Use of Mobile Technology Paired with Heart Rate Monitor to Remotely Quantify Behavioral Health Markers among Military Reservists and First Responders.

INTRODUCTION: Heart rate variability (HRV) is a biological marker that reflects an individual's autonomic nervous system regulation. Psychological resilience is an individual's ability to recover from an adverse event and return to physiological homeostasis and mental well-being, indicated by higher resting HRV. The Biofeedback Assisted Resilience Training (BART) study evaluates a resilience-building intervention, with or without HRV biofeedback. This article evaluates the feasibility of remote psychophysiological research by validating the HRV data collected. MATERIALS AND METHODS: The BART platform consists of a mobile health application (BART app) paired to a wearable heart rate monitor. The BART app is installed on the participant's personal phone/tablet to track and collect self-report psychological and physiological data. The platform collects raw heart rate data and processes HRV to server as online biofeedback. The raw data is processed offline to derive HRV for statistical analysis. The following HRV parameters are validated: inter-beat interval, respiratory sinus arrhythmia, low-frequency HRV, biofeedback HRV, and heart period. Bland-Altman and scatter plots are used to compare and contrast online and offline HRV measures. Repeated-measures ANOVA are used to compared means across tasks during the stress (rest, stress, and recovery) and training (rest and paced breathing) sessions in order to validate autonomic nervous system changes to physiological challenges. RESULTS: The analyses included 245 participants. Bland-Altman plots showed excellent agreement and minimal bias between online and offline unedited inter-beat interval data during the stress session. RMANOVA during the training session indicated a significant strong effect on biofeedback HRV, F(11,390) = 967.96, P < .01. During the stress session, RMANOVA showed significant strong effect on respiratory sinus arrhythmia and low-frequency HRV, and a significant but weak effect on heart period. CONCLUSIONS: The BART digital health platform supports remote behavioral and physiological data collection, intervention delivery, and online HRV biofeedback.

Recurrent thrombosis in patients with antiphospholipid antibodies and an initial venous or arterial thromboembolic event: A systematic review and meta-analysis.

BACKGROUND: Patients with antiphospholipid antibodies (aPL) and thromboembolism (TE) are at risk for recurrent TE. Few studies, however, distinguish patients based on the initial event. OBJECTIVES: We performed a systematic review and meta-analysis to investigate patients with aPL and venous TE (VTE), provoked or unprovoked, and patients with arterial TE (ATE). PATIENTS/METHODS: We conducted searches in PubMed, CINAHL, Cochrane, and EMBASE. Inclusion criteria were prospective trials or cohort studies investigating patients with aPL and ATE or VTE. Excluded studies did not provide estimated recurrence rates, did not specify whether the incident event was ATE or VTE, included patients with multiple events, or included <10 patients. Two-year summary proportions were estimated using a random effects model. RESULTS: Ten studies described patients with VTE, 2 with ATE, and 5 with VTE or ATE. The 2-year proportion for recurrent TE in patients with VTE who were taking anticoagulant therapy was 0.054 (95% confidence interval [CI], 0.037-0.079); the 2-year proportion for patients not taking anticoagulant therapy was 0.178 (95% CI, 0.150-0.209). Most studies did not distinguish whether VTE were provoked or unprovoked. The 2-year proportion for recurrent TE in patients with ATE who were taking anticoagulant therapy was 0.220 (95% CI, 0.149-0.311); the 2-year proportion for patients taking antiplatelet therapy was 0.216 (95% CI, 0.177-0.261). CONCLUSIONS: Patients with aPL and ATE may benefit from a different antithrombotic approach than patients with aPL and VTE. Prospective studies with well-defined cohorts with aPL and TE are necessary to determine optimal antithrombotic strategies.

Mental health, stress, and resilience correlates of heart rate variability among military reservists, guardsmen, and first responders.

The use of heart rate variability (HRV) for monitoring stress has been growing in the behavioral health literature, especially in the areas of posttraumatic stress disorder, stress reactivity, and resilience. Few studies, however, have included general populations under workplace conditions. This study evaluates whether military and other first responders show lower HRV during stress than at baseline and greater post stress rebound, controlling for a myriad of potential confounders. A convenience sample of Reserves, National Guard, veteran, fire, and police personnel provided HRV and self-reported questionnaire responses before, during, and after a cognitive-stressor task with a smart phone application. Timing of HRV application; mental and physical health scores; coping and posttraumatic growth indicators, including being open to new possibilities; and emotional support were predictors of trajectories of the HRV response to stress. Findings from this exploratory study emphasize the strong link between stress and relaxation breathing in both respiratory sinus arrhythmia and low frequency heart rate variability and the need for controlling potential covariates for understanding the relationship between HRV and the stress response and providing a basis for hypothesis driven research.

