Physical activity and exercise have emerged as potential methods to improve brain health among older adults. However, there are currently no physical activity guidelines aimed at improving cognitive function, and the mechanisms underlying these cognitive benefits are poorly understood. The purpose of this narrative review is to present the current evidence regarding the effects of physical activity and exercise on cognition in older adults without cognitive impairment, identify potential mechanisms underlying these effects, and make recommendations for exercise prescription to enhance cognitive performance. The review begins with a summary of evidence of the effect of chronic physical activity and exercise on cognition. Attention then turns to four main biological mechanisms that appear to underlie exercise-induced cognitive improvement, including the upregulation of growth factors and neuroplasticity, inhibition of inflammatory biomarker production, improved vascular function, and hypothalamic-pituitary-adrenal axis regulation. The last section provides an overview of exercise parameters known to optimize cognition in older adults, such as exercise type, frequency, intensity, session duration, and exercise program duration. In 2017, the number of people aged 60 years or over was 962 million worldwide; this figure is expected to reach nearly 2.1 billion by the year 2050  and can Physical activity and exercise have emerged as potential methods to improve brain health among older adults. However, there are currently no physical activity guidelines aimed at improving cognitive function, and the mechanisms underlying these cognitive benefits are poorly understood. Thus, the main purpose of this narrative review is to present the current evidence regarding the effects of chronic physical activity and exercise on cognition, identify potential mechanisms underlying these effects, and make recommendations for exercise prescription to enhance cognitive performance. Our focus is mainly on older adults over 50 years of age without cognitive impairment. The review begins with a summary of evidence regarding the association between exercise and cognition, adding to older literature reviews such as those by Kirk-Sanchez and McGough and Bherer et al. , 10. AttEvidence from prospective and cross-sectional studies suggests that physically active persons have a significantly reduced risk of cognitive impairment and dementia. Hamer and Chida  conducteThere is evidence emerging from randomized controlled trials (RCTs) and meta-analyses to suggest that exercise interventions can improve cognition among older adults. The most common experimental intervention in the meta-analyses evaluating the impact of exercise on cognition is aerobic exercise (AE), followed by resistance exercise (RE), a combination of AE and RE, and mind-body exercise . The meta-analyses are summarized in Meta-analytic evidence supports the positive effects of AE and RE on cognition among older adults. Colcombe and Kramer determined that there were positive effects of AE and combined (AE and RE) training on cognition in their meta-analysis of 18 RCTs in sedentary older adults . ScherdeThere is also evidence that mind-body exercise can have a positive effect on cognition among older adults. Wu et al.  discoverIn contrast with the those findings, Sanders and colleagues  conducteFurther conflicting evidence comes from a meta-analysis by Etnier and colleagues  who deteDespite these conflicting reports, 12 of the 13 meta-analyses we reviewed found a beneficial effect of exercise on at least one aspect of cognition albeit some studies have determined only a modest effect. Taken together, this evidence suggests that exercise may have beneficial effects on cognition among older adults. In the RCT exercise literature, there is a lack of standardized reporting of exercise interventions , which makes it challenging to determine what constitutes an effective intervention. Future research should address methodological concerns and investigate the optimal exercise dose for improving cognition among older adults. The next section of this review addresses biological mechanisms that may explain exercise-induced improvements in cognition. With age, the gray and white matter regions of the human brain begin to atrophy, particularly in the prefrontal cortex and the hippocampus . AccordiNeuroplasticity, the brain's ability to create and reorganize synaptic connections, appears to be an important mechanism for improved cognition with exercise among adults of all ages. An RCT conducted by Colcombe et al.  using fuHigh-level evidence indicates that there is a link between exercise interventions and upregulation of growth factors in older adults. A meta-analysis by Dinoff et al. of 29 studies involving AE and RE in 910 healthy adults of all ages revealed an overall increase in BDNF levels following exercise interventions . The autThere is some evidence that exercise type affects upregulation of specific growth factors. Dinoff et al.'s meta-analysis of AE and RE interventions in healthy adults concluded that AE, but not RE, had a significant effect on peripheral BDNF levels . As wellWhile some growth factors appear to increase with exercise, less is known about how this association impacts cognitive performance. A 2014 RCT of 49 older sedentary women revealed that a 16-week program of twice-weekly aerobic, resistance, and motor exercises elevated serum BDNF levels and improved verbal fluency, processing speed, attention, and mental switching performance in exercisers compared to waitlist controls . ImportaOther RCTs have found contrasting results regarding growth factors and exercise. A study with 40 older adults assigned to an AE intervention or control group revealed that serum BDNF, IGF-1, and VEGF levels were not significantly upregulated with exercise and there were no between-group differences in immediate or delayed recall, but IGF-1 levels were related to hippocampal volume changes, and changes in IGF-I were associated with delayed recall performance . An RCT Clearly, there are significant discrepancies regarding growth factors as a putative mechanism for improving cognitive performance in older adults. There are known problems with the measurement of growth factors in humans, which could help to explain these contrasting results. For example, Knaepen et al. identified significant blood sampling and biochemical analysis concerns regarding measurement of BDNF levels, including clotting time, temperature storage, and a lack of corrected BDNF levels for the shift in plasma volume with exercise . SimilarAlthough there is a considerable discrepancy in the literature, it appears that BDNF levels are increased following AE interventions