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The influence of the TMS-parameters on the efficacy and reliability to induce diaphragmatic motor-evoked potentials (diMEPs) has not been studied so far. Therefore, the objective of the present research is to probe the role of TMS- waveform (monophasic- [Mo] vs. biphasic-pulses [Bi]) and current direction (posterior-anterior [Pa] vs. anterior-posterior [Ap]) in the activation of the diaphragm.Four different pulse-configurations (Mo-Ap, Mo-Pa, Bi-Ap, Bi-Pa) were applied by means of neuronavigated-TMS and surface MEP-recordings at relaxed end-expiration in 19 healthy subjects. The parameters resting motor threshold (RMT), diMEP-amplitude and -latency, as well as best stimulation site (motor hotspot) and central motor conduction time were studied. Diaphragm movements were simultaneously recorded via ultrasound. To control for possible signal contamination the MEPs of muscles neighboring the diaphragm were also obtained.The motor hotspots of the diaphragm showed similar spatial distribution for the Mo-Ap, Mo-Pa, Bi-Ap and Bi-Pa. The biphasic-pulses yielded significantly lower RMTs and higher diMEP-amplitudes as the monophasic-pulses. Anterior to posterior oriented Bi- and Mo-pulses evoked significantly shorter diMEP-latencies than the posterior-anterior oriented ones.The present research demonstrates that biphasic- as compared to monophasic-pulses require significantly less charge and time for inducing diMEPs.The biphasic-TMS is best suited for the demanding stimulation of the diaphragm.

High efficacy in terms of protection from severe COVID-19 has been demonstrated for several SARS-CoV-2 vaccines. However, patients with compromised immune status develop a weaker and less stable immune response to vaccination. Strong immune response may not always translate into clinical benefit, therefore it is important to synthesise evidence on modified schemes and types of vaccination in these population subgroups for guiding health decisions. As the literature on COVID-19 vaccines continues to expand, we aimed to scope the literature on multiple subgroups to subsequently decide on the most relevant research questions to be answered by systematic reviews.To provide an overview of the availability of existing literature on immune response and long-term clinical outcomes after COVID-19 vaccination, and to map this evidence according to the examined populations, specific vaccines, immunity parameters, and their way of determining relevant long-term outcomes and the availability of mapping between immune reactivity and relevant outcomes.We searched the Cochrane COVID-19 Study Register, the Web of Science Core Collection, and the World Health Organization COVID-19 Global literature on coronavirus disease on 6 December 2021. SELECTION CRITERIA: We included studies that published results on immunity outcomes after vaccination with BNT162b2, mRNA-1273, AZD1222, Ad26.COV2.S, Sputnik V or Sputnik Light, BBIBP-CorV, or CoronaVac on predefined vulnerable subgroups such as people with malignancies, transplant recipients, people undergoing renal replacement therapy, and people with immune disorders, as well as pregnant and breastfeeding women, and children. We included studies if they had at least 100 participants (not considering healthy control groups); we excluded case studies and case series.We extracted data independently and in duplicate onto an online data extraction form. Data were represented as tables and as online maps to show the frequency of studies for each item. We mapped the data according to study design, country of participant origin, patient comorbidity subgroup, intervention, outcome domains (clinical, safety, immunogenicity), and outcomes. MAIN RESULTS: Out of 25,452 identified records, 318 studies with a total of more than 5 million participants met our eligibility criteria and were included in the review. Participants were recruited mainly from high-income countries between January 2020 and 31 October 2021 (282/318); the majority of studies included adult participants (297/318). Haematological malignancies were the most commonly examined comorbidity group (N = 54), followed by solid tumours (N = 47), dialysis (N = 48), kidney transplant (N = 43), and rheumatic diseases (N = 28, 17, and 15 for mixed diseases, multiple sclerosis, and inflammatory bowel disease, respectively). Thirty-one studies included pregnant or breastfeeding women. The most commonly administered vaccine was BNT162b2 (N = 283), followed by mRNA-1273 (N = 153), AZD1222 (N = 66), Ad26.COV2.S (N = 42), BBIBP-CorV (N = 15), CoronaVac (N = 14), and Sputnik V (N = 5; no studies were identified for Sputnik Light). Most studies reported outcomes after regular vaccination scheme. The majority of studies focused on immunogenicity outcomes, especially seroconversion based on binding antibody measurements and immunoglobulin G (IgG) titres (N = 179 and 175, respectively). Adverse events and serious adverse events were reported in 126 and 54 studies, whilst SARS-CoV-2 infection irrespective of severity was reported in 80 studies. Mortality due to SARS-CoV-2 infection was reported in 36 studies. Please refer to our evidence gap maps for more detailed information.Up to 6 December 2021, the majority of studies examined data on mRNA vaccines administered as standard vaccination schemes (two doses approximately four to eight weeks apart) that report on immunogenicity parameters or adverse events. Clinical outcomes were less commonly reported, and if so, were often reported as a secondary outcome observed in seroconversion or immunoglobulin titre studies. As informed by this scoping review, two effectiveness reviews (on haematological malignancies and kidney transplant recipients) are currently being conducted.

