Placenta-targeted treatment with nMitoQ prevents an endothelin receptor-A pathway cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.

Prenatal hypoxia is associated with enhanced susceptibility to cardiac ischemia-reperfusion (I/R) injury in adult offspring, however, the mechanisms remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that acts via endothelin A (ETA) and endothelin B (ETB) receptors and is essential in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 system in adult offspring possibly contributing to I/R susceptibility. We previously showed that ex vivo application of ETA antagonist ABT-627 during I/R prevented the recovery of cardiac function in prenatal hypoxia-exposed males but not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this follow-up study, we examined whether placenta-targeted treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic pregnancies could alleviate this hypoxic phenotype observed in adult male offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley rats were exposed to hypoxia (11% O2) from gestational days (GD) 15-21 after injection with 100 µL saline or nMitoQ (125 µM) on GD15. Male offspring were aged to 4 mo and ex vivo cardiac recovery from I/R was assessed. Offspring born from hypoxic pregnancies and treated with nMitoQ had increased cardiac recovery from I/R in the presence of ABT-627 compared with their untreated counterparts where ABT-627 prevented recovery. Cardiac ETA levels were increased in males born from hypoxic pregnancies with nMitoQ treatment compared with saline controls (Western blotting). Our data indicate a profound impact of placenta-targeted treatment to prevent an ETA receptor cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.NEW & NOTEWORTHY In this follow-up study, we showed a complete lack of recovery from I/R injury after the application of an ETA receptor antagonist (ABT-627) in adult male offspring exposed to hypoxia in utero while maternal treatment with nMitoQ during prenatal hypoxia exposure prevented this effect. Our data suggest that nMitoQ treatment during hypoxic pregnancies may prevent a hypoxic cardiac phenotype in adult male offspring.

Sex-Specific Effects of Prenatal Hypoxia and a Placental Antioxidant Treatment on Cardiac Mitochondrial Function in the Young Adult Offspring.

Prenatal hypoxia is associated with placental oxidative stress, leading to impaired fetal growth and an increased risk of cardiovascular disease in the adult offspring; however, the mechanisms are unknown. Alterations in mitochondrial function may result in impaired cardiac function in offspring. In this study, we hypothesized that cardiac mitochondrial function is impaired in adult offspring exposed to intrauterine hypoxia, which can be prevented by placental treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). Cardiac mitochondrial respiration was assessed in 4-month-old rat offspring exposed to prenatal hypoxia (11% O2) from gestational day (GD)15-21 receiving either saline or nMitoQ on GD 15. Prenatal hypoxia did not alter cardiac mitochondrial oxidative phosphorylation capacity in the male offspring. In females, the NADH + succinate pathway capacity decreased by prenatal hypoxia and tended to be increased by nMitoQ. Prenatal hypoxia also decreased the succinate pathway capacity in females. nMitoQ treatment increased respiratory coupling efficiency in prenatal hypoxia-exposed female offspring. In conclusion, prenatal hypoxia impaired cardiac mitochondrial function in adult female offspring only, which was improved with prenatal nMitoQ treatment. Therefore, treatment strategies targeting placental oxidative stress in prenatal hypoxia may reduce the risk of cardiovascular disease in adult offspring by improving cardiac mitochondrial function in a sex-specific manner.

Service Users' Views and Experiences of Alcohol Relapse Prevention Treatment and Adherence: New Role for Pharmacists?

