Telepsychiatry in an Era of Digital Mental Health Startups.

PURPOSE OF REVIEW: Telepsychiatry practiced by psychiatrists is evidence-based, regulated, private, and effective in diverse settings. The use of telemedicine has grown since the COVID-19 pandemic as people routinely obtain more healthcare services online. At the same time, there has been a rapid increase in the number of digital mental health startups that offer various services including online therapy and access to prescription medications. These digital mental health firms advertise directly to the consumer primarily through digital advertising. The purpose of this narrative review is to contrast traditional telepsychiatry and the digital mental health market related to online therapy. RECENT FINDINGS: In contrast to standard telepsychiatry, most of the digital mental health startups are unregulated, have unproven efficacy, and raise concerns related to self-diagnosis, self-medicating, and inappropriate prescribing. The role of digital mental health firms for people with serious mental illness has not been determined. There are inadequate privacy controls for the digital mental health firms, including for online therapy. We live in an age where there is widespread admiration for technology entrepreneurs and increasing emphasis on the role of the patient as a consumer. Yet, the business practices of digital mental health startups may compromise patient safety for profits. There is a need to address issues with the digital mental health startups and to educate patients about the differences between standard medical care and digital mental health products.

Hepatobiliary long-term consequences of COVID-19: dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients.

BACKGROUND: Increasing evidence suggests that secondary sclerosing cholangitis (SSC), which can lead to cirrhosis or liver failure, may be a hepatobiliary long-term complication of COVID-19. The aim of this study was to estimate the frequency and outcome of this COVID-19 sequela and to identify possible risk factors. METHODS: This observational study, conducted at University Hospital Charité Berlin and Unfallkrankenhaus Berlin, Germany, involved hospitalized patients with COVID-19 pneumonia, including 1082 ventilated COVID-19 patients. We compared COVID-19 patients who developed SSC with a COVID-19 control group by univariate and multivariate analyses. RESULTS: SSC occurrence after COVID-19 was observed exclusively in critically ill patients with invasive ventilation, albeit with extreme clustering among them. One in every 43 invasively ventilated COVID-19 patients developed this complication. Risk factors preceding the development of secondary sclerosing cholangitis in critically ill COVID-19 patients (SSC-CIP) were signs of systemic reduced blood oxygen supply (e.g., low PaO2/FiO2, ischemic organ infarctions), multi-organ failure (high SOFA score) at admission, high fibrinogen levels and intravenous ketamine use. Multivariate analysis confirmed fibrinogen and increased plasma lactate dehydrogenase as independent risk factors associated with cholangiopathy onset. The 1-year transplant-free survival rate of COVID-19-associated SSC-CIP was 40%. CONCLUSIONS: COVID-19 causes SSC-CIP in a substantial proportion of critically ill patients. SSC-CIP most likely develops due to severe tissue hypoxia and fibrinogen-associated circulatory disturbances. A significant increase of patients with SSC-CIP is to be expected in the post-COVID era.

Lithium's antiviral effects: a potential drug for CoViD-19 disease?

BackgroundSince its introduction in modern medicine, naturalistic observations emerged about possible uses of lithium treatment for conditions different from recurring affective disorders, for which it is still a first-line treatment option. Some evidence about the antiviral properties of lithium began in the early 1970s, when some reports found a reduction of labial-herpetic recurrences. The present review aims to present most of the pre-clinical and clinical evidence about lithium's ability to inhibit DNA and RNA viruses, including Coronaviridae, as well as the possible pathways and mechanisms involved in such antiviral activity.Main bodyDespite a broad number of in vitro studies, the rationale for the antiviral activity of lithium failed to translate into methodologically sound clinical studies demonstrating its antiviral efficacy. In addition, the tolerability of lithium as an antiviral agent should be addressed. In fact, treatment with lithium requires continuous monitoring of its serum levels in order to prevent acute toxicity and long-term side effects, most notably affecting the kidney and thyroid. Yet lithium reaches heterogeneous but bioequivalent concentrations in different tissues, and the anatomical compartment of the viral infection might underpin a different, lower need for tolerability concerns which need to be addressed.ConclusionsLithium presents a clear antiviral activity demonstrated at preclinical level, but that remains to be confirmed in clinical settings. In addition, the pleiotropic mechanisms of action of lithium may provide an insight for its possible use as antiviral agent targeting specific pathways.

