Day: 06/11/2013

Extreme Bilirubin Levels as a Causal Risk Factor for Symptomatic Gallstone Disease.

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Importance  In individuals without blockage of their bile ducts, levels of plasma bilirubin likely reflect levels of biliary bilirubin; higher biliary bilirubin levels may increase the risk of gallstone disease.

Objective  To test the hypothesis that a lifelong increase in plasma bilirubin levels is a causal risk factor for symptomatic gallstone disease in the general population.

Design, Setting, and Participants  In a prospective study of the Danish general population (N = 61 212), we first tested whether elevated levels of plasma bilirubin predicted greater risk of symptomatic gallstone disease. Second, taking advantage of mendelian randomization, we tested whether a genetic variant in the bilirubin glucoronidating enzyme UGT1A1 (rs6742078) was associated with increased plasma bilirubin levels and, in turn, with an increased risk of symptomatic gallstone disease.

Main Outcomes and Measures  Plasma bilirubin level and symptomatic gallstone disease.

Results  During 34 years of follow-up, 3374 individuals developed symptomatic gallstone disease. In adjusted analyses, persons with plasma bilirubin levels in the 10th decile had a greater risk of symptomatic gallstone disease compared with those with plasma bilirubin levels in deciles 1 through 9; the hazard ratios (HRs) (95% CIs) were 1.57 (1.26-1.96) overall, 1.36 (1.02-1.82) in women, and 2.00 (1.41-2.83) in men. UGT1A1 genotype explained 20% of the total variation in plasma bilirubin levels and was associated with increases in the mean plasma bilirubin level overall of +16% (+0.09 mg/dL) in GT heterozygotes and +90% (+0.50 mg/dL) in TT homozygotes compared with GG homozygotes, with similar effects in women and men (P for trend <.001 for all). The corresponding HRs (95% CIs) for symptomatic gallstone disease were 1.09 (1.02-1.17) for GT heterozygotes and 1.22 (1.09-1.36) for TT homozygotes vs GG homozygotes and similar in women and men (P for trend = .04-<.001).

Conclusions and Relevance  These results are compatible with a causal association between extreme levels of plasma bilirubin and increased risk of symptomatic gallstone disease.

Source: JAMA

 

Association Between Hypoglycemia and Dementia in a Biracial Cohort of Older Adults With Diabetes .

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Importance  Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia.

Objective  To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM.

Design and Setting  Prospective population-based study.

Participants  We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher.

Main Outcome Measures  Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records.

Results  During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0-4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%,P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5-6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results.

Conclusion and Relevance  Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia.

The growing body of evidence that diabetes mellitus (DM) may increase risk for developing cognitive impairment, including Alzheimer disease and vascular dementia,1– 2 has prompted interest in whether DM treatment can prevent cognitive decline. Glycemic control has been proposed as a potential mechanism to improve cognitive outcomes among those with DM.1,3 However, trials evaluating the benefit of glycemic control have also highlighted the risk for hypoglycemia with intensive therapy.4– 6

The brain uses glucose as a primary source of energy. Cognitive function becomes impaired when blood glucose drops to low levels,7 and severe hypoglycemia may cause neuronal damage.7– 9Although the acute effects of hypoglycemia have been well documented, it is unclear if the cognitive effects of hypoglycemia are persistent. Results from the few investigations of hypoglycemia and cognitive impairment have been conflicting, with some studies10– 11 reporting an association but not other studies.12– 13 In addition, little is known about the cognitive effects of hypoglycemia occurring in late life, when the brain may be more vulnerable.14

The direction of the association between hypoglycemia and cognitive impairment is also debated. Those with dementia or even milder forms of cognitive impairment may be less able to effectively manage complex DM behavioral and treatment regimens and recognize the symptoms of hypoglycemia and respond appropriately, increasing the risk for severe hypoglycemia.13,15– 19Whether a bidirectional association exists, in which hypoglycemia increases the risk for dementia and dementia increases the risk for hypoglycemia, has not been determined to our knowledge. Because the incidence of both hypoglycemia and dementia increases with age and duration of DM,20– 21 a better understanding of the association between hypoglycemia and dementia is needed.

We prospectively examined the association between severe hypoglycemia and dementia in a biracial cohort of community-dwelling older adults with DM and without dementia at baseline. We hypothesized that severe hypoglycemia would be associated with an increased risk for dementia and that those diagnosed as having dementia would be at an increased risk for severe hypoglycemia.

DISCUSSION

Among older adults with DM who were without evidence of cognitive impairment at study baseline, we found that clinically significant hypoglycemia was associated with a 2-fold increased risk for developing dementia and a number needed to harm of 5.9. Similarly, participants with dementia were more likely to experience a severe hypoglycemic event, with a number needed to harm of 12.7. The association remained even after adjustment for age, sex, educational level, race/ethnicity, comorbidities, and other covariates. These results provide evidence for a reciprocal association between hypoglycemia and dementia among older adults with DM.