The Effect of Laboratory Test-Based Clinical Decision Support Tools on Medication Errors and Adverse Drug Events: A Laboratory Medicine Best Practices Systematic Review.

BACKGROUND: Laboratory and medication data in electronic health records create opportunities for clinical decision support (CDS) tools to improve medication dosing, laboratory monitoring, and detection of side effects. This systematic review evaluates the effectiveness of such tools in preventing medication-related harm. METHODS: We followed the Laboratory Medicine Best Practice (LMBP) initiative's A-6 methodology. Searches of 6 bibliographic databases retrieved 8508 abstracts. Fifteen articles examined the effect of CDS tools on (a) appropriate dose or medication (n = 5), (b) laboratory monitoring (n = 4), (c) compliance with guidelines (n = 2), and (d) adverse drug events (n = 5). We conducted meta-analyses by using random-effects modeling. RESULTS: We found moderate and consistent evidence that CDS tools applied at medication ordering or dispensing can increase prescriptions of appropriate medications or dosages [6 results, pooled risk ratio (RR), 1.48; 95% CI, 1.27-1.74]. CDS tools also improve receipt of recommended laboratory monitoring and appropriate treatment in response to abnormal test results (6 results, pooled RR, 1.40; 95% CI, 1.05-1.87). The evidence that CDS tools reduced adverse drug events was inconsistent (5 results, pooled RR, 0.69; 95% CI, 0.46-1.03). CONCLUSIONS: The findings support the practice of healthcare systems with the technological capability incorporating test-based CDS tools into their computerized physician ordering systems to (a) identify and flag prescription orders of inappropriate dose or medications at the time of ordering or dispensing and (b) alert providers to missing laboratory tests for medication monitoring or results that warrant a change in treatment. More research is needed to determine the ability of these tools to prevent adverse drug events.

Biofeedback-Assisted Resilience Training for Traumatic and Operational Stress: Preliminary Analysis of a Self-Delivered Digital Health Methodology.

BACKGROUND: Psychological resilience is critical to minimize the health effects of traumatic events. Trauma may induce a chronic state of hyperarousal, resulting in problems such as anxiety, insomnia, or posttraumatic stress disorder. Mind-body practices, such as relaxation breathing and mindfulness meditation, help to reduce arousal and may reduce the likelihood of such psychological distress. To better understand resilience-building practices, we are conducting the Biofeedback-Assisted Resilience Training (BART) study to evaluate whether the practice of slow, paced breathing with or without heart rate variability biofeedback can be effectively learned via a smartphone app to enhance psychological resilience. OBJECTIVE: Our objective was to conduct a limited, interim review of user interactions and study data on use of the BART resilience training app and demonstrate analyses of real-time sensor-streaming data. METHODS: We developed the BART app to provide paced breathing resilience training, with or without heart rate variability biofeedback, via a self-managed 6-week protocol. The app receives streaming data from a Bluetooth-linked heart rate sensor and displays heart rate variability biofeedback to indicate movement between calmer and stressful states. To evaluate the app, a population of military personnel, veterans, and civilian first responders used the app for 6 weeks of resilience training. We analyzed app usage and heart rate variability measures during rest, cognitive stress, and paced breathing. Currently released for the BART research study, the BART app is being used to collect self-reported survey and heart rate sensor data for comparative evaluation of paced breathing relaxation training with and without heart rate variability biofeedback. RESULTS: To date, we have analyzed the results of 328 participants who began using the BART app for 6 weeks of stress relaxation training via a self-managed protocol. Of these, 207 (63.1%) followed the app-directed procedures and completed the training regimen. Our review of adherence to protocol and app-calculated heart rate variability measures indicated that the BART app acquired high-quality data for evaluating self-managed stress relaxation training programs. CONCLUSIONS: The BART app acquired high-quality data for studying changes in psychophysiological stress according to mind-body activity states, including conditions of rest, cognitive stress, and slow, paced breathing.

Interventions to prevent iatrogenic anemia: a Laboratory Medicine Best Practices systematic review.

