Diabetes Rescue, Engagement and Management (D-REM): rationale and design of a pragmatic clinical trial of a community paramedicine programme to improve diabetes care.

INTRODUCTION: Diabetes is one of the most common serious chronic health conditions in the USA. People living with diabetes face multiple barriers to optimal diabetes care, including gaps in access to medical care and self-management education, diabetes distress, and high burden of treatment. Community paramedics (CPs) are uniquely positioned to support multidisciplinary care for patients with diabetes by delivering focused diabetes self-management education and support and bridging the gaps between patients and the clinical and community resources they need to live well with their disease. METHODS AND ANALYSIS: We will conduct a pragmatic single-arm prospective trial of a CP-led Diabetes Rescue, Engagement and Management (D-REM) programme that seeks to reduce diabetes distress. We will enrol 70 adults (≥18 years) with diabetes who have haemoglobin A1c (HbA1c)≥9.0%, experienced an emergency department (ED) visit or hospitalisation for any cause within the prior 6 months, and reside in areas with available CP support in Southeast Minnesota (Olmsted, Freeborn and Mower counties) and Northwest Wisconsin (Barron, Rusk and Dunn counties). Participants will be identified using Mayo Clinic electronic health records, contacted for consent and enrolled into the D-REM programme. Visit frequency will be individualised for each patient, but will be an average of four CP visits over the course of approximately 1 month. Outcomes will be change in diabetes distress (primary outcome), confidence in diabetes self-management, health-related quality of life, self-reported hypoglycaemia and hyperglycaemia, HbA1c, ED visits and hospitalisations. Outcomes will be assessed on enrolment, programme completion and 3 months after programme completion. ETHICS AND DISSEMINATION: The study was approved by Mayo Clinic Institutional Review Board. Findings will be disseminated through peer-reviewed publications and presentations. If demonstrated to be successful, this model of care can be implemented across diverse settings and populations to support patients living with diabetes. TRIAL REGISTRATION NUMBER: NCT04385758.

A Test of the Biogenicity Criteria Established for Microfossils and Stromatolites on Quaternary Tufa and Speleothem Materials Formed in the "Twilight Zone" at Caerwys, UK.

The ability to distinguish the features of a chemical sedimentary rock that can only be attributed to biology is a challenge relevant to both geobiology and astrobiology. This study aimed to test criteria for recognizing petrographically the biogenicity of microbially influenced fabrics and fossil microbes in complex Quaternary stalactitic carbonate rocks from Caerwys, UK. We found that the presence of carbonaceous microfossils, fabrics produced by the calcification of microbial filaments, and the asymmetrical development of tufa fabrics due to the more rapid growth of microbially influenced laminations could be recognized as biogenic features. Petrographic evidence also indicates that the development of "speleothem-like" laminae was related to episodes of growth interrupted by intervals of nondeposition and erosion. The lack of any biogenic characteristics in these laminae is consistent with their development as a result of variation in the physicochemical parameters that drive calcite precipitation from meteoric waters in such environmental settings.

Mine water geochemistry and metal flux in a major historic Pb-Zn-F orefield, the Yorkshire Pennines, UK.

Recent studies have shown up to 6 % of rivers in England and Wales to be impacted by discharges from abandoned metal mines. Despite the large extent of impacts, there are still many areas where mine water impact assessments are limited by data availability. This study provides an overview of water quality, trace element composition and flux arising from one such area; the Yorkshire Pennine Orefield in the UK. Mine drainage waters across the orefield are characterised by Ca-HCO3-SO4-type waters, with moderate mineralization (specific electrical conductance: 160-525 µS cm(-1)) and enrichment of dissolved Zn (≤2003 µg L(-1)), Ba (≤971 µg L(-1)), Pb (≤183 µg L(-1)) and Cd (≤12 µg L(-1)). The major ion composition of the waters reflects the Carboniferous gritstone and limestone-dominated country rock, the latter of which is heavily karstified in parts of the orefield, while sulphate and trace element enrichment is a product of the oxidation of galena, sphalerite and barite mineralization. Contaminant flux measurements at discharge sites highlight the disproportionate importance of large drainage levels across the region, which generally discharge into first-order headwater streams. Synoptic metal loading surveys undertaken in the Hebden Beck sub-catchment of the river Wharfe highlight the importance of major drainage levels to instream baseflow contamination, with diffuse sources from identifiable expanses of waste rock becoming increasingly prominent as river flows increase.

Inventory management.

