The novel coronavirus, SARs-CoV-2, causes a clinical disease known as COVID-19. Since being declared a global pandemic, a significant amount of literature has been produced and guidelines are rapidly changing as more light is shed on this subject. Decisions regarding disposition must be made with attention to comorbidities. Multiple comorbidities portend a worse prognosis. Many clinical decision tools have been postulated; however, as of now, none have been validated. Laboratory testing available to the emergency physician is nonspecific but does show promise in helping prognosticate and risk stratify. Radiographic testing can also aid in the process. Escalating oxygen therapy seems to be a safe and effective therapy; delaying intubation for only the most severe cases in which respiratory muscle fatigue or mental status demands this. Despite thrombotic concerns in COVID-19, the benefit of anticoagulation in the emergency department (ED) seems to be minimal. Data regarding adjunctive therapies such as steroids and nonsteroidal anti-inflammatories are variable with no concrete recommendations, although steroids may decrease mortality in those patients developing acute respiratory distress syndrome. With current guidelines in mind, we propose a succinct flow sheet for both the escalation of oxygen therapy as well as ED management and disposition of these patients. It took just over two months for the novel coronavirus, SARs-CoV-2 to be declared a global pandemic by the World Health Organization (WHO). In the immediate week following this announcement, more than 400 papers were published pertaining to COVID-19. Just two months later, this number had increased to over 2000 releases per week in the literature.We systematically searched the PubMed, LitCovid, Ovid, Cochrane Library, MEDLINE, Google Scholar, and Embase for literature related to “COVID-19,” “SARS-CoV-1,” and “SARS-CoV-2.” We included retrospective studies, case reports, case series, systematic reviews, meta-analyses, and clinical guidelines from the Society of Critical Care Medicine (SCCM), the Surviving Sepsis Campaign (SSC), the National Institutes of Health (NIH), and the European Society of Intensive Care Medicine (ESICM). We included relevant literature if it contained data on epidemiological characteristics, biomarkers, imaging, oxygenation and ventilation management, procedural aerosolization, pathology reports, hematologic abnormalities, and treatment outcomes related to care commonly seen in the ED).Risk stratification in the ED can be difficult for a novel virus such as SARS-CoV-2 as we do not have the luxury of years of research and understanding that we are offered with most disease processes. Decompensation of the otherwise well appearing COVID-19 patient can occur rather rapidly as many patients develop early lung injury and hypoxia before clinical deterioration is appreciated.6severe disease includes those with a respiratory rate greater than 30; blood oxygen saturation level equal to or less than 93% on room air, a ratio of arterial oxygen partial pressure to fractional inspired oxygen < 300 or > 50% of lung involvement on imaging.7Currently, evidence-based practices support using epidemiological, laboratory, radiographic, and clinical features to help us determine who is at risk for decompensation.The largest case series assessing epidemiological risk factors includes a 72,314-patient report from the Chinese Center for Disease Control and Prevention.10An article published by Guo and colleagues showed that COVID-19 patients with diabetes but without other comorbidities were at an independently high risk of severe pneumonia, uncontrolled inflammatory response, and hypercoagulable state.122) with increased risk of mechanical ventilation, severe pneumonia, and death associated with COVID-19.2 in those younger than 60 has been noted to be an independent risk factor with a twofold higher rate of acute care and ICU admission when compared to those with a BMI less than 30 kg/m2.15Several studies have linked obesity and a body mass index (BMI) greater than 30 kilograms (kg) per meter squared , patients above the age of 65 had a particularly significant increased risk of death when compared to their younger counterparts with up to 80% of deaths occurring in those over the age of 65.16Finally, a single-center study of 1193 patients in Lombardia, Italy, showed patients on biologics had a higher rate of hospitalization, but this was not associated with an increased risk of ICU admission or death.The EP should maintain a baseline level of caution when determining disposition of these patients, especially in patients with more than one comorbid condition. In a prediction model from Wang et al, hypertension, advanced age, and coronary heart disease, their model appears to confer the highest risk of in-hospital mortality with an area under the curve of 0.88; sensitivity, 92.31%; specificity, 77.44%; and negative predictive value (NPV) of 99.34%).18Many serum biomarkers have been studied with COVID-19 infections. Alanine transaminase (ALT) and aspartate aminotransferase (AST) tend to be elevated and albumin low. Elevations in lactate dehydrogenase (LDH), CRP, procalcitonin, and abnormalities in coagulation parameters such as ferritin, D-dimer, fibrinogen, activated partial thromboplastin time and prothrombin time all tend to be elevated in patients with poor progression of disease.9 per liter (L) has been consistently shown to correlate with disease severity, ICU admission, and death.9/L tend to have a milder disease process, and values below this could perhaps help identify those at risk for disease progression. A summary of literature addressing ALC has been summarized in An ALC less than 0.8×10An elevated neutrophil count has been shown to correlate with disease severity. However, an absolute value to determine severity is not as apparent in current literature. The NLR may offer greater clinical insight. Normal values of the NLR range between 0.78–3.53 with a mean value of 1.65.An elevated D-dimer has been shown to be an independent marker of unfavorable disease progression in multiple studies.In the previously discussed study by Zhou and colleagues, an LDH greater than 245 was seen in 98% of all patients who did not survive, with an odds ratio for in-hospital mortality of 45.43.CRP is non-specific and frequently elevated in patients with mild disease.Ferritin is another nonspecific marker with elevations seen in up to 63–80% of COVID-19 patients admitted to the hospital.Creatine kinase (CK) appears to be elevated in a minority of COVID-19 patients regardless of severity.47There is a lack of evidence in published literature to suggest that laterality of infiltrates on imaging accurately correlates with disease severity. In a retrospective cohort study out of Wuhan, bilateral infiltrates were seen in 72% of survivors and 83% of non-survivors.42In a multinational consensus statement from the Fleischner Society, chest imaging is recommended in those patients with mild symptoms and any risk factors of disease progression, in all patients with moderate to severe features, or when rapid COVID-19 testing is not available.49Bedside lung ultrasound (LUS) may offer some advantages in the ED for patients with suspected COVID-19.53Focal B-lines in the posterior and inferior lung fields appear to be the primary finding.54Current guidelines for the management of the critically ill adult with COVID-19 have been issued by the SCCM, the SSC, the NIH, and the ESICM. These guidelines are quite similar, if not identical, in regard to most recommendations and will be summarized here.58Current guidelines favor a conservative approach to fluids in these patients. Utilization of early vasopressors is recommended to keep a mean arterial pressure (MAP) of 60–65 millimeters of mercury (mm Hg), although this is based on low quality of available evidence.Dobutamine should be considered a second-line agent after norepinephrine only if there is evidence of cardiac dysfunction and persistent hypoperfusion.64Early discussion of hypoxic patients with COVID-19 prioritized intubation based on the hypothetical risk of patient self-induced lung injury resulting from excessive intrathoracic negative pressure from strong respirator effort and aggressive positive pressure ventilation strategies.The FLORALI trial randomly assigned patients who had acute hypoxemic respiratory failure to either high-flow oxygen therapy or standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation.68Early case reports described COVID-19 patients presenting with ARDS and a ventilatory management strategy typically employed in ARDS was recommended by the WHO and SCCM.Those with “type-H” phenotype present with a clinical picture characteristic of typical ARDS .68Those with the observed “type-L” phenotype frequently have minimal dyspnea and remain alert and conversational despite the degree of observed hypoxia.67This phenotype model is untested and there is a paucity of societal guidelines for patients with preserved compliance requiring mechanical ventilation. We believe a blanket ARDS ventilatory strategy for all patients could have detrimental consequences.Journal of Infectious Disease reported that shows droplets from coughs and sneezes can travel up to eight meters, with SARS-CoV-2 detected in the air up to 3–5 hours after aerosolization.80While the presence of viral particles does not confer transmission, it certainly supports our need to exercise caution to maximize protection to ourselves and our staff. A meta-analysis of 10 studies published in the Exhaled air dispersion during high-flow nasal cannula therapy was compared to continuous positive airway pressure (CPAP) in a study by Hui et al.HFNO at a maximal flow rate of 60 L/minPM actually has a lower dispersion distance than a non-rebreather or venturi mask.Patients with COVID-19 are at an increased risk of VTE. Current documented rates of incidental VTE in hospitalized patients with COVID-19 ranges from 20–69%, despite the use of pharmacological thromboprophylaxis.91Journal of the American College of Cardiology (JACC) panel recommends against routine screening for VTE and recommends against pursuing an elevated D-dimer when it is being used for risk stratification.39In a study of 81 patients with COVID-19 infections, a D-dimer greater than 1.5 μg/mL had a sensitivity of 85.0%, a specificity of 88.5% with a NPV of 94.7% at predicting VTE.JACC panel does not recommend routine use of prophylactic anticoagulation as its role has not yet been well established in the literature.The JACC panel members recommend prophylactic