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Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 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. Those enrolled in an observational study were administered 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). To 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, raising the potential to impact neurological recovery. All results can be interactively explored on the RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Background A low level of cardiorespiratory fitness [CRF; defined as peak oxygen uptake (VO.sub.2peak) or peak power output (PPO)] is a widely reported consequence of spinal cord injury (SCI) and a major risk factor associated with chronic disease. However, CRF can be modified by exercise. This systematic review with meta-analysis and meta-regression aimed to assess whether certain SCI characteristics and/or specific exercise considerations are moderators of changes in CRF. Methods and findings Databases (MEDLINE, EMBASE, CENTRAL, and Web of Science) were searched from inception to March 2023. A primary meta-analysis was conducted including randomised controlled trials (RCTs; exercise interventions lasting >2 weeks relative to control groups). A secondary meta-analysis pooled independent exercise interventions >2 weeks from longitudinal pre-post and RCT studies to explore whether subgroup differences in injury characteristics and/or exercise intervention parameters explained CRF changes. Further analyses included cohort, cross-sectional, and observational study designs. Outcome measures of interest were absolute (AVO.sub.2peak) or relative VO.sub.2peak (RVO.sub.2peak ), and/or PPO. Bias/quality was assessed via The Cochrane Risk of Bias 2 and the National Institute of Health Quality Assessment Tools. Certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random effects models were used in all meta-analyses and meta-regressions. Of 21,020 identified records, 120 studies comprising 29 RCTs, 67 pre-post studies, 11 cohort, 7 cross-sectional, and 6 observational studies were included. The primary meta-analysis revealed significant improvements in AVO.sub.2peak [0.16 (0.07, 0.25) L/min], RVO.sub.2peak [2.9 (1.8, 3.9) mL/kg/min], and PPO [9 (5, 14) W] with exercise, relative to controls (p < 0.001). Ninety-six studies (117 independent exercise interventions comprising 1,331 adults with SCI) were included in the secondary, pooled meta-analysis which demonstrated significant increases in AVO.sub.2peak [0.22 (0.17, 0.26) L/min], RVO.sub.2peak [2.8 (2.2, 3.3) mL/kg/min], and PPO [11 (9, 13) W] (p < 0.001) following exercise interventions. There were subgroup differences for RVO.sub.2peak based on exercise modality (p = 0.002) and intervention length (p = 0.01), but there were no differences for AVO.sub.2peak . There were subgroup differences (p [less than or equal to] 0.018) for PPO based on time since injury, neurological level of injury, exercise modality, and frequency. The meta-regression found that studies with a higher mean age of participants were associated with smaller changes in AVO.sub.2peak and RVO.sub.2peak (p < 0.10). GRADE indicated a moderate level of certainty in the estimated effect for RVO.sub.2peak, but low levels for AVO.sub.2peak and PPO. This review may be limited by the small number of RCTs, which prevented a subgroup analysis within this specific study design. Conclusions Our primary meta-analysis confirms that performing exercise >2 weeks results in significant improvements to AVO.sub.2peak, RVO.sub.2peak, and PPO in individuals with SCI. The pooled meta-analysis subgroup comparisons identified that exercise interventions lasting up to 12 weeks yield the greatest change in RVO.sub.2peak . Upper-body aerobic exercise and resistance training also appear the most effective at improving RVO.sub.2peak and PPO. Furthermore, acutely injured, individuals with paraplegia, exercising for [greater than or equal to]3 sessions/week will likely experience the greatest change in PPO. Ageing seemingly diminishes the adaptive CRF responses to exercise training in individuals with SCI. Registration PROSPERO: CRD42018104342, Author(s): Daniel D. Hodgkiss 1, Gurjeet S. Bhangu 2,3, Carole Lunny 4, Catherine R. Jutzeler 5,6, Shin-Yi Chiou 1,7,8,9, Matthias Walter 2,10, Samuel J. E. Lucas 1,7, Andrei V. Krassioukov [...]

Introduction: New diagnostic techniques are a substantial research focus in degenerative cervical myelopathy (DCM). This cross-sectional study determined the significance of cardiac-related spinal cord motion and the extent of spinal stenosis as indicators of mechanical strain on the cord. Methods: Eighty-four DCM patients underwent MRI/clinical assessments and were classified as MRI+ [T2-weighted (T2w) hyperintense lesion in MRI] or MRI-(no T2w-hyperintense lesion). Cord motion (displacement assessed by phasecontrast MRI) and spinal stenosis [adapted spinal canal occupation ratio (aSCOR)] were related to neurological (sensory/motor) and neurophysiological readouts [contact heat evoked potentials (CHEPs)] by receiver operating characteristic (ROC) analysis. Results: MRI+ patients (N = 31; 36.9%) were more impaired compared to MRI-patients (N = 53; 63.1%) based on the modified Japanese Orthopedic Association (mJOA) subscores for upper {MRI+ [median (Interquartile range)]: 4 (4-5); MRI-: 5 (5-5); p < 0.01} and lower extremity [MRI+: 6 (6-7); MRI-: 7 (6-7); p = 0.03] motor dysfunction and the monofilament score [MRI+: 21 (18-23); MRI-: 24 (22-24); p < 0.01]. Both patient groups showed similar extent of cord motion and stenosis. Only in the MRI-group displacement identified patients with pathologic assessments [trunk/lower extremity pin prick score (T/LEPP): AUC = 0.67, p = 0.03; CHEPs: AUC = 0.73, p = 0.01]. Cord motion thresholds: T/LEPP: 1.67 mm (sensitivity 84.6%, specificity 52.5%); CHEPs: 1.96 mm (sensitivity 83.3%, specificity 65.6%). The aSCOR failed to show any relation to the clinical assessments. Discussion: These findings affirm cord motion measurements as a promising additional biomarker to improve the clinical workup and to enable timely surgical treatment particularly in MRI-DCM patients. [ABSTRACT FROM AUTHOR]

