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Abstract Determining whether someone has cardiometabolic disease (CMD), especially in the early stages, can be complicated. Risk stratification ordinarily depends on an extended process relying on medical history that typically considers blood pressure, cholesterol, smoking and diabetes status. Physicians have long relied on these key patient characteristics to assess CMD risk. However, these widely used clinical assessments are often identified later in life and by definition, in those individuals with progressed disease. This is partly because the onset of CMD naturally occurs in adulthood, however, the underlying processes can occur much earlier in life, even in the absence of obvious symptoms. For one thing, the pathways towards pathology may exist for years before symptom onset. Thus, among other things, there are opportunities to provide doctors with better insights into future disease prediction especially in younger adults with diabetes. The rapid rise in CMD together with the increased rates of obesity and diabetes in this population only emphasises the importance of predictive molecular biomarkers. One notable aspect is that traditional risk scores, such as those based on cholesterol measurements, are frequently found to be within normal ranges in younger populations. At the same time, given the significant overlap in risk factors for cardiovascular disease (CVD) and diabetes, the unmet clinical need is for early biomarkers of CMD that may help improve risk assessment in younger adults. This editorial highlights advances in the use of polygenic risk scores and emerging utility of genetic biomarkers to define intermediate CMD phenotypes discussing new classification criteria involving DNA methylation of genes to improve risk assessment. CMD is the number one cause of mortality and accounts for 31% of all global deaths. CMD is also multifactorial, comprising cardiovascular disease (CVD) and diabetes that have significant overlap in risk factors and disease biology. Diabetes is arguably the strongest risk factor for CVD development. Accounting for almost 90% of diabetes cases worldwide, type 2 diabetes (T2D) affects about 527 million people. The global economic burden is estimated at 1.3 trillion USD annually and is close to 1.8% of global GDP [1]. Despite the progress in preventive and therapeutic measures of CVD, the increasing CMD rates only underscore the important need of molecular biomarkers for early detection [2]. Determining whether someone has CMD usually involves an extended diagnostic process that has become essential for risk stratification and disease prevention [3]. While the onset of CMD typically occurs in adulthood, disease development commences much earlier, and this has scientists questioning whether molecular biomarkers could improve current prognostic risk scores. Predicting which people with T2D are most likely to develop CVD remains a significant challenge despite the recent advances in genetic mapping. Graphical abstract

Abstract Background Libraries in the UK have evolved from traditional book-lending institutions into dynamic community hubs, This study aims to explore the potential of libraries to act as community hubs to promote mental and physical health and wellbeing of community-dwelling adults, drawing on insights from both library users and library staff in England. Design A mixed-method, cross-sectional study using online survey and interviews with community-dwelling adults and library staff. Methods We collected data using a 14-item electronic survey and interviews with library users and staff to gauge perceptions. Descriptive statistics and thematic analysis were used to identify key trends and emergent themes. Results We included 605 respondents from the survey and interviewed 12 library users and staff. Libraries remain popular and are considered a ‘safe place by members of the community, regardless of their frequency of service usage irrespective of whether they are frequent users of services. However, a lack of awareness among library users about community-facing services could act as a hurdle to improving community health and wellbeing. Targeted engagement with residents is needed to increase awareness of libraries’ services, including community interventions to help tackle loneliness and inequalities in digital and health literacy. Library staff often did not feel involved in important decision-making. Various barriers, drivers and practical recommendations were identified to leverage libraries as hubs to promote community health and wellbeing. Conclusion Libraries already offer a variety of resources that directly or indirectly support the health and wellbeing of community-dwelling adults and young people. However, public awareness of these services is limited. As we navigate post-pandemic recovery, libraries can serve as platforms for community engagement, fostering resilience, mental health support and reducing social isolation. Recognising libraries’ untapped potential can lead to healthier communities and improved wellbeing.

