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Robotics is widely seen as a key enabling technology for the society of tomorrow. This work examines the role of robotics and intelligent medical devices in Intensive Care Medicine. Demographics predict that more elderly patients will need to be treated with fewer healthcare personnel, calling for innovations in ICU management. Robotics is a key enabling technology for the 21st century and may help to smooth the foreseeable workload/manpower disparity in medicine. Studying the application of robotics in the ICU in a manner beneficial for patients and accepted by intensive care team is desirable. Financial sustainability is essential for the introduction of these new technologies to the ICU. This study therefore assesses the state of the art in robotics in intensive care medicine and identifies opportunities for progress, using an observational approach in a teaching hospital ICU in combination with an in-depth review of the literature and a survey of the market. Tasks amenable to robotics are identified, their acceptability to patients and caregivers are examined and their quantitative contribution to future management of an intensive care unit is assessed.

Activation of the kynurenine pathway (KP) has been shown to predict outcome in cardiac arrest (CA) patients. We validated these findings in a Swiss cohort.We measured admission tryptophan and kynurenine levels in 270 consecutive CA patients (38 in-hospital CA) and investigated associations with in-hospital mortality and neurological outcome at hospital discharge.120 of 270 (44%) patients died in the hospital. Compared to survivors, non-survivors showed higher median initial kynurenine levels (5.28 μmol/l [IQR 2.91 to 7.40] vs 3.58 μmol/l [IQR 2.47 to 5.46]; p 0.001) and a higher median kynurenine/tryptophan ratio (0.10 μmol/l [IQR 0.07 to 0.17] vs 0.07 μmol/l [IQR 0.05 to 0.1]; p 0.001). In a model adjusted for age, gender and comorbidities, kynurenine (OR 1.16, 95% CI 1.05 to 1.27; p = 0.001) and kynurenine/tryptophan ratio (OR 1.19, 95% CI 1.08 to 1.31; p = 0.003) were significantly associated with mortality. Results were similar for neurological outcome.Our findings validate a previous study and show associations of the activation of the KP with unfavorable outcomes after CA. Future studies should evaluate whether therapeutic modulation of the KP may impact clinical outcomes after CA.

Efficacy of donated COVID-19 convalescent plasma (dCCP) is uncertain and may depend on antibody titers, neutralizing capacity, timing of administration, and patient characteristics.In a single-center hypothesis-generating prospective case-control study with 1:2 matched dCCP recipients to controls according to disease severity at day 1, hospitalized adults with COVID-19 pneumonia received 2 × 200 ml pathogen-reduced treated dCCP from 2 different donors. We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 convalescent plasma donors and recipients using multiple antibody assays including a Coronavirus antigen microarray (COVAM), and binding and neutralizing antibody assays. Outcomes were dCCP characteristics, antibody responses, 28-day mortality, and dCCP -related adverse events in recipients.Eleven of 13 dCCPs (85%) contained neutralizing antibodies (nAb). PRT did not affect dCCP antibody activity. Fifteen CCP recipients and 30 controls (median age 64 and 65 years, respectively) were enrolled. dCCP recipients received 2 dCCPs from 2 different donors after a median of one hospital day and 11 days after symptom onset. One dCCP recipient (6.7%) and 6 controls (20%) died (p = 0.233). We observed no dCCP-related adverse events. Transfusion of unselected dCCP led to heterogeneous SARS CoV-2 antibody responses. COVAM clustered dCCPs in 4 distinct groups and showed endogenous immune responses to SARS-CoV-2 antigens over 14-21 days post dCCP in all except 4 immunosuppressed recipients.PRT did not impact dCCP anti-virus neutralizing activity. Transfusion of unselected dCCP did not impact survival and had no adverse effects. Variable dCCP antibodies and post-transfusion antibody responses indicate the need for controlled trials using well-characterized dCCP with informative assays.

