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

This systematic review of population-based studies of the incidence and early (21 days to 1 month) case fatality of stroke is based on studies published from 1970 to 2008. Stroke incidence (incident strokes only) and case fatality from 21 days to 1 month post-stroke were analysed by four decades of study, two country income groups (high-income countries and low to middle income countries, in accordance with the World Bank's country classification) and, when possible, by stroke pathological type: ischaemic stroke, primary intracerebral haemorrhage, and subarachnoid haemorrhage. This Review shows a divergent, statistically significant trend in stroke incidence rates over the past four decades, with a 42% decrease in stroke incidence in high-income countries and a greater than 100% increase in stroke incidence in low to middle income countries. In 2000-08, the overall stroke incidence rates in low to middle income countries have, for the first time, exceeded the level of stroke incidence seen in high-income countries, by 20%. The time to decide whether or not stroke is an issue that should be on the governmental agenda in low to middle income countries has now passed. Now is the time for action.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(09)70025-0.pdf

Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review

Summary Background Since the early 1980s, imaging techniques have enabled population-based studies of intracerebral haemorrhage. We aimed to assess the incidence, case fatality, and functional outcome of intracerebral haemorrhage in relation to age, sex, ethnic origin, and time period in studies published since 1980. Methods From PubMed and Embase searches with predefined inclusion criteria, we identified population-based studies published between January, 1980, and November, 2008. We calculated incidence and case fatality. Incidences for multiple studies were pooled in a random-effects binomial meta-analysis. Time trends of case fatality were assessed with weighted linear-regression analysis. Findings 36 eligible studies described 44 time periods (mid-year range 1983–2006). These studies included 8145 patients with intracerebral haemorrhage. Incidence did not decrease between 1980 and 2008. Overall incidence was 24·6 per 100 000 person-years (95% CI 19·7–30·7). Incidence was not significantly lower in women than in men (overall incidence ratio 0·85, 95% CI 0·61–1·18). Using the age group 45–54 years as reference, incidence ratios increased from 0·10 (95% CI 0·06–0·14) for people aged less than 45 years to 9·6 (6·6–13·9) for people older than 85 years. Median case fatality at 1 month was 40·4% (range 13·1–61·0) and did not decrease over time, and was lower in Japan (16·7%, 95% CI 15·0–18·5) than elsewhere (42·3%, 40·9–43·6). Six studies reported functional outcome, with independency rates of between 12% and 39%. Incidence of intracerebral haemorrhage per 100 000 person-years was 24·2 (95% CI 20·9–28·0) in white people, 22·9 (14·8–35·6) in black people, 19·6 (15·7–24·5) in Hispanic people, and 51·8 (38·8–69·3) in Asian people. Interpretation Incidence of intracerebral haemorrhage increases with age and has not decreased between 1980 and 2006. Case fatality is lower in Japan than elsewhere, increases with age, and has not decreased over time. More data on functional outcome are needed. Funding Netherlands Heart Foundation.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(09)70340-0.pdf

Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)60283-9.pdf

Prediabetes: a high-risk state for diabetes development

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

https://care.diabetesjournals.org/content/diacare/33/10/2285.full.pdf

Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments

Axonal degeneration is an active process that differs from neuronal death, and it is the hallmark of many disorders affecting the central and peripheral nervous system. Starting from the analyses of Wallerian degeneration, the simplest experimental model, here we describe how the long projecting neuronal populations affected in Parkinson’s disease and chemotherapy-induced peripheral neuropathies share commonalities in the mechanisms and molecular players driving the earliest phase of axon degeneration. Indeed, both dopaminergic and sensory neurons are particularly susceptible to alterations of microtubules and axonal transport as well as to dysfunctions of the ubiquitin proteasome system and protein quality control. Finally, we report an updated review on current knowledge of key molecules able to modulate these targets, blocking the on-going axonal degeneration and inducing neuronal regeneration. These molecules might represent good candidates for disease-modifying treatment, which might expand the window of intervention improving patients’ quality of life.

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Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

A case of Ciguatera poisoning with paradoxical dysaesthesia and degenerative features at skin biopsy.

