Background: We investigated safety and immunogenicity of 1-2 doses of different bivalent virus-like particle (VLP) norovirus vaccine candidate (NoV) formulations in healthy 18-64-year-olds.
Methods: On Days 1 and 28 participants (n=420) randomized to 14 equal groups received intramuscular control vaccine (hepatitis A) or one of 11 NoV formulations contained varying dosages of GI.1 and GII.4c genotype VLP antigens with Al(OH)3, and 0μg, 15μg or 50μg MPL. Immunogenicity was assessed on Days 1, 28, 56, 208 and 393. Solicited local and systemic reactions were recorded for 7 days, unsolicited adverse events until Day 56, and serious adverse events (SAE) throughout the trial.
Results: All NoV formulations induced similar increases in Pan-Ig, IgA and histo-blood group binding antigen-blocking (HBGA) antibodies by Day 56, mostly after 1 dose, that persisted above baseline to Day 393. Higher GI.1 content interfered with GII.4c responses, and responses did not benefit from MPL. Overall reactogenicity consisted of mainly mild injection site pain, headache and fatigue. No vaccine-related SAEs were reported.
Conclusions: All candidate NoV formulations were well tolerated. Overall, 15μg GI.1/50μg GII.4c elicited the best balance of immunogenicity with no clear benefit of MPL, and is the candidate formulation being taken forward in clinical development.
Vaccines (5), Infectious Diseases (1) Hepatitis A (1), Headache (1), more mentions
This letter discusses an important limitation of the literature recently reviewed by Bai et al (Bai AD, Agarwal A, Steinberg M, et al. Clinical predictors and clinical prediction rules to estimate initial patient risk for infective endocarditis in Staphylococcus aureus bacteraemia: a systematic review and meta-analysis. Clin Microbiol Infect 2017. In press). Specifically we discuss the effect that low transoesophageal echocardiography usage on the reliability of the reference standard used in many of these studies, and outline the potential effect this might have on the reliability of the estimates of the diagnostic performance of the clinical prediction rules.
We report a traveler who aquired a Salmonella enterica subsp. enterica serovar Typhi strain with resistance against beta-lactams, cephalosporins (ESBL-SHV-12) and quinolones (PMQR qnrB7). After clinical deterioration using meropenem-monotherapy treatment success was achieved after commencement of fosfomycin in conjunction with high-dose meropenem. The case illustrates clinical challenges of multi-resistant S.Typhi.
BACKGROUND: Staphylococcus aureus is the leading pathogen in surgical site infections (SSIs).
AIM: To explore trends and risk factors associated with S. aureus SSI.
METHODS: We identified risk factors for monomicrobial S. aureus SSI from the Swiss multi-centre SSI surveillance system using multivariate logistic regression. Both in-hospital and post-discharge SSIs were identified using standardized definitions.
FINDINGS: Over a 6 year period, we collected data on 229,765 surgical patients, of whom 499 (0.22%) developed monomicrobial S. aureus SSI; 459 (92.0%) and 40 (8.0%) were due to MSSA and MRSA, respectively. There was a significant decrease in rates of MSSA SSI (p=0.007), but not MRSA (p=0.70). Independent protective factors of S. aureus SSI were older age (≥75 years vs <50 years: odds ratio [OR] 0.60; 95% confidence interval [CI], 0.44-0.83), laparoscopy/minimally invasive surgery (OR 0.68; 95% CI 0.50-0.92), non-clean surgery (OR 0.78 [per increase in wound contamination class], 95% CI 0.64-0.94) and correct timing of preoperative antibiotic prophylaxis (OR 0.80, 95% CI 0.65-0.98). Independent risk factors were male sex (OR 1.38; 95% CI, 1.14-1.66), higher ASA score (per one-point increment: OR 1.30; 95% CI, 1.13-1.51), re-operation for non-infectious reasons (OR 4.59, 95% CI 3.59-5.87) and procedure type: cardiac surgery, laminectomy, and hip or knee arthroplasty had a 2- to 9-fold increased odds of S. aureus SSI compared to other procedures.