Objectives SARS-CoV-2 may cause acute lung injury, and secondary infections are thus relevant complications in patients with COVID-19 pneumonia. However, detailed information on community- and hospital-acquired infections among patients with COVID-19 pneumonia is scarce. Methods We identified 220 SARS-CoV-2-positive patients hospitalized at the University Hospital Basel, Switzerland (between 25 February and 31 May 2020). We excluded patients who declined the general consent (n = 12), patients without clinical evidence of pneumonia (n = 29), and patients hospitalized for n = 17). We evaluated the frequency of community- and hospital-acquired infections using respiratory and blood culture materials with antigen, culture-based, and molecular diagnostics. For ICU patients, all clinical and microbial findings were re-evaluated interdisciplinary (intensive care, infectious disease, and clinical microbiology), and agreement reached to classify patients with infections. Results In the final cohort of 162 hospitalized patients (median age 64.4 years (IQR, 50.4–74.2); 61.1% male), 41 (25.3%) patients were admitted to the intensive care unit, 34/41 (82.9%) required mechanical ventilation, and 17 (10.5%) of all hospitalized patients died. In total, 31 infections were diagnosed including five viral co-infections, 24 bacterial infections, and three fungal infections (ventilator-associated pneumonia, n = 5; tracheobronchitis, n = 13; pneumonia, n = 1; and bloodstream infection, n = 6). Median time to respiratory tract infection was 12.5 days (IQR, 8–18) and time to bloodstream infection 14 days (IQR, 6–30). Hospital-acquired bacterial and fungal infections were more frequent among ICU patients than other patients (36.6% vs. 1.7%). Antibiotic or antifungal treatment was administered in 71 (43.8%) patients. Conclusions Community-acquired viral and bacterial infections were rare among COVID-19 pneumonia patients. By contrast, hospital-acquired bacterial or fungal infections were frequently complicating the course among ICU patients.

Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p p p p p Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

OBJECTIVES: Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is key to the clinical and epidemiological assessment of CoVID-19. We cross-validated manual and automated high-throughput testing for SARS-CoV-2-RNA, evaluated SARS-CoV-2 loads in nasopharyngeal-oropharyngeal swabs (NOPS), lower respiratory fluids, and plasma, and analyzed detection rates after lockdown and relaxation measures. METHODS: Basel-S-gene, Roche-E-gene, and Roche-cobas®6800-Target1 and Target2 were prospectively validated in 1344 NOPS submitted during the first pandemic peak (Week 13). Follow-up cohort (FUP) 1, 2, and 3 comprised 10,999, 10,147, and 19,389 NOPS submitted during a 10-week period until Weeks 23, 33, and 43, respectively. RESULTS: Concordant results were obtained in 1308 cases (97%), including 97 (9%) SARS-CoV-2-positives showing high quantitative correlations (Spearman's r > .95; p < .001) for all assays and high precision by Bland-Altman analysis. Discordant samples (N = 36, 3%) had significantly lower SARS-CoV-2 loads (p < .001). Following lockdown, detection rates declined to

ImportanceGrowing evidence suggests that coronavirus disease 2019 (COVID-19) is associated with neurological sequelae. However, the underlying pathophysiological mechanisms resulting in central nervous system (CNS) derogation remain unclear.ObjectiveTo identify severity-dependent immune mechanisms in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and their association with brain imaging alterations.DesignProspective cross-sectional cohort study.SettingThis study was performed from August 2020 to April 2021. Participants were enrolled in the outpatient clinics, hospital wards and intensive care units (ICU) of two clinical sites in Basel and Zurich, Switzerland.ParticipantsAge >18 years and a positive SARS-CoV-2 test result were inclusion criteria. Potentially matching individuals were identified (n=310), of which 269 declined to participate and 1 did not match inclusion criteria. Paired CSF and plasma samples, as well as brain images, were acquired. The COVID-19 cohort (n=40; mean [SD] age, 54 [20] years; 17 women (42%)) was prospectively assorted by neurological symptom severity (classes I, II and III). Age/sex-matched inflammatory (n=25) and healthy (n=25) CSF and plasma control samples were obtained. For volumetric brain analysis, a healthy age/sex-matched control cohort (n=36) was established.ExposuresLumbar puncture, blood sampling and cranial MRI and/or CT.Main outcomes and measuresProteomics, standard parameters and antibody profiling of paired CSF and plasma samples in COVID-19 patients and controls. Brain imaging and gray matter volumetric analysis in association with biomarker profiles. Follow-up after 10-months.ResultsCOVID-19 patients displayed a plasma cytokine storm but a non-inflammatory CSF profile. Class III patients displayed signs of blood-brain barrier (BBB) impairment and a polyclonal B cell response targeting self- and non-self antigens. Decreased regional brain volumes were present in COVID-19 patients and associated with specific CSF and plasma parameters.Conclusion and relevanceNeuro-COVID class III patients had a strong, peripheral immune response resulting in (1) BBB impairment (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Our data point towards several potentially actionable targets that may be addressed to prevent COVID-19-related neurological sequelae.Trial registrationThe trial (NCT04472013) was registered on clinicaltrials.gov.Key pointsQuestionDoes a severity-dependent pattern of immune mechanisms exist in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and are these associated with clinical and brain imaging findings?FindingsNeuro-COVID patients display a robust class III-specific peripheral immune response resulting in (1) blood-brain barrier (BBB) impairment, (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Integration of MRIs, brain volumetry and proteomics identified biomarkers associated with regional brain volume loss in severe Neuro-COVID.MeaningWe provide a multidimensional framework of mechanisms associated with severe Neuro-COVID and present possible targets to prevent COVID-19-related neurological sequelae.

