Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor.

BACKGROUND: No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. METHODS: Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 10(8) colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. RESULTS: The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). CONCLUSIONS: The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. CLINICAL TRIALS REGISTRATION: NCT01895855.

Building an integrated serosurveillance platform to inform public health interventions: Insights from an experts' meeting on serum biomarkers.

The use of biomarkers to measure immune responses in serum is crucial for understanding population-level exposure and susceptibility to human pathogens. Advances in sample collection, multiplex testing, and computational modeling are transforming serosurveillance into a powerful tool for public health program design and response to infectious threats. In July 2018, 70 scientists from 16 countries met to perform a landscape analysis of approaches that support an integrated serosurveillance platform, including the consideration of issues for successful implementation. Here, we summarize the group's insights and proposed roadmap for implementation, including objectives, technical requirements, ethical issues, logistical considerations, and monitoring and evaluation.

A De in the life of cholera.

The 50-year commemoration of S.N. De's seminal 1959 publication in Nature provides an opportunity to reflect on scientific discovery, recognition, and public health. De's paper marked the first major conceptual advance in cholera research since 1884, when Robert Koch definitively identified Der Kommabazillus as the aetiological agent of cholera. Unfortunately, Koch reported that systemic toxinosis and multi-organ failure led to severe dehydrating diarrhoea, thereby mistaking cause for effect. As a consequence, while work on other microbial pathogens advanced into the development of vaccines and therapeutics, cholera research languished as scientists injected animals parenterally in decades of futile effort to develop an animal model of diarrhoea. This fundamental misconception in cholera pathogenesis was swept away when S.N. De used ligated loops of rabbit ileum to demonstrate lumenal fluid accumulation in the presence of Vibrio cholerae culture filtrates. After some delay, De's observation of a diarrhoeagenic exotoxin became the founding principle of modern cholera research, vaccination, and treatment; and a burst of discovery saw V. cholerae transformed into the enteric pathogen best understood at the molecular level. The scientific basis for orally administering vaccines to induce mucosal immunity was established, and the success of oral rehydration, what has been described as one of the 20 th century's most important medical advances, was explained. Nobel laureate Joshua Lederberg wrote of De's iconoclastic creativity, experimental skill, and observational mastery, and many other leaders in the field concurred. De was nominated for the Nobel Prize in Physiology or Medicine more than once. But despite the passage of half a century from De's work, cholera remains a frustrating problem: we are clearly missing something. In reviewing the scientific and programmatic impact of S.N. De on cholera, it is clear that a defining victory against the disease is achievable, but only if basic scientific discoveries are relentlessly driven towards progress in public health.

Curbing cholera.

Colonization of the gut by virulent Vibrio cholerae is suppressed by probiotic-like activity of a live cholera vaccine candidate and Lactococcus lactis in two animal models (Hubbard et al. and Mao et al., this issue).

Photoacoustic infrared spectroscopy of Syncrude post-extraction oil sand.

Rapid- and step-scan photoacoustic (PA) infrared spectra of three fractions of a Syncrude post-extraction oil sand were analyzed in detail in this work. The rapid-scan spectra showed that the samples were comprised primarily of kaolinite, quartz, silica, siderite, and residual hydrocarbons, and that the proportions of these constituents were different for each fraction. Depth profiling of the three post-extraction oil sands was accomplished using both rapid- and step-scan PA infrared spectroscopy. The results confirmed that kaolinite is more abundant in the near-surface region, whereas quartz and hydrocarbons are concentrated at greater depths. The modulation frequency dependence of the PA intensities for all three fractions was consistent with a model in which the samples are thermally thick; in other words, the thermal diffusion length (roughly equal to the sampling depth) was less than the particle sizes of all three samples. The results of this study are consistent with published reports on the PA infrared spectra of fine tailings generated during bitumen extraction and the spectroscopic and thermophysical characterization of clay soils and an appropriate model clay.

Fluorescence rejection in Raman spectra of Syncrude Sweet Blend distillation fractions.

Four techniques for the reduction or elimination of fluorescence from Raman spectra of Syncrude process samples were examined in this study. These methods are based on the retrieval of Raman bands from differential, or derivative spectra. Differential data were generated by subtracting similar spectra of a given sample obtained in three ways: (a) shifted detection utilizing an array detector and two successive spectrometer settings; (b) shifted excitation (dispersive Raman) where the two spectra are recorded using neighbouring laser lines and ordinary photon counting; (c) shifted excitation (FT-Raman) in which the laser frequency is changed in software before acquisition of the second spectrum. In addition to these differential techniques, derivative spectra were acquired directly with a dispersive Raman system by modulating the wavelength during scanning. These fluorescence rejection methods were applied to two groups of Syncrude Sweet Blend distillation fractions. For light gas oils (boiling range, 195-343 degrees C) the ratio of monocyclic and bicyclic aromatic species was determined and bands due to aliphatic CH(n) groups were characterized. Heavy gas oils (343-524 degrees C) yielded bands that allowed quantitation of monocyclic, bicyclic and total aromatic groups. Bands due to aliphatics were also identified for the heavy gas oils. These results constitute a significant advance compared to the information obtainable using conventional dispersive and FT-Raman spectroscopy for the analysis of hydrocarbon distillation fractions.

