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Objective:To investigate the mortality risk linked to prescription of different anti-diabetic medication classes.Design:Prospective population-based study.Setting:UK Biobank.Participants:410 389 of the 502 536 participants in UK Biobank with covariate data, clinical and prescription records were included in the analyses, 43 610 of which had been diagnosed type 2 diabetes (T2D). A nearest neighbour covariate matching (NNCM) algorithm based on covariates with relevant effects on survival was applied to match cohorts of anti-diabetic medication class users to minimally differing control cohorts, either with a T2D diagnosis or without. Kaplan Meier estimates and Cox proportional models were used to evaluate survival differences and hazard ratio between drug classes and controls.Main outcome measures:All-cause mortality and causes of death.Results:13667 (3.3%) individuals died during a median of 12.2 years of follow-up. After applying NNCM, participants with T2D on metformin (average hazard ratio 0.39, 95% confidence interval 0.31 to 0.49) or SGLT2I (average hazard ratio 0.58, 95% confidence interval 0.36 to 0.93) have an increased survival probability compared to matched individuals with T2D. When compared to matched individuals without T2D, the survival probability of individuals with T2D increases only if prescribed SGLT2I (average hazard ratio 0.31, 95% confidence interval 0.19 to 0.51). NNCM based analysis of matched individuals with T2D on both SGLT2I and metformin versus metformin only reveals increased survival in the presence of SGLT2I (average hazard ratio 0.29, 95% confidence interval 0.09 to 0.91), also when compared to matched identical individuals without T2D (average hazard ratio 0.05, 95% confidence interval 0.01 to 0.19). All the other anti-diabetic drugs analyzed are either detrimental in prolonging lifespan (insulin, thiazolidinediones, and sulfonylureas), or have no effect (DPP4 inhibitors and GLP1 receptor agonists).Conclusion:The use of the current first-line anti-diabetic treatment, metformin, or sodium glucose cotransporter 2 inhibitors (SGLT2I) increases the survival probability compared to matched individuals with diabetes using other anti-diabetic drugs. Only individuals on SGLT2I experience increased survival when compared to individuals without T2D.

Lithium is a nutritional trace element that is also used pharmacologically for the management of bipolar and related psychiatric disorders. Recent studies have shown that lithium supplementation can extend health and lifespan in different animal models. Moreover, nutritional lithium uptake from drinking water was repeatedly found to be positively correlated with human longevity. By analyzing a large observational aging cohort (UK Biobank, n = 501,461 individuals) along with prescription data derived from the National Health Services (NHS), we here find therapeutic supplementation of lithium linked to decreased mortality (p = 0.0017) of individuals diagnosed with affective disorders. Subsequent multivariate survival analyses reveal lithium to be the strongest factor in regards to increased survival effects (hazard ratio = 0.274 [0.119-0.634 CI 95%, p = 0.0023]), corresponding to 3.641 times lower (95% CI 1.577-8.407) chances of dying at a given age for lithium users compared to users of other anti-psychotic drugs. While these results may further support the use of lithium as a geroprotective supplement, it should be noted that doses applied within the UK Biobank/NHS setting require close supervision by qualified medical professionals., Aging, 15 (2), ISSN:1945-4589

Background Spinal cord injury (SCI) leads to various degrees of lifelong functional deficits. Most individuals with incomplete SCI experience a certain degree of functional recovery, especially within the first-year postinjury. However, this is difficult to predict, and surrogate biomarkers are urgently needed. Objective We aimed to (1) determine if routine blood chemistry parameters are related to neurological recovery after SCI, (2) evaluate if such parameters could predict functional recovery, and (3) establish cutoff values that could inform clinical decision-making. Methods We performed a post hoc analysis of routine blood chemistry parameters in patients with traumatic SCI (n = 676). Blood samples were collected between 24 and 72 hours as well as at 1, 2, 4, 8, and 52 weeks postinjury. Linear mixed models, regression analysis, and unbiased recursive partitioning (URP) of blood chemistry data were used to relate to and predict walking recovery 1 year postinjury. Results The temporal profile of platelet counts and serum levels of albumin, alkaline phosphatase, and creatinine differentiated patients who recovered walking from those who remained wheelchair bound. The 4 blood chemistry parameters from the sample collection 8 weeks postinjury predicted functional recovery observed 1 year after incomplete SCI. Finally, URP defined a cutoff for serum albumin at 3.7 g/dL, which in combination with baseline injury severity differentiates individuals who regain ambulation from those not able to walk. Specifically, about 80% of those with albumin >3.7 g/dL recovered walking. Conclusions Routine blood chemistry data from the postacute phase, together with baseline injury severity, predict functional outcome after incomplete SCI.

The cholinergic system is a complex neurotransmitter system with functional involvement at multiple levels of the nervous system including the cerebral cortex, spinal cord, autonomic nervous system, and neuromuscular junction. Anticholinergic medications are among the most prescribed medications, making up one-third to one-half of all medications prescribed for seniors. Recent evidence has linked long-term use of anticholinergic medications and dementia. Emerging evidence implicates the cholinergic system in the regulation of cerebral vasculature as well as neuroinflammation, suggesting that anticholinergic medications may contribute to absolute risk and progression of neurodegenerative diseases. In this review, we explore the involvement of the cholinergic system in various neurodegenerative diseases and the possible detrimental effects of anticholinergic medications on the onset and progression of these disorders. We identified references by searching the PubMed and Cochrane database between January 1990 and September 2019 for English-language animal and human studies including randomized clinical trials (RCTs), meta-analyses, systematic reviews, and observational studies. In addition, we conducted a manual search of reference lists from retrieved studies. Long-term anticholinergic medication exposure may have detrimental consequences beyond well-documented short-term cognitive effects, through a variety of mechanisms either directly impacting cholinergic neurotransmission or through receptors expressed on the vasculature or immune cells, providing a pathophysiological framework for complex interactions across the entire neuroaxis.

