The impact of COVID-19 on epilepsy care: Perspectives from UK healthcare workers

The COVID-19 pandemic has created an immense pressure on healthcare providers, resulting in a shift to remote consultations and the redeployment of healthcare workers (HCWs). We present survey data from the United Kingdom (UK) HCWs to outline how changes in healthcare provision impact clinicians' wellbeing and ability to provide adequate care. We designed an online survey to gather the experiences of HCWs providing care to people with epilepsy. We received seventy-nine responses from UK-based HCWs, of whom 43% reported an impact on their mental health. Changes to service delivery have resulted in 71% of clinicians performing > 75% of their consultations remotely. Diagnosing and treating epilepsy has changed, with a fifth of respondents being significantly less confident in diagnosing epilepsy. Ultimately, these results show that COVID-19 has had an overall negative impact on HCWs and their ability to provide epilepsy care. These results must be considered when reorganizing health services to ensure optimal outcomes for people with epilepsy

A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease

Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors

Compulsory reduced working time in Belarus: Incidence, operation and consequences

This article examines compulsory reduced working time (CRWT) in five Belarusian factories, to assess its impact on employment relationships and evaluate arguments about ‘Soviet legacies’ and labour ‘patience’. Local use of CRWT increased between 2001 and 2012, and took a form more inimical to worker interests, thereby differing from official macro statistics. Managers expressed discontent at being pushed by state policy to use CRWT, but used it as a disciplinary tool. Workers perceived worsening work relationships and threats of collective response were in evidence. Arguments about ‘Soviet legacies’ and labour’s ‘patience’ therefore currently appear inappropriate

Effect of changes over time in the performance of a customized SAPS-II model on the quality of care assessment

Purpose: The aim of our study was to explore, using an innovative method, the effect of temporal changes in the mortality prediction performance of an existing model on the quality of care assessment. The prognostic model (rSAPS-II) was a recalibrated Simplified Acute Physiology Score-II model developed for very elderly Intensive Care Unit (ICU) patients. Methods: The study population comprised all 12,143 consecutive patients aged 80 years and older admitted between January 2004 and July 2009 to one of the ICUs of 21 Dutch hospitals. The prospective dataset was split into 30 equally sized consecutive subsets. Per subset, we measured the model's discrimination [area under the curve (AUC)], accuracy (Brier score), and standardized mortality ratio (SMR), both without and after repeated recalibration. All performance measures were considered to be stable if 1 without and after repeated recalibration for the year 2009. Results: For all subsets, the AUCs were stable, but the Brier scores and SMRs were not. The SMR was downtrending, achieving levels significantly below 1. Repeated recalibration rendered it stable again. The proportions of hospitals with SMR>1 and SMR <1 changed from 15 versus 85% to 35 versus 65%. Conclusions: Variability over time may markedly vary among different performance measures, and infrequent model recalibration can result in improper assessment of the quality of care in many hospitals. We stress the importance of the timely recalibration and repeated validation of prognostic models over tim

SILAC-based proteomic quantification of chemoattractant-induced cytoskeleton dynamics on a second to minute timescale

Cytoskeletal dynamics during cell behaviours ranging from endocytosis and exocytosis to cell division and movement is controlled by a complex network of signalling pathways, the full details of which are as yet unresolved. Here we show that SILAC-based proteomic methods can be used to characterize the rapid chemoattractant-induced dynamic changes in the actin–myosin cytoskeleton and regulatory elements on a proteome-wide scale with a second to minute timescale resolution. This approach provides novel insights in the ensemble kinetics of key cytoskeletal constituents and association of known and novel identified binding proteins. We validate the proteomic data by detailed microscopy-based analysis of in vivo translocation dynamics for key signalling factors. This rapid large-scale proteomic approach may be applied to other situations where highly dynamic changes in complex cellular compartments are expected to play a key role

Efficient Non-Viral Reprogramming of Myoblasts to Stemness with a Single Small Molecule to Generate Cardiac Progenitor Cells

