Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial.

BACKGROUND: WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults. METHODS: We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 or 1 × 1011 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056. FINDINGS: Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 pu (n=20) or 1 × 1011 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 1010 pu group and 545 [276-1078] in the 1 × 1011 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×1010 pu group and 27 [95-156] in the 1 ×1011 pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination. INTERPRETATION: This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions. FUNDING: National Institutes of Health.

An mRNA Vaccine against SARS-CoV-2 - Preliminary Report.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 µg, 100 µg, or 250 µg. There were 15 participants in each dose group. RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-µg group, 109,209 in the 100-µg group, and 213,526 in the 250-µg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-µg dose group reported one or more severe adverse events. CONCLUSIONS: The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).

Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.

BACKGROUND: Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. METHODS: We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 µg or 100 µg of vaccine administered 28 days apart. RESULTS: Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-µg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-µg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. CONCLUSIONS: In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-µg dose induced higher binding- and neutralizing-antibody titers than the 25-µg dose, which supports the use of the 100-µg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).

Abstract analysis method facilitates filtering low-methodological quality and high-bias risk systematic reviews on psoriasis interventions.

BACKGROUND: Article summaries' information and structure may influence researchers/clinicians' decisions to conduct deeper full-text analyses. Specifically, abstracts of systematic reviews (SRs) and meta-analyses (MA) should provide structured summaries for quick assessment. This study explored a method for determining the methodological quality and bias risk of full-text reviews using abstract information alone. METHODS: Systematic literature searches for SRs and/or MA about psoriasis were undertaken on MEDLINE, EMBASE, and Cochrane database. For each review, quality, abstract-reporting completeness, full-text methodological quality, and bias risk were evaluated using Preferred Reporting Items for Systematic Reviews and Meta-analyses for abstracts (PRISMA-A), Assessing the Methodological Quality of Systematic Reviews (AMSTAR), and ROBIS tools, respectively. Article-, author-, and journal-derived metadata were systematically extracted from eligible studies using a piloted template, and explanatory variables concerning abstract-reporting quality were assessed using univariate and multivariate-regression models. Two classification models concerning SRs' methodological quality and bias risk were developed based on per-item and total PRISMA-A scores and decision-tree algorithms. This work was supported, in part, by project ICI1400136 (JR). No funding was received from any pharmaceutical company. RESULTS: This study analysed 139 SRs on psoriasis interventions. On average, they featured 56.7% of PRISMA-A items. The mean total PRISMA-A score was significantly higher for high-methodological-quality SRs than for moderate- and low-methodological-quality reviews. SRs with low-bias risk showed higher total PRISMA-A values than reviews with high-bias risk. In the final model, only 'authors per review > 6' (OR: 1.098; 95%CI: 1.012-1.194), 'academic source of funding' (OR: 3.630; 95%CI: 1.788-7.542), and 'PRISMA-endorsed journal' (OR: 4.370; 95%CI: 1.785-10.98) predicted PRISMA-A variability. Reviews with a total PRISMA-A score < 6, lacking identification as SR or MA in the title, and lacking explanation concerning bias risk assessment methods were classified as low-methodological quality. Abstracts with a total PRISMA-A score ≥ 9, including main outcomes results and explanation bias risk assessment method were classified as having low-bias risk. CONCLUSIONS: The methodological quality and bias risk of SRs may be determined by abstract's quality and completeness analyses. Our proposal aimed to facilitate synthesis of evidence evaluation by clinical professionals lacking methodological skills. External validation is necessary.

Gentamicin therapy for sepsis due to carbapenem-resistant and colistin-resistant Klebsiella pneumoniae.

