Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

IMPACT smoking cessation support for people with severe mental illness in South Asia (IMPACT 4S): A protocol for a randomised controlled feasibility trial of a combined behavioural and pharmacological support intervention.

INTRODUCTION: The prevalence of smoking is high among people living with severe mental illness (SMI). Evidence on feasibility, acceptability and effectiveness of smoking cessation interventions among smokers with SMI is lacking, particularly in low- and middle-income countries. We aim to test the feasibility and acceptability of delivering an evidence-based intervention,i.e., the IMPACT smoking cessation support for people with severe mental illness in South Asia (IMPACT 4S) intervention that is a combination of behavioural support and smoking cessation pharmacotherapies among adult smokers with SMI in India and Pakistan. We will also test the feasibility and acceptability of evaluating the intervention in a randomised controlled trial. METHODS: We will conduct a parallel, open label, randomised controlled feasibility trial among 172 (86 in each country) adult smokers with SMI in India and Pakistan. Participants will be allocated 1:1 to either Brief Advice (BA) or the IMPACT 4S intervention. BA comprises a single five-minute BA session on stopping smoking. The IMPACT 4S intervention comprises behavioural support delivered in upto 15 one-to-one, face-to-face or audio/video, counselling sessions, with each session lasting between 15 and 40 minutes; nicotine gum and/or bupropion; and breath carbon monoxide monitoring and feedback. Outcomes are recruitment rates, reasons for ineligibility/non-participation/non-consent of participants, length of time required to achieve required sample size, retention in study and treatments, intervention fidelity during delivery, smoking cessation pharmacotherapy adherence and data completeness. We will also conduct a process evaluation. RESULTS: Study will address- uncertainty about feasibility and acceptability of delivering smoking cessation interventions, and ability to conduct smoking cessation trials, among adult smokers with SMI in low- and middle-income countries. CONCLUSIONS: This is to inform further intervention adaptation, and the design and conduct of future randomised controlled trials on this topic. Results will be disseminated through peer-review articles, presentations at national, international conferences and policy-engagement forums. TRIAL REGISTRATION: ISRCTN34399445 (Updated 22/03/2021), ISRCTN Registry https://www.isrctn.com/.

Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry.

Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton's Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The epoxide BTK inhibitors described here are the first ever reported to utilize this electrophile for this target.

Smokeless Tobacco Initiation, Use, and Cessation in South Asia: A Qualitative Assessment.

INTRODUCTION: Smokeless tobacco (ST) is a significant South Asian public health problem. This paper reports a qualitative study of a sample of South Asian ST users. METHODS: Interviews, using a piloted topic guide, with 33 consenting, urban dwelling adult ST users explored their ST initiation, continued use, and cessation attempts. Framework data analysis was used to analyze country specific data before a thematic cross-country synthesis was completed. RESULTS: Participants reported long-term ST use and high dependency. All reported strong cessation motivation and multiple failed attempts because of ease of purchasing ST, tobacco dependency, and lack of institutional support. CONCLUSIONS: Interventions to support cessation attempts among consumers of South Asian ST products should address the multiple challenges of developing an integrated ST policy, including cessation services. IMPLICATIONS: This study provides detailed understanding of the barriers and drivers to ST initiation, use, and cessation for users in Bangladesh, India, and Pakistan. It is the first study to directly compare these three countries. The insight was then used to adapt an existing behavioral support intervention for ST cessation for testing in these countries.

Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry.

The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.

Secondhand Smoke Exposure in Primary School Children: A Survey in Dhaka, Bangladesh.

