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Objectives The acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis is one of the main causes of high mortality in patients with COVID-19 (novel coronavirus disease 2019). We systematically reviewed mortality in COVID-19 patients with ARDS and the potential role of systemic corticosteroids in COVID-19 patients. Methods Electronic databases and country-specific healthcare databases were searched to identify relevant studies/reports. The quality assessment of individual studies was conducted using the Newcastle–Ottawa Scale. Country-specific proportion of individuals with COVID-19 who developed ARDS and reported death were combined in a random-effect meta-analysis to give a pooled mortality estimate of ARDS. Results The overall pooled mortality estimate among 10,815 ARDS cases in COVID-19 patients was 39% (95% CI: 23–56%). The pooled mortality estimate for China was 69% (95% CI: 67–72%). In Europe, the highest mortality estimate among COVID-19 patients with ARDS was reported in Poland (73%; 95% CI: 58–86%) while Germany had the lowest mortality estimate (13%; 95% CI: 2–29%) among COVID-19 patients with ARDS. The median crude mortality rate of COVID-19 patients with reported corticosteroid use was 28.0% (lower quartile: 13.9%; upper quartile: 53.6%). Conclusions The high mortality in COVID-19 associated ARDS necessitates a prompt and aggressive treatment strategy which includes corticosteroids. Most of the studies included no information on the dosing regimen of corticosteroid therapy, however, low-dose corticosteroid therapy or pulse corticosteroid therapy appears to have a beneficial role in the management of severely ill COVID-19 patients.

Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine.Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS.26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group.In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

Background Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions. Methods Using data from the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia. Results 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found. Conclusion These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period.

An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK-ALS trial (Eudra-CT-Nr.: 2017-003676-31, NCT03792490) as a multi-national collaboration between centers in Europe and North America that is led by a European investigator. During the set-up of this international trial, however, a number of unanticipated legal, administrative, and financial complexities emerged that required significant adaptation of the proposed trial scheme. Here, we report our experience navigating these obstacles and describe the potential solutions that we explored. Our experience may inform future efforts to implement multi-national investigator-initiated trials that involve both European and United States centers.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS. Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a >= 20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction. Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern. Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.

Background Clinical trials require great effort, time, expertise, and money. For clinicians at university hospitals with their full work load of teaching and medical care, the planning of an investigator-initiated clinical trial seems almost unthinkable. Despite their expertise in distinct diseases, university clinicians lack the time necessary to organize the funding and to initiate and conduct Phase III clinical trials in adults or in children. Objective We sought to determine whether the difficulties faced by a clinician conducting a pediatric clinical trial can be overcome by passionate motivation and external support. Methods Critical aspects of the application process of the world׳s first clinical trial in children with the rare hereditary kidney disease Alport syndrome treated with an angiotensin-converting enzyme inhibitor (Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome [EARLY PRO-TECT Alport]; http://www.clinicaltrials.gov NCT01485978; EudraCT 2010-024300-10) are described. Results The following crucial factors enabled the investigator to complete this trial: (1) support through clinical trial, biometrician, and regulatory experts (Institute for Applied Research and Clinical Studies [IFS], Gottingen, Germany); (2) advice from the university׳s ethics committee (University Medicine Gottingen, Gottingen, Germany); (3) public funding (€1 million from the German Federal Ministry of Education and Research); (4) support from the respective medical society, aiming at the resolution of an important clinical problem (German Society of Pediatric Nephrology); and (5) support from the investigator׳s university as the official sponsor of the trial, providing long-term commitment and covering financial risks (University Medical Center Gottingen, Gottingen, Germany). Conclusions The study could pave the way for approval of ramipril as a drug to treat children with Alport syndrome. Even though the study might not result in label changes, the EARLY PRO-TECT Alport trial provides the basis of an educational campaign to sensitize physicians, especially pediatricians, general practitioners, and nephrologists, to pay special attention to the early detection of kidney diseases in children, which could improve medical care for all children with kidney diseases.

