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.     

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.     

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 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.     

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     

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.     

Assessing and Managing All Aspects of Migraine: Migraine Attacks, Migraine-Related Functional Impairment, Common Comorbidities, and Quality of Life

Migraine can be characterized as a chronic disorder with episodic attacks and the potential for progression to chronic migraine. We conducted a PubMed literature search (January 1, 1970 through May 31, 2008) for studies on the impact of migraine, including disability, health-related quality of life (HRQoL), comorbidities, and instruments used by health care professionals to treat patients with migraine. Numerous studies have shown that migraine substantially impairs a person''s functions during attacks and diminishes HRQoL during and between attacks. Despite its impact, migraine remains underestimated, underdiagnosed, and undertreated. Several tools are available to help physicians assess the impact of migraine on the daily activities and HRQoL of their patients, such as the 36-Item Short-Form Health Survey and the Headache Impact Test. Improving communication during the office visit through active listening, use of open-ended questions, and use of the “ask-tell-ask” strategy can also help in assessing migraine-related impairment. Together, these tools and communication techniques can lead to a more complete assessment of how migraine affects patients'' lives and can aid in the development of the optimal treatment plan for each patient. Both pharmacotherapy (acute and preventive treatment strategies) and nonpharmacological therapies play important roles in the management of migraine.AMCS = American Migraine Communication Study; HIT = Headache Impact Test; HRQoL = health-related quality of life; MIBS = Migraine Interictal Burden Scale; MIDAS = Migraine Disability Assessment; MPQ = Migraine Prevention Questionnaire; MSQ = Migraine-Specific Quality of Life Questionnaire; PHQ = Patient Health Questionnaire; SF = Short-Form Health SurveyMigraine is recognized as a major cause of disability worldwide. The World Health Report 2001—Mental Health: New Understanding, New Hope cited 135 health conditions, particularly mental and neurologic disorders, that accounted for nearly 40% of all years lived with disability worldwide. Migraine was cited as the 19th leading cause of years lived with disability among both males and females of all ages combined and the 12th leading cause of years lived with disability among females of all ages.¹ Females with migraine outnumber males with migraine by nearly 3 to 1.²Migraine can be characterized as a chronic disorder with episodic attacks, with potential for progression to more frequent and severe patterns.³ Some patients whose migraine attacks are initially episodic experience increasing frequency of headaches over months or years, leading to chronic migraine, in which headaches occur at least 15 days per month.⁴ Migraine is associated with substantial functional impairment,⁵ which may include both physical and emotional ramifications. Many aspects of the lives of migraineurs are commonly affected by the condition, including occupational, academic, social, leisure, and family life and responsibilities.^5-8 It is well known that migraine headaches cause substantial impairment during attacks (ictal burden). However, mounting evidence suggests that migraines also cause impairment between attacks (interictal burden). In general, migraineurs report poorer subjective well-being and reduced health-related quality of life (HRQoL) during pain-free periods than do age- and sex-matched persons without migraine.^8-11For editorial comment, see page 397Health care professionals often do not recognize the degree and scope of functional impairment imposed by migraine.^7,10,12-14 This contributes to missed opportunities for providing effective acute treatment (medication taken at the time of an attack) and preventive pharmacological (medication taken on a daily basis or other scheduled protocol to avoid attacks) and biobehavioral interventions.^7,12,14We review the total burden of migraine and strategies for managing both the ictal and the interictal burden. A PubMed search of English-language articles published from January 1, 1970 through May 31, 2008 was conducted. The following keywords were used in our search: migraine, headache, migraine prevention, migraine prophylaxis or treatment, migraine disability, headache disability, migraine quality of life or health-related quality of life, migraine functional impairment, migraine assessment tools or scales or questionnaire, and migraine communication. The inclusion of specific studies was based on subjective, comparative evaluation and standard levels of evidence, with instruments that had the strongest psychosomatic data (validity, reliability) given more weight. Likewise, tools relevant to assist health care professionals with treatment of patients were selected.     

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.     

