The obesity paradox and mortality associated with surrogates of body size and muscle mass in patients receiving hemodialysis

OBJECTIVE: To determine whether dry weight gain accompanied by an increase in muscle mass is associated with a survival benefit in patients receiving maintenance hemodialysis (HD).PATIENTS AND METHODS: In a nationally representative 5-year cohort of 121,762 patients receiving HD 3 times weekly from July 1, 2001, through June 30, 2006, we examined whether body mass index (BMI) (calculated using 3-month averaged post-HD dry weight) and 3-month averaged serum creatinine levels (a likely surrogate of muscle mass) and their changes over time were predictive of mortality risk.RESULTS: In the cohort, higher BMI (up to 45) and higher serum creatinine concentration were incrementally and independently associated with greater survival, even after extensive multivariate adjustment for available surrogates of nutritional status and inflammation. Dry weight loss or gain over time exhibited a graded association with higher rates of mortality or survival, respectively, as did changes in serum creatinine level over time. Among the 50,831 patients who survived the first 6 months and who had available data for changes in weight and creatinine level, those who lost weight but had an increased serum creatinine level had a greater survival rate than those who gained weight but had a decreased creatinine level. These associations appeared consistent across different demographic groups of patients receiving HD.CONCLUSION: In patients receiving long-term HD, larger body size with more muscle mass appears associated with a higher survival rate. A discordant muscle gain with weight loss over time may confer more survival benefit than weight gain while losing muscle. Controlled trials of muscle-gaining interventions in patients receiving HD are warranted.BMI = body mass index; CKD = chronic kidney disease; DEXA = dual-energy X-ray absorptiometry; HD = hemodialysis; Kt/V = dialysis dose; LBM = lean body mass; PEW = protein-energy wasting; UKM = urea kinetic modelingPatients with chronic kidney disease (CKD) who require maintenance hemodialysis (HD) treatment for survival have a high annual mortality of approximately 20% in the United States, mostly as a result of cardiovascular or infectious diseases.¹ Despite decades of ongoing efforts to correct such conventional risk factors as obesity, hypertension, or hypercholesterolemia or other potential risk factors (eg, dialysis dose, anemia, or hyperhomocysteinemia), survival of patients receiving maintenance HD has not improved substantially.¹ Several recent randomized controlled trials in patients with CKD have showed no survival benefit resulting from increasing the dialysis dose, lowering serum cholesterol levels, correcting hyperhomocysteinemia, or improving anemia.²Whereas obesity is a risk factor for CKD,³ many epidemiological studies have indicated inverse associations between obesity or other cardiovascular risk factors and mortality in patients with CKD or cardiac disease.^4,5 A higher death rate has been observed in patients with CKD who have a low, rather than a high, body mass index (BMI [calculated as the weight in kilograms divided by height in meters squared]),⁶ blood pressure,⁷ or serum concentrations of cholesterol⁸ or homocysteine,⁹ whereas high values of these risk factors are associated with improved survival. Other patient populations, including those with heart failure,¹⁰ those with coronary artery disease,^5,11 and those of advanced age,¹² also exhibit this so-called obesity paradox. However, most studies have not examined the relative contribution of fat vs muscle mass or their changes over time to the survival benefits of larger body size. Assessing muscle mass or lean body mass (LBM) is particularly difficult in large epidemiological studies and requires such elaborate tests of body composition as dual-energy X-ray absorptiometry (DEXA).¹³Among biochemical markers of muscle mass, serum creatinine is most routinely measured, but its association with kidney function may limit its utility as such.¹⁴ However, in patients receiving long-term HD who have minimal or no residual renal function and who undergo a stable HD treatment regimen, time-averaged serum creatinine concentration is a more likely surrogate of muscle mass, and its changes over time may represent parallel changes in skeletal muscle mass.^15,16 We studied adjusted dry weight and serum creatinine concentration and their changes over time as predictors of mortality in a large and nationally representative cohort of patients receiving long-term HD. We hypothesized that gain in dry weight over time in patients receiving HD is associated with greater survival, especially if it is associated with an increase in muscle mass as reflected by an increase in the serum creatinine concentration at the same dialysis dose level, whereas weight loss or reduction in muscle mass (ie, a decrease in serum creatinine concentration) is associated with increased mortality.     

Geriatric Nutritional Risk Index as a Prognostic Factor in Peritoneal Dialysis Patients

♦ Background: The Geriatric Nutritional Risk Index (GNRI) might be a useful screening tool for malnutrition in dialysis patients. However, data concerning the GNRI as a prognostic factor in peritoneal dialysis (PD) patients are scarce.♦ Methods: We reviewed the medical records at Yeungnam University Hospital in Korea to identify all adults (>18 years) who received PD; 486 patients were enrolled in the study.♦ Results: The initial low, middle, and high GNRI tertiles included 162, 166, and 158 patients respectively. Significant correlations were noted between the initial GNRI and body mass index, creatinine, albumin, arm circumference, fat mass index, and comorbidities. The cut-off value for the time-averaged GNRI over 1 year was 96.4, and the sensitivity and specificity for a diagnosis of a decline in lean mass were 77.1% and 40.0% respectively. A multivariate analysis adjusted for age, risk according to the Davies comorbidity index, and C-reactive protein showed that an low initial GNRI tertile was associated with mortality in PD patients.♦ Conclusions: The GNRI is a simple method for predicting nutrition status and clinical outcome in PD patients.Key words: Geriatric Nutritional Risk Index, prognostic factor, nutrition, lean massMalnutrition is one of the most common complications encountered in dialysis patients. Depending on the method used to assess nutrition status, the prevalence of malnutrition ranges from 18% to 70% in maintenance dialysis patients (1). Development of malnutrition is associated with dialysis-related factors such as bioincompatibility and unrelated factors such as comorbidities (1,2). Furthermore, studies have linked malnutrition with prognosis in dialysis patients (1-4).The methods for evaluating nutrition status in dialysis patients involve the use of biochemical markers, creatinine kinetics, anthropometric measurements, body composition analyses, and questionnaires (1,2). Biochemical markers such as albumin are the most commonly used markers of nutrition in dialysis patients; however, those markers are affected by various conditions—for example, inflammation and hydration status (1,5). Anthropometric measurements such as body mass index (BMI) cannot distinguish between lean mass and fat or bone (6). Measurement of body composition provides an objective assessment, but it requires expensive equipment.Bouillanne et al. (7) first reported the validity of the Geriatric Nutritional Risk Index (GNRI) for malnutrition screening in elderly patients. The GNRI has both anthropometric and biochemical components (7-9). Some studies demonstrated the usefulness of the GNRI as a new marker for malnutrition screening in dialysis patients (8,9). However, few reports have assessed the effectiveness of the GNRI as a prognostic factor in peritoneal dialysis (PD) patients. The aim of the present study was to evaluate the clinical relevance and usefulness of the GNRI as a prognostic factor in PD patients.     

Body Composition and Coronary Heart Disease Mortality—An Obesity or a Lean Paradox?