INTRODUCTION: We report on second-hand smoke (SHS) exposure based on saliva cotinine levels among children in Bangladesh-a country with laws against smoking in public places. METHODS: A survey of primary school children from two areas of the Dhaka district was conducted in 2015. Participants completed a questionnaire and provided saliva samples for cotinine measurement to assess SHS exposure with a cut-off range of ≥0.1ng/mL. RESULTS: Four hundred and eighty-one children studying in year-5 were recruited from 12 primary schools. Of these, 479 saliva samples were found sufficient for cotinine testing, of which 95% (453/479) were positive for recent SHS exposure. Geometric mean cotinine was 0.36 (95% CI = 0.32 to 0.40); 43% (208/479) of children lived with at least one smoker in the household. Only 21% (100/479) reported complete smoking restrictions for residents and visitors; 87% (419/479) also reported being recently exposed to SHS in public spaces. Living with a smoker and number of tobacco selling shops in the neighborhood had positive associations with recent SHS exposure. CONCLUSIONS: Despite having a ban on smoking in public places, recent SHS exposure among children in Bangladesh remains very high. There is an urgent need to reduce exposure to SHS in Bangladeshi children. IMPLICATIONS: Children bear the biggest burden of disease due to SHS exposure than any other age group. However, children living in many high-income countries have had a sharp decline in their exposure to SHS in recent years. What remains unknown is if children living in low-income countries are still exposed to SHS. Our study suggests that despite having a ban on smoking in public places, most primary school children in Dhaka, Bangladesh are still likely to be exposed to SHS.

The prevalence of nasal obstruction as a consideration in the treatment of opioid overdose.

OBJECTIVES: The intranasal route of administration for naloxone delivery is one treatment for opioid overdose, but treatment failures with this modality have been documented. This study determines the incidence of obstructive nasal pathology in patients who experienced serious opioid-induced respiratory depression (OIRD). DESIGN: Retrospective analysis of the IMS LifeLink: Health Plan Claims Database to detect patients with at least one opioid pharmacy claim from 2009 to 2013 and who experienced serious OIRD. Four controls were randomly assigned to each case. MAIN OUTCOME MEASURES: A multivariable analysis determined the adjusted odds ratio of OIRD for patients with obstructive nasal pathology. RESULTS: A total of 7,234 patients experienced a serious OIRD event; 840 (11.6 percent) had obstructive nasal pathology: 20 (2.4 percent) had deviated nasal septum (International Classification of Disease, 9th revision [ICD-9] 470), 246 (29.3 percent) had polyp of the nasal cavity (ICD-9 470.1), 130 (15.5 percent) had hypertrophy of nasal turbinates (ICD-9 478.0), and 659 (78.5 percent) had other disease of the nasal cavity (ICD-9 478.19). The adjusted odds ratio for patients who experienced serious OIRD having concurrent obstructive nasal pathology was 1.28 (95% confidence interval 1.13-1.46). CONCLUSIONS: Obstructive nasal pathology is relatively common in patients who experience serious OIRD, and in itself is associated with a higher risk of having OIRD.

The challenge of mothers learning about secondhand smoke (MLASS): a quasi-experimental, mixed methods feasibility study.

BACKGROUND: Exposure to secondhand smoke (SHS) in the antenatal and postnatal period is associated with a detrimental health impact to the foetus and newborn baby and is recognised as a preventable public health challenge. The aim of the mother's learning about secondhand smoke (MLASS) study was to test the feasibility of delivering and evaluating the effectiveness of a smoke-free homes (SFH) health education intervention in the antenatal and postnatal period to reduce foetal and newborn exposure to SHS. METHODS: Pregnant women aged 17-40 years old who attended their first community-based antenatal appointment in Leeds, UK, were eligible to participate if they currently smoked, or if they were non-smokers but lived in a household where someone else smoked, or had regular visitors to the home who smoked. A SFH health education intervention was delivered at four time points by community midwives and health visitors. Outcome measures included self-reported level of household smoking restrictions and SHS exposure in pregnant women who did not smoke during pregnancy and in the newborn baby, measured by salivary and urine cotinine levels, respectively. We planned to conduct focus group discussions with participants and health professionals. A post hoc survey of pregnant women was conducted at the recruitment site. RESULTS: Eight pregnant women were recruited over a 6-month recruitment period. Of the 65 eligible pregnant women approached, 57 (88 %) declined to participate in the study. The majority declined to participate due to lack of interest in the study. In the post hoc survey, the majority of pregnant women reported that they were already implementing household smoking restrictions to reduce SHS; only a small number had no household smoking restrictions. CONCLUSIONS: The post hoc survey identified women who could benefit from a SFH intervention; therefore, future studies should consider what SFH means to pregnant women and may wish to target those not currently implementing household smoking restrictions. Future recruitment strategies in studies of an SFH intervention in the context of maternity service pressures needs careful consideration; this includes the capacity to undertake the research, the recruitment setting, the criteria for individuals requiring the intervention, and individuals' willingness to engage with such research.