Abstract Background Even prior to the advent of the COVID-19 pandemic, there was ample evidence that loneliness and social isolation negatively impacted physical and mental health, employability, and are a financial burden on the state. In response, there has been significant policy-level attention on tackling loneliness. The objective of this scoping review was to conduct a loneliness policy landscape analysis across 52 countries of the UN European country groups. Our policy analysis sought to highlight commonalities and differences between the different national approaches to manage loneliness, with the goal to provide actionable recommendations for the consideration of policymakers wishing to develop, expand or review existing loneliness policies. Methods We searched governmental websites using the Google search engine for publicly available documents related to loneliness and social isolation. Seventy-eight documents were identified in total, from which 23 documents were retained. Exclusion of documents was based on predetermined criteria. A structured content analysis approach was used to capture key information from the policy documents. Contextual data were captured in a configuration matrix to highlight common and unique themes. Results We could show that most policies describe loneliness as a phenomenon that was addressed to varying degrees in different domains such as social, health, geographical, economic and political. Limited evidence was found regarding funding for suggested interventions. We synthesised actionable recommendations for the consideration of policy makers focusing on the use of language, prioritisation of interventions, revisiting previous campaigns, sharing best practice across borders, setting out a vision, evaluating interventions, and the need for the rapid and sustainable scalability of interventions. Conclusions Our study provides the first overview of the national loneliness policy landscape, highlighting the increasing prioritisation of loneliness and social isolation as a major public health and societal issue. Our findings suggest that policymakers can sustain this momentum and strengthen their strategies by incorporating rigorous, evidence-based intervention evaluations and fostering international collaborations for knowledge sharing. We believe that policymakers can more effectively address loneliness by directing funds to develop and implement interventions that impact the individual, the community and society.

Abstract Background Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny. Methods and results High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter. Conclusions Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition.

Background Primary care plays a key role in addressing domestic violence and abuse (DVA) globally. However, DVA remains underdiagnosed and inadequately addressed in primary care, necessitating a deeper understanding of patients’ perspectives in the UK.Objectives To explore patients’ perceptions of their awareness of DVA signs and their attitudes towards using the Woman Abuse Screening Tool (WAST)-short during routine primary care encounters.Methods An anonymous 29-item e-Survey, available in 18 languages and including information about DVA support services, was administered via the Qualtrics XM Platform™ from March to October 2022. Eligible UK National Health Service patients aged 18+ were identified by GP practices in Northwest London and invited via SMS to participate.Results Data were collected from 6,967 NHS patients. The majority (78.0%) claimed awareness of the signs of DVA in adults and children, while about 22% were unaware or unsure of the signs of DVA. Nearly 85% reported insufficient public awareness about DVA. Around 70% recommended implementing the WAST-short screening tool during primary care encounters to raise awareness and support survivors. Over 50% viewed general practice as the optimal setting for identifying and referring survivors.Conclusion Improved public education on DVA is needed, as a significant proportion of patients remain unaware or unsure of its signs, with the majority deeming public knowledge insufficient. Patients’ strong support for using standardised screening tools like the WAST-short reflects their trust in healthcare providers to conduct sensitive assessments. Integrating these tools into routine practice could enhance DVA interventions.

Abstract β-cells are a type of endocrine cell found in pancreatic islets that synthesize, store and release insulin. In type 1 diabetes (T1D), T-cells of the immune system selectively destroy the insulin-producing β-cells. Destruction of these cells leads to a lifelong dependence on exogenous insulin administration for survival. Consequently, there is an urgent need to identify novel therapies that stimulate β-cell growth and induce β-cell function. We and others have shown that pancreatic ductal progenitor cells are a promising source for regenerating β-cells for T1D owing to their inherent differentiation capacity. Default transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 methyltransferase. In the present study, we show that transient stimulation of exocrine cells, derived from juvenile and adult T1D donors to the FDA-approved EZH2 inhibitors GSK126 and Tazemetostat (Taz) influence a phenotypic shift towards a β-like cell identity. The transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin modification. Targeting EZH2 is fundamental to β-cell regenerative potential. Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo. These pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration of β-like cell function.

Abstract Background Globally, an estimated 14% of adults live with migraine disease which impacts their physical, emotional and social wellbeing. To target the disease comprehensively, research recommends a multidisciplinary approach to migraine management. Yet, at present, migraine management primarily centers around pharmaceutical treatments. The aim of this study was to investigate the extent to which emotional awareness could influence the uptake of self-care behaviours of community-dwelling adults with migraine. Methods A cross-sectional online survey explored personal experiences with migraine disease and strategies or behaviours to manage migraine attacks. Chi-squared tests were used to investigate differences in ratings of migraine prevention and management strategies between users and non-users of the strategies. Univariable logistic regressions were used to assess the effectiveness of self-care behaviours to manage or prevent migraine attacks. Results We surveyed 170 community-dwelling adults with migraine in the United Kingdom, Austria, Germany and the United States. Most (85%) respondents had experienced migraine for over five years, where 42% of attacks usually lasted several days. Whereas we did not differentiate between diagnosis by a neurologist or self-diagnosis, the most common diagnoses in the cohort were migraine without aura (38.9%) and migraine with aura (29%). Staying hydrated was the most popular preventative strategy (87%), 70.2% used prescription medication and 64.9% changed their diet and/or supplements. Almost all ( 92.4%) respondents stated that their mood or emotions could trigger their migraine attacks. Keeping a headache or mood diary was the lowest-rated prevention strategy and was rated as "probably ineffective" or causing "no change" in preventing migraine attacks. Over a third (39.7%) kept track of their physical wellbeing and symptoms. Reasons stated for tracking symptoms included to identify triggers (65.8%), show reports to a healthcare professional (59.6%), understand when they must take medication (48.1%), track improvements (67.3%) or deteriorations (67.3%). Conclusions Migraine management is dominated by pharmaceutical management for acute pain attacks and lifestyle changes for managing migraine long-term. Perception of the effectiveness of those techniques is high, whereas perception of interventions that target the emotional or psychological components of chronic pain management (keeping a mood diary, and mental health support) is mixed. There exists a gap between the recommended biopsychosocial approach and the current state of migraine management. Graphical Abstract

