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BackgroundVitamin D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in SARS-CoV-2 infection is not known.AimEffect of high dose, oral cholecalciferol supplementation on SARS-CoV-2 viral clearance.DesignRandomised, placebo-controlled.ParticipantsAsymptomatic or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH)D<20 ng/ml) individuals.InterventionParticipants were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for 7 days with therapeutic target 25(OH)D>50 ng/ml (intervention group) or placebo (control group). Patients requiring invasive ventilation or with significant comorbidities were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was continued for those with 25(OH)D <50 ng/ml in the intervention arm. SARS-CoV-2 RNA and inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured periodically.Outcome measureProportion of patients with SARS-CoV-2 RNA negative before day-21 and change in inflammatory markers.ResultsForty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers.ConclusionGreater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation.Trial register numberNCT04459247.

There is a worrying scarcity of drug options for patients with severe COVID-19. Glycine possesses anti-inflammatory, cytoprotective, endothelium-protective, and platelet-antiaggregant properties, so its use in these patients seems promising. In this open label, controlled clinical trial, inpatients with severe COVID-19 requiring mechanical ventilation randomly received usual care (control group) or usual care plus 0.5 g/kg/day glycine by the enteral route (experimental group). Major outcomes included mortality, time to weaning from mechanical ventilation, total time on mechanical ventilation, and time from study recruitment to death. Secondary outcomes included laboratory tests and serum cytokines. Patients from experimental (n = 33) and control groups (n = 23) did not differ in basal characteristics. There were no differences in mortality (glycine group, 63.6% vs control group, 52.2%, p = 0.60) nor in any other major outcome. Glycine intake was associated with lower fibrinogen levels, either evaluated per week of follow-up (p < 0.05 at weeks 1, 2, and 4) or as weighted mean during the whole hospitalization (608.7 ± 17.7 mg/dl vs control 712.2 ± 25.0 mg/dl, p = 0.001), but did not modify any other laboratory test or cytokine concentration. In summary, in severe COVID-19 glycine was unable to modify major clinical outcomes, serum cytokines or most laboratory tests, but was associated with lower serum fibrinogen concentration. Registration: ClinicalTrials.gov NCT04443673, 23/06/2020.

Secondary bacterial infections from snakebites contribute to the high complication rates that can lead to permanent function loss and disabilities. Although common in endemic areas, routine empirical prophylactic use of antibiotics aiming to prevent secondary infection lacks a clearly defined policy. The aim of this work was to estimate the efficacy of amoxicillin clavulanate for reducing the secondary infection incidence in patients bitten by Bothrops snakes, and, secondarily, identify risk factors for secondary infections from snakebites in the Western Brazilian Amazon. This was an open-label, two-arm individually randomized superiority trial to prevent secondary infection from Bothrops snakebites. The antibiotic chosen for this clinical trial was oral amoxicillin clavulanate per seven days compared to no intervention. A total of 345 patients were assessed for eligibility in the study period. From this total, 187 accomplished the inclusion criteria and were randomized, 93 in the interventional group and 94 in the untreated control group. All randomized participants completed the 7 days follow-up period. Enzyme immunoassay confirmed Bothrops envenoming diagnosis in all participants. Primary outcome was defined as secondary infection (abscess and/or cellulitis) until day 7 after admission. Secondary infection incidence until 7 days after admission was 35.5% in the intervention group and 44.1% in the control group [RR = 0.80 (95%CI = 0.56 to 1.15; p = 0.235)]. Survival analysis demonstrated that the time from patient admission to the onset of secondary infection was not different between amoxicillin clavulanate treated and control group (Log-rank = 2.23; p = 0.789).Secondary infections incidence in 7 days of follow-up was independently associated to fibrinogen >400 mg/dL [AOR = 4.78 (95%CI = 2.17 to 10.55; p<0.001)], alanine transaminase >44 IU/L [AOR = 2.52 (95%CI = 1.06 to 5.98; p = 0.037)], C-reactive protein >6.5 mg/L [AOR = 2.98 (95%CI = 1.40 to 6.35; p = 0.005)], moderate pain [AOR = 24.30 (95%CI = 4.69 to 125.84; p<0.001)] and moderate snakebites [AOR = 2.43 (95%CI = 1.07 to 5.50; p = 0.034)]. Preemptive amoxicillin clavulanate was not effective for preventing secondary infections from Bothrops snakebites. Laboratorial markers, such as high fibrinogen, alanine transaminase and C-reactive protein levels, and severity clinical grading of snakebites, may help to accurately diagnose secondary infections. Brazilian Clinical Trials Registry (ReBec): RBR-3h33wy; UTN Number: U1111-1169-1005.