Introducing cholera vaccination in Asia, Africa and Haiti: a meeting report.

Orally-administered cholera vaccine (OCV) has been increasingly examined as an additional tool to intervene against endemic and epidemic cholera. In 2013, short- and long-term field experience with OCV under nine distinctive field settings was reported from India, Bangladesh, Vietnam, Guinea, Haiti, and Thailand. Lead investigators from each of these projects presented their findings at a symposium chaired by Drs. David A. Sack and Robert H. Hall at the Vaccines for Enteric Diseases (VED) Conference in Bangkok on November 7, 2013. The objective of the symposium was to describe the unique features of each setting and project, share field experience of implementing cholera vaccination, discuss results, and identify constraints to the wider use of OCV. The VED provided a forum where >200 attendees engaged with this exciting and potentially decisive new development in the cholera field.

Biosensor technologies for detecting microbiological foodborne hazards.

The convergence of molecular biology and miniaturized instrumentation has accelerated development of biosensors with the specifications necessary to support pathogen reduction and quality programs in the food supply. Advances in optoelectronics, thin layer deposition, and microfabrication have provided many options for achieving microbiological detection goals. Some promising technologies are reviewed.

FT-Raman and photoacoustic infrared spectroscopy of Syncrude heavy gas oil distillation fractions.

FT-Raman and photoacoustic (PA) infrared spectra of six distillation fractions derived from Syncrude heavy gas oil (HGO), which has a boiling range from 343 to 524 degrees C, were analyzed in detail in this study. Most of the information on the fingerprint region (200-1,800 cm(-1)) is provided by the FT-Raman spectra, which display approximately 30 bands that are assignable to functional groups in alkanes or aromatics. Monocyclic, bicyclic and tricyclic aromatics in the six fractions were also monitored using bands in this region. The C-H stretching region in both the FT-Raman and PA infrared spectra of the HGO distillation fractions was analyzed according to a curve-fitting algorithm used in previous investigations of samples with lower boiling points. The PA spectra of the HGO fractions were also analyzed by integration. The curve-fitting results show that the frequencies of the 11 Raman and 8 infrared bands used to model the aliphatic (approximately 2,775-3,000 cm(-1)) parts of the respective spectra are approximately constant across the entire HGO boiling range. These band positions are consistent with the results obtained in earlier studies of other distillation fractions obtained from Syncrude sweet blend. Both curve-fitting and integration show that the respective proportions of CH(2) and CH(3) groups do not vary significantly within the HGO region.

FT-Raman and photoacoustic infrared spectroscopy of syncrude light gas oil distillation fractions.

FT-Raman and photoacoustic (PA) infrared spectra of 12 distillation fractions derived from Syncrude light gas oil (LGO), which has a boiling range from 195 to 343 degrees C, were analyzed in detail in this study. In the fingerprint region (200-1800 cm(-1)) most of the information is obtained from the FT-Raman spectra, which display 36 bands that are assignable to various alkyl or aryl functional groups. Monocyclic, bicyclic and tricyclic aromatics in the 12 fractions were also characterized using Raman bands in this region. The corresponding section of the infrared spectra is much simpler, displaying a relatively small number of bands due to either aromatic or aliphatic CH(n) (n=1, 2 or 3) groups. The Cz.sbnd;H stretching region in both FT-Raman and PA infrared spectra of the LGO distillation fractions was curve-fitted according to procedures established in previous investigations of Syncrude samples with various boiling ranges. The PA spectra of the LGO fractions were also analyzed using an accepted integration strategy that requires no a priori assumptions with regard to the number of constituent bands or their shapes. The curve-fitting results show that the frequencies of the 11 Raman and eight infrared bands used to model the aliphatic ( approximately 2775-3000 cm(-1)) parts of the respective spectra decrease systematically as the median boiling points of the LGO fractions increase. These band positions are consistent with those determined in earlier studies of other distillation fractions. Both curve fitting and integration show that the abundance of CH(2) groups increases at the expense of CH(3) groups as the boiling points of the fractions increase within the LGO region.

Promoting men's health.

