University of Utah Hospital

While medications can improve patients' health, the process of prescribing them is complex and error prone, and medication errors cause many preventable injuries. Computer provider order entry (CPOE) with clinical decision support (CDS), can improve patient safety and lower medication-related costs. To realize the medication-related benefits of CDS within CPOE, one must overcome significant challenges. Healthcare organizations implementing CPOE must understand what classes of CDS their CPOE systems can support, assure that clinical knowledge underlying their CDS systems is reasonable, and appropriately represent electronic patient data. These issues often influence to what extent an institution will succeed with its CPOE implementation and achieve its desired goals. Medication-related decision support is probably best introduced into healthcare organizations in two stages, basic and advanced. Basic decision support includes drug-allergy checking, basic dosing guidance, formulary decision support, duplicate therapy checking, and drug-drug interaction checking. Advanced decision support includes dosing support for renal insufficiency and geriatric patients, guidance for medication-related laboratory testing, drug-pregnancy checking, and drug-disease contraindication checking. In this paper, the authors outline some of the challenges associated with both basic and advanced decision support and discuss how those challenges might be addressed. The authors conclude with summary recommendations for delivering effective medication-related clinical decision support addressed to healthcare organizations, application and knowledge base vendors, policy makers, and researchers.

Cysts and cystic-appearing intracranial masses have a broad imaging and pathologic spectra. The authors review the pathologic findings, origin, radiologic appearance, and differential diagnosis of many different intracranial cysts. A diagnostic algorithm based on most common anatomic locations is presented that helps narrow the differential diagnosis.

A 39-year-old female executive has a several-month history of fatigue, headache, and memory lapse. During a period of feeling worse than usual, she called a friend, who arrived at the residence to find the woman semicomatose and called 911. The patient was given supplemental oxygen and transported to the emergency department, where she is alert and has nonfocal findings on examination. Her carboxyhemoglobin level is 18%. How should she be treated? What is her expected outcome?

BACKGROUND: Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms. METHODS: We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest. RESULTS: Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids. CONCLUSIONS: Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).

Acute respiratory distress syndrome (ARDS) is a disease of acute respiratory failure manifested by severe hypoxemia with a high mortality rate. Previous outcome studies of ARDS have assessed survival and/or pulmonary function as the primary outcome variables. Cognitive or psychological outcomes following ARDS have not been described, despite the possibility that ARDS patients are at risk for brain injury through hypoxemia or other mechanisms. In the current study 55 consecutive ARDS survivors completed a battery of neuropsychological tests and questionnaires regarding health status, cognitive and psychological outcomes at the time of hospital discharge and 1 yr after onset of ARDS. At hospital discharge, 100% (55 of 55) of survivors exhibited cognitive and affective impairments, as well as problems with health status which affected their quality of life. At 1 yr after ARDS, 17 of 55 (30%) patients still exhibited generalized cognitive decline. Forty-three of 55 (78%) patients had all or at least one of the following: impaired memory, attention, concentration and/or decreased mental processing speed. One year after ARDS a substantial portion of ARDS survivors exhibit impaired health status and cognitive sequelae which may be due to hypoxemia, emboli, inflammation, drug toxicity, and/or other etiologies.

Side effects of antidepressants can be predicted by receptor selectivity and site of action. Although the selective serotonin reuptake inhibitors (SSRIs) have better overall safety and tolerability than older antidepressants, broad-based experience with SSRIs has shown the frequency and type of side effects to be increased relative to clinical trial data. The author explores the reasons for the different profiles and discusses adverse effects, especially sexual dysfunction, weight gain, and sleep disturbance, the most troubling adverse events seen during long-term SSRI therapy. The informed management of these side effects by primary care practitioners supports successful treatment of depression.

In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians.