Background Transmission chains within small urban areas (accommodating∼30% of the European population) greatly contribute to case burden and economic impact during the ongoing COVID-19 pandemic, and should be a focus for preventive measures to achieve containment. Here, at very high spatio-temporal resolution, we analysed determinants of SARS-CoV-2 transmission in a European urban area, Basel-City (Switzerland). Methodology. We combined detailed epidemiological, intra-city mobility, and socioeconomic data-sets with whole-genome-sequencing during the first SARS-CoV-2 wave. For this, we succeeded in sequencing 44% of all reported cases from Basel-City and performed phylogenetic clustering and compartmental modelling based on the dominating viral variant (B.1-C15324T; 60% of cases) to identify drivers and patterns of transmission. Based on these results we simulated vaccination scenarios and corresponding healthcare-system burden (intensive-care-unit occupancy). Principal Findings. Transmissions were driven by socioeconomically weaker and highly mobile population groups with mostly cryptic transmissions, whereas amongst more senior population transmission was clustered. Simulated vaccination scenarios assuming 60-90% transmission reduction, and 70-90% reduction of severe cases showed that prioritizing mobile, socioeconomically weaker populations for vaccination would effectively reduce case numbers. However, long-term intensive-care-unit occupation would also be effectively reduced if senior population groups were prioritized, provided there were no changes in testing and prevention strategies. Conclusions. Reducing SARS-CoV-2 transmission through vaccination strongly depends on the efficacy of the deployed vaccine. A combined strategy of protecting risk groups by extensive testing coupled with vaccination of the drivers of transmission (i.e. highly mobile groups) would be most effective at reducing the spread of SARS-CoV-2 within an urban area., medRxiv

Commercially available SARS-CoV-2-directed antibody assays may assist in diagnosing past exposure to SARS-CoV-2 antigens. We cross-compared the following eight immunoassays detecting antibodies against SARS-CoV-2 nucleocapsid (N) or spike (S) antigens in three cohorts consisting of 859 samples from 622 patients: (#1) EDI novel coronavirus COVID-19 (Epitope), (#2) RecomWell SARS-CoV-2 (Mikrogen), (#3) COVID-19 ELISA (VirCell), (#4) Elecsys anti-SARS-CoV-2 N (Roche), (#5) Liaison SARS-CoV-2 S1/S2 (DiaSorin), (#6) anti-SARS-CoV-2 ELISA (EuroImmun), (#7) Elecsys anti-SARS-CoV-2 S (Roche), and (#8) Liaison SARS-CoV-2 TrimericS (DiaSorin). In cross-sectional cohort 1 (68 sera from 38 patients with documented SARS-CoV-2 infection), agreement between assays #1 to #6 ranged from 75% to 93%, whereby discordance mostly resulted from N-based assays #1 to #4. In cross-sectional cohort 2 (510 sera from 510 patients; 56 documented, 454 unknown SARS-CoV-2 infection), assays #4 to #6 were analyzed further together with assays #7 and #8, revealing 94% concordance (44 [9%] positives and 485 [85%] negatives). Discordance was highest within 2 weeks after SARS-CoV-2/COVID-19 diagnosis and confirmed in the longitudinal cohort 3 (281 sera from 74 COVID-19 patients), using assays #4, #6, #7, and #8. Subanalysis of 20 (27%) initially seronegative cohort 3 patients revealed assay-dependent 50% and 90% seroconversion rates after 8 to 11 days and 14 to 18 days, respectively. Increasing SARS-CoV-2 antibodies were significantly associated with declining levels of viral loads, lactate dehydrogenase, interleukin-6, and C-reactive protein and preceded clearance of SARS-CoV-2 detection in the upper respiratory tract by approximately 1 week. SARS-CoV-2-specific antibody assays show substantial agreement, but interpretation of qualitative and semiquantitative results depends on the time elapsed postdiagnosis and the choice of viral antigen. Mounting of systemic SARS-CoV-2-specific antibodies may predict recovery from viral injury and clearance of mucosal replication.

