Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barre syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barre syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.

Neurological Associations of COVID-19

Objective To determine the diagnostic accuracy of
 serological tests for coronavirus disease-2019
 (covid-19). Design Systematic review and meta-analysis. Data sources Medline, bioRxiv, and medRxiv from 1 January to
 30 April 2020, using subject headings or
 subheadings combined with text words for the
 concepts of covid-19 and serological tests for
 covid-19. Eligibility criteria and data
 analysis Eligible studies measured sensitivity or
 specificity, or both of a covid-19 serological
 test compared with a reference standard of viral
 culture or reverse transcriptase polymerase chain
 reaction. Studies were excluded with fewer than
 five participants or samples. Risk of bias was
 assessed using quality assessment of diagnostic
 accuracy studies 2 (QUADAS-2). Pooled sensitivity
 and specificity were estimated using random
 effects bivariate meta-analyses. Main outcome measures The primary outcome was overall sensitivity and
 specificity, stratified by method of serological
 testing (enzyme linked immunosorbent assays
 (ELISAs), lateral flow immunoassays (LFIAs), or
 chemiluminescent immunoassays (CLIAs)) and
 immunoglobulin class (IgG, IgM, or both).
 Secondary outcomes were stratum specific
 sensitivity and specificity within subgroups
 defined by study or participant characteristics,
 including time since symptom onset. Results 5016 references were identified and 40 studies
 included. 49 risk of bias assessments were carried
 out (one for each population and method
 evaluated). High risk of patient selection bias
 was found in 98% (48/49) of assessments and high
 or unclear risk of bias from performance or
 interpretation of the serological test in 73%
 (36/49). Only 10% (4/40) of studies included
 outpatients. Only two studies evaluated tests at
 the point of care. For each method of testing,
 pooled sensitivity and specificity were not
 associated with the immunoglobulin class measured.
 The pooled sensitivity of ELISAs measuring IgG or
 IgM was 84.3% (95% confidence interval 75.6% to
 90.9%), of LFIAs was 66.0% (49.3% to 79.3%), and
 of CLIAs was 97.8% (46.2% to 100%). In all
 analyses, pooled sensitivity was lower for LFIAs,
 the potential point-of-care method. Pooled
 specificities ranged from 96.6% to 99.7%. Of the
 samples used for estimating specificity, 83%
 (10 465/12 547) were from populations tested
 before the epidemic or not suspected of having
 covid-19. Among LFIAs, pooled sensitivity of
 commercial kits (65.0%, 49.0% to 78.2%) was lower
 than that of non-commercial tests (88.2%, 83.6% to
 91.3%). Heterogeneity was seen in all analyses.
 Sensitivity was higher at least three weeks after
 symptom onset (ranging from 69.9% to 98.9%)
 compared with within the first week (from 13.4% to
 50.3%). Conclusion Higher quality clinical studies assessing the
 diagnostic accuracy of serological tests for
 covid-19 are urgently needed. Currently, available
 evidence does not support the continued use of
 existing point-of-care serological tests. Study registration PROSPERO CRD42020179452.

https://www.bmj.com/content/bmj/370/bmj.m2516.full.pdf

Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis.

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection. Objectives To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. Search methods We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. Selection criteria We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria). Data collection and analysis We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). Main results We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. Authors' conclusions The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review.

Antibody tests for identification of current and past infection with SARS‐CoV‐2

Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.

Background: The COVID-19 pandemic, caused by SARS-CoV-2, is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. Based on knowledge of other coronaviruses, especially those that caused the SARS and MERS epidemics, we might expect to see rare cases of central nervous system (CNS) and peripheral nervous system (PNS) disease caused by SARS-CoV-2.

Recent developments: A growing number of case reports and series describe a wide array of neurological manifestations, but many lack detail, reflecting the challenge of studying such patients. Encephalopathy is relatively common, being reported for 93 patients in total, including 16 (7.5%) of 214 hospitalised COVID-19 patients in Wuhan, China, and 40 (69%) of 58 in intensive care with COVID-19 in France. Encephalitis has been described in 8 patients to date, and Guillain-Barre syndrome in 19 patients. SARS-CoV-2 is detected in the cerebrospinal fluid of some patients. Anosmia and ageusia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 1.6-6% of hospitalised COVID-19 cases. So far, 88 patients have been described, mostly with ischaemic stroke, who frequently have vascular events in the context of a pro-inflammatory hypercoagulable state with elevated CRP, D-dimer, and ferritin.

Where next?: Careful clinical, diagnostic and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease, such as hypoxic encephalopathy and critical care neuropathy, from those caused directly or indirectly by the virus; these include infectious, para- and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barre syndrome. Recognising SARS-CoV-2 neurological disease in patients whose respiratory infection is mild or asymptomatic may prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will remain small. However, these patients may be left with severe neurological sequelae. With so much of the population infected, the overall number of neurological patients, and their associated health, social and economic costs, may be large. Healthcare planners and policymakers must prepare for this eventuality. The many ongoing studies investigating the neurological association will increase our knowledge base.

/pdf/neurological-associations-of-covid-19-o39p8yig6g.pdf

Diagnostic value and dynamic variance of serum antibody in coronavirus disease 2019.

