Ending preventable stillbirths and improving bereavement care: a scorecard for high- and upper-middle income countries.

BACKGROUND: Despite progress, stillbirth rates in many high- and upper-middle income countries remain high, and the majority of these deaths are preventable. We introduce the Ending Preventable Stillbirths (EPS) Scorecard for High- and Upper Middle-Income Countries, a tool to track progress against the Lancet's 2016 EPS Series Call to Action, fostering transparency, consistency and accountability. METHODS: The Scorecard for EPS in High- and Upper-Middle Income Countries was adapted from the Scorecard for EPS in Low-Income Countries, which includes 20 indicators to track progress against the eight Call to Action targets. The Scorecard for High- and Upper-Middle Income Countries includes 23 indicators tracking progress against these same Call to Action targets. For this inaugural version of the Scorecard, 13 high- and upper-middle income countries supplied data. Data were collated and compared between and within countries. RESULTS: Data were complete for 15 of 23 indicators (65%). Five key issues were identified: (1) there is wide variation in stillbirth rates and related perinatal outcomes, (2) definitions of stillbirth and related perinatal outcomes vary widely across countries, (3) data on key risk factors for stillbirth are often missing and equity is not consistently tracked, (4) most countries lack guidelines and targets for critical areas for stillbirth prevention and care after stillbirth and have not set a national stillbirth rate target, and (5) most countries do not have mechanisms in place for reduction of stigma or guidelines around bereavement care. CONCLUSIONS: This inaugural version of the Scorecard for High- and Upper-Middle Income Countries highlights important gaps in performance indicators for stillbirth both between and within countries. The Scorecard provides a basis for future assessment of progress and can be used to help hold individual countries accountable, especially for reducing stillbirth inequities in disadvantaged groups.

The Disenfranchisement of Perinatal Grief: How Silence, Silencing and Self-Censorship Complicate Bereavement (a Mixed Methods Study).

Based on an ethnographic and mixed-methods research design, the article explores the social and interactive processes of disenfranchisement of perinatal grief through the mechanisms of silence, silencing and self-censorship in encounters between bereaved women and the social milieu. The analysis finds that disenfranchisement results from the constriction of the social space of bereavement along various lines of discourse, cultural values, practice and materiality, that include: the passing of time (expectations of a quick 'recovery'); competing discourses of loss (simplistic-dominant vs. complex-subordinate meaning-making); the biometrics of pregnancy (lower gestational age being equated with less intense grief); gendered ideas of reproduction and feeling rules; asymmetries in social power; social spheres (hospital, home, community, support groups); socio-materialities and performance/ritual; and structural aspects of social and familial organization (gender, age, intergenerational and kin v. non-kin relations). These processes are intimately linked to the complication of grief by undermining support, meaning-making and continuing bonds.

Beyond emotional support: predictors of satisfaction and perceived care quality following the death of a baby during pregnancy.

OBJECTIVES: To investigate which objective (actions/interventions) and subjective (perceptions of care quality) outcomes of care following stillbirth or termination of pregnancy predict perceived care quality. METHODS: A cross-sectional descriptive study using an anonymous online survey. The population was women who had experienced a stillbirth or termination of pregnancy from ≥16 weeks of gestation, in the Spanish health system. Multiple sequential regression analysis was used to identify predictors of perceived care quality (satisfaction, willingness to recommend, competence and ability to provide loss-focused care). RESULTS: Results from 610 women were analysed. A significant regression equation (p<0.001) was found in each of the objective only and objective-subjective models. In the case of overall care (satisfaction-recommend composite), 72.0% of variance (adj. R2) was explained. In general, subjective evaluations of care are more potent predictors of perceived care quality than objective care interventions (e.g. autopsy performed). Feeling free to 'express emotions', 'teamwork between doctors and nurses/midwives', and 'being well-informed of all steps and procedures' were the three strongest predictors, followed by perception of 'medical negligence'. Information provision and loss-focused interventions had the weakest influence, except in the specific 'loss-focused' model. CONCLUSIONS: The results indicate that the 'atmosphere' of care is a transversal dimension related to the context of loss and trauma and has the single greatest influence on perceptions of care quality. It is necessary to use a specific 'loss-focused' care variable to adequately capture perceptions of the quality of bereavement care and a custom scale to measure the influence of care interventions on perceived quality.

Parents' experiences of care offered after stillbirth: An international online survey of high and middle-income countries.