Dear Editor, Multifocal motor neuropathy (MMN) with conduction block is a disorder characterized by slowly progressive asymmetrical weakness of limbs without sensory loss (Lange et al., 1992; Nobile-Orazio et al., 2001). The disorder is considered to be immunomediated, possibly through immunoglobulin M (IgM) antibodies that bind gangliosides on human peripheral nerves (Freddo et al., 1986; Van Asseldonk et al., 2005). We report a patient who developed MMN at the time of discovery of two unrelated tumors, a gastric and a pulmonary adenocarcinoma, and discuss the possibility that in this patient MMN could be a paraneoplastic condition. The patient is a 67-year-old man with a previous history of hypertension, atrial fibrillation, and myocardial infarction. In August 2010, he was admitted to a medical department for a 2-month history of loss of dexterity and grip weakness in left hand, weight loss, hyporexia, and diffuse asthenia. Endoscopy of the stomach and upper gastrointestinal tract revealed a tumor located in the lesser curvature of the gastric angle and biopsied specimens were compatible with gastric adenocarcinoma. Total-body computed tomography disclosed the presence of a right pulmonary mass and bronchoscopy with multiple biopsies suggested the diagnosis of lung adenocarcinoma. In September 2010, the patient underwent gastrectomy. After surgery he complained of distal weakness in left leg, right hand, and worsening of weakness in left hand; however, these symptoms were attributed to cachexia and he was not further investigated. In October 2010, he underwent pulmonary lobectomy, and only after this intervention a neurological consultation was required. Neurological examination showed bilateral distal upper limb weakness (finger and wrist extensors, interossei, and thumb abductor 3/5 Medical Research Council

A case of multifocal motor neuropathy with conduction block associated with gastric and lung adenocarcinoma.

The ability to generate human induced pluripotent stem cell (hiPSC)-derived neural cells displaying region-specific phenotypes is of particular interest for modeling central nervous system (CNS) biology in vitro. We describe a unique method by which spinal cord hiPSC-derived astrocytes (hiPSC-A) are cultured with spinal cord hiPSC-derived motor neurons (hiPSC-MN) in a multielectrode array (MEA) system to record electrophysiological activity over time. We show that hiPSC-A enhance hiPSC-MN electrophysiological maturation in a time-dependent fashion. The sequence of plating, density, and age in which hiPSC-As are co-cultured with MN, but not their respective hiPSC line origin, are factors that influence neuronal electrophysiology. When compared to co-culture with mouse primary spinal cord astrocytes, we observe an earlier and more robust electrophysiological maturation in the fully human cultures, suggesting that the human origin is relevant to the recapitulation of astrocyte/motor neuron cross-talk. Finally, we test pharmacological compounds on our MEA platform and observe changes in electrophysiological activity which confirm hiPSC-MN maturation. These findings are supported by immunocytochemistry and real time PCR studies in parallel cultures demonstrating human astrocyte mediated changes in the structural maturation and protein expression profiles of the neurons. Interestingly, this relationship is reciprocal and co-culture with neurons influences astrocyte maturation as well. Taken together these data indicate that in a human in vitro spinal cord culture system, astrocytes alter hiPSC-MN maturation in a time-dependent and species specific manner and suggest a closer approximation of in vivo conditions.nnMain PointsO_LIWe developed a method for the co-culture of human iPSC-A/MN for multielectrode array recordings.nC_LIO_LIThe morphological, molecular, pharmacological, and electrophysiological characterization of the co-cultures suggests bidirectional maturation.nC_LI

https://www.biorxiv.org/content/biorxiv/early/2019/04/19/614297.full.pdf

Role of human induced pluripotent stem cell-derived spinal cord astrocytes in the functional maturation of motor neurons in a multielectrode array system

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“Morphometry of dermal nerve fibers in human skin”1 is the first comprehensive analysis of nerve fibers in both the dermal and the intraepidermal portions of 3-mm punch biopsies using widely available laboratory techniques. Expanding the analysis of skin biopsies to include dermal as well as intraepidermal regions might allow 1) examination of longer segments of axons in addition to measures of fiber density, 2) expansion of the range of axon types measured, including larger diameter fibers and axons that innervate mechanoreceptors and sweat glands, and 3) comparison of changes in the distal limb extreme axon terminals with those in more proximal regions.

The report provides clear evidence that the assessment of dermal nerve fibers is feasible; it uses …

https://n.neurology.org/content/neurology/77/19/1770.2.full.pdf

Giuseppe Lauria

Papers

Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

A case of Ciguatera poisoning with paradoxical dysaesthesia and degenerative features at skin biopsy.

A case of multifocal motor neuropathy with conduction block associated with gastric and lung adenocarcinoma.

Role of human induced pluripotent stem cell-derived spinal cord astrocytes in the functional maturation of motor neurons in a multielectrode array system

Morphometry of dermal nerve fibers in human skinAuthor Response