Mechanistic learning refers to the synergistic combination of mechanistic mathematical modeling and data-driven machine or deep learning. This emerging field finds increasing applications in (mathematical) oncology. This review aims to capture the current state of the field and provides a perspective on how mechanistic learning may progress in the oncology domain. We highlight the synergistic potential of mechanistic learning and point out similarities and differences between purely data-driven and mechanistic approaches concerning model complexity, data requirements, outputs generated, and interpretability of the algorithms and their results. Four categories of mechanistic learning (sequential, parallel, extrinsic, intrinsic) of mechanistic learning are presented with specific examples. We discuss a range of techniques including physics-informed neural networks, surrogate model learning, and digital twins. Example applications address complex problems predominantly from the domain of oncology research such as longitudinal tumor response predictions or time-to-event modeling. As the field of mechanistic learning advances, we aim for this review and proposed categorization framework to foster additional collaboration between the data- and knowledge-driven modeling fields. Further collaboration will help address difficult issues in oncology such as limited data availability, requirements of model transparency, and complex input data which are embraced in a mechanistic learning framework. [ABSTRACT FROM AUTHOR]

In this study, we investigate functional correlates of gamma band oscillations in low-noise EEG signals acquired in the LSBB shielded capsule and compare them to signals acquired in a typical hospital environment. Using a research-grade EEG acquisition system, we acquired 64-channel EEG recordings from three volunteers performing several cognitive, sensory, and motor tasks in both LSBB and hospital settings. Time-frequency analysis on the signals acquired in both environments reveals that the task-induced increase in gamma band (>30 Hz) energy relative to the resting state EEG is more prominent in signals acquired at LSBB, suggesting that task-specific changes in EEG are better reflected and more readily detected in signals acquired at LSBB. These results further demonstrate the potential value of low-noise settings such as the LSBB for conducting challenging high-frequency EEG studies.

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. [ABSTRACT FROM AUTHOR]

Background: During the coronavirus-19 (COVID-19) pandemic various containment strategies were employed. Their impact on individuals with neurological conditions, considered vulnerable to COVID-19 complications, remains to be determined. Objective: To investigate associations between physical activity and health-related quality of life outcomes in individuals with a neurological condition during government mandated COVID-19 restrictions. Methods: An e-survey assessing fear of COVID-19, physical activity level and health-related quality of life outcomes (functional disability and pain, anxiety and depression, loneliness, fatigue, and vitality) was distributed to individuals with a neurologically-related mobility disability living in the United Kingdom. Open-ended questions were also included to contextualize barriers and facilitators to engage in physical activity during the COVID-19 pandemic. Gamma-weighted generalized linear models and tree-structured regression models were employed to determine the associations between physical activity and health-related quality of life. Results: Of 199 responses, 69% reported performing less physical activity compared to pre-pandemic. Tree-structured regression models revealed that lower leisure-time physical activity was significantly associated (p ≤ 0.009) with higher depression and fatigue, but lower vitality. The closure of leisure facilities and organized sport (27%) was the most commonly cited barrier to engage in physical activity, while 31% of participants mentioned concerns around their physical and mental health as a facilitator. Conclusion: Our analysis identified homogenous subgroups for depression, fatigue, and vitality based specifically on leisure-time physical activity cut points, irrespective of additional demographic or situational characteristics. Findings highlight the importance of and need to safely promote leisure-time physical activity during the COVID-19 pandemic in this at-risk population to help support health-related quality of life. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The sensitizing effect of capsaicin has been previously characterized using laser and contact heat evoked potentials (LEPs and CHEPs) by stimulating in the primary area of hyperalgesia. Interestingly, only CHEPs reveal changes consistent with notion of peripheral sensitization (i.e., reduced latencies). The aim of this study was to investigate contact heat stimulation parameters necessary to detect peripheral sensitization related to the topical application of capsaicin, and therefore significantly improve the current method of measuring peripheral sensitization via CHEPs. Rapid contact heat stimulation (70°C/s) was applied from three different baseline temperatures (35, 38.5, and 42°C) to a 52°C peak temperature, before and after the topical application of capsaicin on the hand dorsum. Increased pain ratings in the primary area of hyperalgesia were accompanied by reduced N2 latency. Changes in N2 latency were, however, only significant following stimulation from 35 and 38.5°C baseline temperatures. These findings suggest that earlier recruitment of capsaicin-sensitized afferents occurs between 35 and 42°C, as stimulations from 42°C baseline were unchanged by capsaicin. This is in line with reduced thresholds of type II A-delta mechanoheat (AMH) nociceptors following sensitization. Conventional CHEP stimulation, with a baseline temperature below 42°C, is well suited to objectively detect evidence of peripheral sensitization. [ABSTRACT FROM AUTHOR]

