Rift Valley fever is a viral epidemic illness prevalent in Africa that can be fatal or result in debilitating sequelae in humans. No vaccines are available for human use. We aimed to evaluate the ...safety and immunogenicity of a non-replicating simian adenovirus-vectored Rift Valley fever (ChAdOx1 RVF) vaccine in humans.
We conducted a phase 1, first-in-human, open-label, dose-escalation trial in healthy adults aged 18–50 years at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Participants were required to have no serious comorbidities or previous history of receiving an adenovirus-based vaccine before enrolment. Participants were non-randomly allocated to receive a single ChAdOx1 RVF dose of either 5 × 109 virus particles (vp), 2·5 × 1010 vp, or 5 × 1010 vp administered intramuscularly into the deltoid of their non-dominant arm; enrolment was sequential and administration was staggered to allow for safety to be assessed before progression to the next dose. Primary outcome measures were assessment of adverse events and secondary outcome measures were Rift Valley fever neutralising antibody titres, Rift Valley fever GnGc-binding antibody titres (ELISA), and cellular response (ELISpot), analysed in all participants who received a vaccine. This trial is registered with ClinicalTrials.gov (NCT04754776).
Between June 11, 2021, and Jan 13, 2022, 15 volunteers received a single dose of either 5 × 109 vp (n=3), 2·5 × 1010 vp (n=6), or 5 × 1010 vp (n=6) ChAdOx1 RVF. Nine participants were female and six were male. 14 (93%) of 15 participants reported solicited local adverse reactions; injection-site pain was the most frequent (13 87% of 15). Ten (67%) of 15 participants (from the 2·5 × 1010 vp and 5 × 1010 vp groups only) reported systemic symptoms, which were mostly mild in intensity, the most common being headache (nine 60% of 15) and fatigue (seven 47%). All unsolicited adverse events reported within 28 days were either mild or moderate in severity; gastrointestinal symptoms were the most common reaction (at least possibly related to vaccination), occurring in four (27%) of 15 participants. Transient decreases in total white cell, lymphocyte, or neutrophil counts occurred at day 2 in some participants in the intermediate-dose and high-dose groups. Lymphopenia graded as severe occurred in two participants in the 5 × 1010 vp group at a single timepoint, but resolved at the subsequent follow-up visit. No serious adverse events occurred. Rift Valley fever neutralising antibodies were detectable across all dose groups, with all participants in the 5 × 1010 vp dose group having high neutralising antibody titres that peaked at day 28 after vaccination and persisted through the 3-month follow-up. High titres of binding IgG targeting Gc glycoprotein were detected whereas those targeting Gn were comparatively low. IFNγ cellular responses against Rift Valley fever Gn and Gc glycoproteins were observed in all participants except one in the 5 × 1010 vp dose group. These IFNγ responses peaked at 2 weeks after vaccination, were highest in the 5 × 1010 vp dose group, and tended to be more frequent against the Gn glycoprotein.
ChAdOx1 RVF was safe, well tolerated, and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use.
UK Department of Health and Social Care through the UK Vaccines Network, Oak Foundation, and the Wellcome Trust.
For the Swahili translation of the abstract see Supplementary Materials section.
Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of ...traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52–0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18–0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82–0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.
An excess of obstetric complications in the histories of schizophrenic patients is a well-replicated finding, but less consistent results have been found concerning the relationships between ...obstetric complications and family history of schizophrenia, age at onset of schizophrenia, and gender. Small sample size limited the power of previous studies that attempted to assess such relationships. The aim of this study was to use data on individual patients from all available studies to examine the links between a history of obstetric complications and family history of schizophrenia, age at onset, and gender.
Raw data from 854 schizophrenic patients concerning history of obstetric complications rated according to the Lewis and Murray scale were obtained from 11 different research groups. Weighted average estimates were calculated with the use of regression techniques.