Background and Aims. At present, a targeted drug has not been found for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study assessed the effects of different therapeutic schedules on patients with COVID-19. Methods. The clinical characteristics, the prognosis of patients with western medicine (WM) treatment, and the combination of traditional Chinese medicine and western medicine (TCM-WM) treatment were retrospectively explored from January 20, 2020 to February 20, 2021. Results. 19 patients (15.20%) and 7 patients (5.60%) in the WM treatment group developed into severe type and critically ill, which were higher than 5 patients (9.43%) and 0 patients (0.00%) in the TCM-WM treatment group (
 
 p
 =
 0.306
 
 and 
 
 p
 =
 0.08
 
 ). The time from admission to severe in the WM treatment group was significantly shorter than that of the TCM-WM treatment group (7.5 vs. 11.2, 
 
 p
 <
 0.001
 
 ). Compared with patients in the TCM-WM treatment group, the average stay time and the negative nucleic acid time of patients in the WM treatment group were both significantly longer (both 
 
 p
 <
 0.05
 
 ). Besides, there existed no statistical difference for the safety of the two treatment options and nucleic acid test positive 14 days after discharge between the two groups. In line with the performance for severe patients, the average stay, the nucleic acid negative time, and the days of hormone therapy in the WM treatment group were all significantly longer than that of the TCM-WM treatment group (32.5 vs. 18.8, 
 
 p
 <
 0.001
 
 ; 24.5 vs. 14.5, 
 
 p
 <
 0.001
 
 ; 6.5 vs. 3.0, 
 
 p
 <
 0.001
 
 ). Conclusions. TCM-WM has better performance in both the disease progression and treatment of severe patients. We recommended that timely TCM-WM should be treated with patients with COVID-19.

/pdf/effects-of-different-therapeutic-schedules-on-patients-with-3ntmc7c6.pdf

Effects of Different Therapeutic Schedules on Patients with COVID-19: A Prospective Case–Control Study in China

The neutrophil–lymphocyte ratio(NLR) has been used for diagnosing venous thromboembolism (VTE). We aimed to assess the accuracy of NLR to diagnose VTE by meta-analysis. Systematic electronic searches were conducted June 2, 2021 in PubMed, Embase(Ovid), and Cochrane Library. The search did not have any language or time restriction applied. Our search strategy was based on keywords in combination with both medical subject headings (MeSH) terms and text words. The diagnostic odds ratio, summary receiver operating characteristics, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were estimated. 10 articles with 1513 VTE participants and 2593 control participants were included for quantitative synthesis. The pooled values were as follows: sensitivity = 0.68(95% CI 0.45-0.84), specificity = 0.73(95% CI 0.6-0.83), positive likelihood ratio = 2.5(95% CI 1.8-3.4), negative likelihood ratio = 0.44(95% CI 0.26-0.75), diagnostic odds ratio = 6(95% CI 3-11), and SROC = 0.76(95% CI: 0.73-0.8). NLR could be diagnostic factor for the detection of potential VTE, the accuracy thereof in the current meta-analysis exhibited moderate accuracy for diagnosing VTE. Furthermore, further large cohort studies are needed to determine optimal cut-off values of NLR.

The Association of Neutrophil–Lymphocyte Ratio with Venous Thromboembolism: A Systematic Review and Meta-Analysis

Associations between anti-mitochondrial antibodies and cardiac involvement in idiopathic inflammatory myopathy patients

BACKGROUND
Frail patients with atrial fibrillation (AF) are thought to be at a higher risk for cerebral infarction and death than patients who are not frail, making preventive interventions important. Anticoagulants should be used in frailty patients with AF. However, there are limited data about anticoagulants in frail patients with AF. Therefore, we concucted this meta-analysis to find the best anticoagulation strategy.


METHODS
Systematic electronic searches were conducted on 4 July 2022 4 July 2022, in PubMed, Embase (Ovid), and Cochrane Library. Relevant and eligible cohort studies were included. A random-effects model was used to estimate the pooled Hazard ratio (HR) and 95% confidence intervals (CI). Furthermore, we performed a publication bias analysis and subgroup analysis to explore the source of heterogeneity.


RESULT
3 publications (10 cohorts, 188573 participants) met our inclusion criteria. The pooled analysis showed that ischemic strokes (HR: 0.75; 95%CI: 0.71 to 0.79; I2 = 60.2%), systemic embolism (HR: 0.75; 95%CI: 0.64 to 0.87; I  = 68.6%), major bleeding(HR: 0.76; 95%CI: 0.64 to 0.89; I2 = 97.4%), intracranial hemorrhage (HR: 0.57; 95%CI: 0.45 to 0.71; I2 = 54.6%) and cardiovascular death(HR: 0.61; 95%CI: 0.51 to 0.70; I2 = 83.2%) were lower in NOACs as compared with warfarin. Regarding gastrointestinal bleeding, meta-analysis showed no significant differences in the risk of gastrointestinal bleeding (HR: 0.97; 95%CI: 0.69 to 1.36; I2 = 95.9%).   .


CONCLUSION
NOAC was more effective and safety than warfarin in frail patients with AF.

Outcome of novel oral anticoagulant versus warfarin in frail elderly patients with atrial fibrillation: a systematic review and meta-analysis of retrospective studies.

Zhaobin Cai

Papers

Diagnostic value and dynamic variance of serum antibody in coronavirus disease 2019.

Effects of Different Therapeutic Schedules on Patients with COVID-19: A Prospective Case–Control Study in China

The Association of Neutrophil–Lymphocyte Ratio with Venous Thromboembolism: A Systematic Review and Meta-Analysis

Associations between anti-mitochondrial antibodies and cardiac involvement in idiopathic inflammatory myopathy patients

Outcome of novel oral anticoagulant versus warfarin in frail elderly patients with atrial fibrillation: a systematic review and meta-analysis of retrospective studies.