The use of observational data to assess drug effectiveness and safety can provide relevant information, much of which may not be feasible to obtain through randomized clinical trials. Because observational studies provide critical drug safety and effectiveness information that influences drug policy and prescribing practices, transparent, consistent, and accurate reporting of these studies is critical.We provide recommendations to extend existing reporting guidelines, covering the main components of primary research studies (methods, results, discussion).Our recommendations include extending drug safety and effectiveness guidelines to include explicit checklist items on: study registration, causal diagrams, rationale for measures of effect, comprehensive assessment of bias, comprehensive data cleaning steps, drug equivalents, subject-level drug data visualization, sex and gender-based analyses and results, patient-oriented outcomes, and patient involvement in research.

Background The matrix assisted laser desorption/ionization and time-of-flight mass spectrometry (MALDI-TOF MS) technology has revolutionized the field of microbiology by facilitating precise and rapid species identification. Recently, machine learning techniques have been leveraged to maximally exploit the information contained in MALDI-TOF MS, with the ultimate goal to refine species identification and streamline antimicrobial resistance determination. Objectives The aim was to systematically review and evaluate studies employing machine learning for the analysis of MALDI-TOF mass spectra. Data sources Using PubMed/Medline, Scopus and Web of Science, we searched the existing literature for machine learning-supported applications of MALDI-TOF mass spectra for microbial species and antimicrobial susceptibility identification. Study eligibility criteria Original research studies using machine learning to exploit MALDI-TOF mass spectra for microbial specie and antimicrobial susceptibility identification were included. Studies focusing on single proteins and peptides, case studies and review articles were excluded. Methods A systematic review according to the PRISMA guidelines was performed and a quality assessment of the machine learning models conducted. Results From the 36 studies that met our inclusion criteria, 27 employed machine learning for species identification and nine for antimicrobial susceptibility testing. Support Vector Machines, Genetic Algorithms, Artificial Neural Networks and Quick Classifiers were the most frequently used machine learning algorithms. The quality of the studies ranged between poor and very good. The majority of the studies reported how to interpret the predictors (88.89%) and suggested possible clinical applications of the developed algorithm (100%), but only four studies (11.11%) validated machine learning algorithms on external datasets. Conclusions A growing number of studies utilize machine learning to optimize the analysis of MALDI-TOF mass spectra. This review, however, demonstrates that there are certain shortcomings of current machine learning-supported approaches that have to be addressed to make them widely available and incorporated them in the clinical routine., Clinical Microbiology and Infection, 26 (10), ISSN:1470-9465, ISSN:1198-743X

ObjectiveTo explore the hypothesis that earlier administration of acute gabapentinoids is beneficial to motor recovery after spinal cord injury in humans.MethodsThis is an observational study using a cohort from the European Multi-Centre Study about Spinal Cord Injury. Patient charts were reviewed to extract information regarding the administration and timing of gabapentinoid anticonvulsants. The primary outcome measure was motor scores, as measured by the International Standards for Neurological Classification of Spinal Cord Injury, collected longitudinally in the first year after injury. Sensory scores (light touch and pinprick) and functional measures (Spinal Cord Independence Measure) were secondary outcomes. Linear mixed effects regression models included a drug-by-time interaction to determine whether exposure to gabapentinoids altered recovery of muscle strength in the first year after injury.ResultsA total of 201 participants were included in the study and had a median age of 46 and baseline motor score of 50. Participants were mostly men (85%) with sensory and motor complete injuries (50%). Seventy individuals (35%) were administered gabapentinoids within the first 30 days after injury, and presented with similar demographics. In the longitudinal model, the administration of gabapentinoids within 30 days after injury was associated with improved motor recovery when compared to those who did not receive gabapentinoids during this time (3.69 additional motor points from 4 to 48 weeks after injury; p = 0.03). This effect size increased as administration occurred earlier after injury (i.e., a benefit of 4.68 points when administered within 5 days).ConclusionsThis retrospective, observational study provided evidence of the beneficial effect of gabapentinoid anticonvulsants on motor recovery after spinal cord injury. More critically, it highlighted a potential time dependence, suggesting that earlier intervention is associated with better outcomes.Classification of evidence:This study provides Class IV evidence that gabapentinoids improve motor recovery for individuals with acute spinal cord injury.

Objective Descending pain modulation can be experimentally assessed by way of testing conditioned pain modulation. The application of tonic heat as a test stimulus in such paradigms offers the possibility of observing dynamic pain responses, such as adaptation and temporal summation of pain. Here we investigated conditioned pain modulation effects on tonic heat employing participant-controlled temperature, an alternative tonic heat pain assessment. Changes in pain perception are thereby represented by temperature adjustments performed by the participant, uncoupling this approach from direct pain ratings. Participant-controlled temperature has emerged as a reliable and sex-independent measure of tonic heat. Methods Thirty healthy subjects underwent a sequential conditioned pain modulation paradigm, in which a cold water bath was applied as the conditioning stimulus and tonic heat as a test stimulus. Subjects were instructed to change the temperature of the thermode in response to variations in perception to tonic heat in order to maintain their initial rating over a two-minute period. Two additional test stimuli (i.e., lower limb noxious withdrawal reflex and pressure pain threshold) were included as positive controls for conditioned pain modulation effects. Results Participant-controlled temperature revealed conditioned pain modulation effects on temporal summation of pain (P = 0.01). Increased noxious withdrawal reflex thresholds (P = 0.004) and pressure pain thresholds (P Conclusions The measured interaction between conditioned pain modulation and temporal summation of pain supports the participant-controlled temperature approach as a promising method to explore dynamic inhibitory and facilitatory pain processes previously undetected by rating-based approaches.