BACKGROUND: In the past men have declined to follow health authority recommendations to go to their general practitioner for preventive health checks. The BEACH report on male consultations in general practice in Australia 1999-2000 reveals low GP utilisation by men, high smoking rates and high at risk alcohol consumption. Although attendance rates increase in men over 45 years of age, problems managed at that stage are frequently chronic in nature, and rates of obesity are high. OBJECTIVE: This article discusses men's health needs and approaches to preventive health in men, drawing from the experience of nine Victorian projects on Rural Men's Health Promotion. DISCUSSION: At different times in their lives men have differing health experiences and needs, and different degrees of interest in improving their health. Strategies are required at a community level to educate and encourage men to attend GPs and engage in health prevention. At a practice level we need to be employing strategies to encourage men to attend, including appropriate appointment times and going to where men are in workplaces and sporting clubs. Within the consultation when men do present, we need to address the presenting problem but also encourage further health discussion relating to risk factors, and improving resilience.

Enteric vaccines for pediatric use. Workshop summary.

Diarrheal diseases remain a major cause of death in children under 5 in less developed countries (LDCs). Vaccine development and implementation offers the best near-term approach to alleviating this problem. For this reason, a workshop to examine the possibilities for making enteric vaccines available to meet the specific needs of children in LDCs was convened in Virginia on April 24-26, 2004. Discussants considered research and development needs, regulatory and business issues, and previous experiences with enteric vaccine development and implementation. No insurmountable roadblocks to progress in this area were noted, and the possibility currently exists that properly supported efforts will enable the realization of enteric vaccines for pediatric use.

Preoperative "fentanyl challenge" as a tool to estimate postoperative opioid dosing in chronic opioid-consuming patients.

UNLABELLED: When opioids are used for postoperative pain control, it is useful to define the dose-response relationship for analgesia and respiratory depression. We studied 20 chronically opioid-consuming patients having elective multilevel spine fusion. Preoperatively, each patient received a fentanyl infusion of 2 microg x kg(-1) x min(-1) until the respiratory rate was <5 breaths/min. Pharmacokinetic simulations were used to estimate the effect site concentration at the time of respiratory depression and to predict the patient-controlled analgesia settings that would provide an effect-site fentanyl concentration that was 30% of the concentration associated with respiratory depression. Postoperatively, patient-controlled analgesia settings were adjusted to achieve 2-3 demand doses per hour. At steady-state patient-controlled analgesia settings, arterial blood gases and plasma fentanyl levels were measured. Sixteen patients required no adjustment or one patient-controlled analgesia adjustment. The median arterial Pco(2) level was 41 mm Hg and the interquartile range was 39-46 mm Hg. Plasma fentanyl levels demonstrated a significant correlation to the estimated effect-site concentration associated with respiratory depression determined during the preoperative fentanyl challenge. A preoperative fentanyl challenge used with pharmacokinetic simulations may be a useful tool to individualize the administration of analgesics to chronically opioid-consuming patients. IMPLICATIONS: In chronically opioid-consuming patients, doses causing respiratory depression and analgesia may differ from those in opioid-naive individuals. A preoperative infusion of fentanyl, used in conjunction with pharmacokinetic simulation, may be a valuable tool for identifying clinical end-points, such as respiratory depression and analgesia, and individualizing postoperative treatment of pain in patients who chronically consume opioids.

Purification and characterization of a potent hemolytic toxin with phospholipase A2 activity from the venom of Indian Russell's viper.

A potent toxin with phospholipase A2 (PLA2) and hemolytic activity in vitro was purified from the Russell's viper venom of eastern India (RVV-EI). The purified protein (RVV-PFIIc') of 15.3 kDa molecular weight, and a lethal toxicity dose (LD50i.p.) of 0.1 mg/kg body weight, was the most toxic PLA2 so far reported from the Indian subcontinent. The material also possessed anticoagulant activity as it enhanced the prothrombin induced plasma clotting time in vitro. The PLA2 toxin (RVV-PFIIc') was shown to be different from other PLA2s of RVV in respect to one or more of these parameters e.g. molecular weight, isoelectric pH, in vivo toxicity, specific activity of the enzyme and certain other biological activities. The first 19 amino terminal sequence (NLFQFAEMIVKMTGKEAVH) of RVV-PFIIc' showed variable degree of homology (42.1-94.7%) with those of other RVV-PLA2s described in the literature. Antisera raised against RVV-EI or RVV-PFIIc', though completely neutralized the in vivo lethal toxicity of RVV-EI or RVV-PFIIc', failed to inhibit their PLA2 activity in vitro thereby suggesting that in vivo toxicity and in vitro activity of the enzyme may not be directly related. Apart from RVV-PFIIc', at least two other PLA2 isozymes were found to be present in RVV-EI that were distinct from RVV-PFIIc' in respect to their molecular, biological as well as serological properties. The significance of these and related data in antivenom therapy is discussed.