OBJECTIVE: To determine the combined effects of body mass index (BMI) and body fat (BF) on prognosis in coronary heart disease (CHD) to better understand the obesity paradox.PATIENTS AND METHODS: We studied 581 patients with CHD between January 1, 2000, and July 31, 2005, who were divided into low (<25) and high BMI (≥25), as well as low (≤25% men and ≤35% women) and high BF (>25% in men and >35% in women). Four groups were analyzed by total mortality during the 3-year follow-up by National Death Index: low BF/low BMI (n=119), high BF/low BMI (n=26), low BF/high BMI (n=125), and high BF/high BMI (n=311).RESULTS: During the 3-year follow-up, mortality was highest in the low BF/low BMI group (11%), which was significantly (P<.001) higher than that in the other 3 groups (3.9%, 3.2%, and 2.6%, respectively); using the high BF/high BMI group as a reference, the low BF/low BMI group had a 4.24-fold increase in mortality (confidence interval [CI], 1.76-10.23; P=.001). In multivariate logistic regression for mortality, when entered individually, both high BMI (odds ratio [OR], 0.79; CI, 0.69-0.90) and high BF (OR, 0.89; CI, 0.82-0.95) as continuous variables were independent predictors of better survival, whereas low BMI (OR, 3.60; CI, 1.37-9.47) and low BF (OR, 3.52; CI, 1.34-9.23) as categorical variables were independent predictors of higher mortality.CONCLUSION: Although both low BF and low BMI are independent predictors of mortality in patients with CHD, only patients with combined low BF/low BMI appear to be at particularly high risk of mortality during follow-up. Studies are needed to determine optimal body composition in the secondary prevention of CHD.BF = body fat; BMI = body mass index; CHD = coronary heart disease; CI = confidence interval; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; CV = cardiovascular; EF = ejection fraction; HDL-C = high-density lipoprotein cholesterol; HF = heart failure; HR = hazard ratio; HTN = hypertension; LVH = left ventricular hypertrophy; OR = odds ratio; peak = peak oxygen consumption; T2DM = type 2 diabetes mellitusDespite the well-known adverse affects of obesity on almost all aspects of coronary heart disease (CHD) and CHD risk factors, including hypertension (HTN), plasma lipids, inflammation, glucose abnormalities, insulin resistance, metabolic syndrome and type 2 diabetes mellitus (T2DM), as well as left ventricular hypertrophy (LVH), many studies of cohorts with established cardiovascular (CV) disease, including heart failure (HF), HTN, as well as CHD, have demonstrated an inverse relationship between obesity, generally determined by body mass index (BMI [calculated as the weight in kilograms divided by the height in meters squared]), on subsequent mortality, referred to as the obesity paradox.^1,2 The obesity paradox has also been demonstrated in non-CV studies that included patients with advanced renal disease and the elderly.^3,4 Many large studies of cohorts with CHD have demonstrated this obesity paradox,^5-7 which has also been demonstrated in a large meta-analysis by Romero-Corral et al⁸ from Mayo Clinic, who analyzed 40 cohort studies totaling more than 250,000 patients with CHD grouped according to BMI.Although BMI is the most frequently used method to assess overweightness/obesity, especially in large epidemiologic studies, this method has been criticized because BMI does not always reflect true body fatness.^1,2,9-14 Some investigators have theorized that at least part of the inconsistent relationship between obesity and major CV disease events, including mortality, may be due to the inaccurate diagnosis of obesity by the BMI assessment and that defining obesity by other methods, including waist circumference, waist/hip ratio, as well as percent body fat (BF) may be more accurate.^2,9-13 We have recently demonstrated this obesity paradox in a cohort of CHD patients using both BMI and BF determinations.¹⁴To our knowledge, no prior studies have determined the independent effects of both BMI and BF on mortality in a cohort of CHD patients. Therefore, in the current evaluation, we determined the combined and independent impact of both BMI and BF on mortality in a cohort with stable CHD.     

Obesity Paradox and Cardiorespiratory Fitness in 12,417 Male Veterans Aged 40 to 70 Years

OBJECTIVE: To evaluate the influence of cardiorespiratory fitness (fitness) on the obesity paradox in middle-aged men with known or suspected coronary artery disease.PATIENTS AND METHODS: This study consists of 12,417 men aged 40 to 70 years (44% African American) who were referred for exercise testing at the Veterans Affairs Medical Centers in Washington, DC, or Palo Alto, CA (between January 1, 1983, and June 30, 2007). Fitness was quantified as metabolic equivalents achieved during a maximal exercise test and was categorized for analysis as low, moderate, and high (defined as <5, 5-10, and >10 metabolic equivalents, respectively). Adiposity was defined by body mass index (BMI) according to standard clinical guidelines. Separate and combined associations of fitness and adiposity with all-cause mortality were assessed by Cox proportional hazards analyses.RESULTS: We recorded 2801 deaths during a mean ± SD follow-up of 7.7±5.3 years. Multivariate hazard ratios (95% confidence interval) for all-cause mortality, with normal weight (BMI, 18.5-24.9 kg/m²) used as the reference group, were 1.9 (1.5-2.3), 0.7 (0.7-0.8), 0.7 (0.6-0.7), and 1.0 (0.8-1.1) for BMIs of less than 18.5, 25.0 to 29.9, 30.0 to 34.9, and 35.0 or more kg/m², respectively. Compared with highly fit normal-weight men, underweight men with low fitness had the highest (4.5 [3.1-6.6]) and highly fit overweight men the lowest (0.4 [0.3-0.6]) mortality risk of any subgroup. Overweight and obese men with moderate fitness had mortality rates similar to those of the highly fit normal-weight reference group.CONCLUSION: Fitness altered the obesity paradox. Overweight and obese men had increased longevity only if they registered high fitness.BMI = body mass index; BP = blood pressure; CI = confidence interval; CVD = cardiovascular disease; HR = hazard ratio; MET = metabolic equivalent; VETS = Veterans Exercise Testing StudyBody mass index (BMI) has been widely used to evaluate the mortality risk associated with obesity. Although many large epidemiological studies of the general population report a positive association between BMI and mortality,^1-3 consistent inverse associations (the so-called obesity paradox) have been observed among patients with heart failure,⁴ coronary heart disease,^5,6 hypertension,⁷ peripheral artery disease,⁸ type 2 diabetes,⁹ and chronic kidney disease.¹⁰ An obesity paradox has also been observed in healthier populations as diverse as San Francisco longshoremen,¹¹ Native American women of the Pima tribe,¹² men from rural Scotland,¹³ Nauruan men,¹⁴ and the elderly.¹⁵Although substantial evidence for an obesity paradox has accumulated during the past decade,¹⁶ including a recent examination of the influence of weight loss,¹⁷ the influence of cardiorespiratory fitness (fitness) has not been adequately explored. Objective measures of fitness from clinical exercise testing are not readily available. Consequently, few studies have examined the combined effects of fitness and BMI on mortality, and these data come from only 2 cohorts: the Lipid Research Clinics Study^18,19 and the Aerobics Center Longitudinal Study.^20-26 Collectively, these reports provide convincing evidence that fitness is a more powerful predictor of mortality than BMI. However, these findings are from populations without an obesity paradox.For editorial comment, see page 112The Veterans Exercise Testing Study (VETS) affords a unique opportunity to study simultaneous measures of fitness and adiposity in a large patient population exhibiting an obesity paradox. A previous report from our group provided compelling evidence that higher levels of fitness, as well as higher BMI, reduced mortality risk in men referred for exercise testing.²⁷ However, this report did not examine the combined effects of fitness and BMI on mortality. Such joint analyses may identify associations obscured in independent analyses alone. To avoid bias associated with age,²⁸ we confined our investigation to men aged 40 to 70 years. The purpose of the current study was to examine the influence of fitness on the obesity paradox in middle-aged men with known or suspected cardiovascular disease (CVD).     

Clinical Outcomes of Video-Assisted Thoracoscopic Lobectomy

OBJECTIVE: To review our experience with video-assisted thoracoscopic (VATS) lobectomy with respect to morbidity, mortality, and short-term outcome.PATIENTS AND METHODS: VATS lobectomies were performed in 56 patients between July 6, 2006, and February 26, 2008. Two patients declined consent for research participation and were excluded. Clinical data for 54 patients were collected from medical records and analyzed retrospectively.RESULTS: The studied cohort included 19 men (35%) and 35 women (65%) with a median age of 67.5 years (minimum-maximum, 21-87 years; interquartile range [IQR], 59-74 years). Median duration of operation for VATS lobectomy was 139 minutes (minimum-maximum, 78-275 minutes; IQR, 121-182 minutes). Two cases (4%) required conversion to open lobectomy. Median time to chest tube removal was 2 days (minimum-maximum, 1-12 days; IQR, 1.3-3.8 days). Median length of stay was 4 days (minimum-maximum, 1-12 days; IQR, 4-7 days). There was no operative mortality.CONCLUSION: VATS lobectomy is safe and feasible for pulmonary resection. This minimally invasive approach may allow patients to benefit from lobectomy with shorter recovery times and hospital stays compared with conventional open thoracotomy.IQR = interquartile range; NSCLC = non-small cell lung cancer; VATS= video-assisted thoracoscopicVideo-assisted thoracoscopic (VATS) surgery was first described by several groups in the early 1990s. Initial applications included exploration of the chest, management of pleural effusion or pneumothorax, and limited resection of lung nodules.^1-6 In subsequent years it has achieved broad application in clinical practice as a minimally invasive tool for multiple indications.^7-20 Techniques for VATS lobectomy as an oncologic resection emerged after this experience, with many large retrospective series showing the feasibility and safety of this minimally invasive surgical approach.^{11,12,14-16,21-23} Although the existing retrospective data suggest equivalent oncologic outcomes with VATS lobectomy and lobectomy using a conventional open thoracotomy, prospective studies are needed to confirm this hypothesis and are ongoing.²⁴ Compared with the open approach, VATS lobectomies have the potential advantage of decreased postoperative pain and a shorter hospital length of stay.^25-27 Other proposed advantages of a thoracoscopic approach include decreased blood loss, fewer postoperative complications, preserved pulmonary function, decreased inflammatory response, and a more rapid return to preoperative activity.^{10,11,14,15,20,25} If adjuvant chemotherapy or radiation therapy is indicated, a potential shorter postoperative recovery time may allow adjuvant treatment at a shorter postoperative interval with better adherence and treatment completion rates.^12,28VATS lobectomies have been used routinely in our department since July 2006. This report reviews our experience with the VATS approach with respect to morbidity and mortality as well as its potential effect on the length of patient hospitalization.     