Coronavirus disease 2019 (COVID-19) can lead to considerable lung damage and even death. Less is known about the effects of COVID-19 on the cardiovascular system. In their recent JAMA Cardiology article, Shi and colleagues reported an association between cardiac injury and higher risk of in-hospital mortality in patients with COVID-19. Approximately 20% (82 patients) of the study cohort presented with a cardiac injury. The investigators identified cardiac injury as an independent risk factor of mortality during hospitalization (52% with cardiac injury vs. 5% without cardiac injury, p

Background Temporal changes of pain perception to prolonged tonic heat pain are conventionally assessed using a computerized visual analog scale. Such a rating-based approach is, however, prone to floor and ceiling effects, which limit the assessment of temporal changes in perception. Thus, alternative methods that overcome these shortcomings are warranted. New method The aim of this study was to assess the feasibility and reliability of a psychophysical approach, i.e., participant-controlled temperature (PCT), to evaluate ongoing human perception of tonic heat pain. Fifty participants were presented with a 45 °C stimulus on the non-dominant hand, and were instructed to maintain their initial sensation for two minutes via a feedback controller in the dominant hand. A subset of participants (n = 17) performed PCT tonic heat protocols on two different days to determine the test-retest reliability. As participants controlled temperature to maintain a stable pain perception, any adjustments made reflected shifts in their perception of heat. Results In 33 (71.7%) participants, we observed an initial adaptation (participant increased temperature) followed by temporal summation of pain (participant decreased temperature). Twelve participants (26.1%) showed only adaptation and one (2.2%) only temporal summation. No sex differences were observed, nor did the initial rating of pain have an effect on PCT outcomes. Temporal summation of pain showed moderate to substantial reliability upon retest. Conclusions PCT represents can be reliably performed using a contact heat stimulator to measure the temporal summation of pain. The standardized setup and overall good reliability of the outcome measures facilitate a sound implementation into the clinical work-up of patients with pain conditions.

Recent temporal trends in the population prevalence of chronic pain in Canada on a national and provincial level are unknown. Five cycles of the Canadian Community Health Survey (2000/2001, 2007/2008, 2009/2010, 2011/2012, and 2013/2014) were used to derive population-based estimates of the self-reported prevalence of chronic pain. Sensitivity analyses examined chronic pain prevalence among those reporting no other chronic health conditions. The prevalence of chronic pain among the general Canadian population increased by almost 4.0% (to 21.0%) in 2011/2012, after being in the range of 15.7 to 17.2% from 2000 to 2009/2010. The sudden increase in prevalence was observed 1) across all provinces in Canada, 2) in all age categories, and 3) among Canadians with no other chronic health conditions. Increasing chronic pain prevalence in Canada, most significantly occurring between 2010 and 2012, and including among healthy and young individuals, emphasizes the need for targeted research and resources to help alleviate chronic pain. PERSPECTIVE: This study uncovers a significant increase in chronic pain prevalence in Canada between 2009/2010 and 2011/2012, driven by younger Canadians that are free of the most common chronic health conditions. This discovery emphasizes the importance of further directed research and resources to help mitigate the trend of increasing chronic pain.

The objective of our study was to determine whether treatment with baclofen is neurologically safe with respect to exposure during recovery from spinal cord injury. We performed a secondary longitudinal analysis of a cohort of adult patients with traumatic acute spinal cord injury. Cumulative baclofen dose was computed over the first 4 weeks following injury from concomitant medication information from a completed clinical trial. The main outcome measure was neurologic status, which was assessed over 52 weeks with "marked recovery" defined as the conversion to higher sensory and motor function. To complete the drug safety profile, drug toxicity was assessed with assays from standard blood work. Multivariable Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the cohort (n = 651), 18% (n = 115) received baclofen within 4 weeks post injury. Baclofen use was associated with higher rates of marked neurologic recovery, even after adjustment for injury severity (HR = 2.1, 95% CI 1.5-3.0 for high dose vs none). Baclofen exposure was not associated with liver or renal side effects. The use of other medications indicated for spasticity was not associated with neurological outcomes. Overall, this longitudinal analysis provides level 3 evidence on the neurologic safety of baclofen and potential beneficial effects on recovery in the early days after acute traumatic spinal cord injury. The usefulness of concomitant medication files from completed clinical trials is highlighted. We also highlight the importance of incorporating logical patient questions and neurological outcomes into research addressing drug safety.

Objective The objective was to track and compare the progression of neuroplastic changes in a large animal model and humans with spinal cord injury. Methods A total of 37 individuals with acute traumatic spinal cord injury were followed over time (1, 3, 6, and 12 months post‐injury) with repeated neurophysiological assessments. Somatosensory and motor evoked potentials were recorded in the upper extremities above the level of injury. In a reverse‐translational approach, similar neurophysiological techniques were examined in a porcine model of thoracic spinal cord injury. Twelve Yucatan mini‐pigs underwent a contusive spinal cord injury at T10 and tracked with somatosensory and motor evoked potentials assessments in the fore‐ and hind limbs pre‐ (baseline, post‐laminectomy) and post‐injury (10 min, 3 h, 12 weeks). Results In both humans and pigs, the sensory responses in the cranial coordinates of upper extremities/forelimbs progressively increased from immediately post‐injury to later time points. Motor responses in the forelimbs increased immediately after experimental injury in pigs, remaining elevated at 12 weeks. In humans, motor evoked potentials were significantly higher at 1‐month (and remained so at 1 year) compared to normative values. Conclusions Despite notable differences between experimental models and the human condition, the brain's response to spinal cord injury is remarkably similar between humans and pigs. Our findings further underscore the utility of this large animal model in translational spinal cord injury research.

