Does PGA external stenting reduce compliance mismatch in venous grafts?

Background: Autogenous vein grafting is widely used in regular bypassing procedures. Due to its mismatch with the host artery in both mechanical property and geometry, the graft often over expands under high arterial blood pressure and forms a step-depth where eddy flow develops, thus causing restenosis, fibrous graft wall, etc. External stents, such as sheaths being used to cuff the graft, have been introduced to eliminate these mismatches and increase the patency. Although histological and immunochemical studies have shown some positive effects of the external stent, the mechanical mismatch under the protection of an external stent remains poorly analyzed. Methods: In this study, the jugular veins taken from hypercholesterolemic rabbits were transplanted into the carotid arteries, and non-woven polyglycolic acid (PGA) fabric was used to fabricate the external stents to study the effect of the biodegradable external stent. Eight weeks after the operation, the grafts were harvested to perform mechanical tests and histological examinations. An arc tangent function was suggested to describe the relationship between pressure and cross-sectional area to analyse the compliance of the graft. Results: The results from the mechanical tests indicated that grafts either with or without external stents displayed large compliance in the low-pressure range and were almost inextensible in the high-pressure range. This was very different from the behavior of the arteries or veins in vivo. The data from histological tests showed that, with external stents, collagen fibers were more compact, whilst those in the graft without protection were looser and thicker. No elastic fiber was found in either kind of grafts. Furthermore, grafts without protection were over-expanded which resulted in much bigger cross-sectional areas. Conclusion: The PGA external extent contributes little to the reduction of the mechanical mismatch between the graft and its host artery while remodeling develops. For the geometric mismatch, it reduces the cross-section area, therefore matching with the host artery much better. Although there are some positive effects, conclusively the PGA is not an ideal material for external stent.

The bentiromide test using plasma p-aminobenzoic acid for diagnosing pancreatic insufficiency in young children. The effect of two different doses and a liquid meal

The bentiromide test was evaluated using plasma p-aminobenzoic acid as an indirect test of pancreatic insufficiency in young children between 2 months and 4 years of age. To determine the optimal test method, the following were examined: (a) the best dose of bentiromide (15 mg/kg or 30 mg/kg); (b) the optimal sampling time for plasma p-aminobenzoic acid, and; (c) the effect of coadministration of a liquid meal. Sixty-nine children (1.6 ± 1.0 years) were studied, including 34 controls with normal fat absorption and 35 patients (34 with cystic fibrosis) with fat maldigestion due to pancreatic insufficiency. Control and pancreatic insufficient subjects were studied in three age-matched groups: (a) low-dose bentiromide (15 mg/kg) with clear fluids; (b) high-dose bentiromide (30 mg/kg) with clear fluids, and; (c) high-dose bentiromide with a liquid meal. Plasma p-aminobenzoic acid was determined at 0, 30, 60, and 90 minutes then hourly for 6 hours. The dose effect of bentiromide with clear liquids was evaluated. High-dose bentiromide best discriminated control and pancreatic insufficient subjects, due to a higher peak plasma p-aminobenzoic acid level in controls, but poor sensitivity and specificity remained. High-dose bentiromide with a liquid meal produced a delayed increase in plasma p-aminobenzoic acid in the control subjects probably caused by retarded gastric emptying. However, in the pancreatic insufficient subjects, use of a liquid meal resulted in significantly lower plasma p-aminobenzoic acid levels at all time points; plasma p-aminobenzoic acid at 2 and 3 hours completely discriminated between control and pancreatic insufficient patients. Evaluation of the data by area under the time-concentration curve failed to improve test results. In conclusion, the bentiromide test is a simple, clinically useful means of detecting pancreatic insufficiency in young children, but a higher dose administered with a liquid meal is recommended.

'Work it out': Evaluation of a chronic condition self-management program for urban Aboriginal and Torres Strait Islander people with or at risk of cardiovascular disease

This thesis evaluates a chronic condition self-management program for Aboriginal and Torres Strait Islander people in urban south-east Queensland who have or are at risk of cardiovascular disease. Outcomes showed short-term improvements for some anthropometry measures which could be a trend for improvement in other anthropometry indicators over the longer term. The program was of particular benefit for participants who had several social and emotional wellbeing conditions. The use of an Aboriginal and Torres Strait Islander conceptual framework was critical in undertaking culturally competent quantitative research in this project.

Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children

Background Guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) around the world vary greatly. Most institutions recommend the use of heparin to prevent occlusion, however there is debate regarding the need for heparin and evidence to suggest 0.9% sodium chloride (normal saline) may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased cost. Objectives To assess the clinical effects (benefits and harms) of intermittent flushing of heparin versus normal saline to prevent occlusion in long term central venous catheters in infants and children. Search Methods The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (Issue 3, 2015). We also searched the reference lists of retrieved trials. Selection criteria Randomised controlled trials that compared the efficacy of normal saline with heparin to prevent occlusion of long term CVCs in infants and children aged up to 18 years of age were included. We excluded temporary CVCs and peripherally inserted central catheters (PICC). Data Collection and Analysis Two review authors independently assessed trial inclusion criteria, trial quality and extracted data. Rate ratios were calculated for two outcome measures - occlusion of the CVC and central line-associated blood stream infection. Other outcome measures included duration of catheter placement, inability to withdraw blood from the catheter, use of urokinase or recombinant tissue plasminogen, incidence of removal or re-insertion of the catheter, or both, and other CVC-related complications such as dislocation of CVCs, other CVC site infections and thrombosis. Main Results Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin, however, between studies, all used different protocols for the standard and experimental arms with different concentrations of heparin and different frequency of flushes reported. In addition, not all studies reported on all outcomes. The quality of the evidence ranged from low to very low because there was no blinding, heterogeneity and inconsistency between studies was high and the confidence intervals were wide. CVC occlusion was assessed in all three trials (243 participants). We were able to pool the results of two trials for the outcomes of CVC occlusion and CVC-associated blood stream infection. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). The duration of catheter placement was reported to be similar between the two study arms, in one study (203 participants). Authors' Conclusions The review found that there was not enough evidence to determine the effects of intermittent flushing of heparin versus normal saline to prevent occlusion in long term central venous catheters in infants and children. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.

Age-related alterations of immunoreactive pancreatic cationic trypsinogen in sera from cystic fibrosis patients with and without pancreatic insufficiency

Serum immunoreactive cationic trypsinogen levels were determined in 99 control subjects and 381 cystic fibrosis (CF) patients. To evaluate the status of the exocrine pancreas all CF patients had previously undergone fecal fat balance studies and/or pancreatic stimulation tests. Three hundred fourteen CF patients had fat malabsorption and/or had inadequate pancreatic enzyme secretion (pancreatic insufficiency) requiring oral pancreatic enzyme supplements with meals. Sixty-seven CF patients did not have fat malabsorption and/or had adequate enzyme secretion (pancreatic sufficiency) and were not receiving pancreatic enzyme supplements with meals. Mean serum trypsinogen in 99 control subjects was 31.4 ± 14.8 /µg/hter (± 2 SD) and levels did not vary with age or sex. In CF infants (< 2 yr) with pancreatic insufficiency, mean serum trypsinogen was significantly above the non-CF values (p < 0.001). Ninety-one percent of the CF infants had elevated levels. Serum trypsinogen values in the pancreatic insuffi ient group declined steeply up to 5 years, reaching subnormal values by age 6. An equation was developed which described these age-related changes very accurately. Only six CF patients with pancreatic insufficiency had serum trypsinogen levels above the 95% confidence limits of this equation. In contrast, there was no age related decline in serum trypsinogen among the CF group with pancreatic sufficiency. Under 7 yr, serum trypsinogen failed to distinguish the two groups. In those over 7 yr of age, however, serum trypsinogen was significantly higher than the CF group with pancreatic insufficiency (p < 0.001), and 93% had values within or above the control range. In conclusion, serum trypsinogen appears to be a useful screening test for CF in infancy. Between 2 and 7 yr of age this test is of little diagnostic value. After 7 yr of age, serum trypsinogen can reliably distinguish between CF patients with and without pancreatic insufficiency.

Role of pharmacists in collaborative care of travellers with chronic conditions

We refer to a paper recently published in the Journal of travel Medicine and Infectious Disease where clinicians have been shown to have in have many questions related to travellers to multiple destinations, going for prolonged duration of travel, with chronic medical conditions, and potential drug interactions.[1] This study highlighted the inadequacy of available information sources to resolve the wide range of different medical issues for travellers. In addition, the study also highlighted the significance of collaboration in travel health...

Risk factors for delayed healing in venous leg ulcers: A review of the literature [Letter]

We thank Andrea Cariati for his comments in response to our article on ‘Risk factors for delayed healing in venous leg ulcers: a review of the literature’. The relationship between lymphoedema and venous disease has not yet been well explored and we acknowledge that impairment of lymph flow may be a risk factor for delayed healing of venous leg ulcers...

Rituximab for chronic fatigue syndrome?

Most people complain about being tired and wish they could sleep in for a few more hours instead of going to work. However, 'being tired' has a whole different meaning for people living with chronic fatigue syndrome, which is also known as myalgic encephalomyelitis.