Knowledge about the impact of Low-Molecular-Weight Heparin (LMWH) on the coagulation system in patients undergoing minimal invasive lung cancer surgery is sparse. The aim of this study was to assess the effect of LMWH on the coagulation system in patients undergoing Video-Assisted Thoracoscopic Surgery (VATS) lobectomy for primary lung cancer. Sixty-three patients diagnosed with primary lung cancer undergoing VATS lobectomy were randomized to either subcutaneous injection with dalteparin (Fragmin®) 5000 IE once daily or no intervention. Coagulation was assessed pre-, peri-, and the first two days postoperatively by standard coagulation blood test, thromboelastometry (ROTEM®) and thrombin generation. Patients undergoing potential curative surgery for lung cancer were not hypercoagulable preoperatively. There was no statistically significant difference in the majority of the assessed coagulation parameters after LMWH, except that the no intervention group had a higher peak thrombin and a shorter INTEM clotting time on the first postoperative day and a lower fibrinogen level on the second postoperative day. A lower level of fibrin d-dimer in the LMWH group was found on the 1. and 2.postoperative day, although not statistical significant. No differences were found between the two groups in the amount of bleeding or number of thromboembolic events. Use of LMWH administered once daily as thromboprophylaxis did not alter the coagulation profile per se. As the present study primarily evaluated biochemical endpoints, further studies using clinical endpoints are needed in regards of an optimized thromboprophylaxis approach.

Background An early diagnosis of pancreatic cancer (PC) is extremely difficult because of the lack of sensitive liquid biopsy methods and effective biomarkers. We attempted to evaluate whether circulating inflammatory marker could complement CA199 for the detection of early-stage PC. Methods We enrolled 430 patients with early-stage PC, 287 patients with other pancreatic tumors (OPT), and 401 healthy controls (HC). The patients and HC were randomly divided into a training set ( n  = 872) and two testing sets (n 1  = 218, n 2  = 28). The receiver operating characteristic (ROC) curves were investigated to evaluate the diagnostic performance of circulating inflammatory markers ratios, CA199, and combinations of the markers ratios in the training set, which would then be validated in the two testing sets. Results Circulating fibrinogen, neutrophils, and monocytes in patients with PC were significantly higher while circulating albumin, prealbumin, lymphocytes, and platelets of patients with PC were significantly lower compared to those of HC and OPT (all P  < 0.05). The fibrinogen-to-albumin (FAR), fibrinogen-to-prealbumin (FPR), neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), monocyte-to-lymphocyte (MLR), and fibrinogen-to-lymphocyte (FLR) ratios were significantly higher while the prognostic nutrition index values (PNI) were lower in patients with PC than in HC and OPT (all P  < 0.05). Combining the FAR, FPR, and FLR with CA199 exhibited the best diagnostic value for distinguishing patients with early-stage PC from HC with an area under the curve (AUC) of 0.964, and for distinguishing patients with early-stage PC from OPT with an AUC of 0.924 in the training sets. In the testing set, compared with HC, the combination markers had powerful efficiency for PC with an AUC 0.947 and AUC 0.942 when comparing PC with OPT. The AUC was 0.915 for the combination of CA199, FAR, FPR, and FLR for differentiating between patients with pancreatic head cancer (PHC) and other pancreatic head tumors (OPHT), and 0.894 for differentiating between patients with pancreatic body and tail cancer (PBTC) and other pancreatic body and tail tumors (OPBTT). Conclusion A combination of FAR, FPR, FLR, and CA199 may serve as a potential non-invasive biomarker for differentiating early-stage PC from HC and OPT, especially early-stage PHC.

In tropical areas, a major concern regarding snakebites treatment effectiveness relates to the failure in liquid antivenom (AV) distribution due to the lack of an adequate cold chain in remote areas. To minimize this problem, freeze-drying has been suggested to improve AV stability. This study compares the safety and efficacy of a freeze-dried trivalent antivenom (FDTAV) and the standard liquid AV provided by the Brazilian Ministry of Health (SLAV) to treat Bothrops, Lachesis and Crotalus snakebites. This was a prospective, randomized, open, phase IIb trial, carried out from June 2005 to May 2008 in the Brazilian Amazon. Primary efficacy endpoints were the suppression of clinical manifestations and return of hemostasis and renal function markers to normal ranges within the first 24 hours of follow-up. Primary safety endpoint was the presence of early adverse reactions (EAR) in the first 24 hours after treatment. FDTAV thermal stability was determined by estimating AV potency over one year at 56°C. Of the patients recruited, 65 and 51 were assigned to FDTAV and SLAV groups, respectively. Only mild EARs were reported, and they were not different between groups. There were no differences in fibrinogen (p = 0.911) and clotting time (p = 0.982) recovery between FDTAV and SLAV treated groups for Bothrops snakebites. For Lachesis and Crotalus snakebites, coagulation parameters and creatine phosphokinase presented normal values 24 hours after AV therapy for both antivenoms. Since promising results were observed for efficacy, safety and thermal stability, our results indicate that FDTAV is suitable for a larger phase III trial. ISRCTNregistry: ISRCTN12845255; DOI: 10.1186/ISRCTN12845255 (http://www.isrctn.com/ISRCTN12845255).

