Background: Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs in ∼1 to 2 individuals per 1000 each year, corresponding to ∼300 000 to 600 000 events in the United States annually. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about treatment of VTE. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 28 recommendations for the initial management of VTE, primary treatment, secondary prevention, and treatment of recurrent VTE events. Conclusions: Strong recommendations include the use of thrombolytic therapy for patients with PE and hemodynamic compromise, use of an international normalized ratio (INR) range of 2.0 to 3.0 over a lower INR range for patients with VTE who use a vitamin K antagonist (VKA) for secondary prevention, and use of indefinite anticoagulation for patients with recurrent unprovoked VTE. Conditional recommendations include the preference for home treatment over hospital-based treatment for uncomplicated DVT and PE at low risk for complications and a preference for direct oral anticoagulants over VKA for primary treatment of VTE.

The effect of very highly purified gastric inhibitory polypeptide (GIP) on insulin secretion in man was tested in normal volunteers. Administration of physiological doses of GIP together with glucose by IV infusion resulted in potentiation of the rise in IRI in the blood and improvement in glucose tolerance. It is concluded that GIP is a potent insulinotropic hormone and probably takes part in physiological potentiation of insulin secretion in response to hyperglycemia during absorption of nutrients from the intestine.Studies with various preparations containing peptldes derived from extracts of porcine duodenojejunal mucosa have suggested that the intestinal hormones secretin and pancreozymin-cholecystokinin (PZ-CCK) are capable of potentiating the rise in insulin in the blood in response to hyperglycemia in man (1). In addition to stimulating insulin secretion the very highly purified preparation of secretin and the relatively crude preparations of PZ-CCK (10% PZ-CCK) used in earlier experiments produced significant improvement in glucose tolerance during intravenous infusions of glucose of two hours duration (2). However, studies in the secretion of rat insulin have shown that the stimulatory effect of 10% PZ-CCK is not reproduced with highly purified ("pure") PZ-CCK (3). Gastric inhibitory polypeptide (GIP), recently identified and characterized as an inhibitor of gastric acid secretion in dogs (4,5), is probably a physiological enterogastrone, and is present in 10% PZ-CCK to the extent of 10-15% by weight (6). Studies with very highly purified GIP have shown that the stimulation of increments in immunoreactive insulin (IRI) in the blood in rats by 10% PZ-CCK can be reproduced by administration of GIP in amounts corresponding to those present in effective doses of 10% PZ-CCK (7). We have therefore examined the effects of very highly purified GIP in man. Submitted July 27, 1973. S.A.R. was In receipt of an award from the New Zealand Diabetes Association. MATERIALS AND METHODSNormal volunteers were tested in the morning after they had fasted overnight. Very highly purified GIP was infused intravenously at the rate of 1 wg/min for a total period of 30 minutes. GIP was prepared according to procedures employed in its identification (A ,5) and was more than 95% pure. Infusates contained human serum albumin 1 mg/ml in normal saline or in glucose 10g%.Glucose was delivered at 0.5 gm/min for 60 min. Insulin and GIP in serum were estimated by radioimmunoassay. In the assay for GIP no interfering crossreaction was detected with glucagon, secretin, vasoactive intestinal polypeptide, gastrin, or pancreozymincholecystokinin (6). Plasma glucose was estimated using glucose oxidase in a Beckman glucose analyzer. RESULTSIn six subjects who received GIP intravenously at the rate used in this study the concentration of GIP in the serum reached a mean peak value of approximately 1 ng/ml by 30 minutes; this concentration is attained in normal subjects after ingestion of glucose (8). The intravenous infusion of GIP in saline at th...

BackgroundObservational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.Methods and FindingsWe identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10−10 to 2 × 10−109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10−12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7–2.5; p = 7.7 × 10−12; I 2 = 63%, 95% CI: 0%–88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3–2.2; p = 2.3 × 10−5; I 2 = 47%, 95% CI: 0%–85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6–2.6, p = 1 × 10−9; ORmetabolism = 1.9, 95% CI: 1.3–2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.ConclusionsA genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.