Mucus clears from the trachea in a helix: a new twist to understanding airway diseases.

BACKGROUND: Mucociliary clearance (MCC) is critical to lung health and is impaired in many diseases. The path of MCC may have an important impact on clearance but has never been rigorously studied. The objective of this study is to assess the three-dimensional path of human tracheal MCC in disease and health. METHODS: Tracheal MCC was imaged in 12 ex-smokers, 3 non-smokers (1 opportunistically imaged during acute influenza and repeated after recovery) and 5 individuals with primary ciliary dyskinesia (PCD). Radiolabelled macroaggregated albumin droplets were injected into the trachea via the cricothyroid membrane. Droplet movement was tracked via scintigraphy, the path of movement mapped and helical and axial models of tracheal MCC were compared. MEASUREMENTS AND MAIN RESULTS: In 5/5 participants with PCD and 1 healthy participant with acute influenza, radiolabelled albumin coated the trachea and did not move. In all others (15/15), mucus coalesced into globules. Globule movement was negligible in 3 ex-smokers, but in all others (12/15) ascended the trachea in a helical path. Median cephalad tracheal MCC was 2.7 mm/min ex-smokers vs 8.4 mm/min non-smokers (p=0.02) and correlated strongly to helical angle (r=0.92 (p=0.00002); median 18o ex-smokers, 47o non-smokers (p=0.036)), but not to actual speed on helical path (r=0.26 (p=0.46); median 13.6 mm/min ex-smokers vs 13.9 mm/min non-smokers (p=1.0)). CONCLUSION: For the first time, we show that human tracheal MCC is helical, and impairment in ex-smokers is often caused by flattened helical transit, not slower movement. Our methodology provides a simple method to map tracheal MCC and speed in vivo.

Improving the Detection, Assessment, Management and Prevention of Delirium in Hospices (the DAMPen-D study): Feasibility study of a flexible and scalable implementation strategy to deliver guideline-adherent delirium care.

BACKGROUND: Delirium is a complex condition, stressful for all involved. Although highly prevalent in palliative care settings, it remains underdiagnosed and associated with poor outcomes. Guideline-adherent delirium care may improve its detection, assessment and management. AIM: To inform a future definitive study that tests whether an implementation strategy designed to improve guideline-adherent delirium care in palliative care settings improves patient outcomes (reduced proportion of in-patient days with delirium). DESIGN: With Patient Involvement members, we conducted a feasibility study to assess the acceptability of and engagement with the implementation strategy by hospice staff (intervention), and whether clinical record data collection of process (e.g. guideline-adherent delirium care) and clinical outcomes (evidence of delirium using a validated chart-based instrument;) pre- and 12-weeks post-implementation of the intervention would be possible. SETTING/PARTICIPANTS: In-patient admissions in three English hospices. RESULTS: Between June 2021 and December 2022, clinical record data were extracted from 300 consecutive admissions. Despite data collection during COVID-19, target clinical record data collection (n = 300) was achieved. Approximately two-thirds of patients had a delirium episode during in-patient stay at both timepoints. A 6% absolute reduction in proportion of delirium days in those with a delirium episode was observed. Post-implementation improvements in guideline-adherent metrics include: clinical delirium diagnosis 15%-28%; delirium risk assessment 0%-16%; screening on admission 7%-35%. CONCLUSIONS: Collection of data on delirium outcomes and guideline-adherence from clinical records is feasible. The signal of patient benefit supports formal evaluation in a large-scale study.

Developing a typology of interventions to support doctors' mental health and wellbeing.

BACKGROUND: The problem of mental ill-health in doctors is complex, accentuated by the COVID-19 pandemic, and impacts on healthcare provision and broader organisational performance. There are many interventions to address the problem but currently no systematic way to categorise them, which makes it hard to describe and compare interventions. As a result, implementation tends to be unfocussed and fall short of the standards developed for implementing complex healthcare interventions. This study aims to develop: 1) a conceptual typology of workplace mental health and wellbeing interventions and 2) a mapping tool to apply the typology within research and practice. METHODS: Typology development was based on iterative cycles of analysis of published and in-practice interventions, incorporation of relevant theories and frameworks, and team and stakeholder group discussions. RESULTS: The newly developed typology and mapping tool enable interventions to be conceptualised and/or mapped into different categories, for example whether they are designed to be largely preventative (by either improving the workplace or increasing personal resources) or to resolve problems after they have arisen. Interventions may be mapped across more than one category to reflect the nuance and complexity in many mental health and wellbeing interventions. Mapping of interventions indicated that most publications have not clarified their underlying assumptions about what causes outcomes or the theoretical basis for the intervention. CONCLUSION: The conceptual typology and mapping tool aims to raise the quality of future research and promote clear thinking about the nature and purpose of interventions, In doing so it aims to support future research and practice in planning interventions to improve the mental health and wellbeing of doctors.