BackgroundNearly every individual sustaining traumatic spinal cord injury receives multiple types and classes of medications to manage a litany of secondary complications. Prior clinical studies and evidence from animal models suggest that several of these medications could enhance or impede endogenous neurological recovery. However, there is a knowledge gap surrounding the spectrum of pharmacologic agents typically administered in the routine management of spinal cord injury.ObjectiveTo systematically determine the types of medications commonly administered, alone or in combination, in the acute to subacute phase of spinal cord injury.MethodsWe conducted an analysis of two largescale cohorts (the Sygen interventional trial and the SCIRehab observational cohort study) to determine what constitutes “ standards of acute pharmacological care” after spinal cord injury. Concomitant medication use, including dosage, timing and reason for administration, was tracked. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury.ResultsAcross 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in the Sygen trial received 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Patients enrolled in the SCIRehab cohort study received on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections).ConclusionsTo our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, with potential to both positively and negatively impact neurological recovery. This data may provide key insight to achieve better understanding of how the acute pharmacological management of spinal cord injury affects long-term recovery. All results can be interactively explored on theRXSCIweb site (https://jutzelec.shinyapps.io/RxSCI/) and GitHub repository (https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/).

Our objective was to track and quantify the natural course of serological markers over the 1st year following spinal cord injury. For that purpose, data on serological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau study). The primary outcomes were concentration/levels/amount of commonly collected serological markers at multiple time points. Two-way analysis of variance (ANOVA) and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of serological markers contained in both data sources were compared using the slope of progression. Our results show that, at baseline (≤ 2 weeks post-injury), most serological markers were at pathological levels, but returned to normal values over the course of 6–12 months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g., hematocrit, ANOVA test; χ2 = 68.93, df = 3, adjusted p value

Background and ObjectivesTo explore the so-called structure-function paradox in individuals with focal spinal lesions by means of tract-specific MRI coupled with multimodal evoked potentials and quantitative sensory testing.MethodsIndividuals with signs and symptoms attributable to cervical myelopathy (i.e., no evidence of competing neurologic diagnoses) were recruited at the Balgrist University Hospital, Zurich, Switzerland, between February 2018 and March 2019. We evaluated the relationship between the extent of structural damage within spinal nociceptive pathways (i.e., dorsal horn, spinothalamic tract, anterior commissure) assessed with atlas-based MRI and (1) the functional integrity of spinal nociceptive pathways measured with contact heat–, cold-, and pinprick-evoked potentials and (2) clinical somatosensory phenotypes assessed with quantitative sensory testing.ResultsSixteen individuals (mean age 61 years) with either degenerative (n = 13) or posttraumatic (n = 3) cervical myelopathy participated in the study. Most individuals presented with mild myelopathy (modified Japanese Orthopaedic Association score >15; n = 13). A total of 71% of individuals presented with structural damage within spinal nociceptive pathways on MRI. However, 50% of these individuals presented with complete functional sparing (i.e., normal contact heat–, cold-, and pinprick-evoked potentials). The extent of structural damage within spinal nociceptive pathways was not associated with functional integrity of thermal (heat: p = 0.57; cold: p = 0.49) and mechano-nociceptive pathways (p = 0.83) or with the clinical somatosensory phenotype (heat: p = 0.16; cold: p = 0.37; mechanical: p = 0.73). The amount of structural damage to the spinothalamic tract did not correlate with spinothalamic conduction velocity (p > 0.05; ρ = −0.11).DiscussionOur findings provide neurophysiologic evidence to substantiate that structural damage in the spinal cord does not equate to functional somatosensory deficits. This study recognizes the pronounced structure-function paradox in cervical myelopathies and underlines the inevitable need for a multimodal phenotyping approach to reveal the eloquence of lesions within somatosensory pathways.

ObjectiveTo track and quantify the natural course of hematological markers over the first year following spinal cord injury.MethodsData on hematological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau Study). The primary outcomes were concentration/levels/amount of commonly collected hematological markers at multiple time-points. Two-way ANOVA and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of hematological markers contained in both data sources were compared using the slope of progression.ResultsAt baseline (≤ 2 weeks post-injury), most hematological markers were at pathological levels, but returned to normal values over the course of six to twelve months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g. hematocrit, ANOVA test; Chisq = 77.10, df = 3, adjusted p-valueConclusionsDue to trauma-induced physiological perturbations, hematological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance website (https://jutzelec.shinyapps.io/Haemosurveillance/).Code availabilityhttps://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury

This was a secondary analysis on an observational cohort study. To determine if serum albumin significantly associates with long-term neurological outcome (i.e., 1-year post-injury) in a contemporary cohort of individuals with spinal cord injury. Six rehabilitation centers across the United States. A secondary analysis of neurological outcomes and serum albumin concentrations was performed on data from the Spinal Cord Injury Rehabilitation study. Data was accessed from the Archive of Data on Disability to Enable Policy and research (ADDEP). The primary analysis applied unbiased recursive partitioning to examine the relationship between serum albumin, injury severity, and long-term outcomes. The analysis is accessible via https://rpubs.com/AnhKhoaVo/586028 . Serum albumin concentration was significantly associated with lower extremity motor scores (LEMS) and American Spinal Injury Association Impairment Scale (AIS) grade at admission to rehabilitation. Serum albumin concentrations alone were also significantly associated with change of LEMS and marked recovery (improvement of at least 2 AIS grades and/or recovery to walking) at 1-year post injury. However, after adjusting for admission to rehabilitation LEMS and AIS grade, serum albumin was not significant. The current study partially confirms our previous observations that serum albumin concentrations are associated with neurological outcome after spinal cord injury. As a crude prognostic biomarker, serum albumin concentration could be useful in cases where injury severity cannot be accurately assessed.