Previous studies of hypoglycemia and cognitive impairment in older adults have had mixed results. Findings from a retrospective study10 conducted using the Kaiser Permanente Northern California Diabetes Registry demonstrated an almost 2-fold increased risk for dementia among older adults with DM who had a history of 1 or more hypoglycemic episodes. Risk was even greater for those with multiple episodes. Similarly, a population-based cross-sectional study11 found that a lifetime history of severe hypoglycemia was associated with poor late-life cognition, independent of premorbid cognition. Our investigation expands on these studies by prospectively investigating severe hypoglycemia and dementia among older adults who were initially free of cognitive impairment, allowing for a better evaluation of temporality. We were also able to assess the possible scenario that preclinical cognitive impairment is associated with greater risk for severe hypoglycemia and in turn with risk for dementia. Most importantly, after adjustment for change in global cognitive function, severe hypoglycemia remained associated with risk for developing dementia.

In contrast, the Fremantle Diabetes Study13 found no evidence that a history of hypoglycemia was associated with cognitive decline among older adults with normal cognition at baseline, although the short follow-up duration may have limited the ability to detect differences. The Diabetes Control and Complications Trial also did not find an association between hypoglycemia and cognitive impairment among younger adults with type 1 DM.12 Varied results may possibly be due to differences in cohort demographics, frequency or severity of hypoglycemia, or age at which the hypoglycemic event occurred. Older individuals have a higher incidence of hypoglycemia20 and may be more susceptible to adverse cognitive effects than younger age groups.14 Hypoglycemia may also differentially influence cognition depending on overall brain health, perhaps aggravating underlying pathologic conditions or triggering the onset of neurodegenerative processes.

Hypoglycemia may contribute to the pathogenesis of dementia through several possible mechanisms. Recurrent severe hypoglycemia has been shown to result in brain damage,7 with preferential vulnerability found in the cerebral cortex and hippocampus.7– 9 Some evidence suggests that neuronal damage resulting from hypoglycemia may be enhanced in DM compared with non-DM brains, perhaps due to altered glucose metabolism or through insulin deficiency.8Hypoglycemia may cause a loss of ionic homeostasis or increases in reactive oxygen species that can lead to neuronal death.9 Amyloid precursor protein may also be produced as a result of damage.26 In addition, insulin resistance and hyperinsulinemia may have a role in neurodegeneration through disrupting the normal function of insulin within the brain.27 Insulin may affect the metabolism of amyloid beta and tau proteins, and chronic hyperinsulinemia may exacerbate inflammatory markers and oxidative stress.28 Cerebrovascular disease is another potential mechanism. Pathologic microinfarcts have been shown to contribute to brain atrophy and cognitive impairment.29 Although we adjusted for stroke and MI and results were robust, we cannot rule out residual confounding, and we had no information on microinfarcts.

Our finding of a higher risk for hypoglycemia with dementia adds to a small body of literature demonstrating a greater incidence of hypoglycemia with impaired cognitive function.13,18– 19,30However, to our knowledge, no known prior study has prospectively evaluated the association between dementia and severe hypoglycemia among a diverse group of older individuals initially free of dementia. The heightened risk for hypoglycemia among those with dementia may reflect difficulties in managing DM. Insulin therapy13,30 and reported inability to self-manage DM medications13 have been previously identified as additional risk factors for hypoglycemia among those with cognitive impairment. Cognitive dysfunction, including dementia and milder forms of impairment, may also delay recognition of the symptoms of hypoglycemia and interfere with a patient’s ability to respond with corrective measures. Older adults have been shown to be less aware of the symptoms of hypoglycemia than younger persons31; however, it is unknown if this is more pronounced among those with cognitive impairment. More studies are needed to identify risk factors and effective management strategies to reduce the incidence of hypoglycemia among older persons with dementia, as well as in those with less severe forms of cognitive impairment.

Our findings emphasize the importance of cognitive function in the clinical management of older adults with DM. Certain medications known to carry a higher risk for hypoglycemia, such as insulin secretagogues and some sulfonylureas,20 may be inappropriate for older patients with or at risk for cognitive impairment. While physicians should be aware of the higher risk for hypoglycemia in patients with dementia because symptoms of hypoglycemia in older adults could be misinterpreted,20,32 delaying treatment, they should also consider the implications for the management and care of patients with lesser, subclinical levels of cognitive dysfunction. In addition, caretakers may not know the symptoms and treatment of hypoglycemia, and educational efforts may be needed.

This study has several strengths, including a prospective design with a long follow-up period and a large, diverse sample of community-dwelling older adults. Participants were free of dementia at study baseline, and we were able to assess temporality of hypoglycemia and dementia. Hypoglycemia was based on hospital records, which is a more objective measure than self-report. We were also able to adjust for multiple confounders. However, several study limitations also warrant consideration. While we tried to highlight the association of hypoglycemia and dementia defined by clinically important measures (hospitalization diagnostic codes or medication use), we were unable to investigate the effects of subclinical outcomes, such as moderate hypoglycemia or milder forms of cognitive impairment, nor were we able to include history of hypoglycemia before baseline. Although our case definition for dementia was likely very specific, it was probably insensitive to mild cases of cognitive impairment. In this context, power would most likely be affected, but the point estimate for the effect of hypoglycemia on dementia would not be biased.33In addition, we had no brain magnetic resonance imaging measures, which may have helped to ascertain the subtype of dementia.

