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Zoe Moon, Rona Moss-Morris, Myra S Hunter, Sophie Carlisle, Lyndsay D Hughes Health Psychology Section, Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK Purpose: Nonadherence to hormone therapy in breast cancer survivors is common and associated with increased risk of mortality. Consistent predictors of nonadherence and nonpersistence are yet to be identified, and little research has examined psychosocial factors that may be amenable to change through intervention. This review aimed to identify predictors of nonadherence and nonpersistence to hormone therapy in breast cancer survivors in order to inform development of an intervention to increase adherence rates.Methods: Studies published up to April 2016 were identified through MEDLINE, Embase, Web of Science, PsycINFO, CINAHL and gray literature. Studies published in English measuring associations between adherence or persistence and any predictor variables were included. Eligible studies were assessed for methodological quality, data were extracted and a narrative synthesis was conducted.Results: Sixty-one eligible articles were identified. Most studies focused on clinical and demographic factors with inconsistent results. Some evidence suggested that receiving specialist care and social support were related to increased persistence, younger age and increased number of hospitalizations were associated with nonadherence, and good patient–physician relationship and self-efficacy for taking medication were associated with better adherence. A small amount of evidence suggested that medication beliefs were associated with adherence, but more high-quality research is needed to confirm this.Conclusion: Some psychosocial variables were associated with better adherence and persistence, but the results are currently tentative. Future high-quality research should be carried out to identify psychosocial determinants of nonadherence or nonpersistence that are modifiable through intervention. Keywords: breast cancer, adherence, persistence, hormone therapy

Transgender and gender diverse (TGD) individuals represent a population with a heavy burden of HIV. Multi-level stigma encountered by TGD individuals can create significant barriers to discussing topics related to HIV prevention; however, research on communication between TGD patients and primary care providers (PCPs) about HIV vulnerability and prevention remains limited. This study used in-depth qualitative interviews with 25 TGD patients and 15 PCPs conducted in 2022 to explore perspectives on HIV vulnerability communication during primary care encounters. Overall, 14 of the TGD patients were nonbinary, genderqueer, or another gender identity; all but two participants identified as a sexual minority. The majority of PCPs (n = 11) were physicians. The range of years practicing medicine was between two and 39 years. Thematic analysis was used to organize codes and establish themes. Three broad themes regarding factors that facilitate communication regarding HIV vulnerability were identified: (1) focusing on behaviors over identities, (2) conveying impartiality, and (3) acknowledging individuality among TGD patients. Findings corroborate earlier research that identified strengths in providers refraining from behavior-based assumptions tied to a patient's gender identity and sexual orientation and conveying impartial and nonjudgmental attitudes when discussing behaviors that can increase HIV vulnerability. Additionally, these findings underscore the significance of recognizing that, within the TGD community, all persons have unique circumstances, preferences, and needs. Future work should continue to explore the dynamics of HIV vulnerability and prevention discussions, especially among TGD individuals from diverse backgrounds and regions, to identify strategies for strengthening patient-provider communication and reducing vulnerability to HIV., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Older adults with frailty are at increased risk of premature death, and numerous negative sequalae including falls, disability, and dementia alongside increased healthcare costs. Most healthcare interactions for older people with frailty take place in primary care, and there is increasing interface working between primary and secondary care to manage this patient group including virtual wards, frailty management programmes and Hospital @ Home. This commentary aims to place proactive frailty into recent policy perspective, alongside highlighting some of the current challenges around the implementation of proactive frailty programmes., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LDH and TV are Co-Lead GPs for the British Geriatrics Society Community and Primary Care Group. DG and LL also sit on the group.

Around 42% of individuals with cancer experience distress. Acceptance and commitment therapy (ACT) can reduce distress, but effects are small, and mechanisms unclear. This review aimed to identify associations between ACT processes and distress in cancer. Search terms included cancer, ACT processes, self-compassion, and distress. Six online databases and grey literature were searched until March 2022. Of 6555 papers screened, 108 studies were included with 17,195 participants. Five meta-analyses of 77 studies were conducted. Random effects meta-analyses of correlations revealed higher scores on flexible processes (acceptance, present moment awareness, self-compassion) were associated with lower distress ( r pooled  = -0.24, -0.39, -0.48, respectively); whilst higher scores on inflexible processes (experiential avoidance, cognitive fusion) were associated with higher distress ( r pooled  = 0.58, 0.57, respectively). Meta-analyses displayed moderate-to-high heterogeneity with most studies assessed as low risk of bias. Meta-regressions revealed no significant moderators (stage, time since diagnosis, gender and age). This review provides a theoretically aligned evidence base for associations between ACT processes and distress in cancer, supporting elements of ACT theory and providing targeted directions for intervention development. Due to limited evidence, future research should focus on self-as-context, values and committed action and conduct mediation analysis in controlled trials of ACT processes on distress in cancer.

