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The recombinant shingles vaccine is associated with lower risk of dementia.
There is emerging evidence that the live herpes zoster (shingles) vaccine might protect against dementia. However, the existing data are limited, and only refer to the live vaccine now discontinued in the USA and many other countries in favour of a recombinant vaccine. Whether the recombinant shingles vaccine protects against dementia remains unknown. Here we used a natural experiment opportunity created by the rapid transition from the use of live to the use of recombinant vaccines to compare the risk of dementia between vaccines. We show that the recombinant vaccine is associated with a significantly lower risk of dementia in the 6 years post-vaccination. Specifically, receiving the recombinant vaccine is associated with a 17% increase in diagnosis-free time, translating into 164 additional days lived without a diagnosis of dementia in those subsequently affected. The recombinant shingles vaccine was also associated with lower risks of dementia compared to two other vaccines commonly used in older people: influenza and tetanus/diphtheria/pertussis vaccines. The effect was robust across multiple secondary analyses, and present in both men and women but greater in women. These findings should stimulate studies investigating the mechanisms underpinning the protection and could facilitate the design of a large-scale randomised control trial to confirm the possible additional benefit of the recombinant shingles vaccine.
Beriberi following sleeve gastrectomy.
Bariatric surgery is being undertaken more frequently in response to rising levels of obesity but is increasingly also requested as a cosmetic choice. Nutritional deficiencies are a recognised consequence of gastrectomy, with potentially severe and permanent neurological sequelae. We present two cases of acute, severe polyneuropathy following sleeve gastrectomy. Severe thiamine deficiency was considered in both cases but with delayed proof and a significant initial differential diagnosis. Neurologists must have a high index of suspicion for the peripheral as well as central presentations of thiamine deficiency to avoid permanent disability. We also call for explicit information resources warning of the risk and signs of thiamine deficiency to be provided routinely to patients after gastrectomy.
Protective effects of medium chain triglyceride diet in a mouse model of Dravet syndrome.
ObjectiveDravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium chain triglyceride (MCT) diet therapy in a mouse model of DS.MethodsScn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4 weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia-induced seizures was also examined. Medium chain fatty acids, and mitochondrial and antioxidant markers were assessed in brain homogenate.ResultsDietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia-induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status.SignificanceThe results from this study indicate that MCT diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.
Small RNAs in the pathogenesis of preeclampsia.
Preeclampsia is a major contributor to maternal and fetal morbidity and mortality. The disorder can be classified into early- and late-onset subtypes, both of which evolve in two stages. The first stage comprises the development of pre-clinical, utero-placental malperfusion. Early and late utero-placental malperfusion have different causes and time courses. Early-onset preeclampsia (20 % of cases) is driven by dysfunctional placentation in the first half of pregnancy. In late-onset preeclampsia (80 % of cases), malperfusion is a consequence of placental compression within the confines of a limited uterine cavity. In both subtypes, the malperfused placenta releases stress signals into the maternal circulation. These stress signals trigger onset of the clinical syndrome (the second stage). Small RNA molecules, which are implicated in cellular stress responses in general, may be involved at different stages. Micro RNAs contribute to abnormal trophoblast invasion, immune dysregulation, angiogenic imbalance, and syncytiotrophoblast-derived extracellular vesicle signalling in preeclampsia. Transfer RNA fragments are placental signals known to be specifically involved in cell stress responses. Disorder-specific differences in small nucleolar RNAs and piwi-interacting RNAs have also been reported. Here, we summarise key small RNA advances in preeclampsia pathogenesis. We propose that existing small RNA classifications are unhelpful and that non-biased assessment of RNA expression, incorporation of non-annotated molecules and consideration of chemical modifications to RNAs may be important in elucidating preeclampsia pathogenesis.
Prevalence of all epilepsies in urban informal settlements in Nairobi, Kenya: a two-stage population-based study.
