Does proactive care in care homes improve survival? A quality improvement project.

BACKGROUND: NHS England's 'Enhanced Health in Care Homes' specification aims to make the healthcare of care home residents more proactive. Primary care networks (PCNs) are contracted to provide this, but approaches vary widely: challenges include frailty identification, multidisciplinary team (MDT) capability/capacity and how the process is structured and delivered. AIM: To determine whether a proactive healthcare model could improve healthcare outcomes for care home residents. DESIGN AND SETTING: Quality improvement project involving 429 residents in 40 care homes in a non-randomised crossover cohort design. The headline outcome was 2-year survival. METHOD: All care home residents had healthcare coordinated by the PCN's Older Peoples' Hub. A daily MDT managed the urgent healthcare needs of residents. Proactive healthcare, comprising information technology-assisted comprehensive geriatric assessment (i-CGA) and advanced care planning (ACP), were completed by residents, with prioritisation based on clinical needs.Time-dependent Cox regression analysis was used with patients divided into two groups:Control group: received routine and urgent (reactive) care only.Intervention group: additional proactive i-CGA and ACP. RESULTS: By 2 years, control group survival was 8.6% (n=108), compared with 48.1% in the intervention group (n=321), p<0.001. This represented a 39.6% absolute risk reduction in mortality, 70.2% relative risk reduction and the number needed to treat of 2.5, with little changes when adjusting for confounding variables. CONCLUSION: A PCN with an MDT-hub offering additional proactive care (with an i-CGA and ACP) in addition to routine and urgent/reactive care may improve the 2-year survival in older people compared with urgent/reactive care alone.

Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow.

Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.

What is the volume, quality and characteristics of evidence relating to the effectiveness and cost-effectiveness of multi-disciplinary occupational health interventions aiming to improve work-related outcomes for employed adults? An evidence and gap map of systematic reviews.