Importance: Extensive evidence documents health disparities for lesbian, gay, and bisexual (LGB) women, including worse physical, mental, and behavioral health than heterosexual women. These factors have been linked to premature mortality, yet few studies have investigated premature mortality disparities among LGB women and whether they differ by lesbian or bisexual identity., Objective: To examine differences in mortality by sexual orientation., Design, Setting, and Participants: This prospective cohort study examined differences in time to mortality across sexual orientation, adjusting for birth cohort. Participants were female nurses born between 1945 and 1964, initially recruited in the US in 1989 for the Nurses' Health Study II, and followed up through April 2022., Exposures: Sexual orientation (lesbian, bisexual, or heterosexual) assessed in 1995., Main Outcome and Measure: Time to all-cause mortality from assessment of exposure analyzed using accelerated failure time models., Results: Among 116 149 eligible participants, 90 833 (78%) had valid sexual orientation data. Of these 90 833 participants, 89 821 (98.9%) identified as heterosexual, 694 (0.8%) identified as lesbian, and 318 (0.4%) identified as bisexual. Of the 4227 deaths reported, the majority were among heterosexual participants (n = 4146; cumulative mortality of 4.6%), followed by lesbian participants (n = 49; cumulative mortality of 7.0%) and bisexual participants (n = 32; cumulative mortality of 10.1%). Compared with heterosexual participants, LGB participants had earlier mortality (adjusted acceleration factor, 0.74 [95% CI, 0.64-0.84]). These differences were greatest among bisexual participants (adjusted acceleration factor, 0.63 [95% CI, 0.51-0.78]) followed by lesbian participants (adjusted acceleration factor, 0.80 [95% CI, 0.68-0.95])., Conclusions and Relevance: In an otherwise largely homogeneous sample of female nurses, participants identifying as lesbian or bisexual had markedly earlier mortality during the study period compared with heterosexual women. These differences in mortality timing highlight the urgency of addressing modifiable risks and upstream social forces that propagate and perpetuate disparities.

Objective: Psychological distress persists amongst breast cancer survivors, so reliable assessment of symptoms is essential. The Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) is a composite measure of depression and anxiety and has been used to measure distress. This study aimed to evaluate the psychometric properties of the PHQ-ADS within breast cancer survivors., Method: Breast cancer survivors (N = 280) were recruited online and followed up at 12-months. Depression (PHQ-8) and anxiety (GAD-7) items formed the composite PHQ-ADS score. Additional measures included: distress thermometer (convergent validity), fear of cancer recurrence and COVID distress (discriminant validity), and self-compassion (predictive validity). Confirmatory factor analysis (CFA) using weighted least squares mean and variance adjusted estimation was undertaken., Results: One, two, and bifactor models underlying the PHQ-ADS were evaluated. The bifactor model had the most appropriate model fit overall. Omega hierarchical for the general distress factor was 0.914, accounting for 82% of explained variance. This suggests the PHQ-ADS is sufficiently unidimensional to warrant use of a total composite score. The PHQ-ADS demonstrated strong convergent and moderate discriminant validity. Self-compassion was an independent predictor of distress at 12-months., Conclusions: The PHQ-ADS is a valid measure for psychological distress in breast cancer survivors prescribed hormone therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To explore how primary care providers report discussing substance use with transgender and gender diverse (TGD) adult patients within the context of discussing gender-affirming interventions., Methods: Between March and April 2022, in-depth, semi-structured qualitative interviews were conducted with 15 primary care providers who care for TGD patients in the Northeastern US. Thematic analysis was used to analyze interview data and identify themes., Results: Two primary themes emerged among providers: 1) placing a focus on harm reduction, emphasizing reducing negative consequences of substance use, and 2) using access to gender-affirming interventions as an incentive for patients to change their substance use patterns., Conclusions: Focusing on harm reduction can emphasize reducing potential adverse outcomes while working with TGD patients towards their gender-affirmation goals. Future research should explore varying approaches to how substance use is discussed with TGD patients, as well as the interpretation of gender-affirming clinical guidelines., Practice Implications: Findings from this study indicate a need for enhancing provider knowledge around the appropriate application of gender-affirming care guidelines. Investing in training efforts to improve gender-affirming care is critical for encouraging approaches that prioritize harm reduction and do not unnecessarily prevent access to gender-affirming interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: Transgender and gender diverse (TGD) people who use drugs report barriers to accessing substance use treatment, including provider mistreatment. Little research has explored the multilevel factors that shape the capacity of substance use treatment professionals to provide gender-affirmative care (i.e., care that respects and affirms one's gender) to TGD people., Methods: From October 2021 to March 2022, substance use treatment and harm reduction professionals in Rhode Island were surveyed (N = 101) and qualitatively interviewed (N = 19) about the provision of substance use treatment-related services to TGD people. Quantitative data were analyzed descriptively; differences were examined using Fisher exact tests (p < 0.05). Qualitative interviews were coded and analyzed using thematic analysis., Results: Participants reported limited exposure to TGD people and lacked training on TGD health, which resulted in limited cultural and clinical competency and low self-efficacy in their ability to care for TGD people. Participants also highlighted structural factors (e.g., non-inclusive intake forms, limited availability of gender-inclusive ancillary community services) that restricted their ability to provide effective and affirming care to TGD people. Some participants also reported a "gender blind" ethos at their institutions- described by some as ignoring the potential impact of TGD peoples' unique experiences on their substance use and ability to benefit from treatment. While some perceived gender blindness as problematic, others believed this approach enabled substance use treatment professionals to consider all the identities and needs that patients/clients may have. Despite differences in treatment approaches, most participants agreed that their workplaces could benefit from efforts to create a safe and affirming space for people who use drugs, particularly TGD patients/clients., Conclusion: Results underscore how structural, interpersonal, and individual factors contributed to barriers in the provision of gender-affirmative substance use-related care for TGD people. Findings can inform efforts to increase the capacity of providers to deliver gender-affirmative substance use-related services, which is essential to supporting the recovery goals of TGD people., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Real-world gait analysis can aid in clinical assessments and influence related interventions, free from the restrictions of a laboratory setting. Using individual accelerometers, we aimed to use a simple machine learning method to quantify the performance of the discrimination between three self-selected cyclical locomotion types using accelerometers placed at frequently referenced attachment locations. Thirty-five participants walked along a 10 m walkway at three different speeds. Triaxial accelerometers were attached to the sacrum, thighs and shanks. Slabs of magnitude, three-second-long accelerometer data were transformed into two-dimensional Fourier spectra. Principal component analysis was undertaken for data reduction and feature selection, followed by discriminant function analysis for classification. Accuracy was quantified by calculating scalar accounting for the distances between the three centroids and the scatter of each category's cloud. The algorithm could successfully discriminate between gait modalities with 91% accuracy at the sacrum, 90% at the shanks and 87% at the thighs. Modalities were discriminated with high accuracy in all three sensor locations, where the most accurate location was the sacrum. Future research will focus on optimising the data processing of information from sensor locations that are advantageous for practical reasons, e.g., shank for prosthetic and orthotic devices.