BACKGROUND: As many as 90% of patients develop anemia by their third day in an intensive care unit (ICU). We evaluated the efficacy of interventions to reduce phlebotomy-related blood loss on the volume of blood lost, hemoglobin levels, transfusions, and incidence of anemia. METHODS: We conducted a systematic review and meta-analysis using the Laboratory Medicine Best Practices (LMBP) systematic review methods for rating study quality and assessing the body of evidence. Searches of PubMed, Embase, Cochrane, Web of Science, PsychINFO, and CINAHL identified 2564 published references. We included studies of the impact of interventions to reduce phlebotomy-related blood loss on blood loss, hemoglobin levels, transfusions, or anemia among hospital inpatients. We excluded studies not published in English and studies that did not have a comparison group, did not report an outcome of interest, or were rated as poor quality. Twenty-one studies met these criteria. We conducted a meta-analysis if > 2 homogenous studies reported sufficient information for analysis. RESULTS: We found moderate, consistent evidence that devices that return blood from flushing venous or arterial lines to the patient reduced blood loss by approximately 25% in both neonatal ICU (NICU) and adult ICU patients [pooled estimate in adults, 24.7 (95% CI = 12.1-37.3)]. Bundled interventions that included blood conservation devices appeared to reduce blood loss by at least 25% (suggestive evidence). The evidence was insufficient to determine if these devices reduced hemoglobin decline or risk of anemia. The evidence suggested that small volume tubes reduced the risk of anemia, but was insufficient to determine if they affected the volume of blood loss or the rate of hemoglobin decline. CONCLUSIONS: Moderate, consistent evidence indicated that devices that return blood from testing or flushing lines to the patient reduce the volume of blood loss by approximately 25% among ICU patients. The results of this systematic review support the use of blood conservation systems with arterial or venous catheters to eliminate blood waste when drawing blood for testing. The evidence was insufficient to conclude the devices impacted hemoglobin levels or transfusion rates. The use of small volume tubes may reduce the risk of anemia.

Interventions to Improve Follow-Up of Laboratory Test Results Pending at Discharge: A Systematic Review.

Failure to follow up test results pending at discharge (TPAD) from hospitals or emergency departments is a major patient safety concern. The purpose of this review is to systematically evaluate the effectiveness of interventions to improve follow-up of laboratory TPAD. We conducted literature searches in PubMed, CINAHL, Cochrane, and EMBASE using search terms for relevant health care settings, transition of patient care, laboratory tests, communication, and pending or missed tests. We solicited unpublished studies from the clinical laboratory community and excluded articles that did not address transitions between settings, did not include an intervention, or were not related to laboratory TPAD. We also excluded letters, editorials, commentaries, abstracts, case reports, and case series. Of the 9,592 abstracts retrieved, eight met the inclusion criteria and reported the successful communication of TPAD. A team member abstracted predetermined data elements from each study, and a senior scientist reviewed the abstraction. Two experienced reviewers independently appraised the quality of each study using published Laboratory Medicine Best Practices (LMBP™) A-6 scoring criteria. We assessed the body of evidence using the A-6 methodology, and the evidence suggested that electronic tools or one-on-one education increased documentation of pending tests in discharge summaries. We also found that automated notifications improved awareness of TPAD. The interventions were supported by suggestive evidence; this type of evidence is below the level of evidence required for LMBP™ recommendations. We encourage additional research into the impact of these interventions on key processes and health outcomes.

Helping Babies Breathe (HBB) training: What happens to knowledge and skills over time?

