SARS-CoV-2 vaccines are not associated with hypercoagulability in apparently healthy people.

Background: SARS-CoV-2 adenoviral vector DNA vaccines have been linked to the rare but serious thrombotic postvaccine complication vaccine-induced immune thrombotic thrombocytopenia. This has raised concerns regarding the possibility of increased thrombotic risk after any SARS-CoV-2 vaccines. Objectives: To investigate whether SARS-CoV-2 vaccines cause coagulation activation leading to a hypercoagulable state. Methods: This observational study included 567 health care personnel; 521 were recruited after the first dose of adenoviral vector ChAdOx1-S (Vaxzevria, AstraZeneca) vaccine and 46 were recruited prospectively before vaccination with a messenger RNA (mRNA) vaccine, either Spikevax (Moderna, n = 38) or Comirnaty (Pfizer-BioNTech, n = 8). In the mRNA group, samples were acquired before and 1 to 2 weeks after vaccination. In addition to the prevaccination samples, 56 unvaccinated blood donors were recruited as controls (total n = 102). Thrombin generation, D-dimer levels, and free tissue factor pathway inhibitor (TFPI) levels were analyzed. Results: No participant experienced thrombosis, vaccine-induced immune thrombotic thrombocytopenia, or thrombocytopenia (platelet count <100 × 109/L) 1 week to 1 month postvaccination. There was no increase in thrombin generation, D-dimer level, or TFPI level in the ChAdOx1-S vaccine group compared with controls or after the mRNA vaccines compared with baseline values. Eleven of 513 (2.1%) participants vaccinated with ChAdOx1-S had anti-PF4/polyanion antibodies without a concomitant increase in thrombin generation. Conclusion: In this study, SARS-CoV-2 vaccines were not associated with thrombosis, thrombocytopenia, increased thrombin generation, D-dimer levels, or TFPI levels compared with baseline or unvaccinated controls. These findings argue against the subclinical activation of coagulation post-COVID-19 vaccination.

The venous thrombosis registry in Østfold Hospital (TROLL registry) - design and cohort description.

Purpose: The incidence of venous thromboembolism (VTE) is expected to increase over the next decades, further increasing its substantial impact on patients and health care resources. Registries have the benefit of reporting real-world data without excluding clinically important subgroups. Our aim was to describe a Norwegian VTE registry and to provide descriptive data on the population and management. Registry Population: The Venous Thrombosis Registry in Østfold Hospital (TROLL) is an ongoing registry of consecutive patients diagnosed with, treated, and/or followed up for VTE at Østfold Hospital, Norway, since 2005. Baseline and follow-up data, including demographics, clinical features, risk factors, diagnostic procedures, classification of VTE, and treatment were collected during hospitalization, and at scheduled outpatient visits. Findings to Date: From January 2005 to June 2021, 5037 patients were eligible for research in TROLL. Median age was 67 years (interquartile range, 55-77), and 2622 (52.1%) were male. Of these, 2736 (54.3%) had pulmonary embolism (PE), 2034 (40.4%) had deep vein thrombosis (DVT), and 265 (5.3%) had upper-extremity DVT or splanchnic or cerebral sinus vein thrombosis. In total, 2330 (46.3%) were classified as unprovoked VTE, and 1131 (22.5%) had cancer. Direct oral anticoagulants were the most frequent therapeutic agents (39.3%) followed by low-molecular-weight heparins (30.4%) and vitamin K antagonists (30.3%). Outpatient treatment for PE increased from 4% in 2005 to 23% in 2019. Future Plans: TROLL is a population-based ongoing registry that represents a valuable source of real-world data that will be used for future research on the management and outcomes of VTE.

Computational Drug Repositioning and Experimental Validation of Ivermectin in Treatment of Gastric Cancer.

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches. Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice). Results: GC gene expression "signature" and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/ß-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/ß-catenin signaling pathway in "dose-depended" manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/ß-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways. Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.