Purpose This study aimed to investigate the incidence of venous thromboembolism (VTE) after medial opening-wedge high tibial osteotomy (OWHTO) and evaluate the efficacy and safety of edoxaban for the prevention of VTE in patients undergoing OWHTO. Methods A total of 139 patients with osteoarthritis or osteonecrosis undergoing OWHTO were enrolled in this prospective, randomized study. Four patients were excluded because of preoperatively diagnosed VTE, and 135 patients were divided into two groups—an edoxaban group and a non-edoxaban group—and underwent computed tomography venography on day 7 to check for postoperative VTE. Blood samples were taken on the day before OWHTO and on postoperative days 1, 3, 7, and 14. Results Treatment with edoxaban reduced the incidence of VTE after OWHTO; however, there was no statistically significant difference between the two groups. No major bleeding was noted in the edoxaban group. There were significant differences in the D-dimer level, prothrombin time, fibrinogen level, and thrombin antithrombin complex levels between the groups. Conclusions Edoxaban is an oral, once-daily, selective, direct factor Xa inhibitor that is safe and easy to handle. It may offer a new option for preventing VTE after OWHTO. Level of evidence I.

The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.) A rare side effect of ChAdOx1 nCoV-19 vaccination against Covid-19 — venous or arterial thrombosis, which has been termed vaccine-induced immune thrombotic thrombocytopenia — has been reported in recent months. In this Brief Report, investigators describe the use of intravenous immune globulin in the treatment of three such vaccine recipients in Canada.

Background and Objectives: Coronary artery bypass graft (CABG) surgery is the most common cardiac surgery. One of the main causes of postoperative complications and increased mortality after CABG is the inflammatory response. The aim of this study was to investigate whether continuous intraoperative dexmedetomidine can reduce the increase of IL-6 and other inflammatory markers after CABG surgery. Materials and Methods: The study is registered with ClinicalTrials.gov, NCT06378827, accessed on 23 April 2024. This prospective experimental study was conducted from April to December 2024 and included 100 patients undergoing CABG surgery. Patients in the experimental group (50 patients) received a continuous infusion of dexmedetomidine (0.5 μg/kg/h) from anesthesia induction until the end of surgery, while the patients in the control group (50 patients) received the same volume of saline. The primary outcomes were the changes in the values of interleukin-6 (IL-6), C-reactive protein (CRP), white blood cells (WBC), and fibrinogen on the first postoperative day (POD1) compared to the basal, preoperative values. Results: The patients in the control group were on average 65.26 years old, and the patients in the experimental group were 66.28 years old (p = 0.555). From the control group, 40 (80%) patients were male compared to 37 (74%) patients from the experimental group (p = 0.635). Median IL-6 before surgery was 2.0 pg/mL, while on POD 1 it was 76.2 pg/mL (p < 0.001). Median CRP before surgery was 2.5 mg/dL, while the POD1 value was 45.5 mg/dL (p < 0.001). Median WBC values were 6.7 × 109/L before surgery and 13.6 × 109/L on POD1 (p < 0.001). The average value of fibrinogen was 3.19 g/L before surgery, while on POD1 it was 3.37 g/L (p = 0.024). The increase in IL-6 on POD1 (ΔIL-6) was 72.4 pg/mL in the control group and 73.0 pg/mL in the experimental group (p = 0.427). ΔCRP was 41.2 mg/mL (control group) and 38.0 mg/mL (experimental group) (p = 0.725). ΔWBC was 7.45 × 109/L (control group) and 6.81 × 109/L (experimental group) (p = 0.407). Δfibrinogen was 0.16 g/L (control group) and 0.2 g/L (experimental group) (p = 0.771). Conclusions: Intraoperative administration of dexmedetodine during CABG surgery at a dose of 0.5 µg/kg/h without a loading dose does not lead to a decrease in the intensity of the inflammatory response after surgery.

BACKGROUND:Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation. METHODS:We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time–location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short-term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D-dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1. RESULTS:After controlling for confounders, 5 µg/m increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E-selectin. There were no other positive associations between blood markers and short- or long-term air pollution. CONCLUSIONS:These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.