anticoagulation for hospitalized COVID-19 patients without a diagnosis of VTE, while a minority of the panel gives consideration to intermediate- or full-dose anticoagulation.Patients with ARDS secondary to COVID-19 are at a higher risk of thrombosis when compared to non-COVID-19 ARDS patients.Lancet describing a theoretical risk of worsening infection through increased ACE-2 expression with ibuprofen based on animal studies.Controversy surrounds the use of nonsteroidal anti-inflammatory drugs (NSAID) in COVID-19 stemming from a correspondence published on March 11, 2020, in the When the SSC released its guidelines on March 27, they acknowledged the debate on NSAIDs use for fever, and recommended the use of acetaminophen/paracetamol over NSAIDs until more data becomes available. On April 19, the WHO released a systematic review of 73 studies of adults and children with viral respiratory infections, including COVID-19, MERS, and SARS and concluded that, “At present there is no evidence of severe adverse events, acute health care utilization, long-term survival, or quality of life in patients with COVID-19, as a result of the use of NSAIDs.”57Initial concerns in regard to the use of corticosteroids in COVID-19 were based on studies specific to SARS-CoV-1 showing prolonged viral shedding with early corticosteroid treatment and an increased risk of adverse effects such as steroid-induced psychosis, avascular necrosis osteoporosis, and diabetes without an apparent mortality benefit.100A 2016 retrospective review of 5327 patients from the SARS-CoV-1 database in China showed that patients initially treated with an average of 80 mg methylprednisolone daily had a lower mortality with a hazard ratio (HR) of 0.47.101Results from randomized trials in regard to steroids in ARDS from non-coronavirus causes have shown mixed outcomes. High dose (30 mg/kg every 5–6 hours for 24 hours) failed to show improvement in mortality or pulmonary function and was associated with an increased rate of secondary infection.104Data specific to COVID-19 and ARDS is limited. A retrospective study of 201 COVID-19 patients in Wuhan showed that of the patients who developed ARDS, those who received methylprednisolone in some fashion had a decreased risk of death with HR of 0.38.106In summary, corticosteroids may decrease mortality in COVID-19 patients with ARDS. The SSC recommends steroids for mechanically ventilated patients with COVID-19 and evidence of ARDS or for refractory shock despite vasopressors.For patients on chronic oral or inhaled corticosteroids, these should not be discontinued, and stress-dose steroids may be indicated on a case-by-case basis.7A recent meta-analysis of patients admitted with COVID-19 reported 72% receive empiric antimicrobials, while only 8% of patients develop a bacterial or fungal co-infection.Numerous studies done in vitro have reported antiviral and anti-inflammatory effects of azithromycin, although the exact mechanism of antiviral activity is unknown.Inhaled nitric oxide (NO) is a pulmonary vasodilator with theoretic antiviral effects.57Early reports suggested an association of severe COVID-19 with renin-angiotensin-aldosterone system (RAAS) antagonist use leading to advice to discontinue this medication.116Currently, no guidelines specifically mention aspirin in their recommendations. Aspirin has a theoretical benefit for its antiplatelet, anti-inflammatory, and antipyretic effects. Studies have shown that aspirin has in vitro antiviral activity against influenza A, human rhinoviruses, and human cytomegalovirus.This paper has a few notable limitations. First, with the large volume and rapid publication of literature on this previously unknown subject, most lack validation. Some articles regarding COVID-19 have been retracted after publication, although every effort has been made to be sure each citation was valid at the time of publication of this manuscript. Finally, only articles published in English were reviewed.Evidence-based practice in the approach to COVID-19 is mercurial. Current literature focuses on the inpatient evaluation, treatment, and disposition of these patients. Interpretation and adaptation of current recommendations to patients in the ED is a crucial target for future literature. After our review of available literature, we have proposed an ED-specific flowsheet to assist clinicians during this time of medical ambiguity .


Reliable disability EvaLuation in psychiatrY)-studies introduced semi-structured functional interviews in real-life assessments of claimants with mental disorders for evaluating their self-perceived health-related limitations and for investigating the reproducibility of work capacity (WC) estimates. Functional interviews elicit claimants’ self-perceptions about their work-related limitations and capacities in the labour market. This secondary data analysis explored the coverage of work-related key topics in these interviews and investigated whether interviews with high coverage (versus low coverage) of work-related topics resulted in better reproducibility of WC estimates among experts.Functional evaluations establish functional and work (in-)capacities in the context of disability assessments and are increasingly recommended as a modern technique for work disability assessments. The RELY  and inter-rater agreement .psychiatrist between 0 and 1.5, medianpatients between 0 and 9.5). High coverage interviews enquired on more functional topics  = 5.32, p = 0.021) and in more depth  = 141.15, p < 0.001). Interviews with higher functional coverage reached significantly higher inter-rater agreement in WC ratings among experts . Inter-rater reliability was low in both groups .Interviews were broken down in 40,010 coding units, 31% of which addressed functional topics. Enquiries in self-perceived work limitations and work-related health complaints were sparse (coding units medianContent analysis showed little enquiry by experts on claimants’ self-perceived activity limitations and work-related capacity. The association between interviews with higher functional coverage and better expert agreement on the claimants’ remaining WC requires confirmation in prospective studies. What Is Known?Work disability evaluations are frequently criticised for their lack of transparency how experts derive their judgement.Modern thinking of work disability suggests functional evaluations as the way to move forward. There, claimants are assessed for work-related capacities and activity limitations.A recent study showed low reproducibility -studies , the study results were ambiguous to interpret: Had we erred on the concept of functional interviewing or had the training been insufficient? We therefore performed a content analysis of the RELY assessments to examine to what extent expert psychiatrists had applied functional interviewing and in what depth psychiatrists and patients had delved into functional key topics and compared the impact of interviews with low coverage versus those with high coverage of functional topics on reproducibility  of WC ratings.In this cross-sectional study, we performed a content analysis of real-life work disability assessments to examine expert psychiatrists’ adherence to the functional interviewing protocol and investigated whether interviews with high coverage of work-related functional topics (versus low coverage) resulted in better reproducibility of remaining WC among experts. The data were derived from a previous multi-centre study  thaPsychiatrists were eligible to participate in RELY 1 if they worked for one of the following assessment centres: Department of Insurance Medicine, University Hospital Basel, Centre for Medical Assessments Basel, MEDAS Central Switzerland, MEDAS Interlaken, or for the Suva Clearinghouse. Patients who had applied for disability benefits at the Zurich office of the Invalidity Insurance were eligible to participate if they were German-speaking and scheduled for a polydisciplinary disability assessment, including a psychiatric assessment. The recruitment procedure was published in detail elsewhere , 19.We defined 19 functional interview topics , plus four residual categories Table 1.We recorded all interviews on video. After verbatim transcription (RD) , we segmcoding.unit, interquartile range IQR), for psychiatrists and patients. To assure readability, we limited reporting of the IQR to the tables.A key topic was considered as being ‘covered’ by either psychiatrist or patient if at least one functional coding unit had been allocated to that key topic. We calculated coverage of key topics, i.e., number of key topics addressed by at least one functional coding unit, identified key topics that were covered poorly or not at all, and determined in what depth psychiatrists enquired into WC by calculating the number of functional coding units per key topic  number of key topics covered, b) kind of key topics poorly or not at all covered, and c) number of functional coding units per topic to determine the depth of topic coverage, resp. medical/general coding units. We defined interviews with high and low coverage of key topics by assigning one point for each key topic Table 1 To test whether our procedure to determine ‘coverage’ reflected the amount of information obtained on WC , we calculated a simple linear regression to predict the number of functional coding units assigned to key topics per interview (dependent variable) based on the number of key topics covered (independent variable). We interpreted the linear relationship coefficient (R) as small (0.10 to 0.29), medium (0.30 to 0.49), and large (≥0.50) .2-test to compare continuous and categorical variables, respectively.Data collection of expert judgement of patients’ WC was published in detail elsewhere , 19. To Results section, we restrict our report to the primary outcome ‘work capacity for alternative work’ WCalternative.work, and the related measure of inter-rater agreement (SEM) and inter-rater reliability (ICC)  , 19. In in paper .To put the content analysis into context, we compared its findings on functional interviewing with the psychiatrists’ self-report: Following the RELY 1-evaluations, an independent psychiatrist had conducted a semi-structured telephone survey (7 questions) among the 12 interviewing psychiatrists  to eliciTwelve psychiatrists performed 30 interviews for assessing work disability. Most were middle-aged  or older (32%) and male (79%). Their professional experience in performing disability evaluations was 13.8 years . The patients’ age was 47.2 years , 57% were male. The most common diagnoses were mood disorders (26%), followed