Previous studies comparing laser (LEPs) and contact heat evoked potentials (CHEPs) consistently reported higher amplitudes following laser compared to contact heat stimulation. However, none of the studies matched the perceived pain intensity, questioning if the observed difference in amplitude is due to biophysical differences between the two methods or a mismatch in stimulation intensity. The aims of the current study were twofold: (1) to directly compare the brain potentials induced by intensity matched laser and contact heat stimulation and (2) investigate how capsaicin-induced secondary hyperalgesia modulates LEPs and CHEPs. Twenty-one healthy subjects were recruited and measured at four experimental sessions: (1) CHEPs + sham, (2) LEPs + sham, (3) CHEPs + capsaicin, and (4) LEPs + capsaicin. Baseline (sham) LEPs latency was significantly shorter and amplitude significantly larger compared to CHEPs, even when matched for perceived pain. Neither CHEPs nor LEPs was sensitive enough to detect secondary hyperalgesia. These differences provide evidence that a faster heating rate results in an earlier and more synchronized LEPs than CHEPs. To our knowledge, this was the first study to match perceived intensity of contact heat and laser stimulations, revealing distinct advantages associated with the acquisition of LEPs., Scientific Reports, 11 (1), ISSN:2045-2322

Background Neuropathic pain is a major problem following spinal cord injury (SCI). Central mechanisms involved in the modulation of nociceptive signals have been shown to be altered at the chronic stage, and it has been hypothesized that they might play a role in the development of chronic pain. Objective This prospective longitudinal study aimed to describe the evolution of pain modulation mechanisms over time after SCI, and to explore the relationships with the presence of clinical (neuropathic and musculoskeletal) pain. Methods Patients with an SCI were assessed on admission (n = 35; average of 38 days postinjury) and discharge (n = 25; average of 131 days postinjury) using the International Spinal Cord Injury Pain Basic Data Set. Conditioned pain modulation was assessed using the cold pressor test (10 °C; 120 s) as the conditioning stimulus and tonic heat pain, applied above the level of injury, as the test stimulus (120 s). Heat pain threshold was also assessed. Results A marked decrease in the efficacy of conditioned pain modulation was observed over time, with 30.2% of inhibition at admission and only 12.9% at discharge on average ( P = .010). This decrease was observed only in patients already suffering from neuropathic pain at admission and was not explained by a general increase in sensitivity to thermal nociceptive stimuli. Conclusion These results suggest that the presence of neuropathic pain leads to a decrease in conditioned pain modulation over time, rather than supporting the hypothesis that inefficient conditioned pain modulation mechanisms are leading to the development of neuropathic pain.

With the biomedical field generating large quantities of time series data, there has been a growing interest in developing and refining machine learning methods that allow its mining and exploitation. Classification is one of the most important and challenging machine learning tasks related to time series. Many biomedical phenomena, such as the brain's activity or blood pressure, change over time. The objective of this chapter is to provide a gentle introduction to time series classification. In the first part we describe the characteristics of time series data and challenges in its analysis. The second part provides an overview of common machine learning methods used for time series classification. A real-world use case, the early recognition of sepsis, demonstrates the applicability of the methods discussed.

With the biomedical field generating large quantities of time series data, there has been a growing interest in developing and refining machine learning methods that allow its mining and exploitation. Classification is one of the most important and challenging machine learning tasks related to time series. Many biomedical phenomena, such as the brain's activity or blood pressure, change over time. The objective of this chapter is to provide a gentle introduction to time series classification. In the first part we describe the characteristics of time series data and challenges in its analysis. The second part provides an overview of common machine learning methods used for time series classification. A real-world use case, the early recognition of sepsis, demonstrates the applicability of the methods discussed.

Introduction Since December 2019, a novel coronavirus (SARS-CoV-2) has triggered a world-wide pandemic with an enormous medical and societal-economic toll. Thus, our aim was to gather all available information regarding comorbidities, clinical signs and symptoms, outcomes, laboratory findings, imaging features, and treatments in patients with coronavirus disease 2019 (COVID-19). Methods EMBASE, PubMed/Medline, Scopus, and Web of Science were searched for studies published in any language between December 1st, 2019 and March 28th, 2020. Original studies were included if the exposure of interest was an infection with SARS-CoV-2 or confirmed COVID-19. The primary outcome was the risk ratio of comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatments, outcomes, and complications associated with COVID-19 morbidity and mortality. We performed random-effects pairwise meta-analyses for proportions and relative risks, I2, T2, and Cochrane Q, sensitivity analyses, and assessed publication bias. Results 148 studies met the inclusion criteria for the systematic review and meta-analysis with 12′149 patients (5′739 female) and a median age of 47.0 [35.0–64.6] years. 617 patients died from COVID-19 and its complication. 297 patients were reported as asymptomatic. Older age (SMD: 1.25 [0.78–1.72]; p < 0.001), being male (RR = 1.32 [1.13–1.54], p = 0.005) and pre-existing comorbidity (RR = 1.69 [1.48–1.94]; p < 0.001) were identified as risk factors of in-hospital mortality. The heterogeneity between studies varied substantially (I2; range: 1.5–98.2%). Publication bias was only found in eight studies (Egger's test: p < 0.05). Conclusions Our meta-analyses revealed important risk factors that are associated with severity and mortality of COVID-19.