A critical aspect of blood transfusion is the timely provision of high quality blood products. This task remains a significant challenge for many blood services and blood systems reflecting the difficulty of balancing the recruitment of sufficient donors, the optimal utilization of the donor's gift, the increasing safety related restrictions on blood donation, a growing menu of specialized blood products and an ever-growing imperative to increase the efficiency of blood product provision from a cost perspective. As our industry now faces questions about our standard practices including whether or not the age of blood has a negative impact on recipients, it is timely to take a look at our collective inventory management practices. This International Forum represents an effort to get a snap shot of inventory management practices around the world, and to understand the range of different products provided for patients. In addition to sharing current inventory management practices, this Forum is intended to foster an exchange of ideas around where we see our field moving with respect to various issues including specialty products, new technologies, and reducing recipient risk from blood transfusion products.

Positive data in sativex® phase IIb trial: support advancing into phase III development in cancer pain

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End-stage renal disease: factors affecting referral decisions by family physicians in Canada, the United States, and Britain.

The objective of this study is to determine how patient age, sex, creatinine level, and comorbidity affect referral decisions for the treatment of end-stage renal disease (ESRD) and whether these decisions are affected by physician characteristics in three countries: Canada, the United States, and Britain. A vignette-based questionnaire was mailed to a random sample of family physicians in Ontario, Canada (1,818 physicians); all family physicians in the state of New York (1,814 physicians); and a sample of general practitioners from the south of England (2,228 physicians) in 1996. Physicians were presented with clinical scenarios involving a patient with varying degrees of renal insufficiency and a complicating comorbidity, including angina, diabetes, cancer, mental illness, or socioeconomic circumstances. They were asked to indicate the likelihood of referral. Half the physicians received a questionnaire describing a male patient, and half, a female patient. Mean creatinine levels at which physicians would refer were 260 micromol/L for British physicians, 297 micromol/L for Canadian physicians, and 340 micromol/L for American physicians. No difference in referral rates was found based on the sex of the patient or physician. Sixty-five percent of American and Canadian physicians would refer regardless of patient age, but only 49% of British physicians would do so. Family physicians in the United States, Canada, and Britain function as gatekeepers for patients with ESRD. They are less likely to refer based on increasing severity of comorbid conditions. They also discriminate based on age, but not sex.

Effect of kidney function and disease status on urinary tissue factor measurements.

AIM: To investigate factors that influence urinary tissue factor (uTF) measurements: glomerular permeability and filtration, tubular function, haematuria, and urine bacterial growth. METHODS: uTF, protein creatinine index, glomerular filtration rate, retinol binding protein, N-acetyl-beta-D-glucosaminidase (NAG) and urinary haemoglobin (uHb) were measured in patients with hypertension, diabetes mellitus and nephrotic syndrome (n = 342), tubulo-interstitial disease (n = 50), and haematuria of uncertain cause (n = 50); measurements were also made in urine samples from healthy subjects for "simulated" haematuria (n = 6) and bacterial growth (n = 4) studies. RESULTS: There was a weak correlation of uTF with glomerular permeability and filtration (protein creatinine index and glomerular filtration rate) and with markers of tubular function (retinol binding protein and NAG). uTF concentrations were not affected by the presence of blood or bacteria in the urine sample. CONCLUSION: uTF concentrations are relatively stable. This is an important finding if the assay is to be used in clinical practice.

Jejuno-ileal bypass, enteric hyperoxaluria, and oxalate nephrosis: a role for polarised light in the renal biopsy.

Enteric hyperoxaluria, a complication of jejuno-ileal bypass, is associated with renal failure owing to oxalate nephrosis or tubulo-interstitial nephritis. A 54 year old woman developed renal failure 17 months after jejuno-ileal bypass for morbid obesity. Renal biopsy showed widespread acute on chronic damage to the tubulo-interstitial compartment with extensive deposition of oxalate crystals. The extent of oxalate deposition was only evident on polarisation of the biopsy.

The effect of recombinant human erythropoietin on cardiovascular responses to postural stress in dialysis patients.

The normal response to 45 degrees head-up tilt (decreased stroke volume and cardiac output and increased heart rate and peripheral resistance) is not seen in the majority of haemodialysis patients. This is due to both an abnormal baroreceptor reflex and increased venous tone which may be explained by a number of factors including hypoxia, acidosis and sodium retention. We have studied this response by impedance cardiography in eight chronic haemodialysis patients, both before and after 3 months of treatment with human recombinant erythropoietin. Before treatment the cardiovascular parameters were abnormal both at rest and on tilting in each patient. The change in each measurement following tilting was: stroke volume, 0.5 +/- 6%; cardiac output, 6 +/- 5%; peripheral resistance, -8 +/- 4%; and heart rate, 10 +/- 4%. After 3 months of erythropoietin (150 U/kg/week intravenously) the mean haematocrit had risen from 19.5 +/- 3% to 32.9 +/- 4% and all patients felt physically fitter. Impedance showed no change in the supine-indices but after tilting there was a dramatic fall in stroke volume (-26 +/- 7%) and cardiac output (-17 +/- 7%) and an increase in heart rate (15 +/- 4%) and peripheral resistance (28 +/- 10%) each moving towards the normal response. These results indicate that human recombinant erythropoietin normalizes the response to postural stress in these patients and suggest that anaemia is the principal cause of the abnormal venoconstriction seen in haemodialysis patients. The mechanisms involved warrant further investigation.

