Christophe Combescure

Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis

BACKGROUND Health-care-associated infection is the most frequent result of unsafe patient care worldwide, but few data are available from the developing world. We aimed to assess the epidemiology of endemic health-care-associated infection in developing countries. METHODS We searched electronic databases and reference lists of relevant papers for articles published 1995-2008. Studies containing full or partial data from developing countries related to infection prevalence or incidence-including overall health-care-associated infection and major infection sites, and their microbiological cause-were selected. We classified studies as low-quality or high-quality according to predefined criteria. Data were pooled for analysis. FINDINGS Of 271 selected articles, 220 were included in the final analysis. Limited data were retrieved from some regions and many countries were not represented. 118 (54%) studies were low quality. In general, infection frequencies reported in high-quality studies were greater than those from low-quality studies. Prevalence of health-care-associated infection (pooled prevalence in high-quality studies, 15·5 per 100 patients [95% CI 12·6-18·9]) was much higher than proportions reported from Europe and the USA. Pooled overall health-care-associated infection density in adult intensive-care units was 47·9 per 1000 patient-days (95% CI 36·7-59·1), at least three times as high as densities reported from the USA. Surgical-site infection was the leading infection in hospitals (pooled cumulative incidence 5·6 per 100 surgical procedures), strikingly higher than proportions recorded in developed countries. Gram-negative bacilli represented the most common nosocomial isolates. Apart from meticillin resistance, noted in 158 of 290 (54%) Staphylococcus aureus isolates (in eight studies), very few articles reported antimicrobial resistance. INTERPRETATION The burden of health-care-associated infection in developing countries is high. Our findings indicate a need to improve surveillance and infection-control practices. FUNDING World Health Organization.

Perinatal exposure to bisphenol a alters early adipogenesis in the rat

Background The causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has been poorly investigated. Objectives The aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning. Methods Pregnant Sprague-Dawley rats had access to drinking water containing 1 mg/L BPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet. Results Gestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-α (CAAT enhancer binding protein alpha), PPAR-γ (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex- and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet. Conclusions Perinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors.

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

BACKGROUND The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.

BackgroundResection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC.MethodsWe performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors.ResultsTwenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27–1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72–2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35–2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57–2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91–1.64) did not achieve statistical significance.ConclusionsClinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion.

Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis.

Summary.  Background: Pretest probability assessment is necessary to identify patients in whom pulmonary embolism (PE) can be safely ruled out by a negative D‐dimer without further investigations. Objective: Review and compare the performance of available clinical prediction rules (CPRs) for PE probability assessment. Patients/methods: We identified studies that evaluated a CPR in patients with suspected PE from Embase, Medline and the Cochrane database. We determined the 95% confidence intervals (CIs) of prevalence of PE in the various clinical probability categories of each CPR. Statistical heterogeneity was tested. Results: We identified 9 CPR and included 29 studies representing 31215 patients. Pooled prevalence of PE for three‐level scores (low, intermediate or high clinical probability) was: low, 6% (95% CI, 4–8), intermediate, 23% (95% CI, 18–28) and high, 49% (95% CI, 43–56) for the Wells score; low, 13% (95% CI, 8–19), intermediate, 35% (95% CI, 31–38) and high, 71% (95% CI, 50–89) for the Geneva score; low, 9% (95% CI, 8–11), intermediate, 26% (95% CI, 24–28) and high, 76% (95% CI, 69–82) for the revised Geneva score. Pooled prevalence for two‐level scores (PE likely or PE unlikely) was 8% (95% CI,6–11) and 34% (95% CI,29–40) for the Wells score, and 6% (95% CI, 3–9) and 23% (95% CI, 11–36) for the Charlotte rule. Conclusion: Available CPR for assessing clinical probability of PE show similar accuracy. Existing scores are, however, not equivalent and the choice among various prediction rules and classification schemes (three‐ versus two‐level) must be guided by local prevalence of PE, type of patients considered (outpatients or inpatients) and type of D‐dimer assay applied.

Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study

BackgroundIngestion of cranberry (Vaccinium macrocarpon Ait.) has traditionally been utilized for prevention of urinary tract infections. The proanthocyanidins (PACs) in cranberry, in particular the A-type linkages have been implicated as important inhibitors of primarily P-fimbriated E. coli adhesion to uroepithelial cells. Additional experiments were required to investigate the persistence in urine samples over a broader time period, to determine the most effective dose per day and to determine if the urinary anti-adhesion effect following cranberry is detected within volunteers of different origins.MethodsTwo separate bioassays (a mannose-resistant hemagglutination assay and an original new human T24 epithelial cell-line assay) have assessed the ex-vivo urinary bacterial anti-adhesion activity on urines samples collected from 32 volunteers from Japan, Hungary, Spain and France in a randomized, double-blind versus placebo study. An in vivo Caenorhabditis elegans model was used to evaluate the influence of cranberry regimen on the virulence of E. coli strain.ResultsThe results indicated a significant bacterial anti-adhesion activity in urine samples collected from volunteers that consumed cranberry powder compared to placebo (p < 0.001). This inhibition was clearly dose-dependent, prolonged (until 24 h with 72 mg of PAC) and increasing with the amount of PAC equivalents consumed in each cranberry powder regimen. An in vivo Caenorhabditis elegans model showed that cranberry acted against bacterial virulence: E. coli strain presented a reduced ability to kill worms after a growth in urines samples of patients who took cranberry capsules. This effect is particularly important with the regimen of 72 mg of PAC.ConclusionsAdministration of PAC-standardized cranberry powder at dosages containing 72 mg of PAC per day may offer some protection against bacterial adhesion and virulence in the urinary tract. This effect may offer a nyctohemeral protection.