Worldwide, the left ventricular assist device Impella® (Abiomed, Danvers, MA, USA) is increasingly implanted in patients with acute cardiogenic shock or undergoing high-risk cardiac interventions. Despite its long history of use, few studies have assessed its safety and possible complications associated with its use. All patients treated with a left-sided Impella® device at the University Hospital of Basel from 1 January 2011 to 31 December 2019 were enrolled. The primary endpoint was the composite rate of mortality and adverse events (bleeding, acute kidney injury, and limb ischemia). Out of 281 included patients, at least one adverse event was present in 262 patients (93%). Rates of in-hospital, 90-day, and one-year mortality were 48%, 47%, and 50%, respectively. BARC type 3 bleeding (62%) and hemolysis (41.6%) were the most common complications. AKI was observed in 50% of all patients. Renal replacement therapy was required in 97 (35%) of all patients. Limb ischemia occurred in 13% of cases. Bleeding and hemolysis are common Impella®-associated complications. Additionally, we found a high rate of AKI. A careful selection of patients receiving microaxial LV support and defining the indication for its use are essential measures to be taken for the benefits to outweigh potential complications.

BackgroundEvidence to date indicates that mortality of acute coronavirus disease (COVID-19) is higher in men than in women. Conversely, women seem more likely to suffer from long-term consequences of the disease and pronounced negative social and economic impacts. Sex- and gender specific risk factors of COVID-19-related long-term effects are unknown. MethodsWe conducted a multicentre prospective observational cohort study of 5838 (44.6% women) individuals in Switzerland who were tested positive for SARS-CoV-2 RNA between February and December 2020. Of all surviving individuals who met the inclusion criteria, 2799 (1285 [45.9%] women) completed a follow-up questionnaire. FindingsAfter a mean follow-up time of 197{+/-}77 days, women more often reported at least one persistent symptom (43.0% vs 31.5%, p

Objective:To determine whether colonization with extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-PE) predicts the risk for subsequent infection and impacts carbapenem-consumption and outcome in intensive care unit (ICU) patients.Design:Prospective cohort study.Setting:The 2 ICUs in the University Hospital Basel in Switzerland.Patients:All patients admitted to the 2 ICUs providing mechanical ventilation and an expected ICU stay >48 hours.Methods:Patients were routinely screened for ESBL-PE carriage by rectal swab on admission. Competing risk regression analyses were applied to calculate hazard ratios (HRs) for infection with ESBL-PE and mortality. Length of hospital stay, length of ICU stay, and duration of carbapenem exposure were compared using the Mann-Whitney U test.Results:Among 302 patients, 24 (8.0%) were colonized with ESBL-PE on ICU admission. Infections with ESBL-PE occurred in 4 patients, of whom 3 (75%) were identified as ESBL-PE colonized on admission. ESBL-PE colonization on admission was associated with subsequent ESBL-PE infection (hazard ratio [HR], 25.52; 95% confidence interval [CI], 2.40–271.41; P = .007) and exposure to carbapenems (HR, 2.42; 95% CI, 1.01–5.79; P = .047), whereas duration of carbapenem exposure did not differ in relation to ESBL-PE colonization (median, 7 days [IQR, 3–8 days] vs median, 6 days [IQR 3–9 days]; P = 0.983). Patients colonized with ESBL-PE were not at increased risk for death overall (HR, 1.00; 95% CI, 0.44–2.30; P = .993) or death attributable to infection (HR, 1.20; 95% CI, 0.28–5.11; P = .808).Conclusions:Screening strategies for detection of ESBL-PE colonization on ICU admission may allow the identification of patients at highest risk for ESBL-PE infection and the correct allocation of empiric carbapenem treatment.

A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by nsp12-nsp7-nsp8) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting nsp12 (Tajima’s D = −2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic.

The morbidity and mortality of patients requiring mechanical ventilation for coronavirus disease 2019 (COVID-19) pneumonia is considerable. We studied the use of whole-lung low dose radiation therapy (LDRT) in this patient cohort.Patients admitted to the intensive care unit (ICU) and requiring mechanical ventilation for COVID-19 pneumonia were included in this randomized double-blind study. Patients were randomized to 1 Gy whole-lung LDRT or sham irradiation (sham-RT). Treatment group allocation was concealed from patients and ICU clinicians, who treated patients according to the current standard of care. Patients were followed for the primary endpoint of ventilator-free days (VFDs) at day 15 post-intervention. Secondary endpoints included overall survival, as well as changes in oxygenation and inflammatory markers.Twenty-two patients were randomized to either whole-lung LDRT or sham-RT between November and December 2020. Patients were generally elderly and comorbid, with a median age of 75 years in both arms. No difference in 15-day VFDs was observed between groups (p = 1.00), with a median of 0 days (range, 0-9) in the LDRT arm, and 0 days (range, 0-13) in the sham-RT arm. Overall survival at 28 days was identical at 63.6% (95%CI, 40.7-99.5%) in both arms (p = 0.69). Apart from a more pronounced reduction in lymphocyte counts following LDRT (p0.01), analyses of secondary endpoints revealed no significant differences between the groups.Whole-lung LDRT failed to improve clinical outcomes in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