Background: In the UK, tens of millions of working days are lost due to work-related ill health every year, costing billions of pounds. The role of Occupational Health (OH) services is vital in helping workers to maintain employment when they encounter injury or illness. OH providers traditionally rely on a clinical workforce to deliver these services, particularly doctors and nurses with OH qualifications. However, the increasing demand for OH services is unlikely to be met in the future using this traditional model, due to the declining number of OH-trained doctors and nurses in the UK. Multi-disciplinary models of OH delivery, including a more varied range of healthcare and non-healthcare professionals, could provide a way to meet this new demand for OH services. There is a need to identify collaborative models of OH service delivery and review their effectiveness on return-to work outcomes. There is an existing pool of systematic review evidence evaluating workplace based, multi-disciplinary OH interventions, but it is difficult to identify which aspects of the content and/or delivery of these interventions may be associated with improved work-related outcomes. Objectives: The aim of this evidence and gap map (EGM) was to provide an overview of the systematic review evidence that evaluates the effectiveness and cost-effectiveness of multi-disciplinary OH interventions intending to improve work-related outcomes. Search Methods: In June 2021 we searched a selection of bibliographic databases and other academic literature resources covering a range of relevant disciplines, including health care and business studies, to identify systematic review evidence from a variety of sectors of employment. We also searched Google Search and a selection of topically relevant websites and consulted with stakeholders to identify reports already known to them. Searches were updated in February 2023. Selection Criteria: Systematic reviews needed to be about adults (16 years or over) in employment, who have had absence from work for any medical reason. Interventions needed to be multi-disciplinary (including professionals from different backgrounds in clinical and non-clinical professions) and designed to support employees and employers to manage health conditions in the workplace and/or to help employees with health conditions retain and/or return to work following medical absence. Effectiveness needed to be measured in terms of return to work, work retention or measures of absence, or economic evaluation outcomes. These criteria were applied to the title and abstract and full text of each systematic review independently by two reviewers, with disagreements resolved through discussion. We awarded each systematic review a rating of 'High', 'Medium' or 'Low' relevance to indicate the extent to which the populations, interventions and their contexts synthesised within the review were consistent with our research question. We also recorded the number of primary studies included within each of the 'High' and 'Medium' reviews that were relevant to research question using the same screening process applied at review level. Data Collection and Analysis: Summary data for each eligible review was extracted. The quality of the systematic reviews, rated as 'High' or 'Medium' relevance following full text screening, was appraised using the AMSTAR-2 quality appraisal tool. All data were extracted by one reviewer and checked by a second, with disagreements being settled through discussion. Summary data for all eligible systematic reviews were tabulated and described narratively. The data extracted from reviews of 'High' and 'Medium' relevance was imported into EPPI-Mapper software to create an EGM. Stakeholder Involvement: We worked alongside commissioners and policy makers from the Department of Health and Social Care (DHSC) and Department of Work and Pensions (DWP), OH personnel, and people with lived experience of accessing OH services themselves and/or supporting employees to access OH services. Individuals contributed to decision making at all stages of the project. This ensured our EGM reflects the needs of individuals who will use it. Main Results: We identified 98 systematic reviews that contained relevant interventions, which involved a variety of professionals and workplaces, and which measured effectiveness in terms of return to work (RTW). Of these, we focused on the 30 reviews where the population and intervention characteristics within the systematic reviews were considered to be of high or medium relevance to our research questions. The 30 reviews were of varying quality, split evenly between High/Moderate quality and Low/Critically-Low quality ratings. We did not identify any relevant systematic review evidence on any other work-related outcome of interest. Interventions were heterogenous, both within and across included systematic reviews. The EGM is structured according to the health condition experienced by participants, and the effectiveness of the interventions being evaluated, as reported within the included systematic reviews. It is possible to view (i) the quality and quantity of systematic review evidence for a given health condition, (ii) how review authors assessed the effectiveness or cost-effectiveness of the interventions evaluated. The EGM also details the primary studies relevant to our research aim included within each review. Authors' Conclusions: This EGM map highlights the array of systematic review evidence that exists in relation to the effectiveness or cost-effectiveness of multi-disciplinary, workplace-based OH interventions in supporting RTW. This evidence will allow policy makers and commissioners of services to determine which OH interventions may be most useful for supporting different population groups in different contexts. OH professionals may find the content of the EGM useful in identifying systematic review evidence to support their practice. The EGM also identifies where systematic review evidence in this area is lacking, or where existing evidence is of poor quality. These may represent areas where it may be particularly useful to conduct further systematic reviews.

Changes in Oxidised Phospholipids in Response to Oxidative Stress in Microtubule-Associated Protein Tau (MAPT) Mutant Dopamine Neurons.

Microtubule-associated protein Tau (MAPT) is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the MAPT gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that MAPT mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of MAPT were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in MAPT mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in MAPT mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology.

Development of EBV Related Diffuse Large B-cell Lymphoma in Deficiency of Adenosine Deaminase 2 with Uncontrolled EBV Infection.

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.

Rapid spread of the SARS-CoV-2 JN.1 lineage is associated with increased neutralization evasion.

In July/August 2023, the highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2.86 lineage emerged and its descendant JN.1 is on track to become the dominant SARS-CoV-2 lineage globally. Compared to the spike (S) protein of the parental BA.2.86 lineage, the JN.1 S protein contains one mutation, L455S, which may affect receptor binding and antibody evasion. Here, we performed a virological assessment of the JN.1 lineage employing pseudovirus particles bearing diverse SARS-CoV-2 S proteins. Using this strategy, it was found that S protein mutation L455S confers increased neutralization resistance but reduces ACE2 binding capacity and S protein-driven cell entry efficiency. Altogether, these data suggest that the benefit of increased antibody evasion outweighs the reduced ACE2 binding capacity and further enabled the JN.1 lineage to effectively spread in the human population.

The Ottawa Statement implementation guidance document for cluster randomized trials in the hemodialysis setting.