BACKGROUND: The first minutes after birth are critical to reducing neonatal mortality. Helping Babies Breathe (HBB) is a simulation-based neonatal resuscitation program for low resource settings. We studied the impact of initial HBB training followed by refresher training on the knowledge and skills of the birth attendants in facilities. METHODS: We conducted HBB trainings in 71 facilities in the NICHD Global Network research sites (Nagpur and Belgaum, India and Eldoret, Kenya), with a 6:1 ratio of facility trainees to Master Trainers (MT). Because of staff turnover, some birth attendants (BA) were trained as they joined the delivery room staff, after the initial training was completed (catch-up initial training). We compared pass rates for skills and knowledge pre- and post- initial HBB training and following refresher training among active BAs. An Objective Structured Clinical Examination (OSCE) B tested resuscitation skill retention by comparing post-initial training performance with pre-refresher training performance. We identified factors associated with loss of skills in pre-refresher training performance using multivariable logistic regression analysis. Daily bag and mask ventilation practice, equipment checks and supportive supervision were stressed as part of training. RESULTS: One hundred five MT (1.6 MT per facility) conducted initial and refresher HBB trainings for 835 BAs; 76% had no prior resuscitation training. Initial training improved knowledge and skills: the pass percentage for knowledge tests improved from 74 to 99% (p < 0.001). Only 5% could ventilate a newborn mannequin correctly before initial training but 97% passed the post-initial ventilation training test (p < 0.0001) and 99% passed the OSCE B resuscitation evaluation. During pre-refresher training evaluation, a mean of 6.7 (SD 2.49) months after the initial training, 99% passed the knowledge test, but the successful completion rate fell to 81% for the OSCE B resuscitation skills test. Characteristics associated with deterioration of resuscitation skills were BAs from tertiary care facilities, no prior resuscitation training, and the timing of training (initial vs. catch-up training). CONCLUSIONS: HBB training significantly improved neonatal resuscitation knowledge and skills. However, skills declined more than knowledge over time. Ongoing skills practice and monitoring, more frequent retesting, and refresher trainings are needed to maintain neonatal resuscitation skills. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01681017 ; 04 September 2012, retrospectively registered.

A pre-post study of a multi-country scale up of resuscitation training of facility birth attendants: does Helping Babies Breathe training save lives?

BACKGROUND: Whether facility-based implementation of Helping Babies Breathe (HBB) reduces neonatal mortality at a population level in low and middle income countries (LMIC) has not been studied. Therefore, we evaluated HBB implementation in this context where our study team has ongoing prospective outcome data on all pregnancies regardless of place of delivery. METHODS: We compared outcomes of birth cohorts in three sites in India and Kenya pre-post implementation of a facility-based intervention, using a prospective, population-based registry in 52 geographic clusters. Our hypothesis was that HBB implementation would result in a 20 % decrease in the perinatal mortality rate (PMR) among births ≥1500 g. RESULTS: We enrolled 70,704 births during two 12-month study periods. Births within each site did not differ pre-post intervention, except for an increased proportion of <2500 g newborns and deliveries by caesarean section in the post period. There were no significant differences in PMR among all registry births; however, a post-hoc analysis stratified by birthweight documented improvement in <2500 g mortality in Belgaum in both registry and in HBB-trained facility births. No improvement in <2500 g mortality measures was noted in Nagpur or Kenya and there was no improvement in normal birth weight survival. CONCLUSIONS: Rapid scale up of HBB training of facility birth attendants in three diverse sites in India and Kenya was not associated with consistent improvements in mortality among all neonates ≥1500 g; however, differential improvements in <2500 g survival in Belgaum suggest the need for careful implementation of HBB training with attention to the target population, data collection, and ongoing quality monitoring activities. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov: NCT01681017 .

Endovascular therapy for advanced post-thrombotic syndrome: Proceedings from a multidisciplinary consensus panel.

Patients with advanced post-thrombotic syndrome (PTS) and chronic iliac vein obstruction suffer major physical limitations and impairment of health-related quality of life. Currently there is a lack of evidence-based treatment options for these patients. Early studies suggest that imaging-guided, catheter-based endovascular therapy can eliminate iliac vein obstruction and saphenous venous valvular reflux, resulting in reduced PTS severity; however, these observations have not been rigorously validated. A multidisciplinary expert panel meeting was convened to plan a multicenter randomized controlled clinical trial to evaluate endovascular therapy for the treatment of advanced PTS. This article summarizes the findings of the panel, and is expected to assist in developing a National Institutes of Health-sponsored clinical trial and other studies to improve the care of patients with advanced PTS.

The Antenatal Corticosteroids Trial (ACT)'s explanations for neonatal mortality - a secondary analysis.

