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.     

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.     

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.     

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.     

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).     

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.     

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     

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.     

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.     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

Tetralogy of fallot repair in patients 40 years or older

OBJECTIVE: To report the outcomes of patients with tetralogy of Fallot (TOF) undergoing surgical repair at age 40 years or older.PATIENTS AND METHODS: We reviewed records of patients (age, ≥40 years) who underwent TOF repair from January 1, 1970, through December 31, 2007. Symptoms, palliative procedures, surgical reports, and long-term outcomes were analyzed.RESULTS: Fifty-two patients (30 men [58%]) had surgery at a mean ± SD age of 50±8 years; 27 (52%) had prior palliative surgery at a mean ± SD age of 17±11 years. Procedures for TOF repair included pulmonary valve replacement (n=10), transannular patch (n=10), and native pulmonary valve preservation (n=32). The 30-day mortality rate was 6% (stroke, n=2; ventricular fibrillation, n=1). A mean ± SD follow-up of 14.9±9.3 years was feasible in 48 of 49 survivors; improvement in functional class was observed in 42 patients. Reoperation was performed in 7 patients (4 for pulmonary regurgitation). Twenty-nine patients died (mean ± SD age, 65±12 years); causes of death were cardiac (n=7), noncardiac (n=4), and unknown (n=18). Mean ± SD age at death was younger in patients with previous palliation (59±11 years vs 70±12 years; P=.03). The 10-year survival rate was lower than expected compared with an age- and sex-matched population (73% vs 91%; P<.001).CONCLUSION: Complete repair of TOF in patients 40 years or older is feasible but carries increased operative risk. Surgical survivors have improvement in functional class; however, survival remains lower than expected. Reduced survival and need for reoperation emphasize the importance of pulmonary valve replacement at the time of initial repair and long-term follow-up.CI = confidence interval; HR = hazard ratio; NYHA = New York Heart Association; TOF = tetralogy of FallotTetralogy of Fallot (TOF), which was first described in 1888 by Etienne-Louis Fallot,¹ is the most common cyanotic, congenital heart disease; it consists of a ventricular septal defect, right ventricular outflow tract obstruction, aortic override, and right ventricular hypertrophy. Surgical repair of TOF has been performed since 1955.² Early primary repair has been recommended since the 1970s and is now routinely performed with excellent results.³ However, we still occasionally encounter patients who have not undergone repair or have had only a palliative procedure; these patients thus are considered for surgical correction later in life.^4,5 Few studies describe the outcome of such patients. However, the chronic hypoxia that is characteristic of patients with unrepaired or palliated TOF may cause cerebral complications because of the right-to-left shunt, myocardial dysfunction, and an increased incidence of ventricular and atrial arrhythmias.^6-8This study was designed to analyze symptoms, operative technique, and outcome in patients who were 40 years or older when complete TOF repair was undertaken. We further aimed to compare outcomes of patients who did and did not receive prior palliation.     

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.     

Multitissue insulin resistance despite near-normoglycemic remission in Africans with ketosis-prone diabetes