AIMS: To understand service users' views and experiences of alcohol relapse prevention medication, views of a telephone behavioural modification intervention delivered by pharmacists and the use of Contingency Management (CM) to support acamprosate adherence following assisted alcohol withdrawal. METHODS: Four focus groups were conducted within four alcohol treatment and recovery groups across England (UK), with service users with lived experience of alcohol dependence (26 participants). Semi-structured topic guide was used to explore participants' views and experiences of alcohol relapse prevention medication, a telephone behavioural modification medication intervention delivered by pharmacists, and the use of CM to support acamprosate adherence. These were audio-recorded, transcribed verbatim and thematically analysed inductively and deductively. RESULTS: Four themes were identified: concerns about support and availability of alcohol relapse prevention medication; lack of knowledge and understanding about acamprosate treatment; positive perceptions of acamprosate adherence telephone support from pharmacists; and negative perceptions of CM to support acamprosate adherence. There were misunderstandings about acamprosate's mode of action and strong negative beliefs about CM. However, most were positive about pharmacists' new role to support acamprosate adherence. CONCLUSION: This study highlighted challenges service users face to commence alcohol relapse prevention medication. It appears service users could benefit from a pharmacist-led telephone intervention to improve understanding about acamprosate medication, particularly, if delivered in an engaging and motivating way.

Placental treatment improves cardiac tolerance to ischemia/reperfusion insult in adult male and female offspring exposed to prenatal hypoxia.

Offspring born from complicated pregnancies are at greater risk of cardiovascular disease in adulthood. Prenatal hypoxia is a common pregnancy complication that results in placental oxidative stress and impairs fetal development. Adult offspring exposed to hypoxia during fetal life are more susceptible to develop cardiac dysfunction, and show decreased cardiac tolerance to an ischemia/reperfusion (I/R) insult. To improve offspring cardiac outcomes, we have assessed the use of a placenta-targeted intervention during hypoxic pregnancies, by encapsulating the mitochondrial antioxidant MitoQ into nanoparticles (nMitoQ). We hypothesized that maternal nMitoQ treatment during hypoxic pregnancies improves cardiac tolerance to I/R insult in adult male and female offspring. Pregnant Sprague-Dawley rats were exposed to normoxia (21 % O2) or hypoxia (11 % O2) from gestational day 15-20, after injection with 100 µL saline or nMitoQ (125 µM) on GD15 (n=6-8/group). Male and female offspring were aged to 4 months. Both male and female offspring from hypoxic pregnancies showed reduced cardiac tolerance to I/R (assessed ex vivo using the isolated working heart technique) which was ameliorated by nMitoQ treatment. To identify potential molecular mechanisms for the changes in cardiac tolerance to I/R, cardiac levels/phosphorylation of proteins important for intracellular Ca2+ cycling were assessed with Western blotting. In prenatally hypoxic male offspring, improved cardiac recovery from I/R by nMitoQ was accompanied by increased cardiac phospholamban and phosphatase 2Ce levels, and a trend to decreased Ca2+/calmodulin-dependent protein kinase IIδ phosphorylation. In contrast, in female offspring, nMitoQ treatment in hypoxic pregnancies increased phospholamban and protein kinase Cε phosphorylation. Maternal nMitoQ treatment improves cardiac tolerance to I/R insult in adult offspring and thus has the potential to improve the later-life trajectory of cardiovascular health of adult offspring born from pregnancies complicated by prenatal hypoxia.

Maternal treatment with a placental-targeted antioxidant (MitoQ) impacts offspring cardiovascular function in a rat model of prenatal hypoxia.