Interventions to address unprofessional behaviours between staff in acute care: what works for whom and why? A realist review.

BACKGROUND: Unprofessional behaviour (UB) between staff encompasses various behaviours, including incivility, microaggressions, harassment, and bullying. UB is pervasive in acute healthcare settings and disproportionately impacts minoritised staff. UB has detrimental effects on staff wellbeing, patient safety and organisational resources. While interventions have been implemented to mitigate UB, there is limited understanding of how and why they may work and for whom. METHODS: This study utilised a realist review methodology with stakeholder input to improve understanding of these complex context-dependent interventions. Initial programme theories were formulated drawing upon scoping searches and reports known to the study team. Purposive systematic searches were conducted to gather grey and published global literature from databases. Documents were selected if relevant to UB in acute care settings while considering rigour and relevance. Data were extracted from these reports, synthesised, and initial theories tested, to produce refined programme theories. RESULTS: Of 2977 deduplicated records, 148 full text reports were included with 42 reports describing interventions to address UB in acute healthcare settings. Interventions drew on 13 types of behaviour change strategies and were categorised into five types of intervention (1) single session (i.e. one off); (2) multiple session; (3) single or multiple sessions combined with other actions (e.g. training sessions plus a code of conduct); (4) professional accountability and reporting programmes and; (5) structured culture change interventions. We formulated 55 context-mechanism-outcome configurations to explain how, why, and when these interventions work. We identified twelve key dynamics to consider in intervention design, including importance of addressing systemic contributors, rebuilding trust in managers, and promoting a psychologically safe culture; fifteen implementation principles were identified to address these dynamics. CONCLUSIONS: Interventions to address UB are still at an early stage of development, and their effectiveness to reduce UB and improve patient safety is unclear. Future interventions should incorporate knowledge from behavioural and implementation science to affect behaviour change; draw on multiple concurrent strategies to address systemic contributors to UB; and consider the undue burden of UB on minoritised groups. STUDY REGISTRATION: This study was registered on the international database of prospectively registered systematic reviews in health and social care (PROSPERO): https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255490 .

Evaluation of a complex intervention for prisoners with common mental health problems, near to and after release: the Engager randomised controlled trial.

BACKGROUND: Many male prisoners have significant mental health problems, including anxiety and depression. High proportions struggle with homelessness and substance misuse. AIMS: This study aims to evaluate whether the Engager intervention improves mental health outcomes following release. METHOD: The design is a parallel randomised superiority trial that was conducted in the North West and South West of England (ISRCTN11707331). Men serving a prison sentence of 2 years or less were individually allocated 1:1 to either the intervention (Engager plus usual care) or usual care alone. Engager included psychological and practical support in prison, on release and for 3-5 months in the community. The primary outcome was the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM), 6 months after release. Primary analysis compared groups based on intention-to-treat (ITT). RESULTS: In total, 280 men were randomised out of the 396 who were potentially eligible and agreed to participate; 105 did not meet the mental health inclusion criteria. There was no mean difference in the ITT complete case analysis between groups (92 in each arm) for change in the CORE-OM score (1.1, 95% CI -1.1 to 3.2, P = 0.325) or secondary analyses. There were no consistent clinically significant between-group differences for secondary outcomes. Full delivery was not achieved, with 77% (108/140) receiving community-based contact. CONCLUSIONS: Engager is the first trial of a collaborative care intervention adapted for prison leavers. The intervention was not shown to be effective using standard outcome measures. Further testing of different support strategies for prison with mental health problems is needed.

Drivers of unprofessional behaviour between staff in acute care hospitals: a realist review.

