
Impact of Prolonged Antibiotic Therapy on Commensal Microbial Community Gene Expression.
Microbial ColonizationAntibiotics are a mainstay of life-saving interventions used frequently in medical practice to combat infections. These medications not only target the pathogenic bacteria for which they are prescribed but also function against commensal bacterial communities that inhabit the gut, skin, and oropharynx. The role that these native bacterial communities play in normal host function, such as in nutrition and host immunity, is only beginning to be explored, as are the changes in the communities and their function as a result of various alterations of antibiotic use. Short courses of antibiotics have been shown to affect the diversity of native bacterial communities, and to affect the abundance of antibiotic resistance genes present. For example, use of clindamycin in human subjects for 7 days has been demonstrated to result in persistent clindamycin resistance for months or years. The impact of prolonged antibiotic therapy on the host microbiome including both those organisms present and the diversity of antibiotic genes has not been studied, and we have very little understanding of the longitudinal effects of antimicrobial therapy on the genetic repertoire present in human microbial communities. In this study, we will examine changes in the microbiota as well as frequency of antibacterial resistance genes harbored in skin, saliva, and colonic microbiomes longitudinally in subjects on prolonged antimicrobial therapy, as well as household members of the person on antibiotic therapy. Previously well patients with minimal prior antibiotic exposure will be enrolled upon diagnosis of an infection requiring long-term antibiotic therapy, such as osteomyelitis or prosthetic joint infection, prior to starting antibiotic therapy. We will examine the microbiota of the skin, saliva, and gut prior to antibiotics as well as the frequency of antibiotic resistance genes harbored within these microbial communities. We will compare microbial communities and antibiotic resistance gene frequencies before, during and after prolonged course of antibiotics in patients on antibiotics. We will also look for alterations that occur among microbiomes or antibiotic resistance genes among household members of people on antibiotics.

A Study of Acute Respiratory Infections in Global Outpatient Setting
Acute Respiratory InfectionThe purpose of this study is to evaluate the positivity rate of respiratory syncytial virus (RSV), influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in high-risk participants presenting with acute respiratory infections (ARIs) in outpatient settings during the influenza/RSV season and to evaluate the association between lower respiratory tract disease (LRTD) and ARI-related hospitalization in participants positive for RSV.

Patient Safety Learning Laboratory: Making Acute Care More Patient-Centered
Central Line-Associated Bloodstream Infection (CLABSI)Venous Thromboembolism8 moreThe Brigham and Women's Hospital (BWH) Patient Safety Learning Laboratory (PSLL) focuses on developing health information technology (HIT) tools to engage patients, family, and professional care team members in reliable identification, assessment, and reduction of patient safety threats in real-time, before they manifest in actual harm.

Pediatric Immune Response to Infectious Shock
Severe Pediatric Infectious ShockInfectious shocks are associated with high mortality rates (20-40%). Anti-inflammatory strategies based on the postulate that mortality related to sepsis is mainly due to an overwhelming pro-inflammatory immune response have failed. Some patients surviving this initial phase can develop immune dysfunctions because the compensatory mechanisms become deleterious when they persist over time. The persistence of immunosuppression at day 3 or 5 is independently associated with more nosocomial infections and higher mortality rate. The clinical and laboratory evidence for sepsis induced immunosuppression have been recently reviewed by Hotchkiss et al. Apoptosis-induced depletion of immune effector and blood studies from septic patients showed decreased production of pro-inflammatory cytokines, decreased HLA-DR expression, increased percentage of regulatory T cells, and increased production of programmed cell death (PD)-1. Some small positive phase 2 trials of biomarker guided immune enhancing agents granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon γ (IFN γ) have been reported. There are insufficient data showing that such an immunosuppression exists in children. Only one study performed in children with organ dysfunctions admitted to pediatric intensive care unit (PICU), showed that 34% of them developed immunosuppression. This study was performed on a heterogeneous population and immunological analyses were limited. Therefore, there is a crucial need of studies on septic patients with matched controls to provide more evidence that the same paradigm exists in children. The collaboration of laboratories with a high level of experience in this domain, and a clinical unit with a high potential of recruitment of children with severe infectious shock should allow us to perform the first prospective study specifically done in children with infectious shock. The main hypothesis is that children with severe infectious shock developed sepsis-induced immunosuppression as shown in adults. This will be assessed by the expression of HLA-DR on monocytes' surface. We make the hypothesis that children who become immunosuppressed are more prone to develop secondary nosocomial infectious and stayed longer in PICU and in hospital. Children aged from 1 month to 17 years, admitted to PICU at HFME Lyon-Bron are eligible if they have the criteria for severe sepsis or septic shock, defined by the "Surviving Sepsis Campaign 2012" or those of Toxic Shock Syndrome (TSS) (definitions of CDC - Center for Disease Control). An information leaflet will be issued to parents and children / adolescents and they will be informed of their right to object to the search. Are provided as part of this research: Immunological measures (mHLA -DR) in three stages: in the first 48 hours, between D3/5 and D7/9. The volume of collected blood will not exceed 2.4 ml / kg. The collection of nosocomial infections and status at D30 A control group of patients hospitalized for surgery without sepsis or toxic shock criteria will be recruited in the same hospital by ICU investigators and matched for age. Similarly controls will be given oral and written information and they will have the opportunity to deny inclusion. They will have the same exams as the first group of patients.

