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Background The timing at which venous thromboembolism (VTE) occurs after major surgery has major implications for the optimal duration of thromboprophylaxis. The aim of this study was to perform a systematic review and meta-analysis of the timing of postoperative VTE up to 4 weeks after surgery. Methods A systematic search of MEDLINE, Scopus, and CINAHL databases was performed between 1 January 2009 and 1 April 2022. Prospective studies that recruited patients who underwent a surgical procedure and reported at least 20 symptomatic, postoperative VTE events by time were included. Two reviewers independently selected studies according to the eligibility criteria, extracted data, and evaluated risk of bias. Data were analysed with a Poisson regression model, and the GRADE approach was used to rate the certainty of evidence. Results Some 6258 studies were evaluated, of which 22 (11 general, 5 urological, 4 mixed, and 2 orthopaedic postoperative surgical populations; total 1 864 875 patients and 24 927 VTE events) were eligible. Pooled evidence of moderate certainty showed that 47.1 per cent of the VTE events occurred during the first, 26.9 per cent during the second, 15.8 per cent during the third, and 10.1 per cent during the fourth week after surgery. The timing of VTE was consistent between individual studies. Conclusion Although nearly half of symptomatic VTE events in first 4 weeks occur during the first postoperative week, a substantial number of events occur several weeks after surgery. These data will inform clinicians and guideline developers about the duration of postoperative thromboprophylaxis.

ARTS will be the first trial to compare anticoagulation with a direct oral anticoagulant (apixaban) versus no anticoagulation among patients undergoing intra-abdominal, gynecologic, or urologic surgery at sufficiently similar risk of deep vein thrombosis or pulmonary embolism and major bleeding.

Virus-host protein-protein interactions are central to viral infection, but are challenging to identify and characterise, especially in complex systems involving intact viruses and cells. Here, we describe a proteome-wide approach to identify virus-host interactions using chemical cross-linking coupled with mass spectrometry. We adsorbed tick-borne encephalitis virus onto metabolically-stalled neuroblastoma cells, covalently cross-linked interacting virus-host proteins, and performed limited proteolysis to release primarily the surface-exposed proteins for analysis by mass spectrometry. Proteins in the sample were identified using data-dependent acquisition mass spectrometry and cross-linked peptides were identified using the software pLink2. Cross-links are validated using the intraviral cross-links as an internal control.

Virus-host protein-protein interactions are central to viral infection, but are challenging to identify and characterise, especially in complex systems involving intact viruses and cells. In this work, we demonstrate a proteome-wide approach to identify virus-host interactions using chemical cross-linking coupled with mass spectrometry. We adsorbed tick-borne encephalitis virus onto metabolically-stalled neuroblastoma cells, covalently cross-linked interacting virus-host proteins, and performed limited proteolysis to release primarily the surface-exposed proteins for identification by mass spectrometry. Using the intraviral protein cross-links as an internal control to assess cross-link confidence levels, we identified 22 high confidence unique intraviral cross-links and 59 high confidence unique virus-host protein-protein interactions. The identified host proteins were shown to interact with eight distinct sites on the outer surface of the virus. Notably, we identified an interaction between the substrate-binding domain of heat shock protein family A member 5, an entry receptor for four related flaviviruses, and the hinge region of the viral envelope protein. We also identified host proteins involved in endocytosis, cytoskeletal rearrangement, or located in the cytoskeleton, suggesting that entry mechanisms for tick-borne encephalitis virus could include both clathrin-mediated endocytosis and macropinocytosis. Additionally, cross-linking of the viral proteins showed that the capsid protein forms dimers within tick-borne encephalitis virus, as previously observed with purified C proteins for other flaviviruses. This method enables the identification and mapping of transient virus-host interactions, under near-physiological conditions, without the need for genetic manipulation.Author summaryTick-borne encephalitis virus is an important human pathogen that can cause severe infection often resulting in life-long neurological complications or even death. As with other viruses, it fully relies on the host cells, and any successful infection starts with interactions between the viral structural proteins and cellular surface proteins. Mapping these interactions is essential both for the fundamental understanding of viral entry mechanisms, and for guiding the design of new antiviral drugs and vaccines. Here, we stabilise the interactions between tick-borne encephalitis virus and human proteins by chemical cross-linking. We then detect the interactions using mass spectrometry and analyse the data to identify protein-protein complexes. We demonstrate that we can visualise the protein interaction interfaces by mapping the cross-linked sites onto the host and viral protein structures. We reveal that there are eight distinct sites on the outer surface of the viral envelope protein that interact with host. Using this approach, we mapped interactions between the tick-borne encephalitis virus envelope protein, and 59 host proteins, identifying a possible new virus receptor. These results highlight the potential of chemical cross-linking coupled with mass spectrometry to identify and map interactions between viral and host proteins.