BACKGROUND: Unprofessional behaviours (UB) between healthcare staff are rife in global healthcare systems, negatively impacting staff wellbeing, patient safety and care quality. Drivers of UBs include organisational, situational, team, and leadership issues which interact in complex ways. An improved understanding of these factors and their interactions would enable future interventions to better target these drivers of UB. METHODS: A realist review following RAMESES guidelines was undertaken with stakeholder input. Initial theories were formulated drawing on reports known to the study team and scoping searches. A systematic search of databases including Embase, CINAHL, MEDLINE and HMIC was performed to identify literature for theory refinement. Data were extracted from these reports, synthesised, and initial theories tested, to produce refined programme theories. RESULTS: We included 81 reports (papers) from 2,977 deduplicated records of grey and academic reports, and 28 via Google, stakeholders, and team members, yielding a total of 109 reports. Five categories of contributor were formulated: (1) workplace disempowerment; (2) harmful workplace processes and cultures; (3) inhibited social cohesion; (4) reduced ability to speak up; and (5) lack of manager awareness and urgency. These resulted in direct increases to UB, reduced ability of staff to cope, and reduced ability to report, challenge or address UB. Twenty-three theories were developed to explain how these contributors work and interact, and how their outcomes differ across diverse staff groups. Staff most at risk of UB include women, new staff, staff with disabilities, and staff from minoritised groups. UB negatively impacted patient safety by impairing concentration, communication, ability to learn, confidence, and interpersonal trust. CONCLUSION: Existing research has focused primarily on individual characteristics, but these are inconsistent, difficult to address, and can be used to deflect organisational responsibility. We present a comprehensive programme theory furthering understanding of contributors to UB, how they work and why, how they interact, whom they affect, and how patient safety is impacted. More research is needed to understand how and why minoritised staff are disproportionately affected by UB. STUDY REGISTRATION: This study was registered on the international database of prospectively registered systematic reviews in health and social care (PROSPERO): https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255490 .

Development of a peptide vaccine against hookworm infection: Immunogenicity, efficacy, and immune correlates of protection.

BACKGROUND: Approximately 400 million individuals are infected with hookworms globally. Protective vaccines are needed to prevent reinfections, which often occur after drug treatment in endemic areas. Ideal vaccines are highly efficacious and well tolerated, and do not present risks to patient safety. Peptide vaccines can generate specific, highly protective responses because they focus on minimal antigenic target(s) with a specific immunoprotective mechanism. Necator americanus aspartyl protease 1 (Na-APR-1) is one of the most promising hookworm vaccine antigens. The neutralizing epitope p3 (TSLIAGPKAQVEAIQKYIGAEL), together with universal the TH epitope P25 (KLIPNASLIENCTKAEL), has been used previously to produce peptide vaccines and was found to protect BALB/c mice against rodent hookworm infections, resulting in worm burden reductions of up to 98%. However, because of extensive digestion in the gastrointestinal tract, large oral vaccination doses were necessary to achieve this level of efficacy. OBJECTIVE: We sought to overcome the limitations of oral vaccine delivery and to investigate protective efficacy and immune correlates of protection. Herein, we examined 5 different peptide vaccines following intraperitoneal injection, to compare their efficacy with that of the clinical protein antigen APR-1. METHODS: BALB/c mice were immunized with p3-P25-based antigen that was adjuvanted with (1) lipid core peptide, (2) polymethyl methacrylate, (3) linear polyleucine, and (4) branched polyleucine (BL10), or with (5) CpG/aluminum hydroxide adjuvant (alum)-adjuvanted control and protein-based (6) CpG/alum-adjuvanted Na-APR-1. The mice sera, saliva, and feces were sampled for immune response evaluation. The immunized mice were further challenged via hookworm larvae infection, and protection was evaluated by conducting intestinal hookworm counts. RESULTS: BL10 and lipid core peptide generated the highest serum anti-Na-APR-1 IgG and fecal anti-APR-1 IgG titers, but only BL10 generated significant fecal anti-Na-APR-1 IgA titers. Upon challenge, immunization with CpG/alum-adjuvanted p3-P25, BL10, and lipid core peptide provided the highest worm burden reductions of 75%, 77%, and 59%, respectively, whereas the group immunized with Na-APR-1 had only modest worm reduction of 26%. The relationships between serum anti-Na-APR-1 IgG, fecal anti-Na-APR-1 IgA and IgG, and worm burden reduction were established with R2 values greater than or equal to 0.9, and the crucial role of both anti-Na-APR-1 IgG and IgA responses was identified. CONCLUSIONS: We demonstrated for the first time that p3-based vaccine candidates are safer and can deliver higher protection against hookworm infection compared with the clinical vaccine candidate, Na-APR-1.

The biological paradigm of psychosis in crisis: A Kuhnian analysis.

The philosophy of Thomas Kuhn proposes that scientific progress involves periods of crisis and revolution in which previous paradigms are discarded and replaced. Revolutions in how mental health problems are conceptualised have had a substantial impact on the work of mental health nurses. However, despite numerous revolutions within the field of mental health, the biological paradigm has remained largely dominant within western healthcare, especially in orientating the understanding and treatment of psychosis. This paper utilises concepts drawn from the philosophy of Thomas Kuhn to explore the impact of what Kuhn terms 'anomalies' within the dominant biological paradigm: the anomaly of the meaningful utterance, the anomaly of complex aetiology and taxonomy and the anomaly of pharmacological inefficacy in recovery. The paper argues that the biological paradigm for understanding psychosis is in crisis and explores the implications for mental health nursing.

