Design and Synthesis of Triazole-Linked xylo-Nucleoside Dimers

Three triazole-linked nonionic xylo-nucleoside dimers T^L-t-T^xL, T^L-t-A^BzxL and T^L-t-C^BzxL have been synthesized for the first time by Cu(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) of 1-(3′-azido-3′-deoxy-2′-O,4′-C-methylene-β-D-ribo-furanosyl)thymine with different alkynes, i.e., 1-(5′-deoxy-5′-C-ethynyl-2′-O,4′-C-methylene-β-D-xylofuranosyl)thymine, 9-(5′-deoxy-5′-C-ethynyl-2′-O,4′-C-methylene-β-D-xylo-furanosyl)-N6-benzoyladenine and 1-(5′-deoxy-5′-C-ethynyl-2′-O,4′-C-methylene-β-D-xylofuranosyl)-N4-benzoylcytosine in 90%–92% yields. Among the two Cu(I) reagents, CuSO₄.5H₂O-sodium ascorbate in THF:^tBuOH:H₂O (1:1:1) and CuBr.SMe₂ in THF used for cycloaddition (click) reaction, the former one was found to be better yielding than the latter one.     

ICL植入术矫正高度近视的短期临床观察

目的:观察后房型有晶体眼人工晶体(implantable contact lens,ICL)植入术矫正高度近视术后早期的有效性和安全性。方法:选择于我院行ICL植入术的高度近视患者18例(36眼),于术前及术后1周、1个月、3个月随访记录其裸眼视力(uncorrected visual acuity,UCVA),最佳矫正视力(best corrected visual acuity,BCVA),等效球镜(spherical equivalent,SE),前房深度(anterior chamber depth,ACD),眼内压(intraocular pressure,IOP),角膜内皮细胞密度(endothelial cell density,ECD)的变化。结果:所有患者术后3个月裸眼视力和有效球镜度均较术前显著提高(P0.05),前房深度较术前变浅(P0.05),眼内压与术前对比无明显差异(P0.05),角膜内皮细胞密度较术前显著减少(P0.05)。结论:ICL植入手术矫正高度近视的短期临床疗效和安全性均较好。     

Efficacy of Corneal Collagen Cross-Linking for Treatment of Keratoconus: A Meta-Analysis of Randomized Controlled Trials

ObjectiveTo evaluate the efficacy of corneal collagen cross-linking (CXL) for the treatment of keratoconus.MethodsWe performed a literature search for randomized controlled trials that assessed the effect of CXL in slowing progression of keratoconus. The primary outcome measures included changes of topographic parameters, visual acuity, and refraction. Efficacy estimates were evaluated by weighted mean difference (WMD) and 95% confidence interval (CI) for absolute changes of the interested outcomes.ResultsSignificant decrease in mean keratometry value, maximum keratometry value and minimum keratometry value were demonstrated in the CXL group compared with the control group (WMD = -1.65; 95% CI: -2.51 to -0.80; P < 0.00001; WMD = -2.05; 95% CI: -3.10 to -1.00; P < 0.00001; WMD = -1.94; 95% CI: -2.63 to -1.26; P < 0.00001; respectively). Best spectacle-corrected visual acuity improved significantly in CXL group (WMD = -0.10; 95% CI: -0.15 to -0.05; P < 0.00001), whereas uncorrected visual acuity did not differ statistically. Manifest cylinder error decreased significantly in patients undergoing CXL procedure compared with control patients in sensitivity analysis (WMD = -0.388; 95% CI: -0.757 to -0. 019; P = 0.04). The changes in central corneal thickness and intraocular pressure were not statistically significant.ConclusionCXL may be an effective option in stabilizing keratoconus. Further long-term follow-up studies will be necessary to assess the persistence of CXL.     

First Nations status and emergency department triage scores in Alberta: a retrospective cohort study

Background:Previous studies have found that race is associated with emergency department triage scores, raising concerns about potential health care inequity. As part of a project on quality of care for First Nations people in Alberta, we sought to understand the relation between First Nations status and triage scores.Methods:We conducted a population-based retrospective cohort study of health administrative data from April 2012 to March 2017 to evaluate acuity of triage scores, categorized as a binary outcome of higher or lower acuity score. We developed multivariable multilevel logistic mixed-effects regression models using the levels of emergency department visit, patient (for patients with multiple visits) and facility. We further evaluated the triage of visits related to 5 disease categories and 5 specific diagnoses to better compare triage outcomes of First Nations and non–First Nations patients.Results:First Nations status was associated with lower odds of receiving higher acuity triage scores (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.92–0.94) compared with non–First Nations patients in adjusted models. First Nations patients had lower odds of acute triage for all 5 disease categories and for 3 of 5 diagnoses, including long bone fractures (OR 0.82, 95% CI 0.76–0.88), acute upper respiratory infection (OR 0.90, 95% CI 0.84–0.98) and anxiety disorder (OR 0.67, 95% CI 0.60–0.74).Interpretation:First Nations status was associated with lower odds of higher acuity triage scores across a number of conditions and diagnoses. This may reflect systemic racism, stereotyping and potentially other factors that affected triage assessments.

