Guidance on Dravet Syndrome from Infant to Adult Care: Road Map for Treatment Planning in Europe

Dravet syndrome (DS) is a severe, rare and complex developmental and epileptic encephalopathy affecting 1 in 16'000 live births and characterized by a drug resistant epilepsy, cognitive, psychomotor and language impairment, as well as behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and non-pharmaceutical therapeutic options for this disease. This up-to-date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. Theis guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families

The impact of SARS-CoV-2 vaccination in Dravet Syndrome: A UK survey

Background: The COVID-19 pandemic led to the urgent need for accelerated vaccine development. Approved vaccines have proved to be safe and well tolerated across millions of people in the general population. Dravet Syndrome (DS) is a severe, early onset, developmental and epileptic encephalopathy. Vaccination is a precipitating factor for seizures. Whilst there is no evidence that vaccine-precipitated seizures lead to adverse outcomes in people with DS, fear surrounding vaccination can remain for caregivers of people with DS, in some cases resulting in rejection of recommended vaccinations, leaving individuals more vulnerable to the relevant infections. A greater understanding of the safety profile of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in this vulnerable group will help provide guidance for caregivers and clinicians when considering vaccination. / Methods: A cross‐sectional survey regarding COVID-19 and SARS-CoV-2 vaccine, in people with DS, was conducted by Dravet Syndrome UK (DSUK). Concomitantly, a review of individuals with DS who had recently received the SARS-CoV-2 vaccine, and who are resident at the Chalfont Centre for Epilepsy (CCE), or attend epilepsy clinics at the National Hospital for Neurology and Neurosurgery (NHNN), was undertaken. / Results: 38 people completed the DSUK survey. 37% of caregivers reported being concerned about someone with DS receiving the SARS-CoV-2 vaccine; with some reporting that they would decline a vaccine when offered. 77% had not received any advice from a health care professional about the SARS-CoV-2 vaccination. 18/38 were eligible for SARS-CoV-2 vaccination, of whom nine had received their first vaccine dose. Combining the results of the DSUK survey and the review of individuals monitored at CCE or NHNN, fifteen people with DS had received their first dose of the SARS-CoV-2 vaccine. 11/15 (73%) reported at least one side effect, the most common being fatigue (6/15; 40%) and fever (6/15; 40%). Three individuals (20%) reported an increase in seizure frequency after the first vaccine dose. No increase in seizure frequency or duration was reported after the second dose. / Conclusion: Overall, these results suggest that SARS-CoV-2 vaccines are safe and well tolerated in individuals with DS, as they are in most people without DS. In most people with DS, SARS-CoV-2 vaccine does not appear to be associated with an increase in the frequency or duration of seizures, even in those who develop fever post-vaccination. Many caregivers are concerned about a person with DS receiving a SARS-CoV-2 vaccine, with some reporting that they would decline a SARS-CoV-2 vaccine when offered. It is crucial that healthcare professionals are proactive in providing accurate information regarding the risks and benefits of vaccination in this population, given the potential for serious outcomes from infection

Focal epilepsy in SCN1A-mutation carrying patients: is there a role for epilepsy surgery?

Variants in the gene SCN1A are a common genetic cause for a wide range of epilepsy phenotypes ranging from febrile seizures to Dravet syndrome. Focal onset seizures and structural lesions can be present in these patients and the question arises whether epilepsy surgery should be considered. We report eight patients (mean age 13y 11mo [SD 8y 1mo], range 3–26y; four females, four males) with SCN1A variants, who underwent epilepsy surgery. Outcomes were variable and seemed to be directly related to the patient’s anatomo‐electroclinical epilepsy phenotype. Patients with Dravet syndrome had unfavourable outcomes, whilst patients with focal epilepsy, proven to arise from a single structural lesion, had good results. We conclude that the value of epilepsy surgery in patients with an SCN1A variant rests on two issues: understanding whether the variant is pathogenic and the patient’s anatomo‐electroclinical phenotype. Careful evaluation of epilepsy phenotype integrated with understanding the significance of genetic variants is essential in determining a patient’s suitability for epilepsy surgery. Patients with focal onset epilepsy may benefit from epilepsy surgery, whereas those with Dravet syndrome do not

A pivotal role for starch in the reconfiguration of 14C-partitioning and allocation in Arabidopsis thaliana under short-term abiotic stress.

Plant carbon status is optimized for normal growth but is affected by abiotic stress. Here, we used 14C-labeling to provide the first holistic picture of carbon use changes during short-term osmotic, salinity, and cold stress in Arabidopsis thaliana. This could inform on the early mechanisms plants use to survive adverse environment, which is important for efficient agricultural production. We found that carbon allocation from source to sinks, and partitioning into major metabolite pools in the source leaf, sink leaves and roots showed both conserved and divergent responses to the stresses examined. Carbohydrates changed under all abiotic stresses applied; plants re-partitioned 14C to maintain sugar levels under stress, primarily by reducing 14C into the storage compounds in the source leaf, and decreasing 14C into the pools used for growth processes in the roots. Salinity and cold increased 14C-flux into protein, but as the stress progressed, protein degradation increased to produce amino acids, presumably for osmoprotection. Our work also emphasized that stress regulated the carbon channeled into starch, and its metabolic turnover. These stress-induced changes in starch metabolism and sugar export in the source were partly accompanied by transcriptional alteration in the T6P/SnRK1 regulatory pathway that are normally activated by carbon starvation

Patterns of analgesic use, pain and self-efficacy: a cross-sectional study of patients attending a hospital rheumatology clinic

