Improving Outcomes Among Young Adults with type 1 diabetes: The D1 Now Randomised Pilot Study Protocol.

BACKGROUND: Young adults (18-25 years old) living with type 1 diabetes mellitus often have sub-optimal glycaemic levels which can increase their risk of long term diabetes complications. Informed by health psychology theory and using a (public and patient involvement) young adult-centred approach, we have developed a complex intervention, entitled D1 Now, to improve outcomes in this target group. The D1 Now intervention includes three components; 1) a support-worker, 2) an interactive messaging system and 3) an agenda setting tool for use during clinic consultations. AIMS: The aim of the D1 Now pilot study is to gather and analyse acceptability and feasibility data to allow us to (1) refine the D1 Now intervention, and (2) determine the feasibility of a definitive Randomised Control Trial (RCT) of the intervention. METHODS: Diabetes clinics on the island of Ireland will be recruited and randomised to a D1 Now intervention arm or a usual care control arm. For a participant to be eligible they should be 18-25 years old and living with type 1 diabetes for at least 12 months. Participant outcomes (influenced by a Core Outcome Set) include change in HbA1c, clinic attendance, number of episodes of severe hypoglycaemia and of diabetic ketoacidosis, diabetes distress, self-management, quality of life and perceived level of control over diabetes; these will be will be measured at baseline and after 12 months follow-up for descriptive statistics only. An assessment of treatment fidelity, a health economic analysis and a qualitative sub-study will also be incorporated into the pilot study. ISRCTN (ref: ISRCTN74114336).

Behaviour change in diabetes: behavioural science advancements to support the use of theory.

Behaviour is central to the management of diabetes, both for people living with diabetes and for healthcare professionals delivering evidence-based care. This review outlines the evolution of behavioural science and the application of theoretical models in diabetes care over the past 25 years. There has been a particular advancement in the development of tools and techniques to support researchers, healthcare professionals and policymakers in taking a theory-based approach, and to enhance the development, reporting and replication of successful interventions. Systematic guidance, theoretical frameworks and lists of behavioural techniques provide the tools to specify target behaviours, identify why ideal behaviours are not implemented, systematically develop theory-based interventions, describe intervention content using shared terminology, and evaluate their effects. Several examples from a range of diabetes-related behaviours (clinic attendance, self-monitoring of blood glucose, retinal screening, setting collaborative goals in diabetes) and populations (people with type 1 and type 2 diabetes, healthcare professionals) illustrate the potential for these approaches to be widely translated into diabetes care. The behavioural science approaches outlined in this review give healthcare professionals, researchers and policymakers the tools to deliver care and design interventions with an evidence-based understanding of behaviour. The challenge for the next 25 years is to refine the tools to increase their use and advocate for the role of theoretical models and behavioural science in the commissioning, funding and delivery of diabetes care.

Performance of Sri Lankan FRAX algorithm without bone mineral density and with Quantitative Ultrasound data input

Introduction: Fracture risk assessment algorithm (FRAX) is the most validated method available to predict fracture risk. Its use is restricted due to limited availability of Dual Energy X-ray Absorptiometry (DXA). FRAX has the option of assessing facture risk without BMD data. Objectives: To assess the ability of Sri Lankan FRAX algorithm without BMD input in evaluating fracture risk. The possibility of replacing the BMD input with Quantitative Ultrasound (QUS) data of radius in calculating fracture risk also assessed. Method: Data of clinical risk factors associated with fractures were collected from community dwelling postmenopausal women (n=339). DXA scans were performed in all subjects and QUS scans (in radius) were performed in a randomly selected sample (n=207). Ten-year risks of major osteoporotic fracture (MOFR) and hip fracture (HFR) were calculated with BMD, without BMD (FRAX-FN0) and with US T score instead of BMD (FRAX-UST). Result and conclusions: Nearly 35.7% had high risk of fractures. FRAX-FN0 had 79.2% sensitivity, 80.1% specificity, 68.8% positive predictive value (PPV) and 87.4% negative predictive value (NPV). FRAX-UST showed 78.4% sensitivity, 70% specificity, 59.8% PPV and 85% NPV. ROC AUCs were above 0.80 in both FRAX-FN0 and FRAX-UST. The standard errors of estimate (SEE) were less in FRAX-FN0 (3.96 and 2.76 for MOFR-FN0 and HFR-FN0 respectively) compared to FRAX-UST (6.13 and 4.83 for MOFR-UST and HFR-UST, respectively). In conclusion, Sri Lankan FRAX without BMD is an acceptable alternative in areas with restricted DXA facility. Radial QUS data cannot be used as a substitute to FN-BMD in Sri Lankan FRAX.

Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells.

Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.

Chronic warming stimulates growth of marsh grasses more than mangroves in a coastal wetland ecotone.

Increasing temperatures and a reduction in the frequency and severity of freezing events have been linked to species distribution shifts. Across the globe, mangrove ranges are expanding toward higher latitudes, likely due to diminishing frequency of freezing events associated with climate change. Continued warming will alter coastal wetland plant dynamics both above- and belowground, potentially altering plant capacity to keep up with sea level rise. We conducted an in situ warming experiment, in northeast Florida, to determine how increased temperature (+2°C) influences co-occurring mangrove and salt marsh plants. Warming was achieved using passive warming with three treatment levels (ambient, shade control, warmed). Avicennia germinans, the black mangrove, exhibited no differences in growth or height due to experimental warming, but displayed a warming-induced increase in leaf production (48%). Surprisingly, Distichlis spicata, the dominant salt marsh grass, increased in biomass (53% in 2013 and 70% in 2014), density (41%) and height (18%) with warming during summer months. Warming decreased plant root mass at depth and changed abundances of anaerobic bacterial taxa. Even while the poleward shift of mangroves is clearly controlled by the occurrences of severe freezes, chronic warming between these freeze events may slow the progression of mangrove dominance within ecotones.

On reverse engineering of gene interaction networks using time course data with repeated measurements.

MOTIVATION: Gene expression measurements are the most common data source for reverse engineering gene interaction networks. When dealing with destructive sampling in time course experiments, it is common to average any available measurements for each time point and to treat this as the actual time series data for fitting the network, neglecting the variability contained in the repeated measurements. Proceeding in such a way can affect the retrieved network topology. RESULTS: We propose a fully Bayesian method for reverse engineering a gene interaction network, based on time course data with repeated measurements. The observations are treated as surrogate measurements of the underlying gene expression. As these measurements often contain outliers, we use a non-Gaussian specification for dealing with measurement error. The network interactions are assumed linear and an autoregressive model is specified, augmented with indicator variables that allow inference on the topology of the network. We analyse two in silico and one in vivo experiments, the latter dealing with the circadian clock in Arabidopsis thaliana. A systematic attenuation of the estimated regulation strengths and a concomitant overestimation of their precision is demonstrated when measurement error is disregarded. Thus, a clear improvement in the inferred topology for the synthetic datasets is demonstrated when this is included. Also, the influence of outliers in the retrieved network is demonstrated when using the in vivo data. AVAILABILITY: Matlab code and data used in the article are available from http://go.warwick.ac.uk/majuarez/home/materials.

Resolution of proteinuria secondary to bilateral renal vein thrombosis after treatment with systemic thrombolytic therapy.

A case of significant proteinuria occurred as a result of bilateral renal vein thrombosis secondary to dehydration, which resolved after treatment with urokinase. The patient developed nausea and vomiting from viral gastroenteritis with subsequent volume contraction. He later noted the onset of aching lower abdominal and flank pain. On admission, he was noted to have a serum creatinine of 1.7 mg/dL, and 4+ proteinuria on urinalysis. A 24-hour urine collection showed 2.34 g protein. A renal venogram showed bilateral renal vein thrombosis (RVT) without involvement of the inferior vena cava. Therapy was initiated with heparin at 1,000 U/hr, followed by intravenous (IV) urokinase, 4,400 U/kg bolus, followed by 4,400 U/kg/hr with continuous infusion for 12 hours. A repeat renal venogram done at this time showed partial resolution of thrombosis bilaterally. A second 12-hour infusion of urokinase at 5,000 U/kg/hr was performed; at this time, the patient reported resolution of his flank and abdominal pain. A repeat 24-hour urine collection showed 60 mg protein with a normal creatinine clearance. Levels of antithrombin III, protein C, and protein S were all normal. A renal biopsy was performed and showed normal histology on light, immunofluorescent, and electron microscopic evaluation. The patient has done well on no therapy and has had no recurrence of thrombosis or proteinuria after 2.5 years. This is a US government work. There are no restrictions on its use.