BACKGROUND: Women with mutations in either the BRCA1 or the BRCA2 gene have a high lifetime risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they also protect against hereditary forms of ovarian cancer. METHODS: We enrolled 207 women with hereditary ovarian cancer and 161 of their sisters as controls in a case-control study. All the patients carried a pathogenic mutation in either BRCA1 (179 women) or BRCA2 (28 women). The control women were enrolled regardless of whether or not they had either mutation. Lifetime histories of oral-contraceptive use were obtained by interview or by written questionnaire and were compared between patients and control women, after adjustment for year of birth and parity. RESULTS: The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0.5 (95 percent confidence interval, 0.3 to 0.8). The risk decreased with increasing duration of use (P for trend, <0.001); use for six or more years was associated with a 60 percent reduction in risk. Oral-contraceptive use protected against ovarian cancer both for carriers of the BRCA1 mutation (odds ratio, 0.5; 95 percent confidence interval, 0.3 to 0.9) and for carriers of the BRCA2 mutation (odds ratio, 0.4; 95 percent confidence interval, 0.2 to 1.1). CONCLUSIONS: Oral-contraceptive use may reduce the risk of ovarian cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene.

SYNOPSIS. Human fathers are more involved in childcare than males of most other mammalian species. The authors describe several studies designed to determine how much time fathers spend with their children and how this compares with the extent of involvement by mothers. On average, fathers spend 25 to 35% as much time as mothers do in direct interaction with their children. Factors affecting the degree of paternal involvement are then described. These factors include: Motivation, skills, support, and institutional practices. Researchers have demonstrated that human fathers can be as competent as mothers, although lack of practice leads over time to lower levels of competence than evinced by mothers. Mothers and fathers behave differently in interaction with their children, with maternal-child interaction dominated by caretaking and father-child interaction characterized by play.

Of 405 hospitalized patients with temporary closed sterile urinary-catheter drainage, 95 (23 per cent) acquired bacteriuria. The risk was significantly greater for patients who were female, elderly or critically ill (p<0.005 for each with appropriate comparison group). The patients who received systemic antimicrobial agents acquired bacteriuria less frequently than the patients who did not (16 versus 32 per cent —p<0.001). However, the apparent protective effect of antimicrobials occurred only during the first four days in which catheterization was in progress. Breaks in the closed drainage system or improper care of the drainage bag occurred frequently (121 of 405 systems studied) and predisposed to bacteriuria. Bacterial contamination of the drainage bag preceded onset of bacteriuria in 18 per cent of cases. Strict adherence to aseptic care of closed sterile drainage systems can be expected to reduce rates of hospital-acquired, catheter-associated bacteriuria. (N Engl J Med 291:215–219, 1974)

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

AIM: The prevalence of airway obstruction varies widely with the definition used. OBJECTIVES: To study differences in the prevalence of airway obstruction when applying four international guidelines to three population samples using four regression equations. METHODS: We collected predicted values for forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) and its lower limit of normal (LLN) from the literature. FEV(1)/FVC from 40 646 adults (including 13 136 asymptomatic never smokers) aged 17-90+years were available from American, English and Dutch population based surveys. The prevalence of airway obstruction was determined by the LLN for FEV(1)/FVC, and by using the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society/European Respiratory Society (ATS/ERS) or British Thoracic Society (BTS) guidelines, initially in the healthy subgroup and then in the entire population. RESULTS: The LLN for FEV(1)/FVC varied between prediction equations (57 available for men and 55 for women), and demonstrated marked negative age dependency. Median age at which the LLN fell below 0.70 in healthy subjects was 42 and 48 years in men and women, respectively. When applying the reference equations (Health Survey for England 1995-1996, National Health and Nutrition Examination Survey (NHANES) III, European Community for Coal and Steel (ECCS)/ERS and a Dutch population study) to the selected population samples, the prevalence of airway obstruction in healthy never smokers aged over 60 years varied for each guideline: 17-45% of men and 7-26% of women for GOLD; 0-18% of men and 0-16% of women for ATS/ERS; and 0-9% of men and 0-11% of women for BTS. GOLD guidelines caused false positive rates of up to 60% when applied to entire populations. CONCLUSIONS: Airway obstruction should be defined by FEV(1)/FVC and FEV(1) being below the LLN using appropriate reference equations.

