The power of animation: encouraging doctors to access support for psychological wellbeing.

The COVID-19 pandemic has exacerbated already high rates of poor psychological wellbeing in doctors. Many doctors perceive a stigma associated with acknowledging psychological wellbeing concerns, resulting in a reluctance to seek support for those concerns. The aim of this study was to develop a theoretically-informed and evidence-based composite narrative animation (CNA) to encourage doctors to access support for psychological wellbeing, and to evaluate the acceptability of the CNA.A composite narrative was developed from an evidence-base of interviews with 27 GP participants across Scotland (May-July 2020). The Behaviour Change Wheel was used to identify behaviour change techniques (BCTs) to be embedded within the CNA. The narrative was turned into a script in collaboration with an animation company. A brief animation 'Jane the GP' was developed reflecting specific BCTs.Scottish doctors (n = 83) were asked for their views on acceptability of the CNA concept, and subsequently asked to provide views on the acceptability of the CNA after viewing it. Participants thought the concept of a CNA was novel but may not appeal to all. After viewing the CNA, the widespread view was that it portrayed an authentic experience, could reduce stigma around seeking support for psychological wellbeing, and highlighted formal routes to access such support.CNAs are a novel and acceptable intervention method for encouraging doctors to access support for psychological wellbeing. The use of a theory driven intervention development framework to create the CNA facilitates the link between theory and practice.

Screening for Elder Abuse in the Veterans Health Administration: Varied Approaches Across a National Health System.

BACKGROUND: Elder abuse (EA) is common and has devastating health consequences yet is rarely detected by healthcare professionals. While EA screening tools exist, little is known about if and how these tools are implemented in real-world clinical settings. The Veterans Health Administration (VHA) has experience screening for, and resources to respond to, other forms of interpersonal violence and may provide valuable insights into approaches for EA screening. OBJECTIVE: Describe EA screening practices across a national integrated healthcare system serving a large population of older adults at risk for EA. DESIGN: Survey of all 139 VHA medical centers from January to August 2021. PARTICIPANTS: Surveys were completed by the Social Work Chief, or delegate, at each site. MAIN MEASURES: The survey assessed the presence and characteristics of EA-specific screening practices as well as general abuse/neglect screening conducted with patients of all ages, including older adults. Follow-up emails were sent to sites that reported screening requesting additional details not included in the initial survey. KEY RESULTS: Overall, 130 sites (94%) responded. Among respondents, 5 (4%) reported screening older adults for EA using a previously published tool, while 6 (5%) reported screening for EA with an unstudied or locally developed tool. Forty-eight percent reported screening patients of all ages for general abuse/neglect using unstudied questions/tools, and 44% reported no EA screening at their site. Characteristics of screening programs (e.g., frequency, clinical setting, provider type) varied widely between sites, as did respondents' understanding of the definition of screening. CONCLUSIONS: High variability in screening practices for abuse/neglect and lack of EA-specific screening in a system that has successfully deployed other standardized screening approaches present an important opportunity to standardize and improve EA detection practices. Lessons learned in VHA could help advance the evidence base for EA screening more broadly to increase overall detection rates for EA nationally.

"For us, whatever we do is wrong, until we do something really good": a qualitative study of the lived experiences of doctors from minority ethnic backgrounds in Scotland.

OBJECTIVES: To evaluate the lived experiences of doctors from minority ethnic (ME) backgrounds during postgraduate medical training, in particular their experiences of discrimination (if any); any impact of intersectionality and perceptions on how ME doctors may be better supported in their learning and working environments. DESIGN: This was a qualitative study grounded in social constructivism, using semi-structured online individual interviews as the data collection method and an exploratory thematic analysis process. SETTING: Participants were recruited from postgraduate specialist medical training programmes within one Deanery (Scotland Deanery) in the UK. PARTICIPANTS: Fourteen doctors in postgraduate medical specialist training, who self-identified as being from a ME background, were recruited into the study. RESULTS: Doctors from ME backgrounds faced: Barriers to authentic interpersonal connections, with a perceived lack of social inclusion in the workplace community. ME doctors faced challenges in earning others' trust and experienced microaggressions and exclusion behaviours that affected their self-confidence. Impacts on identity and sense of belonging, with perceived challenges in being understood across diverse cultures. Doctors felt negatively pre-judged (by patients and colleagues), with additional challenges of being pre-judged in contexts of intersectionality; and ME doctors felt they needed to conceal parts of their identity in order to assimilate. Unjust systems-a playing field that is not level, where doctors felt unsupported and unable to effectively report/challenge discrimination. ME doctors perceived a lack of appropriate adjustments to the learning environment (e.g., fuller orientation) as well as inequitable processes (e.g., job and academic opportunities for those requiring visas). CONCLUSIONS: Focused interventions to address unjust systems as well as improve intercultural awareness and understanding between all doctors may help to address some of the current inequities in medical education. Any such interventions require appropriate evaluation to determine their efficacy.