• Participant-controlled temperature (PCT) is a reliable measure of temporal summation. • Rating of perceived intensity is not associated with PCT outcomes. • PCT may be useful in future studies for detecting endogenous pain modulation. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Understanding factors associated with high placebo responses in clinical trials increases the likelihood of detecting a meaningful treatment effect. The aim of the present study was to identify subject-level factors that contribute to placebo variability in patients with neuropathic pain due to spinal cord injury (SCI). Methods: Multiple regression analysis of patient data from randomized, double-blind, placebo-controlled trials (duration >4 weeks) involving individuals with SCI was performed. Patient demographics, as well as injury and pain characteristics were examined for their association with changes in pain rating from baseline to the end of the trial (i.e., placebo response). The overall effect of individual predictors was quantified with meta-analysis statistics. Results: A total of 276 patients with SCI from six studies were included in the analysis. Based on the meta-analysis of subject-level predictors, larger placebo responses were associated with male subjects (β=0.635; standard error [SE]=0.262; p=0.016) and higher baseline pain (β=−0.146; SE=0.073; p=0.044). There were no significant effects for injury characteristics (i.e., severity, level, and time since injury) or pain characteristics (i.e., location and evoked). No significant publication bias was detected. Conclusion: The current meta-analysis of individual patient data demonstrated the importance of sex and baseline pain intensity on changes in pain ratings in the placebo arm of SCI central neuropathic pain randomized controlled clinical trials. Overall, our findings indicate that placebo responses occur independent of injury characteristics. [ABSTRACT FROM AUTHOR]

Background: The prevalence of pain among people with a variety of individual neurological conditions has been estimated. However, information is limited about chronic pain among people with neurological conditions overall, and about the conditions for which chronic pain is most prevalent. To fill these information gaps, a common method of pain assessment is required. Data and methods: The data are from the Survey on Living with Neurological Conditions in Canada, a cross-sectional national survey. Based on self-reports, chronic pain was assessed for 16 neurological conditions. Multivariable logistic regression was used to produce odds ratios and 95% confidence intervals (CIs). Results: Close to 1.5 million individuals aged 15 or older who lived in private households reported having been diagnosed with a neurological condition. The overall prevalence of chronic pain for the 16 neurological conditions combined was 36% (95% CI: 31% to 42%). The odds of chronic pain were significantly elevated among individuals with spinal cord trauma. Interpretation: Chronic pain is highly prevalent among people with neurological conditions, particularly those with spinal cord trauma. These results suggest a need to target health services and direct research to improved pain management, and thereby reduce the burden of neurological disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to reveal the sensitivity and responsiveness of contact heat evoked potentials (CHEPs) to assess cervical spondylotic myelopathy (CSM). A total of 81 patients with clinically and radiologically confirmed spinal cord compression were reviewed. All patients underwent full clinical examinations with combined recordings of segmental CHEPs and somatosensory evoked potentials (dSSEPs) compared with healthy controls. Cross-sectional area, maximal canal compression, and maximal spinal cord compression were determined based on T2-weighted MRI. CHEPs exhibited the highest sensitivity (∼ 95%) to disclose at-level impairments in CSM patients. Normally appearing rostral segments above the level of lesion were impaired in 17% of patients. Comparatively, dSSEPs were less affected (24%) and predominantly impaired at and below the level of CSM. Longitudinal evaluation revealed that CHEPs became progressively impaired in parallel with clinical deterioration. CHEPs were sensitive to CSM, revealing evidence of impaired neurophysiology at and below the radiographic level of stenosis. The changes observed above the level of CSM suggest neurophysiological deficits beyond the focally damaged area. Deteriorating CHEPs were observed in a cohort of patients with worsening neurological symptoms, indicating their responsiveness to track CSM. The present study highlights the value of incorporating CHEPs into the diagnosis and prognosis of CSM. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

Background Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N -methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. Methods In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. Results The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. Conclusions Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ. [ABSTRACT FROM AUTHOR]

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons. [ABSTRACT FROM AUTHOR]

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). 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, I 2, T 2, and Cochrane Q, sensitivity analyses, and assessed publication bias. 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 (I 2; range: 1.5–98.2%). Publication bias was only found in eight studies (Egger's test: p < 0.05). Our meta-analyses revealed important risk factors that are associated with severity and mortality of COVID-19. [ABSTRACT FROM AUTHOR]