Creative Long Covid: A qualitative exploration of the experience of Long Covid through the medium of creative narratives.

BACKGROUND: Healthcare is witnessing a new disease with the emergence of Long Covid; a condition which can result in myriad symptoms, varying in frequency and severity. As new data are emerging to help inform treatment guidelines, the perspectives of those living with Long Covid are essential in informing healthcare practice. The research aimed to collect the narratives of people living with Long Covid to better understand the lived experience of this condition. In attempting to narrate complex or traumatic experiences the arts and humanities can offer alternative ways of expressing embodied narratives, representing rich sources of meaning. Therefore, the research specifically sought to elicit creative expressions from participants with lived experience of Long Covid. METHODS: Data were collected via an online repository where participants could submit their pieces of creative writing. Data were collected between August 2021 and January 2022 and a total of 28 submissions were received from participants. These were mostly written creative narratives. However, a small number were submitted as audio or video files of spoken word poetry or songs. Data collection was stopped once data saturation was achieved. RESULTS: The submissions were subjected to thematic analysis and five themes were generated. These five themes are Identity, social relationships, symptoms, interaction with healthcare systems and time. The results provide an insight into the experience of Long Covid as detailed by the participants' creative narratives. CONCLUSION: The results from this study provide a unique insight into the lived experience of Long Covid. In relation to clinical practice, the results suggest that adjustment reaction and loss of sense of self could be added as common symptoms. PATIENT AND PUBLIC CONTRIBUTION: Before undertaking the research, Long Covid community groups were contacted to discuss the potential value of this study and it was widely supported. One of the leading Long Covid support groups was also involved in disseminating information regarding the project. As part of ongoing work within this project, members of the team are actively disseminating the results within Long Covid communities and seeking to develop arts-based workshops specifically for people with Long Covid.

Implementing the battery-operated hand-held fan as an evidence-based, non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD): a qualitative study of the views of specialist respiratory clinicians.

INTRODUCTION: The battery-operated hand-held fan ('fan') is an inexpensive and portable non-pharmacological intervention for chronic breathlessness. Evidence from randomised controlled trials suggests the fan reduces breathlessness intensity and improves physical activity in patients with a range of advanced chronic conditions. Qualitative data from these trials suggests the fan may also reduce anxiety and improve daily functioning for many patients. This study aimed to explore barriers and facilitators to the fan's implementation in specialist respiratory care as a non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD). METHODS: A qualitative approach was taken, using focus groups. Participants were clinicians from any discipline working in specialist respiratory care at two hospitals. Questions asked about current fan-related practice and perceptions regarding benefits, harms and mechanisms, and factors influencing its implementation. Analysis used a mixed inductive/deductive approach. RESULTS: Forty-nine participants from nursing (n = 30), medical (n = 13) and allied health (n = 6) disciplines participated across 9 focus groups. The most influential facilitator was a belief that the fan's benefits outweighed disadvantages. Clinicians' beliefs about the fan's mechanisms determined which patient sub-groups they targeted, for example anxious or palliative/end-stage patients. Barriers to implementation included a lack of clarity about whose role it was to implement the fan, what advice to provide patients, and limited access to fans in hospitals. Few clinicians implemented the fan for acute-on-chronic breathlessness or in combination with other interventions. CONCLUSION: Implementation of the fan in specialist respiratory care may require service- and clinician-level interventions to ensure it is routinely recommended as a first-line intervention for chronic breathlessness in patients for whom this symptom is of concern, regardless of COPD stage.

Drugging an undruggable pocket on KRAS.

The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be "undruggable," between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.

Orally Administered Bacillus Spores Expressing an Extracellular Vesicle-Derived Tetraspanin Protect Hamsters Against Challenge Infection With Carcinogenic Human Liver Fluke.