BACKGROUND: With potential antiviral and anti‐inflammatory properties, Janus kinase (JAK) inhibitors represent a potential treatment for symptomatic severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. They may modulate the exuberant immune response to SARS‐CoV‐2 infection. Furthermore, a direct antiviral effect has been described. An understanding of the current evidence regarding the efficacy and safety of JAK inhibitors as a treatment for coronavirus disease 2019 (COVID‐19) is required. OBJECTIVES: To assess the effects of systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo) on clinical outcomes in individuals (outpatient or in‐hospital) with any severity of COVID‐19, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID‐19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, medRxiv, and Cochrane Central Register of Controlled Trials), Web of Science, WHO COVID‐19 Global literature on coronavirus disease, and the US Department of Veterans Affairs Evidence Synthesis Program (VA ESP) Covid‐19 Evidence Reviews to identify studies up to February 2022. We monitor newly published randomised controlled trials (RCTs) weekly using the Cochrane COVID‐19 Study Register, and have incorporated all new trials from this source until the first week of April 2022. SELECTION CRITERIA: We included RCTs that compared systemic JAK inhibitors plus standard of care to standard of care alone (plus/minus placebo) for the treatment of individuals with COVID‐19. We used the WHO definitions of illness severity for COVID‐19. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using Cochrane's Risk of Bias 2 (RoB 2) tool. We used GRADE to rate the certainty of evidence for the following primary outcomes: all‐cause mortality (up to day 28), all‐cause mortality (up to day 60), improvement in clinical status: alive and without need for in‐hospital medical care (up to day 28), worsening of clinical status: new need for invasive mechanical ventilation or death (up to day 28), adverse events (any grade), serious adverse events, secondary infections. MAIN RESULTS: We included six RCTs with 11,145 participants investigating systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo). Standard of care followed local protocols and included the application of glucocorticoids (five studies reported their use in a range of 70% to 95% of their participants; one study restricted glucocorticoid use to non‐COVID‐19 specific indications), antibiotic agents, anticoagulants, and antiviral agents, as well as non‐pharmaceutical procedures. At study entry, about 65% of participants required low‐flow oxygen, about 23% required high‐flow oxygen or non‐invasive ventilation, about 8% did not need any respiratory support, and only about 4% were intubated. We also identified 13 ongoing studies, and 9 studies that are completed or terminated and where classification is pending. Individuals with moderate to severe disease Four studies investigated the single agent baricitinib (10,815 participants), one tofacitinib (289 participants), and one ruxolitinib (41 participants). Systemic JAK inhibitors probably decrease all‐cause mortality at up to day 28 (95 of 1000 participants in the intervention group versus 131 of 1000 participants in the control group; risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91; 6 studies, 11,145 participants; moderate‐certainty evidence), and decrease all‐cause mortality at up to day 60 (125 of 1000 participants in the intervention group versus 181 of 1000 participants in the control group; RR 0.69, 95% CI 0.56 to 0.86; 2 studies, 1626 participants; high‐certainty evidence). Systemic JAK inhibitors probably make little or no difference in improvement in clinical status (discharged alive or hospitalised, but no longer requiring ongoing medical care) (801 of 1000 participants in the intervention group versus 778 of 1000 participants in the control group; RR 1.03, 95% CI 1.00 to 1.06; 4 studies, 10,802 participants; moderate‐certainty evidence). They probably decrease the risk of worsening of clinical status (new need for invasive mechanical ventilation or death at day 28) (154 of 1000 participants in the intervention group versus 172 of 1000 participants in the control group; RR 0.90, 95% CI 0.82 to 0.98; 2 studies, 9417 participants; moderate‐certainty evidence). Systemic JAK inhibitors probably make little or no difference in the rate of adverse events (any grade) (427 of 1000 participants in the intervention group versus 441 of 1000 participants in the control group; RR 0.97, 95% CI 0.88 to 1.08; 3 studies, 1885 participants; moderate‐certainty evidence), and probably decrease the occurrence of serious adverse events (160 of 1000 participants in the intervention group versus 202 of 1000 participants in the control group; RR 0.79, 95% CI 0.68 to 0.92; 4 studies, 2901 participants; moderate‐certainty evidence). JAK inhibitors may make little or no difference to the rate of secondary infection (111 of 1000 participants in the intervention group versus 113 of 1000 participants in the control group; RR 0.98, 95% CI 0.89 to 1.09; 4 studies, 10,041 participants; low‐certainty evidence). Subgroup analysis by severity of COVID‐19 disease or type of JAK inhibitor did not identify specific subgroups which benefit more or less from systemic JAK inhibitors. Individuals with asymptomatic or mild disease We did not identify any trial for this population. AUTHORS' CONCLUSIONS: In hospitalised individuals with moderate to severe COVID‐19, moderate‐certainty evidence shows that systemic JAK inhibitors probably decrease all‐cause mortality. Baricitinib was the most often evaluated JAK inhibitor. Moderate‐certainty evidence suggests that they probably make little or no difference in improvement in clinical status. Moderate‐certainty evidence indicates that systemic JAK inhibitors probably decrease the risk of worsening of clinical status and make little or no difference in the rate of adverse events of any grade, whilst they probably decrease the occurrence of serious adverse events. Based on low‐certainty evidence, JAK inhibitors may make little or no difference in the rate of secondary infection. Subgroup analysis by severity of COVID‐19 or type of agent failed to identify specific subgroups which benefit more or less from systemic JAK inhibitors. Currently, there is no evidence on the efficacy and safety of systemic JAK inhibitors for individuals with asymptomatic or mild disease (non‐hospitalised individuals).