BACKGROUND: The Antenatal Corticosteroid Trial assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but was associated with an overall increase in neonatal deaths. We aimed to explore plausible pathways through which this intervention increased neonatal mortality. METHODS: We conducted a series of secondary analyses to assess whether ACS or other components of the multifaceted intervention that might have affected the quality of care contributed to the increased mortality observed: 1) we compared the proportion of neonatal deaths receiving ACS between the intervention and control groups; 2) we compared the antenatal and delivery care process in all births between groups; 3) we compared the rates of possible severe bacterial infection between groups; and 4) we compared the frequency of factors related to ACS administration or maternal high risk conditions at administration between the babies who died and those who survived 28 days among all births in the intervention group identified as high risk for preterm birth and received ACS. RESULTS: The ACS exposure among the infants who died up to 28 days was 29 % in the intervention group compared to 6 % in controls. No substantial differences were observed in antenatal and delivery care process between groups. The risk of pSBI plus neonatal death was significantly increased in intervention clusters compared to controls (2.4 % vs. 2.0 %, adjusted RR 1.17, 95 % CI 1.04-1.30, p = 0.008], primarily for infants with birth weight at or above the 25(th) percentile. Regarding factors related to ACS administration, term infants who died were more likely to have mothers who received ACS within 7 days of delivery compared to those who survived 28 days (26.5 % vs 17.9 %, p = 0.014), and their mothers were more likely to have been identified as high risk for hypertension and less likely for signs of preterm labor. CONCLUSIONS: These results suggest that ACS more than other components of the intervention may have contributed to the overall increased neonatal mortality. ACS may have also been involved in the observed increased risk of neonatal infection and death. Further trials are urgently needed to clarify the effectiveness and safety of ACS on neonatal health in low resource settings.

Improvements in well-being and vagal tone following a yogic breathing-based life skills workshop in young adults: Two open-trial pilot studies.

BACKGROUND: While efficacy of Sudarshan Kriya Yoga (SKY) has been demonstrated in a number of prior studies, little is known about the effects of SKY taught as part of the Your Enlightened Side (YES+) workshop designed for college students and other young adults. AIMS: This study aimed to assess the effects of YES+, a yogic breathing-based life skills workshop, on multiple measures of well-being and physiological stress response. MATERIALS AND METHODS: Two nonrandomized open-trial pilot studies were conducted with a total of 74 young adults (age 25.4 ± 6.6 years; 55% female). Study 1 collected a variety of self-report questionnaires at baseline, postworkshop, and 1-month follow-up. Study 2 collected self-report questionnaires in addition to electrocardiography with a stationary cycling challenge at baseline and 1-month follow-up. RESULTS: Study 1: Improvements in self-reported depression (P's ≤ 0.010), perceived stress (P's ≤ 0.002), life satisfaction (P's ≤ 0.002), social connectedness (P's ≤ 0.004), and gratitude (P's ≤ 0.090) were observed at postworkshop and 1-month after workshop relative to baseline. Study 2: Improvements in self-reported emotion regulation were observed at 1-month follow-up relative to baseline (P = 0.019). Positive and Negative Affect Schedule-Expanded Form positive affect increased (P = 0.021), while fatigue and sadness decreased (P's ≤ 0.005). During the stationary cycling challenge, rate to recovery of electrocardiography inter-beat interval also increased from baseline to 1-month follow-up (P = 0.077). CONCLUSIONS: These findings suggest that a life skills workshop integrating yogic breathing techniques may provide self-empowering tools for enhancing well-being in young adults. Future research is indicated to further explore these effects, particularly in regards to vagal tone and other aspects of stress physiology.

A color-coded tape for uterine height measurement: a tool to identify preterm pregnancies in low resource settings.

INTRODUCTION: Neonatal mortality associated with preterm birth can be reduced with antenatal corticosteroids (ACS), yet <10% of eligible pregnant women in low-middle income countries. The inability to accurately determine gestational age (GA) leads to under-identification of high-risk women who could receive ACS or other interventions. To facilitate better identification in low-resource settings, we developed a color-coded tape for uterine height (UH) measurement and estimated its accuracy identifying preterm pregnancies. METHODS: We designed a series of colored-coded tapes with segments corresponding to UH measurements for 20-23.6 weeks, 24.0-35.6 weeks, and >36.0 weeks GA. In phase 1, UH measurements were collected prospectively in the Democratic Republic of Congo, India and Pakistan, using distinct tapes to address variation across regions and ethnicities. In phase 2, we tested accuracy in 250 pregnant women with known GA from early ultrasound enrolled at prenatal clinics in Argentina, India, Pakistan and Zambia. Providers masked to the ultrasound GA measured UH. Receiver operating characteristics (ROC) analysis was conducted. RESULTS: 1,029 pregnant women were enrolled. In all countries the tapes were most effective identifying pregnancies between 20.0-35.6 weeks, compared to the other GAs. The ROC areas under the curves and 95% confidence intervals were: Argentina 0.69 (0.63, 0.74); Zambia 0.72 (0.66, 0.78), India 0.84 (0.80, 0.89), and Pakistan 0.83 (0.78, 0.87). The sensitivity and specificity (and 95% confidence intervals) for identifying pregnancies between 20.0-35.6 weeks, respectively, were: Argentina 87% (82%-92%) and 51% (42%-61%); Zambia 91% (86%-95%) and 50% (40%-60%); India 78% (71%-85%) and 89% (83%-94%); Pakistan 63% (55%-70%) and 94% (89%-99%). CONCLUSIONS: We observed moderate-good accuracy identifying pregnancies ≤ 35.6 weeks gestation, with potential usefulness at the community level in low-middle income countries to facilitate the preterm identification and interventions to reduce preterm neonatal mortality. Further research is needed to validate these findings on a population basis.