Health outcomes are markedly worse for First Nations than non–First Nations people. Although this is largely because of inequities in the social determinants of health,^1–4 inequities in the provision of health care also exist.^5,6 Emergency departments serve as a point of accessible health care. Status First Nations patients make up 4.8% of unique patients and 9.4% of emergency visits in Alberta,⁷ and Canadian studies describe First Nations patients’ experiences with racism when seeking emergency care.^8,9Evaluating triage contributes empirically to understanding the health care of First Nations patients insofar as triage is a quantifiable, intermediate process by which systemic racism¹⁰ may influence patient outcomes. The Canadian Triage Acuity Scale¹¹ is a 5-level scale used to classify the severity of patient symptoms. Triage nurses use a brief assessment, medical history, and presenting signs and symptoms to assign each patient a triage score that determines the priority in which the patient should be seen by a provider. Therefore, accurate triage is important for patient health outcomes.¹² In practice, triage is a social interaction where local practice, biases, stereotypes and communication barriers come into play. Studies have found that women receive less acute triage scores than men,^13,14 and that racial minority^13,15–17 and Indigenous^18–20 patients receive less acute triage scores than white or non-Indigenous patients. Indeed, Indigenous patients in Canada have described a perception “of social triaging in the [emergency department], whereby decisions about who is seen first seemed to them [to be] based less on triaged clinical priorities but on the social positioning of the patient.”²¹ Differential triage scores for minority populations raise health equity concerns.As part of a larger mixed-methods project evaluating the quality of emergency care for First Nations people in Alberta, we sought to evaluate quantitative differences in emergency visit characteristics and outcomes of First Nations and non–First Nations people in Alberta. Specifically, we aimed to estimate the relation between First Nations status and acuity of triage, and to evaluate whether predictors of acuity differ by First Nations status.     

Synthesis of some novel 2-substituted benzothiazole derivatives containing benzylamine moiety as monoamine oxidase inhibitory agents

In the present work, 12 new 2-(5-substituted-benzothiazol-2-ylsulfanyl)-N-(substitutedbenzyl)-N-(4-substitutedphenyl) acetamide derivatives (4a–l) was designed and synthesized. The structures of the synthesized compounds were clarified using Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (¹H-NMR), carbon-13 nuclear magnetic resonance (¹³C-NMR) and high-resolution mass spectrometry (HRMS) spectral data. Purity of synthesized compounds was checked by high-performance liquid chromatography (HPLC) analyses and purity ratio was found between 96.5–99.9%. The inhibitory activity of the compounds against MAO-A and MAO-B enzymes was evaluated by using in vitro flurometric method in which kynuramine was used as a substrate. Most of the compounds exhibited more selective inhibitory activity towards monoamine oxidase B (MAO-B) than monoamine oxidase A (MAO-A). Compound 4h was determined as the most potent compound against both enzyme types. The MAO-B enzyme kinetic of the compound 4h was studied and nature of MAO-B inhibition, caused by this compound, was investigated. The graphical analysis of steady-state inhibition data indicated that compound 4h is a mixed type inhibitor. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME) properties for the synthesized compounds was also carried out and observed data supported the potential of compound 4h.     

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by ¹H NMR, ¹³CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1–S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1–S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with K_is in the range of 1.79?±?0.22–2.73?±?0.08?nM against hCA I and in the range of 1.72?±?0.58–11.64?±?5.21?nM against hCA II, respectively.     

COVID-19 in patients undergoing long-term dialysis in Ontario

BACKGROUND:Patients undergoing long-term dialysis may be at higher risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of associated disease and mortality. We aimed to describe the incidence, risk factors and outcomes for infection in these patients in Ontario, Canada.METHODS:We used linked data sets to compare disease characteristics and mortality between patients receiving long-term dialysis in Ontario who were diagnosed SARS-CoV-2 positive and those who did not acquire SARS-CoV-2 infection, between Mar. 12 and Aug. 20, 2020. We collected data on SARS-CoV-2 infection prospectively. We evaluated risk factors for infection and death using multivariable logistic regression analyses.RESULTS:During the study period, 187 (1.5%) of 12 501 patients undergoing dialysis were diagnosed with SARS-CoV-2 infection. Of those with SARS-CoV-2 infection, 117 (62.6%) were admitted to hospital and the case fatality rate was 28.3%. Significant predictors of infection included in-centre hemodialysis versus home dialysis (odds ratio [OR] 2.54, 95% confidence interval [CI] 1.59–4.05), living in a long-term care residence (OR 7.67, 95% CI 5.30–11.11), living in the Greater Toronto Area (OR 3.27, 95% CI 2.21–4.80), Black ethnicity (OR 3.05, 95% CI 1.95–4.77), Indian subcontinent ethnicity (OR 1.70, 95% CI 1.02–2.81), other non-White ethnicities (OR 2.03, 95% CI 1.38–2.97) and lower income quintiles (OR 1.82, 95% CI 1.15–2.89).INTERPRETATION:Patients undergoing long-term dialysis are at increased risk of SARS-CoV-2 infection and death from coronavirus disease 2019. Special attention should be paid to addressing risk factors for infection, and these patients should be prioritized for vaccination.