Intrauterine growth restriction, a common consequence of prenatal hypoxia, is a leading cause of fetal morbidity and mortality with a significant impact on population health. Hypoxia may increase placental oxidative stress and lead to an abnormal release of placental-derived factors, which are emerging as potential contributors to developmental programming. Nanoparticle-linked drugs are emerging as a novel method to deliver therapeutics targeted to the placenta and avoid risking direct exposure to the fetus. We hypothesize that placental treatment with antioxidant MitoQ loaded onto nanoparticles (nMitoQ) will prevent the development of cardiovascular disease in offspring exposed to prenatal hypoxia. Pregnant rats were intravenously injected with saline or nMitoQ (125 µM) on gestational day (GD) 15 and exposed to either normoxia (21% O2) or hypoxia (11% O2) from GD15-21 (term: 22 days). In one set of animals, rats were euthanized on GD 21 to assess fetal body weight, placental weight and placental oxidative stress. In another set of animals, dams were allowed to give birth under normal atmospheric conditions (term: GD 22) and male and female offspring were assessed at 7 and 13 months of age for in vivo cardiac function (echocardiography) and vascular function (wire myography, mesenteric artery). Hypoxia increased oxidative stress in placentas of male and female fetuses, which was prevented by nMitoQ. 7-month-old male and female offspring exposed to prenatal hypoxia demonstrated cardiac diastolic dysfunction, of which nMitoQ improved only in 7-month-old female offspring. Vascular sensitivity to methacholine was reduced in 13-month-old female offspring exposed to prenatal hypoxia, while nMitoQ treatment improved vasorelaxation in both control and hypoxia exposed female offspring. Male 13-month-old offspring exposed to hypoxia showed an age-related decrease in vascular sensitivity to phenylephrine, which was prevented by nMitoQ. In summary, placental-targeted MitoQ treatment in utero has beneficial sex- and age-dependent effects on adult offspring cardiovascular function.

Alcohol screening and brief interventions for offenders in the probation setting (SIPS Trial): a pragmatic multicentre cluster randomized controlled trial.

AIM: To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in the probation setting. Offender managers were randomized to three interventions, each of which built on the previous one: feedback on screening outcome and a client information leaflet control group, 5 min of structured brief advice and 20 min of brief lifestyle counselling. METHODS: A pragmatic multicentre factorial cluster randomized controlled trial. The primary outcome was self-reported hazardous or harmful drinking status measured by Alcohol Use Disorders Identification Test (AUDIT) at 6 months (negative status was a score of <8). Secondary outcomes were AUDIT status at 12 months, experience of alcohol-related problems, health utility, service utilization, readiness to change and reduction in conviction rates. RESULTS: Follow-up rates were 68% at 6 months and 60% at 12 months. At both time points, there was no significant advantage of more intensive interventions compared with the control group in terms of AUDIT status. Those in the brief advice and brief lifestyle counselling intervention groups were statistically significantly less likely to reoffend (36 and 38%, respectively) than those in the client information leaflet group (50%) in the year following intervention. CONCLUSION: Brief advice or brief lifestyle counselling provided no additional benefit in reducing hazardous or harmful drinking compared with feedback on screening outcome and a client information leaflet. The impact of more intensive brief intervention on reoffending warrants further research.

Using the community readiness model to examine the built and social environment: a case study of the High Point neighborhood, Seattle, Washington, 2000-2010.

BACKGROUND: Residents of many cities lack affordable, quality housing. Economically disadvantaged neighborhoods often have high rates of poverty and crime, few institutions that enhance the quality of its residents' lives, and unsafe environments for walking and other physical activity. Deteriorating housing contributes to asthma-related illness. We describe the redevelopment of High Point, a West Seattle neighborhood, to improve its built environment, increase neighborhood physical activity, and reduce indoor asthma triggers. COMMUNITY CONTEXT: High Point is one of Seattle's most demographically diverse neighborhoods. Prior to redevelopment, it had a distressed infrastructure, rising crime rates, and indoor environments that increased asthma-related illness in children and adolescents. High Point residents and partners developed and implemented a comprehensive redevelopment plan to create a sustainable built environment to increase outdoor physical activity and improve indoor environments. METHODS: We conducted a retrospective analysis of the High Point redevelopment, organized by the different stages of change in the Community Readiness Model. We also examined the multisector partnerships among government and community groups that contributed to the success of the High Point project. OUTCOME: Overall quality of life for residents improved as a result of neighborhood redevelopment. Physical activity increased, residents reported fewer days of poor physical or mental health, and social connectedness between neighbors grew. Asthma-friendly homes significantly decreased asthma-related illness among children and adolescents. INTERPRETATION: Providing affordable, quality housing to low-income families improved individual and neighborhood quality of life. Efforts to create social change and improve the health outcomes for entire populations are more effective when multiple organizations work together to improve neighborhood health.