Research teams are increasingly interested in using cluster randomized trial (CRT) designs to generate practice-guiding evidence for in-center maintenance hemodialysis. However, CRTs raise complex ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues arising within 7 domains: justifying the CRT design, research ethics committee review, identifying research participants, obtaining informed consent, gatekeepers, assessing benefits and harms, and protecting vulnerable participants. But applying the Ottawa Statement recommendations to CRTs in the hemodialysis setting is complicated by the unique features of the setting and population. Here, with the help of content experts and patient partners, we co-developed this implementation guidance document to provide research teams, research ethics committees, and other stakeholders with detailed guidance on how to apply the Ottawa Statement recommendations to CRTs in the hemodialysis setting, the result of a 4-year research project. Thus, our work demonstrates how the voices of patients, caregivers, and all stakeholders may be included in the development of research ethics guidance.

Barriers to smoking interventions in community healthcare settings: a scoping review.

Smoking is one of the major causes of preventable death and is considered the greatest threat to global public health. While the prevalence of smoking has decreased, population growth has led to an increase in the absolute number of smokers. There are many proven smoking cessation interventions available to support smokers in their quit attempts. Most people who smoke, however, underutilize the treatments available to them. This scoping review aimed to identify the current barriers experienced by all stakeholders (smokers, service providers and policymakers) to existing evidence-based smoking cessation interventions in community healthcare settings. Five electronic databases (CINAHL, Ovid MEDLINE, PsycINFO, Scopus and Web of Science) were searched for relevant literature. A total of 40 eligible articles from different countries published between 2015 and 2022 were included in the review and content analysis carried out to identify the key barriers to smoking cessation interventions. Seven key themes were found to be common to all stakeholders: (i) literacy, (ii) competing demands and priorities, (iii) time, (iv) access to product, (v) access to service, (vi) workforce and (vii) motivation/readiness. These themes were mapped to the Capability, Opportunity, Motivation-Behaviour (COM-B) model. This study presents the effect the barriers within these themes have on current smoking cessation services and highlights priorities for future interventions.

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection.

This study investigates the humoral and cellular immune responses and health-related quality of life measures in individuals with mild to moderate long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24 months. LC participants show elevated nucleocapsid IgG levels at 3 months, and higher neutralizing capacity up to 8 months post-infection. Increased spike-specific and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells were observed at 3 and 8 months, but these differences do not persist at 24 months. Some LC participants had detectable IFN-γ and IFN-ß, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at the 24 month timepoint shows similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC and MC. No significant differences in exhaustion scores or antigen-specific T cell clones are observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24 months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count are associated with improvements in health-related quality of life.

Transitioning from interventional radiology: ideas for the inevitable.

BACKGROUND: Interventional Radiology (IR) is a highly rewarding specialty, both for its salutary effects for patients, as will as the satisfaction it provides for the operating radiologists. Nonetheless, arduous work and long hours have led to numerous reports of burnout amongst interventional radiologists (IRs). MATERIALS AND METHODS: Six long-term academic radiologists in leadership positions briefly chronicle their becoming IRs, their type of transitioning from IR, and the pros and cons of those respective transitions. RESULTS: The specific transitions include reduced time in IR, switching to diagnostic radiology, becoming involved in medical school education, ceasing IR leadership, and retirement. Pros and cons of the various transition strategies are highlighted. CONCLUSION: As the taxing work and long hours are so ubiquitous for IRs, and as burnout is so common, transitioning from IR is highly likely eventually for IRs. The varied transition experiences highlighted in this report hopefully will be helpful for current and aspiring IRs.

Performance of VI-RADS in predicting muscle-invasive bladder cancer after transurethral resection: a single center retrospective analysis.