As of Aug. 20, 2020, in Ontario, Canada’s most populous province, almost 41 000 people had tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19),¹ which represented 0.3% of the provincial population. Close to 2800 people had died, a case fatality rate of 6.8%.²Patients undergoing dialysis have high rates of comorbid conditions, are often older adults, have varying degrees of immunosuppression and are more likely to reside in long-term care, which puts them at risk of both acquiring SARS-CoV-2 and developing complicated disease.^3,4 Furthermore, in Ontario, those who receive in-centre hemodialysis typically have 3 treatments per week in outpatient units located in or affiliated with hospitals, and the consequent inability to fully self-isolate means that patients undergoing hemodialysis likely have an even higher risk of SARS-CoV-2 infection.^3,4 Recent studies support this but do not compare infection rates with those in the local population of patients not undergoing dialysis.^5–10 Several studies have reported SARS-CoV-2 infection in single or multicentre cohorts of patients undergoing dialysis,^5–10 but we are unaware of any that have identified risk factors for infection at the level of a large region. Some studies have found that patients with SARS-CoV-2 infection who are undergoing dialysis are at high risk of severe illness and death.^6–10     

Syntheses of 1-[(2-Hydroxyethoxy)methyl]- and 1-[(1,3-Dihydroxy-2-Propoxy)methyl]- Derivatives of 5-Substituted-2,4-difluorobenzene: Unnatural Acyclo Thymidine Mimics for Evaluation as Anticancer and Antiviral Agents

Abstract

A group of 1-[(2-hydroxyethoxy)methyl]- (12) and 1-[(1,3-dihydroxy-2-propoxy)methyl]- (13) derivatives of 2,4-difluorobenzene possessing a variety of C-5 substituents (R = Me, H, I, NO₂) were designed with the expectation that they may serve as acyclic 5-substituted-2′-deoxyuridine (thymidine) mimics. Compounds 12 and 13 (R = Me, H, I) were inactive as anticancer agents (C₅₀ = 10^?3 to 10^?4 M range), whereas the 5-nitro compounds (12d, 13d) exhibited weak-to-moderate cytotoxicity (CC₅₀ = 10^?5 to 10^?6 M range) against a variety of cancer cell lines. All compounds prepared (12a-d, 13a-d) were inactive as antiviral agents in a broad-spectrum antiviral screen that also included the human immunodeficiency virus (HIV-1 and HIV-2) and herpes simplex virus (HSV-1 and HSV-2).     

Shifts in office and virtual primary care during the early COVID-19 pandemic in Ontario,Canada

BACKGROUND:Globally, primary care changed dramatically as a result of the coronavirus disease 2019 (COVID-19) pandemic. We aimed to understand the degree to which office and virtual primary care changed, and for which patients and physicians, during the initial months of the pandemic in Ontario, Canada.METHODS:This population-based study compared comprehensive, linked primary care physician billing data from Jan. 1 to July 28, 2020, with the same period in 2019. We identified Ontario residents with at least 1 office or virtual (telephone or video) visit during the study period. We compared trends in total physician visits, office visits and virtual visits before COVID-19 with trends after pandemic-related public health measures changed the delivery of care, according to various patient and physician characteristics. We used interrupted time series analysis to compare trends in the early and later halves of the COVID-19 period.RESULTS:Compared with 2019, total primary care visits between March and July 2020 decreased by 28.0%, from 7.66 to 5.51 per 1000 people/day. The smallest declines were among patients with the highest expected health care use (8.3%), those who could not be attributed to a primary care physician (10.2%), and older adults (19.1%). In contrast, total visits in rural areas increased by 6.4%. Office visits declined by 79.1% and virtual care increased 56-fold, comprising 71.1% of primary care physician visits. The lowest uptake of virtual care was among children (57.6%), rural residents (60.6%) and physicians with panels of ≥ 2500 patients (66.0%).INTERPRETATION:Primary care in Ontario saw large shifts from office to virtual care over the first 4 months of the COVID-19 pandemic. Total visits declined least among those with higher health care needs. The determinants and consequences of these major shifts in care require further study.

Primary care is considered the cornerstone of most health systems worldwide, and in higher-income countries, primary care visits are about 30 times more frequent than hospital admissions.¹ Health systems with greater availability of primary care are associated with increased access to care, reduced health inequities, better outcomes and lower costs.² Despite the centrality of primary care to health care systems, little is known about how it has been affected by coronavirus disease 19 (COVID-19).On Mar. 11, 2020, the World Health Organization declared COVID-19 a global pandemic.³ On Mar. 15, Ontario’s Chief Medical Officer of Health issued a directive to ramp down elective surgeries and other nonemergent health services, and on Mar. 19, health care providers and organizations were directed to stop or substantially reduce all nonessential or elective services until further notice.⁴ The Ontario Ministry of Health and the Ontario Medical Association negotiated the addition of temporary billing codes in the province’s schedule of benefits to facilitate virtual care, effective as of Mar. 14 (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.202303/tab-related-content). In mid to late May 2020, the province undertook a phased resumption of certain in-person health professional services and surgeries.⁴Initial reports from ongoing COVID-19-related surveys of primary care providers in Canada and the United States showed major disruptions to care, decreased payments, challenges keeping offices functioning, lack of personal protective equipment and widespread uptake of virtual care.^5,6 The degree to which virtual care — such as phone calls, video visits and secure text messages — replaced in-person office visits is not known. It is also not known which patients and physicians were most affected by the challenges to office-based practice or the change to virtual visits. We aimed to understand the degree to which office and virtual primary care changed, and for which patients and physicians, during the initial months of the COVID-19 pandemic in Ontario, Canada.     

