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.

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.

Factors affecting quality of nurse shift handover in the emergency department.

AIM: The aim of this study was to explore and test factors hypothesized to influence quality of Emergency Department nurse-to-nurse shift handover communication. BACKGROUND: Nurse-to-nurse shift handover communication includes the transfer of information and responsibility for patients at shift change. The unique environment of the Emergency Department, where there is a high degree of patient unpredictability, increased patient volumes and rapid patient turnover, can create challenges for high quality handover communication. There is considerable literature addressing handover communication and factors that influence quality or effectiveness. However, few studies have empirically tested those factors. DESIGN: A quantitative, cross-sectional design was used to test a conceptual model of factors hypothesized to influence quality of handover communication. METHODS: In 2014, data were gathered using surveys mailed to Emergency Department nurses across Ontario, Canada. RESULTS: The final eligible sample was 231 of 576 for an overall response rate of 40.1%. Analysis was performed using backwards elimination stepwise multiple linear regression. Four statistically significant explanatory variables were retained in the final multiple regression model, explaining 34% (p < .0001) of variance in handover quality. Handover quality was increased when patients flowed smoothly through triage, when nurses experienced positive intrusions, in the presence of a positive safety climate and when there were positive relationships between incoming and outgoing nurses. CONCLUSIONS: By understanding those factors that contribute to handover quality, it is possible to develop targeted interventions aimed at improving the quality of Emergency Department nurse-to-nurse shift handover.

Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library.

We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets.

Work-related factors influencing home care nurse intent to remain employed.

BACKGROUND: Health care is shifting out of hospitals into community settings. In Ontario, Canada, home care organizations continue to experience challenges recruiting and retaining nurses. However, factors influencing home care nurse retention that can be modified remain largely unexplored. Several groups of factors have been identified as influencing home care nurse intent to remain employed including job characteristics, work structures, relationships and communication, work environment, responses to work, and conditions of employment. PURPOSE: The aim of this study was to test and refine a model that identifies which factors are related to home care nurse intentions to remain employed for the next 5 years with their current home care employer organization. METHODOLOGY/APPROACH: A cross-sectional survey design was implemented to test and refine a hypothesized model of home care nurse intent to remain employed. Logistic regression was used to determine which factors influence home care nurse intent to remain employed. FINDINGS: Home care nurse intent to remain employed for the next 5 years was associated with increasing age, higher nurse-evaluated quality of care, having greater variety of patients, experiencing greater meaningfulness of work, having greater income stability, having greater continuity of client care, experiencing more positive relationships with supervisors, experiencing higher work-life balance, and being more satisfied with salary and benefits. PRACTICE IMPLICATIONS: Home care organizations can promote home care nurse intent to remain employed by (a) ensuring nurses have adequate training and resources to provide quality client care, (b) improving employment conditions to increase income stability and satisfaction with pay and benefits,

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 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.

Economic impact of a novel naloxone autoinjector on third-party payers.

BACKGROUND: Patient overdoses on prescription opioid analgesics in the United States continue to rise, resulting in increased emergency department and hospitalization costs. Opioid overdose is readily reversible with naloxone, a fast-acting opioid antagonist. A new naloxone autoinjector (NAI), Evzio, which does not require medical training to use, was approved by the FDA in April 2014. Payers must decide on reimbursement policies for this product. PURPOSE: To demonstrate to payer decision makers the costs and potential medical resource cost offsets associated with the utilization of a new NAI. DESIGN: A deterministic model using matched controls. METHODOLOGY: An Excel-based cost model was developed for a hypothetical health plan with 1 million adult members. Costs of prescription opioid overdose events for patients appropriately dispensed NAI were compared with matched controls. RESULTS: NAI prescriptions increased from 218 in Year 1 to 2,527 in Year 3. In Year 3, 86 NAI patients (and their matched controls) experienced opioid overdose events. For this period, fatal overdoses in the NAI cohort totaled 11.1 vs. 14.7 for the control group. In Year 3, 2.5 deaths (10.1-7.6) were avoided. NAI acquisition costs rose from $125,000 in Year 1 (PMPM = $0.01) to nearly $1.5 million in Year 3 (PMPM = $0.12).This cost was offset by medical resource savings of approximately $84,000 in Year 1, increasing to $975,000 in Year 3. The total net cost (NAI less offsets) in Year 3, when NAI uptake was assumed to plateau, was $481,000 (PMPM = $0.04). CONCLUSION: A deterministic model demonstrated that NAI acquisition costs can be offset through medical cost reductions with improved timely access to naloxone.