Supplemental Digital Content is available in the text., Objectives: Various ethical challenges are prevalent in ICUs. In order to handle these problems, a highly structured internal ethical case discussion within the multiprofessional team was implemented in 2011 in a Swiss ICU and has been regularly practiced almost weekly until present. To explore the results of all ethical case discussions taking place in a general ICU and to discuss the outcomes of the patients. To identify the conditions facilitating the implementation of regular ethical case discussions. Design: Retrospective case series analysis. Setting: Mixed academic ICU. Patients AND INTERVENTION: All patients who had an ethical case discussion between January 2011 and December 2019 following the approach called Modular, Ethical, Treatment decisions, Allocation of resources at the micro-level, and Process. MEASUREMENTS AND Main Results: Weekly ethical case discussions held regularly on a fixed date were found to be practical for the observed ICU. A total of 314 ethical case discussions were realized in 281 patients. Median patient age was 70 years (interquartile range, 62–77 yr); two thirds were men. The results were categorized into the following groups: established therapy continues, complications to be treated (n = 53; 16.9%); therapy continues, patient’s will to be explored further (n = 77; 24.5%); therapy continues, complications to be treated only after evaluation (n = 62; 19.7%); therapy continues with limitations (e.g., do-not-resuscitate order) (n = 98; 31.2%); and change of treatment plan to end-of-life care (n = 17; 5.4%). Of the discussed patients, 115 (40.9%) died in the ICU and 29 (10.3%) after transfer to the normal ward. Seven patients (2.5%) were transferred to a hospice and 55 (19.6%) to another hospital. Sixty-nine (24.6%) were discharged to a rehabilitative facility and six returned home. Conclusions: Regular ethical case discussions can be successfully implemented, enabling careful review of the patient’s will and balancing it with the prognosis of the disease. This facilitates a necessary change of the therapeutic goal whenever appropriate.

The proportion of asymptomatic carriers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains elusive and the potential benefit of systematic screening during the SARS-CoV-2-pandemic is controversial. We investigated the proportion of asymptomatic inpatients who were identified by systematic screening for SARS-CoV-2 upon hospital admission. Our analysis revealed that systematic screening of asymptomatic inpatients detects a low total number of SARS-CoV-2 infections (0.1%), questioning the cost–benefit ratio of this intervention. Even when the population-wide prevalence was low, the proportion of asymptomatic carriers remained stable, supporting the need for universal infection prevention and control strategies to avoid onward transmission by undetected SARS-CoV-2-carriers during the pandemic.

PURPOSE: The morbidity and mortality of patients requiring mechanical ventilation for coronavirus disease 2019 (COVID-19) pneumonia is considerable. We studied the use of whole-lung low-dose radiation therapy (LDRT) in this patient cohort. METHODS AND MATERIALS: Patients admitted to the intensive care unit and requiring mechanical ventilation for COVID-19 pneumonia were included in this randomized double-blind study. Patients were randomized to 1 Gy whole-lung LDRT or sham irradiation (sham-RT). Treatment group allocation was concealed from patients and intensive care unit clinicians, who treated patients according to the current standard of care. Patients were followed for the primary endpoint of ventilator-free days at day 15 postintervention. Secondary endpoints included overall survival, as well as changes in oxygenation and inflammatory markers. RESULTS: Twenty-two patients were randomized to either whole-lung LDRT or sham-RT between November and December 2020. Patients were generally elderly and comorbid, with a median age of 75 years in both arms. No difference in 15-day ventilator-free days was observed between groups (P = 1.00), with a median of 0 days (range, 0-9) in the LDRT arm and 0 days (range, 0-13) in the sham-RT arm. Overall survival at 28 days was identical at 63.6% (95% confidence interval, 40.7%-99.5%) in both arms (P = .69). Apart from a more pronounced reduction in lymphocyte counts after LDRT (P < .01), analyses of secondary endpoints revealed no significant differences between the groups. CONCLUSIONS: Whole-lung LDRT failed to improve clinical outcomes in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