An ecological assessment of community-based interventions for prevention and health promotion: approaches to measuring community coalitions.

Presented an ecological assessment of a community coalition to prevent alcohol, tobacco, and other drug abuse, and related risks. Ecological assessment is defined as occurring at multiple social levels and along a continuum of stages of coalition readiness. The assessment is aided by the triangulation, or combining of assessment methods and strategies. Measures used to assess the coalition's formation, implementation of community initiatives, and production of community impacts are described, along with the triangulation strategies used to enhance the assessment findings.

Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions.

Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during atherogenesis. The ability of vascular cells to synthesize the components of ECM is well characterized, but less is known about their capacity to degrade ECM and the factors that may regulate this process. We therefore studied the expression of matrix metalloproteinases (MMPs), enzymes that degrade various components of ECM, and of tissue inhibitors of MMPs (TIMPs) by untreated or cytokine-stimulated human smooth muscle cells (SMC). Messenger RNA was studied by Northern blotting, and proteins secreted in culture by SMC were identified by immunoprecipitation. Gelatinolytic and caseinolytic activity of MMPs was detected zymographically. SMC constitutively produced a 72 kDa type IV gelatinase (GL), TIMP-1, and TIMP-2. Upon stimulation with IL1 or TNF alpha, SMC synthesized in addition 92 kDa GL, stromelysin, and interstitial collagenase, MMPs that together can degrade all of the ECM components. IL1 or TNF alpha did not alter the level of TIMP mRNA and protein, suggesting that a net excess of MMP production under these conditions may promote breakdown of the vascular ECM. To test the in vivo relevance of these in vitro findings, we analyzed immunohistochemically normal human arteries and carotid atheromas. Normal tissue and the medial layer underlying lesions stained uniformly for 72 kDa GL and TIMPs 1 and 2. Lesions showed regionally increased MMP expression: the shoulders of atherosclerotic plaques contained stromelysin and 92 kDa GL associated with SMC, and clusters of macrophage-derived foam cells associated with the lipid core stained intensely for all MMPs studied. Endothelial cells covering atheroma or of the plaque microvasculature contained interstitial collagenase. In pathological conditions associated with local release of cytokines in the vessel wall, enhanced regional expression of vascular MMPs may contribute to SMC migration and weakening of matrix that would favor plaque rupture, events associated with the development or complication of the atherosclerotic lesions.

Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion.

Vascular matrix remodeling occurs during development, growth, and several pathological conditions that affect blood vessels. We investigated the capacity of human smooth muscle cells (SMCs) to express matrix metalloproteinases (MMPs), enzymes that selectively digest components of the extracellular matrix (ECM), in the basal state or after stimulation with certain cytokines implicated in vascular homeostasis and pathology. Enzymatic activity associated with various proteins secreted in the culture media was detected by gelatin or casein sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. Proteins were identified by immunoprecipitation and mRNA by Northern blotting. SMCs constitutively secreted a 72-kD gelatinase and the tissue inhibitors of MMPs (TIMPs) types 1 and 2. SMCs stimulated with interleukin-1 or tumor necrosis factor-alpha synthesized de novo 92-kD gelatinase, interstitial collagenase, and stromelysin. Several lines of evidence suggest that when stimulated by cytokines, SMCs produce activated forms of MMPs. Together, the constitutive and the cytokine-induced enzymes can digest all the major components of the vascular ECM. Moreover, since these mediators augment the production of MMPs without appreciably affecting the synthesis of TIMPs, locally secreted cytokines may tip the regional balance of MMP activity in favor of vascular matrix degradation.

Risk factors for end-stage renal disease among minorities.