BACKGROUND: The human liver fluke Opisthorchis viverrini is a food-borne trematode that causes hepatobiliary disease in humans throughout Southeast Asia. People become infected by consuming raw or undercooked fish containing metacercariae. Development of a vaccine to prevent or minimize pathology would decrease the risk of severe morbidity, including the development of bile duct cancer. METHODS: We produced an oral vaccine based on recombinant Bacillus subtilis spores expressing the large extracellular loop (LEL) of O. viverrini tetraspanin-2 (Ov-TSP-2), a protein that is abundant on the surface of O. viverrini secreted extracellular vesicles (EVs). Recombinant spores expressing Ov-TSP-2-LEL were orally administered to hamsters prior to challenge infection with O. viverrini metacercariae. RESULTS: Vaccinated hamsters generated serum IgG as well as bile IgG and IgA responses to Ov-TSP-2-LEL, and serum IgG from vaccinated hamsters blocked the uptake of fluke EVs by a human bile duct epithelial cell line. Vaccinated hamsters had 56% reductions in both adult flukes and fecal eggs compared to the control group. CONCLUSIONS: These findings indicate that oral vaccination of hamsters with recombinant B. subtilis spores expressing Ov-TSP-2-LEL is efficacious at reducing infection intensity and could form the basis of a vaccine for control of carcinogenic liver fluke infection in humans.

Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signalling and drug detoxification and are essential for parasite survival.

Cholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of the S. mansoni genome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1 -smp_154600 and Smache2 -smp_136690) and a butyrylcholinesterase (BChE) (Smbche1 -smp_125350). Antibodies to recombinant forms of each SmChE localized the proteins to the tegument of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence of SmAChE1 and SmBChE1. Parasite survival in vitro and in vivo was significantly impaired by silencing of each smche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided that SmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinant SmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor 2,2- dichlorovinyl dimethyl phosphate-dichlorvos (DDVP), whereas smbche1-silenced parasites displayed increased sensitivity to DDVP.

Publisher Correction: BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read "The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis12,13." The affected text of the right column should read "SMARCA2/4BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel-Lindau (VHL) or cereblon5,6,10,11,25,26,27." The errors have been corrected in the PDF version of the paper.

BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3.

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains.

Data, Social Determinants, and Better Decision-making for Health: the 3-D Commission.

More than a decade after the World Health Organization Commission on the Social Determinants of Health (SDoH), it is becoming widely accepted that social and economic factors, including but not limited to education, energy, income, race, ethnicity, and housing, are important drivers of health in populations. Despite this understanding, in most contexts, social determinants are not central to local, national, or global decision-making. Greater clarity in conceptualizing social determinants, and more specificity in measuring them, can move us forward towards better incorporating social determinants in decision-making for health. In this paper, first, we summarize the evolution of the social framing of health. Second, we describe how the social determinants are conceptualized and contextualized differently at the global, national, and local levels. With this, we seek to demonstrate the importance of analyzing and understanding SDoH relative to the contexts in which they are experienced. Third, we problematize the gap in data across contexts on different dimensions of social determinants and describe data that could be curated to better understand the influence of social determinants at the local and national levels. Fourth, we describe the necessity of using data to understand social determinants and inform decision-making to improve health. Our overall goal is to provide a path for our collective understanding of the foundational causes of health, facilitated by advances in data access and quality, and realized through improved decision-making.

Housing as a Social Determinant of Health: Evidence from Singapore, the UK, and Kenya: the 3-D Commission.

Housing is a paradigmatic example of a social determinant of health, as it influences and is influenced by structural determinants, such as social, macroeconomic, and public policies, politics, education, income, and ethnicity/race, all intersecting to shaping the health and well-being of populations. It can therefore be argued that housing policy is critically linked to health policy. However, the extent to which this linkage is understood and addressed in public policies is limited and highly diverse across and within countries. This analysis seeks to describe the linkages between housing policies and health and well-being using examples from three countries at different levels of the wealth spectrum: Singapore, the UK, and Kenya.We conducted a comparative policy analysis across three country contexts (Singapore, the UK, and Kenya) to document the extent to which housing policies address health and well-being, highlighting commonalities and differences among them. To guide our analysis, we used the United Nations (UN) definition of adequate housing as it offers a broad framework to analyze the impact of housing on health and well-being.The anatomy of housing policies has a strong correlation to the provision of adequate housing across Singapore, the UK, and Kenya, especially for vulnerable groups. The paper demonstrates that contextual factors including population composition (i.e., aging versus youthful), political ideologies, legal frameworks (i.e., welfare versus market-based provision of housing), and presence (or absence) of adequate, quality, timely, reliable, robust data systems for decision-making, which are taken up by stakeholders/state, have strong implications of the type of housing policies developed and implemented, in turn directly and indirectly impacting the overall health and well-being of populations.This analysis demonstrates the value of viewing housing policies as public health policies that could significantly impact the health and well-being of populations, especially vulnerable groups. Moreover, the findings highlight the importance of the Health in All Policies approach to facilitate integrated policy responses to address social determinants of health such as housing. This is more critical than ever, given the context of the global pandemic that has led to worsening overall health and well-being.

Transcriptional plasticity promotes primary and acquired resistance to BET inhibition.

Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.