Non-patient-related SARS-CoV-2 exposure from colleagues and household members poses the highest infection risk for hospital employees in a German university hospital: follow-up of the prospective Co-HCW seroprevalence study.

PURPOSE: The Co-HCW study is a prospective, longitudinal, single-center observational study that aims to assess the SARS-CoV-2 seroprevalence and infection status in staff members of Jena University Hospital (JUH) in Jena, Germany. METHODS: This follow-up study covers the observation period from 19th May 2020 to 22nd June 2021. At each of the three voluntary study visits, participants filled out a questionnaire regarding their SARS-CoV-2 exposure and provided serum samples to detect specific SARS-CoV-2 antibodies. Participants who were tested positive for antibodies against nucleocapsid and/or spike protein without previous vaccination and/or reported a positive SARS-CoV-2 PCR test were regarded to have been infected with SARS-CoV-2. Multivariable logistic regression modeling was applied to identify potential risk factors for infected compared to non-infected participants. RESULTS: Out of 660 participants that were included during the first study visit, 406 participants (61.5%) were eligible for the final analysis as their COVID-19 risk area (high-risk n = 76; intermediate-risk n = 198; low-risk n = 132) did not change during the study. Forty-four participants [10.8%, 95% confidence interval (95%CI) 8.0-14.3%] had evidence of a current or past SARS-CoV-2 infection detected by serology (n = 40) and/or PCR (n = 28). No association between SARS-CoV-2 infection and the COVID-19 risk group according to working place was detected. However, exposure to a SARS-CoV-2 positive household member [adjusted OR (AOR) 4.46, 95% CI 2.06-9.65] or colleague (AOR 2.30, 95%CI 1.10-4.79) was found to significantly increase the risk of a SARS-CoV-2 infection. CONCLUSION: Our results demonstrate that non-patient-related SARS-CoV-2 exposure posed the highest infection risk for hospital staff members of JUH.

ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol.

INTRODUCTION: Sepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome. METHODS AND ANALYSIS: ImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d'éthique de la recherche sur l'être human of Switzerland. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04990232.

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study.

BACKGROUND: Despite the intense global research endeavour to improve the treatment of patients with COVID-19, the current therapy remains insufficient, resulting in persisting high mortality. Severe cases are characterised by a systemic inflammatory reaction driven by the release of pro-inflammatory cytokines such as IL-6 and tumour-necrosis-factor alpha (TNF-α). TNF-α-blocking therapies have proved beneficial in patients with chronic inflammatory diseases and could therefore pose a new treatment option in COVID-19. Hitherto, no results from randomised controlled trials assessing the effectiveness and safety of infliximab-a monoclonal antibody targeting TNF-α-in the treatment of COVID-19 have been published. METHODS: In this phase-2 clinical trial, patients with COVID-19 and clinical and laboratory signs of hyperinflammation will be randomised to receive either one dose of infliximab (5 mg/kg body weight) in addition to the standard of care or the standard of care alone. The primary endpoint is the difference in 28-day mortality. Further assessments concern the safety of infliximab therapy in COVID-19 and the influence of infliximab on morbidity and the course of the disease. For the supplementary scientific programme, blood and urine samples are collected to assess concomitant molecular changes. The Ethics Committee of the Friedrich Schiller University Jena (2021-2236-AMG-ff) and the Paul-Ehrlich-Institute (4513/01) approved the study. DISCUSSION: The results of this study could influence the therapy of patients with COVID-19 and affect the course of the disease worldwide, as infliximab is globally available and approved by several international drug agencies. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov ( NCT04922827 , 11 June 2021) and at EudraCT ( 2021-002098-25 , 19 May 2021).

Sequence-Specific Features of Short Double-Strand, Blunt-End RNAs Have RIG-I- and Type 1 Interferon-Dependent or -Independent Anti-Viral Effects.