Impact of exposure to cooking fuels on stillbirths, perinatal, very early and late neonatal mortality - a multicenter prospective cohort study in rural communities in India, Pakistan, Kenya, Zambia and Guatemala.

BACKGROUND: Consequences of exposure to household air pollution (HAP) from biomass fuels used for cooking on neonatal deaths and stillbirths is poorly understood. In a large multi-country observational study, we examined whether exposure to HAP was associated with perinatal mortality (stillbirths from gestation week 20 and deaths through day 7 of life) as well as when the deaths occurred (macerated, non-macerated stillbirths, very early neonatal mortality (day 0-2) and later neonatal mortality (day 3-28). Questions addressing household fuel use were asked at pregnancy, delivery, and neonatal follow-up visits in a prospective cohort study of pregnant women in rural communities in five low and lower middle income countries participating in the Global Network for Women and Children's Health's Maternal and Newborn Health Registry. The study was conducted between May 2011 and October 2012. Polluting fuels included kerosene, charcoal, coal, wood, straw, crop waste and dung. Clean fuels included electricity, liquefied petroleum gas (LPG), natural gas and biogas. RESULTS: We studied the outcomes of 65,912 singleton pregnancies, 18 % from households using clean fuels (59 % LPG) and 82 % from households using polluting fuels (86 % wood). Compared to households cooking with clean fuels, there was an increased risk of perinatal mortality among households using polluting fuels (adjusted relative risk (aRR) 1.44, 95 % confidence interval (CI) 1.30-1.61). Exposure to HAP increased the risk of having a macerated stillbirth (adjusted odds ratio (aOR) 1.66, 95%CI 1.23-2.25), non-macerated stillbirth (aOR 1.43, 95 % CI 1.15-1.85) and very early neonatal mortality (aOR 1.82, 95 % CI 1.47-2.22). CONCLUSIONS: Perinatal mortality was associated with exposure to HAP from week 20 of pregnancy through at least day 2 of life. Since pregnancy losses before labor and delivery are difficult to track, the effect of exposure to polluting fuels on global perinatal mortality may have previously been underestimated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01073475.

A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial.

BACKGROUND: Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS: In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS: The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). INTERPRETATION: Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Implementation and evaluation of the Helping Babies Breathe curriculum in three resource limited settings: does Helping Babies Breathe save lives? A study protocol.

BACKGROUND: Neonatal deaths account for over 40% of all under-5 year deaths; their reduction is increasingly critical for achieving Millennium Development Goal 4. An estimated 3 million newborns die annually during their first month of life; half of these deaths occur during delivery or within 24 hours. Every year, 6 million babies require help to breathe immediately after birth. Resuscitation training to help babies breathe and prevent/manage birth asphyxia is not routine in low-middle income facility settings. Helping Babies Breathe (HBB), a simulation-training program for babies wherever they are born, was developed for use in low-middle income countries. We evaluated whether HBB training of facility birth attendants reduces perinatal mortality in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network research sites. METHODS/DESIGN: We hypothesize that a two-year prospective pre-post study to evaluate the impact of a facility-based training package, including HBB and essential newborn care, will reduce all perinatal mortality (fresh stillbirth or neonatal death prior to 7 days) among the Global Network's Maternal Neonatal Health Registry births ≥1500 grams in the study clusters served by the facilities. We will also evaluate the effectiveness of the HBB training program changing on facility-based perinatal mortality and resuscitation practices. Seventy-one health facilities serving 52 geographically-defined study clusters in Belgaum and Nagpur, India, and Eldoret, Kenya, and 30,000 women will be included. Primary outcome data will be collected by staff not involved in the HBB intervention. Additional data on resuscitations, resuscitation debriefings, death audits, quality monitoring and improvement will be collected. HBB training will include training of MTs, facility level birth attendants, and quality monitoring and improvement activities. DISCUSSION: Our study will evaluate the effect of a HBB/ENC training and quality monitoring and improvement package on perinatal mortality using a large multicenter design and approach in 71 resource-limited health facilities, leveraging an existing birth registry to provide neonatal outcomes through day 7. The study will provide the evidence base, lessons learned, and best practices that will be essential to guiding future policy and investment in neonatal resuscitation. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov Identifier: NCT01681017.