Patients Dismissed From the Hospital With a Diagnosis of Noncardiac Chest Pain: Cardiac Outcomes and Health Care Utilization

OBJECTIVE: To determine the proportion of patients with noncardiac chest pain (NCCP) who see a gastroenterologist, the type and frequency of gastrointestinal (GI) and cardiac tests performed, and the frequency of cardiac death.PATIENTS AND METHODS: A cohort of Olmsted County, Minnesota, residents presenting to the emergency department (ED) with chest pain between January 1, 1985, and December 31, 1992, was identified through the Rochester Epidemiology Project. We assessed the frequency of ED, cardiology, and gastroenterology visits and corresponding tests after a diagnosis of NCCP (n=320). We also assessed the frequency of cardiac events.RESULTS: During follow-up, 49% of patients sought care in the ED, 42% had repeated cardiology evaluations, and 15% were seen by a gastroenterologist. Thirty-eight percent underwent esophagogastroduodenoscopy, but very few underwent manometry or a pH probe. Patients with NCCP of unknown origin had 3 times the rate of GI consultations as their counterparts with a GI disorder. Survival free of cardiac death in the subset with NCCP with a GI disorder was 90.2% at 10 years and 84.8% at 20 years, compared with 93.7% at 10 years and 88.1% at 20 years for the subset with NCCP of unknown origin.CONCLUSION: The frequency of health care utilization in NCCP patients is high, but relatively few GI consultations and even fewer GI tests are performed. Patients dismissed from the hospital with NCCP continue to experience cardiac events, which may highlight a need for more aggressive cardiovascular risk factor management in this population.CABG = coronary artery bypass graft; CI = confidence interval; ED = emergency department; EGD = esophagogastroduodenoscopy; GERD = gastroesophageal reflux disease; GI = gastrointestinal; MI = myocardial infarction; NCCP = noncardiac chest pain; NCCP-GI = NCCP secondary to GI diagnoses; NCCP-U = NCCP of unknown originIn 2005, the American Heart Association estimated that 80 million Americans have cardiovascular disease.¹ The magnitude of this number has impelled patients and physicians to consider acute chest pain as a harbinger for impending myocardial infarction (MI) and potential death. Along with heightened sensitivity to the evaluation of chest pain has come increasing evidence that a significant proportion of individuals with chest pain have noncardiac chest pain (NCCP).² Noncardiac chest pain is defined by substernal chest pain in the absence of significant epicardial coronary artery stenoses. Previous population-based studies have reported the prevalence of this entity to be 23%.³Noncardiac chest pain is attributed to a variety of disorders, including gastroesophageal reflux disease (GERD) and esophageal hypersensitivity,⁴ panic attack,⁵ musculoskeletal pain,⁶ and microvascular disease (cardiac syndrome X).⁷ GERD is the most prevalent cause of NCCP, accounting for up to 60% of cases.^8-12 The prevalence of GERD in NCCP has been studied by pH monitoring and found to be 41% to 43%.^13,14The cost of evaluation of NCCP is estimated to be between $315 million and $1.8 billion per year.^4,15 The economic impact is further illustrated by a hospital-based prospective study that reported more frequent health care visits by patients with NCCP than by those with ischemic heart disease.¹⁶ Therefore, determining whether subgroups of patients with NCCP use more health care resources than others is important.For editorial comment, see page 309Although it is thought that patients with NCCP have a good prognosis, there is a paucity of data to support this conclusion. A few studies report that patients with normal findings on coronary angiography have minimal cardiac morbidity and mortality.^16,17 However, some studies point to increased cardiac mortality. A 16-year cohort study by Wilhelmsen et al¹⁸ found that men with nonspecific chest pain and normal findings on cardiac evaluation ultimately have high cardiovascular and noncardiovascular mortality rates. No large, long-term community studies have recorded the frequency of cardiac deaths that occur after a diagnosis of NCCP.We identified patients with a diagnosis of NCCP to determine the frequency of gastrointestinal (GI) consultations and testing and to identify the frequency of cardiac death.     

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).     

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.     

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.     

Long-term Maintenance Treatment of Restless Legs Syndrome With Gabapentin Enacarbil: A Randomized Controlled Study