康柏西普预防严重后巩膜裂伤玻璃体切除术后增生性玻璃体视网膜病变的临床疗效

摘要 目的：探讨玻璃体腔注射康柏西普对于严重后巩膜裂伤患者玻璃体切除术后增生性玻璃体视网膜病变发生的预防效果。方法：选取从2018年9月至2020年9月我院收治的40例（40眼）严重后巩膜裂伤患者进行研究,随机分为对照组20眼（行常规巩膜裂伤缝合术及经睫状体平坦部玻璃体切除术）和观察组20眼（行巩膜裂伤缝合术及经睫状体平坦部玻璃体切除术的同时联合玻璃体腔注射康柏西普治疗）。比较两组患者术前及术后的视力、眼压,以及术后增生性玻璃体视网膜病变的发生率、视网膜再脱离的发生率。结果：对照组及观察组术后的最佳矫正视力较术前均提高、术后眼压均正常,观察组术后的增生性玻璃体视网膜病变发生率（15.0 %）明显低于对照组（45.0 %, P<0.05）,观察组术后视网膜脱离复发率（5.0 %）低于对照组（30.0 %, P>0.05）。结论：严重后巩膜裂伤患者玻璃体切除术联合玻璃体注射康柏西普治疗能够有效降低增生性玻璃体视网膜病变的发生率和术后视网膜脱离的复发率,还可以改善患者的视力预后。     

Comparative Study of Initial Post-Therapeutic 131I Single-Photon Emission Computed Tomography/Computed Tomography and Reoperation for the Detection of Residual Lymph Node Metastasis in Patients With Papillary Thyroid Cancer

ObjectiveTo assess the diagnostic performance of initial post-therapeutic ¹³¹I single-photon emission computed tomography/computed tomography (SPECT/CT) compared with that of reoperation in detecting residual lymph node metastasis (LNM).MethodsPatients with iodine-avid LNM detected on the initial post-therapeutic ¹³¹I SPECT/CT and who underwent reoperative dissection within 6 months were included. LNMs (numbers and locations) detected via both methods were compared. The American Thyroid Association dynamic risk stratification was performed for patients receiving second radioactive iodine therapy after reoperation.ResultsFifty-three patients with 95 iodine-avid LNMs detected by ¹³¹I SPECT/CT were enrolled. Fifty-one (96.2%) patients had 212 LNMs confirmed by reoperation (P = .004). The sensitivity and specificity of ¹³¹I SPECT/CT in detecting LNM were 44.8% (95/212) and 91.6% (87/95), respectively. The location frequency of residual LNMs found by ¹³¹I SPECT/CT was similar to that of reoperation (P = .057). Thirty-two patients received a second radioactive iodine treatment, and 6 (18.8%) patients still had residual iodine-avid LNM on SPECT/CT. Therapeutic response was evaluated by American Thyroid Association dynamic risk stratification in 16 patients. The number of patients with structural incomplete response, biochemical incomplete response, indeterminate response, and excellent response was 4 (23.5%), 4 (23.5%), 5 (29.4%), and 3 (17.6%), respectively.Conclusion¹³¹I SPECT/CT has high specificity but relatively low sensitivity in detecting all residual LNMs. Approximately 80% of patients were rendered structurally disease free after reoperation.     

Evaluation of the relative virulence of novel SARS-CoV-2 variants: a retrospective cohort study in Ontario,Canada

Background:Between February and June 2021, the initial wild-type strains of SARS-CoV-2 were supplanted in Ontario, Canada, by new variants of concern (VOCs), first those with the N501Y mutation (i.e., Alpha/B1.1.17, Beta/B.1.351 and Gamma/P.1 variants) and then the Delta/B.1.617 variant. The increased transmissibility of these VOCs has been documented, but knowledge about their virulence is limited. We used Ontario’s COVID-19 case data to evaluate the virulence of these VOCs compared with non-VOC SARS-CoV-2 strains, as measured by risk of hospitalization, intensive care unit (ICU) admission and death.Methods:We created a retrospective cohort of people in Ontario who tested positive for SARS-CoV-2 and were screened for VOCs, with dates of test report between Feb. 7 and June 27, 2021. We constructed mixed-effect logistic regression models with hospitalization, ICU admission and death as outcome variables. We adjusted models for age, sex, time, vaccination status, comorbidities and pregnancy status. We included health units as random intercepts.Results:Our cohort included 212 326 people. Compared with non-VOC SARS-CoV-2 strains, the adjusted elevation in risk associated with N501Y-positive variants was 52% (95% confidence interval [CI] 42%–63%) for hospitalization, 89% (95% CI 67%–117%) for ICU admission and 51% (95% CI 30%–78%) for death. Increased risk with the Delta variant was more pronounced at 108% (95% CI 78%–140%) for hospitalization, 235% (95% CI 160%–331%) for ICU admission and 133% (95% CI 54%–231%) for death.Interpretation:The increasing virulence of SARS-CoV-2 VOCs will lead to a considerably larger, and more deadly, pandemic than would have occurred in the absence of the emergence of VOCs.