In summary, our results provide evidence for a bidirectional association between severe hypoglycemia and dementia. Hypoglycemia may impair cognitive health, and reduced cognitive function may increase the risk for a hypoglycemic event that could further compromise cognition, resulting in a detrimental cycle. Cognitive function should be considered in the clinical management of older individuals with DM.

Source: JAMA

Vegetarian Dietary Patterns and Mortality in Adventist Health Study 2.

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Importance  Some evidence suggests vegetarian dietary patterns may be associated with reduced mortality, but the relationship is not well established.

Objective  To evaluate the association between vegetarian dietary patterns and mortality.

Design  Prospective cohort study; mortality analysis by Cox proportional hazards regression, controlling for important demographic and lifestyle confounders.

Setting  Adventist Health Study 2 (AHS-2), a large North American cohort.

Participants  A total of 96 469 Seventh-day Adventist men and women recruited between 2002 and 2007, from which an analytic sample of 73 308 participants remained after exclusions.

Exposures  Diet was assessed at baseline by a quantitative food frequency questionnaire and categorized into 5 dietary patterns: nonvegetarian, semi-vegetarian, pesco-vegetarian, lacto-ovo–vegetarian, and vegan.

Main Outcome and Measure  The relationship between vegetarian dietary patterns and all-cause and cause-specific mortality; deaths through 2009 were identified from the National Death Index.

Results  There were 2570 deaths among 73 308 participants during a mean follow-up time of 5.79 years. The mortality rate was 6.05 (95% CI, 5.82-6.29) deaths per 1000 person-years. The adjusted hazard ratio (HR) for all-cause mortality in all vegetarians combined vs nonvegetarians was 0.88 (95% CI, 0.80-0.97). The adjusted HR for all-cause mortality in vegans was 0.85 (95% CI, 0.73-1.01); in lacto-ovo–vegetarians, 0.91 (95% CI, 0.82-1.00); in pesco-vegetarians, 0.81 (95% CI, 0.69-0.94); and in semi-vegetarians, 0.92 (95% CI, 0.75-1.13) compared with nonvegetarians. Significant associations with vegetarian diets were detected for cardiovascular mortality, noncardiovascular noncancer mortality, renal mortality, and endocrine mortality. Associations in men were larger and more often significant than were those in women.

Conclusions and Relevance  Vegetarian diets are associated with lower all-cause mortality and with some reductions in cause-specific mortality. Results appeared to be more robust in males. These favorable associations should be considered carefully by those offering dietary guidance.

Source: JAMA

 

 

Vemurafenib and Radiosensitization.

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Importance  The BRAF inhibitor, vemurafenib, was recently approved for the treatment of patients with BRAFV600 metastatic melanoma. Wider use of this drug and longer follow-up periods of treatment are resulting in the emergence of a growing number of reports detailing new adverse effects. Cutaneous adverse effects are preeminent with UV-A–dependent phototoxicity, hyperkeratotic folliculitis, hand-foot skin reaction, hair changes, verrucous papillomas, keratoacanthomas, and squamous cell carcinomas.

Observations  We report 2 cases of dermatitis occurring on a previously irradiated skin area in patients treated with vemurafenib for a BRAFV600-mutated metastatic melanoma. The first case occurred 10 days after a low dose of radiation was delivered that usually does not induce any radiodermatitis, suggesting radiosensitization by vemurafenib. The second case occurred 30 days after radiotherapy and was diagnosed as radiation recall dermatitis.

Conclusions and Relevance  Vemurafenib should be considered a potential cutaneous radiosensitizer and an inducer of radiation recall dermatitis. However, these adverse effects are easily managed with topical corticosteroids. Dose reduction or interruption of vemurafenib is not required. Further studies and reports will enlighten us as to whether this pharmacodynamic interaction between x-rays and vemurafenib is also seen with other BRAF or MEK inhibitors on the same mitogen-activated protein kinase pathway currently under development.

Source: JAMA

 

Sodium Reduction in PopulationsInsights From the Institute of Medicine Committee.

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The recent Institute of Medicine (IOM) report regarding dietary sodium1 has generated considerable interest and debate, as well as misinterpretation by advocates on both sides. Further discussion is necessary to inform the public and the health care community and to inform public health strategies for sodium reduction.

