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BACKGROUND AND OBJECTIVES Bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) can have detrimental effects on eye movement inhibitory control. To investigate this detrimental effect of bilateral STN DBS, we examined the effects of manipulating STN DBS amplitude on inhibitory control during the antisaccade task. The prosaccade error rate during the antisaccade task, that is, directional errors, was indicative of impaired inhibitory control. We hypothesized that as stimulation amplitude increased, the prosaccade error rate would increase. MATERIALS AND METHODS Ten participants with bilateral STN DBS completed the antisaccade task on six different stimulation amplitudes (including zero amplitude) after a 12-hour overnight withdrawal from antiparkinsonian medication. RESULTS We found that the prosaccade error rate increased as stimulation amplitude increased (p

Distinguishing postpartum women with bipolar from unipolar depression remains challenging, particularly in obstetrical and primary care settings. The post-birth period carries the highest lifetime risk for the onset or recurrence of Bipolar Disorder (BD). Characterization of differences between unipolar and bipolar depression symptom presentation and severity is critical to differentiate the two disorders.We performed a secondary analysis of a study of 10,000 women screened by phone with the Edinburgh Postnatal Depression Scale at 4-6 weeks post-birth. Screen-positive mothers completed the Structured Clinical Interview for DSM-4 and those diagnosed with BD and unipolar Major Depressive Disorder (UD) were included. Depressive symptoms were assessed with the 29-item Structured Interview Guide for the Hamilton Rating Scale for Depression (SIGH-ADS).The sample consisted of 728 women with UD and 272 women with BD. Women with BD had significantly elevated levels of depression severity due to the higher scores on 8 of the 29 SIGH-ADS symptoms. Compared to UD, women with BD had significantly higher rates of comorbid anxiety disorders and were twice as likely to report sexual and/or physical abuse.Only women who screened positive for depression were included in this analysis. Postpartum women with unstable living situations, who were hospitalized or did not respond to contact attempts did not contribute data.Severity of specific symptom constellations may be a useful guide for interviewing postpartum depressed women along with the presence of anxiety disorder comorbidity and physical and/or sexual abuse.

BACKGROUND: Overtesting and treatment of older patients is common and may lead to harms. The Choosing Wisely campaign has provided recommendations to reduce overtesting and overtreatment of older adults. Behavioral economics-informed interventions embedded within the electronic health record (EHR) have been shown to reduce overuse in several areas. Our objective is to conduct a parallel arm, pragmatic cluster-randomized trial to evaluate the effectiveness of behavioral-economics-informed clinical decision support (CDS) interventions previously piloted in primary care clinics and designed to reduce overtesting and overtreatment in older adults. METHODS/DESIGN: This trial has two parallel arms: clinician education alone vs. clinician education plus behavioral-economics-informed CDS. There are three co-primary outcomes for this trial: (1) prostate-specific antigen (PSA) screening in older men, (2) urine testing for non-specific reasons in older women, and (3) overtreatment of diabetes in older adults. All eligible primary care clinics from a large regional health system were randomized using a modified constrained randomization process and their attributed clinicians were included. Clinicians were recruited to complete a survey and educational module. We randomized 60 primary care clinics with 374 primary care clinicians and achieved adequate balance between the study arms for prespecified constrained variables. Baseline annual overuse rates for the three co-primary outcomes were 25%, 23%, and 17% for the PSA, urine, and diabetes measures, respectively. DISCUSSION: This trial is evaluating behavioral-economics-informed EHR-embedded interventions to reduce overuse of specific tests and treatments for older adults. The study will evaluate the effectiveness and safety of these interventions.

Background and purpose We evaluated the feasibility of using an activity monitor to support mindfulness practice, reduce self-reported stress and physiological indicators of stress. Materials and methods Adult women (N = 19) who previously participated in a mindfulness intervention wore an activity monitor for eight-weeks. The activity monitor notified them when they were stressed (based on standard deviation pulse pressure). Heart rate and pulse pressure were continuously collected via the activity monitor. Mindfulness, stress, depression and trauma symptoms were collected via self-report surveys. Results There were no significant changes in self-reported stress, depression, post-traumatic stress and mindfulness from baseline to eight-weeks. Pulse pressure and standard deviation of pulse pressure increased over time. Those who were high on the non-judge mindfulness subscale had a lower standard deviation pulse pressure and spent less time stressed. Conclusion Those who are more mindful are less likely to have physiological signs of stress.

Background Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia. Objective We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks’ gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin. Study Design This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight. Results Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects. Conclusion This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.