BACKGROUND: Stillbirth, the death of a baby before birth, is associated with significant psychological and social consequences that can be mitigated by respectful and supportive bereavement care. The absence of high-level evidence to support the broad scope of perinatal bereavement practices means that offering a range of options identified as valued by parents has become an important indicator of care quality. This study aimed to describe bereavement care practices offered to parents across different high-income and middle-income countries. METHODS: An online survey of parents of stillborn babies was conducted between December 2014 and February 2015. Frequencies of nine practices were compared between high-income and middle-income countries. Differences in proportions of reported practices and their associated odds ratios were calculated to compare high-income and middle-income countries. RESULTS: Over three thousand parents (3041) with a self-reported stillbirth in the preceding five years from 40 countries responded. Fifteen countries had atleast 40 responses. Significant differences in the prevalence of offering nine bereavement care practices were reported by women in high-income countries (HICs) compared with women in middle-income countries (MICs). All nine practices were reported to occur significantly more frequently by women in HICs, including opportunity to see and hold their baby (OR = 4.8, 95% CI 4.0-5.9). The widespread occurrence of all nine practices was reported only for The Netherlands. CONCLUSIONS: Bereavement care after stillbirth varies between countries. Future research should look at why these differences occur, their impact on parents, and whether differences should be addressed, particularly how to support effective communication, decision-making, and follow-up care.

Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma.

Intraocular pressure (IOP) is maintained as a result of the balance between production of aqueous humour (AH) by the ciliary processes and hydrodynamic resistance to its outflow through the conventional outflow pathway comprising the trabecular meshwork (TM) and Schlemm's canal (SC). Elevated IOP, which can be caused by increased resistance to AH outflow, is a major risk factor for open-angle glaucoma. Matrix metalloproteinases (MMPs) contribute to conventional aqueous outflow homeostasis in their capacity to remodel extracellular matrices, which has a direct impact on aqueous outflow resistance and IOP. We observed decreased MMP-3 activity in human glaucomatous AH compared to age-matched normotensive control AH. Treatment with glaucomatous AH resulted in significantly increased transendothelial resistance of SC endothelial and TM cell monolayers and reduced monolayer permeability when compared to control AH, or supplemented treatment with exogenous MMP-3.Intracameral inoculation of AAV-2/9 containing a CMV-driven MMP-3 gene (AAV-MMP-3) into wild type mice resulted in efficient transduction of corneal endothelium and an increase in aqueous concentration and activity of MMP-3. Most importantly, AAV-mediated expression of MMP-3 increased outflow facility and decreased IOP, and controlled expression using an inducible promoter activated by topical administration of doxycycline achieved the same effect. Ultrastructural analysis of MMP-3 treated matrices by transmission electron microscopy revealed remodelling and degradation of core extracellular matrix components. These results indicate that periodic induction, via use of an eye drop, of AAV-mediated secretion of MMP-3 into AH could have therapeutic potential for those cases of glaucoma that are sub-optimally responsive to conventional pressure-reducing medications.

Care quality following intrauterine death in Spanish hospitals: results from an online survey.

BACKGROUND: The objective of the study was to evaluate practices in Spanish hospitals after intrauterine death in terms of medical/ technical care and bereavement support care. METHODS: A cross-sectional descriptive study using an online self-completion questionnaire. The population was defined as women who had experienced an intrauterine fetal death between sixteen weeks and birth, either through spontaneous late miscarriage/stillbirth or termination of pregnancy for medical reasons. Respondents were recruited through an online advertisement on a stillbirth charity website and social media. The analysis used Pearson's chi-squared (p ≤ 0.05) test of independence to cross-analyse for associations between objective measures of care quality and independent variables. RESULTS: Responses from 796 women were analysed. Half of the women (52.9%) had postmortem contact with their baby. 30.4% left the hospital with a least one linking object or a photograph. In 35.8% of cases parents weren't given any option to recover the body/remains. 22.9% of births ≥26 weeks gestation were by caesarean, with a significant (p < 0.001) difference between public hospitals (16.8%) and private hospitals (41.5%). 29.3% of respondents were not accompanied during the delivery. 48.0% of respondents recalled being administered sedatives at least once during the hospital stay. The autopsy rate in stillbirth cases (≥ 20 weeks) was 70.5% and 44.4% in cases of termination of pregnancy (all gestational ages). Consistent significant (p < 0.05) differences in care practices were found based on gestational age and type of hospital (public or private), but not to other variables related to socio-demographics, pregnancy history or details of the loss/death. Intrauterine deaths at earlier gestational ages received poorer quality care. CONCLUSIONS: Supportive healthcare following intrauterine death is important to women's experiences in the hospital and beneficial to the grief process. Many care practices that are standard in other high-income countries are not routine in Spanish hospitals. Providing such care is a relatively new phenomenon in the Spanish health system, the results provide a quality benchmark and identify a number of areas where hospitals could make improvements to care practices that should have important psychosocial benefits for women and their families.

Stillbirths: recall to action in high-income countries.

Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.

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.

Sedative administration in Spanish hospitals in the context of perinatal loss: findings from a mixed-methods study.