Novel SARS-CoV-2 variants of concern (VOCs), including viral lineages carrying the N501Y (Alpha/B.1.1.7) or both the N501Y and E484K mutations (Beta/B.1.351 and Gamma/P.1), were first identified in Ontario, Canada, in December 2020.¹ Although initially uncommon in Ontario, these VOCs outcompeted earlier SARS-CoV-2 lineages and, as of late April 2021, were responsible for almost all new infections in Ontario, with Alpha the most prevalent lineage.¹ In April 2021, the B.1.617.2 variant, now known as Delta under the revised nomenclature from the World Health Organization, emerged in the province, outcompeted earlier VOCs and, by July 2021, represented most infections in the province.^2,3This serial replacement by emerging variants reflects progressively higher effective reproduction numbers that allow novel variants to outcompete previously dominant strains in the face of identical measures to control spread of infection.^4–6 However, VOCs are also concerning because emerging evidence points to increased virulence, with increased risk of hospitalization, intensive care unit (ICU) admission and death, after adjustment for age and other predictive factors among patients with VOC infections.^7–10 Although the increased virulence of strains with the N501Y mutation relative to strains that lack this mutation has been described,^7–9 only limited information is available on the virulence of infection with the Delta variant, relative to earlier N501Y-positive VOCs (i.e., Alpha, Beta and Gamma).^10–12 Our objectives were to evaluate the virulence of N501Y-positive variants relative to earlier SARS-CoV-2 lineages and to evaluate the virulence of the Delta variant of SARS-CoV-2 relative to N501Y-positive VOCs using Ontario’s COVID-19 case data.     

Rates of rebleeding,thrombosis and mortality associated with resumption of anticoagulant therapy after anticoagulant-related bleeding

BACKGROUND:Data on resuming oral anticoagulants (OACs) after bleeding are primarily from studies involving patients given warfarin, with few data on direct OACs (DOACs). We aimed to characterize prescribing patterns for OACs after OAC-related bleeding and compare the rates of bleeding, thrombosis and mortality in patients who resumed either type of OAC with those who did not.METHODS:We conducted a population-based cohort study of adults aged 66 years or older who were admitted to hospital for bleeding while receiving OACs from Apr. 1, 2012, to Mar. 31, 2017, using linked administrative health databases from Ontario. We used competing risk methods to calculate cause-specific adjusted hazard ratios (HRs) for thrombosis, bleeding and mortality with resumption of OACs adjusted as a time-varying covariate. We determined time to OAC resumption using the Kaplan–Meier method.RESULTS:We included 6793 patients with gastrointestinal (n = 4297, 63.3%), intracranial (n = 805, 11.9%) or other bleeding (n = 1691, 25.0%). At cohort entry, 3874 patients (57.0%) were prescribed warfarin and 2919 patients (43.0%) were prescribed a DOAC. The most common indication for OAC was atrial fibrillation (n = 5557, 81.8%), followed by venous thromboembolism (n = 1367, 20.1%). Oral anticoagulants were resumed in 4792 patients (70.5%) within 365 days of the index bleed. The median time to resumption was 46 (interquartile range 6–550) days. We found that resuming OAC was associated with reduced rates of thrombosis (adjusted HR 0.60, 95% confidence interval [CI] 0.50–0.72) and mortality (adjusted HR 0.54, 95% CI 0.48–0.60), and an increased rate of rebleeding (adjusted HR 1.88, 95% CI 1.64–2.17).INTERPRETATION:We found that resuming OAC is associated with a reduction in thrombosis and mortality but an increase in bleeding. Randomized controlled trials that evaluate the net benefit of strategies for resumption of OAC after a bleeding event are warranted.

Oral anticoagulants (OACs) are used to prevent and treat arterial and venous thrombosis. Bleeding associated with OACs is the most common adverse drug event that leads to visits to the emergency department, hospital admissions and death.^1,2 When OACs are withheld after a bleed, patients are exposed to an increased risk of thrombosis and possibly death. A challenging clinical problem is determining whether OACs should be resumed after a bleed and, if so, the optimal strategy for resumption.Oral anticoagulant therapy is stopped permanently in a substantial proportion of patients after gastrointestinal (GI) or intracranial bleeding (50% and 64%, respectively)^3,4 despite evidence that suggests a benefit to restarting.^3,5–9 Direct OACs (DOACs) are now recommended for stroke prevention in patients with atrial fibrillation (AF) and for the treatment of venous thromboembolism (VTE) based on substantial evidence.^10–12 However, resumption of OACs after bleeding has been assessed primarily in small studies of patients treated with warfarin that did not report on extracranial non-GI bleeding.^3,4,13Using population-based data, we aimed to characterize prescribing patterns for OACs and compare outcomes between patients who resumed OAC with those who did not after OAC-related bleeding. Our secondary aims were to compare outcomes separately after OAC-related GI bleeding, intracranial hemorrhage, extracranial non-GI bleeding and any bleeding.     

Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PL^pro) than against 3-chymotripsin-like protease (3CL^pro); therefore, we investigated their structural features that were responsible for this selectivity. Compound 4 was the most potent inhibitor of PL^pro with an IC₅₀ value of 3.7?μM. The active compounds displayed kinetic behaviors, and the binding constants of their interaction with PL^pro were determined from surface plasmon resonance analysis. Our results suggest B. papyrifera constituents as promising candidates for development into potential anti-coronaviral agents.     

26例中国先天性晶状体异位患者的基因诊断及手术初步效果观察

摘要 目的：总结26例中国先天性晶状体异位患者的基因诊断及晶状体异位的手术疗效。方法：回顾性收集2019年3月-2020年3月就诊于北京同仁医院眼科来自不同家系的双眼先天性晶状体异位患者26例共52眼。收集详细临床资料，提取外周静脉血全基因组DNA，应用靶向基因捕获技术筛查晶状体异常相关基因突变对所有患者进行基因诊断，采取微创晶状体-玻璃体切除或白内障超声乳化手术，记录视力、人工晶状体位置及主要并发症，采用配对t检验对术前术后最佳矫正视力进行比较。结果：患者均为汉族，男性14例，女性12例，年龄（21.2±15.2）岁。25例患者存在FBN1突变，1例为GJA8突变。22例（84.6%）可确诊为马凡综合征，3例诊为"潜在马凡综合征"。42眼采取微创晶状体-玻璃体切除类手术，7眼采取白内障超声乳化类手术。有31眼（59.6%）存在视网膜变性行网膜激光光凝。平均随诊时间（15.7±3.7）月，术后6个月及末次随访的最佳矫正视力（最小分辨角对数视力，0.30±0.16及0.21±0.11）均高于术前（0.76±0.31），差异有统计学意义（t=12.492，P＜0.001；t=13.171，P＜0.001）。术后所有眼的人工晶状体位置及稳定性良好，未发生视网膜脱离、黄斑水肿、人工晶状体脱位、人工晶状体偏位、继发性青光眼、眼内炎等并发症。结论：马凡综合征是此26例中国人先天性晶状体异位的主要病因，FBN1基因突变检测可为确诊提供有力证据，微创晶状体-玻璃体切除联合人工晶状体悬吊术效果好。     

Burden of noninfluenza respiratory viral infections in adults admitted to hospital: analysis of a multiyear Canadian surveillance cohort from 2 centres

BACKGROUND:Data on the outcomes of noninfluenza respiratory virus (NIRV) infections among hospitalized adults are lacking. We aimed to study the burden, severity and outcomes of NIRV infections in this population.METHODS:We analyzed pooled patient data from 2 hospital-based respiratory virus surveillance cohorts in 2 regions of Canada during 3 consecutive seasons (2015/16, 2016/17, 2017/18; n = 2119). We included patients aged ≥ 18 years who developed influenza-like illness or pneumonia and were hospitalized for management. We included patients confirmed positive for ≥ 1 virus by multiplex polymerase chain reaction assays (respiratory syncytial virus [RSV], human rhinovirus/enterovirus (hRV), human coronavirus (hCoV), metapneumovirus, parainfluenza virus, adenovirus, influenza viruses). We compared patient characteristics, clinical severity conventional outcomes (e.g., hospital length-of stay, 30-day mortality) and ordinal outcomes (5 levels: discharged, receiving convalescent care, acute ward or intensive care unit [ICU] care and death) for patients with NIRV infections and those with influenza.RESULTS:Among 2119 adults who were admitted to hospital, 1156 patients (54.6%) had NIRV infections (hRV 14.9%, RSV 12.9%, hCoV 8.2%) and 963 patients (45.4%) had influenza (n = 963). Patients with NIRVs were younger (mean 66.4 [standard deviation 20.4] yr), and more commonly had immunocompromising conditions (30.3%) and delay in diagnosis (median 4.0 [interquartile range (IQR) 2.0–7.0] days). Overall, 14.6% (12.4%–19.5%) of NIRV infections were acquired in hospital. Admission to ICU (18.2%, median 6.0 [IQR 3.0–13.0] d), hospital length-of-stay (median 5.0 [IQR 2.0–10.0] d) and 30-day mortality (8.4%; RSV 9.5%, hRV 6.6%, hCoV 9.2%) and the ordinal outcomes were similar for patients with NIRV infection and those with influenza. Age > 60 years, immunocompromised state and hospital-acquired viral infection were associated with worse outcomes. The estimated median cost per acute care admission was $6000 (IQR $2000–$16 000).INTERPRETATION:The burden of NIRV infection is substantial in adults admitted to hospital and associated outcomes may be as severe as for influenza, suggesting a need to prioritize therapeutics and vaccines for at-risk people.