BACKGROUND: WHO estimates that more than 50 million people worldwide have epilepsy and 80% of cases are in low-income and middle-income countries. Most studies in Africa have focused on active convulsive epilepsy in rural areas, but there are few data in urban settings. We aimed to estimate the prevalence and spatial distribution of all epilepsies in two urban informal settlements in Nairobi, Kenya. METHODS: We did a two-stage population-based cross-sectional study of residents in a demographic surveillance system covering two informal settlements in Nairobi, Kenya (Korogocho and Viwandani). Stage 1 screened all household members using a validated epilepsy screening questionnaire to detect possible cases. In stage 2, those identified with possible seizures and a proportion of those screening negative were invited to local clinics for clinical and neurological assessments by a neurologist. Seizures were classified following the International League Against Epilepsy recommendations. We adjusted for attrition between the two stages using multiple imputations and for sensitivity by dividing estimates by the sensitivity value of the screening tool. Complementary log-log regression was used to assess prevalence differences by participant socio-demographics. FINDINGS: A total of 56 425 individuals were screened during stage 1 (between Sept 17 and Dec 23, 2021) during which 1126 were classified as potential epilepsy cases. A total of 873 were assessed by a neurologist in stage 2 (between April 12 and Aug 6, 2022) during which 528 were confirmed as epilepsy cases. 253 potential cases were not assessed by a neurologist due to attrition. 30 179 (53·5%) of the 56 425 individuals were male and 26 246 (46·5%) were female. The median age was 24 years (IQR 11-35). Attrition-adjusted and sensitivity-adjusted prevalence for all types of epilepsy was 11·9 cases per 1000 people (95% CI 11·0-12·8), convulsive epilepsy was 8·7 cases per 1000 people (8·0-9·6), and non-convulsive epilepsy was 3·2 cases per 1000 people (2·7-3·7). Overall prevalence was highest among separated or divorced individuals at 20·3 cases per 1000 people (95% CI 15·9-24·7), unemployed people at 18·8 cases per 1000 people (16·2-21·4), those with no formal education at 18·5 cases per 1000 people (16·3-20·7), and adolescents aged 13-18 years at 15·2 cases per 1000 people (12·0-18·5). The epilepsy diagnostic gap was 80%. INTERPRETATION: Epilepsy is common in urban informal settlements of Nairobi, with large diagnostic gaps. Targeted interventions are needed to increase early epilepsy detection, particularly among vulnerable groups, to enable prompt treatment and prevention of adverse social consequences. FUNDING: National Institute for Health Research using Official Development Assistance.
A method to isolate syncytiotrophoblast-derived medium-large extracellular vesicle small RNA from maternal plasma.
Syncytiotrophoblast-derived extracellular vesicles (STB-EVs) have an important role in placental research: both as mediators of feto-maternal signalling and as liquid biopsies reflecting placental health. Recent evidence highlights the importance of STB-EV RNA. Isolation of STB-EV RNA from maternal blood is therefore an important challenge. We describe a novel technique where we first separate medium-large particles from plasma using centrifugation then use a highly specific bead-bound antibody to placental alkaline phosphatase to separate STB-EVs from other similar-sized particles. We demonstrate the yield and size profile of small RNA obtained from plasma STB-EVs. We present data confirming isolation of placenta-derived micro RNA from maternal plasma using this method. The technique has been successfully applied to validate novel RNA discoveries from placental perfusion models. We propose it could offer new insights through transcriptomic analyses, providing a syncytiotrophoblast-specific signal from maternal blood.
Maternal serum soluble fms-like tyrosine kinase-1–to–placental growth factor ratio distinguishes growth-restricted from non–growth-restricted small-for-gestational-age fetuses
BACKGROUND: Fetal growth restriction secondary to chronic placental insufficiency is a major cause of perinatal morbidity and mortality. A significant proportion of fetuses with fetal growth restriction are small for gestational age, defined as a birthweight of ≤10th percentile. However, not all small-for-gestational-age fetuses are growth restricted. Some are constitutionally small and otherwise healthy. It is important to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction to ensure appropriate interventions in small-for-gestational-age fetuses with fetal growth restriction and to minimize unnecessary interventions in healthy small-for-gestational-age fetuses. The maternal serum ratio of soluble fms-like tyrosine kinase-1 and placental growth factor is an indicator of placental insufficiency in the latter half of pregnancy. As such, the soluble fms-like tyrosine kinase-1–to–placental growth factor ratio may be a clinically useful tool to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction. OBJECTIVE: This study aimed to determine whether the soluble fms-like tyrosine kinase-1–to–placental growth factor ratio can distinguish between small-for-gestational-age fetuses with and without fetal growth restriction with a birthweight of ≤10th percentile. STUDY DESIGN: A retrospective audit of 233 singleton pregnancies delivering an infant with a birthweight of ≤10th percentile corrected for gestational age with an antenatal maternal serum soluble fms-like tyrosine kinase-1–to–placental growth factor result was performed. Fetal growth restriction was defined as a birthweight of ≤10th percentile with an umbilical artery pulsatility index of >95th percentile, fetal middle cerebral artery pulsatility index of <5th percentile, amniotic fluid index of <6 cm, and/or cerebroplacental ratio of <1st percentile. The soluble fms-like tyrosine kinase-1–to–placental growth factor ratios before delivery between fetuses with and without fetal growth restriction (121 [fetal growth restriction] vs 112 [no fetal growth restriction]) were compared. The Student t test and Fisher exact test were used to compare cases and controls. The Mann-Whitney U test, linear regression analysis, and Spearman correlation coefficient (Rho) were used to examine associations between the soluble fms-like tyrosine kinase-1–to–placental growth factor ratio and fetal outcomes to determine whether the soluble fms-like tyrosine kinase-1–to–placental growth factor ratio served as a prognostic marker of fetal growth restriction severity. RESULTS: The mean soluble fms-like tyrosine kinase-1–to–placental growth factor ratio was increased in fetal growth restriction cases compared with non–fetal growth restriction controls (234.3±25.0 vs 67.4±7.7, respectively; P
A machine learning artefact detection method for single-channel infant event-related potential studies.