Purpose: The politicization of adolescent gender-affirming care has occurred alongside targeted harassment (e.g., threats of violence, doxing, bomb threats) of adolescent gender-affirming care providers across the United States. This study sought to explore their experiences of targeted harassment., Methods: From October to December 2022, mental and physical health gender-affirming care providers from across the United States completed a survey including open-ended questions about the kinds of harassment they experienced (i.e., method and messages of harassment) and its impact on their lives and practices. Thematic analyses were used to analyze their responses., Results: In total, 117 providers completed the survey and 70% shared that either they, their practice, or their institution had received threats specific to delivering gender-affirming care. The most common experiences were threats via social media or mailed letters. Several received death threats. Providers described how targeted harassment impacted their psychological well-being and required them to reassess clinic safety. Additionally, providers expressed the need for a more accurate representation of gender-affirming care in media and stronger advocacy from institutions and organizations emphasizing the importance of this care., Discussion: Adolescent gender-affirming care providers are experiencing targeted harassment, significantly affecting their ability to deliver care to transgender and gender-diverse adolescents and their families. Providers stressed the importance of receiving support from their institutions to ensure their safety. The ongoing sociopolitical climate related to gender-affirming care coupled with targeted harassment of those providing it will further limit access to this care., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: This study explored the feasibility and acceptability of conducting a larger trial of a self-guided, online self-compassion and acceptance and commitment therapy (ACT) focused treatment among people with type 2 diabetes (T2D) to decrease psychological distress., Materials and Methods: This study was a two-arm, parallel, feasibility randomised controlled trial with nested qualitative methods. UK adults with T2D were randomly (1:1) allocated to a five-week online self-compassion and ACT treatment or waitlist control. Information regarding recruitment, trial retention, and treatment completion was collected, and post-treatment semi-structured interviews were conducted to assess feasibility and acceptability. Self-report measures of psychological distress (depression, anxiety, diabetes distress) and potential treatment processes (self-compassion and psychological flexibility) were completed as secondary feasibility outcomes., Results: Fifty-five (60.44 %) out of 91 people who accessed the study link were eligible to participate. Of these, 33 eligible participants (60 %) were randomly assigned to treatment ( n  = 19) or control arms (waitlist; n  = 14). While treatment completion was 47.37 %, trial retention rates were 39.39 % (5-week follow-up) and 21.2 % (9-week follow-up). Secondary feasibility outcomes of treatment effect estimates are difficult to interpret in light of low treatment completion and trial retention rates., Conclusion: A larger trial of the self-guided, online self-compassion treatment to decrease psychological distress in people with T2D may be beneficial, but it has limited feasibility in its current form. Further efforts are needed to improve treatment acceptability of online self-compassion and ACT focused treatment and trial procedures., Competing Interests: None., (© 2023 The Authors.)

Purpose: COVID-19 pandemic has had long-standing consequences for all aspects of life. Although young people appear less susceptible to severe forms of physical illness due to the coronavirus, they have not escaped unscathed from its' psychological impacts. The present study measured the content of worries in young people residing in the UK during the pandemic and how it varied with sociodemographic factors., Methods: Between May and December 2020, UK-residing participants aged 12-25 years completed an online survey that presented participants with free-text fields to describe their top three worries over the last two weeks, in addition to demographic and other information. Cross-sectional data from 2560 participants (Males = 767; Female = 1793) was analyzed., Results: Irrespective of sociodemographic, a majority of the participants reported worries related to academics, followed by social relationships, own physical health, social and work routines, and physical health of others. Significantly more females reported concerns about academics, finances, physical health, social and work routines, social relationships, mental health and emotions, and physical health of others. Expectedly, more older (18-25 years) than younger (12-17 years) participants reported concerns about career-prospects and finances, while more younger than older ones were worried about academics (98.41% vs. 80.90%). With respect to financial worries, a higher percentage of BAME (Black, Asian and Minority Ethnic) communities in the UK reported such worries. Ethnicity significantly predicted more worries about social relationships among White than BAME participants. Significant differences also existed across different SES groups regarding endorsement of a particular category of worry., Conclusion: These findings highlight the need for tailored interventions depending on the major concerns for young people of different ages, sexes, ethnicities, and SES., Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10396-3., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: Hepatitis C virus (HCV) prevalence among transgender and gender-diverse individuals ranges from 1.8% to 15.7% versus 1% in the general population. Previous HCV studies inclusive of transgender and gender-diverse individuals primarily rely on convenience-based sampling methods or are geographically restricted. The purpose of this study is to compare the prevalence of HCV diagnoses, testing, and care engagement between transgender and gender-diverse and cisgender individuals., Methods: Using Optum's de-identified Clinformatics® Data Mart Database, in 2022, the unadjusted prevalence of HCV testing among all adults and people who inject drugs from January 2001 to December 2019 was measured. Multivariable logistic regression was used to compare the adjusted odds of HCV diagnoses and care engagement by gender subgroup., Results: The overall unadjusted frequency of HCV diagnoses among transgender and gender-diverse individuals was approximately 3 times that of cisgender individuals (1.06% vs 0.38%, p<0.001), including among people who inject drugs (6.36% vs 2.36%, p=0.007). Compared with cisgender women, transfeminine/nonbinary individuals had over 5 times the adjusted odds of a HCV diagnosis and approximately 3.5 times the odds of being tested for HCV. In addition, compared with cisgender women, transfeminine/nonbinary individuals had significantly increased odds of having a HCV‒related procedure (e.g., abdominal ultrasounds, liver biopsies, Fibroscans). Cisgender men had significantly increased odds of receiving HCV medication compared with cisgender women., Conclusions: Although testing was higher among transgender and gender-diverse individuals, the higher overall frequency of HCV diagnoses among transgender and gender-diverse than among cisgender individuals signals persistent health disparities. Interventions are warranted to prevent HCV and increase ongoing testing and treatment uptake among transgender and gender-diverse populations., (Published by Elsevier Inc.)