Purpose: Measurements of cerebrospinal fluid (CSF)-lactate can aid in detecting infections of the central nervous system and surrounding structures. Neurosurgical patients with temporary lumbar or ventricular CSF-drainage harbor an increased risk for developing infections of the central nervous system which require immediate therapeutic responses. Since blood-gas-analyzers enable rapid blood-lactate-measurements we were interested to find out if CSF-lactate may be reliably measured by this point-of-care technique. Methods: Neurosurgical patients on our intensive care unit (ICU) with either lumbar or external ventricular drainage due to a variety of reasons were included in this prospective observational study. Standard of care included measurements of leucocyte counts, total protein and lactate measurements in CSF by the neurochemical laboratory of our University Medical Center twice a week. With respect to this study we additionally performed nearly daily measurements of cerebrospinal-fluid by blood gas analyzers to determine the reliability of CSF-lactate measured by blood-gas-analyzers as compared to the standard measurements with a certified device. Results: 62 patients were included in this study. 514 CSF measurements were performed with blood-gas-analyzers. 180 of these could be compared to the in-house standard CSF-lactate measurements. Both techniques correlated highly significant (Pearson correlation index 0.94) even though lacking full concordance in a Bland-Altman-plotting. Of particular importance, regular measurements enabled immediate detection of central infection in 3 patients who had developed meningitis during the course of their treatment.Conclusion: CSF-lactate was reliably measured by blood-gas-analyzers and detected developing meningitis timely. In addition to and triggering established CSF-diagnostics, CSF-lactate measurements by blood-gas-analyzers may improve surveillance of central nervous infections in patients with CSF-drainage. This study was retrospectively registered on April 20th 2020 in the German trial register. The trial registration number is: DRKS00021466.

Objectives: Severe acute respiratory syndrome coronavirus 2 cell entry depends on angiotensin-converting enzyme 2 and transmembrane serine protease 2 and is blocked in cell culture by camostat mesylate, a clinically proven protease inhibitor. Whether camostat mesylate is able to lower disease burden in coronavirus disease 2019 sepsis is currently unknown. Design: Retrospective observational case series. Setting: Patient treated in ICU of University hospital Göttingen, Germany. Patients: Eleven critical ill coronavirus disease 2019 patients with organ failure were treated in ICU. Interventions: Compassionate use of camostat mesylate (six patients, camostat group) or hydroxychloroquine (five patients, hydroxychloroquine group). Measurements and Main Results: Clinical courses were assessed by Sepsis-related Organ Failure Assessment score at days 1, 3, and 8. Further, viral load, oxygenation, and inflammatory markers were determined. Sepsis-related Organ Failure Assessment score was comparable between camostat and hydroxychloroquine groups upon ICU admission. During observation, the Sepsis-related Organ Failure Assessment score decreased in the camostat group but remained elevated in the hydroxychloroquine group. The decline in disease severity in camostat mesylate treated patients was paralleled by a decline in inflammatory markers and improvement of oxygenation. Conclusions: The severity of coronavirus disease 2019 decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed in patients receiving hydroxychloroquine. Camostat mesylate thus warrants further evaluation within randomized clinical trials.