Behaviour change intervention for smokeless tobacco cessation: its development, feasibility and fidelity testing in Pakistan and in the UK.

BACKGROUND: People of South Asian-origin are responsible for more than three-quarters of all the smokeless tobacco (SLT) consumption worldwide; yet there is little evidence on the effect of SLT cessation interventions in this population. South Asians use highly addictive and hazardous SLT products that have a strong socio-cultural dimension. We designed a bespoke behaviour change intervention (BCI) to support South Asians in quitting SLT and then evaluated its feasibility in Pakistan and in the UK. METHODS: We conducted two literature reviews to identify determinants of SLT use among South Asians and behaviour change techniques (BCTs) likely to modify these, respectively. Iterative consensus development workshops helped in selecting potent BCTs for BCI and designing activities and materials to deliver these. We piloted the BCI in 32 SLT users. All BCI sessions were audiotaped and analysed for adherence to intervention content and the quality of interaction (fidelity index). In-depth interviews with16 participants and five advisors assessed acceptability and feasibility of delivering the BCI, respectively. Quit success was assessed at 6 months by saliva/urine cotinine. RESULTS: The BCI included 23 activities and an interactive pictorial resource that supported these. Activities included raising awareness of the harms of SLT use and benefits of quitting, boosting clients' motivation and self-efficacy, and developing strategies to manage their triggers, withdrawal symptoms, and relapse should that occur. Betel quid and Guthka were the common forms of SLT used. Pakistani clients were more SLT dependent than those in the UK. Out of 32, four participants had undetectable cotinine at 6 months. Fidelity scores for each site varied between 11.2 and 42.6 for adherence to content - maximum score achievable 44; and between 1.4 and 14 for the quality of interaction - maximum score achievable was 14. Interviews with advisors highlighted the need for additional training on BCTs, integrating nicotine replacement and reducing duration of the pre-quit session. Clients were receptive to health messages but most reported SLT reduction rather than complete cessation. CONCLUSION: We developed a theory-based BCI that was also acceptable and feasible to deliver with moderate fidelity scores. It now needs to be evaluated in an effectiveness trial.

Children Learning About Secondhand Smoke (CLASS II): protocol of a pilot cluster randomised controlled trial.

INTRODUCTION: Exposure to secondhand smoke (SHS) increases children's risk of acquiring chest and ear infections, tuberculosis, meningitis and asthma. Smoking bans in public places (where implemented) have significantly reduced adults' exposure to SHS. However, for children, homes remain the most likely place for them to be exposed to SHS. Additional measures are therefore required to protect children from SHS. In a feasibility study in Dhaka, Bangladesh, we have shown that a school-based smoke-free intervention (SFI) was successful in encouraging children to negotiate and implement smoking restrictions in homes. We will now conduct a pilot trial to inform plans to undertake a cluster randomised controlled trial (RCT) investigating the effectiveness and cost-effectiveness of SFI in reducing children's exposure to SHS. METHODS AND ANALYSIS: We plan to recruit 12 primary schools in Dhaka, Bangladesh. From these schools, we will recruit approximately 360 schoolchildren in year 5 (10-12 years old), that is, 30 per school. SFI consists of six interactive educational activities aimed at increasing pupils' knowledge about SHS and related harms, motivating them to act, providing skills to negotiate with adults to persuade them not to smoke inside homes and helping families to 'sign-up' to a voluntary contract to make their homes smoke-free. Children in the control arm will receive the usual education. We will estimate: recruitment and attrition rates, acceptability, fidelity to SFI, effect size, intracluster correlation coefficient, cost of intervention and adverse events. Our primary outcome will consist of SHS exposure in children measured by salivary cotinine. Secondary outcomes will include respiratory symptoms, lung function tests, healthcare contacts, school attendance, smoking uptake, quality of life and academic performance. ETHICS AND DISSEMINATION: The trial has received ethics approval from the Research Governance Committee at the University of York. Findings will help us plan for the definitive trial. TRIAL REGISTRATION NUMBER: ISRCTN68690577.