OBJECTIVE—To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission.RESEARCH DESIGN AND METHODS—At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU · m⁻² body surface · min⁻¹ and 80 mU · m⁻² · min ⁻¹ insulin infusion rates) euglycemic clamp with [6,6-²H₂]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test.RESULTS—The total glucose disposal was reduced in patients compared with control subjects (7.5 ± 0.8 [mean ± SE] vs. 10.5 ± 0.9 mg · kg⁻¹ · min⁻¹; P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 ± 0.3 vs. 3.0 ± 0.1 mg · kg⁻¹ · min⁻¹; P = 0.001) and after 200-min insulin infusion (10 mU · m⁻² · min⁻¹: 1.6 ± 0.2 vs. 0.6 ± 0.1, P = 0.004; 80 mU · m⁻² · min⁻¹: 0.3 ± 0.1 vs. 0 mg · kg⁻¹ · min⁻¹, P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 ± 161.4 vs. 1,230.0 ± 174.1 μmol/l; P = 0.002) and remained higher after 100-min 10 mU · m⁻² · min⁻¹ insulin infusion (706.6 ± 96.5 vs. 381.6 ± 55.9 μmol/l; P = 0.015).CONCLUSIONS—The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.Impairment of insulin sensitivity is considered the background defect that interplays with the add-on progressive β-cell dysfunction to underlie the development of type 2 diabetes (1,2). An atypical form of diabetes, ketosis-prone diabetes (KPD), has been described over the past 2 decades and may represent a significant proportion of diabetes cases in people of sub-Saharan African origin (3,4). Patients with KPD present at onset with acute hyperglycemia, usually >30 mmol/l, and ketosis or ketoacidosis as type 1 diabetes but do not have autoimmune markers against the islet β-cell (3,5–7). The correction of those insulin-requiring acute-phase disorders is followed in >50% of cases by an insulin-free near-normoglycemic remission weeks to months later (8–10), thus resembling the course of type 2 diabetes. The pathogenesis and, consequently, the classification of KPD are still debated. It was classified under idiopathic type 1 diabetes or type 1B diabetes (11). However, growing evidence based on clinical and metabolic studies suggests its high phenotypical likeness to type 2 diabetes, and “ketosis-prone type 2 diabetes” has been proposed as a provisional name and is being used elsewhere (4,8,12). Metabolic studies have evidenced insulin secretion deficiency as the major determinant of the ketotic onset (8–10). This deficit is marked by a loss of acute-phase insulin secretion in response to intravenous glucose (10) or a decrease in C-peptide response to glucagon (9,10). The subsequent remission process is due to a restoration, at least partial, of the β-cell insulin secretory capacity after achievement of good metabolic control (8,10). Insulin action was assessed in three reports, but only toward glucose metabolism, and was found to be normal or decreased while patients were in good metabolic control (6,8,10). Moreover, most studies on KPD have been reported in African-Americans who are more overweight than native Africans and may be metabolically different from them, as suggested earlier (13).In this study, we aimed at characterizing all aspects of insulin action in Africans with KPD when in the near-normoglycemic state without insulin treatment compared with control subjects of the same geographic origin.     