Background Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. Methods We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. Discussion This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. Systematic review registration PROSPERO CRD42021234119

Funding Information: The Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS) project was conducted by the Clinical Urology and Epidemiology (CLUE) Working Group and supported by the Academy of Finland (309387, 340957), Sigrid Jusélius Foundation and Competitive Research Funding of the Helsinki University Hospital (TYH2019321; TYH2020248). The sponsors had no role in the analysis and interpretation of the data or the manuscript preparation, review, or approval. Funding Information: KMA received a research grant from Astra Zeneca, and is consultant for Gedeon Richter, and received reimbursement for attending a scientific meeting from GSK (Tesaro Bio). RMT received reimbursement for attending a scientific meeting from Olympus. LIL, GHG, YL, RC, ALL, VJS, IEJK, PJK, RJC, RLA, KA, KMA, IB-L, MHB, JLC, SC, PJG, HAG-P, FZG, HAG, LH, MLI-K, KMJ, PKK, NK, TPK, AJK, TK, HL, AKM, BTN, TPN, CN, SMO, SP, NP, CBBR, ARR, TS, RMT, RWMV, YW, YX, LY, JH, and KAOT have no financial conflicts of interest. GHG and RC were panel members of the European Association of Urology (EAU) ad hoc Guideline on Thromboprophylaxis in Urological Surgery. KAOT was chair of the European Association of Urology (EAU) ad hoc Guideline on Thromboprophylaxis in Urological Surgery and panel member of the American Society of Hematology (ASH) Guideline Panel on Prevention of Venous Thromboembolism (VTE) in Surgical Hospitalized Patients. Publisher Copyright: © 2021, The Author(s). Background Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. Methods We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. Discussion This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. Systematic review registration PROSPERO CRD42021234119

Additional file 1. PRISMA-P checklist.

ObjectiveTo systematically compare the effect of direct oral anticoagulants and low molecular weight heparin for thromboprophylaxis on the benefits and harms to patients undergoing non-cardiac surgery.DesignSystematic review and network meta-analysis of randomised controlled trials.Data sourcesMedline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), up to August 2021.Review methodsRandomised controlled trials in adults undergoing non-cardiac surgery were selected, comparing low molecular weight heparin (prophylactic (low) or higher dose) with direct oral anticoagulants or with no active treatment. Main outcomes were symptomatic venous thromboembolism, symptomatic pulmonary embolism, and major bleeding. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for network meta-analyses. Abstracts and full texts were screened independently in duplicate. Data were abstracted on study participants, interventions, and outcomes, and risk of bias was assessed independently in duplicate. Frequentist network meta-analysis with multivariate random effects models provided odds ratios with 95% confidence intervals, and GRADE (grading of recommendations, assessment, development, and evaluation) assessments indicated the certainty of the evidence.Results68 randomised controlled trials were included (51 orthopaedic, 10 general, four gynaecological, two thoracic, and one urological surgery), involving 45 445 patients. Low dose (odds ratio 0.33, 95% confidence interval 0.16 to 0.67) and high dose (0.19, 0.07 to 0.54) low molecular weight heparin, and direct oral anticoagulants (0.17, 0.07 to 0.41) reduced symptomatic venous thromboembolism compared with no active treatment, with absolute risk differences of 1-100 per 1000 patients, depending on baseline risks (certainty of evidence, moderate to high). None of the active agents reduced symptomatic pulmonary embolism (certainty of evidence, low to moderate). Direct oral anticoagulants and low molecular weight heparin were associated with a 2-3-fold increase in the odds of major bleeding compared with no active treatment (certainty of evidence, moderate to high), with absolute risk differences as high as 50 per 1000 in patients at high risk. Compared with low dose low molecular weight heparin, high dose low molecular weight heparin did not reduce symptomatic venous thromboembolism (0.57, 0.26 to 1.27) but increased major bleeding (1.87, 1.06 to 3.31); direct oral anticoagulants reduced symptomatic venous thromboembolism (0.53, 0.32 to 0.89) and did not increase major bleeding (1.23, 0.89 to 1.69).ConclusionsDirect oral anticoagulants and low molecular weight heparin reduced venous thromboembolism compared with no active treatment but probably increased major bleeding to a similar extent. Direct oral anticoagulants probably prevent symptomatic venous thromboembolism to a greater extent than prophylactic low molecular weight heparin.Systematic review registrationPROSPERO CRD42018106181.