Long-term Immunogenicity of the HIV gp120-NefTat/AS01B Vaccine (GSK SB732461)
InfectionHuman Immunodeficiency Virus1 moreThe purpose of this study is to evaluate the long-term persistence of binding antibody responses against V1V2 and gp120 in subjects who were vaccinated with the envelope glycoprotein 120 (gp120)-negative factor (Nef)Tat/ Adjuvant System 01B (AS01B) (GSKSB732461) vaccine candidate. Other immune parameters like the HIV-specific cluster of differentiation (CD4+) T cell and CD8+ T cell responses will also be evaluated.

Feasibility of Measuring Immune Resp, Activation in Foreskin/Mucosa in HIV-, Uncircumcised High-HIV-risk...
HIV InfectionsAcquired Immunodeficiency Syndrome10 moreRectal and genital sampling in HIV prevention trials permits assessments at the site of HIV entry. Yet the safety and acceptability of circumcision and sigmoidoscopy (and associated abstinence recommendations) are unknown in uncircumcised men who have sex with men (MSM) at high risk of HIV infection. The purpose of this study is to evaluate the feasibility of methods for assessing baseline characteristics of the mucosa of MSM at risk of HIV infection in Lima, Peru.

Establishing a Controlled Human Hookworm Infection Model at Leiden University Medical Center
Necator Americanus InfectionFour healthy hookworm-naive volunteers will be exposed to 50 L3 Necator americanus larvae once and will retain infection for up to 2 years.

Effect of Antibiotics on Gut Microbiome and Plasma Metabolome
Microbial ColonizationIn recent years it has been observed that the gut microbiome can produce metabolites into systemic circulation and thus have important health effects even outside the gastrointestinal system. These metabolites may play a role in the pathogenesis of common public health problems such as diabetes, obesity and cardiovascular disorders. Modern techniques of mass spectrometry-based metabolomics from peripheral blood and gut metagenome sequencing now enable detailed examination of these processes. Using samples from the FINRISK 2002 cohort, collected by the National Institute for Health and Welfare, we are currently determining the gut microbiome and plasma metabolome from > 7000 participants with 15 years of follow-up for various health outcomes. This is one of the largest materials of its kind world-wide. The design does not, however, allow us to draw causal conclusions on the roles of gut bacteria in the composition of plasma metabolome. To enable conclusions which go beyond statistical associations, we now propose an extension to the FINRISK 2002 study, where we alter the gut bacteriome with a short course of antibiotics and then examine whether a change in plasma metabolomics profile will follow. At the same time the trial will give important novel information about the effects of commonly used antibiotics on gut bacteriome and on general health.

Influence of Freeze Dried Strawberry Consumption on Gut Microbiota and Cardiovascular Health.
Microbial ColonizationCardiovascular Diseases1 moreThis proposal seeks to build upon studies, including ours, on the favorable effects of California strawberries on vascular health. Freeze dried strawberry powder (FDSP) contains a number of nutrients that may have beneficial effects on plasma lipids and vascular function, as well as on the composition of the gut microbiota; changes in the gut microbiota can in turn have secondary positive effects on the vascular system as well as on other physiological functions that are important determinants of health and disease. The proposed project will seek to determine the influence of short-term FDSP intake on the gut microbiota composition, and select microbial-derived metabolites from stool, serum and urine, and their relationship to microvascular function. Secondary outcomes will include the influence of the FDSP on circulating levels of nitrate and nitrite and trimethylamine oxide (TMAO) as markers of vascular health that are influenced by both dietary intake and the oral and gut microflora, with blood pressure as an additional vascular outcome.

Inflammatory Markers After COloRectal Surgery)
Infectious Complications After Colorectal SurgeryThe clinical symptoms of septic complications (SC) (responsible for the majority of morbidity in colorectal surgery) become apparent only 5-7 days after the operation, whereas the efficacy of treatment depends on early diagnosis. By detecting such complications early it could be possible to reduce their severity, the length of hospitalisation, repeat colostomy and the number of readmissions. Our team has shown that C-reactive protein (CRP) > 125 mg/L at postoperative day 4 (D4) was a predictor of SC in this context. Procalcitonin (PCT) is a marker of sepsis currently used in intensive care, but its use in the follow-up of elective surgery, particularly colorectal surgery, has not been fully evaluated. The aim of this study is to compare the ability of CRP and PCT to detect SC as early as postoperative day 2 (D2) (intra-abdominal or systemic SC, such as those defined by the CDC) after elective colorectal surgery. Adult patients about to undergo elective colorectal surgery with anastomosis will be included once they have given their written informed consent. Levels of CRP and PCT will be measured the day before the surgery, then at D1, D2, D3 and D4. The clinical data (temperature, recovery of bowel movement, pain, pain on palpation) will be recorded daily. Imaging examinations will be performed at the discretion of the surgeon; the only obligation will be to perform a contrast-enhanced abdominopelvic CT-scan if CRP at D4 > 125 mg/L with no other clinical anomalies. The discriminating ability (measured by the area under the ROC curve) of CRP at D2 was 0.653 in our previous study. An improvement of at least 0.1 will be necessary to show the superiority of PCT over CRP in clinical terms and with regard to the cost.