Palliative medicine consultation for preparedness planning in patients receiving left ventricular assist devices as destination therapy

OBJECTIVE: To assess the benefit of proactive palliative medicine consultation for delineation of goals of care and quality-of-life preferences before implantation of left ventricular assist devices as destination therapy (DT).PATIENTS AND METHODS: We retrospectively reviewed the cases of patients who received DT between January 15, 2009, and January 1, 2010.RESULTS: Of 19 patients identified, 13 (68%) received proactive palliative medicine consultation. Median time of palliative medicine consultation was 1 day before DT implantation (range, 5 days before to 16 days after). Thirteen patients (68%) completed advance directives. The DT implantation team and families reported that preimplantation discussions and goals of care planning made postoperative care more clear and that adverse events were handled more effectively. Currently, palliative medicine involvement in patients receiving DT is viewed as routine by cardiac care specialists.CONCLUSION: Proactive palliative medicine consultation for patients being considered for or being treated with DT improves advance care planning and thus contributes to better overall care of these patients. Our experience highlights focused advance care planning, thorough exploration of goals of care, and expert symptom management and end-of-life care when appropriate.DT = destination therapy; ICD = implantable cardioverter-defibrillator; LVAD = left ventricular assist device; PM = palliative medicine; QOL = quality of life

You matter because you are you. You matter to the last moment of your life, and we will do all we can, not only to help you die peacefully, but also to live until you die.Dame Cicely Saunders

The left ventricular assist device (LVAD) is a promising technology that supports circulation in patients with advanced heart failure. Originally developed to bridge patients to heart transplant, the LVAD is being used as destination therapy (DT) for patients who are not candidates for heart transplant. Compared with medical therapy, use of DT improves survival, quality of life (QOL), and functional status in appropriately selected patients with advanced heart failure.^1-5 In our experience at Mayo Clinic, the 2-year survival rate of patients receiving DT is 75%.⁶ However, as a result of occasional adverse events (eg, stroke, infection, or multiorgan failure), some patients or their surrogate decision-makers may request withdrawal of LVAD support.^4,7,8 In other situations, patients or caregivers may become overwhelmed with financial and psychosocial issues related to DT^8-11 and are at risk of burnout and isolation because of outpatient needs and limited community support.^11-14Several analyses^7,15,16 have concluded that goals of care of patients receiving DT are often undefined. Many patients either have inadequate advance directives that do not address potential problems (such as worsening comorbid conditions, complications, and worsening QOL) or simply lack advance care documents.^7,16,17 Without clearly defined goals and/or explicit advance directives, DT may merely maintain circulation in a moribund patient, a situation referred to as “destination nowhere.”¹⁸ Also, protocols and processes regarding LVAD management and comfort at the end of life are often lacking^7,17; hence, ethical quandaries (eg, withdrawal of device support) may arise.^19,20To avoid situations in which advance care wishes are unclear or unknown, palliative medicine (PM) consultation has been suggested^8,17,21-23 to address end-of-life preferences, facilitate advance care planning, manage symptoms, and maximize QOL. Several authors have called for PM involvement in patients with advanced heart disease to improve health status and QOL,^24-29 and a recent randomized study of early palliative care vs standard care in advanced lung cancer has demonstrated improved QOL, improved mood, and survival benefit.³⁰ Herein, we describe our initial experience with proactive PM consultation in patients receiving DT.     

Association of TNFSF8 polymorphisms with peripheral neutrophil count

OBJECTIVE: To investigate the association between 347 single-nucleotide polymorphisms within candidate genes of the tumor necrosis factor, interleukin 1 and interleukin 6 families with neutrophil count.PATIENTS AND METHODS: Four hundred cases with heart failure after myocardial infarction (MI) were matched by age, sex, and date of incident MI to 694 controls (MI without post-MI heart failure). Both genotypes and neutrophil count at admission for incident MI were available in 314 cases and 515 controls.RESULTS: We found significant associations between the TNFSF8 poly morphisms rs927374 (P=5.1 x 10^–5) and rs2295800 (P=1.3 x 10^–4) and neutrophil count; these single-nucleotide polymorphisms are in high linkage disequilibrium (r²=0.97). Associations persisted after controlling for clinical characteristics and were unchanged after adjusting for case-control status. For rs927374, the neutrophil count of GG homozygotes (7.6±5.1) was 16% lower than that of CC homozygotes (9.0±5.2).CONCLUSION: The TNFSF8 polymorphisms rs927374 and rs2295800 were associated with neutrophil count. This finding suggests that post-MI inflammatory response is genetically modulated.GWAS = genome-wide association study; HF = heart failure; IL = interleukin; MAF = minor allele frequency; MI = myocardial infarction; SNP = single-nucleotide polymorphism; TNF = tumor necrosis factorMyocardial infarction (MI) triggers an inflammatory response.^1,2 Early in the post-MI inflammatory phase, proinflammatory cytokines with chemoattractant properties are activated and contribute to neutrophil recruitment to the infarcted area.^1,2 In addition, proinflammatory cytokines³ promote demargination of intravascular neutrophils, acceleration of the release of neutrophils by the bone marrow, and activation of neutrophils.^4-6 Indeed, the early post-MI period is frequently marked by activation of neutrophils^7,8 and elevation of the peripheral neutrophil count. We have previously demonstrated that neutrophil count on incident MI presentation is strongly and independently associated with adverse outcomes.⁹ Secondary analysis of clinical trials of ST-elevation MI also showed associations between peripheral neutrophil count and post-MI adverse outcomes.¹⁰The proinflammatory cytokines include the tumor necrosis factor (TNF), interleukin (IL) 1 and IL-6 families,^2,11,12 which are not constitutively expressed in the heart.^13,14 However, these cytokines are consistently and rapidly expressed in response to myocardial injury, including MI.^15-19 The short-term limited expression of cytokines provides the heart with an adaptive response to injury. This protective response may occur at the cost of unwanted deleterious effects, including left ventricular dysfunction,^20-23 which may manifest clinically as heart failure (HF) syndrome. In HF, increased levels of both TNF and IL-6 are associated with worse survival.^6,24 After MI, levels of IL-6 are associated with an increase in left ventricular end-diastolic volume and remodeling.²⁵Production of proinflammatory cytokines is genetically modulated with heritability estimates ranging from 53% to 86%.^26,27 It is unknown whether genetic variants of the proinflammatory cytokine families are associated with post-MI inflammation as assessed by the inflammatory marker of neutrophil count. Therefore, we investigated the association between 347 single-nucleotide polymorphisms (SNPs) within candidate genes of the proinflammatory cytokine families, including TNF (18 genes), IL-1 (10 genes), and IL-6 (12 genes), and peripheral neutrophil count in a nested case-control study from the Olmsted County, Minnesota, cohort of incident MI.²⁸ This study tests the hypothesis that variants within candidate genes of these proinflammatory cytokine families are associated with peripheral neutrophil count in patients with MI.     