Antiviral treatments for COVID-19 have involved many repurposed drugs. Currently, SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded bynsp12-nsp7-nsp8) has been targeted by numerous inhibitors with debated clinical impact. Among these, remdesivir has been conditionally approved for the treatment of COVID-19 patients. Although the emergence of antiviral resistance, an indirect proxy for antiviral efficacy, poses a considerable healthcare threat, an evolutionary perspective on emerging resistant mutants is still lacking.Here we show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare, and unlikely to lead to viral fitness loss.In more than 56,000 viral genomes from 105 countries dating from December 2019 to July 2020 we found negative selective pressure affectingnsp12(Tajima’s D = −2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Those affected known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations found globally,in silicostructural models show that this rarely implies loss of stability in RdRp. No potential escape mutation were found in our local cohort of remdesivir treated patients from the first wave (n=8). Our results indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. Our study could be the starting point of a larger monitoring effort of drug resistance throughout the COVID-19 pandemic. We recommend the application of repetitive genome sequencing of SARS-CoV-2 from patients treated with antivirals to provide early insights into the evolution or antiviral resistance.

The first case of SARS-CoV-2 in Basel, Switzerland was detected on February 26th 2020. We present a phylogenetic study to explore viral introduction and evolution during the exponential early phase of the local COVID-19 outbreak from February 26th until March 23rd. We sequenced SARS-CoV-2 naso-oropharyngeal swabs from 746 positive tests that were performed at the University Hospital Basel during the study period. We successfully generated 468 high quality genomes from unique patients and called variants with our COVID-19 Pipeline (COVGAP), and analysed viral genetic diversity using PANGOLIN taxonomic lineages. To identify introduction and dissemination events we incorporated global SARS-CoV-2 genomes and inferred a time-calibrated phylogeny. Epidemiological data from patient questionnaires was used to facilitate the interpretation of phylogenetic observations. The early outbreak in Basel was dominated by lineage B.1 (83·6%), detected first on March 2nd, although the first sample identified belonged to B.1.1. Within B.1, 68·2% of our samples fall within a clade defined by the SNP C15324T (‘Basel cluster’), including 157 identical sequences at the root of the ‘Basel cluster’, some of which we can specifically trace to regional spreading events. We infer the origin of B.1-C15324T to mid-February in our tri-national region. The other genomes map broadly over the global phylogenetic tree, showing several introduction events from and/or dissemination to other regions of the world via travellers. Family transmissions can also be traced in our data. A single lineage variant dominated the outbreak in the Basel area while other lineages, such as the first (B.1.1), did not propagate. A mass gathering event was the predominant initial source of cases, with travel returners and family transmissions to a lesser extent. We highlight the importance of adding specific questions to epidemiological questionnaires, to obtain data on attendance of large gatherings and their locations, as well as travel history, to effectively identify routes of transmissions in up-coming outbreaks. This phylogenetic analysis in concert with epidemiological and contact tracing data, allows connection and interpretation of events, and can inform public health interventions. Trial Registration: ClinicalTrials.gov NCT04351503., Author summary COVID-19 was first reported in December 2019 in Wuhan, China, and has spread around the globe since. The most common tool for tracking and containing the spread of the disease-causing virus–SARS-CoV-2 –are classical epidemiology and contact tracing, which collapse under too high case burdens as seen in this pandemic. However, whole-genome sequencing and phylogenetic analyses of the viral genomes will be crucial to understand the virus evolution and outbreak dynamics to ultimately stop the spread of the disease. Here we combined epidemiological data and whole-genome sequences originating from the time of the arrival of the virus in early 2020 in a typical medium-sized European city, namely Basel-City, Switzerland. On one hand, we identified limited community spread of very distinct viral variants originating from travel returners, which is possibly due to the heightened attention and restrictions imposed on international travellers. On the other hand, we find evidence for large cryptic community spread of a single virus variant in the city, which we infer to have originated around mid-February 2020 in the larger tri-national area around Basel, and which has epidemiological links to a mass gathering event in the region of Alsace, France.

BACKGROUND End-of-life practices vary among intensive care units (ICUs) worldwide. Differences can result in variable use of disproportionate or non-beneficial life-sustaining interventions across diverse world regions. This study investigated global disparities in end-of-life practices. METHODS In this prospective, multinational, observational study, consecutive adult ICU patients who died or had a limitation of life-sustaining treatment (withholding or withdrawing life-sustaining therapy and active shortening of the dying process) during a 6-month period between Sept 1, 2015, and Sept 30, 2016, were recruited from 199 ICUs in 36 countries. The primary outcome was the end-of-life practice as defined by the end-of-life categories: withholding or withdrawing life-sustaining therapy, active shortening of the dying process, or failed cardiopulmonary resuscitation (CPR). Patients with brain death were included in a separate predefined end-of-life category. Data collection included patient characteristics, diagnoses, end-of-life decisions and their timing related to admission and discharge, or death, with comparisons across different regions. Patients were studied until death or 2 months from the first limitation decision. FINDINGS Of 87 951 patients admitted to ICU, 12 850 (14·6%) were included in the study population. The number of patients categorised into each of the different end-of-life categories were significantly different for each region (p

