Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, ...may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births 95% confidence interval (CI) 216-263. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251-357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139-233), χ2 odds ratio = 1.7 (95% CI 1.3-2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.
Aberrant activation of the WNT/CTNNB1 pathway is notorious in colorectal cancer (CRC). Here, we demonstrate that the expression of specific and crucial WNT signaling pathway genes is linked to ...disease progression in colonic adenomatous (AP) and hyperplastic (HP) polyps in an Iranian patient population. Thus, we highlight potential gene expression profiles as candidate novel biomarkers for the early detection of CRC. From a 12-month study (2016-2017), 44 biopsy samples were collected during colonoscopy from the patients with colorectal polyps and 10 healthy subjects for normalization. Clinical and demographic data were collected in all cases, and mRNA expression of APC, CTNNB1, CDH1, AXIN1, and AXIN2 genes was investigated using real-time polymerase chain reaction (PCR). CTNNB1 and CDH1 expression levels were unaltered in AP and HP subjects, whereas mRNA expression of APC was decreased in AP contrasted with HP subjects, with a significant association between APC downregulation and polyp size. Although AXIN1 showed no changes between AP and HP groups, a significant association between AXIN1 and dysplasia grade was found. Also, significant upregulation of AXIN2 in both AP and HP subjects was detected. In summary, we have shown increased expression of AXIN2 and decreased expression of APC correlating with grade of dysplasia and polyp size. Hence, AXIN2 and APC should be explored as biomarker candidates for early detection of AP and HP polyps in CRC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PastoCovac is a subunit protein vaccine against COVID-19 which contains the tetanus toxoid as a carrier conjugated to SARS-CoV-2 RBD. The primary goal of the tetanus application was to elicit a ...stronger specific response in the individuals. However, conjugate vaccines have the potency to generate anticarrier antibodies in addition to the target antigen. Therefore, the present study aimed to evaluate the PastoCovac vaccine in the humoral immune induction against tetanus. Six groups of individuals, including those who received one, two, or three doses of the PastoCovac vaccine, Td vaccine, and also the controls who received other COVID-19 vaccines (except PastoCovac), were investigated. The anti-tetanus IgG was assessed by an ELISA assay in all vaccinated groups. The antibody persistency against tetanus in the group who received one dose of the PastoCovac vaccine was also assessed on day 60, 90, and 180 after the last injection. The anti-tetanus antibody titer in the three groups of PastoCovac recipients was positive, though additional doses of the vaccine led to a significant antibody rise (
= 0.003). Notably, the comparison of the mean antibody titer between the Td recipients and those who received one/two doses of PastoCovac showed that the mean rise in the antibody titer before and after the injection was not significant. Although the antibody titer on day 180 decreased to a lower level than on day 21, it was still estimated to be highly positive against tetanus. Eventually, none of the PastoCovac recipients presented vaccine side-effects during the follow-up. The current data indicate that the tetanus conjugate vaccine against COVID-19, PastoCovac, could induce immune responses against tetanus, which can persist for at least 6 months. Combination vaccine formulae containing TT and DT as carriers for conjugate vaccines could be considered instead of TT and/or DT boosters in adults if they are indicated.
Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for ...alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
COVID-19 pandemic has been managed through global vaccination programs. However, the antibody waning in various types of vaccines came to notice. Hereby, PastoCovac Plus as a protein subunit vaccine ...was investigated in immunized health care workers by COVAXIN (BBV152). The booster vaccine was recommended at least three months post the second dose of COVAXIN. Sera collection was done before and after each injection. SARS-CoV-2 PCR test was done monthly to detect any asymptomatic and symptomatic vaccine breakthrough.
47.9 and 24.3% of the participants were seronegative for anti-N and anti-S antibodies three months after the second dose of COVAXIN, respectively. On average, fold-rises of 70, 93, 8 and mean-rises of 23.32, 892.4, 5.59 were recorded regarding neutralizing antibody, quantitative and semi-quantitative anti-Spike antibody, respectively. Anti-Spike and neutralizing antibodies seroconversion was seen 59.3% and 45.7%, respectively. The vaccine breakthrough assessment showed that all the isolated samples belonged to SARS-CoV-2 Delta variant. PastoCovac Plus boosting is strongly recommended in combination with inactivated vaccine platforms against SARS-CoV-2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hypoxaemia is an important predictor of severity in individuals with COVID-19 and can present without symptoms. The COVID Oximetry @home (CO@h) programme was implemented across England in November, ...2020, providing pulse oximeters to higher-risk people with COVID-19 to enable early detection of deterioration and the need for escalation of care. We aimed to describe the clinical and demographic characteristics of individuals enrolled onto the programme and to assess whether there were any inequalities in enrolment.
