Using phage Lytic Enzymes to Control Pathogenic Bacteria

Our laboratory has developed phage lytic enzymes to prevent infection by specifically destroying disease bacteria on mucous membranes and in blood. Enzymes specific for S. pneumoniae and S. pyogenes have been developed to be used nasally and orally to control these organisms in environments such as hospitals and nursing homes to prevent or markedly reduce serious infections by these pathogens. In addition, a B. anthracis-specific enzyme was developed to kill the vegetative forms of these bacteria in the blood of infected individuals. In animal studies, >80% of mice colonized mucosally or infected intravenously with pathogenic bacteria were decolonized or survived after a single enzyme treatment delivered to the same site of colonization or infection

Increased production of IL-4 and IL-12p40 from bronchoalveolar lavage cells are biomarkers of Mycobacterium tuberculosis in the sputum

BACKGROUND: Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness. METHODS: We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.5 0 C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model. CONCLUSION: Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness

Diabetes in pregnancy among indigenous women in Australia, Canada, New Zealand, and the United States: a method for systematic review of studies with different designs

<p>Abstract</p> <p>Background</p> <p>Diabetes in pregnancy, which includes gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM), is associated with poor outcomes for both mother and infant during pregnancy, at birth and in the longer term. Recent international guidelines recommend changes to the current GDM screening criteria. While some controversy remains, there appears to be consensus that women at high risk of T2DM, including indigenous women, should be offered screening for GDM early in pregnancy, rather than waiting until 24-28 weeks as is current practice. A range of criteria should be considered before changing screening practice in a population sub-group, including: prevalence, current practice, acceptability and whether adequate treatment pathways and follow-up systems are available. There are also specific issues related to screening in pregnancy and indigenous populations. The evidence that these criteria are met for indigenous populations is yet to be reported. A range of study designs can be considered to generate relevant evidence for these issues, including epidemiological, observational, qualitative, and intervention studies, which are not usually included within a single systematic review. The aim of this paper is to describe the methods we used to systematically review studies of different designs and present the evidence in a pragmatic format for policy discussion.</p> <p>Methods/Design</p> <p>The inclusion criteria will be broad to ensure inclusion of the critical perspectives of indigenous women. Abstracts of the search results will be reviewed by two persons; the full texts of all potentially eligible papers will be reviewed by one person, and 10% will be checked by a second person for validation. Data extraction will be standardised, using existing tools to identify risks for bias in intervention, measurement, qualitative studies and reviews; and adapting criteria for appraising risk for bias in descriptive studies. External validity (generalisability) will also be appraised. The main findings will be synthesised according to the criteria for population-based screening and summarised in an adapted "GRADE" tool.</p> <p>Discussion</p> <p>This will be the first systematic review of all the published literature on diabetes in pregnancy among indigenous women. The method provides a pragmatic approach for synthesizing relevant evidence from a range of study designs to inform the current policy discussion.</p

Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%–80%), and directed essentially against early phase infection.</p> <p>Methods</p> <p>A genome-scale dataset was constructed by analyzing published data of: (1) global gene expression studies under conditions which simulate intra-macrophage stress, dormancy, persistence and/or reactivation; (2) cellular and humoral immunity, and vaccine potential. This information was compiled along with revised annotation/bioinformatic characterization of selected gene products and <it>in silico </it>mapping of T-cell epitopes. Protocols for scoring, ranking and prioritization of the antigens were developed and applied.</p> <p>Results</p> <p>Cross-matching of literature and <it>in silico</it>-derived data, in conjunction with the prioritization scheme and biological rationale, allowed for selection of 189 putative vaccine candidates from the entire genome. Within the 189 set, the relative distribution of antigens in 3 functional categories differs significantly from their distribution in the whole genome, with reduction in the Conserved hypothetical category (due to improved annotation) and enrichment in Lipid and in Virulence categories. Other prominent representatives in the 189 set are the PE/PPE proteins; iron sequestration, nitroreductases and proteases, all within the Intermediary metabolism and respiration category; ESX secretion systems, resuscitation promoting factors and lipoproteins, all within the Cell wall category. Application of a ranking scheme based on qualitative and quantitative scores, resulted in a list of 45 best-scoring antigens, of which: 74% belong to the dormancy/reactivation/resuscitation classes; 30% belong to the Cell wall category; 13% are classical vaccine candidates; 9% are categorized Conserved hypotheticals, all potentially very potent T-cell antigens.</p> <p>Conclusion</p> <p>The comprehensive literature and <it>in silico</it>-based analyses allowed for the selection of a repertoire of 189 vaccine candidates, out of the whole-genome 3989 ORF products. This repertoire, which was ranked to generate a list of 45 top-hits antigens, is a platform for selection of genes covering all stages of <it>M. tuberculosis </it>infection, to be incorporated in rBCG or subunit-based vaccines.</p

A systematic review of economic analyses of telehealth services using real time video communication

Background: Telehealth is the delivery of health care at a distance, using information and communication technology. The major rationales for its introduction have been to decrease costs, improve efficiency and increase access in health care delivery. This systematic review assesses the economic value of one type of telehealth delivery - synchronous or real time video communication - rather than examining a heterogeneous range of delivery modes as has been the case with previous reviews in this area. Methods A systematic search was undertaken for economic analyses of the clinical use of telehealth, ending in June 2009. Studies with patient outcome data and a non-telehealth comparator were included. Cost analyses, non-comparative studies and those where patient satisfaction was the only health outcome were excluded. Results 36 articles met the inclusion criteria. 22(61%) of the studies found telehealth to be less costly than the non-telehealth alternative, 11(31%) found greater costs and 3 (9%) gave the same or mixed results. 23 of the studies took the perspective of the health services, 12 were societal, and one was from the patient perspective. In three studies of telehealth to rural areas, the health services paid more for telehealth, but due to savings in patient travel, the societal perspective demonstrated cost savings. In regard to health outcomes, 12 (33%) of studies found improved health outcomes, 21 (58%) found outcomes were not significantly different, 2(6%) found that telehealth was less effective, and 1 (3%) found outcomes differed according to patient group. The organisational model of care was more important in determining the value of the service than the clinical discipline, the type of technology, or the date of the study. Conclusion Delivery of health services by real time video communication was cost-effective for home care and access to on-call hospital specialists, showed mixed results for rural service delivery, and was not cost-effective for local delivery of services between hospitals and primary care

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013