Retrospective quality review of Department of Transportation (DOT) commercial drivers medical examination forms.

OBJECTIVE: This study aimed to evaluate the quality of completion among both drivers and medical examiners in filling out Commercial Driver's (CD) Medical Examination Report Forms. METHODS: This was a cross-sectional retrospective study of abstracted data from the year 2019. CD Medical Examination Report Forms, collected from a single nationally-based employer and initially reviewed by corporate medical directors, were evaluated by the study team for completeness of documentation provided by both drivers and medical examiners (MEs). Relevant findings included unanswered questions, inconsistency between responses, and lack of necessary elaboration for positive responses. RESULTS: Among 1603 examinations, MEs completed the Medical Examination Report Form incompletely or incorrectly in 30% of examinations (n = 484). Drivers inconsistently filled out their health history with elaborations 38.7% of the time. Most commonly, they failed to elaborate on positive health history responses in 28.7% of examinations, but other types of errors were noted as well. CONCLUSIONS: A considerable proportion of drivers or examiners (n = 890, 55%) failed to adequately or correctly complete CD Medical Examination Report forms.

Co-producing Human and Animal Experimental Subjects: Exploring the Views of UK COVID-19 Vaccine Trial Participants on Animal Testing.

Preclinical (animal) testing and human testing of drugs and vaccines are rarely considered by social scientists side by side. Where this is done, it is typically for theoretically exploring the ethics of the two situations to compare relative treatment. In contrast, we empirically explore how human clinical trial participants understand the role of animal test subjects in vaccine development. Furthermore, social science research has only concentrated on broad public opinion and the views of patients about animal research, whereas we explore the views of a public group particularly implicated in pharmaceutical development: experimental subjects. We surveyed and interviewed COVID-19 vaccine trial participants in Oxford, UK, on their views about taking part in a vaccine trial and the role of animals in trials. We found that trial participants mirrored assumptions about legitimate reasons for animal testing embedded in regulation and provided insight into (i) the nuances of public opinion on animal research; (ii) the co-production of human and animal experimental subjects; (iii) how vaccine and medicine testing, and the motivations and demographics of clinical trial participants, change in an outbreak; and (iv) what public involvement can offer to science.

Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.

BACKGROUND: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. METHODS: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. FINDINGS: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). INTERPRETATION: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. FUNDING: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

Roles and responsibilities of participants, researchers, and the media in the communication of vaccine trials: Experience from the United Kingdom's first COVID-19 vaccine trial.

BACKGROUND: The media have played an important part in presenting arguments for and against vaccination. The potential for the media to influence public attitudes to vaccines is becoming increasingly crucial to address. METHODS: To understand the differing roles and responsibilities in the communication of vaccine trials we draw insight from a retrospective study of 349 survey responses and 102 semi-structured interviews conducted in 2020 with participants in the United Kingdom's first-in-human clinical trial of the Oxford-AstraZeneca COVID-19 vaccine. RESULTS: We found that trial participants had mixed views as to whether their participation conferred responsibility to communicate more widely about their trial experiences. Some participants perceived themselves to have an altruistic obligation to communicate to the media about the trial, and others felt that those who did share their participation had 'attention-seeking' motives. When participants did speak out they preferred to do so anonymously. Frustration was also reported with sensationalised and false media stories. Social media was viewed as a means to accelerate misinformation or as a force for recruitment and public education about trials. Participants were pleased to see trial investigators and trial team playing prominent roles in the media and this instilled confidence in the vaccine and the trial. We discuss these evolving roles and responsibilities for trial communication, concentrating on the views of participants about experiences, opportunities, and risks. CONCLUSIONS: We argue that the pandemic has demonstrated the need for clinical trials to be made more transparent as a scientific practice that requires better public understanding and engagement. For high-profile vaccine trials we recommend; (1) explicit and comprehensive guidance aimed at all participants for interactions with the media; (2) prioritising having open and effectively expressed accounts of trial composition, processes, and participation; (3) offering support and a direct communication channel for journalists to report trials by utilising internal press officers to engage with journalists.

The collective voice of early phase COVID-19 vaccine trial participants: Insights for improving confidence in novel vaccines.

In early 2020, adult volunteers were invited to participate in a first-in-human trial of the COVID-19 vaccine, ChAdOx1 nCoV-19, in the United Kingdom (UK) at the height of the global pandemic when there was uncertainty regarding vaccine efficacy and side-effects. We conducted a retrospective survey of these uniquely situated individuals to gain insight into their views about the risks, motivations, and expectations of the trial and potential vaccine deployment. Our data from 349 respondents show that these volunteers were educated to a high-level with a clear understanding of the seriousness of the COVID-19 pandemic, as well as an appreciation of the role of science and research in developing a vaccine to address this global problem. Individuals were primarily motivated with altruistic intent and expressed a desire to contribute to the scientific effort. Respondents appreciated that their participation was associated with risk but appeared comfortable that this risk was low. Through our analysis, we highlight these individuals as a group with strong levels of trust in science and a sense of societal responsibility, and therefore are a potential valuable resource to improve confidence in novel vaccines. Vaccine trial participants could offer a credible collective voice to support positive messaging around vaccination.