Commentary: Chronic SSRI stimulation of astrocytic 5-HT2B receptors change multiple gene expressions/editings and metabolism of glutamate, glucose and glycogen: A potential paradigm shift

Working on the serotonin (5-hydroxytryptamine, 5-HT) 5-HT2B receptor since several years, we have read with high interest the review by Hertz et al. (2015). Previous studies from our group demonstrated that a direct injection in mouse raphe nucleus of the 5-HT2B agonist BW723C86 has the ability to increase extracellular levels of serotonin, which can be blocked by the selective 5-HT2B receptor antagonist RS127445 (Doly et al., 2008, 2009). We also reported that an acute injection of paroxetine 2 mg/kg in mice knocked out for the 5-HT2B receptor gene or in wild type mice injected with RS127445 (0.5 mg/kg) triggers a strong reduction in extracellular accumulation of 5-HT in hippocampus (Diaz et al., 2012). Following these observations, we showed that acute and chronic BW723C86 injection (3 mg/kg) can mimic the fluoxetine (3 mg/kg) and paroxetine (1 mg/kg) behavioral and biochemical antidepressant effects in mice (Diaz and Maroteaux, 2011; Diaz et al., 2012)...

Relations between chronic regulatory focus and future time perspective: Results of a cross-lagged structural equation model

Future time perspective - the way individuals perceive their remaining time in life - importantly influences socio-emotional goals and motivational outcomes. Recently, researchers have called for studies that investigate relationships between personality and future time perspective. Using a cross-lagged panel design, this study investigated effects of chronic regulatory focus dimensions (promotion and prevention orientation) on future time perspective dimensions (focus on opportunities and limitations). Survey data were collected two times, separated by a 3. month time lag, from 85 participants. Results of structural equation modeling showed that promotion orientation had a positive lagged effect on focus on opportunities, and prevention orientation had a positive lagged effect on focus on limitations.

Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise

Dietary nitrate (NO3−) supplementation with beetroot juice (BR) over 4–6 days has been shown to reduce the O2 cost of submaximal exercise and to improve exercise tolerance. However, it is not known whether shorter (or longer) periods of supplementation have similar (or greater) effects. We therefore investigated the effects of acute and chronic NO3− supplementation on resting blood pressure (BP) and the physiological responses to moderate-intensity exercise and ramp incremental cycle exercise in eight healthy subjects. Following baseline tests, the subjects were assigned in a balanced crossover design to receive BR (0.5 l/day; 5.2 mmol of NO3−/day) and placebo (PL; 0.5 l/day low-calorie juice cordial) treatments. The exercise protocol (two moderate-intensity step tests followed by a ramp test) was repeated 2.5 h following first ingestion (0.5 liter) and after 5 and 15 days of BR and PL. Plasma nitrite concentration (baseline: 454 ± 81 nM) was significantly elevated (+39% at 2.5 h postingestion; +25% at 5 days; +46% at 15 days; P < 0.05) and systolic and diastolic BP (baseline: 127 ± 6 and 72 ± 5 mmHg, respectively) were reduced by ∼4% throughout the BR supplementation period (P < 0.05). Compared with PL, the steady-state V̇o2 during moderate exercise was reduced by ∼4% after 2.5 h and remained similarly reduced after 5 and 15 days of BR (P < 0.05). The ramp test peak power and the work rate at the gas exchange threshold (baseline: 322 ± 67 W and 89 ± 15 W, respectively) were elevated after 15 days of BR (331 ± 68 W and 105 ± 28 W; P < 0.05) but not PL (323 ± 68 W and 84 ± 18 W). These results indicate that dietary NO3− supplementation acutely reduces BP and the O2 cost of submaximal exercise and that these effects are maintained for at least 15 days if supplementation is continued.

Chronic disease risks and use of a smartphone application during a physical activity and dietary intervention in Australian truck drivers

- Objective This study examined chronic disease risks and the use of a smartphone activity tracking application during an intervention in Australian truck drivers (April-October 2014). - Methods Forty-four men (mean age=47.5 [SD 9.8] years) completed baseline health measures, and were subsequently offered access to a free wrist-worn activity tracker and smartphone application (Jawbone UP) to monitor step counts and dietary choices during a 20-week intervention. Chronic disease risks were evaluated against guidelines; weekly step count and dietary logs registered by drivers in the application were analysed to evaluate use of the Jawbone UP. - Results Chronic disease risks were high (e.g. 97% high waist circumference [≥94 cm]). Eighteen drivers (41%) did not start the intervention; smartphone technical barriers were the main reason for drop out. Across 20-weeks, drivers who used the Jawbone UP logged step counts for an average of 6 [SD 1] days/week; mean step counts remained consistent across the intervention (weeks 1–4=8,743[SD 2,867] steps/day; weeks 17–20=8,994[SD 3,478] steps/day). The median number of dietary logs significantly decreased from start (17 [IQR 38] logs/weeks) to end of the intervention (0 [IQR 23] logs/week; p<0.01); the median proportion of healthy diet choices relative to total diet choices logged increased across the intervention (weeks 1–4=38[IQR 21]%; weeks 17–20=58[IQR 18]%). - Conclusions Step counts were more successfully monitored than dietary choices in those drivers who used the Jawbone UP. - Implications Smartphone technology facilitated active living and healthy dietary choices, but also prohibited intervention engagement in a number of these high-risk Australian truck drivers.

Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).