A significant association was found between age at onset of schizophrenia and obstetric complications: the earlier the age at onset, the more likely the history of obstetric complications. Subjects with onset of schizophrenia before age 22 were 2.7 times more likely than those with onset at a later age to have had a history of abnormal presentation at birth and 10 times more likely to have had a history of complicated Cesarean birth. No association was found between obstetric complications and family history of schizophrenia or gender.
The association between obstetric complications and early age at onset of schizophrenia indicates that the pathophysiology of early-onset schizophrenia involves neurodevelopmental impairment.
The majority of reward learning neuroimaging studies have not focused on the motivational aspects of behavior, such as the inherent value placed on choice itself. The experience and affective value ...of personal control may have particular relevance for psychiatric disorders, including depression.
We adapted a functional magnetic resonance imaging reward task that probed the value placed on exerting control over one’s decisions, termed choice value, in 122 healthy participants. We examined activation associated with choice value; personally chosen versus passively received rewards; and reinforcement learning metrics, such as prediction error. Relationships were tested between measures of motivational orientation (categorized as autonomy, control, and impersonal) and subclinical depressive symptoms.
Anticipating personal choice activated left insula, cingulate, right inferior frontal cortex, and ventral striatum (pfamilywise error–corrected < .05). Ventral striatal activations to choice were diminished in participants with subclinical depressive symptoms. Personally chosen rewards were associated with greater activation of the insula and inferior frontal gyrus, cingulate cortex, hippocampus, thalamus, and substantia nigra compared with rewards that were passively received. In participants who felt they had little control over their own behavior (impersonal orientation), prediction error signals in nucleus accumbens were stronger during passive trials.
Previous findings regarding personal choice have been verified and advanced through the use of both reinforcement learning models and correlations with psychopathology. Personal choice has an impact on the extended reward network, potentially allowing these clinically important areas to be addressed in ways more relevant to personality styles, self-esteem, and symptoms such as motivational anhedonia.
An analytic mode-matching method suitable for the solution of problems involving scattering in three-dimensional waveguides with flexible walls is presented. Prerequisite to the development of such ...methods is knowledge of closed form analytic expressions for the natural fluid–structure coupled waveforms that propagate in each duct section and the corresponding orthogonality relations. In this article recent theory J.B. Lawrie, Orthogonality relations for fluid–structural waves in a 3-D rectangular duct with flexible walls, Proc. R. Soc. A. 465 (2009) 2347–2367 is extended to construct the non-separable eigenfunctions for acoustic propagation in a three-dimensional rectangular duct with four flexible walls. For the special case in which the duct cross-section is square, the symmetrical nature of the eigenfunctions enables the eigenmodes for a right-angled, isosceles triangular duct with flexible hypotenuse to be deduced. The partial orthogonality relation together with other important properties of the triangular modes are discussed. A mode-matching solution to the scattering of a fluid–structure coupled wave at the junction of two identical semi-infinite ducts of triangular cross-section is demonstrated for two different sets of “junction” conditions.
► Acoustic propagation in a 3D rectangular duct with four flexible walls is considered. ► The phase speeds of the unattenuated modes are plotted. ► The eigenfunctions for a triangular duct with flexible hypotenuse are deduced. ► A mode-matching method suitable for 3D waveguides with flexible walls is demonstrated.