Sex-specific differences in the mechanisms for enhanced thromboxane A2-mediated vasoconstriction in adult offspring exposed to prenatal hypoxia.

BACKGROUND: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. METHODS: Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. RESULTS: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. CONCLUSIONS: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.

Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease.

Early outcomes following integration of computed tomography (CT) coronary angiography service in an established cardiology practice in disease management.

BACKGROUND: Computed tomography coronary angiography (CTCA) is an established modality for the diagnosis and assessment of cardiovascular disease. However, price and space pressure have mostly necessitated outsourcing CTCA to external radiology providers. Advara HeartCare has recently integrated CT services within local clinical networks across Australia. This study examined the benefits of the presence (integrated) or absence (pre-integrated) of this "in-house" CTCA service in real-world clinical practice. METHODS: De-identified patient data from electronic medical records were used to create an Advara HeartCare CTCA database. Data analysis included clinical history, demographics, CTCA procedure, and 30-day outcomes post-CTCA from two age-matched cohorts: integrated (n â€‹= â€‹495) and pre-integrated (n â€‹= â€‹456). RESULTS: Data capture was more comprehensive and standardised across the integrated cohort. There was a 21% increase in referrals for CTCA from cardiologists observed for the integration cohort vs. pre-integration [n â€‹= â€‹332 (72.8%) pre-integration vs. n â€‹= â€‹465 (93.9%) post-integration, p â€‹< â€‹0.0001] with a parallel increase in diagnostic assessments including blood tests [n â€‹= â€‹209 (45.8%) vs. n â€‹= â€‹387 (78.1%), respectively, p â€‹< â€‹0.0001]. The integrated cohort received lower total dose length product [Median 212 (interquartile range 136-418) mGy∗cm vs. 244 (141.5, 339.3) mGy∗cm, p â€‹= â€‹0.004] during the CTCA procedure. 30-days after CTCA scan, there was a significantly higher use of lipid-lowering therapies in the integrated cohort [n â€‹= â€‹133 (50.5%) vs. n â€‹= â€‹179 (60.6%), p â€‹= â€‹0.04], along with a significant decrease in the number of stress echocardiograms performed [n â€‹= â€‹14 (10.6%) vs. n â€‹= â€‹5 (11.6%), p â€‹= â€‹0.01]. CONCLUSION: Integrated CTCA has salient benefits in patient management, including increased pathology tests, statin usage, and decreased post-CTCA stress echocardiography utilisation. Our ongoing work will examine the effect of integration on cardiovascular outcomes.

Screening for alcohol use in criminal justice settings: an exploratory study.

AIMS: To examine the feasibility and acceptability of alcohol screening and delivery of brief interventions within criminal justice settings. METHODS: A quantitative survey of those aged 18 or over in English criminal justice settings (three custody suites within police stations, three prisons and three probation offices). MEASUREMENTS: The Fast Alcohol Screening Test (FAST) and a modified version of the Single Alcohol Screening Question (M-SASQ) were compared with the Alcohol Use Disorders Identification Test (AUDIT) as the 'gold standard'. Participants completed a health status questionnaire (EQ5D), questions on service utilization and the Readiness to Change Questionnaire. Questions relating to the acceptability and feasibility of delivering brief interventions and about perception of coercion were included. FINDINGS: Five hundred and ninety-two individuals were approached and 251 were eligible. Of these, 205 (82%) consented to take part in the study. The mean AUDIT score was 19.9 (SD 13.5) and 73% scored 8 or more on AUDIT. A higher percentage of those approached in the probation setting consented to take part (81%: prison 36%, police setting 10%). Those scoring AUDIT positive were more likely to be involved in violent offences (36.5 vs 9.4%; P < 0.001) and less likely to be involved in offences involving property (27.7 vs 45.3%; P = 0.03). Three quarters of the sample (74%) reported that they would not feel coerced to engage in an intervention about their alcohol use. FAST and M-SASQ had acceptable screening properties when compared with AUDIT with area under the curves of 0.97 and 0.92, respectively. CONCLUSIONS: The results confirm that there is a major problem with alcohol use in the criminal justice system and this impacts on health and criminal behaviour. Of the three criminal justice settings, probation was found to be the most suitable for screening. Participants were positive about receiving interventions for their alcohol use in probation settings.