Effect of Pregnancy on Postural Tachycardia Syndrome

OBJECTIVES: To compare the clinical presentation, autonomic dysfunction, and pregnancy outcomes in parous and nulliparous women with postural tachycardia syndrome (POTS) and in women with POTS before and after pregnancy.PATIENTS AND METHODS: This study consists of women who had at least 1 pregnancy during which time they met criteria for POTS between May 1993 and July 2009. All patients underwent standard autonomic testing. POTS was defined as a heart rate (HR) increase of greater than 30 beats/min on head-up tilt (HUT) with symptoms of orthostatic intolerance. Patients'' charts were reviewed retrospectively to determine pregnancy outcomes.RESULTS: Clinical characteristics related to POTS did not differ between parous and nulliparous women except for disease duration (parous, 3.7±2.6; nulliparous, 2.1±2.2; P<.001). Autonomic dysfunction did not differ between groups (change in HR on HUT: parous, 42.6±12.0 beats/min; nulliparous, 41.3±10.6 beats/min; P=.39). Of 116 total pregnancies, adverse pregnancy outcomes were reported in 9% and maternal complications in 1%. No complication was related to POTS. There was a trend toward modest improvement in autonomic dysfunction before and after pregnancy (change in HR on HUT: before pregnancy, 38.1±22.7 beats/min; after pregnancy, 21.9±14.9 beats/min; P=.07).CONCLUSION: The long-term impact of pregnancy on POTS does not appear to be clinically important. However, there does appear to be a trend toward improvement in the short-term postpartum period. Adverse pregnancy events were similar to those seen in the general public and do not present a barrier to women with POTS who want to have children.CASS = composite autonomic severity score; HR = heart rate; HUT = head-up tilt; OI = orthostatic intolerance; POTS = postural tachycardia syndrome; TST = thermoregulatory sweat testPostural tachycardia syndrome (POTS) is defined as the development of orthostatic symptoms associated with an increase in heart rate (HR) greater than 30 beats/min. More severe cases are associated with a standing HR increase greater than 120 beats/min.¹ Orthostatic symptoms most often include light-headedness, palpitations, presyncope, and exacerbations with heat or exercise.² Overall, the prognosis of POTS has been reported to be favorable in follow-up studies, with 80% of patients reporting improvement and 60% becoming functionally normal.³Onset of POTS occurs predominantly between the ages of 15 and 50 years,⁴ with a female predominance.^1,2,5-7 The female-to-male ratio has been reported to be as high as 5:1.⁸ Given the female predominance and the occurrence of POTS during the childbearing years, the effects of this disorder on pregnancy is often raised in clinical practice. However, until recently published data have been minimal. A recent study in 22 women indicated that, although the effect on symptoms related to POTS during pregnancy varied, the actual pregnancy was not affected.⁹The objectives of this study were as follows: (1) to determine whether differences exist in clinical presentation, autonomic dysfunction, and/or laboratory parameters between parous and nulliparous women who meet the criteria for the diagnosis of POTS; (2) to describe pregnancy outcomes in women diagnosed with POTS; (3) to determine whether there are differences in autonomic function testing results and orthostatic intolerance (OI) before and after pregnancy in women diagnosed with POTS; and (4) to describe changes with regard to OI that occurs during the course of pregnancy.     

Spontaneous coronary artery dissection: a disease-specific, social networking community-initiated study

OBJECTIVE: To develop and assess the feasibility of a novel method for identification, recruitment, and retrospective and prospective evaluation of patients with rare conditions.PATIENTS AND METHODS: This pilot study is a novel example of “patient-initiated research.” After being approached by several members of an international disease-specific support group on a social networking site, we used it to identify patients who had been diagnosed as having at least 1 episode of spontaneous coronary artery dissection and recruited them to participate in a clinical investigation of their condition. Medical records were collected and reviewed, the original diagnosis was independently confirmed by review of imaging studies, and health status (both interval and current) was assessed via specially designed questionnaires and validated assessment tools.RESULTS: Recruitment of all 12 participants was complete within 1 week of institutional review board approval (March 18, 2010). Data collection was completed November 18, 2010. All participants completed the study questionnaires and provided the required medical records and coronary angiograms and ancillary imaging data.CONCLUSION: This study involving patients with spontaneous coronary artery dissection demonstrates the feasibility of and is a successful model for developing a “virtual” multicenter disease registry through disease-specific social media networks to better characterize an uncommon condition. This study is a prime example of patient-initiated research that could be used by other health care professionals and institutions.From a patient''s perspective, being diagnosed as having a rare condition is challenging. Frustration regarding the treating physicians'' lack of knowledge about and experience with their specific condition is often compounded by repeated reminders regarding its obscurity. Patients grow tired of hearing how little is known and how “unique” and “unusual” they are, and those with sometimes fatal conditions are often frightened by the seeming “shotgun” or inconsistent approach to management and the explicit and implicit messages that their health care professionals have “no data” to guide treatment recommendations. Patients with rare diseases therefore increasingly seek answers, medical information, and peer support on the Internet. Our study aimed to test the feasibility of collecting retrospective and prospective clinical data and original diagnostic imaging studies from persons self-identified with spontaneous coronary artery dissection (SCAD) in an Internet-based heart disease support network.First described in 1931, SCAD is a rare, poorly understood cause of myocardial infarction. It occurs in relatively young persons¹ and represents a tiny proportion (0.07%-1.1%) of patients undergoing angiography in most registries and series.^2-4 Among reported case series ranging from 3 to 47 cases, there is an approximate 2:1 female predominance. About one third of the cases in women occur in the peripartum period. SCAD may present as sudden death,⁵ angina, or myocardial infarction and may be responsible for as many as 1 of 10 episodes of acute coronary syndrome in women younger than 50 years.² Despite hundreds of published case reports and small case series,^2-4,6-13 to our knowledge only 1 SCAD patient registry has been developed,⁵ and no data from multicenter clinical trials are available to guide treatment. Because of the paucity of clinical data and inconsistent follow-up and reporting, the prevalence, recurrence rate, and long-term prognosis after SCAD remain uncertain,^5,14-18 and the underlying etiology and optimal short- and long-term management are ambiguous.^18,19 As with other poorly understood conditions, many survivors are highly active in seeking information from any available source and seek to learn from experiences of others similarly affected.     