Children Learning About Second-Hand Smoking: A Feasibility Cluster Randomized Controlled Trial.

BACKGROUND: Exposure to second-hand smoke is a threat to children's health. We developed a school-based smoke-free intervention (SFI) to support families in implementing smoke-free homes in Bangladesh, and gathered preliminary evidence of its effectiveness. METHODS: A feasibility cluster randomized controlled trial of SFI was conducted in 24 schools in Mirpur, an urban area within Dhaka. Using simple stratified randomization, schools were allocated to: Arm A (SFI only), Arm B (SFI plus reminders), and Arm C (the control group). A total of 781 year-5 children (10-12 years old) in the consenting schools, participated in the study. Outcomes including "smoke-free homes" and "social visibility" that is, not smoking in front of children at home were assessed through questionnaire-based children's surveys, administered by researchers, at baseline and at weeks 1, 12, 27, and 52 in all arms. RESULTS: "Smoke-free homes" were significantly higher in Arm A (odds ratio [OR] = 4.8; 95% CI = 2.6-9.0) and in Arm B (OR = 3.9; 95% CI = 2.0-7.5) than in Arm C, when controlled for the baseline levels, at year 1. Similarly, "social visibility" was significantly reduced in Arm A (OR = 5.8; 95% CI = 2.8-11.7) and in Arm B (OR = 7.2; 95% CI = 3.3-15.9) than Arm C, when controlled for the baseline levels, at year 1. We observed an increasing trend (Cochrane Armitage test statistic [Z] = 3.8; p < .0001) in homes becoming smoke-free with increasing intensity of the intervention (control < Arm A < Arm B), and a decreasing trend (Z = -5.13; p < .0001) in social visibility at homes. CONCLUSION: SFI has the potential to encourage children to negotiate a smoke-free environment in their homes.

Do children overestimate the extent of smoking among their peers? A feasibility study of the social norms approach to prevent smoking.

UNLABELLED: Social norms approaches (SNA) are based on the premise that we frequently overestimate risk behaviours among our peers. By conducting campaigns to reduce these misperceptions, SNAs aim to reduce risk behaviours. This study examines the extent to which 12 to 13year old pupils overestimate smoking among their peers and explores the appropriateness of using SNA in secondary schools to prevent smoking uptake. METHODS: The extent of overestimation of smoking among peers was assessed through an on-line SNA questionnaire in five schools (n=595). Based on questionnaire results, pupils developed SNA campaigns in each school. Qualitative methods of focus groups (7), interviews (7) and observation were used to explore in-depth, from the perspective of staff and pupils, the appropriateness and feasibility of the SNA to prevent smoking uptake in secondary schools. RESULTS: A quarter of pupils, 25.9% (95% CI 25.6% to 26.1%) believed that most of their peers smoked, however, only 3% (95% CI 2.8% to 3.3%) reported that they actually did; a difference of 22.9% (95% CI 19.1% to 26.6%). Self-reported smoking was not significantly different between schools (X(2)=8.7 p=0.064), however, perceptions of year group smoking was significantly different across schools (X(2)=63.9 p<0.001). Qualitative analysis identified full school engagement, minimal teacher time requirements, pupils' belief in questionnaire results and understanding wider context, as key in optimising implementation. CONCLUSION: This study shows significant misperception between self-reported and perceived smoking among peers in secondary schools, thus supporting a key premise of social norms theory. Implementing SNAs and studying effects is feasible within secondary schools.