CURRENT PUBLIC HEALTH RECOMMENDATIONS REGARDING DIETARY SODIUM

Dietary sodium intake averages approximately 3400 mg/d in US adults, far in excess of the Dietary Guidelines for Americans (DGA) recommendation of less than 2300 mg/d for those older than 2 years and less than 1500 mg/d for certain high-risk subgroups, including African Americans, individuals with hypertension, diabetes, or chronic kidney disease (CKD), or those older than 50 years.2 In contrast, the 2005 IOM Panel on Dietary Reference Intakes (DRI) for Water, Potassium, Sodium, Chloride, and Sulfate3 found insufficient evidence to derive a “recommended dietary allowance” for sodium. Instead, an “adequate intake” of 1500 mg/d of dietary sodium was determined, reflecting the minimum needed to achieve a diet adequate in essential nutrients and to cover sweat losses. Additionally, the 2005 IOM panel established a “tolerable upper intake level,” using projections from available data on the effects on blood pressure, that consumption up to 2300 mg/d was unlikely to cause harm.

Based on the strength of the blood pressure data, various US (eg, American Heart Association [AHA]) and international (eg, World Health Organization [WHO]) organizations published recommendations for sodium consumption.4– 5 Although these recommendations were somewhat different from the DGA, there was general agreement that sodium consumption is excessive worldwide and should be reduced. Despite these recommendations, more than 90% of US adults consume more than 2300 mg of sodium per day, and among the high-risk subgroups more than 98% consume more than 1500 mg of sodium per day.6

A substantial body of evidence supports efforts to reduce sodium intake. This evidence links excessive dietary sodium to high blood pressure, stroke, and cardiovascular disease (CVD).1However, effects of sodium on blood pressure cannot always be disentangled from effects of total dietary modification, and effects of other electrolytes on blood pressure remain unresolved.7Concerns have been raised that a very low sodium intake may adversely affect lipids, insulin resistance, renin, and aldosterone levels and potentially may increase risk of CVD and stroke. Some studies link sodium intakes of less than 2300 mg/d to increased risk of CVD, at least in subpopulations. Thus, debate emerged about the sodium intake target that best improves health outcomes.

In response, the US Centers for Disease Control and Prevention commissioned the IOM to convene an expert committee to examine the designs, methods, and conclusions of literature published since the 2005 DRI report.3 Specifically, the committee was asked to review and assess potential benefits and adverse outcomes of reducing sodium intake in the population, particularly in the range of 1500 to 2300 mg/d, with emphasis on the high-risk subgroups. The committee was asked to focus on studies of direct health outcomes (vs surrogate end points such as blood pressure), to comment on implications for population-based strategies to reduce sodium intake, and to identify methodologic gaps and ways to address them. The committee’s full report is published elsewhere.1

SODIUM AND DIRECT HEALTH OUTCOMES

The committee searched literature published through 2012 for relevant publications. Information also was gathered from an open public workshop. Although not its primary emphasis, the committee summarized studies published since 2003 evaluating intermediate markers, particularly blood pressure. Focusing on CVD outcomes, the committee’s assessment of evidence was guided by factors such as study design, quantitative measures of dietary sodium intake, confounder adjustment, and number and consistency of available studies.

FINDINGS AND CONCLUSIONS

General US Population. Studies linking dietary sodium intake with direct health outcomes were highly variable in methodological quality; limitations included overreporting or underreporting of sodium intake. However, when considered collectively, the evidence on direct health outcomes indicates a positive relationship between higher levels of sodium intake and risk of CVD, consistent with the known effects of sodium intake on blood pressure. Furthermore, in some studies, the association between sodium and CVD outcomes persisted after adjusting for blood pressure, suggesting that associations between sodium and CVD may be mediated through other factors (eg, effects of other electrolytes) or through pathways other than blood pressure.

Studies evaluating sodium intake in the range of 1500 to 2300 mg/d demonstrate evidence of blood pressure lowering, but no studies have examined sodium intake in that range in the general population and direct CVD outcomes. The committee found that studies on direct health outcomes were of inconsistent quality and insufficient quantity to conclude whether sodium intake of less than 2300 mg/d was associated with either a greater or lesser risk of CVD.

Population Subgroups. The committee reviewed multiple randomized trials conducted by a single team that indicated low sodium intake (up to 1840 mg/d) may lead to greater risk of adverse events in patients with heart failure (HF) with reduced ejection fraction who received aggressive therapeutic regimens. Because these therapeutic regimens were different from standard US practice, trials using regimens that more closely resemble standard US clinical practice are needed. Of note, due to allegations of duplicate publication in 2 of these trials, a meta-analysis including them was recently retracted, after the IOM report’s completion.8 Another recently published small randomized trial involving patients with acute decompensated HF showed no benefit on weight or clinical stability from a combination of sodium and fluid restriction.9

The committee reviewed 2 related studies in individuals with prehypertension that suggested benefit from lowering sodium intake to 2300 mg/d and perhaps lower, although these studies were based on small numbers of persons with sodium intake in the less than 2300 mg/d range. In contrast, for patients with diabetes, CKD, or preexisting CVD, the committee found no evidence of benefit and some evidence suggesting risk of adverse health outcomes at sodium intake of 1500 to 2300 mg/d. In studies that explored statistical interactions, race, age, hypertension, and diabetes did not modify associations of sodium with health outcomes. The committee concluded that, with the exception of heart failure, evidence of both benefit and harm is not strong enough to indicate that these subgroups should be treated differently from the general US population. Thus, the committee also concluded that evidence on direct health outcomes does not support recommendations to lower sodium intake within these subgroups to or even less than 1500 mg/d.