Safest Roasting Times of Coffee To Reduce Carcinogenicity.

ABSTRACT: Roasting coffee results in not only the creation of carcinogens such as acrylamide, furan, and polycyclic aromatic hydrocarbons but also the elimination of carcinogens in raw coffee beans, such as endotoxins, preservatives, or pesticides, by burning off. However, it has not been determined whether the concentrations of these carcinogens are sufficient to make either light or dark roast coffee more carcinogenic in a living organism. An Ames test was conducted on light, medium, and dark roast coffee from three origins. We found that lighter roast coffee shows higher mutagenicity, which is reduced to the control level in dark roast coffee varieties, indicating that the roasting process is not increasing mutagenic potential but is beneficial to eliminating the existing carcinogens in raw coffee beans. This result suggests that dark roast coffee is safer and promotes further studies of the various carcinogens in raw coffee that have been burned off.

Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Fensomea setacea, gen. & sp. nov. (Cladopyxidaceae, Dinophyceae), is neither gonyaulacoid nor peridinioid as inferred from morphological and molecular data.

Dinophyte evolution is essentially inferred from the pattern of thecal plates, and two different labelling systems are used for the important subgroups Gonyaulacales and Peridiniales. The partiform hypotheca of cladopyxidoid dinophytes fits into the morphological concepts of neither group, although they are assigned to the Gonyaulacales. Here, we describe the thecate dinophyte Fensomea setacea, gen. & sp. nov., which has a cladopyxidoid tabulation. The cells displayed a Kofoidean plate formula APC, 3', 4a, 7″, 7C, 6S, 6''', 2'''', and slender processes were randomly distributed over the echinate or baculate surface. In addition, we obtained rRNA sequences of F. setacea, gen. & sp. nov., but dinophytes that exhibit a partiform hypotheca did not show a close relationship to Gonyaulacales. Character evolution of thecate dinophytes may have progressed from the ancestral state of six postcingular plates, and two more or less symmetrically arranged antapical plates, towards patterns of only five postcingular plates (Peridiniales) or more asymmetrical configurations (Gonyaulacales). Based on our phylogenetic reconsiderations the contact between the posterior sulcal plate and the first postcingular plate, as well as the contact between an antapical plate and the distalmost postcingular plate, do not represent a rare, specialized gonyaulacoid plate configuration (i.e., the partiform hypotheca of cladopyxidoid dinophytes). Instead, these contacts correspond to the common and regular configuration of peridinioid (and other) dinophytes.

Vaccine nationalism and internationalism: perspectives of COVID-19 vaccine trial participants in the United Kingdom.

BACKGROUND: Vaccine nationalism has become a key topic of discussion during the development, testing, and rollout of COVID-19 vaccines. Media attention has highlighted the ways that global, coordinated access to vaccines has been limited during the pandemic. It has also exposed how some countries have secured vaccine supply, through bilateral purchase agreements and the way pharmaceutical companies have priced, negotiated, and delivered these supplies. Much of the focus of this debate has been on the vaccine supply 'winners' and 'losers', but the voices of public opinion have been more limited. METHODS: We explore the concepts of vaccine nationalism and internationalism from the perspective of vaccine trial participants, using an empirical perspectives study that involved interviews with phase I/II COVID-19 vaccine trial participants in Oxford, UK. We surveyed and interviewed participants between September and October 2020 about their views, motivations and experiences in taking part in the trial. RESULTS: First, we show how trial participants describe national and international ideas about vaccination as intertwined and challenge claims that these positions are mutually exclusive or oppositional. Second, we analyse these viewpoints further to show that vaccine nationalism is closely connected with national pride and metaphors of a country's scientific achievements. Participants held a global outlook and were highly supportive of the prioritisation of vaccines by global need, but many were also pessimistic that such a solution could be possible. CONCLUSION: Trial participants constitute an informed public group, with situated public expertise that the global community could draw on as an expert opinion. We argue that vaccine nationalism is strongly attached to national character and, therefore, it is more difficult for ownership of a vaccine to be though of as international.

Cardiorespiratory Fitness of Firefighters: Initial Results of a Multi-Phased Study.