Adult limbal neurosphere cells: a potential autologous cell resource for retinal cell generation.

The Corneal limbus is a readily accessible region at the front of the eye, separating the cornea and sclera. Neural colonies (neurospheres) can be generated from adult corneal limbus in vitro. We have previously shown that these neurospheres originate from neural crest stem/progenitor cells and that they can differentiate into functional neurons in vitro. The aim of this study was to investigate whether mouse and human limbal neurosphere cells (LNS) could differentiate towards a retinal lineage both in vivo and in vitro following exposure to a developing retinal microenvironment. In this article we show that LNS can be generated from adult mice and aged humans (up to 97 years) using a serum free culture assay. Following culture with developing mouse retinal cells, we detected retinal progenitor cell markers, mature retinal/neuronal markers and sensory cilia in the majority of mouse LNS experiments. After transplantation into the sub-retinal space of neonatal mice, mouse LNS cells expressed photoreceptor specific markers, but no incorporation into host retinal tissue was seen. Human LNS cells also expressed retinal progenitor markers at the transcription level but mature retinal markers were not observed in vitro or in vivo. This data highlights that mouse corneal limbal stromal progenitor cells can transdifferentiate towards a retinal lineage. Complete differentiation is likely to require more comprehensive regulation; however, the accessibility and plasticity of LNS makes them an attractive cell resource for future study and ultimately therapeutic application.

Children's exposure to second-hand smoke at home in Bangladesh: a community survey.

OBJECTIVES: In Bangladesh, second-hand smoke (SHS) is recognised as a principal source of indoor air pollution and a major public health problem. However, we know little about the extent to which people are aware of the risks of second-hand smoking, or restrict smoking indoors or in the presence of children. We report findings of a community survey exploring these questions. DESIGN AND SETTING: A total of 722 households were surveyed in urban and rural settings, using a multistage cluster random sampling approach and a semistructured questionnaire. In addition, we used qualitative methods to further explore the determinants of smoking-related behaviours inside homes. FINDINGS: 55% of households in our sample had at least one regular smoker. Smoking indoors was common. In 30% of households, smoking occurred in the presence of children, exposing nearly 40% of children to SHS. Overall, we found a lack of awareness about the harms associated with second-hand smoking. CONCLUSIONS: Our study highlights that a sizeable proportion of children and non-smokers are exposed to SHS at homes in Bangladesh, posing a significant and grave public health problem. In the absence of any impetus to legislate against smoking in private places, an educational approach is recommended to change smoking practices at home. Such a shift toward voluntary smoking restrictions at home would require behaviour change among smokers and support from non-smoking family members.

Muslim communities learning about second-hand smoke (MCLASS): study protocol for a pilot cluster randomised controlled trial.

BACKGROUND: In the UK, 40% of Bangladeshi and 29% of Pakistani men smoke cigarettes regularly compared to the national average of 24%. As a consequence, second-hand smoking is also widespread in their households which is a serious health hazard to non-smokers, especially children. Smoking restrictions in households can help reduce exposure to second-hand smoking. This is a pilot trial of 'Smoke Free Homes', an educational programme which has been adapted for use by Muslim faith leaders, in an attempt to find an innovative solution to encourage Pakistani- and Bangladeshi-origin communities to implement smoking restrictions in their homes. The primary objectives for this pilot trial are to establish the feasibility of conducting such an evaluation and provide information to inform the design of a future definitive study. METHODS/DESIGN: This is a pilot cluster randomised controlled trial of 'Smoke Free Homes', with an embedded preliminary health economic evaluation and a qualitative analysis. The trial will be carried out in around 14 Islamic religious settings. Equal randomisation will be employed to allocate each cluster to a trial arm. The intervention group will be offered the Smoke Free Homes package (Smoke Free Homes: a resource for Muslim religious teachers), trained in its use, and will subsequently implement the package in their religious settings. The remaining clusters will not be offered the package until the completion of the study and will form the control group. At each cluster, we aim to recruit around 50 households with at least one adult resident who smokes tobacco and at least one child or a non-smoking adult. Households will complete a household survey and a non-smoking individual will provide a saliva sample which will be tested for cotinine. All participant outcomes will be measured before and after the intervention period in both arms of the trial. In addition, a purposive sample of participants and religious leaders/teachers will take part in interviews and focus groups. DISCUSSION: The results of this pilot study will inform the protocol for a definitive trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03035510.