Pathogen-associated molecular patterns, including cytoplasmic DNA and double-strand (ds)RNA trigger the induction of interferon (IFN) and antiviral states protecting cells and organisms from pathogens. Here we discovered that the transfection of human airway cell lines or non-transformed fibroblasts with 24mer dsRNA mimicking the cellular micro-RNA (miR)29b-1* gives strong anti-viral effects against human adenovirus type 5 (AdV-C5), influenza A virus X31 (H3N2), and SARS-CoV-2. These anti-viral effects required blunt-end complementary RNA strands and were not elicited by corresponding single-strand RNAs. dsRNA miR-29b-1* but not randomized miR-29b-1* mimics induced IFN-stimulated gene expression, and downregulated cell adhesion and cell cycle genes, as indicated by transcriptomics and IFN-I responsive Mx1-promoter activity assays. The inhibition of AdV-C5 infection with miR-29b-1* mimic depended on the IFN-alpha receptor 2 (IFNAR2) and the RNA-helicase retinoic acid-inducible gene I (RIG-I) but not cytoplasmic RNA sensors MDA5 and ZNFX1 or MyD88/TRIF adaptors. The antiviral effects of miR29b-1* were independent of a central AUAU-motif inducing dsRNA bending, as mimics with disrupted AUAU-motif were anti-viral in normal but not RIG-I knock-out (KO) or IFNAR2-KO cells. The screening of a library of scrambled short dsRNA sequences identified also anti-viral mimics functioning independently of RIG-I and IFNAR2, thus exemplifying the diverse anti-viral mechanisms of short blunt-end dsRNAs.

Greater Emotional Distress Due to Social Distancing and Greater Symptom Severity during the COVID-19 Pandemic in Individuals with Bipolar Disorder: A Multicenter Study in Austria, Germany, and Denmark.

Throughout the COVID-19 pandemic, mental health of individuals with bipolar disorders (BD) is potentially more vulnerable, especially regarding COVID-19-related regulations and associated symptomatic changes. A multicentric online study was conducted in Austria, Germany, and Denmark during the COVID-19 pandemic. Overall, data from 494 participants were collected (203 individuals with BD, 291 healthy controls (HC)). Participants filled out questionnaires surveying emotional distress due to social distancing, fear of COVID-19, and the Brief Symptom Inventory-18 to assess symptom severity at four points of measurement between 2020 and 2021. General linear mixed models were calculated to determine the difference between the groups in these pandemic specific factors. Individuals with BD reported higher distress due to social distancing than HC, independently of measurement times. Fear of COVID-19 did not differ between groups; however, it was elevated in times of higher infection and mortality due to COVID-19. Individuals with BD reported higher psychiatric symptom severity than HC; however, symptom severity decreased throughout the measured time in the pandemic. Overall, individuals with BD experienced more distress due to the COVID-19 situation than HC. A supportive mental health system is thus recommended to ensure enhanced care, especially in times of strict COVID-19-related regulations.

Redefining critical illness.

Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence-supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-suggests that the current syndrome-based framework of critical illness should be reconsidered. Here we discuss recent findings from basic science and clinical research in critical care and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus on the underlying biological changes that underpin critical illness states and that may be amenable to treatment. We hypothesize that such an approach will accelerate critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside.

„Kriseninternes Lernen“ und „krisenübergreifendes Lernen“ in der deutschen Kommunalverwaltung : Eine empirische Analyse von Verwaltungshandeln während der Flüchtlingskrise und der Corona-Pandemie “Intracrisis-learning” and “intercrisis-learning” in the German Local AdministrationLessons from a comparative analysis of the “migration crisis” in 2015/17 and the first wave of the COVID 19 pandemic

Krisen testen die Leistungsfähigkeit von Verwaltungen unter Realbedingungen. Vor diesem Hintergrund analysiert der vorliegende Beitrag Reaktion der deutschen Kommunalverwaltung auf die Fluchtmigration zwischen 2015 und 2017 und auf die erste Welle der COVID-19-Pandemie in 2020. Mit Blick auf die Debatte zum organisationalen Lernen in Ausnahmesituationen liegt der Schwerpunkt der Analyse auf der Rolle administrativer Netzwerke sowie der Lernfähigkeit von öffentlichen Behörden während sowie zwischen Krisensituationen. Die Auswertung zweier Umfragen unter Mitarbeitern der deutschen Kommunalverwaltung zeigt erstens, dass die Qualität der verwaltungsinternen und der zivilgesellschaftlichen Vernetzung von zentraler Bedeutung für administrative Krisenperformanz sind. Zweitens korrespondiert Leistungsfähigkeit in Krisen mit der Bereitschaft sowie mit der Fähigkeit, Lehren aus früheren Krisen zu ziehen.