A randomized, rater-blinded, crossover study of the effects of oxymorphone extended release, fed versus fasting, on cognitive performance as tested with CANTAB in opioid-tolerant subjects.

BACKGROUND: The maximum plasma concentration (Cmax ) of oxymorphone extended release (ER) 20 mg and 40 mg is approximately 50% higher in fed than in fasted subjects, with most of the difference in area-under-the-curve (AUC) occurring in the first 4 hours post-dose. Hence, the US FDA recommends in the approved labeling that oxymorphone ER is taken at least 1 hour before or 2 hours after eating. METHODS: In order to determine the potential impact on cognitive performance of the increased absorption of oxymorphone ER, fed versus fasting, we conducted a randomized, rater-blinded, crossover study in 30 opioid-tolerant subjects, using tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The subjects randomly received 40 mg oxymorphone ER after a high-fat meal of approximately 1,010 kCal or after fasting for 8-12 hours, and were tested 1 hour and 3 hours post-dose. RESULTS: The CANTAB tests, Spatial Recognition Memory (SRM) and Spatial Working Memory (SWM), showed no statistically significant differences between the fed and fasting conditions. However, sustained attention, as measured by the Rapid Visual Information Processing (RVP) CANTAB test, showed a statistically significant interaction of fed versus fasting and post-dose time of testing (F[1,28] = 6.88, P = 0.01), suggesting that 40 mg oxymorphone ER after a high-fat meal versus fasting mitigates the learning effect in this particular cognition domain from 1 hour to 3 hours post-dose. CONCLUSION: Oxymorphone 40 mg ER affected cognitive performance similarly within 3 hours post-dose, whether given on an empty stomach or after a high-fat meal, suggesting that the effect of food on plasma concentration may not be relevant in the medication's impact on cognition.

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.

Factors influencing home care nurse intention to remain employed.

AIM: To identify factors affecting Canadian home care nurse intention to remain employed (ITR). BACKGROUND: In developed nations, healthcare continues to shift into community settings. Although considerable research exists on examining nurse ITR in hospitals, similar research related to nurses employed in home care is limited. In the face of a global nursing shortage, it is important to understand the factors influencing nurse ITR across healthcare sectors. METHODS: A qualitative exploratory descriptive design was used. Focus groups were conducted with home care nurses. Data were analysed using qualitative content analysis. RESULTS: Six categories of influencing factors were identified by home care nurses as affecting ITR: job characteristics; work structures; relationships/communication; work environment; nurse responses to work; and employment conditions. CONCLUSION: Findings suggest the following factors influence home care nurse ITR: having autonomy; flexible scheduling; reasonable and varied workloads; supportive work relationships; and receiving adequate pay and benefits. Home care nurses did not identify job satisfaction as a single concept influencing ITR. IMPLICATIONS FOR NURSING MANAGEMENT: Home care nursing management should support nurse autonomy, allow flexible scheduling, promote reasonable workloads and create opportunities for team building that strengthen supportive relationships among home care nurses and other health team members.

Experiencing COVID-19 Through the Patient Lens to Promote Empathy: Pilot Testing a Virtual Reality Learning Opportunity.

Understanding the patient's experience with COVID-19 was essential to providing high-quality, person-centered care during the pandemic. Having empathy or being able to understand and respond to the patient's experience may lead to improved outcomes for both patients and clinicians. There is mixed evidence about how best to teach empathy, particularly related to promoting empathy during COVID-19. Literature suggests that virtual reality may be effective in empathy-related education. In collaboration with four patient partners with lived experience, a 360° VR video was developed reflecting their stories and interactions with the healthcare system. The aim of this study was to pilot test the video with interprofessional healthcare providers (HPs) to explore acceptability and utility, while also seeking input on opportunities for improvement. Eleven HPs reviewed the video and participated in one of three focus groups. Focus group data were analyzed using thematic analysis. Data suggest that video content is acceptable and useful in promoting a better understanding of the patient's experience. Building on these encouraging findings, additional iterations of videos to promote empathy will be developed and tested.

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.

Generation-specific incentives and disincentives for nurses to remain employed in acute care hospitals.