Objective Automated detection of artefact in stimulus-evoked electroencephalographic (EEG) data recorded in neonates will improve the reproducibility and speed of analysis in clinical research compared with manual identification of artefact. Some studies use very short, single-channel epochs of EEG data with little recorded EEG per infant - for example because the clinical vulnerability of the infants limits access for recording. Current artefact-detection methods that perform well on adult data and resting-state and multi-channel data in infants are not suitable for this application. The aim of this study was to create and test an automated method of detecting artefact in single-channel 1500 ms epochs of infant EEG. Approach A total of 410 epochs of EEG were used, collected from 160 infants of 28-43 weeks postmenstrual age. This dataset - which was balanced to include epochs of background activity and responses to visual, auditory, tactile and noxious stimuli - was presented to seven independent raters, who independently labelled the epochs according to whether or not they were able to visually identify artefacts. The data was split into a training set (340 epochs) and an independent test set (70 epochs). A random forest model was trained to identify epochs as either artefact or not artefact. Main results This model performs well, achieving a balanced accuracy of 0.81, which is as good as manual review of data. Accuracy was not significantly related to the infant age or type of stimulus. Significance This method provides an objective tool for automated artefact rejection for short epoch, single-channel EEG in neonates and could increase the utility of EEG in neonates in both the clinical and research setting. .
Mechanisms of neurodynamic treatments (MONET): a protocol for a mechanistic, randomised, single-blind controlled trial in patients with carpal tunnel syndrome
Abstract Background Physiotherapeutic management is the first-line intervention for patients with entrapment neuropathies such as carpal tunnel syndrome (CTS). As part of physiotherapy, neurodynamic interventions are often used to treat people with peripheral nerve involvement, but their mechanisms of action are yet to be fully understood. The MONET (mechanisms of neurodynamic treatment) study aims to investigate the mechanisms of action of neurodynamic exercise intervention on nerve structure, and function. Methods This mechanistic, randomised, single-blind, controlled trial will include 78 people with electrodiagnostically confirmed mild or moderate CTS and 30 healthy participants (N = 108). Patients will be randomly assigned into (1) a 6-week progressive home-based neurodynamic exercise intervention (n = 26), (2) a steroid injection (= 26), or (3) advice (n = 26) group. The primary outcome measure is fractional anisotropy of the median nerve at the wrist using advanced magnetic resonance neuroimaging. Secondary outcome measures include neuroimaging markers at the wrist, quantitative sensory testing, electrodiagnostics, and patient reported outcome measures. Exploratory outcomes include neuroimaging markers at the cervical spine, inflammatory and axonal integrity markers in serial blood samples and biopsies of median nerve innervated skin. We will evaluate outcome measures at baseline and at the end of the 6-week intervention period. We will repeat questionnaires at 6-months. Two-way repeated measures ANCOVAs, followed by posthoc testing will be performed to identify differences in outcome measures among groups and over time. Discussion This study will advance our understanding of the mechanisms of action underpinning neurodynamic exercises, which will ultimately help clinicians to better target these treatments to those patients who may benefit from them. The inclusion of a positive control group (steroid injection) and a negative control group (advice) will strengthen the interpretation of our results. Trial registration NCT05859412, 20/4/2023.
Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people.