Determination of phenols and phenates in disinfectant formulations by liquid chromatography with UV detection: collaborative study.

Fourteen collaborating laboratories assayed o-phenylphenol (OPP), p-t-amylphenol (PTAP), and o-benzyl-p-chlorophenol (OBPCP) in formulated products, both ready-to-use and concentrates, by RP-HPLC. The actives in the samples ranged from 0.03 to 11% OPP, 0.06 to 4% PTAP, and 0.07 to 10% OBPCP either in free forms or as salts. Seven blind duplicates were analyzed. The samples were diluted/extracted with acidified methanol, filtered, and analyzed by LC on a C18 column using gradient elution and UV detection at 285 nm. The concentration of the active ingredients was calculated from a standard curve. Each laboratory weighed each test sample twice within a single analytical run. The data were analyzed using all 14 laboratory results, with appropriate statistical tests to detect outliers. The repeatability RSDs ranged from 0.98 to 3.40% for the free phenols, and 1.26 to 2.51% for the salts. The reproducibility RSDs ranged from 5.31 to 7.80% for the free phenols, and 5.50 to 8.67% for the salts. The HorRat ranged from 0.86 to 2.17 for the free phenols, and 1.54 to 2.72 for the salts.

Methamphetamine and lentivirus interactions: reciprocal enhancement of central nervous system disease.

Use of methamphetamine is increasingly a significant factor for the spread of human immunodeficiency virus type 1, for in certain populations, there is a convergence of methamphetamine abuse with human immunodeficiency virus type 1 infection. Methamphetamine and human immunodeficiency virus type 1 are both individually neuropathogenic, and the neuropathology caused by these two agents occurs in overlapping brain regions. However, the biological interaction of methamphetamine with lentiviruses remains unknown. Here, we investigate the effects of simultaneous exposure of these two agents on disease progression using the feline immunodeficiency virus model. The study models the bingeing methamphetamine user with sequential and repeated episodes of use, which were interrupted by periods of abstinence. Methamphetamine exposure significantly accelerated and enhanced the severity of the feline immunodeficiency virus model-induced central nervous system functional pathology, as measured in delays in brainstem auditory evoked potentials. Reciprocally, feline immunodeficiency virus enhanced the severity of the methamphetamine-induced effects on brain monoamine neurotransmitter and dopamine transporter levels. The results of this study indicate that a dual potentiation occurred. That is, methamphetamine enhanced feline immunodeficiency virus model-induced central nervous system disease and feline immunodeficiency virus model enhanced the toxic effects of methamphetamine, heralding a significant concern for those individuals that are exposed to both agents.

Screening and brief interventions for hazardous and harmful alcohol use in primary care: a cluster randomised controlled trial protocol.