The global burden of lower respiratory tract infections is substantial, leading to many hospital admissions and deaths, especially among young children and older adults.¹ Respiratory viruses are responsible for almost half of such infections in adults that require in-hospital management; previous studies estimate that 28%–62% are caused by noninfluenza respiratory viruses (NIRVs).^2–4 With some geographical and seasonal variations, respiratory syncytial virus (RSV), human rhinovirus (hRV) and human coronavirus (hCoV) are among the most frequently identified NIRV infections.^1–7 Most infected adults develop mild, self-limiting illnesses, but increasing evidence suggest that NIRVs, either alone or with coinfecting bacteria, can result in severe pneumonia and death.^8,9 For instance, RSV has been shown to cause severe respiratory failure, with fatality rates comparable to or exceeding those observed among adults admitted to hospital with influenza.^10–12 Data on hRV, hCoV and other NIRVs are more limited, owing to the lack of accurate diagnostics and systematic case-finding approaches.^7–9 However, with the increasing availability of multiplex polymerase chain reaction (PCR) assays that can simultaneously detect influenza and NIRVs, these infections are now readily diagnosed as part of a syndromic approach in patients who present with acute respiratory illnesses.^2–5,13,14 The burden, clinical significance and impacts of NIRVs on the health care system remain inadequately characterized.To address this gap, we analyzed the relative frequencies, patient characteristics, location of acquisition (community or hospital), severity and clinical outcomes of patients with NIRV and influenza infections diagnosed by multiplex PCR in a cohort of adults admitted to hospital in 2 large Canadian health care centres during a 3-year surveillance period. The associated health care resource use was also estimated.     

SARS-CoV-2 seroprevalence in health care workers from 10 hospitals in Quebec,Canada: a cross-sectional study

Background:The COVID-19 pandemic has disproportionately affected health care workers. We sought to estimate SARS-CoV-2 seroprevalence among hospital health care workers in Quebec, Canada, after the first wave of the pandemic and to explore factors associated with SARS-CoV-2 seropositivity.Methods:Between July 6 and Sept. 24, 2020, we enrolled health care workers from 10 hospitals, including 8 from a region with a high incidence of COVID-19 (the Montréal area) and 2 from low-incidence regions of Quebec. Eligible health care workers were physicians, nurses, orderlies and cleaning staff working in 4 types of care units (emergency department, intensive care unit, COVID-19 inpatient unit and non-COVID-19 inpatient unit). Participants completed a questionnaire and underwent SARS-CoV-2 serology testing. We identified factors independently associated with higher seroprevalence.Results:Among 2056 enrolled health care workers, 241 (11.7%) had positive SARS-CoV-2 serology. Of these, 171 (71.0%) had been previously diagnosed with COVID-19. Seroprevalence varied among hospitals, from 2.4% to 3.7% in low-incidence regions to 17.9% to 32.0% in hospitals with outbreaks involving 5 or more health care workers. Higher seroprevalence was associated with working in a hospital where outbreaks occurred (adjusted prevalence ratio 4.16, 95% confidence interval [CI] 2.63–6.57), being a nurse or nursing assistant (adjusted prevalence ratio 1.34, 95% CI 1.03–1.74) or an orderly (adjusted prevalence ratio 1.49, 95% CI 1.12–1.97), and Black or Hispanic ethnicity (adjusted prevalence ratio 1.41, 95% CI 1.13–1.76). Lower seroprevalence was associated with working in the intensive care unit (adjusted prevalence ratio 0.47, 95% CI 0.30–0.71) or the emergency department (adjusted prevalence ratio 0.61, 95% CI 0.39–0.98).Interpretation:Health care workers in Quebec hospitals were at high risk of SARS-CoV-2 infection, particularly in outbreak settings. More work is needed to better understand SARS-CoV-2 transmission dynamics in health care settings.

The COVID-19 pandemic has disproportionately affected health care workers. In France, Spain, Italy, Germany and the United States, at least 10% of cases reported in spring 2020 were in health care workers.¹ In Quebec, 25% (14 177 of 56 565) of all cases declared during the first wave of the pandemic, from March to July 2020, were in health care workers,² about one-third of whom were working in acute care hospitals.¹ The Montréal area was the most affected region in Quebec and Canada during the first wave, reaching a COVID-19 incidence rate of 1336 per 100 000 population.²The number of COVID-19 cases reported among health care workers underestimated the number of those infected with SARS-CoV-2 during that period, given limited testing leading to undiagnosed asymptomatic or paucisymptomatic infections.³ Seroprevalence studies are an important tool to determine the proportion of people infected with SARS-CoV-2, both in the general population and among health care workers.⁴ After the first wave in Quebec, SARS-CoV-2 seroprevalence in adults aged 18–69 years was found to be low (3.1% in Montréal and 1.3% in less affected regions), but this proportion could be much higher among health care workers who had to work despite the general shutdown of social and economic activities, especially if they were exposed to major outbreaks.⁵Only 2 other Canadian studies provide SARS-CoV-2 seroprevalence estimates among health care workers, and both studies were from a single centre.^6,7 Outside Canada, most seroprevalence studies among health care workers include a single site and do not provide a representative estimate for a defined region.⁸ Several studies have reported a higher seroprevalence among health care workers from units treating patients with COVID-19 (COVID-19 units) compared with other units (non–COVID-19 units), emergency departments or intensive care units.^9,10 Other studies have not identified such associations.^11,12 In this study, we aimed to assess the seroprevalence of SARS-CoV-2 antibody among hospital health care workers from a variety of settings after the first pandemic wave in Quebec, and to explore factors associated with SARS-CoV-2 seropositivity.     