„Kriseninternes Lernen“ und „krisenübergreifendes Lernen“ in der deutschen Kommunalverwaltung

Krisen testen die Leistungsfähigkeit von Verwaltungen unter Realbedingungen. Vor diesem Hintergrund analysiert der vorliegende Beitrag Reaktion der deutschen Kommunalverwaltung auf die Fluchtmigration zwischen 2015 und 2017 und auf die erste Welle der COVID-19-Pandemie in 2020. Mit Blick auf die Debatte zum organisationalen Lernen in Ausnahmesituationen liegt der Schwerpunkt der Analyse auf der Rolle administrativer Netzwerke sowie der Lernfähigkeit von öffentlichen Behörden während sowie zwischen Krisensituationen. Die Auswertung zweier Umfragen unter Mitarbeitern der deutschen Kommunalverwaltung zeigt erstens, dass die Qualität der verwaltungsinternen und der zivilgesellschaftlichen Vernetzung von zentraler Bedeutung für administrative Krisenperformanz sind. Zweitens korrespondiert Leistungsfähigkeit in Krisen mit der Bereitschaft sowie mit der Fähigkeit, Lehren aus früheren Krisen zu ziehen.

Web-Based Technologies to Support Carers of People Living With Dementia: Protocol for a Mixed Methods Stepped-Wedge Cluster Randomized Controlled Trial.

BACKGROUND: Informal carers play a significant role in supporting people living with dementia; however, carers in rural areas are often isolated, with limited access to support services. Although dementia-friendly communities provide valued support for carers, access to them is limited as they are few and geographically dispersed. OBJECTIVE: This study's aim was to increase support and services for rural informal carers of people living with dementia by using information and communication technologies accessed through an integrated website and mobile app-the Verily Connect app. The objective of this protocol is to detail the research design used in a complex study that was situated in a challenging real-world setting integrating web-based and on-ground technology and communication. Therefore, it is anticipated that this protocol will strengthen the research of others exploring similar complex concepts. METHODS: A stepped-wedge, open-cohort cluster randomized controlled trial was conducted to implement Verily Connect across 12 rural Australian communities. The Verily Connect intervention delivered web-based, curated information about dementia, a localized directory of dementia services and support, group and individual chat forums, and peer support through videoconference. During the implementation phase of 32 weeks, Verily Connect was progressively implemented in four 8-weekly waves of 3 communities per wave. Usual care, used as a comparator, was available to carers throughout the study period. Participants and researchers were unblinded to the intervention. There were 3 cohorts of participants: carers, volunteers, and staff; participants were recruited from their communities. The primary outcome measure was perceived carer social support measured using the Medical Outcomes Study-Social Support Survey. Volunteers and staff provided feedback on their participation in Verily Connect as qualitative data. Qualitative data were collected from all cohorts of participants through interviews and focus groups. Process evaluation data were collected through interviews and memos written by research staff. Data on the costs of implementing Verily Connect were collected by the research team members and evaluated by a health economist. RESULTS: Between August 2018 and September 2019, a total of 113 participants were recruited. There were 37 (32.7%) carers, 39 (34.5%) volunteers, and 37 (32.7%) health service staff. The study was complex because of the involvement of multiple and varied communities of carers, volunteers, health service staff, and research team members originating from 5 universities. Web-based technologies were used as intervention strategies to support carers and facilitate the process of undertaking the study. CONCLUSIONS: The Verily Connect trial enabled the testing and further development of a web-based approach to increasing support for carers of people living with dementia across a diverse rural landscape in Australia. This protocol provides an example of how to conduct a pragmatic evaluation of a complex and co-designed intervention involving multiple stakeholders. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618001213235; https://tinyurl.com/4rjvrasf. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/33023.

Psychological and behavioral response on the COVID-19 pandemic in individuals with bipolar disorder: A multicenter study.

The COVID-19 pandemic affects both mentally healthy and ill individuals. Individuals with bipolar disorder (BD) constitute an especially vulnerable group. A multicentric online study was conducted in Austria, Denmark, and Germany after the first lockdown phase in 2020. In total, 117 healthy controls (HC) were matched according to age and sex to 117 individuals with BD. The survey included the Brief Symptom Inventory-18, Beck Depression Inventory-2, Pittsburgh Sleep Quality Index, and a self-constructed questionnaire assessing COVID-19 fears, emotional distress due to social distancing, lifestyle, and compliance to governmental measures. In individuals with BD, increased symptoms of depression, somatization, anxiety, distress due to social distancing, and poorer sleep quality were related to emotional distress due to social distancing. The correlation between emotional distress due to social distancing and anxiety showed 26% of shared variance in BD and 11% in HC. Negative lifestyle changes and lower compliance with COVID-19 regulatory measures were more likely to be observed in individuals with BD than in HC. These findings underscore the need for ongoing mental health support during the pandemic. Individuals with BD should be continuously supported during periods of social distancing to maintain a stable lifestyle and employ strategies to cope with COVID-19 fears.