The Association Between Cardiorespiratory Fitness and Risk of All-Cause Mortality Among Women With Impaired Fasting Glucose or Undiagnosed Diabetes Mellitus

OBJECTIVE: To evaluate the independent and joint associations among cardiorespiratory fitness (CRF), body mass index, and risk of mortality from any cause among women with impaired fasting glucose (IFG) or undiagnosed diabetes mellitus (DM).PATIENTS AND METHODS: Female patients (N=3044; mean age, 47.4 years) with IFG or undiagnosed DM completed a maximal exercise treadmill test (between January 26, 1971, and March 21, 2001). The women had no history of a cardiovascular disease event or diagnosed DM at baseline. Cardiorespiratory fitness was defined categorically as low (bottom 20%), moderate (middle 40%), or high (upper 40%) according to previously published Aerobics Center Longitudinal Study guidelines. Body mass index was calculated as the weight in kilograms divided by the height in meters squared (kg/m²).RESULTS: During a 16-year follow-up period, 171 deaths occurred. There was an inverse association between CRF and all-cause mortality risk. Women with moderate or high CRF were at lower risk of mortality (moderate CRF, 35% lower; high CRF, 36% lower; P_trend=.03) than those with low CRF. An exercise capacity lower than 7 metabolic equivalents was associated with a 1.5-fold higher risk of death than an exercise capacity of 9 metabolic equivalents or higher (P_trend=.05). The multivariate adjusted hazard ratios (HRs), including adjustments for CRF, were higher for heavier patients than for patients of normal weight (overweight patients: HR, 0.86; 95% confidence interval, 0.57-1.30; obese patients: HR, 1.19; 95% confidence interval, 0.70-2.03; P_trend=.84). Combined analyses showed that women who were overweight or obese and unfit (low CRF) were at more than twice the risk of death than women who were of normal weight and fit (moderate or high CRF).CONCLUSION: Cardiorespiratory fitness, not body mass index, is a significant predictor of all-cause mortality among women with IFG or undiagnosed DM. Assessing CRF levels provides important prognostic information independent of traditional risk factors.ACLS = Aerobics Center Longitudinal Study; BMI = body mass index; CI = confidence interval; CRF = cardiorespiratory fitness; CVD = cardiovascular disease; DM = diabetes mellitus; HR = hazard ratio; IFG = impaired fasting glucose; MET = metabolic equivalentImpaired fasting glucose (IFG) has been associated with an elevated risk of premature mortality.^1,2 Recently, greater attention has been directed toward IFG in efforts to reduce the development of diabetes mellitus (DM) and cardiovascular disease (CVD). In 2003, the American Diabetes Association recommended that the definition of IFG be expanded to include fasting glucose concentrations between 100 mg/dL and 125 mg/dL (to convert to mmol/L, multiply by 0.0555), as opposed to the previous concentrations of 110 mg/dL to 125 mg/dL.³ In 2002, 54 million people in the United States aged 20 years or older had IFG, representing 26% of the total US population; this number would be higher if the more stringent definition were used.⁴ In 2005, 20.8 million people (7% of the total US population) in the same age group had DM.⁴ Half of these cases of DM were expected to be undiagnosed and asymptomatic.⁵ The risk of premature CVD and death is 2 to 4 times higher for persons with DM than for those of equivalent age without DM.^6,7 Therefore, the detection and treatment of CVD risk factors may be particularly important for preventing CVD among persons with asymptomatic IFG and DM.A low cardiorespiratory fitness (CRF) level is a predictor of all-cause mortality among men with type 2 DM.⁸ Recent studies^9,10 have also reported a strong and independent association between CRF and mortality among men with DM in all body mass index (BMI) and body fatness groups.¹¹ However, most previous studies have focused on the association between CRF and mortality among either men only or men and women who are sedentary but apparently healthy.^8,9,12For editorial comment, see page 771There is a strong independent association between obesity and all-cause mortality among both men and women.^13-17 Most studies have found that this association is J-shaped or U-shaped. Like CRF studies, most obesity studies have focused on the association between obesity and mortality in women, men, or both men and women in the general population, regardless of any disease state.^13-16 Few studies have focused on persons with IFG and undiagnosed DM, especially women. To our knowledge, no previous study has concurrently evaluated the association between CRF, overweight or obesity status as reflected by BMI, and death among women with IFG. Therefore, the primary aim of this study was to evaluate the association between CRF and risk of all-cause mortality among women with IFG or undiagnosed DM.     

Waist Circumference as a Predictor of Adiponectin Levels in Peritoneal Dialysis Patients: A 12-Month Follow-Up Study

♦ Objectives: This prospective study, conducted at the dialysis unit of the Nephrology Division, Federal University of Sao Paulo-Oswaldo Ramos Foundation, Brazil, aimed to evaluate whether waist circumference (WC) can predict adiponectin levels in patients undergoing peritoneal dialysis (PD).♦ Methods: Among 115 patients on PD at a single dialysis center who were evaluated at 6 and 12 months, 57% were men, 31% had diabetes, mean age was 52.8 ± 16.1 years, body mass index was 25 ± 4.3 kg/m², and dialysis vintage was 13 months (range: 5 - 33 months). We measured WC at the umbilicus level. Adiponectin was determined by an enzyme-linked immunosorbent assay.♦ Results: At baseline, WC was inversely associated with adiponectin (r = -0.48, p < 0.01). After adjustment for sex, age, diabetes, peritoneal clearance, and residual renal function, WC was an independent determinant of serum adiponectin (β = -0.52; 95% confidence interval: -0.73 to -0.31; p < 0.001). In the prospective analysis, after adjustment for confounders, changes in WC predicted changes in adiponectin. For each unit increase in WC, adiponectin declined by 0.39 mg/L (p < 0.001).♦ Conclusions: This study demonstrates that WC is associated with adiponectin and, more importantly, that this simple marker of central adiposity was able to predict changes in adiponectin levels over time.Key words: Adipokines, abdominal obesity, waist circumferenceSecreted exclusively by adipocytes, adiponectin is a 30-kDa protein with anti-atherogenic, anti-inflammatory, and insulin-sensitizing properties (1). Body fat has been described as one of the most important determinants of serum adiponectin in the general population as well as in patients with chronic kidney disease (CKD). In fact, a number of studies have demonstrated the inverse relationship between adiponectin and parameters of body fat (2-8). More specifically, accumulation of fat in the abdominal region appears to significantly affect serum adiponectin levels (6,8). It seems that subcutaneous and visceral fat tissue in the abdomen are both important for lowering adiponectin secretion (9). In a recent study, Zoccali et al. (10) demonstrated that abdominal fat, assessed by waist circumference (WC), is a key modifier of the relationship between adiponectin and mortality in a large cohort of hemodialysis patients.Among the simple methods used to assess abdominal fat, the anthropometric measure of WC, compared with either computed tomography (visceral and subcutaneous abdominal fat) or dual-energy X-ray absorptiometry (trunk fat), has been shown to be a reliable marker of total abdominal fat in various populations (11-14), including CKD patients (15). In patients undergoing peritoneal dialysis (PD), we recently confirmed that WC is a reliable marker of abdominal adiposity (16).There is evidence showing that abdominal fat accumulates in PD patients over time (17,18), but few studies have investigated the association of central adiposity with circulating adiponectin levels in such patients. We therefore aimed to investigate whether WC is able to predict adiponectin levels in a cohort of PD patients.     

Sedation Depth During Spinal Anesthesia and the Development of Postoperative Delirium in Elderly Patients Undergoing Hip Fracture Repair