Using a Multidisciplinary Training Program to Reduce Peritonitis in Peritoneal Dialysis Patients

♦ Objectives: The present study evaluated the tool used to assess patients’ skills and the impact on peritonitis rates of a new multidisciplinary peritoneal dialysis (PD) education program (PDEP).♦ Methods: After the University Hospital Ethics Committee approved the study, the educational and clinical records of PD patients were retrospectively analyzed in two phases. In phase I, an Objective Structured Assessment (OSA) was used during August 2008 to evaluate the practical skills of 25 patients with adequate Kt/V and no mental disabilities who had been on PD for more than 1 month. Test results were correlated with the prior year’s peritonitis rate. In phase II, the new PDEP, consisting of individual lessons, a retraining schedule, and group meetings, was introduced starting 1 September 2008. Age, sex, years of education, time on PD, number of training sessions, and peritonitis episodes were recorded. Statistical analyses used t-tests, chi-square tests, and Poisson distributions; a p value of less than 0.05 was considered significant.♦ Results: In phase I, 25 patients [16 men, 9 women; mean age: 54 ± 15 years (range: 22 - 84 years); mean time on PD: 35 ± 30 months (range: 1 - 107 months)] were studied. The OSA results correlated with peritonitis rates: patients who passed the test had experienced significantly lower peritonitis rates during the prior year (p < 0.05). In phase II, after the new PDEP was introduced, overall peritonitis rates significantly declined (to 0.28 episodes/patient-year from 0.55 episodes/patient-year, p < 0.05); the Staphylococcus peritonitis rate also declined (to 0.09 episodes/patient-year from 0.24 episodes/patient-year, p < 0.05).♦ Conclusions: The OSA is a reliable tool for assessing patients’ skills, and it correlates with peritonitis rates. The multidisciplinary PDEP significantly improved outcomes by further lowering peritonitis rates.Key words: Objective structured assessment, therapeutic education, peritonitis ratePeritonitis is a major complication and the main cause of peritoneal dialysis (PD) failure, severely affecting patient morbidity and mortality. Despite regularly updated guidelines from the International Society for Peritoneal Dialysis (ISPD) on PD-related infections and their prevention and treatment (1-3), peritonitis continues to be a worrisome problem throughout the world (4-8).Patient training is recognized to be very important in preventing this complication (9-11). The impact of patients’ knowledge about their illness on outcome is well known in diabetes and other chronic conditions (12,13). Education programs with a theoretical basis, using cognitive framing and motivational interviewing principles, are associated with improved outcomes (14-20). A multidisciplinary approach with a precise schedule—“therapeutic education” (11)—has became an important therapeutic tool (21,22). The ISPD guidelines (10) assert that a new PD education program (PDEP) may be evaluated by observing changes in peritonitis rates, but the value of individual evaluation at the end of a training period is still controversial (11). Chen et al. (23) found no correlation between post-training test scores and peritonitis rates. Russo et al. (24) proposed a theoretical questionnaire and a practical evaluation of patient performance using the Nurse Score Card as a checklist.In an effort to lower the peritonitis incidence, we decided to change our PD training and retraining program and also our evaluation tool. We used questionnaires during training and a practical evaluation tool similar to the Objective Structured Clinical Assessment, first introduced by Harden et al. in the evaluation of medical students in 1975 (25) and today widely used for that purpose.In the present study, we evaluated the tool used to assess patients’ skills and the impact on peritonitis rates of a new multidisciplinary PDEP.     