Improved yield of recombinant human IFN-α2b from mammalian cells using heterologous signal peptide approach.

The Type I Interferon cytokine family member, Interferon-α2b (hIFN-α2b), modulates a number of important biological mechanisms including anti-proliferation, immunoregulation and antiviral responses. Due to its role in the immune system, hIFN-α2b has been used as a therapeutic modulator in hepatitis C as well as some forms of leukaemia. Clinical grade hIFN-α2b is typically produced in bacterial expression systems that involves complex refolding protocols and subsequent loss of yields. In this study, we describe an expression and purification system for hIFN-α2b from mammalian cells. Application of the Trypsin-1 signal peptide-propeptide domain significantly improved the expression and secretion of hIFN-α2b from HEK293 cells. We established a simple purification strategy that yields homogenous, pure hIFN-α2b that is stable and biologically active.

Supporting doctors' well-being and resilience during COVID-19: A framework for rapid and rigorous intervention development.

This paper aims to outline the development of a theoretically informed and evidence-based intervention strategy to underpin interventions to support the well-being of doctors during COVID-19 and beyond; delineate new ways of working were employed to ensure a rapid and rigorous process of intervention development and present the resulting novel framework for intervention development. The research comprised four workstreams: literature review (WS1), qualitative study (WS2), intervention development and implementation (WS3) and evaluation (WS4). Due to time constraints, we employed a parallel design for WS1-3 with the findings of WS1-2 informing WS3 on a continual basis. WS3 was underpinned by the Behaviour Change Wheel. We recruited expert panels to assist with intervention development. We reflected on decisions taken to facilitate the rapid yet rigorous process of intervention development. The empirical output was a theoretically informed and evidence-based intervention strategy to underpin interventions to support doctors' well-being during COVID-19 and beyond. The methodological output was a novel framework that facilitates rapid and rigorous development of interventions. The intervention strategy provides a foundation for development and evaluation of tailored interventions to support doctors' well-being. The novel framework provides guidance for the development of interventions where the situation demands a rapid yet rigorous development process.

Heard, valued, supported? Doctors' wellbeing during transitions triggered by COVID-19.

INTRODUCTION: Supporting doctors' wellbeing is crucial for medical education to help minimise negative long-term impacts on medical workforce retention and ultimately patient care. There is limited study of how doctors' transitions experiences impact wellbeing, particularly socially and culturally. Multiple Multidimensional Transitions (MMT) theory views transitions as dynamic, incorporating multiple contexts and multiple domains. Using MMT as our lens, we report a qualitative analysis of how transitions experienced by doctors during the pandemic impacted on social and cultural aspects of wellbeing. METHODS: Longitudinal narrative inquiry was employed, using interviews and audio-diaries. Data were collected over 6 months in three phases: (i) interviews with doctors from across the career spectrum (n = 98); (ii) longitudinal audio-diaries for 2-4 months (n = 71); (iii) second interviews (n = 83). Data were analysed abductively, narrowing focus to factors important to social and cultural wellbeing. RESULTS: Doctors described experiencing multiple interacting transitions triggered by the pandemic in multiple contexts (workplace, role, homelife and education). Patterns identifiable across the dataset allowed us to explore social and cultural wellbeing crosscutting beyond individual experience. Three critical factors contributed to social and cultural wellbeing both positively and negatively: being heard (e.g., by colleagues asking how they are); being valued (e.g., removal of rest spaces by organisations showing lack of value); and being supported (e.g., through regular briefing by education bodies). CONCLUSIONS: This study is the first to longitudinally explore the multiple-multidimensional transitions experienced by doctors during the COVID-19 pandemic. Our data analysis helped us move beyond existing perceptions around wellbeing and articulate multiple factors that contribute to social and cultural wellbeing. It is vital that medical educators consider the learning from these experiences to help pinpoint what aspects of support might be beneficial to trainee doctors and their trainers. This study forms the basis for developing evidenced-based interventions that ensure doctors are heard, valued and supported.

Opening up the black box of a Gateway to Medicine programme: a realist evaluation.