Background: Biomedical researchers are strongly encouraged to make their research outputs more Findable, Accessible, Interoperable, and Reusable (FAIR). While many biomedical research outputs are more readily accessible through open data efforts, finding relevant outputs remains a significant challenge. Schema.org is a metadata vocabulary standardization project that enables web content creators to make their content more FAIR. Leveraging Schema.org could benefit biomedical research resource providers, but it can be challenging to apply Schema.org standards to biomedical research outputs. We created an online browser-based tool that empowers researchers and repository developers to utilize Schema.org or other biomedical schema projects., Results: Our browser-based tool includes features which can help address many of the barriers towards Schema.org-compliance such as: The ability to easily browse for relevant Schema.org classes, the ability to extend and customize a class to be more suitable for biomedical research outputs, the ability to create data validation to ensure adherence of a research output to a customized class, and the ability to register a custom class to our schema registry enabling others to search and re-use it. We demonstrate the use of our tool with the creation of the Outbreak.info schema-a large multi-class schema for harmonizing various COVID-19 related resources., Conclusions: We have created a browser-based tool to empower biomedical research resource providers to leverage Schema.org classes to make their research outputs more FAIR., (© 2023. The Author(s).)

In response to the emergence of SARS-CoV-2 variants of concern, the global scientific community, through unprecedented effort, has sequenced and shared over 11 million genomes through GISAID, as of May 2022. This extraordinarily high sampling rate provides a unique opportunity to track the evolution of the virus in near real-time. Here, we present outbreak.info , a platform that currently tracks over 40 million combinations of Pango lineages and individual mutations, across over 7,000 locations, to provide insights for researchers, public health officials and the general public. We describe the interpretable visualizations available in our web application, the pipelines that enable the scalable ingestion of heterogeneous sources of SARS-CoV-2 variant data and the server infrastructure that enables widespread data dissemination via a high-performance API that can be accessed using an R package. We show how outbreak.info can be used for genomic surveillance and as a hypothesis-generation tool to understand the ongoing pandemic at varying geographic and temporal scales., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Outbreak.info Research Library is a standardized, searchable interface of coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) publications, clinical trials, datasets, protocols and other resources, built with a reusable framework. We developed a rigorous schema to enforce consistency across different sources and resource types and linked related resources. Researchers can quickly search the latest research across data repositories, regardless of resource type or repository location, via a search interface, public application programming interface (API) and R package., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Biomedical datasets are increasing in size, stored in many repositories, and face challenges in FAIRness (findability, accessibility, interoperability, reusability). As a Consortium of infectious disease researchers from 15 Centers, we aim to adopt open science practices to promote transparency, encourage reproducibility, and accelerate research advances through data reuse. To improve FAIRness of our datasets and computational tools, we evaluated metadata standards across established biomedical data repositories. The vast majority do not adhere to a single standard, such as Schema.org, which is widely-adopted by generalist repositories. Consequently, datasets in these repositories are not findable in aggregation projects like Google Dataset Search. We alleviated this gap by creating a reusable metadata schema based on Schema.org and catalogued nearly 400 datasets and computational tools we collected. The approach is easily reusable to create schemas interoperable with community standards, but customized to a particular context. Our approach enabled data discovery, increased the reusability of datasets from a large research consortium, and accelerated research. Lastly, we discuss ongoing challenges with FAIRness beyond discoverability., (© 2023. The Author(s).)

Objectives. To compare survival by gender and race among transgender and cisgender people enrolled in private insurance in the United States between 2011 and 2019. Methods. We examined Optum's Clinformatics Data Mart Database. We identified transgender enrollees using claims related to gender-affirming care. Our analytic sample included those we identified as transgender and a 10% random sample of cisgender enrollees. We limited our sample to those 18 years or older who were non-Hispanic Black or White. We identified 18 033 transgender and more than 4 million cisgender enrollees. We fit Kaplan-Meier survival curves and calculated standardized mortality ratios while adjusting for census region. Results. Black transfeminine and nonbinary people assigned male sex at birth were 2.73 times more likely to die than other Black transgender people and 2.38 and 3.34 times more likely than Black cisgender men and women, respectively; similar results were found when White transfeminine and nonbinary people assigned male sex at birth were compared with White cisgender cohorts. Conclusions. Our findings highlight glaring inequities in mortality risks among Black transfeminine and nonbinary people assigned male sex at birth and underscore the need to monitor mortality risks in transgender populations and address the social conditions that increase these risks. ( Am J Public Health . 2022;112(10):1507-1514. https://doi.org/10.2105/AJPH.2022.306963).