Blacks, Hispanics, and American Indians are at increased risk of ESRD. Among blacks, hypertension, type II DM, and possibly type I DM are classic risk factors and pose an increased risk for disease. A unifying concept in both DM and hypertension appears to be increased glomerular pressures. The role of diuretics as an independent risk factor for ESRD is further advanced. At a minimum diuretics appear not to be renal protective. Glomerulonephritis also occurs more commonly in blacks. The underlying pathology is largely unknown. There is an increased rate of HAN- and HIV-associated nephropathy which does not explain the excess risk. Patterns of referral or other biases may be in effect. The increased incidence of ESRD in Hispanics is mainly related to DM although, hypertension also plays a role. There is also evidence that HIV-associated nephropathy may occur relatively more often than in whites. We have alluded to the increased incidence of ESRD among American Indians and noted that diabetes mellitus occurs more commonly in most tribal groups while glomerulonephritis occurs more frequently in the Zuni. That groups at increased risk of ESRD are at the lower spectrum of the SES raises this issue as a common risk factor for disease. It is unlikely that SES is an independent risk factor. Education, access to early interventions, and social behavioral factors must be incorporated into any model which proposes a reduction in the rate of ESRD in these groups. The treatment of hypertension with medications that may be renal protective or pose increased risk, especially insofar as diuretics are concerned, must be considered urgent grounds for future research.

Sources of urinary catecholamines in renal denervated transplant recipients.

When a human kidney is transplanted, sympathetic nerves to that kidney are cut. We infused 3H-noradrenaline and then measured noradrenaline, dopamine and 3H-noradrenaline levels in the plasma and urine of renal transplant recipients and uninephrectomized control subjects. Less than 10% of 3H-noradrenaline cleared from the plasma appeared in the urine. Noradrenaline and dopamine appeared in the urine of transplant recipients at one-third the rate of control subjects, even though 3H-noradrenaline levels were slightly higher in the urine of transplant recipients. Transplant patients had a noradrenaline clearance of 128 +/- 50 ml/min, compatible with simple glomerular filtration, while controls had a higher calculated clearance of 229 +/- 41 ml/min. Plasma dopamine levels were very low compared with urinary dopamine. These results suggest that two-thirds of renal noradrenaline and dopamine depend on the presence of renal nerves. Almost all urinary dopamine comes from the kidney. For noradrenaline, urinary excretion is a very minor pathway for clearance from the plasma.

Coping resources and depression in the caregiving spouses of Alzheimer patients.

This study deals with the self-rated impact of caring for a spouse with Alzheimer's disease at home. Impacts on the caregiver's marriage, work, recreation and mood were investigated as a function of the patient's disability level and of the coping resources which caregivers reported were available to and/or used by them. The patient's disability level had a more negative impact on the caregiver's marriage and recreation than did the coping resource variables whereas the reverse was true for work. The caregiver's work was the only life area in which the availability and mobilization of coping resources influenced the caregiver's level of depression. To clarify these results, additional regression analyses were conducted separately for homemakers and employed subjects. While mobilized coping resources (social activity level and homemaking activity level) were correlated with depression among homemakers, none of the indicators of mobilized coping resources was correlated with depression among workers. These findings suggest that the role in which stress occurs is an important factor in understanding stress and the coping process.

Norepinephrine clearance, chromogranin A and dopamine beta hydroxylase in renal failure.

Plasma norepinephrine (NE) levels are normal or elevated in patients with renal failure even though uremia often damages the sympathetic nerves that release NE. We infused 3H-NE into subjects with normal, mildly depressed, or absent renal function. 3H-NE clearance was depressed 20% in mild renal failure and 40% in patients on hemodialysis. The calculated rate of NE release into plasma was low in uremics even though their plasma NE was normal. Dopamine beta hydroxylase (D beta H) and chromogranin A are released from sympathetic nerve endings along with NE. D beta H levels were low in uremia and D beta H levels doubled following hemodialysis. Chromogranin A levels were very high in uremics and increased slightly following hemodialysis. Plasma clearance of both NE and chromogranin A appears low in renal failure. The calculated rate of NE release is diminished in uremics, which is in accord with reports of autonomic neuropathy in these patients.

Catecholamine and thyroid hormones in traumatic injury.

During hyperthyroidism, hypothyroidism, and severe stress there is often an inverse relationship between plasma norepinephrine (NE) and thyroid hormones. We evaluated this relationship in patients who were severely burned, patients who had injury to both brain and body, patients with head injury, and patients receiving high dose barbiturates for head injury. Head-injured patients had a low thyroxine (T4), low triiodothyronine (T3), and high reverse T3. Phenytoin for control of seizures lowered T3 and T4 and increased thyroid-stimulating hormone. Burned patients had a strong negative correlation between NE and T3 (r = -.88, p less than .001). Patients with injury to both brain and body had a weak negative correlation between NE and T3 (r = -.5, p = .06). Patients with head injury showed no correlation between NE and T3. Severely injured patients had a close inverse relationship between elevated NE levels and depressed T3 levels. This relationship appears to depend on an intact CNS, as the relationship was disrupted by head injury and barbiturates.