Informatics Infrastructure for Syndrome Surveillance, Decision Support, Reporting, and Modeling of Critical Illness

OBJECTIVE: To develop and validate an informatics infrastructure for syndrome surveillance, decision support, reporting, and modeling of critical illness.METHODS: Using open-schema data feeds imported from electronic medical records (EMRs), we developed a near-real-time relational database (Multidisciplinary Epidemiology and Translational Research in Intensive Care Data Mart). Imported data domains included physiologic monitoring, medication orders, laboratory and radiologic investigations, and physician and nursing notes. Open database connectivity supported the use of Boolean combinations of data that allowed authorized users to develop syndrome surveillance, decision support, and reporting (data “sniffers”) routines. Random samples of database entries in each category were validated against corresponding independent manual reviews.RESULTS: The Multidisciplinary Epidemiology and Translational Research in Intensive Care Data Mart accommodates, on average, 15,000 admissions to the intensive care unit (ICU) per year and 200,000 vital records per day. Agreement between database entries and manual EMR audits was high for sex, mortality, and use of mechanical ventilation (κ, 1.0 for all) and for age and laboratory and monitored data (Bland-Altman mean difference ± SD, 1(0) for all). Agreement was lower for interpreted or calculated variables, such as specific syndrome diagnoses (κ, 0.5 for acute lung injury), duration of ICU stay (mean difference ± SD, 0.43±0.2), or duration of mechanical ventilation (mean difference ± SD, 0.2±0.9).CONCLUSION: Extraction of essential ICU data from a hospital EMR into an open, integrative database facilitates process control, reporting, syndrome surveillance, decision support, and outcome research in the ICU.EMR = electronic medical record; ICU = intensive care unit; IRB = Institutional Review Board; METRIC = Multidisciplinary Epidemiology and Translational Research in Intensive Care; SQL = structured query languageThe relevance of care in the intensive care unit (ICU) to public health in the United States is reflected in annual figures of 4.4 million ICU admissions, 500,000 deaths, 13.3% of hospital costs, 4.2% of national health expenditures, and 0.56% of the gross domestic product.^1,2 This demand is expected to increase as the US population ages; patients older than 65 years currently account for more than 55% of all ICU days.^3,4 Unmeasured burdens include the high degree of disability and loss of productivity for both ICU survivors and their caregivers.^5-7The complexity of the ICU environment, characterized by a vast amount of information and the critical importance of timing of interventions, presents a major barrier to safe and efficient care delivery.^8,9 Recent advances in medical informatics and the anticipated widespread implementation of electronic medical records (EMRs) combine to provide an opportunity to facilitate processes for delivery of safe, high-quality care in the ICU.This article describes the development and implementation of the Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Data Mart, an informatics infrastructure for syndrome surveillance, decision support, reporting, and modeling of critical illness at Mayo Clinic.     

Mature Survival Data for 176 Patients Younger Than 60 Years With Primary Myelofibrosis Diagnosed Between 1976 and 2005: Evidence for Survival Gains in Recent Years