Abstract The current conflict in Sudan severely hinders the accessibility of health services across the country. To address this, several initiatives were proposed including offering services using teleconsultations. This study aimed to assess Sudanese doctors' teleconsultation experience, perception, and concerns during the recent conflict. This cross-sectional survey focused on Sudanese medical officers, residents, specialists, and consultants living inside or outside the country having a practice license from the Sudan Medical Council and conducting teleconsultations with Sudanese patients during the conflict period. The questionnaire was distributed to personal and professional contacts and via social media platforms in the English language among doctors who provided teleconsultation during the conflict. Data analysis was performed using the Statistical Package for Social Sciences software version 26. The study enrolled 2463 clinicians from 17 different specialties, and females represented more than half the sample (56.8%). Internal medicine was the most frequent specialty (36.1%) and the majority (68.7%) of clinicians had less than 5 years of work experience. Voice call was the most frequent platform (50.1%) used for teleconsultation during the conflict and had the highest convenience score (p

Abstract The sustainability of groundwater aquifers requires evaluating several parameters, the most important of which are hydraulic parameters. Therefore, the essential aim of this research is to develop a management plan for the Moghra aquifer in order to prevent the expanding of water level decline and degradation of groundwater quality due to overexploitation and scarcity of recharge. To achieve this goal, all aquifer hydraulic parameters such as transmissivity, hydraulic conductivity, radius of interference, specific capacity, resulted drawdown, well loss, formation loss, well efficiency, and optimum safe yield had been measured for 40 groundwater wells drilled in the new reclaimed areas of Moghra Oasis. Based on geographic information system (GIS), hydrogeological cross sections and thematic maps for all parameters were created such as aquifer thickness, water table, groundwater flow direction, drawdown and groundwater salinity maps. The results revealed that clay and shale beds separated the three water-bearing formations of the Moghra aquifer. The aquifer-saturated thickness ranged from 30 and 102 m, and the groundwater level was below the mean sea level for all wells (ranges from − 72 to − 26.6 m). The calculated hydraulic parameters based on the analysis of long-duration pumping tests indicated that the studied aquifer has a wide variety of transmissivity (T) between 631 and 3768 m2/day, hydraulic conductivity (K) between 13.4 and 104.6 m/day, radius of influence from 126.3 to 581.3 m and specific capacity between 377.14 and 883.72 m2/day. On the other hand, the evaluation of existing drilled wells performance based on the results of step tests showed that well loss coefficient ranges between 0.0004749 and 0.0676 (h2/m5), formation loss coefficient varies from 3.34 × 10–8 to 4.80 × 10–6 (h/m2), well efficiency (γ) ranged from 50.53 to 98.08%, and optimum safe yield ranged from 40 to 98 (m3/h). Results of aquifer mapping and pumping tests can be more important for solving water scarcity issues, non-polluting water issues, health issues, and source of fresh water on the surface of the earth. The characterization of aquifer parameters in the study area, however, should be a significant component in the scientific planning and sustainability of groundwater.

Abstract Background The COVID-19 pandemic exposed the health equity gap between and within countries. Western countries were the first to receive vaccines and mortality was higher among socially deprived, minority and indigenous populations. Surprisingly, many sub-Saharan countries reported low excess mortalities. These countries share experiences with community organization and participation in health. The aim of this article was to analyse if and how this central role of people can promote a successful pandemic response. Methods This analysis was partly based on local and national experiences shared during an international and Latin American conference on person-and people-centred care in 2021. Additionally, excess mortality data and pandemic control-relevant data, as well as literature on the pandemic response of countries with an unexpected low excess mortality were consulted. Results Togo, Mongolia, Thailand and Kenya had a seven times lower mean excess mortality for 2020 and 2021 than the United States of America. More successful pandemic responses were observed in settings with experience in managing epidemics like Ebola and HIV, well-established community networks, a national philosophy of mutual aid, financial government assistance, more human resources for primary care and paid community health workers. Discussion Since trust in authorities and health needs vary greatly, local strategies are needed to complement national and international pandemic responses. Three key levers were identified to promote locally-tailored pandemic management: well-organized communities, community-oriented primary care, and health information systems. An organized community structure stems from a shared ethical understanding of humanity as being interconnected with each other and the environment. This structure facilitates mutual aid and participation in decision making. Community-oriented primary care includes attention for collective community health and ways to improve health from its roots. A health information system supports collective health and health equity analysis by presenting health needs stratified for social deprivation, ethnicity, and community circumstances. Conclusions The difference in excess mortality between countries during the COVID-19 pandemic and various country experiences demonstrate the potential of the levers in promoting a more just and effective health emergency response. These same levers and strategies can promote more inclusive and socially just health systems.