OBJECTIVES: A Gateway to Medicine programme, developed in partnership between a further and higher education setting and implemented to increase the socioeconomic diversity of medicine, was examined to identify precisely what works within the programme and why. DESIGN: This study employed realist evaluation principles and was undertaken in three phases: document analysis and qualitative focus groups with widening access (WA) programme architects; focus groups and interviews with staff and students; generation of an idea of what works. SETTING: Participants were recruited from a further/higher education setting and were either enrolled or involved in the delivery of a Gateway to Medicine programme. PARTICIPANTS: Twelve staff were interviewed either individually (n=3) or in one of three group interviews. Nine focus groups (ranging from 5 to 18 participants in each focus group) were carried out with Gateway students from three consecutive cohorts at 2-3 points in their Gateway programme year. RESULTS: Data were generated to determine what 'works' in the Gateway programme. Turning a realist lens on the data identified six inter-relating mechanisms which helped students see medicine as attainable and achievable and prepared them for the transition to medical school. These were academic confidence (M1); developing professional identity (M2); financial support/security (M3); supportive relationships with staff (M4) and peers (M5); and establishing a sense of belonging as a university student (M6). CONCLUSIONS: By unpacking the 'black box' of a Gateway programme through realist evaluation, we have shown that such programmes are not solely about providing knowledge and skills but are rather much more complex in respect to how they work. Further work is needed to further test the mechanisms identified in our study in other contexts for theory development and to identify predictors of effectiveness in terms of students' preparedness to transition.

A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome.

Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome.

The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding.

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Patient-reported outcome measures in core outcome sets targeted overlapping domains but through different instruments.

OBJECTIVE: There is no comprehensive assessment of which patient-reported outcomes (PROs) are recommended in core outcome sets (COS), and how they should be measured. The aims of this study are to review COS that include patient-reported outcomes measures (PROMs), identify their target health domains, main characteristics, and their overlap within and across different disease areas. STUDY DESIGN AND SETTING: We selected COS studies collected in a publicly available database that included at least one recommended PROM. We gathered information on study setting, disease area, and targeted outcome domains. Full-text of recommended instruments were obtained, and an analysis of their characteristics and content performed. We classified targeted domains according to a predefined 38-item taxonomy. RESULTS: Overall, we identified 94 COS studies that recommended 323 unique instruments, of which: 87% were included in only one COS; 77% were disease-specific; 1.5% preference-based; and 61% corresponded to a full questionnaire. Most of the instruments covered broad health-related constructs, such as global quality of life (25%), physical functioning (22%), emotional functioning and wellbeing (7%). CONCLUSION: The wealth of recommended instruments observed even within disease areas does not fit with a vision of systematic, harmonized collection of PROM data in COS within and across disease areas.

Improved secretion of recombinant human IL-25 in HEK293 cells using a signal peptide-pro-peptide domain derived from Trypsin-1.

OBJECTIVE: To compare the effects of human Trypsin-1 signal peptide and pro-peptide on the expression and secretion efficiency of human Interleukin-25 from mammalian cells. RESULTS: The signal peptide and combined signal peptide-pro-peptide sequence of human Trypsin-1 improved the secretion of human IL-25 from 1.7 to 3.2 µg/ml and 1.7 to 8.2 µg/ml, respectively. Deletion analysis identified the minimal Trypsin-1 derived secretion domain that maintains improved human Interleukin-25 production and secretion. The presence of Trypsin-1 pro-peptide sequence does not affect the function of secreted human Interleukin-25. CONCLUSION: The Trypsin-1 signal peptide-pro-peptide sequence increased human IL-25 expression and secretion in mammalian cells by fivefold.

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency.

Rapid identification of highly potent human anti-GPCR antagonist monoclonal antibodies.

Complex cellular targets such as G protein-coupled receptors (GPCRs), ion channels, and other multi-transmembrane proteins represent a significant challenge for therapeutic antibody discovery, primarily because of poor stability of the target protein upon extraction from cell membranes. To assess whether a limited set of membrane-bound antigen formats could be exploited to identify functional antibodies directed against such targets, we selected a GPCR of therapeutic relevance (CCR1) and identified target binders using an in vitro yeast-based antibody discovery platform (AdimabTM) to expedite hit identification. Initially, we compared two different biotinylated antigen formats overexpressing human CCR1 in a 'scouting' approach using a subset of the antibody library. Binders were isolated using streptavidin-coated beads, expressed as yeast supernatants, and screened using a high-throughput binding assay and flow cytometry on appropriate cell lines. The most suitable antigen was then selected to isolate target binders using the full library diversity. This approach identified a combined total of 183 mAbs with diverse heavy chain sequences. A subset of clones exhibited high potencies in primary cell chemotaxis assays, with IC50 values in the low nM/high pM range. To assess the feasibility of any further affinity enhancement, full-length hCCR1 protein was purified, complementary-determining region diversified libraries were constructed from a high and lower affinity mAb, and improved binders were isolated by fluorescence-activated cell sorting selections. A significant affinity enhancement was observed for the lower affinity parental mAb, but not the high affinity mAb. These data exemplify a methodology to generate potent human mAbs for challenging targets rapidly using whole cells as antigen and define a route to the identification of affinity-matured variants if required.

TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide-HLA Complex.

The molecular rules driving TCR cross-reactivity are poorly understood and, consequently, it is unclear the extent to which TCRs targeting the same Ag recognize the same off-target peptides. We determined TCR-peptide-HLA crystal structures and, using a single-chain peptide-HLA phage library, we generated peptide specificity profiles for three newly identified human TCRs specific for the cancer testis Ag NY-ESO-1157-165-HLA-A2. Two TCRs engaged the same central peptide feature, although were more permissive at peripheral peptide positions and, accordingly, possessed partially overlapping peptide specificity profiles. The third TCR engaged a flipped peptide conformation, leading to the recognition of off-target peptides sharing little similarity with the cognate peptide. These data show that TCRs specific for a cognate peptide recognize discrete peptide repertoires and reconciles how an individual's limited TCR repertoire following negative selection in the thymus is able to recognize a vastly larger antigenic pool.

A cross-sectional survey of the pharmacy workforce in general practice in Scotland.

BACKGROUND: In Scotland, there has been significant investment in pharmacy teams in general medical practices over recent years, aligned to current government policy. OBJECTIVES: To characterize the national pharmacy workforce including activities undertaken, perceived competence and confidence, as well as perception of integration of the intervention. METHODS: A cross-sectional survey of all pharmacists and pharmacy technicians in general practices. Survey items were demographics, activities undertaken and experiences. The NoMAD tool (Improving the Normalization of Complex Interventions) was included as a measure of perspectives of implementation. Post-piloting, a questionnaire link was sent to all pharmacists (n = 471) and pharmacy technicians (n = 112). A total NoMAD score was obtained by assigning 1 (strongly disagree) to 5 (strongly agree) to each item. RESULTS: Responses were received from 393 (83.4%) pharmacists and 101 (91.8%) pharmacy technicians. Three quarters of pharmacists (74.6%) and pharmacy technicians (73.3%) had been qualified for over 10 years. Two-thirds of pharmacists (68.4%) were independent prescribers, with three quarters (72.3%) currently prescribing. Respondents worked in a median of two practices and were providing a range of activities including medication/polypharmacy reviews, medicines reconciliation, prescribing efficiencies and training. Respondents reported high levels of competence and confidence (median 8, scale 0-10 highest). Median NoMAD total score (scale 20-100 highest, Cronbach's alpha 0.89) was 80 for pharmacists and 75 for pharmacy technicians, P ≤ 0.001. CONCLUSIONS: The general practice pharmacy workforce in Scotland is experienced, well-qualified and integrated within general practices, delivering a range of activities. These findings have implications for workforce planning and future education and training.

An evaluation of mental health clinical pharmacist independent prescribers within general practice in remote and rural Scotland.

Background A 12-month pilot was implemented in two general practices in remote and rural Scotland, with patients referred by general practitioners to specialist mental health pharmacist independent prescribers. Objective The objective was to evaluate the pilot service from the perspectives of the patients and the care team. Methods The pharmacists routinely recorded patient-specific data of all clinical issues and their actions at the time of each consultation. Further datasets comprised baseline and follow-up Patient Health Questionnaire (PHQ-9) and/or Generalised Anxiety Disorder (GAD-7) rating scales, a patient survey and interviews with members of the care team. Results Of the 75 patients, two-thirds (n = 47, 62.7%) were referred with a diagnosis of mixed depression and anxiety. There were 324 consultations (median 3, IQR 2-5, range 1-14) and 181 prescribing actions. At pilot completion, 34 patients (45.3%) had PHQ-9 and/or GAD-7 scores reduced by 50%. Patient questionnaires and staff interviews generated positive responses. Conclusion This pilot has provided evidence that specialist mental health pharmacist independent prescribers delivered quality care to patients with diagnoses of moderate to severe depression and/or anxiety. Whilst accepting study limitations, there is potential to translate the pilot model of care to sustained services throughout general practice.