OBJECTIVE: To determine whether limiting intraoperative sedation depth during spinal anesthesia for hip fracture repair in elderly patients can decrease the prevalence of postoperative delirium.PATIENTS AND METHODS: We performed a double-blind, randomized controlled trial at an academic medical center of elderly patients (≥65 years) without preoperative delirium or severe dementia who underwent hip fracture repair under spinal anesthesia with propofol sedation. Sedation depth was titrated using processed electroencephalography with the bispectral index (BIS), and patients were randomized to receive either deep (BIS, approximately 50) or light (BIS, ≥80) sedation. Postoperative delirium was assessed as defined by Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) criteria using the Confusion Assessment Method beginning at any time from the second day after surgery.RESULTS: From April 2, 2005, through October 30, 2008, a total of 114 patients were randomized. The prevalence of postoperative delirium was significantly lower in the light sedation group (11/57 [19%] vs 23/57 [40%] in the deep sedation group; P=.02), indicating that 1 incident of delirium will be prevented for every 4.7 patients treated with light sedation. The mean ± SD number of days of delirium during hospitalization was lower in the light sedation group than in the deep sedation group (0.5±1.5 days vs 1.4±4.0 days; P=.01).CONCLUSION: The use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation. Limiting depth of sedation during spinal anesthesia is a simple, safe, and cost-effective intervention for preventing postoperative delirium in elderly patients that could be widely and readily adopted.Trial Registration: clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00590707","term_id":"NCT00590707"}}NCT00590707BIS = bispectral index; CAM = Confusion Assessment Method; CI = confidence interval; ICU = intensive care unit; MMSE = Mini-Mental State Examination; NNT = number needed to treat; OR = odds ratio; PACU = postanesthesia care unitPostoperative delirium occurs in elderly patients at an overall prevalence of 10% to 37%.^1,2 The prevalence ranges from 0% to 73%, depending on the study and type of surgery,² with a prevalence of 16% to 62% after hip fracture repair.^3-5 Although postoperative delirium usually resolves within 48 hours of onset,⁶ delirium can persist and is associated with poor functional recovery, increased length of stay, higher costs, and greater likelihood of placement in an assisted living facility after surgery.^3,5,7-13 Therefore, interventions capable of reducing the occurrence of postoperative delirium would be important from a public health perspective, but relatively few proposed interventions have proven efficacious.^14-16Several demographic and perioperative variables are associated with postoperative delirium in elderly patients after hip fracture repair, the most important of which is preoperative dementia.^3,7,17-20 Other risk factors for postoperative delirium include age, systemic disease, functionality, and psychoactive medications.^3,19 Inhalational and intravenous anesthetics, opioids, benzodiazepines, and anticholinergic drugs are all known or suspected risk factors for postoperative delirium.^21-26 Although perioperative opioids are a risk factor for postoperative delirium, they are difficult to avoid after major surgery,^17,25 especially because undertreated pain may increase the risk of postoperative delirium.¹⁷ Transfusion and perioperative medical complications may also be important.³ Unfortunately, most of these risk factors are not readily modified at the time of surgery.For editorial comment, see page 12Anesthetic technique is a potentially modifiable risk factor for postoperative delirium. Although administration of many drugs can be avoided or limited with regional anesthetic techniques and reductions in the prevalence of postoperative delirium have been observed with regional anesthesia, these results are inconsistent.^27,28 This inconsistency may be explained by reports that sedation levels consistent with general anesthesia are frequently observed during regional anesthesia^29-32 and, at least in an intensive care setting, that sedation level is an important risk factor for delirium.²³ The intravenous anesthetic propofol is commonly used to provide intraoperative sedation during spinal anesthesia and other regional anesthetics. Although propofol may have longer-term effects on some neurons of the central nervous system in vitro,³³ it is generally considered safe and without persistent aftereffects.We hypothesized that minimizing sedation depth during spinal anesthesia for hip fracture repair in elderly patients could decrease the occurrence of postoperative delirium. Therefore, we performed a randomized controlled trial that compared the prevalence of postoperative delirium after hip fracture repair with spinal anesthesia with either deep or light propofol sedation.     

The association of active cancer with venous thromboembolism location: a population-based study

OBJECTIVE: To test active cancer for an association with venous thromboembolism (VTE) location.PATIENTS AND METHODS: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN, residents with incident VTE during the 35-year period 1966-2000 (N=3385). We restricted analyses to residents with objectively diagnosed VTE during the 17-year period from January 1, 1984, to December 31, 2000 (N=1599). For each patient, we reviewed the complete medical records in the community for patient age, gender, and most recent body mass index at VTE onset; VTE event type and location; and previously identified independent VTE risk factors (ie, surgery, hospitalization for acute medical illness, active cancer, leg paresis, superficial venous thrombosis, and varicose veins). Using logistic regression we tested active cancer for an association with each of 4 symptomatic VTE locations (arm or intra-abdominal deep venous thrombosis [DVT], intra-abdominal DVT, pulmonary embolism, and bilateral leg DVT), adjusted for age, gender, body mass index, and other VTE risk factors.RESULTS: In multivariate analyses, active cancer was independently associated with arm or intra-abdominal DVT (odds ratio [OR], 1.76; P=.01), intra-abdominal DVT (OR, 2.22; P=.004), and bilateral leg DVT (OR, 2.09; P=.02), but not pulmonary embolism (OR, 0.93).CONCLUSION: Active cancer is associated with VTE location. Location of VTE may be useful in decision making regarding cancer screening.BMI = body mass index; CI = confidence interval; CTEPH = chronic thromboembolic pulmonary hypertension; DVT = deep venous thrombosis; OR = odds ratio; PE = pulmonary embolism; VTE = venous thromboembolismThe association between cancer and venous thromboembolism (VTE) is well-established and strong.^1-4 Active cancer with and without chemotherapy increases VTE risk by 5- to 6-fold.⁵ Furthermore, active cancer accounts for about 20% of the entire VTE burden occurring in a community.⁶ Indeed, VTE is the second most common cause of death among patients with cancer.⁷ Cancer patients with VTE have a 2-fold or greater increase in mortality compared with cancer patients without VTE, even after adjusting for stage.^8,9 Nearly half of the patients with cancer-associated VTE have distant metastases at the time of VTE diagnosis.⁸ The incidence of cancer in patients with recurrent idiopathic VTE is higher than that in patients with secondary VTE.³Opinions differ regarding screening for an underlying occult cancer after an idiopathic VTE event.^10,11 Although a small randomized clinical trial found that more occult cancers were detected at an early stage with extensive screening, which theoretically could improve cancer treatment potential, no difference in survival was noted between this strategy and usual care.¹⁰ Because anticoagulant therapy improves the outcomes of patients with VTE and cancer, it is still important to recognize which patients with VTE have an underlying active cancer.¹² The diagnosis of VTE may help to uncover previously occult cancer by prompting a complete physical examination and testing consistent with standard health care maintenance. However, indiscriminate cancer screening is not cost-effective.^13,14 To provide a more organized and cost-effective approach to cancer detection among patients with VTE, the VTE characteristics associated with cancer must be recognized. Although evidence shows that idiopathic VTE and bilateral deep venous thrombosis (DVT) correlate with subsequent cancer diagnosis,^3,15 there is a paucity of data regarding the association between active cancer and VTE location. The current study aims to determine whether underlying cancer is associated with particular VTE locations.     

Blood storage duration and biochemical recurrence of cancer after radical prostatectomy

OBJECTIVE: To test the hypothesis that perioperative transfusion of allogeneic and autologous red blood cells (RBCs) stored for a prolonged period speeds biochemical recurrence of prostate cancer after prostatectomy.PATIENTS AND METHODS: We evaluated biochemical prostate cancer recurrence in men who had undergone radical prostatectomy and perioperative blood transfusions from July 6, 1998, through December 27, 2007. Those who received allogeneic blood transfusions were assigned to nonoverlapping “younger,” “middle,” and “older” RBC storage duration groups. Those who received autologous RBC transfusions were analyzed using the maximum storage duration as the primary exposure. We evaluated the association between RBC storage duration and biochemical recurrence using multivariable Cox proportional hazards regression.RESULTS: A total of 405 patients received allogeneic transfusions. At 5 years, the biochemical recurrence–free survival rate was 74%, 71%, and 76% for patients who received younger, middle, and older RBCs, respectively; our Cox model indicated no significant differences in biochemical recurrence rates between the groups (P=.82; Wald test). Among patients who received autologous transfusions (n=350), maximum RBC age was not significantly associated with biochemical cancer recurrence (P=.95). At 5 years, the biochemical recurrence–free survival rate was 85% and 81% for patients who received younger and older than 21-day-old RBCs, respectively.CONCLUSION: In patients undergoing radical prostatectomy who require RBC transfusion, recurrence risk does not appear to be independently associated with blood storage duration.PSA = prostate-specific antigen; RBC = red blood cellProstate cancer is the most common malignant neoplasm in men, and radical prostatectomy is among the primary therapies for localized prostate cancer. The biochemical recurrence rate 5 years after prostatectomy ranges from 70% to 90%.^1,2 Improvements in the surgical technique have decreased the amount of intraoperative blood loss occurring during radical prostatectomy³; however, substantial numbers of patients still require perioperative blood transfusions.^4-6Blood transfusions are associated with adverse reactions, including postoperative infections and transfusion-related immune perturbations.^7,8 Allogeneic leukocytes present in the transfused blood are thought to suppress host cellular immune responses.^9,10 Furthermore, the immunodepressant effect is secondary to an imbalance of accumulated cytokines and proinflammatory mediators in the transfused blood against decreased production of lymphocyte stimulating cell-mediated cytokines, such as interleukin 2,^9,10 and increased release of immunosuppressive prostaglandins in the patient undergoing transfusion.^11,12In cancer patients, perioperative blood transfusion has long been suspected of reducing long-term survival,^4,13 but available evidence is inconsistent. It is also unclear which components of transfused blood underlie the cancer-promoting effects reported by some studies.^14,15 An important factor associated with the deleterious effects of blood transfusion is the storage age of the transfused blood units.¹⁶ A recent study using 2 animal models demonstrated that prolonged storage (>9 days) of transfused red blood cells (RBCs) was a critical deleterious factor.¹⁷ Therefore, it seems likely that cancer recurrence may also be worsened after the transfusion of older blood. No clear cutoff point has been established to define old vs young blood; however, a recent large clinical study defined old blood as RBCs with a storage time longer than 14 days.¹⁸We thus evaluated the association between RBC storage duration and biochemical prostate cancer recurrence after radical prostatectomy. Specifically, we tested the hypothesis that perioperative transfusion of allogeneic and autologous RBCs stored for a prolonged period is associated with earlier biochemical recurrence of prostate cancer after prostatectomy.     