BACKGROUND: Some studies have shown that the incidence of type 2 diabetes increases after a diagnosis of COVID-19, although the evidence is not conclusive. However, the effects of the COVID-19 vaccine on this association, or the effect on other diabetes subtypes, are not clear. We aimed to investigate the association between COVID-19 and incidence of type 2, type 1, gestational and non-specific diabetes, and the effect of COVID- 19 vaccination, up to 52 weeks after diagnosis. METHODS: In this retrospective cohort study, we investigated the diagnoses of incident diabetes following COVID-19 diagnosis in England in a pre-vaccination, vaccinated, and unvaccinated cohort using linked electronic health records. People alive and aged between 18 years and 110 years, registered with a general practitioner for at least 6 months before baseline, and with available data for sex, region, and area deprivation were included. Those with a previous COVID-19 diagnosis were excluded. We estimated adjusted hazard ratios (aHRs) comparing diabetes incidence after COVID-19 diagnosis with diabetes incidence before or in the absence of COVID-19 up to 102 weeks after diagnosis. Results were stratified by COVID-19 severity (categorised as hospitalised or non-hospitalised) and diabetes type. FINDINGS: 16 669 943 people were included in the pre-vaccination cohort (Jan 1, 2020-Dec 14, 2021), 12 279 669 in the vaccinated cohort, and 3 076 953 in the unvaccinated cohort (both June 1-Dec 14, 2021). In the pre-vaccination cohort, aHRs for the incidence of type 2 diabetes after COVID-19 (compared with before or in the absence of diagnosis) declined from 4·30 (95% CI 4·06-4·55) in weeks 1-4 to 1·24 (1·14-1.35) in weeks 53-102. aHRs were higher in unvaccinated people (8·76 [7·49-10·25]) than in vaccinated people (1·66 [1·50-1·84]) in weeks 1-4 and in patients hospitalised with COVID-19 (pre-vaccination cohort 28·3 [26·2-30·5]) in weeks 1-4 declining to 2·04 [1·72-2·42] in weeks 53-102) than in those who were not hospitalised (1·95 [1·78-2·13] in weeks 1-4 declining to 1·11 [1·01-1·22] in weeks 53-102). Type 2 diabetes persisted for 4 months after COVID-19 in around 60% of those diagnosed. Patterns were similar for type 1 diabetes, although excess incidence did not persist beyond 1 year after a COVID-19 diagnosis. INTERPRETATION: Elevated incidence of type 2 diabetes after COVID-19 is greater, and persists for longer, in people who were hospitalised with COVID-19 than in those who were not, and is markedly less apparent in people who have been vaccinated against COVID-19. Testing for type 2 diabetes after severe COVID-19 and the promotion of vaccination are important tools in addressing this public health problem. FUNDING: UK National Institute for Health and Care Research, UK Research and Innovation (UKRI) Medical Research Council, UKRI Engineering and Physical Sciences Research Council, Health Data Research UK, Diabetes UK, British Heart Foundation, and the Stroke Association.
Cross-sectional experimental assessment of pain modulation as part of multidimensional profiling of people with cervicogenic headache: protocol for a feasibility study.
BACKGROUND: An endogenous pain modulation profile, reflecting antinociceptive and pronociceptive mechanisms, may help to direct management by targeting the involved pain mechanism. For individuals with cervicogenic headache (CeH), the characteristics of such profiles were never investigated. However, the individual nature of experiencing pain demands profiling within a multidimensional framework including psychosocial lifestyle characteristics. The objective of the current protocol is to assess the pain modulation profile, which includes psychosocial lifestyle characteristics among people with CeH. METHODS AND ANALYSIS: A protocol is described to map pain modulation profiles in people with CeH. A cross-sectional non-randomised experimental design will be used to assess feasibility of mapping these profiles. The pain modulation profile is composed based on results on the Depression, Anxiety, Stress Scale, Pittsburgh Sleep Quality Index, Headache Impact Test and on responses to temporal summation of pain (pinprick), conditioned pain modulation and widespread hyperalgesia (mechanical pressure pain threshold and cuff algometry). Primary analyses will report results relating to outcomes on feasibility. Secondary analyses will involve an analysis of proportions (%) of the different psychosocial lifestyle profiles and pain profiles. ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee Research UZ/KU Leuven (Registration number B3222024001434) on 30 May 2024. Results will be published in peer-reviewed journals, at scientific conferences and, through press releases. Protocol V.3. protocol date: 3 June 2024.
Beta and theta oscillations track effort and previous reward in the human basal ganglia and prefrontal cortex during decision making.
Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.