Summary Background Over the past few years, plasma medicine has become an important field in medical science. Cold plasma has proven anti-inflammatory, antimicrobial and antineoplastic effects. Aim To test the decontamination power of two cold plasma sources [low-temperature atmospheric pressure plasma jet (APPJ) and dielectric barrier discharge plasma (DBD)] in vivo on human fingertips. Methods After 3, 15, 30, 60, 90, 120, 150, 180, 210 and 240 s of spot treatment with the APPJ and DBD, the log reduction factors (RFs) of physiological (PF) and artificially (AF) contaminated flora ( Staphylococcus epidermidis and Micrococcus luteus ) were calculated. The bacterial load was determined after counting. Tolerance (paresthesia, pain and heat) was measured using a numerical rating scale. Findings Both plasma devices led to a significant reduction in PF and AF. The maximum log reduction factors for PF were 1.3 for the DBD at 210 s and 0.8 for the APPJ at 60 s. For AF, the maximum log reduction factors were 1.7 for the DBD at 90 s and 1.4 for the APPJ at 120 s. Treatment with both devices was well tolerated. Conclusion Both the APPJ and DBD were highly effective in eradicating PF and AF from the fingertips of healthy volunteers. No plasma-resistant isolates were observed. Cold plasma appears to have potential for skin disinfection. For hand hygiene purposes, plasma exposure times would need to be reduced significantly by technical means.

To assess the safety of direct trocar insertion (DTI) before creating pneumoperitoneum in laparoscopic procedures.An observational study.Combined Military Hospital (CMH) Kohat, Pakistan from November 2013 to January 2015.All the cases undergoing laparoscopy at the study centre in the above duration were included in the study after approval from the Hospital Ethical Committee and informed written consent. Out of the 200 cases, DTI was successfully used to establish peritoneal access in 190 cases, while open Hassen's technique (OL) was used in ten cases. Body mass index (BMI) of all the patients was calculated before surgery. All the cases were performed under general anaesthesia with adequate relaxation. A 10 mm permanent re-useable sharp metallic trocar was inserted through umbilical scar after lifting the abdominal wall using towel clamps. Studied variables included age, gender, BMI, operations, history of previous surgery, number of attempts for DTI and complications.Mean age of the patients in DTI group was 46.58 ±13.94 years, while 48.70 ±10.08 years in OL group. Female to male ratio in DTI group was 1.43:1; and 2.33:1 in OL group. Increase in BMI had a relation with number of unsuccessful attempts of DTI, so obesity was the main reason of failure of DTI.DTI is a safe and effective method of peritoneal access for laparoscopy with very low failure rate related to BMI and minimal complications.

Background Very few data exist on the management of community-acquired pneumonia (CAP) in patients admitted to hospitals in the Gulf region. The objectives of this study were to describe treatment patterns for CAP in 38 hospitals in five Gulf countries (United Arab Emirates, Kuwait, Bahrain, Oman, and Qatar) and to compare the findings to the most recent Infectious Diseases Society of America (IDSA) / American Thoracic Society (ATS) guidelines. Methods This was a prospective, observational study conducted between January 2009 and February 2011. Adult patients hospitalised (excluding intensive care units) for CAP and subsequently discharged were included. Data were collected retrospectively at hospital discharge, and prospectively during two follow-up visits. Data on medical history, mortality-risk scores, diagnostic criteria, antibiotic treatment, isolated pathogens and clinical and radiographic outcomes were collected. Care practices were compared to the IDSA/ATS guidelines. Results A total of 684 patients were included. The majority (82.9 %) of patients were classified as low risk for mortality (pneumonia severity index II and III). The majority of patients fulfilled criteria for treatment success at discharge, although only 77.6 % presented a normalised leukocyte count. Overall, the management of CAP in Gulf countries is in line with the IDSA/ATS guidelines. This applied to the diagnosis of CAP, to the identification of high-risk CAP patients, to the identification of etiologic agent responsible for CAP and to the type of treatment despite the fact that combinations of antimicrobial agents were not consistent with the guidelines in 10 % of patients. In all patients, information about Gram’s staining was not captured as recommended by the IDSA/ATS and in the majority of patients (>85 %) chest radiography was not systematically performed at the post-discharge follow-up visits. Discussion The management of CAP in the Gulf region is globally in line with current IDSA/ATS guidelines, although rates of pathogen characterisation and post-discharge follow-up need to be improved. Conclusion Compliance with established guidelines should be encouraged in order to improve the management of the disease in this region.