Influence of Adipokines and Ghrelin on Bone Mineral Density and Fracture Risk: A Systematic Review and Meta-Analysis

CONTEXT Adipokines (leptin, adiponectin, resistin, visfatin) and ghrelin may be implicated in bone metabolism. OBJECTIVE The aim was to perform an overview of the influence of blood levels of adipokines or ghrelin on bone mineral density (BMD), osteoporotic status, and fracture risk in healthy men and women. DATA SOURCES We reviewed Medline, Embase, and Cochrane databases up to March 2010 and abstracts of international meetings from 2008 to 2009. STUDY SELECTION Fifty-nine studies meeting the inclusion criteria (healthy men or women evaluated for both BMD or fracture risk and at least one adipokine and/or ghrelin levels) were analyzed in the systematic review of the 931 references found in the electronic databases. DATA EXTRACTION We used a predefined extraction sheet. DATA SYNTHESIS We performed meta-analyses using the method of the inverse of the variance estimated pooled correlations between adipokines/ghrelin and BMD. Inverse correlations between adiponectin levels and BMD were highlighted (pooled r from -0.14 to -0.4). Leptin is positively associated to BMD, especially in postmenopausal women (pooled r from 0.18 to 0.33). High levels of leptin were reported to be predictive of low risk of fractures, whereas high levels of adiponectin may be predictive of high risk of vertebral fractures in men only. No discriminative capacity of osteoporotic status was reported. We found no convincing data to support an association between resistin, visfatin, or ghrelin and BMD. CONCLUSION Adiponectin is the most relevant adipokine negatively associated with BMD, independent of gender and menopausal status. Inconsistent associations between adipokines and BMD are probably confounded by body composition, in particular fat mass parameters.

The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial

BACKGROUND Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. METHODS The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. FINDINGS Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 × 10(5) pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 × 10(5) pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 ×10(7) pfu (p<0·0001). Subjective fever (p<0·0001), myalgia (p=0·036), and chills (p=0·026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0·0001) and blood monocyte-activation patterns (p=0·0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344·5 [95% CI 229·7-516·4] vs 1064·2 [757·6-1495·1]; p<0·0001; and 35·1 [24·7-50·7] vs 127·0 [86·0-187·6]; p<0·0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9-14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality. INTERPRETATION Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa. FUNDING Wellcome Trust through WHO.

Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis

Aim Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of haemorrhage. We reviewed the risks and benefits of thrombolytic therapy in the management of patients with acute PE. Methods and results We systematically reviewed randomized controlled studies comparing systemic thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with acute PE. Fifteen trials involving 2057 patients were included in our meta-analysis. Compared with heparin, thrombolytic therapy was associated with a significant reduction of overall mortality (OR; 0.59, 95% CI: 0.36–0.96). This reduction was not statistically significant after exclusion of studies including high-risk PE (OR; 0.64, 95% CI: 0.35–1.17). Thrombolytic therapy was associated with a significant reduction in the combined endpoint of death or treatment escalation (OR: 0.34, 95% CI: 0.22–0.53), PE-related mortality (OR: 0.29; 95% CI: 0.14–0.60) and PE recurrence (OR: 0.50; 95% CI: 0.27–0.94). Major haemorrhage (OR; 2.91, 95% CI: 1.95–4.36) and fatal or intracranial bleeding (OR: 3.18, 95% CI: 1.25–8.11) were significantly more frequent among patients receiving thrombolysis. Conclusions Thrombolytic therapy reduces total mortality, PE recurrence, and PE-related mortality in patients with acute PE. The decrease in overall mortality is, however, not significant in haemodynamically stable patients with acute PE. Thrombolytic therapy is associated with an increase of major and fatal or intracranial haemorrhage.

Efficacy of cardiorespiratory aerobic exercise in rheumatoid arthritis: Meta‐analysis of randomized controlled trials

Several lines of evidence have emphasized an improvement in aerobic capacity and muscle strength after physical exercise programs in rheumatoid arthritis (RA) patients. Our objective was to evaluate the efficacy of aerobic exercises in RA on quality of life, function, and clinical and radiologic outcomes by a systematic literature review and a meta‐analysis.