by neurotic, stress-related and somatoform disorders (19%). Detailed psychiatrist and patient characteristics are listed in The first 60 minutes of the 30 assessment interviews contained 40,010 coding units, of which 31% were assigned to functional key topics and 69% to medical/general issues Table 2.coding.unit: 3.5; 4; 9.5 respectively)  Table 2.Any enquiry of WC requires some background about previous jobs and specifications of the work activities. Psychiatrists conducted a balanced interview with the claimants covering almost all topics: job title, employer details, employment duration, activities, and feelings towards these activities. The medians of coding units ranged between 0 and 6.5 per topic for psychiatrists and between 2.5 and 18.5 for claimants.coding.unit: 0 for previous activities, suitable alternative activities, and conditions necessary for successful performance) nor by claimants . Enquiry into work-related health complaints was slightly more informative for complaints and symptoms , exacerbating and attenuating circumstances , and emotional-cognitive coping .Self-perceived work limitations and work-related health complaints are the centrepiece of functional interviewing where psychiatrists are expected to get to the bottom of what prevents the claimant from working. Self-perceived work limitations have barely been addressed, neither by psychiatrists .Once claimants had described their self-perceived work limitations and work-related health complaints, the methodology of functional interviewing expects the psychiatrists to provide a summary of the information for clarification to ensure a common understanding of the claimants’ self-perception. This was quasi non-existent  = 0.17, p = 0.71)  = 0.46, p = 0.65) and gender  Table 2.2 = 5.32, p = 0.021) with an in-depth enquiry of 36% functional coding units  = 141.15, p < 0.001. The strong relationship between the number of key topics and the number of functional coding units assigned to these key topics  of functional key topics, with an in-depth enquiry of 16% functional coding units. In contrast, those with high coverage addressed 68% (26/38) of functional key topics , suitable alternative activities , and work-related health complaints .Interviews with low and high coverage did not differ much in length regarding orientation and enquiry of last job and previous activities. They differed, however, with regards to self-perceived work limitations where interviews with low coverage of key topics failed to enquire into previous activities  than their colleagues whose interviews covered functional key topics inadequately  and attributed claimants a significantly higher level of WC (WCequately Table 3.Ten of the 12 psychiatrists who had conducted 27 (90%) of the work disability evaluations confirmed the use of the functional interview protocol in RELY 1, nine psychiatrists declared having benefitted from the training in functional interviewing and reported continued use in their practice.This is the first content analysis on real-life work disability assessments in 30 claimants with mental disorders illustrating current practice of functional interviewing on work-related issues. Interviews covered 61% of predefined functional topics during the first hour of the assessment. The majority of experts failed to elicit claimants’ self-perceived work limitations and work-related health complaints, both centrepieces of functional interviewing. Experts who rated interviews with high coverage of functional topics achieved significantly better inter-rater agreement on the claimants’ WC and attributed significantly higher level of remaining WC than experts with low coverage interviews. Inter-rater reliability was poor in both groups.We conducted a content analysis of real-life work disability assessments in a heterogeneous group of patients with mental disorders performed by a broad spectrum of psychiatric experts . This apLow coverage of functional key topics was associated with lower levels of estimated WC. One explanation could be that an interviewing expert’s prior judgments of the claimant’s WC from medical files and other documents shaped the enquiry on work issues. As a consequence, the effort to probe on work-related issues might have been less in claimants with more severe impairments than in those perceived as less impaired. Higher ambiguity in prior knowledge about a patient’s disability to work might have fostered the interviewing expert’s endeavour for intensive enquiry of work issues. This is all the more significant as functional interviewing has the potential to improve agreement in more vague data situations. However, it is noteworthy that other studies observed that functional interviewing detected more activity limitations , 29.The lack of adherence to functional interviewing allows two interpretations: The one-year time gap between training and implementation in the study had caused a substantial decline in the previously acquired skills of functional interviewing. Alternatively, the training had been insufficient in the first place. Both interpretations would support our scepticism that the content analysis rather documents current practice of psychiatric work disability assessments than functional interviewing .By using a single functional coding unit to define ‘coverage of a functional topic’, our threshold to call a key topic ‘covered’ was low. It would be overoptimistic to assume that a single functional coding unit would comprehensively encompass the content of a key topic. The disproportionate increase in functional coding units, however, along an increase in functional key topics assures that ‘number of functional topics covered’ can be considered as surrogate for a comprehensive assessment in this study.Research on sickness certification reports about general practitioners’ reluctance to shift from the description of symptoms and underlying mechanisms towards a functional and work-related perspective , 31. LacFunctional interviewing has proven merits: a recent cluster-randomised trial on injured workers claiming work disability benefits compared a formal 2-day functional capacity evaluation with semi-structured functional interviews of 1.5 to 3 h duration. Assessment based on functional interviews versus those based on functional capacity evaluation showed similar results on all main outcomes, i.e. return-to-work recommendations by the clinicians, effective return-to-work and sustained work level at 1, 3 and 6 months post-assessment, and compensation outcomes for the insurers , 36.The content analysis revealed important gaps about the collection of work-related functional information in RELY 1, which is crucial for well-founded WC assessments and a prerequisite for applying any ICF-measures and -instruments . The gapIn the RELY 1-survey about endorsement of functional interviewing and its implementation during the study and otherwise , the vasThe overarching goal of work disability assessments is appropriate allocation of societal resources to those who lost their capacity to earn their own living and prevention of inappropriate allocation to those with remaining WC. Our content analysis indicated that the RELY 1-interviews rather reflect current practice than functional evaluation as planned. Despite these shortcomings in practice, it was possible to demonstrate that WC assessments with higher coverage of functional topics achieved substantial improvement in agreement when experts determined the remaining WC of claimants. While such findings seem plausible, it would be important to confirm these findings in a second independent sample, e.g., the interviews performed in the RELY 2-study . FurtherThe interest in improving current practice becomes apparent from the international attention that was reached by a recent systematic review on the reproducibility of work disability evaluations with more than 20,000 full text hits . If instLikewise, we need more studies comparing assessment strategy A versus B, including their precision on prognostic predictions like successful return-to-work. Initiatives are emerging , 40–43, In conclusion, content analysis revealed that RELY 1 did not succeed in integrating semi-structured functional interviewing as an integrated part of independent medical evaluations. The positive association between interviews with higher functional coverage and expert agreement on the claimants’ remaining WC is promising. It requires confirmation in prospective studies.Raw data generated for this study are transcripts of patient interviews and they can not be made publicly available, due to patient confidentiality and privacy. However, the frequency tables of the coded interviews supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by: All study procedures were approved by the cantonal ethics committees in Basel, Bern, Luzern, Zürich; the data protection officers of Basel-Stadt; Swiss National Science Foundation, Federal Social Insurance Office, Swiss National Accident Insurance Fund (Suva), and Disability Insurance Office in Zürich. All patients provided written informed consent according to procedures approved by the ethics committees. The patients/participants provided their written informed consent to participate in this study.DA, WB, and RK conceived and designed the study. RD performed the transcription. DA, WB, RD, SK, and NV developed the category system and performed the coding. DA performed the analysis. All interpreted the findings. DA and RK drafted the manuscript. All authors contributed to the article and approved the submitted version. RK and DA are accountable for all aspects of the work.This secondary research draws on data of the RELY-studies , 19 and After data collection had been finished (07/2016), RK became head of the Medical Competence Centre of Suva, Lucerne.