Following baseline microcirculatory and blood pressure measurements, as well as the collection of urine and saliva samples, participants on the "beetroot" group were asked to consume 140ml beetroot juice (James White Drinks Company, Suffolk, UK). The 140 ml of beetroot juice equate to approximately 8.4 mmol of NO3- .

Following baseline microcirculatory and blood pressure measurements, as well as the collection of urine and saliva samples, participants on the "placebo" group were asked to consume 140 ml nitrate-depleted beetroot juice (James White Drinks Company, Suffolk, UK).

Aging

Drink consumption was followed by regular BP measurements and collection of saliva samples every 30 minutes for four hours. Microcirculatory measurements were then repeated and saliva and urine samples were collected again.
After the last measurement subjects were provided with a standardized meal with a very low nitrate intake to eat within 30minutes. Participant then left the research centre and they were asked to collect a saliva sample after two hours from the completion of the meal. This was immediately followed a dose of labelled nitrate (4mg in 100ml of distilled water) to drink within one minute. Subjects were then asked to collect six additional saliva samples until the next morning (four before going to bed and two in the morning), accompanied by measurements of resting BP.
Cross-over assessments were then repeated in the same order at Visit 3, followed a wash-out period of at least one week before entering the second arm of the study.

Crossover intervention

Exploring the Effect of Inorganic Nitrates on the Human Microvascular Physiology - a Pilot Study.

Non-invasive laser Doppler flowmetry (LDF) measurements (Periflux 5000 System, Perimed, Sweden) will be used as an index of cutaneous (microcirculatory) function and red blood cell flux. To obtain a measure of microcirculatory, NO-dependent, endothelial-function (26) measurements will be taken once at Visit 1 and twice (prior to and 3 hrs. after beverage ingestion) on Visits 2 and 3, using thermal hyperaemia. For this, four 7-point integrating probes (Model 413, Perimed) housed within local heating units (Model 455, Perimed) will be placed on the ventral aspect of the left forearm. The heating units will be initially set at 33 °C. After a 10-min baseline recording, the temperature of the heating unit will then be increased to 42 °C at a rate of 1 °C every 10 seconds to obtain maximum skin blood flow; this (i.e., a stable plateau in skin blood flow) is usually observed after approx. 25 minutes of localised heating.

Resting BP sure will be recorded intermittently throughout the test using an automated system (Dinamap Dash 2500, GE Healthcare. Duplicate measurements of BP wil be performed covertly and only showed to the participant at the end of the study visit. Before each measurement participants will be invited to rest in a sitting position for at least 15 minutes.

Nitrate reductase activity will be investigated by evaluating the differences in salivary nitrite concentrations according to a validated method. Briefly, ten millilitres of a solution of potassium nitrate in distilled water will be held in the mouth for 5 min and then collected. Background levels of nitrate reduction were estimated by subtracting values obtained from holding distilled water alone in the mouth. NO3- and NO2- concentrations will be measured by chemiluminescence.

A non-invasive stable isotopic method will be used to assess whole-body NO production (ONT Method). Subjects will receive an oral dose of labelled sodium nitrate in 100ml of distilled water (4mg Na15NO3) and the isotopic decay of the tracer in saliva samples will be used to derive estimates of NO production. Nitrate concentrations will be measured by chemiluminescence. Nitrate enrichments will be measured using Gas Chromatography Mass Spectrometry (GCMS).

Mid-stream urine samples will be collected into sterile containers and an aliquot and will stored at -80 ⁰C until analysis at a later date. Saliva will be collected into sterile eppendorfs and stored at -80 ⁰C until analysis at a later date. Both salivary and urinary samples will be used for NO3- and NO2- measurements. Saliva samples will also be used to assess isotopic enrichment of labelled NO3- as previously described. Sodium hydroxide will be added to urine and saliva samples to avoid nitrate degradation.

Due to ethical approval restrictions there were no plans for IPD available to other researchers.

Sheffield Hallam University

University of Sheffield

University of Nottingham

Patients switch from taking warfarin in the evening to taking warfarin in the morning.

Patients continue taking warfarin in the evening as per their usual routine.

Atrial Fibrillation

Thrombus Due to Heart Valve Prosthesis

Deep Venous Thrombosis

Thromboembolism

Warfarin

University of Alberta

Vancouver Coastal Health Research Institute

The Effect of Medication Timing on Anticoagulation Stability in Users of Warfarin: The "INRange" RCT

Our primary outcome, percentage change in time spent OUTSIDE of therapeutic range is chosen because we believe this is a measure more likely to be shared by patients across a wide range of TTR (i.e. a patient with high baseline TTR and a patient with low baseline TTR may still share a similar % change in time outside of therapeutic range as a response to our intervention). This would not be true for change in TTR itself. It is also the time spent outside of range which contributes more directly to risk of thrombosis and hemorrhage and hence the change in this measure is more clinically meaningful than the change in TTR itself.

The percentage of patients with TTR > 75% provides the percentage of patients considered to have excellent control.

The percentage of patients with TTR < 60% provides the percentage of patients for whom other anticoagulation strategies may be indicated.

Includes all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis / pulmonary embolism.

For those patients with at least one INR value above the therapeutic range, the maximum INR observed.

For those patients with at least one INR value below the therapeutic range, the minimum INR value observed.

Includes non-hemorrhagic stroke, deep vein thrombosis, pulmonary embolus and acute arterial occlusion

Includes all bleeding events requiring hospitalization such as hemorrhagic stroke and GI bleeding

Patient self-reports of adherence to their allocated intervention during telephone follow-up occurring at 1 week, 1 month and upon study completion

Upon publication of all planned manuscripts stemming from this work, anonymized patient level trial data will be posted on www.PragmaticTrials.ca

Scott Garrison

Associate Professor

6 gram dose of betaine delivered in encapsulated form

6 gram dose of dextrose delivered in encapsulated form

Insulin Sensitivity

6 gram one-time dose of betaine delivered in encapsulated form with an unsweetened beverage

Betaine

6 gram one-time dose of dextrose delivered in encapsulated form with an unsweetened beverage

spinacia/antijamur

Exploring the Effect of Inorganic Nitrates on the Human Microvascular Physiology - a Pilot Study.

The Effect of Medication Timing on Anticoagulation Stability in Users of Warfarin: The "INRange" RCT

Modulation of Insulin Sensitivity by Betaine Upregulation of FGF21

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