Background: Many people attending rheumatology clinics use analgesics and non-steroidal anti-inflammatories for persistent musculoskeletal pain. Guidelines for pain management recommend regular and pre-emptive use of analgesics to reduce the impact of pain. Clinical experience indicates that analgesics are often not used in this way. Studies exploring use of analgesics in arthritis have historically measured adherence to such medication. Here we examine patterns of analgesic use and their relationships to pain, self-efficacy and demographic factors. Methods: Consecutive patients were approached in a hospital rheumatology out-patient clinic. Pattern of analgesic use was assessed by response to statements such as 'I always take my tablets every day.' Pain and self-efficacy (SE) were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Arthritis Self-Efficacy Scale (ASES). Influence of factors on pain level and regularity of analgesic use were investigated using linear regression. Differences in pain between those agreeing and disagreeing with statements regarding analgesic use were assessed using t-tests. Results: 218 patients (85% of attendees) completed the study. Six (2.8%) patients reported no current pain, 26 (12.3%) slight, 100 (47.4%) moderate, 62 (29.4%) severe and 17 (8.1%) extreme pain. In multiple linear regression self efficacy and regularity of analgesic use were significant (p < 0.01) with lower self efficacy and more regular use of analgesics associated with more pain. Low SE was associated with greater pain: 40 (41.7%) people with low SE reported severe pain versus 22 (18.3%) people with high SE, p < 0.001. Patients in greater pain were significantly more likely to take analgesics regularly; 13 (77%) of those in extreme pain reported always taking their analgesics every day, versus 9 (35%) in slight pain. Many patients, including 46% of those in severe pain, adjusted analgesic use to current pain level. In simple linear regression, pain was the only variable significantly associated with regularity of analgesic use: higher levels of pain corresponded to more regular analgesic use (p = 0.003). Conclusion: Our study confirms that there is a strong inverse relationship between self-efficacy and pain severity. Analgesics are often used irregularly by people with arthritis, including some reporting severe pain

Acceptability and feasibility of peer assisted supervision and support for intervention practitioners: a Q-methodology evaluation

Evidence-based interventions often include quality improvement methods to support fidelity and improve client outcomes. Clinical supervision is promoted as an effective way of developing practitioner confidence and competence in delivery; however, supervision is often inconsistent and embedded in hierarchical line management structures that may limit the opportunity for reflective learning. The Peer Assisted Supervision and Support (PASS) supervision model uses peer relationships to promote the self-regulatory capacity of practitioners to improve intervention delivery. The aim of the present study was to assess the acceptability and feasibility of PASS amongst parenting intervention practitioners. A Q-methodology approach was used to generate data and 30 practitioners volunteered to participate in the study. Data were analyzed and interpreted using standard Q-methodology procedures and by-person factor analysis yielded three factors. There was consensus that PASS was acceptable. Participants shared the view that PASS facilitated an environment of support where negative aspects of interpersonal relationships that might develop in supervision were not evident. Two factors represented the viewpoint that PASS was also a feasible model of supervision. However, the third factor was comprised of practitioners who reported that PASS could be time consuming and difficult to fit into existing work demands. There were differences across the three factors in the extent to which practitioners considered PASS impacted on their intervention delivery. The findings highlight the importance of organizational mechanisms that support practitioner engagement in supervision

Static stretching of the hamstring muscle for injury prevention in football codes: a systematic review

Purpose: Hamstring injuries are common among football players. There is still disagreement regarding prevention. The aim of this review is to determine whether static stretching reduces hamstring injuries in football codes. Methods: A systematic literature search was conducted on the online databases PubMed, PEDro, Cochrane, Web of Science, Bisp and Clinical Trial register. Study results were presented descriptively and the quality of the studies assessed were based on Cochrane’s ‘risk of bias’ tool. Results: The review identified 35 studies, including four analysis studies. These studies show deficiencies in the quality of study designs. Conclusion: The study protocols are varied in terms of the length of intervention and follow-up. No RCT studies are available, however, RCT studies should be conducted in the near future

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial

Aim: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). Method: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18–70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). Results: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately −0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (−0.03 points; 95% CI −0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; −0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. Conclusion: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches

Atomic Force Microscopy Images Label-Free, Drug Encapsulated Nanoparticles In Vivo and Detects Difference in Tissue Mechanical Properties of Treated and Untreated: A Tip for Nanotoxicology

Overcoming the intractable challenge of imaging of label-free, drug encapsulated nanoparticles in tissues in vivo would directly address associated regulatory concerns over 'nanotoxicology'. Here we demonstrate the utility of Atomic Force Microscopy (AFM) for visualising label-free, drug encapsulated polyester particles of ~280 nm distributed within tissues following their intravenous or peroral administration to rodents. A surprising phenomenon, in which the tissues' mechanical stiffness was directly measured (also by AFM) and related to the number of embedded nanoparticles, was utilised to generate quantitative data sets for nanoparticles localisation. By coupling the normal determination of a drug's pharmacokinetics/pharmacodynamics with post-sacrifice measurement of nanoparticle localisation and number, we present for the first time an experimental design in which a single in vivo study relates the PK/PD of a nanomedicine to its toxicokinetics

Automated Analysis of Cryptococcal Macrophage Parasitism Using GFP-Tagged Cryptococci

The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic immune effector cells, a phenomenon that correlates strongly with virulence in rodent models of infection. Despite the importance of phagocyte/Cryptococcus interactions to disease progression, current methods for assaying virulence in the acrophage system are both time consuming and low throughput. Here, we introduce the first stable and fully characterised GFP–expressing derivatives of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Both strains show unaltered responses to environmental and host stress conditions and no deficiency in virulence in the macrophage model system. In addition, we report the development of a method to effectively and rapidly investigate macrophage parasitism by flow cytometry, a technique that preserves the accuracy of current approaches but offers a four-fold improvement in speed