Lassa fever is a severe viral hemorrhagic fever caused by a zoonotic virus that repeatedly spills over to humans from its rodent reservoirs. It is currently not known how climate and land use changes could affect the endemic area of this virus, currently limited to parts of West Africa. By exploring the environmental data associated with virus occurrence using ecological niche modelling, we show how temperature, precipitation and the presence of pastures determine ecological suitability for virus circulation. Based on projections of climate, land use, and population changes, we find that regions in Central and East Africa will likely become suitable for Lassa virus over the next decades and estimate that the total population living in ecological conditions that are suitable for Lassa virus circulation may drastically increase by 2070. By analysing geotagged viral genomes using spatially-explicit phylogeography and simulating virus dispersal, we find that in the event of Lassa virus being introduced into a new suitable region, its spread might remain spatially limited over the first decades., (© 2022. The Author(s).)

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO mice. Mertk KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of Mertk alone is not sufficient for retinal degeneration. The widely used Mertk KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the Mertk paralog Tyro3 . Retinal degeneration manifests only when the function of Tyro3 is concomitantly lost. Furthermore, Mertk KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in Mertk KO mice is not, however, phenocopied by the loss of Mertk alone. Neither Tyro3 nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits., Competing Interests: YA, MM, MA, LH, JN, EA, XL, YK, WP, MB, SF, AI, AL No competing interests declared, LH, DA, TK is affiliated with Celldex Therapeutics. The author has no financial interests to declare, CR Senior editor, eLife, SG has received grant support from Mirati Therapeutics, (© 2022, Akalu, Mercau et al.)

Regional connectivity and land travel have been identified as important drivers of SARS-CoV-2 transmission. However, the generalizability of this finding is understudied outside of well-sampled, highly connected regions. In this study, we investigated the relative contributions of regional and intercontinental connectivity to the source-sink dynamics of SARS-CoV-2 for Jordan and the Middle East. By integrating genomic, epidemiological and travel data we show that the source of introductions into Jordan was dynamic across 2020, shifting from intercontinental seeding in the early pandemic to more regional seeding for the travel restrictions period. We show that land travel, particularly freight transport, drove introduction risk during the travel restrictions period. High regional connectivity and land travel also drove Jordan's export risk. Our findings emphasize regional connectedness and land travel as drivers of transmission in the Middle East., (© 2022. The Author(s).)

Heart failure (HF) is a syndrome associated with high mortality and morbidity. HF patients tend to be at a high risk of poor clinical and psychosocial outcomes. This study aimed to capture patients' and carers perspectives of HF, the impact on their health reported QoL, and the factors associated with their poor health outcomes. To explore HF patients' and carers' views on their QoL since diagnosis. This study used a cross-sectional, qualitative design with semi-structured interviews conducted with participating patients and carers. Thirteen adults (> 18 years) with HF and 21 carers were interviewed over the telephone, following a semi-structured interview schedule. Interviews were transcribed verbatim and analysed using inductive thematic analysis. Three main themes were identified, with an overarching theme . Themes included impact on patients' lifestyle including diet, smoking and inability to part-take in social activities, adjusting to HF diagnosis and co-morbidity management, and psychological/mental health issues such as anxiety and depression . Patients with HF are at high-risk of various issues which can negatively impact their QoL. Additionally, Carers play a vital role in the management of HF patients. Effective patient centred care and better communication between patients, carers and healthcare professionals is vital in HF management.

Background: Medical gender affirmation (i.e., hormone use) is one-way transgender (trans) people affirm their gender and has been associated with health benefits. However, trans people face stigmatization when accessing gender-affirming healthcare, which leads some to use non-prescribed hormones (NPHs) that increase their risk for poor health., Purpose: We examined whether healthcare policy stigma, as measured by state-level trans-specific policies, was associated with NPHs use and tested mediational paths that might explain these associations. Because stigmatizing healthcare policies prevent trans people from participation in healthcare systems and allow for discrimination by healthcare providers, we hypothesized that healthcare policy stigma would be associated with NPHs use by operating through three main pathways: skipping care due to anticipated stigma in healthcare settings, skipping care due to cost, and being uninsured., Methods: We conducted analyses using data from the 2015 U.S. Transgender Survey. The analytic sample included trans adults using hormones (N = 11,994). We fit a multinomial structural equation model to examine associations., Results: Among trans adults using hormones, we found that healthcare policy stigma was positively associated with NPHs use and operated through insurance coverage and anticipating stigma in healthcare settings. The effect sizes on key predictor variables varied significantly between those who use supplemental NPHs and those who only use NPHs suggesting the need to treat NPHs use as distinct from those who use supplemental NPHs., Conclusions: Our work highlights the importance of healthcare policy stigma in understanding health inequities among trans people in the USA, specifically NPHs use., (Published by Oxford University Press on behalf of the Society of Behavioral Medicine 2021.)

Few studies have analyzed mortality rates among transgender (trans) populations in the United States and compared them to the rates of non-trans populations. Using private insurance data from 2011 to 2019, we estimated age-specific all-cause mortality rates among a subset of trans people enrolled in private insurance and compared them to a 10% randomly selected non-trans cohort. Overall, we found that trans people were nearly twice as likely to die over the period as their non-trans counterparts. When stratifying by gender, we found key disparities within trans populations, with people on the trans feminine to nonbinary spectrum being at the greatest risk of mortality compared to non-trans males and females. While we found that people on the trans masculine to nonbinary spectrum were at a similar risk of overall mortality compared to non-trans females, their overall mortality rate was statistically smaller than that of non-trans males. These findings provide evidence that some trans and non-trans populations experience substantially different mortality conditions across the life course and necessitate further study., (Copyright © 2022 The Authors.)