CONCLUSIONS: SSI due to S. aureus are decreasing and becoming rare events in Switzerland. We identified high-risk procedures that may benefit from specific preventive measures. Only few independent risk factors are easily modifiable.
Multifocal necrotising leucoencephalopathy is a rare disorder affecting the central nervous system. It is characterised pathologically by microscopic areas of necrosis with pontine predilection but also involvement of extrapontine regions, including the cerebellum, medulla and cerebral hemispheres. It usually occurs on the background of immunosuppression. Here we describe an immunocompetent patient with a recent history of Salmonella infection who presented with subacute neurological deterioration. At postmortem, she had evidence of multifocal necrotising leucoencephalopathy.
BACKGROUND: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD.
METHODS: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters.
RESULTS: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV1) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results.
CONCLUSIONS: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients.
Kartagener Syndrome (2), Lung Diseases (1), Infections (1), more mentions
Recurrence of Clostridium difficile infection (CDI) has major consequences for both patients and the health system. The ability to predict which patients are at an increased risk of recurrent CDI makes it possible to select candidates for therapy with new drugs and therapies (including fecal microbiota transplantation) that have proven to reduce the incidence of recurrence of CDI. Our objective was to develop a clinical prediction tool, the GEIH-CDI score, to determine the risk of recurrence of CDI. Predictors of recurrence of CDI were investigated using logistic regression in a prospective cohort of 274 patients diagnosed with CDI. The model was calibrated using the Hosmer-Lemeshow test. The tool comprises 4 factors: age (70-79 years and ≥80 years), history of CDI during the previous year, direct detection of toxin in stool, and persistence of diarrhea on the fifth day of treatment. The functioning of the GEIH-CDI score was validated in a prospective cohort of 183 patients. The area under the ROC curve was 0.72 (0.65 - 0.79). Application of the tool makes it possible to select patients at high risk (>50%) of recurrence and patients with low risk (<10%) of recurrence. GEIH-CDI score may be useful for clinicians treating patients with CDI.
Background: Fluoroquinolone resistance is mediated by mutations in the quinolone-resistance determining region (QRDR) of the topoisomerase genes. Denaturing high performance liquid chromatography (DHPLC) was evaluated for detection of clinically important mutations in gyrB among Salmonella.
Methods: Salmonella Typhi and S. Paratyphi A characterised for mutation in QRDR of gyrA, parC and parE were studied for mutation in gyrB by DHPLC and validated by sequencing.
Results: The DHPLC analysis was able to resolve the test mutant from isolates with wild type gyrB and distinguished mutants from other mutant by peak profile and shift in retention time. Three sequence variants were detected at codon 464, and a novel mutation Ser→Thr was also detected. gyrB mutation was associated with non classical quinolone resistance (NALS-CIPDS) in 34 isolates of S. Typhi only and was distinct from classical quinolone resistance associated with gyrA mutations (NALR-CIPDS).
Conclusions: DHPLC is effective for the detection of mutation and can reduce the need for sequencing to detect clinically significant gyrB mutations.
GenBank accession nos: KF993966, KF993965 and KF993964.