IMPLICATIONS FOR POPULATION-BASED STRATEGIES TO GRADUALLY REDUCE SODIUM INTAKE

Although not asked to specify targets for dietary sodium, the committee noted factors that precluded establishing these targets. These include lack of consistency in methods for defining sodium intakes at both high and low ends of typical intakes and extreme variability in intake levels across studies. The committee could only consider sodium intake levels within the context of each individual study because there were impediments to calibrating sodium assessment measures across studies.

After release of the IOM report, several news outlets highlighted disagreement among health agencies about targets for dietary sodium intake and reported that experts disagreed about the importance of blood pressure. Focusing the debate on specific targets misses the larger conclusion with which all are in agreement and may hinder implementation of important public health policy. Rather than focusing on disagreements about specific targets that currently affect less than 10% of the US population (ie, sodium intake of <2300 mg/d vs <1500 mg/d), the IOM, AHA, WHO, and DGA are congruent in suggesting that excess sodium intake should be reduced, and this is likely to have significant public health effects. Accomplishing such a reduction will require efforts to decrease sodium in the food environment10 and provide individual consumers more choice in their dietary consumption of sodium.

REFERENCES

1

Institute of Medicine.  Sodium Intake in Populations: Assessment of Evidence. Washington, DC: National Academies Press.http://www.iom.edu/Reports/2013/Sodium-Intake-in-Populations-Assessment-of-Evidence.aspx. May 2013. Accessed June 4, 2013

2

US Department of Agriculture and US Department of Health and Human Services.  Dietary Guidelines for Americans, 2010. 7th ed. Washington, DC: US Government Printing Office; 2010

3

Institute of Medicine.  Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: National Academies Press; 2005

4

Appel LJ, Frohlich ED, Hall JE,  et al.  The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association.  Circulation. 2011;123(10):1138-1143
PubMed   |  Link to Article

5

World Health Organization.  Guideline: Sodium Intake for Adults and Children. Geneva, Switzerland: World Health Organization; 2012

6

Cogswell ME, Zhang Z, Carriquiry AL,  et al.  Sodium and potassium intakes among US adults: NHANES 2003-2008.  Am J Clin Nutr. 2012;96(3):647-657
PubMed   |  Link to Article

7

US Department of Agriculture and US Department of Health and Human Services.  Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2010, to the Secretary of Agriculture and the Secretary of Health and Human Services. Washington, DC: USDA/ARS; 2010

8

Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis [retraction]. heart.bmj.com/content/early/2013/03/12/heartjnl-2012-302337.extract. Accessed May 23, 2013

9

Aliti GB, Rabelo ER, Clausell N, Rohde LE, Biolo A, Beck-da-Silva L. Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial.  JAMA Intern Med
PubMed  |  Link to Article

10

Institute of Medicine.  Strategies to Reduce Sodium Intake in the United States. Washington, DC: National Academies Press; 2010

Source: JAMA

Bariatric Surgery for Weight Loss and Glycemic Control in Nonmorbidly Obese Adults With DiabetesA Systematic Review

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Importance  Bariatric surgery is beneficial in persons with a body mass index (BMI) of 35 or greater with obesity-related comorbidities. There is interest in using these procedures in persons with lower BMI and diabetes.

Objective  To assess the association between bariatric surgery vs nonsurgical treatments and weight loss and glycemic control among patients with diabetes or impaired glucose tolerance and BMI of 30 to 35.

Evidence Review  PubMed, EMBASE, and Cochrane Library databases were searched from January 1985 through September 2012. Of 1291 screened articles, we included 32 surgical studies, 11 systematic reviews on nonsurgical treatments, and 11 large nonsurgical studies published after those reviews. Weight loss, metabolic outcomes, and adverse events were abstracted by 2 independent reviewers.

Findings  Three randomized clinical trials (RCTs) (N = 290; including 1 trial of 150 patients with type 2 diabetes and mean BMI of 37, 1 trial of 80 patients without diabetes [38% with metabolic syndrome] and BMI of 30 to 35, and 1 trial of 60 patients with diabetes and BMI of 30 to 40 [13 patients with BMI <35]) found that surgery was associated with greater weight loss (range, 14.4-24 kg) and glycemic control (range, 0.9-1.43 point improvements in hemoglobin A1c levels) during 1 to 2 years of follow-up than nonsurgical treatment. Indirect comparisons of evidence from observational studies of bariatric procedures (n ≈ 600 patients) and meta-analyses of nonsurgical therapies (containing more than 300 RCTs) support this finding at 1 or 2 years of follow-up. However, there are no robust surgical data beyond 5 years of follow-up on outcomes of diabetes, glucose control, or macrovascular and microvascular outcomes. In contrast, some RCT data of nonsurgical therapies show benefits at 10 years of follow-up or more. Surgeon-reported adverse events were low (eg, hospital deaths of 0.3%-1.0%), but data were from select centers and surgeons. Long-term adverse events are unknown.