OBJECTIVES: Antimicrobial therapy for sepsis caused by carbapenem- and colistin-resistant Klebsiella pneumoniae is not well established. We hypothesized that the early use of gentamicin in cases due to susceptible organisms would decrease the crude mortality rate of this infection. METHODS: This retrospective cohort study examined 50 cases of sepsis caused by carbapenem-resistant K. pneumoniae occurring between June 2012 and February 2013 during an outbreak of K. pneumoniae ST512 producing KPC-3, SHV-11 and TEM-1. Survival curves categorized by the use of gentamicin were constructed using the Kaplan-Meier method and compared using the log-rank test. Eight multivariate models using Cox regression were designed to study the risk factors for mortality and test the hypothesis. RESULTS: The 30 day crude mortality rate was 38%. The use of targeted gentamicin was associated with reduced mortality (20.7% versus 61.9%, P = 0.02). In all multivariate regression models, the use of gentamicin was independently associated with lower mortality until Day 30 (HR 0.17-0.29, P = 0.03-0.002 depending on the model) after controlling for other potential confounding variables such as age, optimal treatment, renal function, severity of infection, underlying disease, use of tigecycline and previous hospitalization. CONCLUSIONS: Gentamicin reduced the mortality from sepsis caused by this K. pneumoniae ST512 clone producing KPC-3, SHV-11 and TEM-1.

Safety, tolerability, and immunogenicity of the Ebola Sudan chimpanzee adenovirus vector vaccine (cAd3-EBO S) in healthy Ugandan adults: a phase 1, open-label, dose-escalation clinical trial.

BACKGROUND: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available. METHODS: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 1010 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed. FINDINGS: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41-75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30-73) to 4 weeks after vaccination (196, 125-308). INTERPRETATION: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks. FUNDING: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.

Robust humoral and cellular recall responses to AZD1222 attenuate breakthrough SARS-CoV-2 infection compared to unvaccinated.

Background: Breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19) vaccinees typically produces milder disease than infection in unvaccinated individuals. Methods: To explore disease attenuation, we examined COVID-19 symptom burden and immuno-virologic responses to symptomatic SARS-CoV-2 infection in participants (AZD1222: n=177/17,617; placebo: n=203/8,528) from a 2:1 randomized, placebo-controlled, phase 3 study of two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccination (NCT04516746). Results: We observed that AZD1222 vaccinees had an overall lower incidence and shorter duration of COVID-19 symptoms compared with placebo recipients, as well as lower SARS-CoV-2 viral loads and a shorter median duration of viral shedding in saliva. Vaccinees demonstrated a robust antibody recall response versus placebo recipients with low-to-moderate inverse correlations with virologic endpoints. Vaccinees also demonstrated an enriched polyfunctional spike-specific Th-1-biased CD4+ and CD8+ T-cell response that was associated with strong inverse correlations with virologic endpoints. Conclusion: Robust immune responses following AZD1222 vaccination attenuate COVID-19 disease severity and restrict SARS-CoV-2 transmission potential by reducing viral loads and the duration of viral shedding in saliva. Collectively, these analyses underscore the essential role of vaccination in mitigating the COVID-19 pandemic.

T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire.

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T-cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 280 unique vaccine recipients aged 18-85 years who enrolled in the phase 2/3 COV002 trial. Total spike-specific CD4+ T cell helper type 1 (Th1) and CD8+ T-cell responses were significantly increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T-cell receptor (TCR) ß sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for the AZD1222-induced CD4+ and CD8+ T-cell responses. Overall, AZD1222 vaccination induced a robust, polyfunctional Th1-dominated T-cell response, with broad CD4+ and CD8+ T-cell coverage across the SARS-CoV-2 spike protein. ONE SENTENCE SUMMARY: Polyfunctional CD4+ and CD8+ T-cell responses are elicited against the SARS-CoV-2 spike protein following vaccination with AZD1222.

AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein-specific TH1 response with a diverse TCR repertoire.

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus­vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 in clinical trials and real-world studies. We characterized CD4+ and CD8+ T cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells from 296 unique vaccine recipients aged 18 to 85 years who enrolled in the phase 2/3 COV002 trial. Total spike protein­specific CD4+ T cell helper type 1 (TH1) and CD8+ T cell responses were increased in AZD1222-vaccinated adults of all ages after two doses of AZD1222. CD4+ TH2 responses after AZD1222 vaccination were not detected. Furthermore, AZD1222-specific TH1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T cell receptor ß (TCRß) sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for both AZD1222-induced CD4+ and CD8+ T cell responses. Overall, AZD1222 vaccination induced a polyfunctional TH1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein.

The differential impact of scientific quality, bibliometric factors, and social media activity on the influence of systematic reviews and meta-analyses about psoriasis.