Endothelin-1 in the rabbit: interactions with cyclo-oxygenase and NO-synthase products.

1. Endothelin-1 infusion (5-40 pmol kg-1 min-1) in the normal anaesthetized rabbit, produced a dose-dependent increase in mean arterial blood pressure (MAP) and reduced renal blood flow (RBF) and glomerular filtration rate (GFR), when compared with an equivalent infusion of physiological saline. 2. Endothelin, 20 pmol kg-1 min-1, was also assessed in animals pretreated with either indomethacin (2 mg kg-1), methylene blue (1.6 mg kg-1 h-1) or NG-monomethyl L-arginine (L-NMMA, 10 mg kg-1 h-1). 3. The effect of endothelin on MAP and RBF was enhanced (P = 0.05 and < 0.01 respectively) by the cyclo-oxygenase inhibitor, indomethacin, without any significant change in the effect on GFR. 4. Methylene blue and L-NMMA, inhibitors of endothelium-derived relaxant factor (EDRF), enhanced the effect of endothelin on each of the parameters measured (P < 0.01). 5. Our results are consistent with endothelin having a predominant effect on pre-glomerular vascular resistance to reduce GFR. Endothelin appears to stimulate the release of vasodilator prostanoids and EDRF which oppose its effects. Thus endothelin may have an important role in the complex control of GFR in the rabbit.

Regional heterogeneity of endothelium-dependent vasodilatation in the rabbit kidney.

1. Regional heterogeneity of endothelial function exists but its role in the local regulation of vascular tone is uncertain. This heterogeneity may be very important in the control of the glomerular filtration rate (GFR) in which the differential tone in the afferent and efferent arterioles is crucial. 2. When an endothelium-independent vasodilator, prostacyclin (PGI2) or nitroprusside, was infused into anaesthetized rabbits there were dose-dependent falls in both mean arterial pressure (MAP) and GFR; PGI2 (0.4 nmol kg-1 min-1) altered MAP and GFR by -18.5 +/- 3.6% (mean +/- S.E.M.) and -37.7 +/- 13.3% respectively and nitroprusside (30 nmol kg-1 min-1) by -29.7 +/- 3.1% and -67.0 +/- 2.4%. In contrast infusion of an endothelium-dependent vasodilator, acetylcholine (ACh) or substance P, produced dose-dependent decreases in MAP but dose-dependent increases in GFR; ACh (10 nmol kg-1 min-1) -15.1 +/- 2.0% and +43.8 +/- 16.5% and substance P (30 nmol kg-1 min-1) -18.7 +/- 1.9% and +45.3 +/- 23.1% respectively. The effects of endothelium-dependent and independent vasodilators on GFR was significantly different (p less than 0.005). 3. Simultaneous administration of indomethacin, Methylene Blue or NG-monomethyl-L-arginine (L-NMMA), inhibitors of cyclo-oxygenase and endothelium-derived relaxing factor (EDRF) respectively, attenuated or reversed the effect of ACh (10 nmol kg-1 min-1) on MAP and GFR. 4. These data suggest that endothelium-dependent vasodilatation in the kidney has a heterogeneous effect on the renal microvasculature, exerting a preferential effect on afferent glomerular arterioles and thereby preserving GFR despite the fall in MAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue distribution of lipogenesis in vivo in the common murre (Uria aalge) and the domestic chicken (Gallus domesticus).

1. Total body lipogenesis was similar in the murre and the chicken. 2. The liver contributes 10.4% to whole body lipogenesis in fed murres when measured in vivo using 3H2O. 3. The liver contributes 28.0% to whole body lipogenesis in the fed chicken. 4. The lower contribution of the liver in the murre may be a consequence of the high fat diet of the murre relative to the chicken.

Endothelin induces an increase in renal vascular resistance and a fall in glomerular filtration rate in the rabbit isolated perfused kidney.