AIM: This is a report on generation-specific incentives and disincentives selected by acute care nurses that promote and discourage them to remain employed in hospitals. BACKGROUND: Recent literature indicates that nurse preferences for strategies to promote their retention may differ across generational cohorts. However, current literature is primarily anecdotal with few studies focused on evidence-based generation-specific nurse retention-promoting strategies. METHODS: Data were gathered from a cross-sectional survey administered to a random sample of 9904 registered nurses working in Alberta and Ontario, Canada. Two survey items asking nurses to identify preferences for incentives to remain employed and disincentives that encourage them to leave employment were included. Survey items were based on information gathered from previous focus groups exploring determinants of nurse retention. RESULTS: There were statistically significant differences in the rates of selection across generations of nurses for eight of 10 incentives to remain employed and for eight of 15 disincentives. All generational cohorts selected the same two incentives most frequently: reasonable workloads and manageable nurse-patient ratios. Two of the three most frequently selected disincentives were the same across generations: inadequate staffing and unmanageable workloads. IMPLICATIONS FOR NURSING MANAGEMENT: Leaders should implement and evaluate strategies that ensure workloads are reasonable and nurse-patient ratios are manageable to promote retention among all generations of nurses in the acute care hospital workforce.

Relationships between headache frequency, disability, and disability-related unemployment among adults with migraine.

BACKGROUND: Migraine is the second most common cause of disability worldwide. Understanding the relationship between migraine and employment status is critical for policymakers, as disability-related unemployment is associated with eligibility for private or governmental disability insurance payments and other associated support for those unable to work because of disability. OBJECTIVE: To assess the association between migraine frequency and selfreported employment status and overall disability in a US representative survey. METHODS: Using data from the 2019 National Health and Wellness Survey (NHWS) (Kantar Health), adults in the United States (aged 18-65 years) reporting at least 1 migraine day in the past 30 days were categorized by headache frequency: low-frequency episodic migraine (LFEM) (≤4 days/month), moderate-frequency EM (MFEM) (5-9 days/month), high-frequency EM (HFEM) (10-14 days/month), or chronic migraine (CM) (≥15 days/month). A control group of adults without migraine with similar baseline characteristics was identified by propensity score matching. Disability-related unemployment was defined as participants responding "short-term disability" or "long-term disability" to occupational status on the NHWS. The frequency of short- or long-term disability was then evaluated across headache frequency groups. In addition, participants were asked to assess migraine-related disability via the Migraine Disability questionnaire (MIDAS). RESULTS: A total of 1,962 respondents with LFEM, 987 with MFEM, 554 with HFEM, and 926 with CM were included in this analysis, along with 4,429 matched controls. Headache frequency was associated both with increased MIDAS score and with employment disability (P < 0.001); 12.3% (n = 114 of 926) of participants with CM reported employment disability, as did 4.4% (n = 86 of 1,962) of the LFEM group and 6.9% (n = 306 of 4,429) of matched controls. There was considerable discordance between the proportion of participants classified as disabled via MIDAS vs those reporting employment-related disability. CONCLUSIONS: More frequent migraine headaches are associated with a higher likelihood of self-reported short- and long-term employment disability and overall migraine-related disability, suggesting that health and economic policymakers must seek ways to maximize the employment opportunities for people living with migraine that may benefit from novel preventive treatments. DISCLOSURES: Robert E Shapiro is a research consultant for Eli Lilly and Lundbeck. Ashley A Martin and Martine C Maculaitis are employees of Cerner Enviza (formerly Kantar Health), which received payment from Lundbeck to conduct the research. Shiven Bhardwaj was an employee of Lundbeck at the time of study and manuscript development. Heather Thomson and Carlton Anderson are employees of Lundbeck. Steven M Kymes is an employee and stockholder of Lundbeck. Financial support for research conducted and manuscript preparation was provided by Lundbeck.

Global COVID-19 childhood disability data coordination: A collaborative initiative of the International Alliance of Academies of Childhood Disability.

PURPOSE: The International Alliance of Academies of Childhood Disability created a COVID-19 Task Force with the goal of understanding the global impact of COVID-19 on children with disabilities and their families. The aim of this paper is to synthesize existing evidence describing the impact of COVID-19 on people with disabilities, derived from surveys conducted across the globe. METHODS: A descriptive environmental scan of surveys was conducted. From June to November 2020, a global call for surveys addressing the impact of COVID-19 on disability was launched. To identify gaps and overlaps, the content of the surveys was compared to the Convention on the Rights of the Child and the International Classification of Functioning, Disability and Health. RESULTS: Forty-nine surveys, involving information from more than 17,230 participants around the world were collected. Overall, surveys identified that COVID-19 has negatively impacted several areas of functioning - including mental health, and human rights of people with disabilities and their families worldwide. CONCLUSION: Globally, the surveys highlight that impact of COVID-19 on mental health of people with disabilities, caregivers, and professionals continues to be a major issue. Rapid dissemination of collected information is essential for ameliorating the impact of COVID-19 across the globe.

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/.

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.