Introduction Although the Diabetes Prevention Program and other clinical trials demonstrated the efficacy of intensive lifestyle interventions (ILI) and metformin to prevent type 2 diabetes, no studies have tested their comparative effects in pragmatic settings. This study was designed to compare the real-world effectiveness of ILI, metformin, and standard care among Hispanic women (Latinas) with prediabetes. Study design RCT. Setting/participants Ninety-two Latinas, who had a mean hemoglobin A1c of 5.9%, BMI of 33.3 kg/m 2 , and waist circumference of 97.4 cm (38.3 inches), were recruited from an urban community and randomly assigned to ILI, metformin, or standard care using 1:1:1 allocation. Data were collected from 2013–2015 and analyzed in 2016. Intervention The 12-month ILI was adapted from the Diabetes Prevention Program's ILI and delivered by community health workers ( promotoras ) over 24 sessions. Metformin participants received 850 mg twice daily. Those randomized to standard care continued their regular medical care. Main outcome measures Weight and secondary outcomes (waist circumference, blood pressure, hemoglobin A1c, fasting plasma glucose, insulin, and lipids) were assessed at baseline and 12 months. Results ILI participants demonstrated significantly greater mean weight loss (–4.0 kg, 5.0%) than metformin (–0.9 kg, 1.1%) and standard care participants (+0.8 kg, 0.9%) ( p p =0.001), and a marginal improvement in hemoglobin A1c compared with metformin and standard care ( p =0.063). Conclusions In the first comparative effectiveness trial of diabetes prevention treatments, a 12-month ILI produced significantly greater weight loss than metformin and standard care among Latinas with prediabetes. These data suggest that ILI delivered by promotoras is an effective strategy for preventing diabetes in this high-risk group, which may be superior to metformin. Future pragmatic trials involving larger samples should examine differences in diabetes incidence associated with these treatments.

Objective To determine whether full-term neonates with in utero exposure to selective serotonin reuptake inhibitors (SSRI) require respiratory support in the delivery room, as indicated by the standardized Neonatal Resuscitation Program algorithm, significantly more often than nonexposed neonates. Study design In this retrospective cohort study, we extracted data from medical records of full-term neonates with and without in utero SSRI exposure, defined as documentation of third trimester maternal SSRI treatment. A hospital-based sample was identified at Northwestern Medical Hospital in Chicago, Illinois. Full-term singleton newborns identified in a 6-month period (n = 4933) were selected for study. Neonates with a major congenital anomaly were excluded. The primary outcome was initiation of respiratory support in the delivery room, as indicated by the Neonatal Resuscitation Program algorithm. Results Of the 4933 full-term singleton neonates, 3.3% were exposed to SSRI in utero. Respiratory support was initiated significantly more often in SSRI exposed (12.9%) than unexposed (4.2%) neonates (covariate-adjusted OR, 4.04; 95% CI, 2.40-6.49). In utero SSRI exposure also was associated with a higher rate of neonatal intensive care unit admission (covariate-adjusted OR, 2.19; 95% CI, 1.30-3.50) and 1-minute Apgar score of ≤5 (covariate-adjusted OR, 3.51; 95% CI, 2.07-5.67). Conclusions In this cohort, in utero SSRI exposure was associated with a significantly greater odds of resuscitation in the delivery room as well as neonatal intensive care unit admission. Although the mechanism underlying these associations have not been determined and causality cannot be assumed, these findings support a recommendation that third trimester SSRI exposure be considered a risk factor for needing resuscitation.

Many prescribers are knowledgeable about randomized controlled trials (RCT), but are less familiar with pharmacoepidemiology studies; that is, observational studies in which a pharmacologic agent is the exposure of interest. To date, few clinical trials include pregnant women. With the absence of RCT data, prescribers must largely rely on the pharmacoepidemiology literature to guide prescribing decisions for pregnant patients. We describe different types of pharmacoepidemiology studies and present a flowchart and table checklist to support clinicians to assess the quality of, and thus the validity of conclusions from, pharmacoepidemiology studies. We provide illustrative examples of published observational studies examining antidepressant treatment during pregnancy and fetal and infant outcomes.

Oftentimes valid statistical analyses for clinical trials involve adjustment for known influential covariates, regardless of imbalance observed in these covariates at baseline across treatment groups. Thus, it must be the case that valid interim analyses also properly adjust for these covariates. There are situations, however, in which covariate adjustment is not possible, not planned, or simply carries less merit as it makes inferences less generalizable and less intuitive. In this case, covariate imbalance between treatment groups can have a substantial effect on both interim and final primary outcome analyses. This paper illustrates the effect of influential continuous baseline covariate imbalance on unadjusted conditional power (CP), and thus, on trial decisions based on futility stopping bounds. The robustness of the relationship is illustrated for normal, skewed, and bimodal continuous baseline covariates that are related to a normally distributed primary outcome. Results suggest that unadjusted CP calculations in the presence of influential covariate imbalance require careful interpretation and evaluation.