It is estimated that 20.8 million people, i.e., 7.0% of the U.S. population, have diabetes (1). Type 2 diabetes, with its core defects of insulin resistance and relative insulin deficiency, accounts for 90–95% of those with the disease. Another 5.2 million people are estimated to have undiagnosed type 2 diabetes. It is the sixth leading cause of death (1) in the U.S. and accounts for 17.2% of all deaths for those aged >25 years (2). Liver disease is an important cause of death in type 2 diabetes. In the population-based Verona Diabetes Study (3), cirrhosis was the fourth leading cause of death and accounted for 4.4% of diabetes-related deaths. The standardized mortality ratio (SMR), i.e., the relative rate of an event compared with the background rate, for cirrhosis was 2.52 compared with 1.34 for cardiovascular disease (CVD). In another prospective cohort study (4), cirrhosis accounted for 12.5% of deaths in patients with diabetes. Diabetes, by most estimates, is now the most common cause of liver disease in the U.S. Cryptogenic cirrhosis, of which diabetes is, by far, the most common cause, has become the third leading indication for liver transplantation in the U.S. (5,6). Virtually the entire spectrum of liver disease is seen in patients with type 2 diabetes. This includes abnormal liver enzymes, nonalcoholic fatty liver disease (NAFLD), cirrhosis, hepatocellular carcinoma, and acute liver failure. In addition, there is an unexplained association of diabetes with hepatitis C. Finally, the prevalence of diabetes in cirrhosis is 12.3–57% (7). Thus, patients with diabetes have a high prevalence of liver disease and patients with liver disease have a high prevalence of diabetes. The management of diabetes in patients with liver disease is theoretically complicated by liver-related alterations in drug metabolism, potential interactions between the drugs, and a low, albeit …

BACKGROUND: Chlamydia pneumoniae infection has been associated with atherosclerosis by serological studies and detection of bacterial antigen within plaque. We sought to evaluate a possible causal role in an animal model. METHODS AND RESULTS: Thirty New Zealand White rabbits were given three separate intranasal inoculations of either C pneumoniae (n = 20) or saline (n = 10) at 3-week intervals and fed chow enriched with a small amount (0.25%) of cholesterol. Immediately after the final inoculation, infected and control rabbits were randomized and begun on a 7-week course of azithromycin or no therapy. Three months after the final inoculation, rabbits were euthanatized and sections of thoracic aortas were blindly evaluated microscopically for maximal intimal thickness (MIT), percentage of luminal circumference involved (PLCI), and plaque area index (PAI) of atherosclerosis. Vascular chlamydial antigen was assessed by direct immunofluorescence. MIT differed among treatment groups (P=.009), showing an increase in infected rabbits (0.55 mm; SE = 0.15 mm) compared with uninfected controls (0.16 mm; SE = 0.06 mm) and with infected rabbits receiving antibiotics (0.20 mm; SE = 0.03 mm) (both P<.025), whereas MIT in infected/treated versus control rabbits did not differ. PLCI also tended to differ (P<.1) and PAI differed significantly (P<.01) among groups with a similar pattern. Chlamydial antigen was detected in 2 untreated, 3 treated, and 0 control animals. CONCLUSIONS: Intranasal C pneumoniae infection accelerates intimal thickening in rabbits given a modestly cholesterol-enhanced diet. In addition, weekly treatment with azithromycin after infectious exposure prevents accelerated intimal thickening. These findings strengthen the etiologic link between C pneumoniae and atherosclerosis and should stimulate additional animal and human studies, including clinical antibiotic trials.

