BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).
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Microbioma Gastrointestinal , Trasplante de Células Madre Hematopoyéticas/mortalidad , Adulto , Biodiversidad , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Trasplante Homólogo/mortalidadRESUMEN
OBJECTIVES: The objectives are to determine how medical faculty members use scholarly journals, whether print or electronic journals are read more, whether there is a pattern among types of users, and what similarities and differences there are between the use of journals by medical faculty and faculty in other disciplines. METHODS: Medical faculty of the University of Tennessee Health Science Center (UTHSC) multi-campus system were surveyed, and their responses estimated using critical incident technique to characterize the different aspects of their use of print and electronic journals. RESULTS: Medical faculty read a great deal, especially compared to scientists. The most frequently reported principal purpose of reading is to support their primary research (30% of reading). The majority of reading comes from recently published articles, mostly from personal subscriptions. Medical faculty continue to rely on print journals (approximately 70% of readings) versus electronic journals. Age of faculty does not appear to influence the choice of print or electronic format. Medical faculty read more articles than others on average and need information digested and verified in a way to save them time. Convenience and currency are highly valued attributes. CONCLUSIONS: It can be asserted that librarians and publishers must find ways to provide the attributes of convenience and currency and match the portability of personal subscriptions in an electronic journal format for medical faculty.