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cancer patients may have a higher risk of severe events and unfavourable outcomes in the setting of COVID-19. This review addresses the question of whether to test asymptomatic cancer patients before initiating systemic cancer treatments.This systematic review was conducted based on the PRISMA framework. Pubmed, Embase, Web of Science and Cochrane Central Register of Controlled Trials were systematically searched, as well as guidelines from international institutions involved in cancer care and COVID-19 research. Studies published in English, from 1 December 2019 to 27 May 2020 were considered eligible. We included studies which mentioned testing strategies for SARS-CoV-2 of asymptomatic cancer patients before starting immunosuppressive treatments.We identified 1,163 studies and 4 guidelines through the literature search. A total of 18 articles were considered eligible and were included in the final analysis. Two articles were cohort studies, and the remaining were expert consensuses and published guidelines. The most common recommendation among the studies in this systematic review was to test asymptomatic patients for SARS-CoV-2 prior to treatment.There is a lack of studies which directly address COVID-19 testing of asymptomatic patients before treatment. Our systematic review showed that most of the published data favours routine test for SARS-CoV-2 before initiating systemic treatment but failed to identify a good level of evidence to support these recommendations. Based upon this review, we proposed local recommendations at our centre. Each institution should consider the pros and cons of testing asymptomatic patients, evaluating accessibility to testing resources and local epidemiology. In December 2019, a rising number of patients with pneumonia of unknown cause was detected in China. A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered to be the cause of this new type of respiratory illness, called coronavirus disease-2019, or COVID-19 . As of 2Special concern is raised for patients with cancer, potentially exposed to a higher incidence of COVID-19. Moreover, they seem to have a higher risk of severe events, such as admission in intensive care units, invasive ventilation or death –9, and eNevertheless, a large proportion of cancer patients require prompt initiation of treatment because of potential risk of deteriorating their clinical status and presenting complications attributable to disease progression. Moreover, treatment delays may incur in a detrimental impact on the risk of recurrence, potentially compromising survival outcomes , 14. ConThis systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework . The eleWe have included studies which mentioned testing strategies for SARS-CoV-2 of asymptomatic patients before receiving some systemic treatment, such as chemotherapy, targeted-therapy or immunotherapy. Only studies published in English, from 1 December 2019 to 27 May 2020 were considered eligible. We excluded studies published as case reports or systematic reviews, duplicated articles and studies focused on only surgical or paediatric patients.Titles and abstracts identified by the search strategy were imported into Rayyan QCRI web application and blindly and independently reviewed by two investigators (G.H. and F.F.A.). Full texts of screened papers were retrieved and reviewed by the same authors for inclusion criteria. Disagreements between the two reviewers were resolved by consultation with a third investigator (G.C.J). Study design, date of publication, authors, tumour subtypes, recommendations in relation to SARS-CoV-2 test were extracted from included articles by two reviewers (G.H. and F.F.A.) using a data extraction form. Quality assessment was performed based on Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence . As mostWe identified 1,163 studies based on database searches and 4 guidelines through the literature search. After removing 242 duplicated studies and reviewing the titles and abstracts, 144 were selected for full-text evaluation. One hundred twenty-six studies were excluded, mainly due to the fact that they did not mention any strategy for testing asymptomatic cancer patients and did not fulfil the inclusion criteria. Therefore, a total of 18 articles were considered eligible and were included in the final analysis, of which 14 studies were identified based on database searches, and four were guidelines . Among tAll included studies were published in 2020. Out of 18 articles, five alluded exclusively to solid tumours, seven to hematologic malignancies and six to both groups of diseases. Two cohorts were identified. All other studies were expert consensuses.Two cohort studies which discuss some strategies of testing for SARS-Cov-2 asymptomatic patients were identified , 18. TheFor patients considered at risk of COVID-19 infection, a triage process was started, which included a low-dose computed tomography (CT) scan of lungs. A nasopharyngeal swab real-time polymerase chain reaction (RT-PCR) test was performed on all radiologically or clinically suspected patients. For specifically asymptomatic patients who needed treatment which induced neutropenia or lymphopenia, a simplified triage process has been developed, including a swab test before the treatment. Only a preliminary result of the effects of this process was reported and did not contain the asymptomatic population outcomes separately .The second cohort is from Alzahra Hospital Dubai, in the United Arab Emirates. Eighty-five asymptomatic cancer patients were enrolled. All patients underwent a RT-PCR for SARS-CoV-2 and, if positive, a chest X-ray was performed. RT-PCR was repeated until two consecutive negative results.RT-PCR was found to be positive in 7 (8.24%) out of the 85 patients, five of them (71.4%) on systemic therapy and two who had not yet initiated therapy. Cancer types among the positive patients were breast (2 (28.6%)), colorectal (2 (28.6%)), lymphoma (2 (28.6%)), and lung (1(14.1%)). All RT-PCR positive patients eventually became symptomatic: five with mild symptoms and two with severe, requiring intensive care unit (ICU) admission. The patients with mild symptoms resumed therapy after virologic clearance median 18 days). One of the patients admitted on ICU had lung cancer in treatment with anti-PD-L1 therapy and died of acute respiratory distress syndrome, and the other had colorectal cancer and remained hospitalised. Importantly, no patient recalled having anosmia or dysgeusia and no health care workers of the screening site were diagnosed with COVID-19. This cohort had some limitations, such as: single-centre experience, with no control group and small sample size [ days. OnFive articles discussed systematic testing for SARS-CoV-2 in asymptomatic patients with solid tumours –23. Two et al [ et al [Considering that lung cancer patients can present similar clinical symptoms to COVID-19, and oncologic radiological findings can resemble or overlap with virus infections, these concordances can pose a challenge to diagnose SARS-CoV-2 infection in this specific population. Banna  [ et al  suggest  et al [Head and neck cancers also deserve particular considerations, mainly because of the unique location in the aerodigestive tract, a recognised region that harbours coronavirus. Chaves et al  recommen et al [Regarding breast and gynaecological cancer, both studies suggest, if tests are available, testing for COVID-19 before initiating immunosuppressive therapies, even for asymptomatic patients , 23. PotPatients with haematologic malignancies may have a higher risk of developing COVID-19 for multiple and potentially overlapping reasons. They often receive highly immunosuppressive treatments in addition to the cancer-related immunosuppression and are at high risk of opportunistic infections. Seven articles discuss the management of SARS-CoV-2 testing all patients before starting treatment –29 Tabl. NeverthAt the Seattle Cancer Care Alliance, the haematologic cancer patients are not routinely being tested for SARS-CoV-2 before beginning standard chemotherapy. The capability of performing tests should be considered, and the risks of delaying effective therapies when a test is positive are uncertain. Therefore, the tests are prioritised to symptomatic patients and prior to surgeries, stem-cell transplantation (SCT), and chimeric antigen receptor (CAR) T-cell therapy In some cases, depending on the risk and the disease, such as asymptomatic patients with indolent lymphoma, can be considered deferring therapy for few weeks or months .et al [Paul et al  recommen et al [Koffman et al  reported et al . For all et al . et al [et al [Patients with multiple myeloma (MM) may be at a higher risk of SARS-CoV-2 infection for several reasons, including disease, treatment and patient characteristics. These patients have a higher age at diagnosis and are more likely to have comorbidities. In addition, the disease can cause immunodeficiency and the treatment can aggravate the immunosuppression. three articles mentioned a strategy of COVID-19 testing these patients before treatment initiation. All three articles recommend performing SARS-CoV-2 testing for all patients before autologous SCT –30. Al S et al  and TerpFour guidelines of the main international institutions involved with oncology and COVID-19 research were selected and discuss systematic testing for SARS-CoV-2 in asymptomatic cancer patients .All ASCO recommendations are based upon available testing resources and laboratory capacity; therefore, they allocated cancer patients into priority groups to be tested. Asymptomatic individuals prior to receipt of immunosuppressive therapy are priority 3 for testing, after symptomatic and hospitalised patients. ASCO recommends that all new patients prior to receiving cytotoxic chemotherapy, SCT, biologic therapy, immunotherapy or high-dose corticosteroids, should be tested 72 to 48 hours before commencing treatment and, during treatment, every patient should be screened with a standardised questionnaire. If possible, they recommend the test occurs at a site other than the hospital or cancer care clinic .ESMO consensus also suggests that SARS-CoV-2 RT-PCR testing should be recommended to all patients undergoing chemotherapy or immunotherapy and ideally before each treatment cycle. Considering the availability of resources in each cancer centre, and limited access to testing, RT-PCR should be offered only to symptomatic patients .IDSA recommends routinely testing all cancer patients, including asymptomatic individuals, before immunosuppressive therapies, regardless of a known exposure to COVID-19. IDSA also advises that testing should ideally be performed as close to the planned treatment as possible (within 48–72 hours). In the outpatient setting, where patients require frequent visits to the clinic or infusion room, IDSA recommends regular screening with a standardised questionnaire for symptoms and known exposures between visits .Opposed to the other guidelines, NCCN does not recommend testing for all asymptomatic patients being considered for systemic therapy. Instead, they suggest several measures that can be implemented to provide cancer care safely, such as considering alternative dosing schedules, switching to oral therapies (if available) and administration at home through home care nurses. There is only one exception, namely, patients