Background. Given individuals with spinal cord injury (SCI) approaching 2 million, viable options for regenerative repair are desperately needed. Human central nervous system stem cells (HuCNS-SC) are self-renewing, multipotent adult stem cells that engraft, migrate, and differentiate in appropriate regions in multiple animal models of injured brain and spinal cord. Preclinical improved SCI locomotor function provided rationale for the first-in-human SCI clinical trial of HuCNS-SC cells. Evidence of feasibility and long-term safety of cell transplantation into damaged human cord is needed to foster translational progression of cellular therapies. Methods. A first-ever, multisite phase I/IIa trial involving surgical transplantation of 20 million HuCNS-SC cells into the thoracic cord in 12 AIS A or B subjects (traumatic, T2-T11 motor-complete, sensory-incomplete), aged 19 to 53 years, demonstrated safety and preliminary efficacy. Six-year follow-up data were collected (sensory thresholds and neuroimaging augmenting clinical assessments). Findings. The study revealed short- and long-term surgical and medical safety (well-tolerated immunosuppression in population susceptible to infections). Preliminary efficacy measures identified 5/12 with reliable sensory improvements. Unfortunately, without thoracic muscles available for manual muscle examination, thoracic motor changes could not be measured. Lower limb motor scores did not change during the study. Cervical cord imaging revealed, no tumor formation or malformation of the lesion area, and secondary supralesional structural changes similar to SCI control subjects. Interpretation. Short- and long-term safety and feasibility support the consideration of cell transplantation for patients with complete and incomplete SCI. This report is an important step to prepare, foster, and maintain the therapeutic development of cell transplantation for human SCI.

Spinal cord injury results in devastating neurological deficits accompanied by lifelong disability and significant economic burden. While the development of novel compounds or cell-based interventions for spinal cord injury is unquestionably worthwhile, a complementary approach examines current standards of care and the degree to which these can be optimized to benefit long-term neurological function. Numerous classes of drugs, already in use in the acute phase of spinal cord injury, are intriguing because they (1) readily cross the blood-spinal cord barrier to modulate activity in the central nervous system and (2) are administered during a window of time in which neuroprotection, and even some repair, are feasible. Here, we review a rare case of convergent lines of evidence from both preclinical and human studies to support the early administration of a class of drug (ie, gabapentinoids) to both foster motor recovery and reduce the severity of neuropathic pain.

The pursuit of a physiological indicator of noxious stimulation is desirable as it has the potential to provide mechanistic information regarding acute pain and may ultimately improve pain management strategies. Currently, there are no specific neurophysiological markers of pain to evaluate treatments. Recent attempts to identify neural correlates of pain have focused on different neuroimaging modalities. The purpose of this review is to discuss common neuroimaging techniques and findings thus far.

Background. There is a need to identify reliable biomarkers of spinal cord injury recovery for clinical practice and clinical trials. Objective. Our objective was to correlate serum albumin levels with spinal cord injury neurological outcomes. Methods. We performed a secondary analysis of patients with traumatic spinal cord injury (n = 591) participating in the Sygen clinical trial. Serum albumin concentrations were obtained as part of routine blood chemistry analysis, at trial entry (24-72 hours), 1, 2, and 4 weeks after injury. The primary outcomes were “marked recovery” and lower extremity motor scores, derived from the International Standards for the Neurological Classification of Spinal Cord Injury. Data were analyzed with multivariable logistic and linear regression to adjust for potential confounders. Results. Serum albumin was significantly associated with spinal cord injury neurological outcomes. Higher serum albumin concentrations at 1, 2, and 4 weeks were associated with higher 52-week lower extremity motor score. Similarly, the odds of achieving “marked neurological recovery” was greater for individuals with higher serum albumin concentrations. The association between serum albumin concentrations and neurological outcomes was independent of initial injury severity, treatment with GM-1, and polytrauma. Conclusions. In spinal cord injury, serum albumin is an independent marker of long-term neurological outcomes. Serum albumin could serve as a feasible biomarker for prognosis at the time of injury and stratification in clinical trials.

The anticonvulsant pregabalin promotes neural regeneration in a mouse model of spinal cord injury (SCI). We have also previously observed that anticonvulsants improve motor outcomes following human SCI. The present study examined the optimal timing and type of anticonvulsants administered in a large, prospective, multi-center, cohort study in acute SCI. Mixed-effects regression techniques were used to model total motor scores at 1, 3, 6, and 12 months post injury. We found that early (not late) administration of anticonvulsants significantly improved motor recovery (6.25 points over 1 year). The beneficial effect of anticonvulsants remained significant after adjustment for differences in 1-month motor scores and injury characteristics. A review of a subset of patients revealed that gabapentinoids were the most frequently administrated anticonvulsant. Together with preclinical findings, intervention with anticonvulsants represents a potential pharmacological strategy to improve motor function after SCI.

Background and aims Elite athletes reportedly have superior pain tolerances, but it is unclear if results extend to conditioned pain modulation (CPM). The aim of our study was to synthesize existing literature in order to determine whether CPM is increased in elite athletes compared to healthy controls. Methods A systematic review and random-effects meta-analysis was conducted. Cochrane Central Register of Controlled Trials, SPORTDiscus, PsycINFO, CINAHL, Web of Science, and PubMed were searched for English-language studies that examined CPM in adult elite athlete populations. Results Seven studies were identified; all were of poor to fair methodological quality. There was no overall difference in CPM between elite athletes and controls (Hedges g = 0.37, CI95 −0.03−0.76; p = 0.07). There was heterogeneity between studies, including one that reported significantly less CPM in elite athletes compared to controls. An exploratory meta-regression indicated that a greater number of hours trained per week was associated with higher CPM. Conclusions The overall number and quality of studies was low. Despite nominally favoring higher CPM in elite athletes, aggregate results indicate no significant difference compared to healthy controls. A possible factor explaining the high degree of variability between studies is the number of hours elite athletes spent training. Implications Based on available evidence, athletes do not have remarkable endogenous pain modulation compared to controls. High quality experimental studies are needed to address the effect of hours trained per week on CPM in athletes.