Association between low serum 25-hydroxyvitamin D and depression in a large sample of healthy adults: the Cooper Center longitudinal study

OBJECTIVE: To investigate the association between serum vitamin D levels and depression in a large database of patients from the Cooper Clinic.PATIENTS AND METHODS: We conducted a cross-sectional study of 12,594 participants seen at the Cooper Clinic from November 27, 2006, to October 4, 2010. Serum 25-hydroxyvitamin D [25(OH)D] was analyzed, and depression was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score of 10 or more. Those with and those without a history of depression represented 2 distinct populations with respect to CES-D scores; accordingly, they were analyzed separately.RESULTS: In the total sample, higher vitamin D levels were associated with a significantly decreased risk [odds ratio, 0.92 (95% confidence interval, 0.87-0.97)] of current depression based on CES-D scores. The finding was stronger in those with a prior history of depression [odds ratio, 0.90 (95% confidence interval, 0.82-0.98)] and not significant in those without a history of depression [odds ratio, 0.95 (95% confidence interval, 0.89-1.02)].CONCLUSION: We found that low vitamin D levels are associated with depressive symptoms, especially in persons with a history of depression. These findings suggest that primary care patients with a history of depression may be an important target for assessment of vitamin D levels.BMI = body mass index; CCLS = Cooper Center Longitudinal Study; CES-D = Center for Epidemiologic Studies Depression Scale; 25(OH)D = serum 25-hydroxyvitamin DDepression occurs in persons of all ages and backgrounds and both sexes and is a leading cause of disability worldwide.¹ Depression affects overall health-related quality of life to an equal or greater degree than other chronic medical conditions.² Therefore, identifying risk factors for depression or biomarkers associated with depressive symptoms is of considerable importance.Low vitamin D level is implicated as a risk factor for numerous medical conditions, including autoimmune diseases, vascular disease, infectious diseases, osteoporosis, obesity, diabetes, cardiovascular disease, and certain cancers.^3,4 More recently, low vitamin D level has also been associated with neurologic disorders such as multiple sclerosis, Alzheimer disease, Parkinson disease, and cognitive decline.^3-7 Vitamin D receptors and the vitamin D–activating enzyme 1α–hydroxylase are found in most organ systems of the human body, including the brain.⁸ Within the hypothalamus and the dopaminergic neurons of the substantia nigra is found a high density of vitamin D receptors as well as the vitamin D–activating enzyme.⁸ Recent evidence suggests that damage to these aspects of the brain is associated with depression, at least in the elderly.⁹ In addition, vitamin D may have an effect on neurotransmitters, inflammatory markers, calcium homeostasis in the brain, and nerve growth factor synthesis.^6,10-15 Vitamin D receptor knockout mice exhibit depression-like behaviors such as poorer performance on swim tests, less activity, and more anxiety than wild-type controls.¹⁶ Thus, these data on animals and humans suggest that vitamin D may have a role in depression.Prior studies in humans have shown conflicting associations between vitamin D levels and depression. Several small clinical studies have found an association between low 25-hydroxyvitamin D [25(OH)D] levels and depression.^17-19 To date, 5 population-based studies have explored the association between 25(OH)D and depression, with conflicting results.^20-24 Hoogendijk et al²⁰ examined 1282 people aged 65 to 95 years in Amsterdam and found 14% lower 25(OH)D levels in those with major and minor depression, defined by a Center for Epidemiologic Studies Depression Scale (CES-D) score of 16 or more, when compared with controls. Stewart and Hirani²¹ studied 2070 adults aged 65 years and older in England and found that depressive symptoms were associated with low vitamin D levels. However, negative studies have also been reported. Pan et al²² examined 3262 people aged 50 to 70 years in Beijing and Shanghai, China. Depressive symptoms were less prevalent in those in the top tertile of 25(OH)D concentrations compared with those in the lowest tertile, but this association disappeared after controlling for geographic location (Beijing vs Shanghai). Nanri et al²³ examined 527 Japanese employees aged 21 to 67 years at 2 municipal offices and found no significant association between CES-D scores and 25(OH)D levels in the workers surveyed at either workplace. Finally, Zhao et al²⁴ studied 3916 adults in the United States and found that 25(OH)D and parathyroid hormone levels were not significantly associated with depressive symptoms after adjusting for demographic variables, lifestyle factors, and existing chronic conditions.In this report, we present data on 25(OH)D levels and depressive symptoms from the largest sample studied to date. The purpose of this project was to determine whether depressive symptoms, as defined by CES-D scores, are associated with 25(OH)D levels in a larger and generally healthy population. We hypothesized that vitamin D levels would be lower in the group with current depression as judged by CES-D score.     

A prospective study of fasting plasma glucose and risk of stroke in asymptomatic men

OBJECTIVE: To examine the association between levels of fasting plasma glucose (FPG) and incidence of stroke outcomes in a large cohort of asymptomatic men.PATIENTS AND METHODS: Participants were 43,933 men (mean ± SD age, 44.3±9.9 years) who were free of known cardiovascular disease at baseline and whose FPG levels were assessed during a preventive medical examination at the Cooper Clinic, Dallas, TX, between January 7, 1971, and March 11, 2002. Patients with diagnosed diabetes mellitus (DM) or low FPG (<80 mg/dL [to convert to mmol/L, multiply by 0.0555]) were excluded. Fatal stroke was identified through the National Death Index, and nonfatal stroke was ascertained from mail-back surveys.RESULTS: A total of 595 stroke events (156 fatal and 456 nonfatal strokes; 17 men reported a nonfatal stroke before they died of stroke) occurred during 702,928 person-years of exposure. Age-adjusted fatal, nonfatal, and total stroke event rates per 10,000 person-years for normal FPG (80-109 mg/dL), impaired fasting glucose (110-125 mg/dL), and undiagnosed DM (≥126 mg/dL) were 2.1, 3.4, and 4.0 (P_trend=.002); 10.3, 11.8, and 18.0 (P_trend=.008); and 8.2, 9.6, and 12.4 (P_trend=.008), respectively. After further adjusting for potential confounders, the direct association between FPG and fatal, nonfatal, or total stroke events remained significant (P_trend=.02, .03, and .01, respectively). For FPG levels of 110 mg/dL or greater, each 10-unit increment of FPG was associated with a 6% higher risk of total stroke events (P=.05).CONCLUSION: Hyperglycemia (FPG, ≥110 mg/dL), even below the DM threshold (such as with impaired fasting glucose), was associated with a higher risk of fatal, nonfatal, or total stroke events in asymptomatic men.ACLS = Aerobics Center Longitudinal Study; ADA = American Diabetes Association; BMI = body mass index; CI = confidence interval; CVD = cardiovascular disease; DM = diabetes mellitus; ECG = electrocardiography; FPG = fasting plasma glucose; ICD = International Classification of Diseases; IFG = impaired fasting glucose; MetS = metabolic syndrome; NDI = National Death IndexThe primary causes of death and disability in patients with diabetes mellitus (DM) are cardiovascular and cerebrovascular complications.^1-5 Previous studies have reported an independent and direct association of clinically diagnosed DM and stroke^2,5-7; however, about half of all patients with type 2 DM are undiagnosed because they remain asymptomatic for long periods.⁸ Those with undiagnosed DM often have elevated levels of fasting plasma glucose (FPG) but no symptoms of DM. To date, few studies have examined the effect of FPG on stroke events, and the findings are inconclusive.^6,9-13 Some have reported a positive association between elevated FPG levels and stroke,^9,10 whereas others failed to identify impaired glucose levels as a significant risk predictor for stroke.^6,11-13 The inconsistent findings may be due to differences in study populations, length of follow-up, stroke outcome definition (such as fatal, nonfatal, or a combination), confounders selection, or a combination of these factors.For editorial comment, see page 1038In 2003, the American Diabetes Association (ADA) recommended changing the lower limit for the diagnosis of impaired fasting glucose (IFG) from 110 to 100 mg/dL (to convert to mmol/L, multiply by 0.0555).¹⁴ However, the need for this change has since been questioned, and concerns have been raised regarding the potential public health implications.^15-18 Therefore, we used the widely accepted 1997 ADA guidelines¹⁹ to define the IFG (FPG, 110-125 mg/dL) and DM (FPG, ≥126 mg/dL). We evaluated the association between FPG (including undiagnosed DM and IFG, as well as lower levels of FPG [100-109 mg/dL]) and fatal, nonfatal, and fatal/nonfatal combined stroke in a large cohort of men while controlling for cardiorespiratory fitness, an independent predictor of mortality and morbidity.^20,21     

Determinants of body fat in infants of women with gestational diabetes mellitus differ with fetal sex

OBJECTIVE

Neonatal adiposity is a well-recognized complication of gestational diabetes mellitus (GDM). This study aimed to identify factors influencing adiposity in male and female infants of women treated for GDM.