with hematologic malignancies and/or undergoing SCT .Cancer centres all over the world are dealing with different challenges regarding cancer care during the COVID-19 pandemic, which go from lower availability of diagnostic/workup studies to deciding which patients should go in-person to the centre and even if treatments should be postponed , 35. In Our systematic review failed to identify a good level of evidence to support the routine test for SARS-CoV-2 before initiating systemic treatment even though this routine was uniformly recommended among the selected publications. This brings some limitations that should be considered when interpreting the results of this review.4+ lymphocyte counts and a shorter duration of viral shedding, but this has not yet been reported in cancer patients [A positive SARS-CoV-2 RT-PCR test could guide the decision of delaying the systemic oncologic treatment and possibly avoiding COVID-19 severe complications in an immunosuppressed patient , but thipatients . In addipatients . TestingIn contrast, there are negative points in performing the SARS-CoV-2 test before starting the systemic treatment. The RNA test for prevalent infection is an essential part of the diagnosis strategy . The RT-A review analysed seven previously published studies providing results on 1,330 RT-PCR testing for SARS-CoV-2 and time since onset of symptoms or exposure. The results demonstrated over the 4 days of infection before the typical time of symptom onset, the probability of a false-negative result in an infected person decreased from 100 on day 1 to 67%  on day 4. On the day of symptom onset, the median false-negative rate was 38% . Thus, the false-negative rate for SARS-CoV-2 RT-PCR testing is highly variable especially within the days of no symptoms .Overall, potential RT-PCR vulnerabilities are related to multiple pre-analytical and analytical factors . The maiHealth systems can be overwhelmed during a viral pandemic emergency in all areas, from preventive and diagnostic measures to resources for treatment . The rapOther concerns on this theme would be the ideal frequency for performing RT-PCR and the possibility of patients being infected between the test day and the medical appointment. In this systematic review, we were unable to answer this question, and hence, these are matters that each service tended to follow its own recommendation.As mentioned, the main oncological societies in the world have developed guidelines to mitigate the negative effects of the COVID-19 pandemic on the diagnosis and treatment of cancer patients. The scope of these proposed guidelines is to categorise patients as high, medium or low priority, based on the clinical criteria intrinsic to the patient and the disease, in order to plan their management course accordingly –34. ThatGiven the current unusual situation, pragmatic approaches are required to deal with the challenges of treating cancer patients, without risking their care. Clear communication and education about hand hygiene, face masks, infection control measures, signs and symptoms of the COVID-19, high-risk travel or exposure and the importance of reporting new symptoms to their health care providers should be reinforced.Due to the paucity of structured data to routinely submit patients initiating treatment to COVID testing and the high false-negative rates, our institution has considered among our group of oncologists and haematologists all the pros and cons in regard to SARS-CoV-2 testing for asymptomatic patients before initiating oncologic treatment, and decided to follow a selective approach. We do not recommend routinely testing all cancer patients before initiating systemic treatments. Based upon the highest frequency of severe events, we advise testing asymptomatic patients prior to SCTs, any systemic treatment of hematopoietic neoplasms, concurrent chemoradiation regimens (presenting with high frequency of post-treatment lymphopenia) or in those patients with lung cancer or head and neck cancer initiating systemic treatments with immunosuppressive properties.Suggested steps to reduce the risk of exposure include a call to the patient 48 hours prior to their scheduled appointment and on the day of treatment to screen for any symptoms associated with COVID-19, contact history, as well as recent travel history. During treatment, all patients should be screened 48 hours before each new cycle of therapy. We strongly recommend a detailed questionnaire that embraces all relevant aspects of COVID-19. The questionnaire which we proposed in our institution is presented in the Appendix This systematic review has demonstrated that there is a lack of robust evidence to support SARS-CoV-2 testing of asymptomatic patients before cancer treatment even though this routine is mostly suggested among the guidelines and expert consensuses.The crucial point is to individualise the centres and their socioeconomic circumstances, considering the accessibility to testing resources, laboratory capacity and regional epidemiology. Based upon this review our group proposed our own recommendations. We plan to collect and publish prospective data after adopting our institution`s consensus. Finally, it is important to mention that these recommendations may change in the future, depending on new scientific evidence.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare that they have no conflicts of interest.


Caenorhabditis elegans have uncovered a vast number of gap junctions present in the nervous system and non-neuronal tissues. The genome also has 25 innexin genes that are expressed in spatial and temporal dynamic pattern. Recent findings have begun to reveal novel roles of innexins in the regulation of multiple processes during formation and function of neural circuits both in normal conditions and under stress. Here, we highlight the diverse roles of gap junctions and innexins in the C. elegans nervous system. These findings contribute to fundamental understanding of gap junctions in all animals.Gap junctions are evolutionarily conserved structures at close membrane contacts between two cells. In the nervous system, they mediate rapid, often bi-directional, transmission of signals through channels called innexins in invertebrates and connexins in vertebrates. Connectomic studies from  Summary: Studies from C. elegans have illustrated many roles of gap junctions in neural connectivity and circuit regulation, during normal conditions and under stress. In all animals, neurons transmit signals through two main types of synaptic connections: chemical synapses and electrical synapses, the latter also known as gap junctions. Chemical synapses are morphologically and functionally asymmetric junctions formed between a neuron and its targets (neuron or muscle). The presynaptic terminal is characterized by an aggregation of neurotransmitter-filled synaptic vesicles around the electron-dense membranes, whereas the postsynaptic side contains receptors for neurotransmitters and signal transduction molecules. Pre- and postsynaptic membranes are separated by a 20–30 nm wide extracellular space, known as the synaptic cleft, which is generally wider than non-synaptic space between two adjacent neurons and consists of specialized extracellular matrix and signaling molecules to facilitate milli-second transmission of neural information . In contCaenorhabditis elegans is a small (1 mm long as adult), optically transparent and genetically tractable model organism with a generation time of 3–4 days. Pioneering work completed nearly 40 years ago led to the complete reconstruction of nervous system connectivity at the ultrastructural level . unc mutants were later grouped into phenotypic subclasses  or unc-2/unc-36  mutants  are broadly expressed in the nervous system. A given neuron expresses at least one innexin, with most neurons generally expressing seven to nine innexins. Other inx genes show restricted expression, for example, inx-6 and eat-5 show exclusive expression in only one neuron type. About ten innexins  are non-neuronally expressed. Regulation at the levels of transcription or mRNA splicing further contributes to inx gene expression complexity. For example, two different isoforms of innexins can have similar (inx-1a and inx-1b) or different (inx-18a and inx-18b) expression patterns, and the inx-10a isoform is only expressed in I6 neuron. The expression profiling data provide a foundation for investigating the roles of innexins in the nervous system. For example, eat-5 and inx-3 have partially overlapping expression in the pharynx, but likely function independently, since when expressed separately in the two oocytes they do not form intercellular channels between paired Xenopus oocytes  STR-2 as AWCr AWCoff . The spee neuron . The difnsy ’ mutants showing loss of asymmetric STR-2 expression in AWC. For example, loss of function in nsy-5 causes both AWC neurons to differentiate into the AWCoff subtype , to be required in both PLM and BDU for the proper contact between them. Expression of cam-1, which encodes a Wnt receptor necessary for the PLM-BDU contact, was significantly reduced in aha-1 mutants. It remains to be determined whether UNC-9 localization at PLM-BDU contact site also requires Wnt signaling and AHA-1. This study demonstrates that tight regulation of gap junction formation between neurons is important for proper neurite formation.Mechanosensory neuron PLM and interneuron BDU are physically connected to each other, and form innexin UNC-9 clusters at their interface only upon contact  Fig. 2BBFig. 2B.unc-7 mutants. Despite its impact on the active zone, UNC-7 was not critical for SV distribution. The closely related innexin UNC-9 was also shown to be critical for active zone protein localization. UNC-7 and UNC-9 colocalized at perisynaptic regions adjacent to active zone protein or SV proteins. However, gap junctions are not present near active zones in motor neurons at the ultrastructural level  and amplify the spontaneous activity in VA into PSC bursts  and B-type (DB and VB) motor neurons are connected to interneurons AVA and AVB, respectively, via unctions . Intraceectively . In wildC bursts D. At res animals . These rinx-4 mutant, suggesting that cGMP transfer from ADF to ASH neurons dampens quinine sensitivity  , and alssitivity . When ensitivity , loss of neurons . Howeversitivity .C. elegans show three types of nociceptive avoidance behaviors: long turn, short turn and omega turn. Weak sorbitol stimuli result in higher probability of short or long reversal behaviors, while strong sorbitol stimuli often result in omega turn avoidance behavior  or separately (as hemichannels) in synaptogenesis, locomotor circuit and mechanosensation. However, most other innexins do not seem to be as strongly paired as unc-7 and unc-9, and can have redundant or partly overlapping function. Several open questions remain to be further addressed: (1) 17 innexins (including different isoforms) are expressed in neurons, six of which have been functionally characterized in the nervous system  In other organisms including Drosophila, gap junctions and hemichannels can function as heteromeric channels that are composed of a mixture of innexins (C. elegans innexins remain to be determined. (5) Maintenance of chemical synapses is important for neuronal function and health, and defects in cellular maintenance mechanisms, such as chemical synaptic protein turnover, can lead to neurodegeneration. How gap junctions and gap junction proteins are turned over in a healthy brain, and how gap junction plasticity is regulated and maintained remain open questions. Whether these mechanisms are coupled with the maintenance mechanisms for chemical synapses would further our fundamental understanding of how chemical and electrical synapses coordinate brain development and function.Since the discovery of innexin genes in s system , but theinnexins . The pre