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with Olea europaea have been explored. Here, the OliveNetTM library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway. Our first aim was to perform enzymatic assays to evaluate the inhibitory activity of a selection of phenolic compounds and fatty acids against COX isoforms (COX-1 and COX-2) and 15-lipoxygenase (15-LOX). Olive compounds were found to inhibit COX isoforms, with minimal activity against 15-LOX. Subsequent molecular docking indicated that the olive compounds possess strong binding affinities for the active site of COX isoforms, and molecular dynamics (MD) simulations confirmed the stability of binding. Moreover, olive compounds were predicted to have favorable pharmacokinetic properties, including a readiness to cross biological membranes as highlighted by steered MD simulations and umbrella sampling. Importantly, olive compounds including OLC were identified as non-inhibitors of the human ether-à-go-go-related gene (hERG) channel based on patch clamp assays. Overall, this study extends our understanding of the bioactivity of Olea-europaea-derived compounds, many of which are now known to be, at least in part, accountable for the beneficial health effects of the Mediterranean diet.

In recent times, drilling groundwater wells for irrigation, domestic, and industrial uses is increasing at a high rate in Saudi Arabia, meaning that groundwater is becoming a primary water resource. In the study region, over-exploitation and unsustainable performance severely deteriorate groundwater. Therefore, it is important to monitor the groundwater levels and quality as well as to detect the hydraulic parameters in order to plan and maintain groundwater sustainability. Knowledge of aquifer hydraulic parameters and groundwater quality is essential for the productivity planning of an aquifer. Therefore, this study carried out a thorough analysis on measured depth to groundwater data (2017 and 2022), borehole pumping test records, and chemical analysis of the collected water samples, especially in the presence of overexploitation and scarcity of recharge scale. To accomplish this aim, measurements of 113 groundwater wells (including 103 water samples) and analysis of 29 pumping tests between step and long-duration tests were made of all aquifer characteristics. These parameters consist of well loss, formation loss, well efficiency, specific capacity, transmissivity, hydraulic conductivity, resulted drawdown, and physiochemical parameters. Thematic maps were generated for all parameters using the geographic information system (GIS) and diagrams to strategize the groundwater productivity in Al-Madinah Al-Munawarah Province. The estimated hydraulic parameters are highly variable. Four distinct portions were identified for aquifer potentiality based on these varying ranges. Both the north and east of the region are good for groundwater productivity due to good aquifer materials, whereas the southwestern and western portions have relatively poor values. The analyzed groundwater was categorized as fresh to slightly salty water, with two primary chemical types identified showing a prevalence of mixed NaCl and Ca-Mg-SO4/Cl water. Finally, groundwater productivity assessment predicts that the aquifers can support the Al-Madinah Al-Munawarah Province demand for several years if certain well distributions are adopted and for a few hours/day of pumping rate. The maps that have been created can be examined to aid in making decisions related to hydrology.

