Prospective Cohort Study

Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

BACKGROUND: More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures. METHODS: We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year. RESULTS: Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent). CONCLUSIONS: Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.

Early Identification of Refractory Epilepsy

Sudden Unexpected Death in Epilepsy (SUDEP) is the commonest cause of epilepsy-related premature mortality in people with chronic epilepsy. It is the most devastating epilepsy outcome. We describe and discuss risk factors and possible pathophysiological mechanisms to elucidate possible preventative strategies to avert SUDEP. Sudden death accounts for a significant proportion of premature mortality in people with epilepsy compared to the general population. Unmodifiable risk factors include a history of neurologic insult, younger age of seizure-onset, longer epilepsy duration, a history of convulsions, symptomatic epilepsy, intellectual disability, and non-ambulatory status. Modifiable risk factors include the presence of convulsive seizures, increased seizure frequency, timely and appropriate use of antiseizure medications, polytherapy, alcoholism, and supervision while sleeping. Pathophysiology is unclear, but several possible mechanisms such as direct alteration of cardiorespiratory function, pulmonary impairment, electrocerebral shutdown, adenosine dysfunction, and genetic susceptibility suggested. Methods to prevent SUDEP include increasing awareness of SUDEP, augmenting knowledge of unmodifiable risk factors, obtaining full seizure remission, addressing lifestyle factors such as supervision and prone positioning, and enacting protocols to increase the detection of and intervention for SUDEP. Further studies are required to characterize precisely and comprehensively SUDEP risk factors and pathophysiological drivers and develop evidence-based algorithms to minimize SUDEP in people with epilepsy.

/pdf/reducing-sudden-unexpected-death-in-epilepsy-considering-4uj8ljqi27.pdf

Reducing Sudden Unexpected Death in Epilepsy: Considering Risk Factors, Pathophysiology and Strategies

Fits, faints and funny turns - the differential diagnosis of epilepsy

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

/pdf/author-correction-zoonotic-and-vector-borne-parasites-and-4zmf2wu6dv.pdf

Author Correction: Zoonotic and vector-borne parasites and epilepsy in low-income and middle-income countries.

Long-term retention and efficacy of levetiracetam in a large cohort of patients with chronic epilepsy

Epilepsy and intellectual disabilities are both relatively common in the general population, each affecting between 0.5% and 1%. Both conditions share a common heritage of heterogeneity, dearth of care expertise outside major centers, and an unfortunate degree of stigmatization.1 They are often comorbid, as up to one-third of people with active epilepsy have an intellectual and developmental disability and up to half of people with a severe intellectual and developmental disability may have a seizure disorder. There is clearly a paucity of authoritative studies on most aspects of this common association and this is particularly true for assessments of effective management.1 This limitation reduces the quality of care of these individuals, and thus their quality of life, also affecting other involved persons, such as families, and, potentially, their careers.

Josemir W. Sander

Papers

Reducing Sudden Unexpected Death in Epilepsy: Considering Risk Factors, Pathophysiology and Strategies

Fits, faints and funny turns - the differential diagnosis of epilepsy

Author Correction: Zoonotic and vector-borne parasites and epilepsy in low-income and middle-income countries.

Long-term retention and efficacy of levetiracetam in a large cohort of patients with chronic epilepsy

Comment: Improving the care of people with epilepsy and intellectual disabilities.