RESEARCH DESIGN AND METHODS

This was a prospective study of 84 women with GDM. Daily blood glucose levels (BGLs) were retrieved from glucose meters, and overall mean fasting and mean 2-h postprandial BGLs were calculated for each woman. Infant body composition was measured at birth, and regression analysis was used to identify significant predictors of infant body fat separately in male and female infants.

RESULTS

Maternal fasting BGL was the major predictor of adiposity in male infants but had little relationship to adiposity in female infants. In male infants, percent fat was increased by 0.44% for each 0.1 mmol/L increase in mean maternal fasting BGL. Maternal BMI was the primary predictor in female infants but had little effect in males. In female infants, percent fat was increased by 0.11% for each 1 kg/m² increase in maternal prepregnancy BMI.

CONCLUSIONS

Fetal sex may influence the impact that treatment strategies for GDM have on infant adiposity.The maternal metabolic disturbance of gestational diabetes mellitus (GDM) affects fetal development and alters birth weight, BMI, and percent body fat at birth (1,2). Current treatment of GDM achieves normalization of birth weight and reduces neonatal complications (3). However, the effects of GDM on the offspring extend well beyond the fetal period and, thus, offspring of women with GDM also have an increased risk of unfavorable long-term outcomes such as obesity and diabetes, well above that explained by genetics alone (4), even after treatment.To date, studies designed to inform optimal treatment of GDM have focused on normalization of birth weight, but neonatal adiposity may be a more sensitive marker of disturbed in utero metabolism, risk of obesity, and poor long-term health than birth weight alone (1). Body fat at birth is elevated in infants born to women with GDM even when birth weight is normal (1). In a group of 6- to 12-year-old children born to women with GDM, percent body fat in childhood was significantly correlated to body fat at birth, but there was no relationship between birth weight and weight at the time of study (5). Even though treatment of mild GDM does reduce the incidence of macrosomia, it does not reduce the incidence of obesity in the offspring at 4–5 years (6).To interrupt the obesity cycle and reduce the risk of future poor adult health, it may be necessary to normalize neonatal adiposity as well as birth weight. To do this, it is essential to understand the factors that determine adiposity in infants of women with GDM.While genetic factors may be the primary determinant of lean body mass, fetal fat mass may be more strongly influenced by the in utero environment (7). A range of maternal factors have been identified as determinants of neonatal size and body fat, including maternal BMI, parity, maternal glucose concentration, and insulin sensitivity (8–10). Higher gestational weight gain is associated with increased infant birth weight in lean and moderately overweight women (11) and in women with normal glucose tolerance (9) but not in obese women (11) or women with GDM (9). However, the factors influencing fetal fat accretion remain poorly understood.Both body weight and body composition at birth are different in male and female infants (12), and sex of the infant has been reported as a significant determinant of each (9). We hypothesized that the determinants of fetal body composition may also differ with fetal sex. The aim of this study was to identify factors that influence adiposity in male and female infants born to women treated for GDM.     

Comparison of body habitus in patients with pulmonary arterial hypertension enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management with normative values from the National Health and Nutrition Examination Survey

OBJECTIVE: To investigate the correlation between body mass index (BMI) and pulmonary artery systolic pressure in a large population of patients with pulmonary arterial hypertension (PAH).PATIENTS AND METHODS: The BMI of patients with group 1 PAH enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) was compared with that of age- and sex-matched controls in the National Health and Nutrition Examination Survey (NHANES) to clarify whether obesity is linked with PAH. The diagnosis of PAH was defined in REVEAL by right-sided heart catheterization. Differences in BMI and the percentage of patients considered obese (BMI ≥30) and underweight (BMI <18.5) in various subgroups of patients enrolled in REVEAL from March 30, 2006, through September 11, 2007, were determined.RESULTS: Mean BMI was no different for patients with PAH (n=2141) than for the NHANES normal comparison group; however, the proportion of obese and underweight patients was increased in patients with PAH. Subgroup analysis demonstrated that subgroups with idiopathic PAH and those with PAH associated with drugs and toxins had both higher BMI and percentage of obese patients, whereas 3 other subgroups (those with PAH associated with congenital heart disease, connective tissue disease, and human immunodeficiency virus) had lower mean BMI.CONCLUSION: Mean BMI of the REVEAL patients was the same as that of the NHANES normal comparison group; however, there were higher percentages of obese and underweight patients in REVEAL. This discrepancy can be explained by the balancing effect of more overweight and underweight patients in different PAH subgroups. The reason for the increased frequency of obesity in idiopathic PAH is unknown, and additional study is needed.Trial Registration: clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00370214","term_id":"NCT00370214"}}NCT00370214APAH = associated PAH; BMI = body mass index; CHD-APAH = congenital heart disease–APAH; CTD-APAH = connective tissue disease–APAH; FPAH = familial PAH; HIV-APAH = human immunodeficiency virus infection–APAH; IPAH = idiopathic PAH; LVEDP = left ventricular end-diastolic pressure; NHANES = National Health and Nutrition Examination Survey; PAH = pulmonary arterial hypertension; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PH = pulmonary hypertension; REVEAL = Registry to Evaluate Early and Long-term PAH Disease Management; RHC = right-sided heart catheterizationData from the National Health and Nutrition Examination Survey (NHANES) have demonstrated that 35% of US adults are classified as obese (body mass index [BMI], calculated as the weight in kilograms divided by the height in meters squared, ≥30).^1,2 In addition, up to 46% of patients with pulmonary arterial hypertension (PAH) have no clear cause for the disease (ie, idiopathic PAH [IPAH]).³ Although obesity is epidemic in the United States,^1,2 comprehensive reviews have listed obesity as an unlikely risk factor for PAH.⁴ However, there are no confirmed reports of a direct correlation of obesity with clinically significant PAH. Although a correlation between BMI and pulmonary artery systolic pressure has been identified in otherwise echocardiographically normal persons (Spearman rank correlation, 0.19; P<.01; N=3790),⁵ a retrospective review of 401 patients in the pulmonary hypertension (PH) database of Mayo Clinic in Florida found no correlation between BMI and diagnosis of PH when these patients were compared with controls (n=578).⁶PAH is characterized by mean pulmonary artery pressure (PAP) of 25 mm Hg or greater and pulmonary capillary wedge pressure (PCWP) of 15 mm Hg or less.^3,7 Group 1 PH comprises 5 categories: IPAH, familial PAH (FPAH; now referred to as heritable PAH), associated PAH (APAH; including PAH associated with connective tissue disease [CTD-APAH], drugs and toxins-PAH), congenital heart disease [CHD-APAH], human immunodeficiency virus infection [HIV-APAH], portal hypertension, schistosomiasis, and chronic hemolytic anemia), and persistent PH of the newborn.⁸The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) represents a unique opportunity to examine the potential relationship between obesity and PAH. REVEAL is a prospective study initiated to characterize the demographics, clinical course, hemodynamic features, and disease management of about 3500 US patients with group 1 PH.^3,9 This large database of patients with PAH permits a robust analysis of BMI and the percentage of overweight and underweight patients with PAH. REVEAL also provides an opportunity to identify potential associated risk factors in patients with IPAH, which, if confirmed, may generate hypothesis-based investigations to help determine causal links. In the current study, we compared patients in the REVEAL database with age- and sex-matched controls from NHANES to determine whether a relationship exists between BMI and the presence of PAH.     