Abstract Background Almost all women will experience menopause, and the symptoms can have a severely detrimental impact on their quality of life. However, there is limited research exploring health-seeking behaviours and alternative service design or consultation formats. Group consultations have been successfully deployed in perinatal and diabetic care, improving accessibility and outcomes. This cross-sectional online survey was conducted to explore women’s personal experiences of menopause, including perspectives on group consultations. Methods An online survey investigated the experiences of individuals at all stages of menopause and their receptiveness towards group consultations for menopause. Respondents were categorised by menopause stage according to the STRAW + 10 staging system. Associations between menopause stage, acceptability of group consultations and participant demographics were assessed using logistic regression. Results Respondents experienced an average of 10.7 menopausal symptoms, but only 47% of respondents felt they had the knowledge and tools to manage their symptoms. Advice on menopause was sought from a healthcare professional (HCP) by 61% of respondents, the largest trigger for this being severity of symptoms and the main barrier for this was the perception that menopause wasn’t a valid enough reason to seek help. Of the respondents seeking advice from HCPs, 32% were prescribed transdermal HRT, 29% received oral HRT, 19% were offered antidepressants, 18% received local oestrogen and 6% were prescribed testosterone. Over three quarters (77%) of respondents indicated that they would join a group consultation for menopause and would be comfortable sharing their experiences with others (75%). Logistic regression indicated premenopausal respondents were 2.84 times more likely than postmenopausal women to be interested in a group consultation where they can meet or learn from others’ experiences. Conclusions This study highlighted a strong willingness of women aged 35–70 to participate in group consultations for menopause, with motivation being strongest amongst premenopausal women. Low awareness of self-management and lifestyle interventions to manage the symptoms of menopause highlight the need for greater outreach, research and interventions to build knowledge and confidence in the general population at scale. Future studies should focus on investigating the effectiveness and economic impact of menopause group consultations and the lived experience of individuals participating in group consultations.

Abstract Background Our ability to self-care can play a crucial role in the prevention, management and rehabilitation of diverse conditions, including chronic non-communicable diseases. Various tools have been developed to support the measurement of self-care capabilities of healthy individuals, those experiencing everyday self-limiting conditions, or one or more multiple long-term conditions. We sought to characterise the various non-mono-disease specific self-care measurement tools for adults as such a review was lacking. Objective The aim of the review was to identify and characterise the various non-mono-disease specific self-care measurement tools for adults. Secondary objectives were to characterise these tools in terms of their content, structure and psychometric properties. Design Scoping review with content assessment. Methods The search was conducted in Embase, PubMed, PsycINFO and CINAHL databases using a variety of MeSH terms and keywords covering 1 January 1950 to 30 November 2022. Inclusion criteria included tools assessing health literacy, capability and/or performance of general health self-care practices and targeting adults. We excluded tools targeting self-care in the context of disease management only or indicated to a specific medical setting or theme. We used the Seven Pillars of Self-Care framework to inform the qualitative content assessment of each tool. Results We screened 26,304 reports to identify 38 relevant tools which were described in 42 primary reference studies. Descriptive analysis highlighted a temporal shift in the overall emphasis from rehabilitation-focused to prevention-focused tools. The intended method of administration also transitioned from observe-and-interview style methods to the utilisation of self-reporting tools. Only five tools incorporated questions relevant to the seven pillars of self-care. Conclusions Various tools exist to measure individual self-care capability, but few consider assessing capability against all seven pillars of self-care. There is a need to develop a comprehensive, validated tool and easily accessible tool to measure individual self-care capability including the assessment of a wide range of self-care practices. Such a tool could be used to inform targeted health and social care interventions.

Abstract Background Therapeutic replacement of pancreatic endocrine β-cells is key to improving hyperglycaemia caused by insulin-dependent diabetes . Whilst the pool of ductal progenitors, which give rise to the endocrine cells, are active during development, neogenesis of islets is repressed in the human adult. Recent human donor studies have demonstrated the role of EZH2 inhibition in surgically isolated exocrine cells showing reactivation of insulin expression and the influence on the H3K27me3 barrier to β-cell regeneration. However, those studies fall short on defining the cell type active in transcriptional reactivation events. This study examines the role of the regenerative capacity of human pancreatic ductal cells when stimulated with pharmacological inhibitors of the EZH2 methyltransferase. Results Human pancreatic ductal epithelial cells were stimulated with the EZH2 inhibitors GSK-126, EPZ6438, and triptolide using a 2- and 7-day protocol to determine their influence on the expression of core endocrine development marker NGN3, as well as β-cell markers insulin, MAFA, and PDX1. Chromatin immunoprecipitation studies show a close correspondence of pharmacological EZH2 inhibition with reduced H3K27me3 content of the core genes, NGN3, MAFA and PDX1. Consistent with the reduction of H3K27me3 by pharmacological inhibition of EZH2, we observe measurable immunofluorescence staining of insulin protein and glucose-sensitive insulin response. Conclusion The results of this study serve as a proof of concept for a probable source of β-cell induction from pancreatic ductal cells that are capable of influencing insulin expression. Whilst pharmacological inhibition of EZH2 can stimulate secretion of detectable insulin from ductal progenitor cells, further studies are required to address mechanism and the identity of ductal progenitor cell targets to improve likely methods designed to reduce the burden of insulin-dependent diabetes.

Introduction: Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies. Methods: This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate. Results: A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%–60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%–17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%–27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%–33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%–27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%–100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors. Conclusions: Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

[This corrects the article DOI: 10.1371/journal.pone.0281172.].