OBJECTIVE: To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS).PATIENTS AND METHODS: This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression–Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food. The primary end point was the proportion of patients experiencing relapse (worse scores on the IRLS and investigator-rated Clinical Global Impression of Change scale on 2 consecutive visits at least 1 week apart or withdrawal because of lack of efficacy) during the DB phase.RESULTS: A total of 221 of 327 patients completed the SB phase, 194 (96 in the gabapentin enacarbil group and 98 in the placebo group) were randomized to DB treatment, and 168 (84 in the gabapentin enacarbil group and 84 in the placebo group) completed the DB phase. A significantly smaller proportion of patients treated with gabapentin enacarbil (9/96 [9%]) experienced relapse compared with the placebo-treated patients (22/97 [23%]) (odds ratio, 0.353; 95% confidence interval, 0.2-0.8; P=.02). Somnolence and dizziness were the most common adverse events. One death occurred (unintentional choking during the SB phase) and was judged as being unrelated to the study drug. No clinically relevant changes were observed in laboratory values, in vital signs, or on electrocardiograms.CONCLUSION: Gabapentin enacarbil, 1200 mg, maintained improvements in RLS symptoms compared with placebo and showed long-term tolerability in adults with moderate to severe primary RLS for up to 9 months of treatment.AE = adverse event; AMTD = adjusted mean treatment difference; CGI-C = Clinical Global Impression of Change; CGI-I = Clinical Global Impression–Improvement; CI = confidence interval; DB = double blind; IRLS = International Restless Legs Scale; ITT = intent to treat; LOCF = last observation carried forward; MOS = Medical Outcomes Study; OR = odds ratio; PIVOT = Patient Improvements in Vital Outcomes following Treatment; PSQ = Post-Sleep Questionnaire; QoL = quality of life; RLS = restless legs syndrome; SB = single blindThe sensorimotor disorder restless legs syndrome (RLS) is characterized by an urge to move the legs, usually accompanied or caused by uncomfortable sensations in the legs. Symptoms typically begin or worsen at rest, are worse in the evening or at night, and are temporarily relieved by movement.¹ Patients with RLS often report sleep disturbance that results in daytime fatigue, decreased alertness, and emotional distress.^2-4Dopamine agonists are currently the only approved treatment for RLS in the United States, but prolonged use may be associated with augmentation (a worsening of symptoms while receiving treatment)⁵ that can limit long-term use. Other dopaminergic-related adverse events (AEs), such as nausea, vomiting, orthostatic hypotension, syncope, and impulse control disorders, are reported to be treatment limiting in some patients.^6-11 Therefore, additional therapies for RLS are needed.Small studies have indicated that the nondopaminergic agent gabapentin may be an effective treatment of RLS.^12-14 However, gabapentin displays dose-dependent exposure because of saturable absorption and high interpatient variability,^15,16 resulting from absorption via low-capacity nutrient transporters located in a narrow region of the small intestine that start to become saturated at clinically relevant doses.^17-19 In studies of patients with epilepsy, these pharmacokinetic limitations have been shown to lead to varied treatment effectiveness and the need for more frequent daily dosing.^15,20 Gabapentin enacarbil is a transported prodrug of gabapentin that is being investigated for the treatment of RLS. After administration, gabapentin enacarbil is actively absorbed via high-capacity nutrient transporters throughout the small and large intestine and is rapidly converted to gabapentin, providing dose-proportional exposure and low interpatient variability.^21-23 Gabapentin enacarbil provides sustained gabapentin exposure and once-daily dosing for the treatment of RLS.^23,24For editorial comment, see page 508In a large placebo-controlled, 12-week study, gabapentin enacarbil, 1200 mg once daily, significantly improved RLS symptoms compared with placebo in adults with moderate to severe primary RLS and was generally well tolerated,²⁴ with an AE profile consistent with that of gabapentin.¹² The current study (PIVOT [Patient Improvements in Vital Outcomes following Treatment] RLS Maintenance) assessed the maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary RLS for up to 9 months.     

Fluorescence In Situ Hybridization to Visualize Genetic Abnormalities in Interphase Cells of Acinar Cell Carcinoma, Ductal Adenocarcinoma, and Islet Cell Carcinoma of the Pancreas