Expression of osteoprotegerin from a replicating adenovirus inhibits the progression of prostate cancer bone metastases in a murine model.

Metastatic involvement of the skeleton is a frequent consequence of advanced prostate cancer. These skeletal metastases cause a number of debilitating complications and are refractory to current treatments. New therapeutic options are being explored, including conditionally replicating adenoviruses (CRAds). CRAds are engineered to selectively replicate in and destroy tumor cells and can be 'armed' with exogenous transgenes for enhanced potency. We hypothesized that a CRAd armed with osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, would inhibit the progression of prostate cancer bone metastases by directly lysing tumor cells and by reducing osteoclast activity. Although prostate cancer bone metastases are predominantly osteoblastic in nature, increased osteoclast activity is critical for the growth of these lesions. Ad5-Δ24-sOPG-Fc-RGD is a CRAd that carries a fusion of the ligand-binding domains of OPG and the Fc region of human IgG1 in place of the viral E3B genes. To circumvent low tumor cell expression of the native adenoviral receptor, an arginine-glycine-aspartic acid (RGD) peptide insertion within the viral fiber knob allows infection of cells expressing α(v) integrins. A 24-base pair deletion (Δ24) within viral E1A limits replication to cells with aberrant retinoblastoma cell cycle regulator/tumor suppressor expression. We have confirmed that Ad5-Δ24-sOPG-Fc-RGD replicates within and destroys prostate cancer cells and, in both murine and human coculture models, that infection of prostate cancer cells inhibits osteoclastogenesis in vitro. In a murine model, progression of advanced prostate cancer bone metastases was inhibited by treatment with Ad5-Δ24-sOPG-Fc-RGD but not by an unarmed control CRAd.

Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.

CONTEXT: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). OBJECTIVE: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. INTERVENTIONS: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. MAIN OUTCOME MEASURES: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. RESULTS: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. CONCLUSION: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603304.

Performance of the American Urological Association Symptom Index with and without an additional urge incontinence item.

OBJECTIVE: To examine the value of adding an urge incontinence question to the American Urological Association Symptom Index (AUASI) among men in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) trial. METHODS: The CAMUS study was a randomized trial of Saw palmetto fruit extract versus placebo among men aged ≥45 years with an AUASI score of ≥8 and ≤24. The baseline measurements included the AUASI, a question about urge incontinence (UI), the International Prostate Symptom Score quality of life question, and the Benign Prostatic Hyperplasia Impact Index. We correlated the items and scales and examined whether adding the UI question resulted in better prediction of disease-specific health status. RESULTS: The mean age of the 369 men in the CAMUS trial was 61 years, and mean baseline AUASI score was 14.6. UI was reported infrequently; about 82% of the respondents answered the question "not at all" or "<1 time in 5." UI correlated significantly with all other AUASI items, except for weak stream; the strongest correlation was to urgency (R=0.51, P<.0001). The correlation between the AUASI score and the AUASI+UI score was 0.98 (P<.0001). In a logistic regression analysis predicting the International Prostate Symptom Score quality of life score, adding UI to the AUASI slightly increased the discriminating ability (c statistic increased from 0.77 to 0.78, P<.0001). Similarly, in a linear regression analysis predicting the Benign Prostatic Hyperplasia Impact Index score, adding UI to the AUASI slightly increased the predictive ability (R2 statistic increased from 0.22 to 0.26, P<.0001). CONCLUSION: According to our analysis in the CAMUS trial population, the value of adding a UI question to the AUASI in terms of predicting bother seemed small at best.