Conclusions and Relevance  Current evidence suggests that, when compared with nonsurgical treatments, bariatric surgical procedures in patients with a BMI of 30 to 35 and diabetes are associated with greater short-term weight loss and better intermediate glucose outcomes. Evidence is insufficient to reach conclusions about the appropriate use of bariatric surgery in this population until more data are available about long-term outcomes and complications of surgery.

Source: JAMA

 

Roux-en-Y Gastric Bypass vs Intensive Medical Management for the Control of Type 2 Diabetes, Hypertension, and HyperlipidemiaThe Diabetes Surgery Study Randomized Clinical Trial.

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Importance  Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown.

Objective  To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors.

Design, Setting, and Participants  A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008.

Interventions  Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized.

Main Outcomes and Measures  Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg.

Results  All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group.

Conclusions and Relevance  In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events.

DISCUSSION

Of the patients with suboptimally controlled type II diabetes and a BMI that ranged from 30.0 through 39.9 who underwent Roux-en-Y gastric bypass surgery, 49% achieved established diabetes management goals compared with 19% of patients in the lifestyle-medical management group. Only about half of the participants achieved the composite treatment goal despite surgery and their simultaneous participation in intensive medical and lifestyle therapy; however, the patients in the gastric bypass group who achieved the composite goal took 66% fewer medications than did those in the lifestyle-medical management group.

To our knowledge, this is the first trial comparing Roux-en-Y gastric bypass surgery with intense lifestyle and medical management to treat type 2 diabetes using composite specified therapeutic goals. The rationale for these end points is that achieving a HbA1c of 7.0% or less protects against vascular complications of type 1 diabetes.17– 18 Decreasing LDL cholesterol and blood pressure reduce the risk of macrovascular events in populations of patients with diabetes.1 Previous randomized trials involving patients with diabetes who underwent gastric bypass reported effects on glycemia, and sometimes on blood pressure and lipids, as individual variables but not as a composite end point. The proportion of participants in both groups who achieved the composite goal was greater than the 10.2% cross-sectional rates reported in the National Health and Nutrition Survey database3 and the 10.1% in the baseline Look AHEAD study population.19 The Look AHEAD intensive lifestyle intervention improved achievement of the composite goal from 10.8% to 23.6% of participants at 1 year,16 similar to the 19% (95% CI, 10%-32%) achieved by those participating in the current lifestyle-medical management group. In our trial, the proportion of patients in both groups who achieved the composite goal was less than we projected in our power analysis. This was because of the smaller than expected improvements in systolic blood pressure and serum LDL cholesterol levels. Between-group differences in the triple end point were consistent with our projections.

Glycemic control results are comparable with the experience of other controlled trials testing bariatric surgery treatment of diabetes. In the current study, the mean (SD) HbA1c at baseline was 9.6% (1.1%), substantially greater than the baseline reported in the Look AHEAD trial,16 the gastric band trial of Dixon et al,6 and the bariatric surgery study by Mingrone et al,7 but similar to the trial by Schauer and colleagues.8 The generally greater mean HbA1c likely reflects our entry criteria requiring an HbA1c higher than 8.0% and is relevant to balancing the risks of poorly controlled diabetes with surgical risks. The glycemic goal of an HbA1c lower than 7.0%, achieved by 75% of those in the gastric bypass group cannot be directly compared with the other randomized trials of bariatric surgery involving patients with diabetes because the current study target was different. The mean (SD) HbA1c in our gastric bypass group was 6.3% (0.9%) at 1 year, comparable with 6.4% for those undergoing Roux-en-Y gastric bypass surgery in the Schauer et al study and 6.3% at 2 years in the Mingrone et al study. The lifestyle-medical management group improved its mean HbA1c to 7.8% (1.5%), similar to the 7.2% achieved in the Look AHEAD intense treatment group and the medical treatment groups of the other 3 studies.6– 8,16 Overall, both of the treatment groups in the current study were congruent with our prior hypotheses on glycemic control.

The gastric bypass procedure did not significantly improve LDL cholesterol or blood pressure outcomes with more than 70% of both groups having achieved these goals. The mean (SD) 1-year LDL cholesterol concentration of 89 mg/dL (31 mg/dL) among those in the lifestyle-medical management group was lower than among patients who had participated in the Look AHEAD intense treatment group and the Mingrone et al study medical group. The mean (SD) LDL of 83 mg/dL (25 mg/dL) among patients in the gastric bypass group was similar to what was reported by Mingrone et al. The 84% rates in the gastric bypass and the 79% rates in lifestyle-medical management groups of achieving the blood pressure goal approximate what was achieved in the Look AHEAD and other diabetes-focused bariatric surgery studies.6– 8,16

Compared with previous randomized surgical studies, we pursued optimal medical management including the use of weight-lowering medications. In addition to lifestyle modification, sibutramine (until removed from the market) and orlistat were used to facilitate weight loss. Glucagon-like peptide-1 analog mimetics, known to produce sustained weight loss in this population, were used early in the diabetes treatment algorithm. Weight loss in the lifestyle-medical management group averaged 7.9% at 1 year compared with 5.4% in Schauer et al,6 4.7% at 2 years in Mingrone et al,7and 1.4% at 2 years in Dixon et al.8 Interestingly, all metabolic benefits in the lifestyle-medical management group were realized by 6 months with subsequent decrease in the number meeting composite goal by 12 months. In contrast, treatment benefits continued to increase in the gastric bypass group throughout the year.