In the past 20 years, management of primary myelofibrosis (PMF) has incorporated new treatment approaches, but survival benefits have not been confirmed in controlled studies. This retrospective study includes 176 consecutive patients younger than age 60 years in whom PMF was diagnosed during a 30-year period (1976-2005). Median age at diagnosis was 50 years (range, 18-59 years), and 98 patients (55%) were men. At the time of this report, 99 patients (56%) had died; the 77 surviving patients were followed up for a median of 8 years (range, 4-24 years). Overall median survival was 9.2 years, and 15- and 20-year survival rates were 32% and 20%, respectively. According to the Dupriez Prognostic Scoring System (PSS), median survivals were 12.7, 4.8, and 2.4 years in low- (n=117), intermediate- (n=44) and high- (n=15) risk patients (P<.001). According to the International PSS, median survivals were 13.4, 9.7, 3.3, and 2.4 years in low- (n=76), intermediate-1 (n=50), intermediate-2 (n=29), and high-risk patients (n=8; P<.001). To examine the effect of decade of diagnosis on survival, we divided study patients into 3 groups by year of diagnosis: 1976-1985 (n=36), 1986-1995 (n=45), and 1996-2005 (n=95). The corresponding median survivals were 4.8, 7.3, and “not reached” (P=.003), and the difference in survival was significant during multivariable analysis that included risk scores according to the aforementioned PSSs and age as covariates. The improvement in survival in recent years was most apparent in patients with high/intermediate-risk disease (P<.002), not in those with low-risk disease (P=.42). These observations are encouraging and suggest a salutary effect from modern therapeutic approaches in PMF.allo-HCT = allogeneic hematopoietic cell transplant; CIC = conventional intensity conditioning; PMF = primary myelofibrosis; PSS = Prognostic Scoring System; RIC = reduced-intensity conditioningPrimary myelofibrosis (PMF) is a hematologic malignancy currently classified as a myeloproliferative neoplasm.¹ Pathogenetic mechanisms in PMF include stem cell—derived clonal myeloproliferation and recurrent but nonspecific cytogenetic and molecular abnormalities.^2-4 Clinical manifestations include anemia, marked hepatosplenomegaly, constitutional symptoms, cachexia, and extramedullary hematopoiesis.⁵ Blood and bone marrow changes include leukoerythroblastosis seen in the peripheral blood smear, bone marrow fibrosis, and osteosclerosis.⁵ Primary myelofibrosis should be distinguished from post—polycythemia vera myelofibrosis or post—essential thrombocythemia myelofibrosis,⁶ although management of all 3 is similar.Primary myelofibrosis is associated with both short-ened survival and poor quality of life.⁷ Causes of death include progression to blast phase disease.⁸ Currently, 5 main treatment approaches are available for PMF⁹: (1) observation alone for asymptomatic disease without severe anemia or marked splenomegaly; (2) conventional drug therapy for either anemia (eg, androgen preparations, danazol, cortico steroids, erythropoiesis-stimulating agents, thalidomide, or lenalidomide) or splenomegaly, thrombocytosis, or leukocytosis (eg, hydroxyurea)¹⁰; (3) use of experimental drugs such as pomalidomide¹¹ or JAK2 inhibitors¹²; (4) palliative surgery (eg, splenectomy) or radiation therapy for symptomatic extramedullary hematopoiesis; and (5) allogeneic hematopoietic cell transplant (allo-HCT).¹³Currently, allo-HCT is the only treatment approach for PMF (or post—polycythemia vera or post—essential thrombocythemia myelofibrosis) that is potentially curative.¹⁴ The first series of reports on the value of con ventional intensity conditioning (CIC) allo-HCT for myelofibrosis appeared in the 1990s and included a seminal paper published in 1999.¹⁵ Since then, reduced-intensity conditioning (RIC) regimens have been used and promoted as being less toxic and as effective as CIC regimens.¹⁶ The overall value of both RIC and CIC allo-HCT is undermined by high incidences of treatment-related mortality and morbidity, and survival benefit has not been shown in a controlled setting.¹⁷ Similarly, the first report on the use of thalidomide for PMF appeared in 2000,¹⁸ but its value, as well as that of other new drugs for PMF,¹⁹ in terms of survival has not been systematically analyzed. Furthermore, an increasing number of patients with PMF are participating in clinical trials. Considering all these issues, it is reasonable to examine survival trends in PMF during the past few decades.