New Syntheses of (R)-(+)-3-Acetoxy-2,6-dimethyl-l,5-heptadiene,the Pheromone of the Comstock Mealybug

L-Phenylalanine was converted to optically impure (R)-(+)-2,6-dimethyl-1,5-heptadien-3-ol 2 (19% e.e.) .(R)-(+)-2 (96% e.e.) was prepared by a kinetic resolution of (±)-2. Acetylation of the pure (R)-(+ )- 2 gave the pheromone of the Comstock mealybug ( Pseudococcus comstockii KUWANA) [(R)-(+)-1].     

Effectiveness of intrapartum fetal surveillance to improve maternal and neonatal outcomes: a systematic review and network meta-analysis

BACKGROUND:Cesarean delivery is the most common surgical procedure worldwide. Intrapartum fetal surveillance is routinely offered to improve neonatal outcomes, but the effects of different methods on the risk of emergency cesarean deliveries remains uncertain. We conducted a systematic review and network meta-analysis to evaluate the effectiveness of different types of fetal surveillance.METHODS:We searched MEDLINE, Embase and CENTRAL until June 1, 2020, for randomized trials evaluating any intrapartum fetal surveillance method. We performed a network meta-analysis within a frequentist framework. We assessed the quality and network inconsistency of trials. We reported primarily on intrapartum emergency cesarean deliveries and other secondary maternal and neonatal outcomes using risk ratios (RRs) and 95% confidence intervals (CIs).RESULTS:We included 33 trials (118 863 patients) evaluating intermittent auscultation with Pinard stethoscope/handheld Doppler (IA), cardiotocography (CTG), computerized cardiotocography (cCTG), CTG with fetal scalp lactate (CTG-lactate), CTG with fetal scalp pH analysis (CTG-FBS), CTG with fetal pulse oximetry (FPO-CTG), CTG with fetal heart electrocardiogram (CTG-STAN) and their combinations. Intermittent auscultation reduced the risk of emergency cesarean deliveries compared with other types of surveillance (IA v. CTG: RR 0.83, 95% CI 0.72–0.97; IA v. CTG-FBS: RR 0.71, 95% CI 0.63–0.80; IA v.CTG-lactate: RR 0.77, 95% CI 0.64–0.92; IA v. FPO-CTG: RR 0.75, 95% CI 0.65–0.87; IA v.FPO-CTG-FBS: RR 0.81, 95% CI 0.67–0.99; cCTG-FBS v. IA: RR 1.21, 95% CI 1.04–1.42), except STAN-CTG-FBS (RR 1.17, 95% CI 0.98–1.40). There was a similar reduction observed for emergency cesarean deliveries for fetal distress. None of the evaluated methods was associated with a reduced risk of neonatal acidemia, neonatal unit admissions, Apgar scores or perinatal death.INTERPRETATION:Compared with other types of fetal surveillance, intermittent auscultation seems to reduce emergency cesarean deliveries in labour without increasing adverse neonatal and maternal outcomes.

Cesarean delivery is the most common surgical procedure worldwide, performed to expedite delivery and avoid neonatal complications. Fetal surveillance is routinely offered to patients in labour to reduce the risk of adverse neonatal outcomes, as well as the risk of unnecessary emergency cesarean deliveries and other maternal interventions. Fetal surveillance aims to detect intrapartum hypoxia from acute or subacute adverse events in labour requiring medical intervention and to reduce the risk of serious complications such as neonatal cerebral palsy, hypoxic–ischemic encephalopathy or stillbirth.Monitoring the fetal heart rate to detect intrapartum hypoxia using simple surveillance techniques, such as the Pinard stethoscope, has been practised for decades.¹ Over the last 50 years, several newer surveillance methods have been evaluated, with varied uptake in practice.² Cardiotocography (CTG) remains the most common surveillance method used in high-risk pregnancies.³ However, given its limited accuracy, many researchers have evaluated its use in combination with other surveillance methods, such as fetal heart electrocardiogram (STAN), fetal scalp pH analysis (FBS) or fetal pulse oximetry (FPO), and with computer-aided decision models (cCTG) to improve its diagnostic value.^4–6 Despite extensive investment in clinical research, the overall effectiveness of such methods in improving maternal and neonatal outcomes remains debatable as stillbirth rates have plateaued worldwide, while cesarean delivery rates continue to rise.^7,8Existing meta-analyses evaluating different intrapartum fetal surveillance methods remain limited to head-to-head comparisons of monitoring techniques, without a comprehensive assessment of their effectiveness in improving maternal and neonatal pregnancy outcomes.^4,9–13 We conducted a systematic review of randomized trials and a network meta-analysis to evaluate the effectiveness of all available fetal surveillance methods in improving maternal and neonatal outcomes.