Background: The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). COVID-19 may take a severe course, resulting in sepsis, and antivirals are urgently needed to combat the disease. However, at present, only drugs developed against other diseases are available including the Malaria drug hydroxychloroquine but their therapeutic efficacy is unclear. Camostat mesylate, a clinically-proven protease inhibitor for treatment of pancreatitis, was shown to block SARS-CoV-2 entry into lung cells. Whether camostat mesylate dampens COVID-19 induced sepsis and the associated organ failure is unknown. Here we compare clinical courses of critically ill COVID-19 patients treated with either camostat mesylate or hydroxychloroquine. Methods: Eleven COVID-19 patients with organ failure were treated in intensive care unit (ICU) at our institution. Five patients (group 1) received hydroxychloroquine and six patients (group 2) camostat mesylate. Clinical disease status was assessed by Simplified Acute Physiology Score (SAPS) II and Sequential/ Sepsis-related Organ Failure Assessment (SOFA) score at day 1, 3 and 8. Viral load was determined from nasopharyngeal swabs. Findings: Patient age ranged from 45 to 76 years, all but one had histories of chronic disease and cardiovascular risk factors. Median symptomatic period was 2-10 days before being transferred to ICU. No differences in SAPS II scores or SOFA scores were observed upon ICU admission. In group 1, SOFA and SAPS II scores remained elevated (2 patients died) while in group 2 SOFA and SAPS II score decreased from 9 to 4 points (1 patient died). The decline in disease severity for group 2 was paralleled by a decline in inflammatory markers, which was not observed in group 1. The virus load in the nasopharynx was variable between patients, did not correlate with organ failure and no marked differences were observed between groups 1 and 2. Interpretation: The severity of COVID-19 sepsis markedly decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed upon hydroxychloroquine treatment. Camostat mesylate thus warrants further evaluation within randomized clinical studies. Funding Statement: Authors were employed at the University of Gottingen or at the Infection Biology Unit of the German Primate Center (Leibniz Institute for Primate Research). All expenses were covered by publicly funded institutions. Stefan Pohlmann received funding from the German Federal Ministry of Education and Research (BMBF), RAPID Fund (#01KI1723D). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Compassionate use was approved by our local ethical committee at the University of Gottingen.

Epileptic visual auras are elementary to complex and sometimes occur as colourful visual phenomena located close to or within the central part of the contralateral hemi-field. They typically last from seconds to a few minutes, which discriminates them from the usually longer-lasting visual auras (5-30 minutes) of patients suffering from migraine. We present an adult patient with occipital lobe epilepsy whose visual aura under epilepsy monitoring lasted for more than 30 minutes with almost no propagation, demonstrating a rare, but remarkable, sustained local epileptic network activity associated with resection of an occipital arterio-venous malformation.

Parkinson’s disease (PD) is a neurodegenerative disorder affecting a variety of brain structures. Its prevalence in the general population is around 0.3% and increases considerably with age (de Lau & Breteler, 2006). The median age of onset is 60 years and the incidence is equal in both sexes (Katzenschlager et al., 2008). While initially symptoms are subtle severe disability often requiring permanent care is present in many patients within a time-frame of about ten years. On the other hand, there are patients who do not show relevant progression of PD over up to ten years (Hoehn & Yahr, 1967). Indeed, the most severe state of PD with regard to the Hoehn and Yahr (H&Y) scale may be reached after 6 to 40 years according to a variety of epidemiological studies (Poewe, 2006). Yet, overall the mortality rate of patients with PD is increased by a factor of 1.5-2.5 compared to the general population (Poewe, 2006). The existence of at least two of the criteria resting tremor, bradykinesia and rigidity in an asymmetrical distribution leads the way to the diagnosis of this movement disorder. Accordingly, the pentamerous unified Parkinson’s disease rating scale (UPDRS) mainly reflects the state of the motor symptoms of PD. Only the first item of the UPDRS takes into account psychiatric symptoms of the disease. However, cognitive decline as well as psychiatric disturbances are common in patients with PD and pose major problems. While the non-motor aspects of PD have been less well studied for a long time, they have received more attention in recent years. Nevertheless, therapy of these symptoms is less advanced compared to the numerous therapeutic options for the motor symptoms of PD. And not infrequently, treatment of motor symptoms and treatment of psychiatric and cognitive aspects of PD interfere with each other. For this chapter the literature on some factors of non-motor aspects of PD has been reviewed and is summarized here.

The ability of the brain to process information relies on its control of the conduction of electric currents. Brain diseases invariably affect this capability. One of the therapeutic approaches to a variety of neurological disorders therefore includes the application of electric currents and fields to the brain. A successful example of this strategy is the introduction of deep brain stimulation which has become a cornerstone of the therapy of advanced Parkinson’s disease (PD), dystonia and essential tremor. Several studies have proven its effectiveness and often patients respond immediately to this therapy. Invasiveness and complexity of this treatment restrict its indication. On the other hand, there are techniques for the non-invasive modulation of cortical excitability namely transcranial magnetic stimulation (TMS) as well as transcranial direct current stimulation (tDCS). These techniques have been investigated in several studies including patients with PD. However results so far are heterogeneous and limit their therapeutic value. In the following chapter the basic principles of as well as therapeutic experiences with invasive and non-invasive electrical stimulation techniques and their applications in patients with PD will be discussed.