1,721,046 research outputs found
Case-control investigation of invasive Salmonella disease in Malawi reveals no evidence of environmental or animal transmission of invasive strains, and supports human to human transmission
Full text linkBackground Invasive Salmonella infections cause significant morbidity and mortality in Sub-Saharan Africa. However, the routes of transmission are uncertain. We conducted a case-control study of index-case and geographically-matched control households in Blantyre, Malawi, sampling Salmonella isolates from index cases, healthy people, animals, and the household environment. Methodology Sixty index cases of human invasive Salmonella infection were recruited (March 2015-Oct 2016). Twenty-eight invasive Non-Typhoidal Salmonella (iNTS) disease and 32 typhoid patients consented to household sampling. Each index-case household was geographically matched to a control household. Extensive microbiological sampling included stool sampling from healthy household members, stool or rectal swabs from household-associated animals and boot-sock sampling of the household environment. Findings 1203 samples from 120 households, yielded 43 non-Typhoidal Salmonella (NTS) isolates from 25 households (overall sample positivity 3.6%). In the 28 iNTS patients, disease was caused by 3 STs of Salmonella Typhimurium, mainly ST313. In contrast, the isolates from households spanned 15 sequence types (STs). Two S . Typhimurium isolates from index cases closely matched isolates from their respective asymptomatic household members (2 and 3 SNP differences respectively). Despite the recovery of a diverse range of NTS, there was no overlap between the STs causing iNTS disease with any environmental or animal isolates. Conclusions The finding of NTS strains from index cases that matched household members, coupled with lack of related animal or environmental isolates, supports a hypothesis of human to human transmission of iNTS infections in the household. The breadth of NTS strains found in animals and the household environment demonstrated the robustness of NTS sampling and culture methodology, and suggests a diverse ecology of Salmonella in this setting. Healthy typhoid ( S . Typhi) carrier state was not detected. The lack of S . Typhi isolates from the household environment suggests that further methodological development is needed to culture S . Typhi from the environment. Author summary Invasive Salmonella infections cause the loss of millions of disability adjusted life years (DALYs) every year globally. The two main types of invasive Salmonella infections in Africa are i) typhoid fever, caused by Salmonella Typhi, and ii) invasive Non-Typhoidal Salmonella (iNTS) disease, primarily caused in our setting by Salmonella Typhimurium. Despite the high disease burden, and the observed differences between the epidemiology of typhoid and iNTS disease, we lack an understanding of the reservoirs and transmission routes of iNTS. Therefore, we carried out extensive microbiological sampling of the household members, domestic animals, and living environments of patients with invasive Salmonella infections, and of geographically-matched control households, and investigated the genetic relationships between household Salmonella and index-case blood-stream isolates by whole genome sequencing (WGS). We identified a wide range of NTS serovars / sequence types across all households and sample-types, but only identified Salmonella that matched iNTS that matched invasive cases strains in the stool of healthy people from the same households. Our findings support, but cannot prove, the hypothesis that iNTS-associated strains are transmitted from person-to-person. Boot-sock sampling of the household environment gave the highest yield of Salmonella of any of our sampling strategies. None of the 41 environmental Salmonella isolates from non-human sources, including 4 domestic animal-associated isolates, matched the disease-causing sequence types. Our findings are consistent with a hypothesis that the reservoir of Typhimurium iNTS infections is the human gastrointestinal tract, and transmission occurs within households. Longitudinal studies are required, however, to confirm this hypothesis
Rainfall and other meteorological factors as drivers of urban transmission of leptospirosis
No full textBackground: Leptospirosis is an important public health problem affecting vulnerable urban slum populations in developing country settings. However, the complex interaction of meteorological factors driving the temporal trends of leptospirosis remain incompletely understood. Methods and findings: From March 1996—March 2010, we investigated the association between the weekly incidence of leptospirosis and meteorological anomalies in the city of Salvador, Brazil by using a dynamic generalized linear model that accounted for time lags, overall trend, and seasonal variation. Our model showed an increase of leptospirosis cases associated with higher than expected rainfall, lower than expected temperature and higher than expected humidity. There was a lag of one-to-two weeks between weekly values for significant meteorological variables and leptospirosis incidence. Independent of the season, a weekly cumulative rainfall anomaly of 20 mm increased the risk of leptospirosis by 12% compared to a week following the expected seasonal pattern. Finally, over the 14-year study period, the annual incidence of leptospirosis decreased significantly by a factor of 2.7 (8.3 versus 3.0 per 100,000 people), independently of variations in climate. Conclusions: Strategies to control leptospirosis should focus on avoiding contact with contaminated sources of Leptospira as well as on increasing awareness in the population and health professionals within the short time window after low-level or extreme high-level rainfall events. Increased leptospirosis incidence was restricted to one-to-two weeks after those events suggesting that infectious Leptospira survival may be limited to short time intervals
Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model.