Recent observational studies have shown an association between gabapentinoid anticonvulsants and greater motor recovery after spinal cord injury. There is preclinical evidence to suggest that other anticonvulsants, such as sodium channel blockers, may also confer beneficial effects. The aim of the current study was to determine if non-gabapentinoid anticonvulsants were associated with neurological recovery after acute, traumatic spinal cord injury. This was an observational cohort study using data from the Sygen clinical trial. The primary outcome was total motor score recovery in the first year after injury. Anticonvulsant use was extracted from concomitant medication records; individuals were classified based on early administration (within 30 days of injury), or late/no administration. Motor recovery was compared using linear mixed effects regression models with a drug-by-time interaction, and adjustment for confounders. A secondary analysis incorporated a propensity score matched cohort. Of the cohort (n = 570), 6% received anticonvulsants (carbamazepine, phenytoin, clonazepam, phenobarbital, and valproic acid) early after injury. After adjustments for initial injury level and severity, early exposure to non-gabapentinoid anticonvulsants was not associated with motor neurological outcomes (p = 0.38 for all anticonvulsants, p = 0.83 for sodium channel blockers, p = 0.82 in propensity-matched cohort). Non-gabapentinoid anticonvulsant exposure was not associated with greater or lesser neurological recovery. This suggests that these medications, as administered for the acute management of spinal cord injury, do not impact long-term neurological outcomes.

Narrative review. To discuss how electrophysiology may contribute to future clinical trials in spinal cord injury (SCI) in terms of: (1) improvement of SCI diagnosis, patient stratification and determination of exclusion criteria; (2) the assessment of adverse events; and (3) detection of therapeutic effects following an intervention. An international expert panel for electrophysiological measures in SCI searched and discussed the literature focused on the topic. Electrophysiology represents a valid method to detect, track, and quantify readouts of nerve functions including signal conduction, e.g., evoked potentials testing long spinal tracts, and neural processing, e.g., reflex testing. Furthermore, electrophysiological measures can predict functional outcomes and thereby guide rehabilitation programs and therapeutic interventions for clinical studies. Objective and quantitative measures of sensory, motor, and autonomic function based on electrophysiological techniques are promising tools to inform and improve future SCI trials. Complementing clinical outcome measures, electrophysiological recordings can improve the SCI diagnosis and patient stratification, as well as the detection of both beneficial and adverse events. Specifically composed electrophysiological measures can be used to characterize the topography and completeness of SCI and reveal neuronal integrity below the lesion, a prerequisite for the success of any interventional trial. Further validation of electrophysiological tools with regard to their validity, reliability, and sensitivity are needed in order to become routinely applied in clinical SCI trials.

This report documents the first-in-man investigational trial and long-term follow-up of HuCNS-SC transplantation in chronic SCI. The small study size and open-label design reflect the pilot nature of this investigation, and the focus on determining feasibility, safety and preliminary efficacy. Based on the short- and long-term safety profile established in this study for individuals with thoracic SCI, a larger-scale, randomized, study in people with cervical SCI was approved in the US. These trials have established that the human spinal cord is a promising target for neural stem cell transplantation.

Background: Complications arising from acute traumatic spinal cord injury are routinely managed by various pharmacological interventions. Despite decades of clinical application, the potential impact on neurological recovery has been largely overlooked. Methods: We first performed an analysis of available clinical trial and observational data to determine what constitutes "standards of acute pharmacological care" after spinal cord injury. Then, we conducted an in-depth literature review to evaluate evidence that commonly administered drugs have potential disease-modifying properties in animal models of spinal cord injury. Finally, we searched available databases (e.g., Drug Bank) and literature to determine drugs that have been shown to alter the effectiveness of emerging investigational treatments (e.g., riluzole). Findings: Over 780 unique drugs were administered within the first month after injury. On average, patients received 20 unique drugs (range 1-58) - often in a combinatorial or overlapping fashion (i.e., polypharmacy). Approximately 10% of drugs were administered acutely as prophylaxis (e.g., pain, infections). From our initial review of preclinical literature, 329 studies evaluating 95 unique drugs demonstrate evidence of disease-modifying properties (i.e., beneficial or detrimental) on histological and/or functional outcomes in animal models. A total of 222 commonly administered drugs were found to interact with emerging investigational therapies and alter their efficacy. Interpretation: Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, with potential to both positively and negatively impact neurological recovery. This raises the distinct possibility of drug repositioning, either by broadly introducing or reducing the administration of a drug, in order to enhance neurological outcomes after acute injury. In addition to modifying effects, the potential for interactions between commonly administered drugs and novel therapies warrants caution in emergent clinical trials. Funding Statement: Dr. Jutzeler was supported by a Craig H. Nielsen Foundation, Blusson Integrated Cures Partnership Wings for Life, the Swiss National Science Foundation (Ambizione Grant, PZ00P3_186101). This study was funded in part by the Alfried Krupp Prize for Young University Teachers of the Alfried Krupp von Bohlen und Halbach-Stiftung (Dr. Borgwardt). Dr. Harel was supported by Veterans Affairs Rehabilitation Research and Development Service grant B-0881W. Dr. Ferguson is supported by National Institutes of Health grants R01NS088475, UG3NS106899, and Veterans Affairs RR&D grants 1I01RX002245, I01RX002787. Dr. Kwon is the Canada Research Chair in Spinal Cord Injury and the Dvorak Chair in Spine Trauma. Dr. Bradke is supported by International Foundation for Research in Paraplegia, Wings for Life, Deutsche Forschungsgesellschaft (DFG), ERA-NET AXON REPAIR, and ERA-NET RATER SCI, the excellence cluster ImmunoSensation2, the Special Research Grants 1089 and 1158. Dr. Kramer is supported by a Scholar Award from the Michael Smith Foundation for Health Research and Rick Hansen Institute, as well as the Canadian Institutes of Health Research (ERA-NET RATER SCI), Wings for Life, and the International Foundation for Research in Paraplegia (IRP). Declaration of Interests: Catherine Jutzeler: Nothing to disclose. Bobo Tong: Nothing to disclose. Eric Bailey: Nothing to disclose Noam Y. Harel: Nothing to disclose Fred Geisler: Nothing to disclose Karsten Borgwardt: Reports personal fees from Mentoring and Consulting for Roche Pharmaceutical Research and Early Development (pRED), Basel, outside the submitted work. Adam R. Fergus0n: Nothing to disclose Brian Kwon: Nothing to disclose. Frank Bradke: Nothing to disclose. Jacquelyn J. Cragg: Nothing to disclose Lukas Grassner: Nothing to disclose John L.K. Kramer: Nothing to disclose. Ethics Approval Statement: Approval for this study (secondary analysis) was received by an institutional ethical standards committee on human experimentation at the University of British Columbia.