BACKGROUND: There have been many randomized controlled trials of screening and brief alcohol intervention in primary care. Most trials have reported positive effects of brief intervention, in terms of reduced alcohol consumption in excessive drinkers. Despite this considerable evidence-base, key questions remain unanswered including: the applicability of the evidence to routine practice; the most efficient strategy for screening patients; and the required intensity of brief intervention in primary care. This pragmatic factorial trial, with cluster randomization of practices, will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in primary care and different intensities of brief intervention to reduce excessive drinking in primary care patients. METHODS AND DESIGN: GPs and nurses from 24 practices across the North East (n=12), London and South East (n=12) of England will be recruited. Practices will be randomly allocated to one of three intervention conditions: a leaflet-only control group (n=8); brief structured advice (n=8); and brief lifestyle counselling (n=8). To test the relative effectiveness of different screening methods all practices will also be randomised to either a universal or targeted screening approach and to use either a modified single item (M-SASQ) or FAST screening tool. Screening randomisation will incorporate stratification by geographical area and intervention condition. During the intervention stage of the trial, practices in each of the three arms will recruit at least 31 hazardous or harmful drinkers who will receive a short baseline assessment followed by brief intervention. Thus there will be a minimum of 744 patients recruited into the trial. DISCUSSION: The trial will evaluate the impact of screening and brief alcohol intervention in routine practice; thus its findings will be highly relevant to clinicians working in primary care in the UK. There will be an intention to treat analysis of study outcomes at 6 and 12 months after intervention. Analyses will include patient measures (screening result, weekly alcohol consumption, alcohol-related problems, public service use and quality of life) and implementation measures from practice staff (the acceptability and feasibility of different models of brief intervention.) We will also examine organisational factors associated with successful implementation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN06145674.

Screening and brief interventions for hazardous and harmful alcohol use in probation services: a cluster randomised controlled trial protocol.

BACKGROUND: A large number of randomised controlled trials in health settings have consistently reported positive effects of brief intervention in terms of reductions in alcohol use. However, although alcohol misuse is common amongst offenders, there is limited evidence of alcohol brief interventions in the criminal justice field. This factorial pragmatic cluster randomised controlled trial with Offender Managers (OMs) as the unit of randomisation will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in probation and different intensities of brief intervention to reduce excessive drinking in probation clients. METHODS AND DESIGN: Ninety-six OMs from 9 probation areas across 3 English regions (the North East Region (n = 4) and London and the South East Regions (n = 5)) will be recruited. OMs will be randomly allocated to one of three intervention conditions: a client information leaflet control condition (n = 32 OMs); 5-minute simple structured advice (n = 32 OMs) and 20-minute brief lifestyle counselling delivered by an Alcohol Health Worker (n = 32 OMs). Randomisation will be stratified by probation area. To test the relative effectiveness of different screening methods all OMs will be randomised to either the Modified Single Item Screening Questionnaire (M-SASQ) or the Fast Alcohol Screening Test (FAST). There will be a minimum of 480 clients recruited into the trial. There will be an intention to treat analysis of study outcomes at 6 and 12 months post intervention. Analysis will include client measures (screening result, weekly alcohol consumption, alcohol-related problems, re-offending, public service use and quality of life) and implementation measures from OMs (the extent of screening and brief intervention beyond the minimum recruitment threshold will provide data on acceptability and feasibility of different models of brief intervention). We will also examine the practitioner and organisational factors associated with successful implementation. DISCUSSION: The trial will evaluate the impact of screening and brief alcohol intervention in routine probation work and therefore its findings will be highly relevant to probation teams and thus the criminal justice system in the UK.Ethical approval was given by Northern & Yorkshire REC. TRIAL REGISTRATION NUMBER: ISRCTN 19160244.

Screening and brief interventions for hazardous alcohol use in accident and emergency departments: a randomised controlled trial protocol.

BACKGROUND: There is a wealth of evidence regarding the detrimental impact of excessive alcohol consumption on the physical, psychological and social health of the population. There also exists a substantial evidence base for the efficacy of brief interventions aimed at reducing alcohol consumption across a range of healthcare settings. Primary research conducted in emergency departments has reinforced the current evidence regarding the potential effectiveness and cost-effectiveness. Within this body of evidence there is marked variation in the intensity of brief intervention delivered, from very minimal interventions to more intensive behavioural or lifestyle counselling approaches. Further the majority of primary research has been conducted in single centre and there is little evidence of the wider issues of generalisability and implementation of brief interventions across emergency departments. METHODS/DESIGN: The study design is a prospective pragmatic factorial cluster randomised controlled trial. Individual Emergency Departments (ED) (n = 9) are randomised with equal probability to a combination of screening tool (M-SASQ vs FAST vs SIPS-PAT) and an intervention (Minimal intervention vs Brief advice vs Brief lifestyle counselling). The primary hypothesis is that brief lifestyle counselling delivered by an Alcohol Health Worker (AHW) is more effective than Brief Advice or a minimal intervention delivered by ED staff. Secondary hypotheses address whether short screening instruments are more acceptable and as efficient as longer screening instruments and the cost-effectiveness of screening and brief interventions in ED. Individual participants will be followed up at 6 and 12 months after consent. The primary outcome measure is performance using a gold-standard screening test (AUDIT). Secondary outcomes include; quantity and frequency of alcohol consumed, alcohol-related problems, motivation to change, health related quality of life and service utilisation. DISCUSSION: This paper presents a protocol for a large multi-centre pragmatic factorial cluster randomised trial to evaluate the effectiveness and cost-effectiveness of screening and brief interventions for hazardous alcohol users attending emergency departments. TRIAL REGISTRATION: ISRCTN 93681536.