Distal oesophageal spasm is a rare and under-investigated motility abnormality. Recent studies indicate effective bolus transit in varying percentages of distal oesophageal spasm patients.Explore functional aspects including contraction onset velocity and contraction amplitude cut-off values for simultaneous contractions to predict complete bolus transit.We re-examined data from 107 impedance-manometry recordings with a diagnosis of distal oesophageal spasm. Receiver operating characteristic analysis was conducted, regarding effects of onset velocity on bolus transit taking into account distal oesophageal amplitude and correcting for intra-individual repeated measures.Mean area under the receiver operating characteristic curve for saline and viscous swallows were 0.84±0.05 and 0.84±0.04, respectively. Velocity criteria of30 cm/s when distal oesophageal amplitude100 mmHg and 8 cm/s when distal oesophageal amplitude100 mmHg for saline and 32cm/s when distal oesophageal amplitude100 mmHg and7 cm/s when distal oesophageal amplitude100 mmHg for viscous had a sensitivity of 75% and specificity of 80% to identify complete bolus transit. Using these criteria, final diagnosis changed in 44.9% of patients. Abnormal bolus transit was observed in 50.9% of newly diagnosed distal oesophageal spasm patients versus 7.5% of patients classified as normal. Distal oesophageal spasm patients with distal oesophageal amplitude100 mmHg suffered twice as often from chest pain than those with distal oesophageal amplitude100 mmHg.The proposed velocity cut-offs for diagnosing distal oesophageal spasm improve the ability to identify patients with spasm and abnormal bolus transit.

Motivated by potentially serious imbalances of continuous baseline covariates in clinical trials, we investigated the cost in statistical power of ignoring the balance of these covariates in treatment allocation design for a logistic regression model. Based on data from a clinical trial of acute ischemic stroke treatment, computer simulations were used to create scenarios varying from the best possible baseline covariate balance to the worst possible imbalance, with multiple balance levels between the two extremes. The likelihood of each scenario occurring under simple randomization was evaluated. The power of the main effect test for treatment was examined. Our simulation results show that the worst possible imbalance is highly unlikely, but it can still occur under simple random allocation. Also, power loss could be nontrivial if balancing distributions of important continuous covariates were ignored even if adjustment is made in the analysis for important covariates. This situation, although unlikely, is more serious for trials with a small sample size and for covariates with large influence on primary outcome. These results suggest that attempts should be made to balance known prognostic continuous covariates at the design phase of a clinical trial even when adjustment is planned for these covariates at the analysis.

Background Sleep impairment has been described in patients with cystic fibrosis (CF). Pain is a known cause of sleep disturbance and as pain is commonly reported in patients with CF, we sought to find an association between impaired sleep quality and pain. Methods Fifty adult CF patients completed surveys of pain and sleep quality. The results were analyzed with additional clinical data including age, sex, nutritional status, and lung function. Results Thirty-two patients (64%) reported recent pain and 33 patients (66%) reported abnormal sleep quality. The patients with pain report worse sleep quality than those without pain ( p =0.006). There was a strong correlation between impaired sleep quality and pain ( p Conclusions We found that pain and poor sleep quality are reported in a majority of adult CF patients and there is a strong correlation between the two. This will have important clinical implications in the evaluation and treatment of adult patients.

Background & Aims Quality esophageal high-resolution manometry (HRM) studies require competent interpretation of data. However, there is little understanding of learning curves, training requirements, or measures of competency for HRM. We aimed to develop and use a competency assessment system to examine learning curves for interpretation of HRM data. Methods We conducted a prospective multicenter study of 20 gastroenterology trainees with no experience in HRM, from 8 centers, over an 8-month period (May through December 2015). We designed a web-based HRM training and competency assessment system. After reviewing the training module, participants interpreted 50 HRM studies and received answer keys at the fifth and then at every second interpretation. A cumulative sum procedure produced individual learning curves with preset acceptable failure rates of 10%; we classified competency status as competency not achieved, competency achieved, or competency likely achieved. Results Five (25%) participants achieved competence, 4 (20%) likely achieved competence, and 11 (55%) failed to achieve competence. A minimum case volume to achieve competency was not identified. There was no significant agreement between diagnostic accuracy and accuracy for individual HRM skills. Conclusions We developed a competency assessment system for HRM interpretation; using this system, we found significant variation in learning curves for HRM diagnosis and individual skills. Our system effectively distinguished trainee competency levels for HRM interpretation and contrary to current recommendations, found that competency for HRM is not case-volume specific.