The mechanisms responsible for improvement in diabetes and cardiovascular risk factors in this study cannot be determined with certainty. The underlying assumption for the original application of bariatric surgery to treat type 2 diabetes was that greater sustained weight loss would benefit patients. In other studies, weight loss among patients who had gastric band surgery correlated with improvement in type 2 diabetes control,6 but other bariatric surgery studies have not found a correlation with weight loss or reduction of BMI.7– 8,20 Regression analyses of the present data indicate that the effect of gastric bypass on achieving the composite end point is attributable to weight loss. This finding does not preclude the possible contribution of changes in the secretion of gastrointestinal hormones to glucose control improvement,21 nor does it take into account between-group differences in medication use.

There was substantial difference in the frequency of serious adverse events between groups. Patients in the gastric bypass group experienced 50% more serious and 55% more nonserious adverse events than did those in the lifestyle-medical management group (Table 4). The 2 most serious complications of gastric bypass were related to problems with gastrointestinal anastomotic leakage. All surgeons performing gastric bypass in this study were experts, thus the occurrence of serious complications must be factored into the design of larger trials of effectiveness for patients with moderate obesity. Although the published incidence of anastomotic leakage after gastric bypass has decreased from as high as 5%22 to 0.8%,10 even in the hands of experienced surgeons serious complications occur at a modest rate. Our leak rate of 3% is likely a function of random effects, but it is important to emphasize the differences in our patient population compared with other reported complications. The reported complication rates reflect data to 1 year and do not reflect internal hernias, the potential for later development of anastomotic ulcers, suicide, substance addiction, and failure of maintenance of weight loss known to occur beyond the first year after gastric bypass. As expected, the number of nutritional deficiencies was greater in the gastric bypass group despite monitoring of laboratory values and prescription of appropriate nutritional supplements.

Proponents have suggested that bariatric surgery for type 2 diabetes be considered earlier and for patients with lower BMIs, based on evidence of lower mortality, decreased rate of malignancy, and better glycemic control durability.23– 24 Others hesitate to recommend widespread use of a costly surgical procedure with inherent risks without support from large, prospective randomized clinical trials. The American Diabetes Association and the National Institutes of Health have been conservative about application of bariatric surgery in treatment algorithms for type 2 diabetes.1Emerging data suggest that recurrence of type 2 diabetes is associated with weight regain after bariatric surgery.25 This study provides an indication of the potential benefit as well as the risks of adding gastric bypass to best lifestyle and medical management for diabetes. However, to determine the long-term cardiovascular effects of bariatric surgery would require a large-scale, multiinstitutional study.

Strengths of this study include randomized design, multiple sites, surgeons, and an intention-to-treat comparison to a group treated with best practices for lifestyle and pharmacological management, as well as examining gastric bypass in combination with existing best medical practices. A high level of participant follow-up was obtained. Weaknesses include relatively small sample size, use of surrogate end points for cardiovascular disease, and evaluation of the primary outcome at 1 year. Because recruitment emphasized participants with suboptimally controlled diabetes among patients whose BMI ranged from 30 to 40 and who were willing to attend the lifestyle program, generalizability of the study to patients with better control of their diabetes, those in other BMI ranges, or those less able to engage with lifestyle change treatment is uncertain.

It is important to comment that recruitment for the study with 4 participating clinical centers proved to be considerably more difficult than anticipated: for every patient enrolled in the study, an additional 21 potential candidates were screened.

CONCLUSIONS

The Diabetes Surgery Study examined Roux-en-Y gastric bypass surgery as an adjunct to intensive behavioral intervention and intensive medical management using a composite primary end point of cardiovascular disease risk factors in the treatment of diabetes. This trial provides data about efficacy and safety for the first year of treatment.

The merit of gastric bypass treatment of moderately obese patients with type 2 diabetes depends on whether potential benefits make risks acceptable. Bariatric surgery can result in dramatic improvements in weight loss and diabetes control in moderately obese patients with type 2 diabetes who are not successful with lifestyle changes or medical management. The benefits of applying bariatric surgery must be weighed against the risk of serious adverse events.

Source: JAMA

Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary DiseaseThe REDUCE Randomized Clinical Trial.

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Importance  International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown.

Objective  To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids.

Design, Setting, and Patients  REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011.

Interventions  Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%.

Main Outcome and Measure  Time to next exacerbation within 180 days.

Results  Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of −1.2% (95% CI, −12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.

Conclusions and Relevance  In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.

 

Source: JAMA

 

How to Improve Your Virtual Communication Skills.