Purpose: Few studies have examined specific cognitive and behavioural responses to symptoms, which may impact health-related outcomes, in conjunction with illness representations, as outlined by the Common-Sense-Model. Patients with atrial fibrillation (AF) report poor quality-of-life (QoL) and high distress. This cross-sectional study investigated patterns/clusters of cognitive and behavioural responses to illness, and illness perceptions, and relationships with QoL, depression and anxiety., Methods: AF patients (N = 198) recruited at cardiology clinics completed the AF-Revised Illness Perception Questionnaire, Atrial-Fibrillation-Effect-on-Quality-of-Life Questionnaire, Patient Health Questionnaire-8 and Generalized Anxiety Disorder Questionnaire. Cluster analysis used Ward's and K-means methods. Hierarchical regressions examined relationships between clusters with QoL, depression and anxiety., Results: Two clusters of cognitive and behavioural responses to symptoms were outlined; (1) 'high avoidance'; (2) 'low symptom-focussing'. Patients in Cluster 1 had lower QoL (M = 40.36, SD = 18.40), greater symptoms of depression (M = 7.20, SD = 5.71) and greater symptoms of anxiety (M = 5.70, SD = 5.90) compared to patients in Cluster 2 who had higher QoL (M = 59.03, SD = 20.12), fewer symptoms of depression (M = 3.53, SD = 3.56) and fewer symptoms of anxiety (M = 2.56, SD = 3.56). Two illness representation clusters were outlined; (1) 'high coherence and treatment control', (2) 'negative illness and emotional representations'. Patients in Cluster 2 had significantly lower QoL (M = 46.57, SD = 19.94), greater symptoms of depression (M = 6.12, SD = 5.31) and greater symptoms of anxiety (M = 4.70, SD = 5.27), compared with patients in Cluster 1 who had higher QoL (M = 61.52, SD = 21.38), fewer symptoms of depression (M = 2.85, SD = 2.97) and fewer symptoms of anxiety (M = 2.16, SD = 3.63). Overall, clusters of cognitive and behavioural responses to symptoms, and illness perceptions significantly explained between 14 and 29% of the variance in QoL, depression and anxiety., Conclusion: Patterns of cognitive and behavioural responses to symptoms, and illness perceptions are important correlates of health-related outcomes in AF patients., (© 2021. The Author(s).)

Purpose: Since May 2021, numerous state legislatures in the United States have introduced bills to restrict the participation of transgender and gender diverse (trans) youth in gender-segregated sports in a manner consistent with their gender identity. The purpose of this study was to understand how medical providers of pediatric gender-affirming care for trans youth view these legislative efforts and how they believe these bills will affect their practice and patients. Methods: In March 2021, we recruited participants using listservs known to be frequented by providers of gender-affirming medical care to complete a survey about bills that restrict trans youths' participation in sex-segregated sports. Eligible participants were over the age of 18, currently worked as a physician, nurse practitioner, or physician's assistant, and provided gender-affirming care to trans youth under the age of 18 in the United States. Results: We analyzed the responses of 103 providers from all 50 states and the District of Columbia. Most participants identified as White (77%), cisgender women (70%), and specialized in pediatric care (52%). The most salient theme, described by nearly all participants, was that legislation banning trans youth from sports participation would lead to worsening discrimination and stigmatization. Other themes included worsening mental and physical health of trans youth, forced changes to clinical practice, politicization of trans youth, and efforts required to stop these bills. Conclusions: Providers of gender-affirming care in this study overwhelmingly opposed legislation that bans trans youth from sports participation citing the severe consequences to the well-being of trans youth. More research is needed to examine stakeholder's opinions regarding legislation that does not ban but otherwise restricts sports participation by trans youth.

Objectives: Self-compassion and psychological flexibility appear to benefit wellbeing and quality of life (QoL) in the general population and in people with long-term conditions like Type 2 Diabetes (T2D). However, both variables share similarities and their unique roles in relation to distress and QoL in people with diabetes over time are not clear., Design: This was a longitudinal study with online assessments of self-compassion, psychological inflexibility, distress (depression, anxiety, diabetes-distress), and QoL at baseline (T1) and six (T2) and 12 months (T3)., Methods: In total, 173 UK adults with T2D completed baseline questionnaires; T2 and T3 follow-ups were completed by 82 and 52 participants, respectively. Correlations were conducted to understand the relationships between variables at each time point. Hierarchical regressions were conducted to understand the unique predictive role of baseline self-compassion and psychological inflexibility in relation to distress and QoL at T2 and T3, controlling for age and baseline distress and QoL., Results: There were large significant negative correlations between self-compassion and psychological inflexibility (r > -0.50), and both had significant large correlations with distress (r > -0.50) but not QoL across time points. Regressions indicated that psychological inflexibility uniquely predicted depression (T2) and anxiety symptoms (T2 and T3) and QoL (T3). Self-compassion did not uniquely predict any of the outcomes., Conclusions: Psychological inflexibility may play an important role in distress in T2D, but prospective studies with larger samples are needed to replicate these findings. Given the overlap between psychological inflexibility and self-compassion, treatments targeting either variable may be useful., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The number of e-health interventions developed for breast cancer survivors continues to increase. However, issues with engagement and retention are common. This study aimed to explore e-health literacy rates and access to smartphones and tablets in a large sample of breast cancer survivors., Methods: In study 1, women were recruited from outpatient breast clinics across England and Wales. Eligible women were asked to complete a questionnaire pack to assess their access to devices and their e-health literacy. Multiple regression analyses were run to assess the relationship between technology access and e-health literacy with sociodemographic variables such as age, social deprivation, and education. Study 2 presents a smaller sample recruited through social media who answered a questionnaire relating to use of mobile devices and e-health, and apps., Results: Two thousand nine women participated in the study. Seventy-one percent had access to a smartphone, 54% had access to a tablet, and 20% did not have access to either device. Multiple logistic regressions showed that women who were younger, had higher levels of education, and who were from less deprived areas were more likely to have access to either device. Poorer e-health literacy was associated with being older, having less education, and not having access to a mobile device., Conclusions: Whilst the results show relatively widespread access to mobile devices, there is evidence of a digital divide across some groups. Online interventions should be developed with consideration of individuals who are less e-health-literate and less technologically adept in order to increase the likelihood of engagement., (© 2021. The Author(s).)