Background Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia. Methods A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007–2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly. Results There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 ( p = .53, effect size=.09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group ( p = .047, effect size=.30), limited to day 21. Conclusions Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

We report the first case of native aortic and mitral valve endocarditis due to Gemella bergeriae from the Middle East in a young patient with rheumatic heart disease. Our case illustrates a fulminant course of infection with G. bergeriae endocarditis that was complicated by embolic stroke, as well as intracerebral and subarachnoid haemorrhage secondary to rupture of a mycotic aneurysm in the right middle cerebral artery. This case highlights the dire, unreported neurological complications of infective endocarditis due to a rare causative organism—G. bergeriae.

Gastrointestinal toxicity is a common adverse effect of mycophenolic acid (MPA) treatment in organ transplant patients, through poorly understood mechanisms. Phosphorylation of myosin light chain 2 (MLC2) is associated with epithelial tight junction (TJ) modulation which leads to defective epithelial barrier function, and has been implicated in GI diseases. The aim of this study was to investigate whether MPA could induce epithelial barrier permeability via MLC2 regulation. Caco-2 monolayers were exposed to therapeutic concentrations of MPA, and MLC2 and myosin light chain kinase (MLCK) expression were analyzed using PCR and immunoblotting. Epithelial cell permeability was assessed by measuring transepithelial resistance (TER) and the flux of paracellular permeability marker FITC-dextran across the epithelial monolayers. MPA increased the expression of MLC2 and MLCK at both the transcriptional and translational levels. In addition, the amount of phosphorylated MLC2 was increased after MPA treatment. Confocal immunofluorescence analysis showed redistribution of TJ proteins (ZO-1 and occludin) after MPA treatment. This MPA mediated TJ disruption was not due to apoptosis or cell death. Additionally ML-7, a specific inhibitor of MLCK was able to reverse both the MPA mediated decrease in TER and the increase in FITC-dextran influx, suggesting a modulating role of MPA on epithelial barrier permeability via MLCK activity. These results suggest that MPA induced alterations in MLC2 phosphorylation and may have a role in the patho-physiology of intestinal epithelial barrier disruption and may be responsible for the adverse effects (GI toxicity) of MPA on the intestine.

Cold plasma, a new treatment principle in dermatology based on ionic discharge delivering reactive molecular species and UV-light, exhibits strong antimicrobial efficacy in vitro and in vivo. Before implementing plasma as new medical treatment tool, its safety must be proven, as well as assessing skin tolerance and patient acceptance.We investigated the plasma effects of three different plasma sources (pulsed, non-pulsed atmospheric pressure plasma jet (APPJ) and a dielectric barrier discharge (DBD)) on the transepidermal water loss (TEWL) and skin moisture after treating the fingertips of four healthy male volunteers.TEWL values were reduced by pulsed APPJ and DBD by about 20% but increased after non-pulsed APPJ by 5-20%. TEWL values normalized 30 min after all forms of plasma treatment. Skin moisture was increased immediately and 30 min after treatment with pulsed APPJ but was not affected by non-pulsed APPJ and DBD.All plasma treatments were well-tolerated and did not damage the skin barrier nor cause skin dryness. Cold plasma fulfils basic recommendations for safe use on human skin and as future option may serve as the first physical skin antiseptic.