An observational study to identify the prevalence of thrombocytopenia and anti-PF4/polyanion antibodies in Norwegian health care workers after COVID-19 vaccination.

BACKGROUND: The COVID-19 vaccine from AstraZeneca (AZD1222) is one of several vaccines introduced to provide immunity against SARS-CoV-2. Recently, more than 50 cases have been reported presenting a combination of thrombosis, thrombocytopenia, and remarkably high levels of anti-platelet factor 4 (PF4)/polyanion antibodies post-AZD1222 vaccination. Now linked to the vaccine, the condition is referred to as vaccine-induced immune thrombotic thrombocytopenia. The European Medicines Agency still recommends vaccination with AZD1222, but several European countries have temporally paused and/or restricted its use because of the perceived risk of this severe side effect. Because there is no description of PF4/polyanion antibody testing in the clinical trials, knowledge about the prevalence of such antibodies in a vaccinated cohort is needed. OBJECTIVES: To investigate prevalence of thrombocytopenia and anti-PF4/polyanion antibodies in a population recently vaccinated with AZD1222. PATIENTS/METHODS: Four hundred and ninety-two health care workers recently vaccinated with the first dose of AZD1222 were recruited from two hospitals in Norway. Study individuals were screened for thrombocytopenia and the presence of anti-PF4/polyanion antibodies with a PF4/PVS immunoassay. Side effects after vaccination were registered. RESULTS: The majority of study participants had normal platelet counts and negative immunoassay. Anti-PF4/polyanion antibodies without platelet activating properties were only detected in six individuals (optical density ≥0.4, range 0.58-1.16), all with normal platelet counts. No subjects had severe thrombocytopenia. CONCLUSIONS: We found low prevalence of both thrombocytopenia and antibodies to PF4/polyanion-complexes among Norwegian health care workers after vaccination with AZD1222.

Neural signaling modulates metabolism of gastric cancer.

Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/α-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.

Persistent symptoms 1.5-6 months after COVID-19 in non-hospitalised subjects: a population-based cohort study.

This study assessed symptoms and their determinants 1.5-6 months after symptom onset in non-hospitalised subjects with confirmed COVID-19 until 1 June 2020, in a geographically defined area. We invited 938 subjects; 451 (48%) responded. They reported less symptoms after 1.5-6 months than during COVID-19; median (IQR) 0 (0-2) versus 8 (6-11), respectively (p<0.001); 53% of women and 67% of men were symptom free, while 16% reported dyspnoea, 12% loss/disturbance of smell, and 10% loss/disturbance of taste. In multivariable analysis, having persistent symptoms was associated with the number of comorbidities and number of symptoms during the acute COVID-19 phase.

Seventy patients treated for COVID-19 by Østfold Hospital Trust. / 70 pasienter med covid-19 innlagt ved Sykehuset Østfold.

BACKGROUND: There is a need for further data on the COVID-19 situation in Norway. Our aim was to describe the patients admitted to our local hospital with COVID-19 in the spring of 2020. MATERIAL AND METHOD: Data were retrieved retrospectively from our local quality register for COVID-19 and include all patients admitted to Østfold Hospital in the period 10 March 2020-31 May 2020. RESULTS: A total of 70 patients were admitted, of whom 47 (67 %) were men. The mean age was 59 years (range 18-95). The most common comorbid conditions were obesity (n = 22, 31 %), chronic coronary artery disease (n = 21, 30 %) and diabetes (n = 17, 24 %). Thirteen patients (19 %) had no comorbidities. The most common symptoms were cough (n = 56, 80 %), dyspnoea (n = 51, 73 %) and fever (n = 48, 69 %). The most frequent complications were cardiac manifestations (n = 18, 26 %), acute respiratory distress syndrome (n = 14, 20 %) and acute kidney injury (n = 9, 13 %). Four (6 %) patients developed venous thromboembolism. Twenty patients (29 %) became critically ill. Thirteen (19 %) received treatment in the intensive care unit, and seven (10 %) died while in hospital. INTERPRETATION: Most of those admitted were middle-aged men. Many had no comorbidities. The most frequent non-respiratory complications were cardiac manifestations and kidney injury. A large proportion of patients became critically ill secondary to acute respiratory distress syndrome.