PURPOSE: To assess VIRADS performance and inter-reader agreement for detecting muscle-invasive bladder cancer (MIBC) following transurethral resection of bladder tumor (TURBT). METHODS: An IRB-approved, HIPAA-compliant, retrospective study from 2016 to 2020 included patients with bladder urothelial carcinoma who underwent MRI after TURBT, and cystectomy within 3 months without post-MRI treatments. Three radiologists blinded to pathology results independently reviewed MR images and assigned a VI-RADS score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of VI-RADS were assessed for diagnosing MIBC using VI-RADS scores ≥ 3 and ≥ 4. Inter-reader agreement was assessed using Gwet's agreement coefficient (AC) and percent agreement. RESULTS: The cohort consisted of 70 patients (mean age, 68 years ± 11 [SD]; range 39-85; 58 men) and included 32/70 (46%) with MIBC at cystectomy. ROC analysis revealed an AUC ranging from 0.67 to 0.77 and no pairwise statistical difference between readers (p-values, 0.06, 0.08, 0.97). Percent sensitivity, specificity, PPV, NPV and accuracy for diagnosing MIBC for the three readers ranged from 81.3-93.8, 36.8-55.3, 55.6-60.5, 77.3-87.5, and 62.9-67.1 respectively for VI-RADS score ≥ 3, and 78.1-81.3, 47.4-68.4, 55.6-67.6, 72.0-78.8 and 61.4-72.9 respectively for VI-RADS score ≥ 4. Gwet's AC was 0.63 [95% confidence interval (CI): 0.49,0.78] for VI-RADS score ≥ 3 with 79% agreement [95% CI 72,87] and 0.54 [95%CI 0.38,0.70] for VI-RADS score ≥ 4 with 76% agreement [95% CI 69,84]. VIRADS performance was not statistically different among 31/70 (44%) patients who received treatments prior to MRI (p ≥ 0.16). CONCLUSION: VI-RADS had moderate sensitivity and accuracy but low specificity for detection of MIBC following TURBT, with moderate inter-reader agreement.

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

Clinical indications, safety, and effectiveness of percutaneous image-guided adrenal mass biopsy: an 8-year retrospective analysis in 160 patients.

PURPOSE: To assess indications, safety, and effectiveness of percutaneous adrenal mass biopsy in contemporary practice. METHODS: This institutional review board-approved, retrospective study included all patients undergoing percutaneous image-guided adrenal mass biopsies at an academic health system from January 6, 2015, to January 6, 2023. Patient demographics, biopsy indications, mass size, laboratory data, pathology results, and complications were recorded. Final diagnoses were based on pathology or ≥ 1 year of imaging follow-up when biopsy specimens did not yield malignant tissue. Test performance calculations excluded repeat biopsies. Continuous variables were compared with Student's t test, dichotomous variables with chi-squared test. RESULTS: A total of 160 patients underwent 186 biopsies. Biopsies were indicated to diagnose metastatic disease (139/186; 74.7%), for oncologic research only (27/186; 14.5%), diagnose metastatic disease and oncologic research (15/186; 8%), and diagnose an incidental adrenal mass (5/186; 2.7%). Biopsy specimens were diagnostic in 154 patients (96.3%) and non-diagnostic in 6 (3.8%). Diagnostic biopsies yielded malignant tissue (n = 136), benign adrenal tissue (n = 12), and benign adrenal neoplasms (n = 6) with sensitivity = 98.6% (136/138), specificity = 100% (16/16), positive predictive value = 100% (136/136), and negative predictive value = 88.9% (16/18). Adverse events followed 11/186 procedures (5.9%) and most minor (7/11, 63.6%). The adverse event rate was similar whether tissue was obtained for clinical or research purposes (10/144; 6.9% vs. 1/42; 2.4%, p = 0.27), despite more specimens obtained for research (5.8 vs. 3.7, p < 0.001). CONCLUSION: Percutaneous adrenal mass biopsy is safe, accurate, and utilized almost exclusively to diagnose metastatic disease or for oncologic research. The negative predictive value is high when diagnostic tissue samples are obtained. Obtaining specimens for research does not increase adverse event risk.

Reporting of equity in observational epidemiology: A methodological review.