Researchers are increasingly using on line social networks to promote their work. Some authors have suggested that measuring social media activity can predict the impact of a primary study (i.e., whether or not an article will be highly cited). However, the influence of variables such as scientific quality, research disclosures, and journal characteristics on systematic reviews and meta-analyses has not yet been assessed. The present study aims to describe the effect of complex interactions between bibliometric factors and social media activity on the impact of systematic reviews and meta-analyses about psoriasis (PROSPERO 2016: CRD42016053181). Methodological quality was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. Altmetrics, which consider Twitter, Facebook, and Google+ mention counts as well as Mendeley and SCOPUS readers, and corresponding article citation counts from Google Scholar were obtained for each article. Metadata and journal-related bibliometric indices were also obtained. One-hundred and sixty-four reviews with available altmetrics information were included in the final multifactorial analysis, which showed that social media and impact factor have less effect than Mendeley and SCOPUS readers on the number of cites that appear in Google Scholar. Although a journal's impact factor predicted the number of tweets (OR, 1.202; 95% CI, 1.087-1.049), the years of publication and the number of Mendeley readers predicted the number of citations in Google Scholar (OR, 1.033; 95% CI, 1.018-1.329). Finally, methodological quality was related neither with bibliometric influence nor social media activity for systematic reviews. In conclusion, there seems to be a lack of connectivity between scientific quality, social media activity, and article usage, thus predicting scientific success based on these variables may be inappropriate in the particular case of systematic reviews.

Evaluating characteristics of PROSPERO records as predictors of eventual publication of non-Cochrane systematic reviews: a meta-epidemiological study protocol.

BACKGROUND: Epidemiology and the reporting characteristics of systematic reviews (SRs) and meta-analyses (MAs) are well known. However, no study has analyzed the influence of protocol features on the probability that a study's results will be finally reported, thereby indirectly assessing the reporting bias of International Prospective Register of Systematic Reviews (PROSPERO) registration records. OBJECTIVE: The objective of this study is to explore which factors are associated with a higher probability that results derived from a non-Cochrane PROSPERO registration record for a systematic review will be finally reported as an original article in a scientific journal. METHODS/DESIGN: The PROSPERO repository will be web scraped to automatically and iteratively obtain all completed non-Cochrane registration records stored from February 2011 to December 2017. Downloaded records will be screened, and those with less than 90% fulfilled or are duplicated (i.e., those sharing titles and reviewers) will be excluded. Manual and human-supervised automatic methods will be used for data extraction, depending on the data source (fields of PROSPERO registration records, bibliometric databases, etc.). Records will be classified into published, discontinued, and abandoned review subgroups. All articles derived from published reviews will be obtained through multiple parallel searches using the full protocol "title" and/or "list reviewers" in MEDLINE/PubMed databases and Google Scholar. Reviewer, author, article, and journal metadata will be obtained using different sources. R and Python programming and analysis languages will be used to describe the datasets; perform text mining, machine learning, and deep learning analyses; and visualize the data. We will report the study according to the recommendations for meta-epidemiological studies adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for SRs and MAs. DISCUSSION: This meta-epidemiological study will explore, for the first time, characteristics of PROSPERO records that may be associated with the publication of a completed systematic review. The evidence may help to improve review workflow performance in terms of research topic selection, decision-making regarding team selection, planning relationships with funding sources, implementing literature search strategies, and efficient data extraction and analysis. We expect to make our results, datasets, and R and Python code scripts publicly available during the third quarter of 2018.

Author-paper affiliation network architecture influences the methodological quality of systematic reviews and meta-analyses of psoriasis.