This article explores the contexts, processes and motivations behind the administration of sedatives (minor tranquilisers) in the time around perinatal loss. Using a mixed methods design, an online survey of 796 women and 13 narrative interviews were conducted. The participants had experienced a stillbirth or termination of pregnancy from 16 weeks or a neonatal death in Spanish hospitals. The quantitative (univariate and CHAID decision-tree) and qualitative (narrative-linguistic) analysis found that sedative administration was pervasive across care contexts and appears to be naturalised despite contradicting practice recommendations. Sedative administration was associated with emotional control and avoidance of loss, lack of accompaniment and on occasion with managing disruptive patients. Lack of informed consent was very common, with little explanation of side-effects prior to administration. In the participants' narratives, health professionals tended to construct sedatives as benign, but for some women the effects were counterproductive to loss and grief and related to persistent regrets about decisions. The study concludes that, in the context of perinatal loss, sedative administration was highly integrated into the fabric of medicalised care. As a socio-political and cultural practice underscored by gender-based care dynamics, there seems to be an imbalance between benefit and risk to women's welfare.

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.

Intervention against excessive alcohol consumption in primary health care: a survey of GPs' attitudes and practices in England 10 years on.

AIMS: To ascertain the views of general practitioners (GPs) regarding the prevention and management of alcohol-related problems in practice, together with perceived barriers and incentives for this work; to compare our findings with a comparable survey conducted 10 years earlier. METHODS: In total, 282 (73%) of 419 GPs surveyed in East Midlands, UK, completed a postal questionnaire, measuring practices and attitudes, including the Shortened Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ). RESULTS: GPs reported lower levels of post-graduate education or training on alcohol-related issues (<4 h for the majority) than in 1999 but not significantly so (P = 0.031). In the last year, GPs had most commonly requested more than 12 blood tests and managed 1-6 patients for alcohol. Reports of these preventive practices were significantly increased from 1999 (P < 0.001). Most felt that problem or dependent drinkers' alcohol issues could be legitimately (88%, 87%) and adequately (78%, 69%) addressed by GPs. However, they had low levels of motivation (42%, 35%), task-related self-esteem (53%, 49%) and job satisfaction (15%, 12%) for this. Busyness (63%) and lack of training (57%) or contractual incentives (48%) were key barriers. Endorsement for government policies on alcohol was very low. CONCLUSION: Among GPs, there still appears to be a gap between actual practice and potential for preventive work relating to alcohol problems; they report little specific training and a lack of support. Translational work on understanding the evidence-base supporting screening and brief intervention could incentivize intervention against excessive drinking and embedding it into everyday primary care practice.

Embedding assessment of liver fibrosis into routine diabetic review in primary care.

BACKGROUND & AIMS: Individuals with type 2 diabetes (T2DM) are at high risk of developing non-alcoholic fatty liver disease (NAFLD) and advanced fibrosis/cirrhosis. Screening patients with T2DM and normal liver enzymes for NAFLD in primary care remains contentious. Our aim was to develop and assess a primary care pathway integrating two-tier (Fib-4 then transient elastography [TE]) liver fibrosis assessment, irrespective of aetiology, into routine annual review of all patients with T2DM. METHODS: All patients aged >35 years with T2DM attending annual review at 2 primary care practices in North East England between April 2018 and September 2019 (n = 467) had Fib-4 requested via the electronic patient record. Those with a Fib-4 score above the 'high-sensitivity' threshold (>1.3 for ≤65 years and >2.0 for >65 years) underwent TE and were reviewed in secondary care if the liver stiffness measurement (LSM) was >8 kPa. The number of patients identified with advanced disease, service uptake, and predictors of advanced disease were assessed. RESULTS: A total of 85/467 (18.5%) patients had raised Fib-4; 27/467(5.8%) were excluded as a result of frailty or known cirrhosis. A total of 58/467 (12.2%) were referred for TE. Twenty-five of 58 (43.1%) had an LSM of >8 kPa and 13/58 (22.4%) had an LSM >15 kPa; 4/58 (6.7%) did not attend and 5/58 (9.3%) had an invalid reading. Twenty of 440 (4.5%) patients were found to have advanced liver disease following specialist review, compared to 3 patients previously identified through standard care (odds ratio [OR] 6.71 [2.0-22.7] p = 0.0022). Alcohol (OR 1.05 [1.02-1.08] p = 0.001) and BMI (OR 1.09 [1.01-1.17] p = 0.021) were predictors of advanced disease, particularly drinking >14/21 units/week (p <0.0001). CONCLUSIONS: Incorporating 2-tier assessment of liver fibrosis into routine annual diabetes review in primary care significantly improves identification of advanced liver disease in patients with T2DM. LAY SUMMARY: People with type 2 diabetes are at increased risk of developing non-alcoholic fatty liver disease and developing more significant complications. This study looks at introducing screening for advanced liver disease into the annual diabetes reviews performed routinely in primary care; we found that significantly more people were identified as having significant liver disease through this pathway than with current standard care.

siRNA targeting Schlemm's canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model.