Modeling the Potential Impact of Changing Access Rates to Specialist Treatment for Alcohol Dependence for Local Authorities in England: The Specialist Treatment for Alcohol Model (STreAM).

OBJECTIVE: We modeled the impact of changing Specialist Treatment Access Rates to different treatment pathways on the future prevalence of alcohol dependence, treatment outcomes, service capacity, costs, and mortality. METHOD: Local Authority numbers and the prevalence of people "potentially in need of assessment for and treatment in specialist services for alcohol dependence" (PINASTFAD) are estimated by mild, moderate, severe, and complex needs. Administrative data were used to estimate the Specialist Treatment Access Rate per PINASTFAD person and classify 22 different treatment pathways. Other model inputs include natural remission, relapse after treatment, service costs, and mortality rates. "What-if" analyses assess changes to Specialist Treatment Access Rates and treatment pathways. Model outputs include the numbers and prevalence of people who are PINASTFAD, numbers treated by 22 pathways, outcomes (successful completion with abstinence, successfully moderated nonproblematic drinking, re-treatment within 6 months, dropout, transfer, custody), mortality rates, capacity requirements (numbers in contact with community services or staying in residential or inpatient places), total treatment costs, and general health care savings. Five scenarios illustrate functionality: (a) no change, (b) achieve access rates at the 70th percentile nationally, (c) increase access by 25%, (d) increase access to Scotland rate, and (e) reduce access by 25%. RESULTS: At baseline, 14,581 people are PINASTFAD (2.43% of adults) and the Specialist Treatment Access Rate is 10.84%. The 5-year impact of scenarios on PINASTFAD numbers (vs. no change) are (B) reduced by 191 (-1.3%), (C) reduced by 477 (-3.3%), (D) reduced by almost 2,800 (-19.2%), and (E) increased by 533 (+3.6%). The relative impact is similar for other outputs. CONCLUSIONS: Decision makers can estimate the potential impact of changing Specialist Treatment Access Rates for alcohol dependence.

Low identification of alcohol use disorders in general practice in England.

AIMS: The prevalence of alcohol use disorders (AUDs) in the United Kingdom is estimated at 25%, and primary care has been identified as the first line of treatment for this population. However, there is a paucity of evidence regarding the current rates of identification of AUDs in primary care. The aim of the present study was to compare the observed rates of AUDs in general practice with expected rates, which are based on general population prevalence rates of AUDs. DESIGN, PARTICIPANTS AND MEASUREMENTS: Epidemiological data on individuals aged 16-64 years with an AUD was obtained from the General Practice Research Database. General population prevalence rates of AUDs were obtained from the Psychiatric Morbidity Survey. Chi(2) tests and identification ratios were used to analyse the data. RESULTS: There was a significant relationship between type of AUD and identification (chi(2)=1466.89, P<0.001), and general practitioners were poorer at identifying harmful/hazardous drinkers when compared with dependent drinkers. No gender differences in the identification of hazardous/harmful drinking were found, but female dependent drinkers were significantly more likely to be identified than males (identification ratio 0.07; 95% confidence interval 0.06-0.07). The identification of AUDs was significantly lower for the 16-24-year age group compared with all other age groups. CONCLUSION: Despite attempts at targeting hazardous/harmful drinkers for brief interventions in primary care, the present findings suggest that this group are still under-identified. Furthermore, this under-identification is even more apparent in men and in young people who have high general population prevalence rates for AUDs. In conclusion, increasing identification rates could be incorporated into brief intervention strategies in primary care.