BackgroundTransmission chains within small urban areas (accommodating∼30% of the European population) greatly contribute to case burden and economic impact during the ongoing COVID-19 pandemic, and should be a focus for preventive measures to achieve containment. Here, at very high spatio-temporal resolution, we analysed determinants of SARS-CoV-2 transmission in a European urban area, Basel-City (Switzerland). Methodology. We combined detailed epidemiological, intra-city mobility, and socioeconomic data-sets with whole-genome-sequencing during the first SARS-CoV-2 wave. For this, we succeeded in sequencing 44% of all reported cases from Basel-City and performed phylogenetic clustering and compartmental modelling based on the dominating viral variant (B.1-C15324T; 60% of cases) to identify drivers and patterns of transmission. Based on these results we simulated vaccination scenarios and corresponding healthcare-system burden (intensive-care-unit occupancy). Principal Findings. Transmissions were driven by socioeconomically weaker and highly mobile population groups with mostly cryptic transmissions, whereas amongst more senior population transmission was clustered. Simulated vaccination scenarios assuming 60-90% transmission reduction, and 70-90% reduction of severe cases showed that prioritizing mobile, socioeconomically weaker populations for vaccination would effectively reduce case numbers. However, long-term intensive-care-unit occupation would also be effectively reduced if senior population groups were prioritized, provided there were no changes in testing and prevention strategies. Conclusions. Reducing SARS-CoV-2 transmission through vaccination strongly depends on the efficacy of the deployed vaccine. A combined strategy of protecting risk groups by extensive testing coupled with vaccination of the drivers of transmission (i.e. highly mobile groups) would be most effective at reducing the spread of SARS-CoV-2 within an urban area.Author summaryWe examined SARS-CoV-2 transmission patterns within a European city (Basel, Switzerland) to infer drivers of the transmission during the first wave in spring 2020. The combination of diverse data (serological, genomic, transportation, socioeconomic) allowed us to combine phylogenetic analysis with mathematical modelling on related cases that were mapped to a residential address. As a result we could evaluate population groups driving SARS-CoV-2 transmission and quantify their effect on the transmission dynamics. We found traceable transmission chains in wealthier or more senior population groups and cryptic transmissions in the mobile, young or socioeconomic weaker population groups - these were identified as transmission drivers of the first wave. Based on this insight, we simulated vaccination scenarios for various vaccine efficacies to reflect different approaches undertaken to handle the epidemic. We conclude that vaccination of the mobile inherently younger population group would be most effective to handle following waves.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China as the cause of coronavirus disease 2019 in December 2019 and reached Europe by late January 2020, when community-acquired respiratory viruses (CARVs) are at their annual peak. We validated the World Health Organization (WHO)–recommended SARS-CoV-2 assay and analyzed the epidemiology of SARS-CoV-2 and CARVs. Methods Nasopharyngeal/oropharyngeal swabs (NOPS) from 7663 patients were prospectively tested by the Basel S-gene and WHO-based E-gene (Roche) assays in parallel using the Basel N-gene assay for confirmation. CARVs were prospectively tested in 2394 NOPS by multiplex nucleic acid testing, including 1816 (75%) simultaneously for SARS-CoV-2. Results The Basel S-gene and Roche E-gene assays were concordant in 7475 cases (97.5%) including 825 (11%) SARS-CoV-2 positives. In 188 (2.5%) discordant cases, SARS-CoV-2 loads were significantly lower than in concordant positive ones and confirmed in 105 (1.4%). Adults were more frequently SARS-CoV-2 positive, whereas children tested more frequently CARV positive. CARV coinfections with SARS-CoV-2 occurred in 1.8%. SARS-CoV-2 replaced CARVs within 3 weeks, reaching 48% of all detected respiratory viruses followed by rhinovirus/enterovirus (13%), influenza virus (12%), coronavirus (9%), respiratory syncytial virus (6%), and metapneumovirus (6%). Conclusions Winter CARVs were dominant during the early SARS-CoV-2 pandemic, impacting infection control and treatment decisions, but were rapidly replaced, suggesting competitive infection. We hypothesize that preexisting immune memory and innate immune interference contribute to the different SARS-CoV-2 epidemiology among adults and children., Community-acquired respiratory viruses were dominant during the early severe acute respiratory syndrome coronavirus 2 pandemic in winter 2020, but were rapidly replaced, suggesting competitive infection. Preexisting immune memory and innate immune interference may contribute to the different epidemiology among adults and children.