The current protocols for generation of induced pluripotent stem (iPS) cells involve genome integrating viral vectors which may induce tumorgenesis. The aim of this study was to develop and optimize a non-viral method without genetic manipulation for reprogramming of skeletal myoblasts (SMs) using small molecules

Using knowledge brokers to facilitate the uptake of pediatric measurement tools into clinical practice: a before-after intervention study

<p>Abstract</p> <p>Background</p> <p>The use of measurement tools is an essential part of good evidence-based practice; however, physiotherapists (PTs) are not always confident when selecting, administering, and interpreting these tools. The purpose of this study was to evaluate the impact of a multifaceted knowledge translation intervention, using PTs as knowledge brokers (KBs) to facilitate the use in clinical practice of four evidence-based measurement tools designed to evaluate and understand motor function in children with cerebral palsy (CP). The KB model evaluated in this study was designed to overcome many of the barriers to research transfer identified in the literature.</p> <p>Methods</p> <p>A mixed methods before-after study design was used to evaluate the impact of a six-month KB intervention by 25 KBs on 122 practicing PTs' self-reported knowledge and use of the measurement tools in 28 children's rehabilitation organizations in two regions of Canada. The model was that of PT KBs situated in clinical sites supported by a network of KBs and the research team through a broker to the KBs. Modest financial remuneration to the organizations for the KB time (two hours/week for six months), ongoing resource materials, and personal and intranet support was provided to the KBs. Survey data were collected by questionnaire prior to, immediately following the intervention (six months), and at 12 and 18 months. A mixed effects multinomial logistic regression was used to examine the impact of the intervention over time and by region. The impact of organizational factors was also explored.</p> <p>Results</p> <p>PTs' self-reported knowledge of all four measurement tools increased significantly over the six-month intervention, and reported use of three of the four measurement tools also increased. Changes were sustained 12 months later. Organizational culture for research and supervisor expectations were significantly associated with uptake of only one of the four measurement tools.</p> <p>Conclusions</p> <p>KBs positively influenced PTs' self-reported knowledge and self-reported use of the targeted measurement tools. Further research is warranted to investigate whether this is a feasible, cost-effective model that could be used more broadly in a rehabilitation setting to facilitate the uptake of other measurement tools or evidence-based intervention approaches.</p

Response to gefitinib and erlotinib in Non-small cell lung cancer: a retrospective study

<p>Abstract</p> <p>Background</p> <p>In Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype. Two tyrosine kinase inhibitors (TKIs) of EGFR, gefinitib and erlotinib, have been used with variable benefit.</p> <p>Methods</p> <p>We have analyzed outcome data of a population of NSCLC patients that received these TKIs to determine the benefit derived and to define the clinical and molecular parameters that correlate with response. Tumor tissue from a subgroup of these patients was analyzed by immunohistochemistry to measure the expression level of EGFR and four activated (phosphorylated) members of the pathway, pEGFR, pERK, pAKT, and pSTAT3.</p> <p>Results</p> <p>Erlotinib was slightly superior to gefitinib in all measures of response, although the differences were not statistically significant. The most robust clinical predictors of time to progression (TTP) were best response and rash (p < 0.0001). A higher level of pEGFR was associated with longer TTP, while the total EGFR level was not associated with response. Higher levels of pAKT and pSTAT3 were also associated with longer TTP. In contrast, a higher level of pERK1/2 was associated with shorter TTP.</p> <p>Conclusion</p> <p>These observations suggest the hypothesis that tumor cells that have activated EGFR pathways, presumably being utilized for survival, are clinically relevant targets for pathway inhibition. An accurate molecular predictive model of TKI response should include activated members of the EGFR pathway. TKIs may be best reserved for tumors expressing pEGFR and pAKT or pSTAT, and little pERK. In the absence of molecular predictors of response, the appearance of a rash and a positive first scan are good clinical indicators of response.</p