Pancreatic cancer is a leading cause of cancer-related death. Desmoplastic pancreatic tumors exhibit excessive extracellular matrix (ECM) and are thus highly resistant to anticancer therapeutics, since the ECM restricts drug penetration and dispersion. Here, we designed and generated two hypoxia-responsive and cancer-specific hybrid promoters, H(mT)E and H(E)mT. Transgene expression driven by each hybrid promoter was markedly higher under hypoxic conditions than normoxic conditions. Moreover, H(E)mT-driven transgene expression was highly cancer-specific and was superior to that of H(mT)E-driven expression. A decorin-expressing oncolytic adenovirus (Ad; oH(E)mT-DCN) replicating under the control of the H(E)mT promoter induced more potent and highly cancer-specific cell death compared with its cognate control oncolytic Ad, which harbored the endogenous Ad E1A promoter. Moreover, oH(E)mT-DCN exhibited enhanced antitumor efficacy compared with both the clinically approved oncolytic Ad ONYX-015 and its cognate control oncolytic Ad lacking DCN. oH(E)mT-DCN treatment also attenuated the expression of major ECM components, such as collagen I/III, elastin, and fibronectin, and induced tumor cell apoptosis, leading to extensive viral dispersion within orthotopic pancreatic tumors and pancreatic cancer patient-derived tumor spheroids. Collectively, these findings demonstrate that oH(E)mT-DCN exhibits potent antitumor efficacy by degrading the ECM and inducing apoptosis in a multifunctional process. This process facilitates the dispersion and replication of oncolytic Ad, making it an attractive candidate for the treatment of aggressive and desmoplastic pancreatic cancer. This article is protected by copyright. All rights reserved.
In 2007, a waterborne outbreak of Cryptosporidium hominis infection occurred in western Ireland, resulting in 242 laboratory-confirmed cases and an uncertain number of unconfirmed cases. A boil water notice was in place for 158 days that affected 120,432 persons residing in the area, businesses, visitors, and commuters. This outbreak represented the largest outbreak of cryptosporidiosis in Ireland. The purpose of this study was to evaluate the cost of this outbreak. We adopted a societal perspective in estimating costs associated with the outbreak. Economic cost estimated was based on totaling direct and indirect costs incurred by public and private agencies. The cost of the outbreak was estimated based on 2007 figures. We estimate that the cost of the outbreak was >€19 million (≈€120,000/day of the outbreak). The US dollar equivalent based on today's exchange rates would be $22.44 million (≈$142,000/day of the outbreak). This study highlights the economic need for a safe drinking water supply.
A significant proportion of C. difficile infection (CDI) cases recur after completion of antibiotic therapy, and antibiotic cure rates diminish with each recurrence of CDI. Fecal microbiota transplantation (FMT) is an effective therapy for recurrent FMT, which otherwise requires prolonged or indefinite antibiotic treatment. FMT is performed by introducing the fecal microbial community obtained from a healthy donor or pool of donors into the stomach, small intestine, or colon of a patient with CDI. Multiple clinical trials support the utility of FMT in treating recurrent CDI, and CDI treatment guidelines now include consideration of FMT at the third CDI recurrence. However, there remain significant challenges to incorporating FMT into clinical practice: (1) Methods of fecal bacterial community processing vary, as do methods of FMT administration. (2) The optimal dosing strategy and expected benefit of FMT for refractory CDI, particularly for severe and severe-complicated cases, are uncertain. (3) The Food and Drug Administration (FDA) considers FMT an investigational treatment. And (4) insurance reimbursement for FMT usually falls short of FMT administration costs. In the setting of rising C. difficile incidence and growing evidence for FMT efficacy, the demand for FMT has increased. However, uncertainty surrounding optimal FMT preparation and administration methods, FDA oversight, and insurance reimbursement presently limits the clinical practice of FMT.
An increase in the number of staphylococcal infections and carriers among medical staff has forced us to seek more and more effective antibacterial agents. Bacteria from the Staphylococcus genus possessing different mechanisms of resistance are the cause of nosocomial infections. The objective of our investigations was susceptibility of S. aureus strains isolated from nasal vestibule of medical students to fennel essential oil. The GC-MS analysis of fennel essential oil revealed eleven constituents among which a majority of trans-anethole (80%) was found. The D-tests showed iMLSB (80%), cMLSB and MSB (10%) resistant phenotypes of S. aureus. The S. aureus isolates were intermediate to mupirocin (45%). Fennel essential oil increased the inhibition zone around cefoxitin, mupirocin, co-trimoxazole and ciprofloxacin with statistical significance. Our research showed that the fennel essential oil in combination with mupirocin may be considered as a natural alternative in eradication of S. aureus with iMLSB, cMLSB, MSB resistant phenotypes and is able to decrease the growth rate of antibiotic resistance.