Background: Given the large number of individuals living with disabling sensorimotor impairment due to spinal cord injury (SCI) approaching 2 million, viable options for regenerative repair strategies of the injured spinal cord are desperately needed. Human central nervous system stem cells (HuCNS-SC®) are self-renewing, multi-potent adult stem cells exhibiting successful engraftment, migration, and region-appropriate differentiation as demonstrated in multiple animal models for the injured brain and spinal cord. In preclinical SCI models, improved locomotor function provided the rationale for the first human thoracic SCI clinical trial of HuCNS-SC cells. Methods: Safety and preliminary efficacy data were collected within a first ever multi-site phase I/IIa trial involving surgical transplantation of 20 million HuCNS-SC cells into the thoracic cord in 12 subjects with sensory or motor complete traumatic paraplegia. Up to 6 years follow-up data was collected applying an extended protocol design augmenting clinical assessments through corroborating measures of sensory thresholds and neuroimaging to improve readouts of safety and efficacy. Findings: The study revealed promising short and long term surgical and medical safety. Measures of preliminary efficacy could discern responders (5/12 patients) with reliable improvements in sensory function albeit without measurable motor changes in thoracic injuries. Imaging of the spinal cord at and rostral the site of injection revealed dynamic structural changes similar to findings in non-transplanted SCI subjects. Interpretation: Findings of safety and feasibility supported the regulatory approval for a Phase II HuCNS-SC transplantation study in cervical spinal cord injured patients. Funding: The initial study (short term follow-up of the first year; STFU) and part of the second study (long term follow-up; LTFU) was funded by Stem Cells Inc, Newark, California, USA. After dissolution of Stem Cells Inc. Q3 2016 grants from Wings for Life (WfL), and the Bright Oceans Corporation (BOCO) enabled completion of the LTFU, compilation of the full set of monitored data (initial Phase I/IIa STFU trial and LTFU study), data analysis and manuscript completion. Declaration of Interest: Armin Curt has no competing interests. Principal Investigator for multi-site Phase I/IIa trial of 12 subjects and primary author (corresponding author). Jane Hsieh, with no competing interests, is an independent consultant to the Spinal Cord Injury Center Balgrist initiating data analysis and the first draft of the manuscript, as well as coordinating contributions from collaborating authors. Martin Schubert with no competing interests, participated in care of 9 enrolled subjects, data analysis and review of manuscript. Markus Hupp has no competing interests. Participated in the care of 9 enrolled subjects and reviewed the manuscript. Susi Friedl has no competing interests. Participated in the care of 9 enrolled subjects and reviewed the manuscript. Patrick Freund has no competing interests. Collected and analyzed neuroimaging data for 9 enrolled subjects and reviewed the manuscript. Eveline Huber has no competing interests. Collected and analyzed neuroimaging data for 9 enrolled subjects and reviewed the manuscript. Dario Pfyffer has no competing interests. Collected and analyzed neuroimaging data for 9 enrolled subjects, assisted with figure creation and reviewed the manuscript. Safety of neural stem cell transplantation into the human spinal cord Draft version: V6.1 20190128 Reto Sutter has no competing interests. Collected and analysed neuroimaging data for 9 enrolled subjects and reviewed the manuscript. Catherine Jutzeler has no competing interests. Collected and analysed electrophysiological data for 9 enrolled subjects and reviewed the manuscript. Rudolf P. Wuthrich has no competing interests. Provided immunosuppression for 9 enrolled subjects and reviewed the manuscript. Kan Min has no competing conflicts of interest. Performed orthopaedic spinal surgery for 9 HuCNS-SC transplantations at Balgrist site and reviewed the manuscript. Steve Casha has no competing interests. Site investigator at University of Calgary with 2 patients enrolled and transplanted, and reviewed the manuscript. Michael Fehlings has no competing interests. Site investigator at University of Toronto with 1 patient enrolled and transplanted, and reviewed the manuscript. Raphael Guzmann has no competing interests. Performed neurosurgery and HuCNS-SC transplantation for 9 enrolled subjects and reviewed the manuscript. Ethical Approval: The study protocol and all amendments were approved by related Ethics Committees and regulatory agencies in accordance with the Declaration of Helsinki.

Following a traumatic spinal cord injury, a 53-year-old male developed a central cord syndrome with at-level neuropathic pain. Magnetic resonance imaging revealed a classical "snake eye" appearance myelopathy, with marked hyperintensities at C5-C7. Clinical examination revealed intact pinprick sensation coupled with lost or diminished thermal/heat sensation. This dissociation could be objectively confirmed through multi-modal neurophysiological assessments. Specifically, contact heat evoked potentials were lost at-level, while pinprick evoked potentials were preserved. This pattern corresponds with that seen after surgical commissural myelotomy. To our knowledge, this is the first time such a dissociation has been objectively documented, highlighting the diagnostic potential of multi-modal neurophysiological assessments. In future studies, a comprehensive assessment of different nociceptive modalities may help elucidate the pathophysiology of neuropathic pain.