This retrospective observational study was based on data from a cohort of people resident in England recorded as having a positive COVID-19 test between Oct 1, 2020, and May 3, 2021. The proportion of participants enrolled onto the CO@h programmes in the 7 days before and 28 days after a positive COVID-19 test was calculated for each clinical commissioning group (CCG) in England. Two-level hierarchical multivariable logistic regression with random intercepts for each CCG was run to identify factors predictive of being enrolled onto the CO@h programme.
CO@h programme sites were reported by NHS England as becoming operational between Nov 21 and Dec 31, 2020. 1 227 405 people resident in 72 CCGs had a positive COVID-19 test between the date of programme implementation and May 3, 2021, of whom 19 932 (1·6%) were enrolled onto the CO@h programme. Of those enrolled, 14 441 (72·5%) were aged 50 years or older or were identified as clinically extremely vulnerable (ie, having a high-risk medical condition). Higher odds of enrolment onto the CO@h programme were found in older individuals (adjusted odds ratio 2·21 95% CI 2·19–2·23, p<0·001, for those aged 50–64 years; 3·48 3·33–3·63, p<0·001, for those aged 65–79 years; and 2·50 2·34–2·68, p<0·001, for those aged ≥80 years), in individuals of non-White ethnicity (1·35 1·28–1·43, p<0·001, for Asian individuals; 1·13 1·04–1·22, p=0·005, for Black individuals; and 1·17 1·03–1·32, p=0·015, for those of mixed ethnicity), in those who were overweight (1·31 1·26–1·37, p<0·001) or obese (1·69 1·63–1·77, p<0·001), or in those identified as clinically extremely vulnerable (1·58 1·51–1·65, p<0·001), and lower odds were reported in those from the least socioeconomically deprived areas compared with those from the most socioeconomically deprived areas (0·75 0·69–0·81; p<0·001).
Nationally, uptake of the CO@h programme was low, with clinical judgment used to determine eligibility. Preferential enrolment onto the pulse oximetry monitoring programme was observed in people known to be at the highest risk of developing severe COVID-19.
NHS England, National Institute for Health Research, and The Wellcome Trust.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background and study aims Safety attitudes are linked to patient outcomes. The Joint Advisory Group on Gastrointestinal Endoscopy (JAG) identifies the need to improve our understanding of ...safety culture in endoscopy. We describe the development and validation of the Endo-SAQ (endoscopy safety attitudes questionnaire) and the results of a national survey of staff attitudes.
Methods Questions from the original SAQ were adapted to reflect endoscopy-specific content. This was refined by an expert group, followed by a pilot study to assess acceptability. The refined Endo-SAQ (comprising 35 questions across six domains) was disseminated to endoscopy staff across the UK and Ireland. Outcomes were domain scores and the percentage of positive responses (score ≥75/100) per domain. Descriptive and comparative analyses were performed. Binary logistic regression identified staff and service factors associated with positive scores. Validity and reliability of Endo-SAQ were assessed through psychometric analysis.
Results After expert review, four questions in the preliminary Endo-SAQ were adjusted. Sixty-one participants undertook the pilot study with good acceptability. A total of 453 participants completed the refined Endo-SAQ. There were positive responses in teamwork, safety climate, job satisfaction, and working conditions domains. Endoscopists had significantly more positive responses to stress recognition and working conditions than nursing staff. JAG accreditation was associated with positive scores in safety climate and job satisfaction domains. Endo-SAQ met thresholds of construct validity and reliability.
Conclusions Endoscopy staff had largely positive safety attitudes scores but there were significant differences across domains and staff. There is evidence for the validity and reliability of Endo-SAQ. Endo-SAQ could complement current measures of patient safety in endoscopy and be used in evaluation and research.
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