1. The effects of endothelin infusion on renal vascular resistance (RVR), glomerular filtration rate (GFR) and the interaction with locally generated endothelium-derived relaxant factor (EDRF) were studied in the rabbit isolated perfused kidney (IPK). For comparison the effects of infusions of angiotensin II (AII) and noradrenaline (NA) were also assessed. 2. Each kidney was perfused at a constant rate of 10 ml min-1 and alterations in RVR determined by measuring changes in perfusion pressure. GFR was determined by the clearance of [51Cr]-EDTA, using timed urine collections. 3. Endothelin (10(-11)-10(-9) M) produced a dose-related increase in RVR. Endothelin was approximately 30 times more potent in molar terms than AII and 500 times more than NA at inducing a 50 mmHg increase in perfusion pressure. 4. Endothelin appeared to be a weak inducer of EDRF release in the IPK as EDRF inhibitors methylene blue (10 microM) or haemoglobin (10 microM) only slightly augmented the increase in RVR at a given concentration of endothelin. In contrast the effect of NA on RVR was significantly increased by methylene blue (10 microM) whereas that induced by AII was not affected. 5. Endothelin infusion produced a significant, dose-dependent decrease in GFR of the IPK, contrasting with an increase in GFR during AII infusion and a minimal effect of NA on GFR. This supports evidence that AII is predominantly a constrictor of effernt glomerular arterioles and that NA constricts both afferent and efferent glomerular vessels. We suggest that the vasoconstrictive effect of endothelin in the kidney is predominantly preglomerular, which explains its effect on GFR.

The effect of dietary fish oil on muscle and adipose tissue lipoprotein lipase.

The activity of lipoprotein lipase (LPL) in the adipose tissue and skeletal muscle of rats fed glucose- or fructose-based diets containing fish oil, corn oil or tallow was examined. In addition, heart LPL activity was measured in rats fed a glucose-based diet containing either corn oil or fish oil. Adipose tissue LPL activity was unaffected by dietary fat. In both heart and skeletal muscle, LPL activity was higher in rats fed the fish oil diet. These results suggest that increased removal of triglyceride by muscle may contribute to the blood triglyceride lowering effect of dietary fish oil.

Carnitine and weakness in haemodialysis patients.

Weakness in haemodialysis patients has been attributed to several factors including carnitine deficiency. Malnutrition, neuropathy, uraemic myopathy and parathyroid hormone excess may all be important. Six haemodialysis patients were shown to have reduced muscle power compared with a normal population, and to be malnourished by dietary assessment, and features of their weakness were investigated. Total carnitine was normal in plasma but elevated in muscle, with an excess of esterified carnitine in both plasma and muscle and diminished free plasma carnitine. Muscle biopsy showed no features of carnitine deficiency and electromyography showed a non-specific neuropathy with additional myopathic changes in some. Dietary supplementation with L-carnitine (2 g/day) for 6 weeks in a placebo-controlled trial showed a redistribution of carnitine fractions but no subjective or objective improvement in muscle function. There was no improvement in the plasma lipid profile. The weakness of haemodialysis patients is multifactorial. We have not demonstrated total carnitine depletion in either muscle or plasma, and oral supplementation of L-carnitine has no demonstrable effect in this group.

Hepatic fatty acid synthesis and triglyceride secretion in rats fed fructose- or glucose-based diets containing corn oil, tallow or marine oil.

The effects of three dietary fats, corn oil (CO), tallow (T) and marine oil (MO), on serum triglycerides, hepatic lipogenic enzyme activity and lipogenesis in vivo using 3H2O were measured in fed and fasted rats that had been consuming diets in which the carbohydrate was either glucose or fructose. Hepatic triglyceride secretion was also measured in fasted rats fed the same diets. In both the fed and fasted state, hepatic enzyme activity and lipogenesis in vivo were greater in fructose-fed rats than in glucose-fed rats and less in both CO- and MO-fed rats than in T-fed rats. In rats fed glucose, serum triglycerides were lower in fasted rats fed MO than in fasted rats fed CO. In rats fed glucose or fructose, hepatic triglyceride secretion was lower in rats fed MO than in those fed CO or T.

Gluconeogenesis in liver and kidney of common murre (Uria aalge).

Phosphoenolpyruvate carboxykinase (PEPCK) in murre liver occurs in both cytoplasmic and mitochondrial forms. During a 3-day fast, hepatic PEPCK increases from 9.1 U/g with 19% cytosolic to 12.2 U/g with 35% cytosolic. The increase in activity is due almost entirely to increased cytosolic activity. PEPCK in murre kidney was present only in the mitochondrial compartment. Gluconeogenesis in vitro was determined in both hepatocytes and kidney tubules isolated from 3-day-fasted murres. In hepatocytes, lactate was the best substrate, but both pyruvate and alanine were good gluconeogenic substrates. This observation is consistent with the existence of a cytosolic form of PEPCK. In the kidney, glycerol was the best substrate but was only slightly better than lactate. Alanine and pyruvate were not as effective as gluconeogenic precursors, presumably because of the lack of cytosolic PEPCK. We propose that the major site of gluconeogenesis from amino acids in the murre is the liver, since this is a much larger organ than the kidney and has a cytosolic form of PEPCK necessary for gluconeogenesis from oxidized substrates.