Chronic pain and pain medication use in chronic obstructive pulmonary disease. A cross-sectional study.

RATIONALE: Pain is a common problem for patients with chronic obstructive pulmonary disease (COPD). However, pain is minimally discussed in COPD management guidelines. OBJECTIVES: The objective of this study was to describe chronic pain prevalence among patients with COPD compared with similar patients with other chronic diseases in a managed care population in the southwestern United States (age ≥ 40 yr). METHODS: Using data for the period January 1, 2006 through December 31, 2010, patients with COPD were matched to two control subjects without COPD but with another chronic illness based on age, sex, insurance, and healthcare encounter type. Odds ratios (OR) for evidence of chronic pain were estimated using conditional logistic regression. Pulmonary function data for 200 randomly selected patients with COPD were abstracted. MEASUREMENTS AND MAIN RESULTS: Retrospectively analyzed recurrent pain-related utilization (diagnoses and treatment) was considered evidence of chronic pain. The study sample comprised 7,952 patients with COPD (mean age, 69 yr; 42% male) and 15,904 patients with other chronic diseases (non-COPD). Patients with COPD compared with non-COPD patients had a higher percentage of chronic pain (59.8 vs. 51.7%; P < 0.001), chronic use of pain-related medications (41.2 vs. 31.5%; P < 0.001), and chronic use of short-acting (24.2 vs. 15.1%; P < 0.001) and long-acting opioids (4.4 vs. 1.9%; P < 0.001) compared with non-COPD patients. In conditional logistic regression models, adjusting for age, sex, Hispanic ethnicity, and comorbidities, patients with COPD had higher odds of chronic pain (OR, 1.56; 95% confidence interval [CI], 1.43-1.71), chronic use of pain-related medications (OR, 1.60; 95% CI, 1.46-1.74), and chronic use of short-acting or long-acting opioids (OR, 1.74; 95% CI, 1.57-1.92). CONCLUSIONS: Chronic pain and opioid use are prevalent among adults with COPD. This finding was not explained by the burden of comorbidity.

Action to stop smoking in suspected tuberculosis (ASSIST) in Pakistan: a cluster randomized, controlled trial.

BACKGROUND: Tobacco use is responsible for a large proportion of the total disease burden from tuberculosis. Pakistan is one of the 10 high-burden countries for both tuberculosis and tobacco use. OBJECTIVE: To assess the effectiveness of a behavioral support intervention and bupropion in achieving 6-month continuous abstinence in adult smokers with suspected pulmonary tuberculosis. DESIGN: Cluster randomized, controlled trial. (Current Controlled Trials: ISRCTN08829879) SETTING: Health centers in the Jhang and Sargodha districts in Pakistan. PATIENTS: 1955 adult smokers with suspected tuberculosis. INTERVENTION: Health centers were randomly assigned to provide 2 brief behavioral support sessions (BSS), BSS plus 7 weeks of bupropion therapy (BSS+), or usual care. MEASUREMENTS: The primary end point was continuous abstinence at 6 months after the quit date and was determined by carbon monoxide levels in patients. Secondary end points were point abstinence at 1 and 6 months. RESULTS: Both treatments led to statistically significant relative risks (RRs) for abstinence compared with usual care (RR for BSS+, 8.2 [95% CI, 3.7 to 18.2]; RR for BSS, 7.4 [CI, 3.4 to 16.4]). Equivalence between the treatments could not be established. In the BSS+ group, 275 of 606 patients (45.4% [CI, 41.4% to 49.4%]) achieved continuous abstinence compared with 254 of 620 (41.0% [CI, 37.1% to 45.0%]) in the BSS group and 52 of 615 (8.5% [CI, 6.4% to 10.9%]) in the usual care group. There was substantial heterogeneity of program effects across clusters. LIMITATIONS: Imbalances in the urban and rural proportions and smoking habits among treatment groups, and inability to confirm adherence to bupropion treatment and validate longer-term abstinence or the effect of smoking cessation on tuberculosis outcomes. CONCLUSION: Behavioral support alone or in combination with bupropion is effective in promoting cessation in smokers with suspected tuberculosis. PRIMARY FUNDING SOURCE: International Development Research Centre.