Pilot Study of Providing Online Care in a Primary Care Setting

OBJECTIVE: To study the use of e-visits in a primary care setting.PATIENTS AND METHODS: A pilot study of using the Internet for online care (“e-visits”) was conducted in the Department of Family Medicine at Mayo Clinic in Rochester, MN. Patients in the department preregistered for the service, and then were able to use the online portal for consultations with their primary care physician. Use of the online portal was monitored and data were collected from November 1, 2007, through October 31, 2009.RESULTS: During the 2-year period, 4282 patients were registered for the service. Patients made 2531 online visits, and billings were made for 1159 patients. E-visits were submitted primarily by women during working hours and involved 294 different conditions. Of the 2531 e-visits, 62 (2%) included uploaded photographs, and 411 (16%) replaced nonbillable telephone protocols with billable encounters. The e-visits made office visits unnecessary in 1012 cases (40%); in 324 cases (13%), the patient was asked to schedule an appointment for a face-to-face encounter.CONCLUSION: Although limited in scope, to our knowledge this is the largest study of online visits in primary care using a structured history, allowing the patient to enter any problem, and billing the patient when appropriate. The extent of conditions possible for treatment by online care was far-ranging and was managed with a minimum of message exchanges by using structured histories. Processes previously given as a free service or by nurse triage and subject to malpractice (protocols) were now documented and billed.Some fundamental aspects of transforming primary care include eliminating barriers to access, using technology to communicate with patients, and enhancing financial performance.¹ Currently, it is possible for patients to use the Internet to see laboratory test results, make appointments, pay bills, and review their charts.² Some reports have shown improved patient satisfaction with use of these options.^3-5 Several articles have discussed electronic messaging (e-mails) as a way to improve efficiency by decreasing patient telephone calls to the physician''s office.^6-9 Various reports have described the use of the Internet to manage conditions such as depression,^10,11 diabetes mellitus,¹² hypertension,^13,14 and sexually transmitted diseases¹⁵ and also to assist with breastfeeding support,¹⁶ previsit well child encounters,¹⁷ and communication with patients in safety net practices.¹⁸ Guidelines have been established for providing medical care on the Internet (“e-visits”).¹⁹ Patients in primary care practices also have indicated a willingness to pay for online services.²⁰However, implementation of billable e-visits has been slow. “Reasons for provider hesitation to adopt e-visit technologies include fears of being overburdened by electronic communication, improper use of electronic communication by patients, lack of reimbursement schemes, legal and regulatory issues, and concerns over security, privacy, and confidentiality.”²¹ Also, electronic consultations to date have generally used online forms or secure e-mail. The information in these formats is unstructured and often lacks sufficient information, prompting the clinician to respond to the patient to request further information, which results in delays.²² Furthermore, the lack of organization in an e-mail makes it difficult to code complexity; consequently, the same fee is often charged for all online consultations, regardless of complexity.²³For editorial comment, see page 701Isolated reports of the use of online consultations have been disappointing. For example, despite indications that electronic communication could decrease health care costs²⁴ and provide reimbursement from patients,^25,26 Fairview Health System has reported only 10 e-visits per week in a system with 400 physicians,²⁷ and Blue Cross of Minnesota processed about 30 e-visits per month in July 2008 and 90 e-visits per month in July 2009 (D. Hiza, MD, written communication, February 2010).Studies have not described a portal for online patient consultations that has a structured medical history. Structured computerized histories were first described in the 1960s by Mayne et al²⁸ and Slack et al.²⁹ Their work included using the telephone and teletype with patients from distant locations providing their histories.³⁰ The evidence for using computerized histories to produce more organized histories, detect new symptoms, and provide greater patient satisfaction with improved clinician performance has been reviewed.³¹We conducted a pilot study of online patient visits in a primary care setting using structured histories and the possibility of the patients being billed for the service.     

Hypoglycemia and Outcome in Critically Ill Patients

OBJECTIVE: To determine whether mild or moderate hypoglycemia that occurs in critically ill patients is independently associated with an increased risk of death.PATIENTS AND METHODS: Of patients admitted to 2 hospital intensive care units (ICUs) in Melbourne and Sydney, Australia, from January 1, 2000, to October 14, 2004, we analyzed all those who had at least 1 episode of hypoglycemia (glucose concentration, <81 mg/dL). The independent association between hypoglycemia and outcome was statistically assessed.RESULTS: Of 4946 patients admitted to the ICUs, a cohort of 1109 had at least 1 episode of hypoglycemia (blood glucose level, <81 mg/dL). Of these 1109 patients (22.4% of all admissions to the intensive care unit), hospital mortality was 36.6% compared with 19.7% in the 3837 nonhypoglycemic control patients (P<.001). Even patients with a minimum blood glucose concentration between 72 and 81 mg/dL had a greater unadjusted mortality rate than did control patients (25.9% vs 19.7%; unadjusted odds ratio, 1.42; 95% confidence interval, 1.12-1.80; P=.004.) Mortality increased significantly with increasing severity of hypoglycemia (P<.001). After adjustment for insulin therapy, hypoglycemia was independently associated with increased risk of death, cardiovascular death, and death due to infectious disease.CONCLUSION: In critically ill patients, an association exists between even mild or moderate hypoglycemia and mortality. Even after adjustment for insulin therapy or timing of hypoglycemic episode, the more severe the hypoglycemia, the greater the risk of death.APACHE = Acute Physiology and Chronic Health Evaluation; AUC = area under the curve; CI = confidence interval; ICU = intensive care unit; IIT = intensive insulin therapy; NICE-SUGAR = Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation; OR = odds ratioUntil recently, intensive insulin therapy (IIT) had been recommended to improve patient outcome^1-3 despite its association with an increased risk of hypoglycemia.^4-11 However, hypoglycemia, like hyperglycemia,^12-16 has emerged as a possible predictor of mortality and morbidity in critically ill patients.^5,17-21The NICE-SUGAR (Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) trial found that IIT increased 90-day mortality compared with conventional treatment in critically ill patients.^22,23 In that trial, the incidence of severe hypoglycemia (blood glucose level, ≤40 mg/dL (to convert to mmol/L, multiply by 0.0555) was significantly higher with IIT. Furthermore, the relative risk of severe hypoglycemia was 13.7, more than twice that seen in prior randomized controlled trials.^5,9-11 Thus, the incidence of hypoglycemia might be a key element of blood glucose control in critically ill patients, although no causal link between hypoglycemia and mortality has been demonstrated. However, no consensus exists on the definition of hypoglycemia in patients with critical illness.²⁴ Studies thus far have mainly focused on severe hypoglycemia.For editorial comment, see page 215We sought to determine the epidemiology and independent association of hypoglycemia in the intensive care unit (ICU). We hypothesized that mild or moderate hypoglycemia would be common and would be independently associated with an increased risk of death.     

Tracheobronchial Pulmonary Disease Associated With Pyoderma Gangrenosum

We report a tracheobronchial pulmonary manifestation caused by pyoderma gangrenosum, a neutrophilic dermatosis of unknown etiology. A 54-year-old man presented with pulmonary infiltrates followed by multiple painful cutaneous pustules on the scrotum. Skin biopsy showed pronounced neutrophilic infiltration without microorganism or granuloma, consistent with pyoderma gangrenosum. Bronchoscopy revealed multiple scattered polypoid nodules with a yellowish irregular surface from the trachea to bilateral bronchi; the appearance closely mimicked that of a skin lesion. Endobronchial biopsy demonstrated inflamed granulation and necrosis with infiltration by numerous neutrophils without vasculitis or granulomas, interpreted as pyoderma gangrenosum of the bronchi. Although the etiology of pyoderma gangrenosum is poorly understood, this case suggests that a common pathogenesis may account for the simultaneous cutaneous and airway inflammation.Pyoderma gangrenosum is an uncommon inflammatory cutaneous disease characterized by sterile neutrophilic dermatosis of unknown etiology.^1,2 The disease has been reported in association with various systemic disorders, including inflammatory bowel disease, rheumatoid arthritis, and hematologic disease.^1,2 Pulmonary involvement in pyoderma gangrenosum has also been reported,^3-6 but few reports have described endobronchial lesions of pyoderma gangrenosum.⁶ In the current report, we demonstrate tracheobronchial pulmonary manifestation of pyoderma gangrenosum, the bronchoscopic appearance of which closely mimicked that of a skin lesion.