OBJECTIVE: To use fluorescence in situ hybridization (FISH) to visualize genetic abnormalities in interphase cell nuclei (interphase FISH) of acinar cell carcinoma, ductal adenocarcinoma, and islet cell carcinoma of the pancreas.PATIENTS AND METHODS: Between April 4, 2007, and December 4, 2008, interphase FISH was used to study paraffin-embedded preparations of tissue obtained from 18 patients listed in the Mayo Clinic Biospecimen Resource for Pancreas Research with a confirmed diagnosis of acinar cell carcinoma, ductal adenocarcinoma, islet cell carcinoma, or pancreas without evidence of neoplasia. FISH probes were used for chromosome loci of APC (see glossary at end of article for expansion of all gene symbols), BRCA2, CTNNB1, EGFR, ERBB2, CDKN2A, TP53, TYMP, and TYMS. These FISH probes were used with control probes to distinguish among various kinds of chromosome abnormalities of number and structure.RESULTS: FISH abnormalities were observed in 12 (80%) of 15 patients with pancreatic cancer: 5 of 5 patients with acinar cell carcinoma, 5 of 5 patients with ductal adenocarcinoma, and 2 (40%) of 5 patients with islet cell carcinoma. All 3 specimens of pancreatic tissue without neoplasia had normal FISH results. Gains of CTNNB1 due to trisomy 3 occurred in each tumor with acinar cell carcinoma but in none of the other tumors in this study. FISH abnormalities of all other cancer genes studied were observed in all forms of pancreatic tumors in this investigation.CONCLUSION: FISH abnormalities of CTNNB1 due to trisomy 3 were observed only in acinar cell carcinoma. FISH abnormalities of genes implicated in familial cancer, tumor progression, and the 5-fluorouracil pathway were common but were not associated with specific types of pancreatic cancer.5FU = 5-fluorouracil; FISH = fluorescence in situ hybridization; ND-FISH = interphase FISH to detect abnormalities of chromosome number and structure; SSC = standard saline citratePancreatic cancer afflicts more than 200,000 new patients worldwide each year, including more than 37,600 in the United States.^1-4 Surgery seldom cures pancreatic cancer and effective chemotherapies are largely unknown.⁵ Survival varies among patients with pancreatic cancer but is often measured in months.^6,7 Thus, novel genetic research of pancreatic cancer is urgently needed to help establish accurate diagnoses and to develop effective treatments for this important public health problem.This investigation used fluorescence in situ hybridization (FISH) to visualize chromosomal loci in interphase nuclei (interphase FISH) of acinar cell carcinoma, ductal adenocarcinoma, and islet cell carcinoma of the pancreas. Acinar cell carcinoma and ductal adenocarcinoma, which are nonendocrine tumors, and islet cell carcinomas, which are neuroendocrine tumors, reportedly occur in less than 1%, 95%, and 5%, respectively, of patients with pancreatic cancer.^3,8,9 In 2 retrospective studies of large series of patients, median survival for unresected ductal adenocarcinoma was 3 months⁸; for unresected acinar cell carcinoma, 25 months⁸; for nonfunctional islet cell carcinoma, 26 months⁹; and for functional islet cell carcinoma, 54 months.⁹Although some genetic studies of pancreatic cancer have been published, most focus on ductal adenocarcinoma. An assortment of genetic procedures have been attempted to investigate pancreatic cancer, including family history studies,¹ conventional cytogenetic techniques,¹⁰ interphase FISH,^11-13 comparative genomic hybridization,¹⁴ RNA expression analyses,^15,16 and evaluation of sequence variations.¹⁷ These studies implicate a variety of point mutations and chromosomal anomalies in most, if not all, patients with pancreatic cancer. Nevertheless, the biology of various forms of pancreatic cancer remains poorly understood, and this problem precludes efforts to establish novel genetic treatments for these disorders.This investigation used interphase FISH to visualize genetic abnormalities in individual normal and neoplastic cells in acinar cell carcinoma, ductal adenocarcinoma, and islet cell carcinoma of the pancreas.¹⁸ This research project was specifically designed to detect genetic abnormalities that have been shown via other genetic technologies to be associated with acinar cell carcinoma of the pancreas, familial pancreatic cancer, tumor progression in pancreatic cancer, or genes linked with the molecular pathway of 5-fluorouracil (5FU) chemotherapy.     

A ��Hot�� Topic in Dyslipidemia Management����How to Beat a Flush��: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

Niacin is the most effective lipid-modifying agent for raising high-density lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 1985, through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptor-mediated, mainly prostaglandin D₂–driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events.GPR = G_i protein–coupled receptor; HDL-C = high-density lipoprotein cholesterol; NSAID = nonsteroidal anti-inflammatory drug; PG = prostaglandin; RCT = randomized controlled trialReducing low-density lipoprotein cholesterol levels is the primary treatment for preventing cardiovascular disease, largely because of robust evidence from randomized controlled trials (RCTs) involving statins.^1,2 However, many patients optimally treated with statins have residual cardiovascular risk³ associated with low levels of high-density lipoprotein cholesterol (HDL-C), elevated levels of triglycerides, and a preponderance of small, dense (atherogenic) low-density lipoprotein particles.Niacin (3-pyridine-carboxylic acid; C₆H₅N0₂) is the most effective medication to raise HDL-C levels. A water-soluble B-complex (B₃) vitamin used to treat pellagra, niacin was discovered to lower cholesterol levels at higher (gram) doses in 1955.⁴ It was also the first lipid-lowering therapy proven in RCTs to significantly lower (by 27%) the risk of myocardial infarction and the risk of all-cause mortality in the long term (by 11%),^5,6 as well as confer significant angiographic benefits (7,10-15

TABLE 1.