(1) Background: In patients with shock, the L-arginine nitric oxide pathway is activated, causing an elevation of nitric oxide, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels. Whether these metabolites provide prognostic information in patients after out-of-hospital cardiac arrest (OHCA) remains unclear. (2) Methods: We prospectively included OHCA patients, recorded clinical parameters and measured plasma ADMA, SDMA and Arginine levels by liquid chromatography tandem mass spectrometry (LC-MS). The primary endpoint was 90-day mortality. (3) Results: Of 263 patients, 130 (49.4%) died within 90 days after OHCA. Compared to survivors, non-survivors had significantly higher levels of ADMA and lower Arginine and Arginine/ADMA ratios in univariable regression analyses. Arginine levels and Arginine/ADMA ratio were significantly associated with 90-day mortality (OR 0.51 (95%CI 0.34 to 0.76), p &lt, 0.01 and OR 0.40 (95%CI 0.26 to 0.61), p &lt, 0.001, respectively). These associations remained significant in several multivariable models. Arginine/ADMA ratio had the highest predictive value with an area under the curve (AUC) of 0.67 for 90-day mortality. Results for secondary outcomes were similar with significant associations with in-hospital mortality and neurological outcome. (4) Conclusion: Arginine and Arginine/ADMA ratio were independently associated with 90-day mortality and other adverse outcomes in patients after OHCA. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated.

Background In Switzerland, long-term circulatory support programs have been limited to heart transplant centers. In 2014, to improve the management of patients with end-stage heart failure not eligible for transplantation, we implemented a left ventricular assist device (LVAD) program for destination therapy at the University Hospital of Basel. Methods We described the program set-up with practical aspects. Patients aged 65 and above with therapy refractory end-stage heart failure without major contraindication for LVAD implantation were included. Younger patients with bridge-to-candidacy profile were also considered. Using the Kaplan-Meier estimate, we retrospectively analyzed the overall survival and freedom from major adverse events after LVAD implantation. We compared our results to internationally reported data. Results Between October 2014 and September 2019, 16 patients received an LVAD in our center. The mean age at implantation was 67.1 years. The mean EuroSCORE II was 24.4% and the median INTERMACS level was 4. Thirteen patients received an LVAD as destination therapy and three patients as bridge-to-candidacy. The overall survival was 87.5 and 70% at 1 and 2 years, respectively. Freedom from stroke was 81.3% at 1 and 2 years. Freedom from device infection was 67.7 and 58.7% at 1 and 2 years, respectively. Freedom from gastrointestinal bleeding was 75 and 56.3% at 1 and 2 years, respectively. Freedom from readmission was 50 and 31.3% and at 6 months and 1 year, respectively. Conclusions The Basel experience demonstrated the possible implementation of an LVAD program for destination therapy or bridge-to-candidacy in a non-transplant comprehensive heart-failure center with midterm survival results and freedom from major adverse events comparable to international registries. Patient selection remains crucial. Trial registration This study was registered on the ClinicalTrials.gov database (NCT04263012).

IntroductionSARS-CoV-2-detection is critical for clinical and epidemiological assessment of the ongoing CoVID-19 pandemic.AimTo cross-validate manual and automated high-throughput (Roche-cobas®6800-Target1/Target2) testing for SARS-CoV-2-RNA, to describe detection rates following lockdown and relaxation, and to evaluate SARS-CoV-2-loads in different specimens.MethodThe validation cohort prospectively compared Basel-S-gene, Roche-E-gene, and Roche-cobas®6800-Target1/Target2 in 1344 naso-oropharyngeal swabs (NOPS) taken in calendar week 13 using Basel-ORF8-gene-assay for confirmation. Follow-up-cohort-1 and -2 comprised 12363 and 10207 NOPS taken over 10 weeks until calendar week 24 and 34, respectively. SARS-CoV-2-loads were compared in follow-up NOPS, lower respiratory fluids, and plasma.ResultsConcordant results were obtained in 1308 cases (97%) including 97 (9%) SARS-CoV-2-positives showing high quantitative correlations (Spearman r>0.95; pConclusionEvaluated manual and automated assays are highly concordant and correlate quantitatively. Following successful lockdown, declining positive predictive values require dual-target-assays for clinical and epidemiologic assessment. Confirmatory and quantitative follow-up testing should be considered within