The effectiveness and cost-effectiveness of opportunistic screening and stepped care interventions for older hazardous alcohol users in primary care (AESOPS) - a randomised control trial protocol.

BACKGROUND: There is a wealth of evidence regarding the detrimental impact of excessive alcohol consumption. In older populations excessive alcohol consumption is associated with increased risk of coronary heart disease, hypertension, stroke and a range of cancers. Alcohol consumption is also associated with an increased risk of falls, early onset of dementia and other cognitive deficits. Physiological changes that occur as part of the ageing process mean that older people experience alcohol related problems at lower consumption levels. There is a strong evidence base for the effectiveness of brief psychosocial interventions in reducing alcohol consumption in populations identified opportunistically in primary care settings. Stepped care interventions involve the delivery of more intensive interventions only to those in the population who fail to respond to less intensive interventions and provide a potentially resource efficient means of meeting the needs of this population. METHODS/DESIGN: The study design is a pragmatic prospective multi-centre two arm randomised controlled trial. The primary hypothesis is that stepped care interventions for older hazardous alcohol users reduce alcohol consumption compared with a minimal intervention at 12 months post randomisation. Potential participants are identified using the AUDIT questionnaire. Eligible and consenting participants are randomised with equal probability to either a minimal intervention or a three step treatment approach. The step treatment approach incorporates as step 1 behavioural change counselling, step 2 three sessions of motivational enhancement therapy and step 3 referral to specialist services. The primary outcome is measured using average standard drinks per day and secondary outcome measures include the Drinking Problems Index, health related quality of life and health utility. The study incorporates a comprehensive economic analysis to assess the relative cost-effectiveness of the interventions. DISCUSSION: The paper presents a protocol for the first pragmatic randomised controlled trial evaluating the effectiveness and cost-effectiveness of stepped care interventions for older hazardous alcohol users in primary care. TRIAL REGISTRATION: ISRCTN52557360.

Preeclamptic placentae release factors that damage neurons: implications for foetal programming of disease.

Prenatal development is a critical period for programming of neurological disease. Preeclampsia, a pregnancy complication involving oxidative stress in the placenta, has been associated with long-term health implications for the child, including an increased risk of developing schizophrenia and autism spectrum disorders in later life. To investigate if molecules released by the placenta may be important mediators in foetal programming of the brain, we analysed if placental tissue delivered from patients with preeclampsia secreted molecules that could affect cortical cells in culture. Application of culture medium conditioned by preeclamptic placentae to mixed cortical cultures caused changes in neurons and astrocytes that were related to key changes observed in brains of patients with schizophrenia and autism, including effects on dendrite lengths, astrocyte number as well as on levels of glutamate and γ-aminobutyric acid receptors. Treatment of the placental explants with an antioxidant prevented neuronal abnormalities. Furthermore, we identified that bidirectional communication between neurons and astrocytes, potentially via glutamate, is required to produce the effects of preeclamptic placenta medium on cortical cells. Analysis of possible signalling molecules in the placenta-conditioned medium showed that the secretion profile of extracellular microRNAs, small post-transcriptional regulators, was altered in preeclampsia and partially rescued by antioxidant treatment of the placental explants. Predicted targets of these differentially abundant microRNAs were linked to neurodevelopment and the placenta. The present study provides further evidence that the diseased placenta may release factors that damage cortical cells and suggests the possibility of targeted antioxidant treatment of the placenta to prevent neurodevelopmental disorders.