Bacterial sepsis has been used as a prototype to understand the pathogenesis of severe coronavirus disease 2019 (COVID-19). In addition, some management programs for critically ill COVID-19 patients are also based on experience with bacterial sepsis. However, some differences may exist between these two types of sepsis.This retrospective study investigated whether there are differences in the immune system status of these two types of sepsis. A total of 64 bacterial sepsis patients and 43 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sepsis were included in this study. Demographic data were obtained from medical records. Laboratory results within 24 h after the diagnosis of sepsis were provided by the clinical laboratory.The results of blood routine , infection biomarkers , lymphocyte subset counts , and lymphocyte subset functions  were similar in bacterial sepsis patients and SARS-CoV-2 sepsis patients. Cytokine storm was milder, and immunoglobulin and complement protein levels were higher in SARS-CoV-2 sepsis patients.There are both similarities and differences in the immune system status of bacterial sepsis and SARS-CoV-2 sepsis. Our findings do not support blocking the cytokine storm or supplementing immunoglobulins in SARS-CoV-2 sepsis, at least in the early stages of the disease. Treatments for overactivation of the complement system and lymphocyte depletion may be worth exploring further. Coronavirus disease 2019 (COVID-19) has become a global pandemic. As of the submission of this study, about 38 million infections have been confirmed and approximately 1 million deaths have been reported. These shocking numbers are still growing at an alarming rate. Since the outbreak of the epidemic, huge efforts have been made to deal with the challenges of the virus. Among these, clinicians have focused their attention on how to improve the prognosis of critically ill COVID-19 patients.In clinical practice, it has been noticed that many critically ill COVID-19 patients developed severe organ dysfunction due to dysregulated response to infection and met the diagnostic criteria for sepsis . In suchThe optimal management of sepsis patients requires a clear understanding of alterations in immune system. In this study, we compared changes observed in the immune system of bacterial sepsis patients and SARS-CoV-2 sepsis patients. We also provide recommendations concerning appropriate immunotherapy for SARS-CoV-2 sepsis based on these comparisons.This retrospective study was performed at a university-affiliated hospital designated by the government as a center for the treatment of severe COVID-19 patients in Wuhan. Approval was obtained from the Medical Ethics Committee of the hospital with a waiver of informed consent.Sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to infection . BacteriDemographic data, medical history, the SOFA score, and the Acute Physiology and Chronic Health Evaluation (APACHE) II score were obtained from the clinical information systems. The results of blood routine, infection biomarkers, cytokines, immunoglobulins, complement proteins, as well as lymphocyte subset counts and functions, were detected and reported by the clinical laboratory. Lymphocyte subset functions were evaluated by the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+, CD8+ T cells, and NK cells. Flow cytometry analysis was performed as previously described . SOFA scp-value of less than 0.05 was considered statistically significant.Continuous and categorical variables are presented as median (interquartile range) and number (percentage) in this study. Comparisons of two independent samples were performed using the Wilcoxon rank-sum test , chi-square tests  or Fisher exact probability test . Statistical analyses and graphics were developed using SPSS v26.0  and GraphPad Prism v8.3.0 . A two-sided A total of 64 bacterial sepsis patients with pulmonary infection and 43 SARS-CoV-2 sepsis patients were included in the present study Figure 1Overall, the results of blood routine  and infection biomarkers  in SARS-CoV-2 sepsis patients and bacterial sepsis patients showed the same upward and downward trend relative to normal ranges Figure 1p-values in italics are all < 0.05 in As shown in As shown in Reduction in the counts of all lymphocyte subsets  were common for both bacterial sepsis and SARS-CoV-2 sepsis groups .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Supplemental Digital Content is available in the text The use of a drug-eluting stent (DES) in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention is conventional. However, the effect of DES on new-onset atrial fibrillation (AF) after AMI still remains unclear.By using data from Taiwan's National Health Insurance Research Database, a total of 17,741 patients with ST-elevation myocardial infarction (STEMI) and 17,631 patients with non-ST-elevation myocardial infarction (NSTEMI) treated with percutaneous coronary intervention were analyzed to investigate the risk of new-onset AF after index admission of AMI.P = .009) after adjustment for clinical relevant variables. This benefit was consistent with that in the patients with NSTEMI who were ≥75 years old, had a CHA2DS2-VASc score of ≥2, and did not receive intra-aortic balloon pump insertion . However, DES placement had a neutral effect on the risk of new-onset AF in the patients with STEMI.There were 26.5% (N = 4696) of patients with STEMI and 39.5% (N = 6967) of patients with NSTEMI received DES implantation. Upon 1-year follow-up, we observed that DES placement was associated with a reduced 1-year risk of new-onset AF in the patients with NSTEMI (adjusted hazard ratio [aHR] = 0.74, 95% confidence interval [CI] = 0.59–0.93, Compared with the use of BMS, the use of DES might reduce the risk of new-onset AF in patients with NSTEMI. Additionally, patients with new-onset AF occurring >30 days after receiving a diagnosis of AMI had an increased risk of death during a mean follow-up of 6.6 years  compared with patients without AF. These data indicate the importance of prevention of the occurrence of new-onset AF following AMI.Atrial fibrillation (AF) is a common arrhythmia that occurs during acute myocardial infarction (AMI), with the incidence reported to vary between 6% and 21%.–8 Recent randomized clinical trials have demonstrated that the use of drug-eluting stents (DES) in patients with AMI treated invasively with PCI is associated with reduced rates of cardiac death, reinfarction, and target vessel revascularization compared with the use of bare-metal stents (BMS).,10 Despite these positive findings, the association between DES use and the risk of new-onset AF following AMI is unknown. Additionally, whether the risk of new-onset AF associated with DES use differs between patients with ST-elevation myocardial infarction (STEMI) and those with non-ST-elevation myocardial infarction (NSTEMI) remains unclear.Prompt and early invasive treatment with percutaneous coronary intervention (PCI) for patients with AMI yields lower rates of adverse cardiovascular events than does medical treatment.Although the use of DES in patients with AMI is conventional, the cost of DES use is paid by patients whereas the cost of BMS use is fully covered by National Health Insurance (NHI) in Taiwan. This mentioned situation provided an opportunity to investigate the association between the risk of new-onset AF and stent types which was difficultly answered by randomized clinical trials. In the present retrospective cohort study, we investigated the effect of DES on the risk of new-onset AF in patients with STEMI and those with NSTEMI treated invasively with PCI at 1-year follow-up by using data from Taiwan's National Health Insurance Research Database (NHIRD).22.1This study was approved by the Institutional Review Board of Taipei MacKay Memorial Hospital . In this study, we used the NHIRD, a claim-based database that covers 99% of the residents in Taiwan under the purview of the NHI program. Because individuals are deidentified in the NHIRD data released to researchers, informed consent was waived under the full review process of the Institutional Review Board.The NHIRD includes inpatient, outpatient, and prescription drug claims. Prescribed medications are classified according to the anatomical therapeutic chemical system, and the disease diagnosis is coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Death records from the National Death Registry are also linked to the NHIRD based on patients’ encrypted identifiers.2.2 In addition, patients who had received prior PCI before the index AMI admission and who did not receive PCI or stent implantation during the index AMI admission were excluded. Patients diagnosed as having 2 different subtypes of AMI, STEMI, and NSTEMI, were identified. Figure Within the retrospective cohort, we included patients who had received a primary diagnosis of AMI (ICD-9-CM code 410) based on the discharge claim between 2007 and 2013. The date of admission for AMI was considered the index of AMI. We excluded patients who were <20 years old; were not residents of Taiwan; had died at the index AMI admission; had preexisting AF or atrial flutter (AFL); had a record of AF or AFL at index AMI admission; and had received coronary artery bypass grafting, ventricular assist device