Efficacy and Tolerability Findings From Major Randomized Controlled Trials of Niacin-Containing Therapies^aOpen in a separate windowNiacin improves the entire lipid panel in patients with dyslipidemia, lowering apolipoprotein B–containing lipoproteins and raising apolipoprotein A–containing lipoproteins (eg, high-density lipoproteins).¹⁶ Putative mechanisms for these multidimensional lipid benefits involve interactions of niacin with its G_i protein–coupled receptor (GPR109A) in adipose tissue, reducing free fatty acid release.^17,18One potential obstacle to effective use of lipid therapies is suboptimal treatment adherence and long-term persistence.^19-27 In recent studies, approximately 53% of niacin users did not reach recommended daily maintenance doses of 1.0 g or higher, 92% did not reach doses of 2 g, and flushing severity significantly predicted niacin treatment discontinuation.^28,29 This systematic review (1) explores the pathophysiology of niacin flushing, (2) characterizes its typical clinical presentation, (3) assesses the approximate frequency of niacin flushing and of discontinuations ascribed to flushing in clinical trials, (4) explores potential strategies to prevent or minimize flushing, and (5) surveys ongoing controversies.     

A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Armodafinil for Excessive Sleepiness Associated With Jet Lag Disorder

OBJECTIVE: To assess the effect of armodafinil, the longer-lasting isomer of modafinil, on jet lag disorder.PARTICIPANTS AND METHODS: This double-blind, randomized, parallel-group, multicenter study was conducted between September 18, 2008, and February 9, 2009. Adults with a history of jet lag symptoms on previous flights through multiple time zones flew from the United States to France (a 6-hour time zone change) for a 3-day laboratory-based study period. Participants received armodafinil (50 or 150 mg/d) or placebo each morning. Wakefulness was assessed by the coprimary outcomes, mean sleep latency on the Multiple Sleep Latency Test (MSLT) (average of all MSLT sessions across days 1 and 2) and Patient Global Impression of Severity in relation to jet lag symptoms (averaged across days 1 and 2).RESULTS: A total of 427 participants received armodafinil at 50 mg/d (n=142), armodafinil at 150 mg/d (n=143), or placebo (n=142). Armodafinil at 150 mg/d provided a significant benefit in sleep latency on the MSLT (days 1-2: mean, 11.7 minutes vs 4.8 minutes for placebo; P<.001) and participants'' perception of their overall condition in relation to jet lag symptoms (Patient Global Impression of Severity, days 1-2: mean, 1.6 vs 1.9 for placebo; P<.05). The most frequently reported adverse events for armodafinil at 150 mg/d were headache (27%), nausea (13%), diarrhea (5%), circadian rhythm sleep disorder (5%), and palpitations (5%).CONCLUSION: Armodafinil increased wakefulness after eastward travel through 6 time zones.Trial Registration: clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00758498","term_id":"NCT00758498"}}NCT00758498ANCOVA = analysis of covariance; KSS = Karolinska Sleepiness Scale; MSLT = Multiple Sleep Latency Test; NPSG = nocturnal polysomnography; PGI-S = Patient Global Impression of Severity; STAI = State and Trait Anxiety Inventory; SWD = shift work disorderJet lag disorder is a circadian rhythm sleep disorder that occurs as a consequence of rapid travel through multiple time zones.¹ The traveler may experience excessive sleepiness, fatigue, insomnia, irritability, gastrointestinal disturbance, or other symptoms after arrival at the destination.^2-4 Jet lag symptoms arise from the desynchronization between the body''s circadian rhythm, which is synchronous with the location of departure, and the new sleep/wake cycle required at the destination.^1-4 Effects tend to be more severe when a greater number of time zones are traversed, and following eastbound travel.^2,5,6 Although the percentage of people flying across multiple time zones who develop jet lag disorder is unclear, it is estimated that possibly up to two-thirds of all travelers experience jet lag and may experience symptoms such as excessive sleepiness during the day or insomnia.² A treatment for excessive sleepiness that promotes daytime wakefulness may be especially beneficial to travelers who have a limited amount of time at their destination, precluding a circadian readjustment.Armodafinil, the longer-lasting R-isomer of racemic modafinil,⁷ is a wakefulness-promoting medication. The terminal half-life of the R-isomer is approximately 15 hours, compared with 3 to 4 hours for the S-isomer.^8,9 In a study of patients with shift work disorder (SWD), another circadian rhythm disorder, armodafinil 150 mg/d significantly improved wakefulness and clinicians'' perception of patients'' overall condition, compared with placebo.¹⁰ The primary objective of this study was to evaluate armodafinil (50 mg/d and 150 mg/d) for treatment of excessive sleepiness associated with jet lag disorder due to eastbound travel in a population of travelers with a history of jet lag symptoms.     