Atrial natriuretic factor in renal failure and posthemodialytic postural hypotension.

Atrial natriuretic factor (ANF) levels were ten times normal in hemodialysis patients before dialysis. ANF was not cleared by the dialyzer membrane but plasma levels decreased 47% by the end of dialysis. Patients undergoing peritoneal dialysis had plasma ANF levels four times normal and had detectable ANF in their dialysate. Hemodialysis patients with a marked fall in BP after dialysis had higher ANF levels (P less than 0.05) and lower norepinephrine (NE) levels (P less than 0.05) associated with a failure to increase NE in response to dialysis. Elevated ANF levels are associated with postdialysis hypotension in hemodialysis patients.

Difficulties in assessing depressive-like reactions to chronic severe external stress as exemplified by spouse caregivers of Alzheimer patients.

Problems in making differential diagnoses and severity ratings of depressive-like reactions in chronically, heavily stressed persons are described. These assessment concerns are especially pertinent to older persons. The assessment concern discussed relates to difficulties in determining the extent to which stress reactions are inevitable consequences of stressor demands versus excessive pathological reactions versus natural manifestations of aging. The newly revised criteria of the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III-R) and its associated structured interviews do not lessen the difficulties described. However, they reflect progress in specifying the amount of cross-sectional and longitudinal consistency required before maladaptive behaviours meet diagnostic and/or severity criteria as pathological indicators. Stressor level is important among the criteria for the less severe DSM-III-R depression-related disorders, but the specific response demands of the stressors are ignored. By contrast, biomedical factors are consistently given significant weight. To clarify these matters, the five DSM-III-R diagnostic axes, depressive diagnostic criteria, and associated structured interviews for eliciting relevant data are reviewed.

The stress of children's births: gender differences in the impact on alcoholics.

Previously reported gender differences regarding the role of discrete life change events in the onset of alcoholism are examined through a systematic evaluation of the histories of 586 alcoholics. Several methodological features of this research distinguish it from investigations reported in the past. The use of a structured, topically organized interview protocol eliminated possible biases introduced by gender differences in the tendency to attribute the onset of alcoholism to life change. The application of an actuarial analytic procedure allowed an examination of the temporal relationship between life change (births of children) and the onset of alcoholism and a restriction of the period of risk for the onset of alcoholism following discrete life change to two years. The focus on a single type of life change event, births of children, reflects an established concern with the role of gynecological events in the onset of alcoholism among women and allows of the general comparisons. Results indicate that, among those ever at risk of first experiencing alcohol-related problems during the two year period following the birth of a child, males show a statistically significantly higher percentage with the onset of alcoholism during this time period than do females. The birth of a first child was found to be most strongly related to the development of problem drinking. Among males, but not among females, the birth of a first child was also found to follow the onset of alcoholism by two years in a significant number of cases.

The measurement of multiple drug use and its relationship to the patterning of alcohol intake.

The increasing prevalence of multiple drug use among adolescents presents researchers with complex conceptual and measurement issues. This work examines definitions of and indicators of multiple drug use involvement, as well as the interrelationships between indices of drug involvement incorporating different dimensions. Data regarding the relationship between patterns of alcohol use and illicit drug use in a population of 1473 teenagers interviewed in a northwestern metropolitan community indicate that : (1) regardless of the dimensions incorporated into four different indices of drug involvement examined, intercorrelations between indices were strong; (2) although the correlations between indices of drug involvement and overall levels of alcohol intake were uniformly weak, it was shown that levels of drug involvement vary directly with the maximum volume of alcohol used. Although the results of the current investigation must be viewed cautiously because of the concentration of heavy users of both alcohol and drugs in the population upon which the research is based, among adolescents, the spacing of drinking episodes and the patterning of alcohol intake may be more important determinants of polydrug involvement thant the quantity of alcohol consumed.