support, extracorporeal membrane oxygenation, or heart transplantation during the study period. Patients who had medical conditions requiring anticoagulant treatment  and received chronic vitamin K antagonist or nonvitamin K antagonist oral anticoagulants that may negatively influence the tolerance of dual antiplatelet therapy (DAPT) and preclude the physicians’ choice of DES were also excluded.2.3The principal outcome in the present study was the new-onset AF requiring new prescriptions of vitamin K antagonist or nonvitamin K antagonist oral anticoagulants that can be defined from diagnostic claim of ICD-9-CM code of 427.31 and drug claims. The patients were followed up for 1 year, and the data of those who died or did not have the events of interest during the study periods were treated as censored cases.2.4t test for continuous variables. The Kaplan–Meier method was used to report the cumulative incidence of events over time, and log-rank tests were applied to evaluate differences between the 2 groups. A multivariable Cox proportional hazard regression model was used to compare the risk of new-onset AF between DES groups and BMS groups after adjustment for clinical relevant variables, comorbidities, and prescribed medications. Clinical relevant variables included age, year of AMI admission, complex PCI procedures , and the use of intra-aortic balloon pump (IABP) counterpulsation during PCI. Patients’ comorbidities included diabetes mellitus, hypertension, hyperlipidemia, cerebrovascular disease, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease or asthma, dementia, Parkinson disease, osteoarthritis, rheumatoid arthritis or rheumatism, and CHA2DS2-VASc scores .,14 Prescribed medications included angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blockers, nitrate, antiplatelets, statins, proton pump inhibitors, nonsteroidal anti-inflammatory drugs, and steroids. A subgroup analysis of patients who were ≥75 years old, had a CHA2DS2-VASc score ≥2, and had received treatment with or without IABP insertion during AMI admission was also performed. Due to enrichment of data from the NHIRD, no data were missing during adjustment for differences in baseline characteristics. The ICD-9-CM codes for disease diagnosis and the anatomical therapeutic chemical codes for medication are listed in Supplementary Table A. All analyses were performed using SAS/STAT 9.4 software  and STATA 14 software . P < .05 was considered significant.Continuous variables are presented as mean ± standard deviation, and categorical variables are expressed as percentages. Comparisons between the baseline characteristics in the DES and BMS groups were performed using the chi-squared test for categorical variables and Student 33.1Among the patients admitted for AMI treated invasively by PCI with stent placement, 50.2% had STEMI and 33.0% had received DES placement. The rate of receiving DES placement was lower in the patients with STEMI than that in those with NSTEMI (26.5% vs 39.5%) Table . In both3.2P = .989)  Table .3.3P = .009) compared with BMS use . Additionally, the use of DES was associated with a reduced risk of new-onset AF  in the patients with NSTEMI who had a CHA2DS2-VASc score of ≥2   Table .42DS2-VASc score of ≥2, and did not receive IABP insertion during PCI. However, the use of DES did not show a reduced risk of new-onset AF in the patients with STEMI treated with PCI.The current study revealed that the use of DES was associated with a reduced 1-year risk of new-onset AF in the patients with NSTEMI treated invasively with PCI. These benefits were also observed in the patients with NSTEMI who were ≥75 years old, had a CHA Additionally, patients with NSTEMI more often developed new-onset AF than patients with STEMI, as observed in the Global Registry of Acute Coronary Events study as well as in the present study. In this study, we observed a reduced risk of new-onset AF associated with DES use in the patients with NSTEMI treated invasively with PCI. The aforementioned results are consistent with those of the patients with NSTEMI who were ≥75 years old and had a CHA2DS2-VASc score of ≥2, as seen in previous studies.,14,15Information on the risk of new-onset AF in patients with STEMI and NSTEMI treated with PCI with stent placement is limited. A retrospective observational study reported by Batra et al, who analyzed 155,071 patients admitted for AMI, showed that AF was recorded in 15.5% of patients, and the most common type of AF was new-onset AF with sinus rhythm at discharge.–8 A retrospective study that analyzed 652 patients with AMI and cardiogenic shock enrolled in the Intra-aortic Balloon Pump in Cardiogenic Shock II trial revealed that the 1-year risk of mortality and reinfarction of patients treated with DES was similar to those of patients treated with BMS. However, we did not observe that DES use was associated with a reduced risk of new-onset AF in patients with IABP insertion compared with BMS placement. This might be due to the relatively small numbers of patients with IABP insertion and hence, a statistically significant difference was not observed. This finding of the present study must be confirmed using an appropriately powered randomized clinical trial.Data on DES use in patients with AMI who received IABP insertion is limited. The use of IABP counterpulsation does not improve clinical outcomes and may be only considered in critically ill patients who develop mechanical complications or refractory cardiogenic shock.,19 The administration of triple therapy, including DAPT and an oral anticoagulant (OAC), is usually required for patients who develop new-onset AF following AMI to prevent the occurrence of ischemic stroke.,21 However, triple therapy results in a 2- to 3-fold increase in bleeding complications compared with OAC therapy alone. A possible clinical implication of the present study is that DES placement be considered in patients with NSTEMI to reduce not only the risk of new-onset AF but also the requirement of OAC therapy and the occurrence of potential drug-related bleeding complications.The current guidelines recommend that DAPT should be given for at least 12 months in patients with AMI regardless of DES or BMS implantation.,21 A reduced risk of reinfarction and target vessel revascularization associated with DES use might lead to decreased recurrent atrial ischemia, limited atrial remodeling, and a reduced risk of AF formation. In the Swedish Coronary Angiography and Angioplasty Registry, PCI with DES placement was associated with a lower risk of stent thrombosis compared to that with BMS placement. Additionally, the superiority of DES over BMS for a lower risk of stent thrombosis became obviously in early months during the follow-up period in the Swedish Coronary Angiography and Angioplasty Registry data, which might also explain our findings. In the current study, patients with STEMI were mostly younger and had fewer comorbidities compared with patients with NSTEMI, as observed in previous studies.,15 The favorable baseline characteristics of patients with STEMI themselves lead to a lowered risk of AF regardless of stent types.Any disturbance of atrial architecture potentially increases the susceptibility to AF. Atrial ischemia from coronary artery disease tends to increase the atrial pressure, cause atrial dilation, and result in structural and electrophysiological abnormalities, which promote abnormal impulse generation and propagation.; however, they might not be associated with the risk of AF. To estimate the association between the DES use and AF, this study used multiple regression methods to adjust potential confounding factors listed in Table The price of each DES paid by patients in Taiwan was approximately USD $2300 in the year of 2007 whereas the cost of BMS was fully covered by NHI. This mentioned gap in medical cost may introduce a bias in patients undergone either DES or BMS stent implantation, resulting in a difficulty to design a randomized study, especially in an emergent clinical situation with AMI. The strength of the present study is the nationwide population-based design with a large sample size and the use of real-world data, which can reflect the actual application of DES in patients with AMI. However, this study has some limitations. First, the NHIRD does not provide some clinical information, such as the extent of a patient's coronary artery disease, the angiographic findings of PCI, and some cardiac parameters  that might influence the incidence of AF. Second, we did not analyze the differences between first-generation and newer-generation DES. In addition, we did not compare the effects of the different types of DES . Moreover, polymer-free drug coating stents and bioabsorbable vascular scaffolds were not commercially available in Taiwan until 2013 and were beyond the scope of the present study. Third, the baseline characteristics of patients might influence the choice of DES. For example, patients who had received DES implantation were more likely to have a higher socioeconomic status than those patients who had received BMS implantation because the medical cost of DES was not fully covered by NHI in Taiwan. This mentioned situation may somewhat influence the patients’ choice of stent types and needs to be addressed by further studies to investigate the benefits of DES compared with that of BMS. Besides, the patients with a high bleeding risk were more likely to receive BMS because of undetermined compliance of DAPT. We acknowledged that the socioeconomic status and bleeding risks would influence the choice of DES in the present study, as also seen in other research5In this population-based cohort study, the use of DES, compared with the use of BMS, is associated with a decreased risk of new-onset AF in the patients with NSTEMI treated with PCI at 1-year follow-up; these results are consistent with those for patients with a high risk to develop AF. Overall, our findings suggest that DES placement significantly hinders new-onset AF following NSTEMI, whereas the use of DES in the patients with STEMI results in a neutral effect compared with BMS placement.Conceptualization: Fa-Chang Yu.Data curation: Fa-Chang Yu, Hung-Yi Liu, Chao-Feng Lin, Li-Nien Chien.Formal analysis: Hung-Yi Liu, Chao-Feng Lin, Li-Nien Chien.Methodology: Fa-Chang Yu, Chao-Feng Lin, Li-Nien Chien.Resources: I-Ming Chen.Validation: Ya-Hui Chang, Hung-Yi Liu.Visualization: Ya-Hui Chang, I-Ming Chen.Writing – original draft: Fa-Chang Yu, Chao-Feng Lin, Li-Nien Chien.Writing – review & editing: Fa-Chang Yu, Ya-Hui Chang, I-Ming Chen, Hung-Yi Liu, Chao-Feng Lin, Li-Nien Chien.