Objectives: To evaluate the efficacy of EXOGEN in achieving union and common pitfalls in its use within the Manchester Foundation Trust (MFT) and Salford Royal Foundation Trust (SRFT)., Method: Patients receiving EXOGEN therapy between 01/01/2017 and 31/12/2019 at hospitals within MFT and SRFT were identified using EXOGEN logbooks and hospital IT systems. An equal number of patients were included from both sites. Data were retrospectively collected from clinical documents detailing clinical presentation comorbidities, and radiographic images, determining the radiological union post EXOGEN therapy. In addition, local practices were observed and compared to EXOGEN's standardized guidance for clinicians., Results: Fifty-eight patients were included in the primary review, with 9 subsequently excluded based on insufficient clinical data. 47% of patients achieved radiological union following completion of EXOGEN therapy. Outcomes of the 23 patients with persistent non-union were as follows - 18 were referred for revision surgery, 5 were prescribed further EXOGEN therapy, 2 refused or were unfit for further intervention, and 1 did not have a plan documented. No significant baseline differences were present in both outcome groups. However, at MFT and SRFT, rates of union with EXOGEN are below that previously published in the literature., Conclusion: EXOGEN has proven successful in facilitating union in established cases of non-union without the risk and cost associated with revision surgery. Centre outcome differences may be explained by failure to educate clinicians and patients on the correct use of the EXOGEN device, failure to standardize follow-up or monitor compliance, and must be addressed to improve current services., (© The Authors, published by EDP Sciences, 2022.)

Background: Ankle-foot and knee components are important determinants of mobility for individuals with transfemoral amputation. Individually, advanced ankle-foot and knee components have been shown to benefit mobility in this group of people. However, it is not clear what effect a variety of combinations of ankle-foot and knee components have on mobility test performance., Objectives: To assess whether outcomes from mobility tests in people with unilateral transfemoral amputation are influenced by varying combinations of ankle-foot and knee components., Study Designs: Repeated measures., Methods: Nine adults with unilateral transfemoral amputation completed the two-minute walk test, the timed up-and-go test, the L-test, and a custom locomotion course in four randomized prosthetic conditions. These conditions were each a combination of an ankle-foot component (rigid, nonarticulating [RIG] or hydraulically articulating [HYD]) and a knee component (non-microprocessor-controlled [NMPK] or microprocessor-controlled [MPK]). The test-retest reliability and concurrent validity of the custom locomotion course were also established., Results: The best performance in all mobility tests was associated with the MPK + HYD combination, followed by the MPK + RIG, NMPK + HYD, and NMPK + RIG combinations. This effect was statistically significant for the two-minute walk test (P = 0.01, = 0.36) and on threshold for the L-test (P = 0.05, = 0.36), but not statistically significant for the locomotion course (P = 0.07, = 0.38) or the timed up-and-go test (P = 0.12, = 0.22). Locomotion course performance had good to excellent test-retest reliability and strong concurrent validity., Conclusion: Using a combination of a HYD ankle-foot and a MPK knee resulted in the highest performance in mobility tests. This was observed in contrast to combinations of prosthetic components that included a rigid ankle-foot component and/or a NMPK knee component., (Copyright © 2021 International Society for Prosthetics and Orthotics.)

Purpose: The standards of care for transgender and gender diverse youth (TGDY) experiencing gender dysphoria are well-established and include gender-affirming medical interventions. As of July 2021, 22 states have introduced or passed legislation that bans the provision of gender-affirming medical care to anyone under the age of 18 even with parent or guardian consent. The purpose of this study is to understand what providers who deliver gender-affirming medical care to TGDY think about this legislation., Methods: In March 2021, we recruited participants via listservs known to be frequented by providers of gender-affirming medical care. Eligible participants were over the age of 18, currently working as a physician, nurse practitioner, or physician's assistant, and providing gender-affirming care to TGDY under the age of 18 in the U.S., Results: We analyzed the responses of 103 providers from all 50 states and DC. Most participants identified as white (77%), cisgender women (70%), specializing in pediatric care (52%). The most salient theme, described by nearly all participants, was the fear that legislation banning gender-affirming care would lead to worsening mental health including increased risk for suicides among TGDY. Other themes included the politicization of medical care, legislation that defies the current standards of care for TGDY, worsening discrimination toward TGDY, and adverse effects on the providers., Conclusions: Providers of gender-affirming care overwhelmingly opposed legislation that bans gender-affirming care for TGDY citing the severe consequences to the health and well-being of TGDY along with the need to practice evidence-based medicine without fear., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Innovations in virtual reality (VR) technologies have improved the adaptability of its use in therapeutic settings, and VR has shown to be a promising treatment for fear of medical procedures, with research increasing in this area in recent years., Purpose: This review aims to collate evidence for the impact of VR on fear of medical procedures., Methods: CENTRAL (Cochrane), MEDLINE, EMBASE, and PsychINFO databases were searched up to October 2020. A mix of experimental and case-control studies were included for review, which evaluated the effectiveness of VR for fear, anxiety, and pain of medical procedures for people with needle phobia, dental phobia, claustrophobia of medical scans, and burn wound care anxiety. Risk of bias (RoB) was assessed by Cochrane and ROBINS-I tools., Results: Twenty-eight studies were selected. Some studies included mixed participant groups of young people adults. The interventions varied, with VR used for distraction, hypnosis, or exposure. These were shown to be effective for reducing fear of medical procedures. However, effectiveness for blood-injection-injury phobias and burn wound care patients was unclear., Conclusions: Evidence on the effectiveness of VR suggests that it does decrease fear of medical procedures in some situations. However, the RoB assessment illustrated a poor quality of studies across those included in this review, limiting the ability to draw firm general conclusions from the study findings. There is a need for further research exploring the use of VR technologies in the management of anxiety in physical health care settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana had limited diversity compared to other U.S. states and that one introduction of SARS-CoV-2 led to almost all of the early transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras, and the festival dramatically accelerated transmission. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate epidemics., Competing Interests: Declaration of interests M.A.S. reports grants from the National Institutes of Health, European Research Council, and Wellcome Trust during the conduct of this research and grants and contracts from the Bill & Melinda Gates Foundation, Janssen Research and Development, Private Health Management, IQVIA, and the U.S. Department of Veterans Affairs outside the submitted work. S.L.L., R.R., and D.J.N. are employed by BioInfoexperts LLC. R.F.G. reports grants from the National Institutes of Health, the Coalition for Epidemic Preparedness Innovations, the Burroughs Wellcome Fund, the Wellcome Trust, the Center for Disease Prevention and Control, and the European & Developing Countries Clinical Trials Partnership. He is the co-founder and Chief Scientific Advisor of Zalgen Labs, a biotechnology company developing countermeasures to emerging viruses, including SARS-CoV-2. K.G.A. has received consulting fees and compensated expert testimony on SARS-CoV-2 and the COVID-19 pandemic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Up to 50% of women prescribed tamoxifen do not take it as prescribed for the full duration, which increases risk of recurrence and mortality. The current paper describes the development of a self-management intervention aiming to improve adherence in breast cancer survivors taking tamoxifen., Methods: The intervention was developed following an Intervention Mapping approach. The content of the intervention was determined by theories of health behaviour and empirical evidence. Development was an iterative process involving input from expert researchers, clinicians and patient representatives., Results: The intervention was designed to improve both intentional and unintentional non-adherence. Key features included modifying unhelpful illness and treatment beliefs, improving confidence for coping with side effects and developing strategies for remembering to take tamoxifen., Conclusion: Intervention Mapping proved a useful tool for developing an intervention which is grounded in theory and empirical evidence. The intervention has the potential to improve adherence in breast cancer survivors but needs to be trialled before the effectiveness of the intervention can be determined.