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VR2

Healthy communication is the cornerstone of cultivating and sustaining healthy relationships. We connect and express ourselves through the spoken and written word, which ultimately allows us to develop our “voice” in the world.

How well you communicate directly correlates with how understood and heard you feel by the response you receive from the other end of the dialogue.

When it comes to communicating through text or email, the rules and guidelines for good communication don’t change. The integrity of your words should remain the same, and all the skills and etiquette you would apply in real life need to be applied.

Words are powerful with or without voice, and it’s even more important to be clear when tone is absent. Words are vulnerable to being twisted and misconstrued when they lack intonation, and human expression.

How many times have you sent an email or text to someone only to find that they have completely misinterpreted or misread what you were trying to say? Your correspondence with others reflects your ability to express yourself in real time, so if you struggle with getting your point across in general, you will most likely bump into obstacles when trying to do it through the written word.

Whether you are writing a work email, communicating with your Ex about something uncomfortable, or responding to a difficult situation, here are 5 skills to help you draft better correspondence.

These are skills that work both on and off the computer or smart phone, and should be applied in any conversation that requires a delicate touch.

1. Make sure your intention is clear

In any correspondence you always want to make your intention clear. There is usually one point you want to get across, but if you just let your words flow without much reflection you are bound to step into a landmine. Before you even start drafting clarify your ultimate intention. Is it to get the person to do something? Are you looking for an answer or response? Do you want an apology? Knowing what you are hoping to get will increase your chances of actually achieving that goal. Asking, “what is my intention?” is a good practice before beginning any conversation.

2. Establish boundaries

Believe it or not, boundaries can be conveyed as much through written word as they can in person. A boundary is a clear line defining what you are willing to accept or tolerate, and what is too much. Boundaries are conveyed through language like “I can’t allow you to…” or “I cannot accept the fact that…”

Boundaries can also come from your strong belief in how you feel. This is different then needing to be right, it’s more about being very clear that your experience is valid and true for you. This works when you are being accused of something, or blamed for something you don’t feel you did. A response to this might look something like “I appreciate your perspective, but I am confident that this isn’t true for me…”

3. Empathy

Using language that conveys a sense of empathy in your correspondence is always a good practice. Everyone wants to feel acknowledged and understood on some level, so you will need to pause and understand where the other person is coming from. Even if you don’t agree, it’s always a good idea to say that you can understand why or how they see things the way they do, and to let them know that you understand their position on the issues at hand.

Empathy is diffuser in communication, and it can calm even the most upset person. Look at it like a virtual hug. Empathy is contagious, and it’s hard to respond to it in a negative way.

4. Accountability

In any two-way conversation there are always two opinions, two perspectives and two subjective experiences. It’s rarely always the other person. Being accountable to how you might have contributed to the breakdown of what is happening, or acknowledging that you didn’t communicate well is a great habit to develop. Stepping back and asking yourself how you could have done things differently will help you clarify your point as well. Simply writing something like “I recognize that I have some responsibility in this situation…” opens up space for the other person to do the same.

5. Always maintain integrity

The written word can be as much a trigger as speaking with someone in person. There are some situations where even the most skillfully drafted communication will still ignite a negative response from the other party. If you are dealing with verbal attacks, and you know you aren’t going to get anywhere step out of the power struggle and end it with integrity. This is a graceful exit without being pulled down to the other person’s level.

Stepping out requires letting go of needing to feel validated or heard, and accepting that this person simply cannot engage on a healthy and productive level. This is a great practice in both virtual and real life because it shows you that you are always in control of how you feel, and how you respond.

Source: Purpose fairy

Borage Seed Oil Natural Healing.

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borage-seed-starflower

 Native to Mediterranean region it grows abundantly in such areas such as Spain and North Africa, and now is cultivated almost in all European countries and across N. America. It is known for its wonderful healing properties and over the years has become a very popular and effective treatment in skin care and skin conditions such as eczema and psoriasis.

Bees love the star like beautiful flower of borage, which with its beautiful star-like shape has given borage a new name of “starflower”. Its flowers are beautiful sky blue and they blossom from May to September, the plant is rich in honey-producing nectar, and the seeds yield about 40% of their weight in lipids.

What is borage famous for and why it is so effective?

It is well known for its GLA content. It is one of the richest sources known and readily available everywhere.

That’s why it is so valuable for any skin care routine.  The seed is used for extracting oil rich in GLA. It is very soothing and moisturizing to dry, sensitive, inflamed skin conditions. It also purifies and tones combination and tired skin and brightens dry and gray hair, It is very common for anti-aging and wrinkle preparations to fight dehydration and loss of skin elasticity, and borage seed oil contains super regenerative and firming properties.

It is also consumed internally for boosting the immune system and is an important part, (the GLA) of human breast milk. Which when passed on to the infant can significantly reduce risk of developing allergies.

However borage oil is heavy in nature and if you get cold pressed and virgin oil then the aroma is pretty strong. So, for skin preparation adding the oil at 10 to 20% is all you need to get the benefits of the oil.

Source: http://www.naturalcuresnotmedicine.com