OBJECTIVE: To address which body composition (BC) measures best correlate with cardiorespiratory fitness (CRF) in firefighters and develop a model for accurate CRF estimation compared with traditional methods. METHODS: Career firefighters had body mass index (BMI) and waist circumference (WC) measured in addition to body fat percentage (FM%) by dual-energy x-ray absorptiometry (DXA). CRF as maximum oxygen uptake (VO2max) was estimated by rowing machine and measured by indirect calorimetry in a treadmill exercise test. RESULTS: Fifty two firefighters participated (92.3% men). Univariate correlations with BMI were best with WC. Univariate correlations with VO2max were best with FM%. Obesity classifications by BC measures agreed weakly at best. Multivariate analysis of several variables yielded an improved VO2max estimate (R2 = 0.70). CONCLUSIONS: Fire departments may benefit from more sophisticated measures of BC and CRF to evaluate firefighter fitness.

Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses.

More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.

T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.

Thalidomide and rituximab in Waldenstrom macroglobulinemia.

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie,

Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model.

Enteric 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.

Treatment responses to Azithromycin and Ciprofloxacin in uncomplicated Salmonella Typhi infection: A comparison of Clinical and Microbiological Data from a Controlled Human Infection Model.

BACKGROUND: The 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. METHODS: We 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). FINDINGS: In 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], p<0.001) and prolonged fever clearance times <37.5°C (hazard ratio 2.4 [95%CI: 1.2-5.0]; p = 0.02). Results were consistent when studies were analysed independently and in a sub-group of participants with no history of vaccination or previous challenge. A prolonged treatment response was observed significantly more frequently in the azithromycin group (28/52 [54.9%]) compared with the ciprofloxacin group (1/29 [3.5%]; p<0.001). In participants treated with azithromycin, observed systemic plasma concentrations of azithromycin did not exceed the minimum inhibitory concentration (MIC), whilst predicted intracellular concentrations did exceed the MIC. In participants treated with ciprofloxacin, the observed systemic plasma concentrations and predicted intracellular concentrations of ciprofloxacin exceeded the MIC. INTERPRETATION: Azithromycin 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 REGISTRATION: ClinicalTrials.gov (NCT02324751 and NCT02192008).

Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a.

BACKGROUND: Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. METHODS AND FINDINGS: We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. CONCLUSIONS: Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).

Late measures of brain injury after neonatal hypoxia-ischemia in mice.

BACKGROUND AND PURPOSE: This work was undertaken to determine to what degree long-term neurofunctional outcome of neonatal hypoxic-ischemic (HI) brain injury in mice correlates with anatomical extent of cerebral damage assessed by magnetic resonance imaging (MRI) and histopathology. METHODS: On postnatal day 7, mice were subjected to HI. At 7 to 9 weeks after HI neurofunctional outcome was assessed by water-maze, rota-rod, and open-field test performance, followed by cerebral MRI and histopathology evaluation. RESULTS: At 10 weeks after HI, MRI revealed ipsilateral brain atrophy alone or with porencephalic cyst formation and contralateral ventriculomegaly. Adult HI-affected mice, especially those that developed a porencephalic cyst, demonstrated significant neurofunctional deficit compared with age-matched naïve mice. HI-affected mice with ipsilateral cerebral atrophy but without porencephaly demonstrated no or an intermediate level of neurofunctional deficit. Neurobehavioral assessment of mice subjected to HI insult revealed a strong correlation between degree of brain injury and functional neurohandicap. CONCLUSIONS: This is the first study to demonstrate that long-term neurofunctional outcome in mice after a neonatal HI correlates tightly with anatomical pattern/extent of cerebral damage, defined by MRI and histopathology.

Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice.

BACKGROUND: As a key regulator of serotonergic activity and target of many antidepressant treatments, the serotonin transporter (SERT) represents a potential mediator of anxiety- and depression-related behaviors. Using mice lacking the SERT (SERT KO), we examined the role of SERT function in anxiety- and depression-related behaviors and serotonergic neuron function. METHODS: Serotonin transporter knockout mice were evaluated in paradigms designed to assess anxiety-, depression-, and stress-related behaviors. Dorsal raphe nucleus (DRN) function was assessed by quantitative serotonergic cell counting and extracellular electrical recording of neuronal firing properties. RESULTS: Serotonin transporter knockout mice showed an increase in latency to feed in a novel situation, more immobility in a forced swim, increased escape latency in a shock escape paradigm, and decreased immobility in tail suspension. No differences in anxiety-related behaviors were seen in the open field and the elevated plus maze. Serotonin transporter knockout mice exhibit a 50% reduction in serotonergic cell number and a fourfold decrease in firing rate in the DRN. CONCLUSIONS: Developmental loss of SERT produces altered behaviors in models of depression that are generally opposite to those produced by antidepressant treatment. The reduced serotonergic cell number and firing rate in the DRN of adult SERT KO mice suggest a mechanism for these altered behaviors.