Moderate-to-severe psoriasis is associated with significant comorbidity, an impaired quality of life, and increased medical costs, including those associated with treatments. Systematic reviews (SRs) and meta-analyses (MAs) of randomized clinical trials are considered two of the best approaches to the summarization of high-quality evidence. However, methodological bias can reduce the validity of conclusions from these types of studies and subsequently impair the quality of decision making. As co-authorship is among the most well-documented forms of research collaboration, the present study aimed to explore whether authors' collaboration methods might influence the methodological quality of SRs and MAs of psoriasis. Methodological quality was assessed by two raters who extracted information from full articles. After calculating total and per-item Assessment of Multiple Systematic Reviews (AMSTAR) scores, reviews were classified as low (0-4), medium (5-8), or high (9-11) quality. Article metadata and journal-related bibliometric indices were also obtained. A total of 741 authors from 520 different institutions and 32 countries published 220 reviews that were classified as high (17.2%), moderate (55%), or low (27.7%) methodological quality. The high methodological quality subnetwork was larger but had a lower connection density than the low and moderate methodological quality subnetworks; specifically, the former contained relatively fewer nodes (authors and reviews), reviews by authors, and collaborators per author. Furthermore, the high methodological quality subnetwork was highly compartmentalized, with several modules representing few poorly interconnected communities. In conclusion, structural differences in author-paper affiliation network may influence the methodological quality of SRs and MAs on psoriasis. As the author-paper affiliation network structure affects study quality in this research field, authors who maintain an appropriate balance between scientific quality and productivity are more likely to develop higher quality reviews.

Most systematic reviews of high methodological quality on psoriasis interventions are classified as high risk of bias using ROBIS tool.

OBJECTIVES: No gold standard exists to assess methodological quality of systematic reviews (SRs). Although Assessing the Methodological Quality of Systematic Reviews (AMSTAR) is widely accepted for analyzing quality, the ROBIS instrument has recently been developed. This study aimed to compare the capacity of both instruments to capture the quality of SRs concerning psoriasis interventions. STUDY DESIGN AND SETTING: Systematic literature searches were undertaken on relevant databases. For each review, methodological quality and bias risk were evaluated using the AMSTAR and ROBIS tools. Descriptive and principal component analyses were conducted to describe similarities and discrepancies between both assessment tools. RESULTS: We classified 139 intervention SRs as displaying high/moderate/low methodological quality and as high/low risk of bias. A high risk of bias was detected for most SRs classified as displaying high or moderate methodological quality by AMSTAR. When comparing ROBIS result profiles, responses to domain 4 signaling questions showed the greatest differences between bias risk assessments, whereas domain 2 items showed the least. CONCLUSION: When considering SRs published about psoriasis, methodological quality remains suboptimal, and the risk of bias is elevated, even for SRs exhibiting high methodological quality. Furthermore, the AMSTAR and ROBIS tools may be considered as complementary when conducting quality assessment of SRs.

Immature rats show ovulatory defects similar to those in adult rats lacking prostaglandin and progesterone actions.

Gonadotropin-primed immature rats (GPIR) constitute a widely used model for the study of ovulation. Although the equivalence between the ovulatory process in immature and adult rats is generally assumed, the morphological and functional characteristics of ovulation in immature rats have been scarcely considered. We describe herein the morphological aspects of the ovulatory process in GPIR and their response to classical ovulation inhibitors, such as the inhibitor of prostaglandin (PG) synthesis indomethacin (INDO) and a progesterone (P) receptor (PR) antagonist (RU486). Immature Wistar rats were primed with equine chorionic gonadotropin (eCG) at 21, 23 or 25 days of age, injected with human chorionic gonadotropin (hCG) 48 h later, and sacrificed 16 h after hCG treatment, to assess follicle rupture and ovulation. Surprisingly, GPIR showed age-related ovulatory defects close similar to those in adult rats lacking P and PG actions. Rats primed with eCG at 21 or 23 days of age showed abnormally ruptured corpora lutea in which the cumulus-oocyte complex (COC) was trapped or had been released to the ovarian interstitum, invading the ovarian stroma and blood and lymphatic vessels. Supplementation of immature rats with exogenous P and/or PG of the E series did not significantly inhibit abnormal follicle rupture. Otherwise, ovulatory defects were practically absent in rats primed with eCG at 25 days of age. GPIR treated with INDO showed the same ovulatory alterations than vehicle-treated ones, although affecting to a higher proportion of follicles. Blocking P actions with RU486 increased the number of COC trapped inside corpora lutea and decreased ovulation. The presence of ovulatory defects in GPIR, suggests that the capacity of the immature ovary to undergo the coordinate changes leading to effective ovulation is not fully established in Wistar rats primed with eCG before 25 days of age.

Characterisation of the first ongoing outbreak due to KPC-3-producing Klebsiella pneumoniae (ST512) in Spain.