Translating evidence-based guidelines into practice: a survey of practices of commissioners and managers of the English stop smoking services.

BACKGROUND: The English National Health Service's (NHS) Stop Smoking Services (SSSs) constitute one of the most highly developed behavioural support programmes in the world. However, there is significant variation in success rates across the approximately 150 services, some of which may be due to variation in practice. This study aimed to assess these differences in practice. METHODS: Two online surveys were administered. All commissioners (people who purchase services for the NHS) and managers (those who run the services) of NHS SSSs in England were invited to participate. Items included details of current practices and services provided, what informed the commissioning of SSSs, what targets were included within service specifications and whether the types of treatment model to be delivered were specified. RESULTS: Both surveys had a response rate of 35%, with 50 commissioners and 58 managers participating. There were no significant differences between the characteristics of the Primary Care Trusts (PCTs) from which commissioners and managers responded to this survey and those PCTs from which there was no response. Managers reported that the treatment model most frequently offered by SSSs was one-to-one (98%). A total of 16% of managers reported that some approved medications were not available as first-line treatments. Just over one third (38%) of commissioners reported consulting national guidelines or best evidence to inform local commissioning. Almost one third (30%) of commissioners reported that they specified the types of stop smoking interventions to be delivered by the providers. CONCLUSIONS: A substantial part of commissioning of Stop Smoking Services in England appears to take place without adequate consultation of evidence-based guidelines or specification of the service to be provided. This may account for at least some of the variation in success rates.

The chemistry of retinal transplantation: the influence of polymer scaffold properties on retinal cell adhesion and control.

Age-related macular degeneration is the most common cause of blindness in the UK. Cellular replacement of retinal pigment epithelium cells is a potential therapeutic option to treat the cellular loss and dysfunction which is characteristic of age-related macular degeneration and other progressive retinopathies. A supportive scaffold, natural or artificial, may be required to facilitate cell delivery to the eye. Research to improve the biomimetic properties of such scaffolds, in order to optimise cell attachment and functionality following implantation, is ongoing. This short review will focus on the potential of biomaterials for ocular tissue engineering and how surface modification and the physical properties of these scaffolds can be tailored to help realise the full clinical potential of retinal pigment epithelium cell transplantation.

Can a community-based 'smoke-free homes' intervention persuade families to apply smoking restrictions at homes?

BACKGROUND: Children are commonly exposed to second-hand smoke (SHS). The aim of this study is to evaluate the feasibility, acceptability and outcome of Smoke-Free Homes (SFH), a community-based intervention; and assess potential evaluation methods. METHODS: SFH, designed to encourage families to implement smoking restrictions at home, was delivered over a period of 6 months through schools, healthcare settings and community events in Beeston, South Leeds, UK. It was evaluated using baseline and post-implementation surveys, focus group discussions and promise forms follow-up. RESULTS: We surveyed 318 households before, and 217 households after, the intervention. The proportion of all surveyed households reporting being completely smoke free significantly increased from 35% [95% confidence interval (CI) 30, 40] at baseline to 68% (95% CI: 61, 74) 6 months post-implementation (P < 0.0001). Ninety per cent of people, followed-up by telephone 3 months after signing SFH promise form, said they were still keeping their promise. Focus group discussions with children and parents conveyed acceptability of the intervention, in particular, the schools element, where children are encouraged to discuss the concept of SFH with the adults in their households. CONCLUSIONS: Our study shows that SFH can be implemented effectively and has the potential to improve children's health through preventing exposure to SHS in the home.