Full text linkEnteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41-1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16-1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov
The diversity, evolution and ecology of Salmonella in venomous snakes
No full textBackground: Reptile-associated Salmonella bacteria are a major, but often neglected cause of both gastrointestinal and bloodstream infection in humans globally. The diversity of Salmonella enterica has not yet been determined in venomous snakes, however other ectothermic animals have been reported to carry a broad range of Salmonella bacteria. We investigated the prevalence and diversity of Salmonella in a collection of venomous snakes and non-venomous reptiles. Methodology/Principle findings: We used a combination of selective enrichment techniques to establish a unique dataset of reptilian isolates to study Salmonella enterica species-level evolution and ecology and used whole-genome sequencing to investigate the relatedness of phylogenetic groups. We observed that 91% of venomous snakes carried Salmonella, and found that a diverse range of serovars (n = 58) were carried by reptiles. The Salmonella serovars belonged to four of the six Salmonella enterica subspecies: diarizonae, enterica, houtanae and salamae. Subspecies enterica isolates were distributed among two distinct phylogenetic clusters, previously described as clade A (52%) and clade B (48%). We identified metabolic differences between S. diarizonae, S. enterica clade A and clade B involving growth on lactose, tartaric acid, dulcitol, myo-inositol and allantoin. Significance: We present the first whole genome-based comparative study of the Salmonella bacteria that colonise venomous and non-venomous reptiles and shed new light on Salmonella evolution. Venomous snakes examined in this study carried a broad range of Salmonella, including serovars which have been associated with disease in humans such as S. Enteritidis. The findings raise the possibility that venomous snakes could be a reservoir for Salmonella serovars associated with human salmonellosis
Biased efficacy estimates in phase-III dengue vaccine trials due to heterogeneous exposure and differential detectability of primary infections across trial arms
Full text linkVaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation.</div
Treatment responses to Azithromycin and Ciprofloxacin in uncomplicated <i>Salmonella</i> Typhi infection: A comparison of Clinical and Microbiological Data from a Controlled Human Infection Model
Full text linkBackgroundThe treatment of enteric fever is complicated by the emergence of antimicrobial resistant Salmonella Typhi. Azithromycin is commonly used for first-line treatment of uncomplicated enteric fever, but the response to treatment may be sub-optimal in some patient groups when compared with fluoroquinolones.MethodsWe performed an analysis of responses to treatment with azithromycin (500mg once-daily, 14 days) or ciprofloxacin (500mg twice-daily, 14 days) in healthy UK volunteers (18–60 years) enrolled into two Salmonella controlled human infection studies. Study A was a single-centre, open-label, randomised trial. Participants were randomised 1:1 to receive open-label oral ciprofloxacin or azithromycin, stratified by vaccine group (Vi-polysaccharide, Vi-conjugate or control Men-ACWY vaccine). Study B was an observational challenge/re-challenge study, where participants were randomised to challenge with Salmonella Typhi or Salmonella Paratyphi A. Outcome measures included fever clearance time, blood-culture clearance time and a composite measure of prolonged treatment response (persistent fever ≥38.0°C for ≥72 hours, persistently positive S. Typhi blood cultures for ≥72 hours, or change in antibiotic treatment). Both trials are registered with ClinicalTrials.gov (NCT02324751 and NCT02192008).FindingsIn 81 participants diagnosed with S. Typhi in two studies, treatment with azithromycin was associated with prolonged bacteraemia (median 90.8 hours [95% CI: 65.9–93.8] vs. 20.1 hours [95% CI: 7.8–24.3], pInterpretationAzithromycin at a dose of 500mg daily is an effective treatment for fully sensitive strains of S. Typhi but is associated with delayed treatment response and prolonged bacteraemia when compared with ciprofloxacin within the context of a human challenge model. Whilst the cellular accumulation of azithromycin is predicted to be sufficient to treat intracellular S. Typhi, systemic exposure may be sub-optimal for the elimination of extracellular circulating S. Typhi. In an era of increasing antimicrobial resistance, further studies are required to define appropriate azithromycin dosing regimens for enteric fever and to assess novel treatment strategies, including combination therapies.Trial registrationClinicalTrials.gov (NCT02324751 and NCT02192008).</div
Evaluation of a Smartphone Decision-Support Tool for Diarrheal Disease Management in a Resource-Limited Setting.
Full text linkThe emergence of mobile technology offers new opportunities to improve clinical guideline adherence in resource-limited settings. We conducted a clinical pilot study in rural Bangladesh to evaluate the impact of a smartphone adaptation of the World Health Organization (WHO) diarrheal disease management guidelines, including a modality for age-based weight estimation. Software development was guided by end-user input and evaluated in a resource-limited district and sub-district hospital during the fall 2015 cholera season; both hospitals lacked scales which necessitated weight estimation. The study consisted of a 6 week pre-intervention and 6 week intervention period with a 10-day post-discharge follow-up. Standard of care was maintained throughout the study with the exception that admitting clinicians used the tool during the intervention. Inclusion criteria were patients two months of age and older with uncomplicated diarrheal disease. The primary outcome was adherence to guidelines for prescriptions of intravenous (IV) fluids, antibiotics and zinc. A total of 841 patients were enrolled (325 pre-intervention; 516 intervention). During the intervention, the proportion of prescriptions for IV fluids decreased at the district and sub-district hospitals (both p < 0.001) with risk ratios (RRs) of 0.5 and 0.2, respectively. However, when IV fluids were prescribed, the volume better adhered to recommendations. The proportion of prescriptions for the recommended antibiotic azithromycin increased (p < 0.001 district; p = 0.035 sub-district) with RRs of 6.9 (district) and 1.6 (sub-district) while prescriptions for other antibiotics decreased; zinc adherence increased. Limitations included an absence of a concurrent control group and no independent dehydration assessment during the pre-intervention. Despite limitations, opportunities were identified to improve clinical care, including better assessment, weight estimation, and fluid/ antibiotic selection. These findings demonstrate that a smartphone-based tool can improve guideline adherence. This study should serve as a catalyst for a randomized controlled trial to expand on the findings and address limitations
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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