SNYDER, CHIFFORD C. M.D.; LEVINE, GEORGE A. M.D.; SWASSON, HOWARD M. D.D.S.; BROWNE, EARL Z. JR. M.D. Author Information

For an occupational therapist unfamiliar with a culturally diverse treatment population, ethnographic interview is described as an appropriate method for assessing client group needs. This study describes the use of ethnographic interview as a tool which was culturally sensitive to the occupational behaviors of American Indians and Alaska Natives of the Northwest involved in drug and alcohol treatment. Results of the interviews helped the researcher identify sociocultural factors in the acquisition and maintenance of maladaptive behaviors. Recurring themes of the extended family network, the strength and complexity of social norms and codes, and the pervasiveness of alcohol use among this population are described in review of the literature and results of the interviews. Results of the Tennessee Self-concept Scale revealed an overall measure of self-esteem significantly lower than that of the normed population, and enerally supported rehabilitation issues originally identified by the f iterature and expanded on in the interviews. Implications for treatment discuss acceptance of the therapist by members of the culture, the concept of nonmterference, the role of purposeful activity, cultural identification and assimilation, and the use of group work.

DISCLAIMER: Veno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly being deployed for selected patients in cardiac arrest who do not attain a native circulation with conventional CPR (ECPR). This ELSO guideline is intended to be a practical guide to implementing ECPR and the early management following establishment of ECMO support. Where a paucity of high-quality evidence exists, a consensus has been reached amongst the authors to provide guidance to the clinician. This guideline will be updated as further evidence in this field becomes available.

BACKGROUND: Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. METHODS AND RESULTS: Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QTc >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (KVLQT1 on 11p15.5), 62 LQT2 carriers (HERG on 7q35-36), and 31 LQT3 carriers (SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8+/-7 versus 14+/-10 years, P<0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QTc duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (P<0.001), and it was 1.87 (P=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (P<0.001) by age 15 years, and it was 3.25 (P<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. CONCLUSIONS: Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.

Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose-response curve; the up-and-down method of Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose-response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose-the target dose-associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies.

BACKGROUND: The relative efficacies of various antiarrhythmic drugs in the treatment of ventricular tachyarrhythmias are not well known. This study examined the effectiveness of imipramine, mexiletine, pirmenol, procainamide, propafenone, quinidine, and sotalol in patients with ventricular tachyarrhythmias who were enrolled in the Electrophysiologic Study versus Electrocardiographic Monitoring trial. METHODS: Patients were randomly assigned to undergo serial testing of the efficacy of the seven antiarrhythmic drugs by one of two strategies: electrophysiologic study or Holter monitoring together with exercise testing. The seven drugs were then tested for efficacy in random order in patients who were eligible to receive them. The frequencies of predictions of drug efficacy and of adverse drug effects during the initial drug titration were tabulated for all 486 randomized subjects. Patients received long-term treatment with the first antiarrhythmic drug that was predicted to be effective on the basis of drug testing. Recurrences of arrhythmia, deaths, and adverse drug effects during long-term follow-up were recorded for the 296 patients in whom an antiarrhythmic drug was predicted to be effective. RESULTS: In the electrophysiologic-study group, the percentage of patients who had predictions of drug efficacy was higher with sotalol (35 percent) than with the other drugs (16 percent, P < 0.001). There was no significant difference among the drugs in the Holter-monitoring group. The percentage of patients with adverse drug effects was lowest among those receiving sotalol. The actuarial probability of a recurrence of arrhythmia after a prediction of drug efficacy by either strategy was significantly lower for patients treated with sotalol than for patients treated with the other drugs (risk ratio, 0.43; 95 percent confidence interval, 0.29 to 0.62; P < 0.001). With sotalol, as compared with the other drugs combined, there were lower risks of death from any cause (risk ratio, 0.50; 95 percent confidence interval, 0.30 to 0.80; P = 0.004), death from cardiac causes, (0.50; P = 0.02), and death from arrhythmia (0.50; P = 0.04). The cumulative percentage of patients in whom a drug was predicted to be effective and in whom it remained effective and tolerated was higher for sotalol than for the other drugs (P < 0.001). CONCLUSIONS: Sotalol was more effective than the other six antiarrhythmic drugs in preventing death and recurrences of arrhythmia. In patients similar to those in this study, if antiarrhythmic-drug therapy is to be used to prevent recurrences of ventricular tachyarrhythmias, treatment with sotalol and assessment of its potential efficacy by Holter monitoring are a reasonable initial strategy.