30 years of study of Kingella kingae: post tenebras, lux

Kingella kingae is a Gram-negative bacterium that is today recognized as the major cause of joint and bone infections in young children. This microorganism is a member of the normal flora of the oropharynx, and the carriage rate among children under 4 years of age is approximately 10%. K. kingae is transmitted from child to child through close personal contact. Key virulence factors of K. kingae include expression of type IV pili, Knh-mediated adhesive activity and production of a potent RTX toxin. The clinical presentation of K. kingae invasive infection is often subtle and may be associated to mild-to-moderate biologic inflammatory responses, highlighting the importance a high index of suspicion. Molecular diagnosis of K. kingae infections by nucleic acid amplification techniques enables identification of this fastidious microorganism. Invasive infections typically respond favorably to medical treatment, with the exception of cases of endocarditis, which may require urgent valve replacement

Anti-Ebola therapy for patients with Ebola virus disease: a systematic review

Background: Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014–2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. Methods: We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. Results: From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, − 36 to 7%). Studies of convalescent plasma, interferon-β-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. Conclusions: Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal.Medicine, Faculty ofNon UBCInfectious Diseases, Division ofMedicine, Department ofPediatrics, Department ofReviewedFacult

A systematic review of the anatomical findings of multiple gallbladders

International audienc

Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.

[This corrects the article DOI: 10.1371/journal.pmed.1001967.]

Experimental treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial) : a historically controlled, single-arm proof-of-concept trial in Guinea

BACKGROUND:Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.METHODS AND FINDINGS:Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in "cycle threshold" [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A "target value" of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%-32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%-91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated.CONCLUSIONS:In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia.TRIAL REGISTRATION:ClinicalTrials.gov NCT02329054.Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humansEbola Virus Disease - correlates of protection, determinants of outcome, and clinical managemen

JIKI trial: participants’ characteristics, according to age and baseline Ct value.

<p>JIKI trial: participants’ characteristics, according to age and baseline Ct value.</p

JIKI trial: evolution of RNA viral load in adolescents and adults.

<p>(A) Evolution of RNA viral load in adolescents and adults who survived. The <i>x</i>-axis represents the time since favipiravir initiation (day 0). Each blue line represents one patient (<i>n</i> = 48). Circles represent baseline and follow-up values. Asterisks represent values under the limit of detection (3.4 log₁₀ copies/ml). The black line represents the mean log₁₀ viral load decline estimated from a linear mixed effect model. The mean initial viral load was estimated at 6.65 log₁₀ copies/ml (SD 0.86), and the mean slope of viral load evolution at −0.33 log₁₀ copies/ml (SD 0.03) per day of follow-up. (B) Evolution of RNA viral load in adolescents and adults who died. The <i>x</i>-axis represents the time since favipiravir initiation (day 0). Each red line represents one patient (<i>n</i> = 49). Circles represent baseline and follow-up values. The black line represents the mean log₁₀ viral load evolution estimated from a linear mixed effect model. The mean initial viral load was estimated at 8.54 log₁₀ copies/ml (SD 0.21), and the mean slope of viral load evolution at −0.001 log₁₀ copies/ml (SD 0.15) per day of follow-up.</p

JIKI trial progress.

<p>ALIMA, Alliance for International Medical Action; CRF, Croix Rouge Française (French Red Cross); EU, European Union; Inserm, Institut National de la Santé et de la Recherche Médicale; SSA, Service de Santé des Armées (French military health service).</p

JIKI trial: baseline serum creatinine in adolescents and adults and outcomes according to baseline values.

<p>Creat, creatinine.</p