Changes in factor XIII level during pregnancy Sharief, L. T.; Lawrie, A. S.; Mackie, I. J. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
March 2014, Volume:
20, Issue:
2
Journal Article
Peer reviewed
Summary
Pregnancy is associated with significant haemostatic changes, with a progressive rise in most clotting factors. There is limited data on the changes of factor XIII (FXIII) level during ...pregnancy. This study assesses changes in FXIII activity during normal pregnancy and establish FXIII reference range during each trimester of pregnancy and immediate postnatal period. This is a cross sectional study of 376 women with normal uneventful pregnancies. Plasma FXIII activity was measured during first (weeks 0–12, n = 116), second (weeks13–28, n = 132), third trimester (weeks 29–42, n = 128) and postnatal (day 0–3; n = 30). Samples were also collected from non‐pregnant women (n = 25) as a control group. FXIII was assayed on CS‐5100 analyser using chromogenic reagent. The mean ± SD FXIII activity was 112 ± 29 IU dL−1 during first trimester, 96 ± 26 IU dL−1 during second trimester, 83 ± 21 IU dL−1 during third trimester, 90 ± 19 IU dL−1 during postnatal period, and 113 ± 26 IU dL−1 in the control. The reference range was calculated during the first (55–169 IU dL−1), second (45–147 IU dL−1), third trimester (42–125 IU dL−1) and postnatal period (61–137 IU dL−1). There was a significant reduction in the mean FXIII activity during the second and third trimester compared to the first trimester and control group (P < 0.0001). During the immediate postnatal period, the mean FXIII activity was not statistically different compared to the third and second trimester levels but was significantly lower compared to the first trimester (P < 0.0001) level and the control group (P = 0.0002). This study establishes the reference range for FXIII activity during the three trimesters of normal pregnancy and immediate postnatal period. Women have a significantly decreased level of FXIII activity during a normal uneventful pregnancy.
Aim: To determine the constellation of lifestyle and demographic factors that are associated with poor mental health in an adolescent population.
Methods: The Raine Study 14‐year follow‐up involved ...primary care givers and their adolescent children (n= 1860). The Child Behaviour Checklist (CBCL) was used to assess adolescent mental health. We examined diet, socio‐demographic data, family functioning, physical activity, screen use and risk‐taking behaviours with mental health outcomes using linear regression.
Results: Adolescents with higher intakes of meat and meat alternatives and ‘extras’ foods had poorer mental health status. Adverse socio‐economic conditions, higher hours of screen use and ever partaking in the health risk behaviours of smoking and early sexual activity were significantly associated with increasing CBCL scores, indicative of poorer functioning.
Conclusions: By identifying the lifestyle and demographic factors that accompany poorer mental health in early adolescence, we are able to better understand the context of mental health problems as they occur within an adolescent population.
Boron neutron capture therapy (BNCT) is a binary approach for cancer treatment in which boron‐10 atoms and thermal neutrons need to colocalize to become effective. Recent research in the development ...of BNCT drug candidates focuses increasingly on nanomaterials, with the advantages of high boron loadings and passive targeting due to the enhanced permeability and retention (EPR) effect. The use of small boron‐rich gold nanoparticles (AuNPs) in combination with a pretargeting approach is proposed. Small sized polyethylene glycol–stabilized AuNPs (core size 4.1 ± 1.5 nm), are synthesized and functionalized with thiolated cobalt bis(dicarbollide) and tetrazine. To enable in vivo tracking of the AuNPs by positron emission tomography (PET), the core is doped with 64CuCuCl2. For the pretargeting approach, the monoclonal antibody Trastuzumab is functionalized with trans‐cyclooctene‐N‐hydroxysuccinimide ester. After proving in vitro occurrence of the antibody conjugation onto the AuNPs by click reaction and the low toxicity of the AuNPs, the boron delivery system is evaluated in vivo using breast cancer xenograft bearing mice and PET imaging. Tumor uptake due to the EPR effect can be witnessed with ≈5% injected dose (ID) cm−3 at 24 h postinjection, but with slower clearance than expected. Therefore, no increased retention can be observed using the pretargeting strategy.
Small‐sized polyethylene glycol–stabilized gold nanoparticles functionalized with cobalt bis(dicarbollide) and tetrazine are radiolabeled with copper‐64 to enable in vivo tracking using positron emission tomography and evaluated in a mouse model of breast cancer under a pretargeting approach. Tumor uptake is observed, although slow clearance prevents increased retention under pretargeting conditions.
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