Gastric sleeve resection as day-case surgery: what affects the discharge time?

BACKGROUND: Sleeve gastrectomy, with its short operating time, is possible to perform as same-day surgery, with the most common reason for requiring overnight hospital stay being postoperative nausea and vomiting. OBJECTIVE: To demonstrate the feasibility and safety of sleeve gastrectomy as same-day surgery with regard to complication rate. Additionally, the study aimed to evaluate factors determining the duration of hospital stay, such as type of anesthesia, time of procedure, degree of postoperative nausea and pain, American Society of Anesthesiologists score, or previous abdominal surgery. SETTING: Nonacademic primary referral center. METHODS: A substudy of a single-center, double-blind, randomized controlled trial. Patients included in this study underwent sleeve gastrectomy and were randomized into 1 of the following 2 types of anesthesia: total intravenous anesthesia with propofol or desflurane. Primary endpoint was the number of patients discharged the same day as surgery. Secondary endpoints were unplanned telephone calls, readmission rate, and complication rate. Time of procedure was registered by the staff at the operation theatre. Visual analog scales score estimating patients' intensity of pain and nausea were completed at the postoperative unit, surgical ward, and 24 to 48 hours postoperatively. RESULTS: Ninety-three patients were included in the study. Fifty-nine (63%) were discharged the same day as surgery (32 desflurane and 27 total intravenous anesthesia), 30 patients (32%) were discharged 1 day after surgery, and 4 patients (4%) were discharged after >2 days (15 desflurane and 19 total intravenous anesthesia). The most common reasons for prolonged stay were pain, nausea, and fatigue. Statistical analyses showed no association between day of discharge and the type of anesthesia, time of the procedure, degree of postoperative nausea and vomiting, pain intensity, American Society of Anesthesiologists score, or previous abdominal surgery. CONCLUSION: Same-day surgery is feasible and safe in terms of low complication rate. The type of anesthesia, time of procedure, degree of postoperative nausea and vomiting and pain, American Society of Anesthesiologists score and previous abdominal surgery does not appear to affect length of hospital stay.

Pain and nausea after bariatric surgery with total intravenous anesthesia versus desflurane anesthesia: a double blind, randomized, controlled trial.

BACKGROUND: There is limited evidence-based knowledge regarding optimal anesthesia in obese patients. OBJECTIVE: To evaluate optimal anesthetic approach for patients undergoing bariatric surgery by determining and comparing peri- and postoperative outcomes in patients receiving intravenous anesthesia with propofol versus desflurane anesthesia. SETTING: Nonacademic primary referral center. METHODS: Patients who underwent laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass between 2016 and 2017 were randomized into 1 of the following 2 types of anesthesia: intravenous anesthesia with propofol, or desflurane. Perioperative outcomes were registered by the operation staff. A form based on visual analog scale estimating the patient's intensity of pain and nausea was completed postoperatively at the postoperative unit, surgical ward, and 24 to 48 hours postsurgery. The primary outcome was postoperative nausea and vomiting or postoperative pain between treatment groups. The secondary outcome was to evaluate the "time of awakening," peritoneal stretch, and use of perioperative muscle relaxants. RESULTS: One hundred eighty-three patients were randomized to receive intravenous anesthesia (n = 90) or desflurane anesthesia (n = 93). Mean time ± standard deviation of surgery for both procedures was 41 ± 17 minutes, whereas mean time of awakening was 2 ± 2 minutes for both the intravenous anesthesia and desflurane group. There was no significant difference in visual analog scale for pain or for nausea and vomiting postoperatively, nor in the number of patients receiving muscle relaxants for peritoneal stretch between the 2 groups. CONCLUSIONS: We found no significant differences between the 2 anesthetic regimens regarding postoperative nausea and pain, awakening time, peritoneal stretch, or the use of perioperative muscle relaxants.