Colonic polyposis and neoplasia in Cowden syndrome

OBJECTIVE: To identify and describe the frequency, histologic features, and clinical outcome of colon polyposis and neoplasia in Cowden syndrome—a rare familial hamartoma tumor syndrome associated with mutations in the PTEN gene.PATIENTS AND METHODS: Patients with a clinical diagnosis of PTEN hamartoma tumor syndrome-Cowden phenotype were retrospectively identified and studied. Only those who underwent colonoscopy or colon pathologic interpretation were included in the final analysis.RESULTS: From 1994 to 2009, 13 patients met study inclusion criteria. Of the 10 patients who underwent colonoscopy, 9 (90%; 95% confidence interval [CI], 57%-100%) had polyps, and 7 (70%; 95% CI, 39%-90%) were estimated to have more than 50 polyps. Pathologic findings of the colon were reviewed in 11 patients, and the spectrum of tumors included hamartomatous, inflammatory, adenomatous, ganglioneuromatous, hyperplastic, and juvenile polyps. Of the 13 patients, 2 (15%; 95% CI, 3%-43%) had left-sided adenocarcinoma without microsatellite instability. Five (38%) of the 13 patients underwent colectomy secondary to polyp dysplasia.CONCLUSION: Patients with Cowden syndrome have a heavy colon polyp burden with a wide pathologic spectrum, both benign and malignant. The colon polyposis results in a previously unreported morbidity with a high colectomy rate.AJCC = American Joint Committee on Cancer; CI = confidence interval; CS = Cowden syndrome; GI = gastrointestinal; NCCN = National Comprehensive Cancer Network; PHTS = PTEN hamartoma tumor syndromeThe PTEN hamartoma tumor syndrome (PHTS) is a spectrum of autosomal dominant clinical disorders associated with mutations of the PTEN or phosphatase and tensin homolog gene on chromosome 10.^1,2 Cowden syndrome (CS) is the most common phenotype, with an estimated incidence of 1 in 200,000 to 250,000 people.³ The pathognomonic features of CS are mucocutaneous and include trichilemmomas, acral keratoses, and papillomatous lesions. Patients with CS also have a high risk of thyroid, breast, and endometrial neoplasms.⁴ Gastrointestinal (GI) polyposis is a common manifestation and can occur throughout the entire tract; however, the frequency of colon involvement in patients with CS is unclear.⁵Cowden syndrome is classified as a hamartomatous polyposis syndrome—hamartomas being disorganized overgrowths of cells and tissue native to the anatomic location in which they occur. In the GI tract, these include both epithelial and stromal proliferations. Hamartomatous colon polyps, which can histologically resemble juvenile or Peutz-Jeghers polyps, are thought to predominate in CS. However, a wide variety of other polyp histologic findings have been described, including adenomatous, inflammatory, hyperplastic, lymphoid, ganglioneuromatous, and leiomyomatous polyps.^6-8 Despite reports of multiple colon polyp histologic diagnoses from single patients,^9,10 it is uncertain whether this is a common phenomenon.¹¹Traditionally, patients with CS have not been considered to have an increased risk of colorectal cancers.^6,12 This impression has started to change. Several case reports have described colorectal cancer in CS, including one describing multiple colorectal cancers in a single patient.^13-15 A recent study of a multicenter cohort of PTEN mutation carriers reported 13% with colorectal cancer; all affected patients were younger than age 50 years.¹⁶ Furthermore, a recent compilation of cases reported a 16% (95% confidence interval [CI], 8%-24%) lifetime colorectal cancer risk in patients with CS.¹⁷The uncertainty of the prevalence and risks of colorectal polyposis in patients with CS is reflected in the lack of recommendations regarding colorectal screening or surveillance in the National Comprehensive Cancer Network (NCCN) treatment guidelines.¹⁸ The purpose of this study was to investigate the spectrum of colon disease in patients with CS, with special emphasis on polyp frequency, histopathologic findings, and clinical outcomes.