Systemic or localized application of glucocorticoids (GCs) can lead to iatrogenic ocular hypertension, which is a leading cause of secondary open-angle glaucoma and visual impairment. Previous work has shown that dexamethasone increases zonula occludens-1 (ZO-1) protein expression in trabecular meshwork (TM) cells, and that an antisense oligonucleotide inhibitor of ZO-1 can abolish the dexamethasone-induced increase in trans-endothelial flow resistance in cultured Schlemm's canal (SC) endothelial and TM cells. We have previously shown that intracameral inoculation of small interfering RNA (siRNA) targeting SC endothelial cell tight junction components, ZO-1 and tricellulin, increases aqueous humor outflow facility ex vivo in normotensive mice by reversibly opening SC endothelial paracellular pores. In this study, we show that targeted siRNA downregulation of these SC endothelial tight junctions reduces intraocular pressure (IOP) in vivo, with a concomitant increase in conventional outflow facility in a well-characterized chronic steroid-induced mouse model of ocular hypertension, thus representing a potential focused clinical application for this therapy in a sight-threatening scenario.

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.

Development of a Readiness Ruler for use with alcohol brief interventions.

BACKGROUND: A quick method of assessing readiness to change was needed for a major study of implementing screening and alcohol brief intervention in England. For this purpose, a Readiness Ruler that had been validated among a sample of male college students in the USA was adapted and applied to a sample of excessive drinkers in a general medical practice located in a deprived area of Gateshead, England. METHODS: 72 participants identified as excessive drinkers by health professionals completed a single-item Readiness Ruler, the 12-item Readiness to Change Questionnaire (RCQ) and the AUDIT questionnaire. RESULTS: In terms of concurrent validity, the relationships between the Readiness Ruler, on the one hand, and either stage of change allocation or a dimensional score derived from the RCQ, on the other hand, were highly significant but weaker than expected. When patients who endorsed the "maintenance" point on the Readiness Ruler were excluded from the analysis, the above relationships were considerably strengthened for reasons that are discussed. On this basis and with another small change, a final Readiness Ruler was developed. CONCLUSION: If the validity of the Readiness Ruler is confirmed in subsequent research, a quick and simple way of measuring readiness to change will be available for research or clinical work with alcohol brief interventions.

Manipulating ocular endothelial tight junctions: Applications in treatment of retinal disease pathology and ocular hypertension.

Protein levels of endothelial tight-junctions of the inner retinal microvasculature, together with those of Schlemm's canal, can be readily manipulated by RNA interference (RNAi), resulting in the paracellular clefts between such cells to be reversibly modulated. This facilitates access to the retina of systemically-deliverable low molecular weight, potentially therapeutic compounds, while also allowing potentially toxic material, for example, soluble Amyloid-ß1-40, to be removed from the retina into the peripheral circulation. The technique has also been shown to be highly effective in alleviation of pathological cerebral oedema and we speculate that it may therefore have similar utility in the oedematous retina. Additionally, by manipulating endothelial tight-junctions of Schlemm's canal, inflow of aqueous humour from the trabecular meshwork into the Canal can be radically enhanced, suggesting a novel avenue for control of intraocular pressure. Here, we review the technology underlying this approach together with specific examples of clinical targets that are, or could be, amenable to this novel form of genetic intervention.

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway.

INTRODUCTION: Ocular hypertension in open-angle glaucoma is caused by a reduced rate of removal of aqueous humour (AH) from the eye, with the majority of AH draining from the anterior chamber through the conventional outflow pathway, comprising the trabecular meshwork (TM) and Schlemm's Canal. Resistance to outflow is generated, in part, by the extracellular matrix (ECM) of the outflow tissues. Current pressure-lowering topical medications largely suppress AH production, or enhance its clearance through the unconventional pathway. However, therapies targeting the ECM of the conventional pathway in order to decrease intraocular pressure have become a recent focus of attention. Areas covered: We discuss the role of ECM of the TM in outflow homeostasis and its relevance as a target for glaucoma therapy, including progress in development of topical eye formulations, together with gene therapy approaches based on inducible, virally-mediated expression of matrix metalloproteinases to enhance aqueous outflow. Expert opinion: There remains a need for improved glaucoma medications that more specifically act upon sites causative to glaucoma pathogenesis. Emerging strategies targeting the ECM of the conventional outflow pathway, or associated components of the cytoskeleton of TM cells, involving new pharmacological formulations or genetically-based therapies, are promising avenues of future glaucoma treatment.

Enhancement of Outflow Facility in the Murine Eye by Targeting Selected Tight-Junctions of Schlemm's Canal Endothelia.

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm's canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.