Background: Observational studies can inform how we understand and address persisting health inequities through the collection, reporting and analysis of health equity factors. However, the extent to which the analysis and reporting of equity-relevant aspects in observational research are generally unknown. Thus, we aimed to systematically evaluate how equity-relevant observational studies reported equity considerations in the study design and analyses. Methods: We searched MEDLINE for health equity-relevant observational studies from January 2020 to March 2022, resulting in 16 828 articles. We randomly selected 320 studies, ensuring a balance in focus on populations experiencing inequities, country income settings, and coronavirus disease 2019 (COVID-19) topic. We extracted information on study design and analysis methods. Results: The bulk of the studies were conducted in North America (n = 95, 30%), followed by Europe and Central Asia (n = 55, 17%). Half of the studies (n = 171, 53%) addressed general health and well-being, while 49 (15%) focused on mental health conditions. Two-thirds of the studies (n = 220, 69%) were cross-sectional. Eight (3%) engaged with populations experiencing inequities, while 22 (29%) adapted recruitment methods to reach these populations. Further, 67 studies (21%) examined interaction effects primarily related to race or ethnicity (48%). Two-thirds of the studies (72%) adjusted for characteristics associated with inequities, and 18 studies (6%) used flow diagrams to depict how populations experiencing inequities progressed throughout the studies. Conclusions: Despite over 80% of the equity-focused observational studies providing a rationale for a focus on health equity, reporting of study design features relevant to health equity ranged from 0-95%, with over half of the items reported by less than one-quarter of studies. This methodological study is a baseline assessment to inform the development of an equity-focussed reporting guideline for observational studies as an extension of the well-known Strengthening Reporting of Observational Studies in Epidemiology (STROBE) guideline.

Advances in Pharyngeal Surgery Over the Past 10 Years: New Techniques and Technology.

This article is a review of advances in pharyngeal surgery over the past 10 years regarding literature, surgical technique, assessment, collaboration, and future direction in the management of adult and pediatric obstructive sleep apnea.

Motivations for investigating health inequities in observational epidemiology: a content analysis of 320 studies.

OBJECTIVES: To enhance equity in clinical and epidemiological research, it is crucial to understand researcher motivations for conducting equity-relevant studies. Therefore, we evaluated author motivations in a randomly selected sample of equity-relevant observational studies published during the COVID-19 pandemic. STUDY DESIGN AND SETTING: We searched MEDLINE for studies from 2020 to 2022, resulting in 16,828 references. We randomly selected 320 studies purposefully sampled across income setting (high vs low-middle-income), COVID-19 topic (vs non-COVID-19), and focus on populations experiencing inequities. Of those, 206 explicitly mentioned motivations which we analyzed thematically. We used discourse analysis to investigate the reasons behind emerging motivations. RESULTS: We identified the following motivations: (1) examining health disparities, (2) tackling social determinants to improve access, and (3) addressing knowledge gaps in health equity. Discourse analysis showed motivations stem from commitments to social justice and recognizing the importance of highlighting it in research. Other discourses included aspiring to improve health-care efficiency, wanting to understand cause-effect relationships, and seeking to contribute to an equitable evidence base. CONCLUSION: Understanding researchers' motivations for assessing health equity can aid in developing guidance that tailors to their needs. We will consider these motivations in developing and sharing equity guidance to better meet researchers' needs.

Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research.

BACKGROUND: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. METHODS: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. DISCUSSION: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.

Engaging patients as partners or collaborators in clinical research is becoming more common, but it is still new in preclinical research. Preclinical researchers work in laboratories on cell and animal experiments. They traditionally don't have frequent interactions with patients compared to their clinical research colleagues. Integrating patient engagement in preclinical laboratory research may help ensure that patient perspectives and values are considered. To help preclinical laboratory research align with patient-centred priorities we propose the development of a practical framework. This framework will facilitate patient engagement in preclinical laboratory research. To achieve this, we will first hold in-depth discussions with patient partners, researchers, and other collaborators to understand views on patient engagement in preclinical laboratory research. Together, we will identify key considerations to draft a framework, including motivations for patient engagement in preclinical laboratory research, and defining the roles of those who need to be involved. We will refine the framework through an international survey where we will collect feedback from researchers, patient partners, and other collaborators to make further improvements. The framework will then be tested and refined by preclinical laboratory teams inclusive of patient partners. The finalized framework and other resources to facilitate patient engagement in preclinical laboratory research will be hosted in a 'one-stop-shop' of online resources. Ultimately, this framework will enable partnerships between patients and researchers and provide a roadmap for patient engagement in preclinical laboratory research. This presents an exciting new opportunity for patients and researchers to collaborate and potentially improve translation of laboratory-based research.

Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.