In this study, we aimed to evaluate the initial hematological findings analyzed on admission in confirmed COVID-19 patients who were transferred to the intensive care unit (ICU), to predict possible hematological indices. Initial neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), red cell distribution width to platelet ratio (RPR), mean platelet volume to platelet ratio, and lymphocyte multiplied by platelet count (LYM × PLT), of 695 patients with laboratory-confirmed COVID-19 were investigated and comparisons were made between the mild/moderate and severe groups.The proportion of COVID-19 cases admitted to the ICU was 3.9%. The median age of patients admitted to the ICU was significantly higher than those who were not;  years vs. 41.0  years; P < 0.001.Severe cases had higher NLR , and MLR  and lower PLR  compared to that of mild or moderate patients. Among all of the parameters, the ROC curve of NLR gave us the best ability to distinguish serious patients at an early stage .These data showed that age, initial NLR, PLR, and LYM × PLT were associated with the severity of COVID-19 disease and patients’ need for the ICU. Therefore, initial hemogram parameters may be essential to predict the prognosis of COVID-19 patients. WHO: Novel coronavirus (2019-nCoV) situation report-51 2020 [online]. Website https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf?2 [accessed 10 May 2020].. In our country, the first PCR positive COVID-19 case was detected on March 11th, 20202Republic of Turkey Ministry of Health (2020). COVID-19 Information Page [online]. Website https://covid19.saglik.gov.tr/ [accessed 14 May 2020]..In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan, China; and quickly spread around the World [1]. The World Health Organization named this infection COVID-19 and announced a pandemicThe clinical spectrum of COVID-19 infection can vary from asymptomatic to severe disease  . Up to 32% of all positive patients require intensive care unit (ICU) admission, and death can occur . Therefore, early identification of patients with severe disease risk and those that may potentially develop a life-threatening condition is important.Increasing evidence supports the role of a dysfunctional immune response to the airway damage and the progression of various viral pneumonia, including COVID-19 . Hematological indices, such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte (PLR) ratio, monocyte to lymphocyte ratio (MLR), lymphocyte count multiplied by platelet count (LYM × PLT), red cell distribution width to platelet ratio (RPR), are indicators of the systemic inflammatory response and have been extensively investigated in various diseases [6–9]. Abnormal blood count results were detected in patients with COVID-19 , which are considered to be potential predictors of the outcomes . In this study, we aimed to identify hematological indices of confirmed COVID-19 patients that were analyzed on admission and their relationship with the disease severity, in order for them to be used in predicting the disease progression. The study was approved by the ethics committee of SBU Bursa Yüksek İhtisas Training and Research Hospital (No. 2020/05-02); a pandemic hospital with 1430 beds served as the setting for the present retrospective cohort study. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki.Combined nasopharyngeal and oropharyngeal swabs were taken from 1100 patients who met the suspected case definitions for COVID-19. Real-time quantitative amplification of SARS CoV RNA was performed with SARS-CoV-2 (2019-nCoV) RT-qPCR Detection Kit  with a thermal cycler device  according to the manufacturer’s instructions. Six-hundred and ninety-five confirmed SARS-CoV-2 patients admitted to our hospital between March 27th and April 30th, 2020, were included in the study. Individuals younger than 18 years old, those who required aggressive treatment within 24 h of admission, and those with an absence of initial complete blood count (CBC) test results were excluded from the study.Twenty-seven patients who fulfilled one of the following criteria; dyspnea and respiratory distress; respiratory rate > 30/min, PaO2 / FiO2 <300; SPO2 <90 despite 5 L/min oxygen treatment, PaO2 <70, hypotension , tachycardia >100/min, acute kidney injury, development of acute organ dysfunction, patients with immunosuppression, acute bleeding diathesis, troponin increase, arrhythmia, lactate > 2 mmol, capillary return disorder, and cutis marmaratus were transferred to ICU. 9 / L) [15].The initial triage protocol of COVID-19 patients involves drawing blood samples upon admission. CBCs were analyzed within 1 h after venipuncture using an automatic blood counter . Mean platelet volume divided by platelet count (MPV to PLT) and lymphocyte multiplied by platelet (LYM × PLT) were recorded. NLR, PLR, and MLR were calculated by dividing the number of neutrophils, platelet, and monocyte count by the lymphocyte count. RDW to platelet ratio (RPR) was calculated using the formula  for Windows , and P values of <0.05 were considered significant. Descriptive statistics are presented as frequency distribution and percentage. The Kolmogorov–Smirnov test was used to identify the distribution of variables. Statistically significant differences between the variables were established using the MannWhitney U test. A binary logistic regression analysis was performed to determine the influence of age and all other significant factors.The proportion of COVID-19 cases admitted to ICU was 3.9%. Signs and symptoms of severe cases on admission included self-reported fever (52%), cough (44%), shortness of breath (52%), sore throat (19%), myalgia/arthralgia (19%), fatigue (15%), chest pain/discomfort (11%), nasal symptoms (11%), headache (11%), nausea/vomiting (11%) and diarrhea (4%).During the study period, the median age of patients who were transferred to ICU was significantly higher than those who were not transferred .When comparing the initial hemoglobin concentration  and lymphocyte count [12.7% (12.6) vs. 26.6% (15.7)] both values were found to be lower than that of nonsevere cases (Table 1).It is observed that severe cases had higher NLR , and MLR  and lower PLR  compared to mild or moderate patients (Table 1). The ROC curve of NLR gave us the best prediction opportunity for distinguishing patients with severe disease from an earlier stage .Potential risk factors, including age, NLR, PLR, LYM × PLT, and RDW were investigated using binary logistic regression analysis. Age was found to be the only significant  positive predictor for ICU requirement, with the OR 1.073  (Table 3).  On admission, the COVID-19 patients who needed to be taken to the ICU were older than those that did not require ICU intervention, as reported before . In the ICU-patient group, the initial absolute neutrophil count was higher, and the lymphocyte count was lower among patients who were transferred to the ICU compared to mild cases who were not. This is in accordance with the previous publications that reported the increase in leukocyte count and a decrease in lymphocyte count as an indicator for clinical deterioration in COVID patients .Neutrophils are the most important cellular defense line against infections, which first respond to viral invasion, and limit the viral replication and spread. However, neutrophils have also been reported to mediate deleterious effects on the host during viral infection [18].The immune response to a viral infection is mainly based on lymphocytes. It has been assumed that a significant decrease in lymphocyte count may be due to increased lymphocyte consumption, destruction of lymphatic tissues, and cytokine-induced T-cell apoptosis in patients with COVID-19 . Lymphopenia, as a sign of the severe disease, is not specific to COVID-19. It has also been seen in other viral causes of pneumonia, such as influenza .Notably, we observed that COVID-19 patients who were transferred to the ICU had lower lymphocyte count and higher NLR and PLR. In consistency with our study, Yang et al. suggested NLR ≥3.3 as an indicator with clinical symptoms to change disease status from mild to severe disease [22]. NLR is reported to be used as an early indicator for the severe disease, similar to previous findings from a different patient population .In the current study, the median PLR of severe COVID patients was higher compared to that of nonsevere cases. The PLR, which reflects both aggregation and inflammation control, is a better marker for the decision of patients for transfer to the ICU than platelet or lymphocyte count alone. Changes in platelet count and activity are closely related to various diseases [24]. It has been shown in several studies that low platelet count is directly related to the severity of the disease in COVID-19 patients . Platelets not only contribute to hemostasis but also participate in the inflammation and host defense. Decreased platelet production and increased consumption due to diffuse alveolar damage are thought to cause thrombocytopenia in COVID-19 patients .In accordance with previous studies, the hemoglobin level was found to be lower in COVID patients who needed to be taken to the ICU when compared to that of milder COVID patients . RDW is a measure of the change in erythrocyte volume and has been reported to be a predictor of mortality in some conditions, including infections [30]. The higher RDW is associated to increased inflammation markers which have been tightly correlated with the critical disease .According to the results of this study, the variables, including the age of the patients, NLR, PLR, and LYM × PLT, are related to the severity of COVID-19 disease and may contribute to decision making for transferring patients to the ICU on admission. Therefore, initial CBC parameters should be monitored for predicting the prognosis of COVID-19 patients.Limitation: This study was a retrospective, single-center study. Prospective and multicenter clinical studies might be required to avoid a certain degree of deviation and to support the findings. SBU Bursa Yüksek İhtisas Etik Kurul 2011-KAEK-25 2020/05-02.