The aim of this study was to characterise carbapenem-resistant Klebsiella pneumoniae isolates that caused an outbreak in a hospital in the south of Spain, originating from a patient transferred in 2012 from Italy. Forty-four K. pneumoniae isolates, recovered from 28 patients, were screened by PCR for extended-spectrum ß-lactamase (ESBL) and carbapenemase genes and the products were further sequenced. Plasmids were transferred by electroporation and were classified using PCR-based Inc/rep typing and IncF subtyping. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to determine the genetic relatedness of the isolates. All isolates yielded positive modified Hodge test results, harboured bla(SHV-11), bla(TEM-1) and bla(KPC-3) genes, showed an identical PFGE pattern, and were assigned to clone sequence type 512 (ST512). The bla(KPC-3) gene was located on a 140-kb K2:A-:B-plasmid. In conclusion, the successful K. pneumoniae ST512 clone caused a major outbreak in Spain from an imported case and is the first description of an outbreak in this country due to the KPC-3-producing K. pneumoniae ST512 clone.

Epidemiology and clinical impact of infection in patients awaiting heart transplantation.

OBJECTIVES: The aim of this study was to determine the epidemiology and clinical impact of infections in patients awaiting heart transplantation. METHODS: We evaluated all patients considered for a heart transplant in our center over a period of 18 months over a period of 18 months from 2007 to 2009. The patients were followed up for 8 months or until death, transplant, or loss to follow-up. RESULTS: Ninety patients were included in the study. During follow-up, 25 infections were recorded in 22 heart transplant candidates (24.4%). Respiratory infections were the most frequent infection (12 bronchitis; 48.0%), followed by skin and soft tissue infections (four infections; 16.0%), intra-abdominal infections (four infectious diarrhea; 16.0%), bacteremia (three infections; 12.0%), and urinary tract infections (two infections; 2.0%). Age, comorbidity, sex, and diabetes were not found to be risk factors for infection. Twenty-four patients (26.7%) were transplanted during follow-up. Infection before transplantation was not associated with an increased risk of mortality or a higher rate of infection in the immediate post-transplant period. CONCLUSIONS: Infections are common in heart transplant candidates, affecting almost 25% of them. Respiratory tract infections are the most frequent type of infection. However, they are not associated with increased mortality in the immediate post-transplant period.

Age-dependent association between low frequency of CD27/CD28 expression on pp65 CD8+ T cells and cytomegalovirus replication after transplantation.

In this cross-sectional study of 42 solid organ transplant recipients, the association of human cytomegalovirus (HCMV) replication and age with the phenotype of the HCMV-specific CD8(+) T cells was analyzed by using the CMV pp65 HLA-A*0201 pentamer. A correlation between the proportion of CD28(-) HCMV-specific CD8(+) T cells and age was observed in patients without HCMV replication (r = 0.50; P = 0.02) but not in patients with HCMV replication (r = -0.05; P = 0.83), a finding which differs from that observed for total CD8(+) T cells. Within the group of patients younger than 50 years of age, patients with HCVM replication after transplantation had higher percentages of CD28(-) HCMV-specific CD8(+) T cells (85.6 compared with 58.7% for patients without HCMV replication; P = 0.004) and CD27(-) HCMV-specific CD8(+) T cells (90.7 compared with 68.8% for patients without HCMV replication; P = 0.03). However, in patients older than age 50 years, a high frequency of these two subpopulations was observed in patients both with and without previous HCMV replication (for CD28(-) HCMV-specific CD8(+) T cells, 84.4 and 80.9%, respectively [P = 0.39]; for CD27(-) HCMV-specific CD8(+) T cells 86.6 and 81.5%, respectively [P = 0.16]). In conclusion, the present study shows that in the group of recipients younger than age 50 years, HCMV replication after transplantation is associated with a high percentage of CD27(-) and CD28(-) HCMV-specific CD8(+) T cells. These results suggest that the increased percentage of CD27(-) or CD28(-) HCMV-specific subsets can be considered a biomarker of HCMV replication in solid organ transplant recipients younger than age 50 years but not in older patients. Further studies are necessary to define the significance of these changes in HCMV-associated clinical complications posttransplantation.

Foliculitis del jacuzzi: descripción de un brote de 6 casos / Whirlpool folliculitis: 6 cases outbreak report

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