To determine the correlation and diagnostic utility of impaired left atrial emptying fraction, an indicator of diastolic dysfunction, with raised intravascular volume determined by vascular pedicle width on upright postero-anterior chest roentgenogram.Cohort study.Department of Medicine, King Abdulaziz National Guard Hospital, Alhasa, Saudi Arabia from October till December 2002.Thirty-two out of 56 patients with normal systolic function (ejection fraction50%) on echocardiogram were included in the study. Left atrial dimensions were measured at the end of left ventricular diastole (LADed) and systole (LADes) on M-mode tracing. Left atrial emptying fraction (LAEF) was calculated by dividing LADed by LADes. Ratio of peak early diastolic velocity (E/A) to peak late diastolic velocity, isovolemic relaxation time (IVRT) and deceleration time of E-wave (DT) were also recorded on transmitral Doppler signal. Postero-anterior views of chest X-rays done within 48 hours of echocardiogram were studied for the measurement of vascular pedicle width (VPW) and cardiothoracic ratio (CTR). Univariate and multiple regression analysis were performed to identify possible predictors of VPW. Receiver operator curves were constructed to see diagnostic utility of impaired LAEF for raised intravascular volume measured by VPW.Mean age for the patients was 58.56 +/- 17 years. There were 15 females (46.9%) and 17 males (54.1%). LADes, LADed, LAEF and DT were 2.89 +/- 0.63 cm, 3.81 +/- 0.53 cm, 0.75 +/- 0.10 and 202 +/- 49.9 msec respectively. VPW and CTR were 55.81 +/- 10.2 mm and 0.54 +/- 0.08. Significant independent predictors of VPW on univariate regression analysis were entered into multiple regression models, which revealed LAEF and DT as the only predictors of VPW. The final regression equation was VPW = 15.43 + 35.7 (LAEF) + 0.06 (DT), R2 = 0.35, p = 0.0008. LAEF0.75 had a sensitivity of 74% and specificity of 94% for diagnosing raised intravascular volume defined as VPW53 mm.LAEF0.75 is a reliable indicator of intravascular volume expansion in patients with normal systolic function signifying diastolic dysfunction and activation of salt and water retaining mechanisms.

Whole lung lavage is still the most effective treatment for pulmonary alveolar proteinosis. We report a 21-year-old male diagnosed with pulmonary alveolar proteinosis by open lung biopsy and who underwent whole lung lavage with a modified technique. He showed significant improvement in clinical and functional parameters. The technique of intermittent double lung ventilation during lavage procedure keeps the oxygen saturation in acceptable limits in patients at risk for severe hypoxemia and allows the procedure to be completed in a single setting.

Many neoplastic tumors exhibit paraneoplastic syndromes manifested by endocrinopathy. This is particularly true of intrathoracic tumors such as lung cancers, thymomas, carcinoid tumors and mediastinal germ cell neoplasm. Fibrous tumors of the pleura are rare intrathoracic tumors, which are usually benign and often grow to huge size. A subset of these neoplasms present with the syndrome of hypoglycemia. Although first reported more than 70 years ago, the diagnosis is rarely considered when a patient presents with syncope and hypoglycemia. This article reports a patient who presented with a large pleural mass and a hypoglycemic syndrome. (The disease was surgically cured.) The probable mechanism of hypoglycemia is discussed.

We describe the case of a young man who presented with abdominal pain, vomiting and acute symmetric peripheral polyneuropathy. He was noted to have high anion gap metabolic acidosis with high lactate levels and persistently high arterial and venous pO2 values. The cerebrospinal fluid was acellular with a high protein and the nerve conduction study was consistent with axonal sensorimotor neuropathy. His clinical condition deteriorated rapidly despite full supportive care and he subsequently died of multiorgan failure. An extensive workup for various infectious, autoimmune and other possible aetiologies was carried out to identify the underlying cause for his fulminant illness. All diagnostic workup was non-conclusive except for a significantly elevated serum aluminium level. We have discussed the possibility of aluminium phosphide poisoning in view of the clinical presentation.