Removal of apoptotic cells by phagocytes (also called efferocytosis) is a crucial process for tissue homeostasis. Professional phagocytes express a plethora of surface receptors enabling them to sense and engulf apoptotic cells, thus avoiding persistence of dead cells and cellular debris and their consequent effects. Dysregulation of efferocytosis is thought to lead to secondary necrosis and associated inflammation and immune activation. Efferocytosis in primarily murine macrophages and dendritic cells has been shown to require TAM RTKs, with MERTK and AXL being critical for clearance of apoptotic cells. The functional role of human orthologs, especially the exact contribution of each individual receptor is less well studied. Here we show that human macrophages differentiated in vitro from iPSC-derived precursor cells express both AXL and MERTK and engulf apoptotic cells. TAM RTK agonism by the natural ligand growth-arrest specific 6 (GAS6) significantly enhanced such efferocytosis. Using a newly-developed mouse model of kinase-dead MERTK, we demonstrate that MERTK kinase activity is essential for efferocytosis in peritoneal macrophages in vivo. Moreover, human iPSC-derived macrophages treated in vitro with blocking antibodies or small molecule inhibitors recapitulated this observation. Hence, our results highlight a conserved MERTK function between mice and humans, and the critical role of its kinase activity in homeostatic efferocytosis.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality., Competing Interests: Declaration of interests N.L.W., A.B., E.T.C., K.M.S.B., S.W., C.R.-G., E. Sandoval, T.C., X.W., J.N., J.M.R., G.L., D.W., D.B., M.L., M.I., S.J., J.T.L., and W.L. are employees of Helix. K. Gietzen, B.S., J.A., K.H., J.L., E.d.F., and P.G.F. are employees of Illumina. J.N., C.R.-G., and M.L. own stock in ILMN. K.G.A. has received consulting fees for advising on SARS-CoV-2, variants, and the COVID-19 pandemic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Self-compassion, defined as a mindful way of coping with pain and suffering by showing kindness, care, and concern towards the self, may improve psychological adjustment in people living with a chronic physical health condition (CPHC). Various studies illustrate that self-compassion is associated with positive outcomes in general. The aim of this systematic review is to establish the effect of compassion-related therapies on self-compassion specifically in people with CPHCs. Secondary aims are to (a) establish the effect on other psychological and physiological outcomes and (b) explore the relative effectiveness of different therapy types among those identified. Cochrane, Embase, Medline, PsycINFO, and CINAHL databases were searched using "compassion" AND "chronic disease" AND "psychological outcomes" and their synonyms, from 2004 to March 2019. Eligible studies had an experimental design using a self-compassion scale with an adult population. Risk of bias (RoB) was assessed using the Cochrane RoB tool. Effect sizes were calculated for study outcomes. Fifteen studies, including a total of 1,190 participants, 7 different CPHCs, and 11 types of therapies, were included in the review. Nearly all included therapies significantly increased self-compassion with medium to large effect sizes, and reported positive outcomes, such as decreased depression. None of the therapy types appeared clearly superior to the others. Findings from this review show that included therapies increased self-compassion and improved various outcomes, which may represent clinically significant benefits for patients. However, there is a need to further understand how self-compassion exerts its benefits and determine the best methods to increase self-compassion., (Copyright © 2020. Published by Elsevier Ltd.)

Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider ( a ) the varying contexts during which different cell death modalities are observed, ( b ) the nature of the information that can be passed on by cell corpses, and ( c ) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.