Covid-19: Contributions from Psychopharmacology.

The COVID-19 pandemic is causing a major burden on personal health, healthcare systems and the global economy. For the last two years the COVID-19 pandemic has dramatically changed our lives in many personal and professional areas. For millions of us, due to infection rates, but also to protection measures such as lockdowns the corona pandemic has significantly changed the way we work, how we live, and how we interact with technology. In addition to the development of effective vaccines, anti-viral and anti-inflammation strategies are of eminent importance to treat people with acute infection or at least prevent serious negative outcomes. In contrast to the fast development of several effective vaccines that were remarkably available already after one year of the pandemic, novel effective anti-viral compounds are still in development. The only currently used effective medications against severe SARS-CoV-2 virus infection are corticosteroids 1.

Identification of broad anti-coronavirus chemical agents for repurposing against SARS-CoV-2 and variants of concern.

Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV-229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counter selection and challenge with the ß-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability. Methylene blue (MB, used for the treatment of methemoglobinemia), Mycophenolic acid (MPA, used in organ transplantation) and the anti-fungal agent Posaconazole (POS) had the broadest anti-CoV spectrum. They inhibited the shedding of SARS-CoV-2 and variants-of-concern (alpha, beta, gamma, delta) from HAEEC in either pre- or post exposure regimens at clinically relevant concentrations. Co-treatment of cultured cells with MB and the FDA-approved SARS-CoV-2 RNA-polymerase inhibitor Remdesivir reduced the effective anti-viral concentrations of MB by 2-fold, and Remdesivir by 4 to 10-fold, indicated by BLISS independence synergy modelling. Neither MB, nor MPA, nor POS affected the cell delivery of SARS-CoV-2 or OC43 (+)sense RNA, but blocked subsequent viral RNA accumulation in cells. Unlike Remdesivir, MB, MPA or POS did not reduce the release of viral RNA in post exposure regimen, thus indicating infection inhibition at a post-replicating step as well. In summary, the data emphasize the power of unbiased, full cycle compound screens to identify and repurpose broadly acting drugs against coronaviruses.

Comparison of fatigue, cognitive dysfunction and psychological disorders in post-COVID patients and patients after sepsis: is there a specific constellation?

BACKGROUND: Sequelae of COVID-19 can be severe and longlasting. We compared frequencies of fatigue, depression and cognitive dysfunction in survivors of SARS-CoV-2-infection and sepsis. METHODS: We performed a prospective cohort study of 355 symptomatic post-COVID patients who visited our out-patient clinic for post-COVID-19 care. We compared them with 272 symptomatic patients from the Mid-German Sepsis Cohort, which investigates the long-term courses of sepsis survivors. Possible predictors for frequent clinical findings (fatigue, signs of depression, cognitive dysfunction) in post-COVID were investigated with multivariable logistic regression. RESULTS: Median age of the post-COVID patients was 51 years (range 17-86), 60.0% were female, and 31.8% required hospitalization during acute COVID-19. In the post-COVID patients (median follow-up time: 163 days) and the post-sepsis patients (180 days), fatigue was found in 93.2% and 67.8%, signs of depression were found in 81.3% and 10.9%, and cognitive dysfunction was found in 23.5% and 21.3%, respectively. In post-COVID, we did not observe an association between fatigue or depression and the severity of acute COVID-19. In contrast, cognitive dysfunction was associated with hospitalization (out-patient versus in-patient) and more frequent in post-COVID patients treated on an ICU compared to the MSC patients. CONCLUSION: In post-COVID patients, fatigue and signs of depression are more common than in sepsis survivors, independent from the acute SARS-CoV-2-infection. In contrast, cognitive dysfunction is associated with hospitalization. Despite the differences in frequencies, owing to the similarity of post-COVID and post-sepsis sequelae, this knowledge may help in implementing follow-up approaches after SARS-CoV-2 infection.

Activation of Sphingomyelinase-Ceramide-Pathway in COVID-19 Purposes Its Inhibition for Therapeutic Strategies.

Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs. Here, we report the activation of sphingomyelinase-ceramide pathway in 23 intensive care patients with severe COVID-19. We observed an increase of circulating activity of sphingomyelinase with subsequent derangement of sphingolipids in serum lipoproteins and from red blood cells (RBC). Consistent with increased ceramide levels derived from the inert membrane constituent sphingomyelin, increased activity of acid sphingomyelinase (ASM) accurately distinguished the patient cohort undergoing intensive care from healthy controls. Positive correlational analyses with biomarkers of severe clinical phenotype support the concept of an essential pathophysiological role of ASM in the course of SARS-CoV-2 infection as well as of a promising role for functional inhibition with anti-inflammatory agents in SARS-CoV-2 infection as also proposed in independent observational studies. We conclude that large-sized multicenter, interventional trials are now needed to evaluate the potential benefit of functional inhibition of this sphingomyelinase in critically ill patients with COVID-19.

Erythrocytes increase endogenous sphingosine 1-phosphate levels as an adaptive response to SARS-CoV-2 infection.

Low plasma levels of the signaling lipid metabolite sphingosine 1-phosphate (S1P) are associated with disrupted endothelial cell (EC) barriers, lymphopenia and reduced responsivity to hypoxia. Total S1P levels were also reduced in 23 critically ill patients with coronavirus disease 2019 (COVID-19), and the two main S1P carriers, serum albumin (SA) and high-density lipoprotein (HDL) were dramatically low. Surprisingly, we observed a carrier-changing shift from SA to HDL, which probably prevented an even further drop in S1P levels. Furthermore, intracellular S1P levels in red blood cells (RBCs) were significantly increased in COVID-19 patients compared with healthy controls due to up-regulation of S1P producing sphingosine kinase 1 and down-regulation of S1P degrading lyase expression. Cell culture experiments supported increased sphingosine kinase activity and unchanged S1P release from RBC stores of COVID-19 patients. These observations suggest adaptive mechanisms for maintenance of the vasculature and immunity as well as prevention of tissue hypoxia in COVID-19 patients.

Towards an ecological definition of sepsis: a viewpoint.

In critically ill patients with sepsis, there is a grave lack of effective treatment options to address the illness-defining inappropriate host response. Currently, treatment is limited to source control and supportive care, albeit with imminent approval of immune modulating drugs for COVID-19-associated lung failure the potential of host-directed strategies appears on the horizon. We suggest expanding the concept of sepsis by incorporating infectious stress within the general stress response of the cell to define sepsis as an illness state characterized by allostatic overload and failing adaptive responses along with biotic (pathogen) and abiotic (e.g., malnutrition) environmental stress factors. This would allow conceptualizing the failing organismic responses to pathogens in sepsis with an ancient response pattern depending on the energy state of cells and organs towards other environmental stressors in general. Hence, the present review aims to decipher the heuristic value of a biological definition of sepsis as a failing stress response. These considerations may motivate a better understanding of the processes underlying "host defense failure" on the organismic, organ, cell and molecular levels.

Physical Health Profile and Associated Behavior During the COVID-19 Pandemic in Patients With Bipolar Disorder.

Background: The COVID-19 pandemic has led to an increased psychological strain on public mental health and may impact behavioral, mental, and physical health, presumably with effects on patients with severe mental disorders. This study examines pandemic-related physical and mental health and (compensatory) behavioral changes, in patients with BD as compared to healthy control individuals. Method: Physical and mental health and self-reported changes in daily structure and behavior due to the pandemic were assessed using a self-constructed questionnaire and the brief symptom inventory (BSI) in Germany, Austria, and Denmark in individuals with BD and a healthy control group. Results: The present study included 118 individuals with BD and 215 healthy controls. Individuals with BD reported statistically significant higher physical risk burden, increased weight gain, more physical comorbidities, and a decrease in physical activity and they further reported higher rates of COVID-19 testing, had more worries concerning health, and experienced more anxiety but less social distancing. Conclusion: The COVID-19 pandemic seems to have a greater impact on physical health in individuals with BD than in healthy controls. Individuals with BD appear to be having more difficulties compensating their behavior due to the pandemic which could amplify the effect of risk factors associated with poorer physical health. This highlights the necessity for optimizing and targeting the overall treatment of both mental and physical health in patients with BD during periods with far-reaching changes such as the COVID-19 pandemic. Limitations: Sampling issues and self-report forms, selectivity (missing elderly, and those lacking access or knowledge of technology).