Time-restricted feeding on weekdays restricts weight gain: A study using rat models of high-fat diet-induced obesity.

A recent study reported that a special weekly scheduled time-restricted feeding regimen (TRF), i.e., no food consumption for 15h during the light (inactive) phase per day for 5 weekdays, attenuated the outcome of diverse nutritional challenges in response to high-fat diet in mice. In the present study, we wanted to further test whether this TRF could restrict body weight gain in both juvenile and adult animals when fed a high-fat diet. Fifty male Sprague-Dawley rats at ages from 5 to 27weeks were used. First, we found that freely fed rats with 60% fat diet gained weight significantly, which was associated with more calorie intake (particularly during light phase) than those fed standard food (7% fat). Secondly, we found that TRF restricted high-fat diet-induced weight gain in both groups of juvenile rats (5 and 13weeks of age) compared to freely fed rats with high-fat diet, despite the same levels of 24h-calorie intake during either weekdays or the weekend. Thirdly, we found that TRF did not restrict high-fat diet-induce weight gain in adult rats (27weeks of age). Thus, we suggest that this special TRF regimen could be further tested in humans (particularly young adults) for the purpose of obesity prevention.

Steady-state energy balance in animal models of obesity and weight loss.

OBJECTIVE: We wanted to exam the steady-state energy balance by using high-fat diet-induced obese (DIO) rats and mice as models for positive energy balance, and gastric bypassed (GB) rats and gene knockout of muscarinic acetylcholine M3 receptor (M3KO) mice as models for negative energy balance. METHODS: One hundred and thirty-two rats and mice were used. Energy balance was measured by a comprehensive laboratory animal monitoring system. Gene expression was analysed by in situ hybridisation in M3KO mice. RESULTS: DIO rats reached the plateau of body weight 28 weeks after starting high-fat diet (25% heavier than controls), whereas DIO mice reached the plateau after 6 weeks (23% heavier than controls). At the plateau, DIO rats had higher calorie intake during the light phase but not during the dark phase, while mice had the same calorie intake per day as controls. DIO rats and mice had lower energy expenditure (EE) and respiratory exchange ratio (RER) than controls. GB-rats reached the plateau (15% weight loss) 2 weeks after surgery and had the same calorie intake as sham-operated controls. EE, but not RER, was higher in GB rats than controls during the dark phase. The lean M3KO mice (25% lighter than wild-type (WT) mice at the plateau between 6 and 15 months of age) had the same calorie intake but higher EE, RER and hypothalamic mRNA expression of NPY, AgRP and leptin receptor than WT mice. CONCLUSION: When body weight gain or loss reached a plateau, the steady-state energy balance was mainly maintained by EE and/or RER rather than calorie intake.

PYY-Dependent Restoration of Impaired Insulin and Glucagon Secretion in Type 2 Diabetes following Roux-En-Y Gastric Bypass Surgery.

Roux-en-Y gastric bypass (RYGB) is a weight-reduction procedure resulting in rapid resolution of type 2 diabetes (T2D). The role of pancreatic islet function in this restoration of normoglycemia has not been fully elucidated. Using the diabetic Goto-Kakizaki (GK) rat model, we demonstrate that RYGB restores normal glucose regulation of glucagon and insulin secretion and normalizes islet morphology. Culture of isolated islets with serum from RYGB animals mimicked these effects, implicating a humoral factor. These latter effects were reversed following neutralization of the gut hormone peptide tyrosine tyrosine (PYY) but persisted in the presence of a glucagon-like peptide-1 (GLP-1) receptor antagonist. The effects of RYGB on secretion were replicated by chronic exposure of diabetic rat islets to PYY in vitro. These findings indicate that the mechanism underlying T2D remission may be mediated by PYY and suggest that drugs promoting PYY release or action may restore pancreatic islet function in T2D.