Overall, there was no difference in the primary endpoint of days alive without delirium or coma during the intervention period of 14 days (adjusted median 10.7 vs 10.8 days; OR 0.96; 95% CI 0.74 to ...1.26). ...there was no difference between the secondary endpoints of ventilator-free days at 28 days (adjusted median 23.7 vs 24.0 days; OR 0.98; 95% CI 0.63 to 1.51) and death at 90 days (38% vs 39%; HR 1.06; 95% CI 0.74 to 1.52). ...this trial reinforces current sedation guidance. Overall, ICU mortality was 43.3%, as expected this was significantly higher in those with refractory hypoxaemia over first 7 days of their admission (60.4% vs 17.6%; p<0.001). ...the median arterial oxygen pressure/fractional inspired oxygen on the day of death was 12.3 (8.9 to 18.4) kPa, indicating that many patients died with or from refractory hypoxaemia.
Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral ...vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.
Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.
Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.
Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.
UK Vaccine Task Force and National Institute for Health Research.
Glucocorticoids, also known as steroids, are a class of anti-inflammatory drugs utilised widely in clinical practice for a variety of conditions. They are associated with a range of side effects ...including abnormalities of glucose metabolism. Multiple guidelines have been published to illustrate best management of glucocorticoid-induced hyperglycaemia and diabetes in a variety of settings. This article discusses current best clinical practice including diagnosis, investigations and ongoing management of glucocorticoid-induced dysglycaemia in both in- and outpatient settings.
Autism and attention-deficit/hyperactivity disorder (ADHD) often co-occur. This survey of 288 New Zealand parents of children diagnosed with autism (n = 111), ADHD (n = 93), or both conditions (n = ...84), examined the relations between age of diagnosis and early atypical development, the age specialist consultation was needed and types of specialists seen. Co-occurring autism and ADHD was associated with an earlier ADHD diagnosis and a later autism diagnosis. Parents of children with both diagnoses reported less atypical development in language and social behaviours compared to parents of children of autism, and this co-occurring group also experienced longer wait times to diagnosis, and saw more types of specialists prior to a diagnosis, than those with autism.
Early identification and intervention are recognised as important elements of the clinical pathway for autism spectrum disorder (ASD). Children with ASD and attention deficit hyperactivity disorder ...(ADHD) may be diagnosed at a different age than children who only have one of these diagnoses. This systematic review aimed to identify the age at which children were diagnosed with both ASD and ADHD. Of the 9552 articles screened, 12 were included in the review. The findings suggest that ASD is typically diagnosed later when ADHD is present, and ADHD is typically diagnosed earlier when ASD is present. Further research is needed to understand the factors impacting a delayed ASD diagnosis and an earlier ADHD diagnosis when the two conditions co-occur.
Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased ...incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was partially reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals’ USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions.
•Prenatal exposure to valproic acid (VPA) in mice significantly reduces synaptic δ-catenin protein and AMPA receptor levels in the pups' brains.•VPA treatment impairs dendritic branching in cultured neurons, partially reversed by increased δ-catenin expression.•VPA-exposed pups exhibit impaired communication such as ultrasonic vocalization.•Neuronal activation linked to ultrasonic vocalization is absent in VPA-exposed pups.•The loss of δ-catenin functions underlies VPA-induced autism spectrum disorder (ASD) in early childhood.
The hazel dormouse (
Muscardinus avellanarius
) population in the UK continues to decline due to habitat loss, despite reintroductions of captive-bred individuals being conducted nationally for over ...30 years. Disease surveillance of captive-bred and wild dormice is performed to identify novel and existing disease threats which could impact populations. In this study, we firstly investigated cause of death in seven hazel dormice found dead in England, through next-generation sequencing identifying a virus closely related to a wood mouse encephalomyocarditis virus-2 (EMCV-2). Subsequently, lung tissue samples from 35 out of 44 hazel dormice tested positive for EMCV-2 RNA using a reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing methods developed in this study. Formalin-fixed tissues available for nine hazel dormice which tested positive for EMCV-2 RNA were examined microscopically. Three cases showed moderate interstitial pneumonia with minimal to mild lymphoplasmacytic myocarditis, but no evidence of encephalitis. However, the presence of possible alternative causes of death in these cases means that the lesions cannot be definitively attributed to EMCV-2. Here, we report the first detection of EMCV-2 in hazel dormice and conclude that EMCV-2 is likely to be endemic in the hazel dormouse population in England and may be associated with clinical disease.
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