OBJECTIVE: Proton pump inhibitors (PPIs) can kill some human protozoan parasites in cell culture better than the drug metronidazole. Clinical data showing an antiprotozoal effect for PPIs are lacking. The objective of the study is to determine if PPI use is associated with a reduced risk of having intestinal parasites.
METHODS: We obtained electronic medical record data for all persons who received a stool ova and parasite (O & P) examination at our tertiary care academic medical center in Cleveland, Ohio, between January 2000 and September 2014. We obtained the person's age, whether they were taking a PPI at the time of the O & P examination, and whether the pathology report indicated the presence of any parasites. χ(2) with Yates correction was used to determine if PPI use was associated with stool protozoa.
RESULTS: Three intestinal protozoa were identified in 1199 patients taking a PPI (0.3%), and 551 intestinal parasites were identified in the 14,287 patients not taking a PPI (3.9%). There was a statistically significant lower likelihood of finding protozoa in the stool of a person taking a PPI compared with those not taking a PPI (P < .0001).
CONCLUSIONS: Patients taking a PPI were statistically less likely to have an intestinal protozoa reported on stool O & P examination compared with those not taking a PPI.
Gene delivery vectors that do not rely on host cell genome integration offer several advantages for gene transfer, chiefly the avoidance of insertional mutagenesis and position effect variegation. However, unless engineered for replication and segregation, nonintegrating vectors will dilute progressively in proliferating cells, and are not exempt of epigenetic effects. This article provides an overview of the main nonintegrating viral (adenoviral, adeno-associated viral, integration-deficient retro-lentiviral, poxviral), and nonviral (plasmid vectors, artificial chromosomes) vectors used for preclinical and clinical cell and gene therapy applications. Particular emphasis is placed on their use in hematologic disease.
The paper entitled "Rosacea and demodicidosis with gain of function mutation in STAT1″ by Second et al.(1) is of indubitable interest and prompted us to make some observations. The Authors described a patient with cutaneous and ocular rosacea that they related to demodicidosis since oral ivermectin improved the cutaneous lesions(1) . However, the Authors did not demonstrate by skin scraping nor by standardized skin surface biopsy (SSSB) an excessive number of Demodex folliculorum (DF) mites in the pilosebaceous units to justify an oral antiparasitic treatment as a drug of first choice(1) . This article is protected by copyright. All rights reserved.
BACKGROUND: Previous studies have found an increased risk for colonic neoplasm in patients with Barrett's esophagus. It is unknown whether such risk applies similarly to other types of gastroesophageal reflux disease (GERD).
AIMS: To test whether GERD represents a risk factor for the occurrence of colon polyps.
METHODS: The Miraca Life Sciences Database is a large national electronic repository of histopathologic records of patients distributed throughout the entire USA. A case-control study evaluated whether presence of (1) Barrett's metaplasia, (2) erosive esophagitis on endoscopy or histologic signs of reflux esophagitis, (3) clinical diagnosis of GERD, (4) any type of GERD affected the occurrence hyperplastic polyps (HP), sessile serrated adenomas/polyps (SSA/P), or tubular adenomas (TA) among 228,506 subjects undergoing bidirectional endoscopy. Multivariate logistic regression analyses were used to calculate odds ratios and their 95% confidence intervals for the risk of HP, TA or SSA/P associated with various types of GERD and adjusted for age, sex, and presence of H. pylori.
RESULTS: The analysis revealed positive associations between GERD and all types of colon polyps. These associations applied similarly to HP (1.47, 1.44-1.50), TA (1.30, 1.27-1.32), and SSA/P (1.52, 1.46-1.58). They also applied to different forms of GERD, showing a trend toward stronger associations, that is higher odds ratios, with Barrett's metaplasia or erosive esophagitis than clinical diagnosis of GERD.
CONCLUSION: All types of GERD represent a risk factor for the occurrence of different colon polyps, such as HP, TA, or SSA/P.