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.

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/.

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.

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.

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.

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.

Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor ß-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency.

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.

Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition.

The structural mechanisms of single-pass transmembrane enzymes remain elusive. Kynurenine 3-monooxygenase (KMO) is a mitochondrial protein involved in the eukaryotic tryptophan catabolic pathway and is linked to various diseases. Here, we report the mammalian full-length structure of KMO in its membrane-embedded form, complexed with compound 3 (identified internally) and compound 4 (identified via DNA-encoded chemical library screening) at 3.0 Å resolution. Despite predictions suggesting that KMO has two transmembrane domains, we show that KMO is actually a single-pass transmembrane protein, with the other transmembrane domain lying laterally along the membrane, where it forms part of the ligand-binding pocket. Further exploration of compound 3 led to identification of the brain-penetrant compound, 5. We show that KMO is dimeric, and that mutations at the dimeric interface abolish its activity. These results will provide insight for the drug discovery of additional blood-brain-barrier molecules, and help illuminate the complex biology behind single-pass transmembrane enzymes.

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.

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.

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.

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,

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.