in people of all ages. Less is known regarding the upregulation of growth factors as a putative mechanism for improved cognitive performance in older adults. High-quality RCTs and meta-analyses that address measurement issues are needed to determine both the effect of exercise on growth factors and the relationship between exercise-induced increases in growth factors and cognitive performance in older adults.In aging adults, microglia and cytokines stimulate the production of proinflammatory markers, which promote changes in blood vessel permeability, endothelial cell function, and microvascular structure , resultiAs people age, proinflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6 and -1 beta, and tumor necrosis factor alpha  increase  and are There is encouraging evidence from a recent systematic review of 13 RCTs that healthy sedentary adults of all ages who participate in AE and RE can reduce inflammatory biomarkers . StrongeSome promising evidence has emerged indicating that aerobic exercise in particular can reduce inflammatory markers in older adults. While there is evidence that inflammation can have a direct impact on cognition, little is known regarding the mediating role of exercise-induced changes in inflammation on cognitive performance in older adults. Future studies could further investigate the mechanisms underlying the effect of exercise on inflammatory markers and cognition.Cardiovascular and cerebrovascular disease risk factors such as hypertension, dyslipidemia, diabetes, and hyperinsulinemia increase the risk of cognitive impairment and dementia , 67. An The positive effects of AE on cardiovascular –76 and cSome investigators have posited that there may be a link between improved cardiovascular and cerebrovascular function and cognitive performance. Vidoni et al. determined that changes in fitness levels mediated cognitive improvements in older adults who participated in an AE intervention . Brown aDespite the evidence that improved cardiovascular fitness is associated with improved cognition, two meta-analytic reviews have failed to support cardiovascular fitness as a moderator of exercise-induced cognitive gains in older adults , 88. FurThere is no question that exercise has beneficial effects on cardiovascular and cerebrovascular function among older adults. Although the cardiovascular hypothesis for exercise-induced changes in cognitive performance in older adults is intuitive, the evidence from meta-analyses and RCTs indicates that this hypothesis alone is unable to explain improvements in cognition with exercise. Is it possible, however, that older adults can experience cognitive benefits with exercise without changes in aerobic fitness. Future research should further elucidate these relationships in order to develop recommendations regarding exercise dose.Another mechanism by which exercise could improve cognitive function is via the HPA axis. As individuals age, their ability to adapt and cope with stress diminishes . ChronicExercise can downgrade the stress response in individuals of all ages by regulating the release of catecholamines and cortisol . During There is evidence that mind-body exercise has a downregulating effect on the sympathetic nervous system and the HPA axis . A systeFour meta-analyses have found beneficial effects of mind-body exercise on cognition among older adults , 26, 28.Mind-body exercise is an effective intervention for improving cognition among older adults, possibly by reducing stress levels and restoring parasympathetic-sympathetic nervous system balance. Though this evidence is encouraging, this topic has only begun to be studied. Mediational RCTs and meta-analyses examining these outcomes are needed to examine the relationship between mind-body exercise, the HPA axis, and cognitive function among older adults.exercise type, most investigations have focused on the effectiveness of AE [Currently, there are no exercise guidelines that specifically target cognitive gains in older adults, but clues can be gleaned from the literature on exercise-induced cognitive change. Factors related to an exercise program—exercise type, intensity, session duration and frequency, and program duration—may determine the extent to which exercise impacts cognition. In terms of ss of AE , 23, 24 ss of AE , 20, 21 ss of AE , 26, 28 Some trials have reported beneficial effects of combined AE and RE exercise , 64, 109frequency also appears to be an important predictor of cognition. Northey et al. performed a moderator analysis within their meta-analysis and determined that more frequent (5–7 sessions per week) exercise of all types was more beneficial for cognition than less frequent (≤2) or moderately-frequent (3–4) exercise in older adults [Exercise r adults . These fr adults . Howeverr adults . As suchintensity may be a significant predictor of cognitive benefit [Exercise  benefit , 110. In benefit . In cont benefit , 27, 89. benefit , 26, 28  benefit . As suchexercise session duration may be an important predictor of cognition among older adults [Longitudinal studies have reported that r adults , 15. Thir adults . An RCT r adults . A dose r adults . We concexercise program duration, some investigators argue that cognitive improvements may not be apparent until 6 months [In relation to 6 months  or a yea6 months , while o6 months , 12 [84,6 months , or 16 w6 months . A 2018 6 months . Further6 months . In cont6 months , while A6 months . It is iThe present paper has provided a review of the literature regarding the effect of exercise on cognition and an overview of the likely biological mechanisms underlying this interaction. The evidence indicates that physical activity, notably multimodal and mind-body exercise, offers benefits to cognition in older individuals. The mechanisms underlying these benefits are numerous and overlapping. However, there are many gaps in the literature, such as a lack of high-quality studies evaluating moderators of cognitive function among older adults. Future research using is needed to determine optimal exercise parameters and exercise subtypes aimed at improving cognition in this population.


Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target. We discuss the development and testing of a bispecific LTT targeting EGFR and urokinase-type plasminogen activator receptor (uPAR) as two attractive targets implicated in tumor growth and in the regulation of the tumor microvasculature in solid tumors. In vitro and mouse xenograft studies have shown that EGFR-targeted bispecific angiotoxin (eBAT) is effective against human solid tumors. Canine studies have shown that eBAT is both safe and effective against canine hemangiosarcoma, which is physiologically similar to human angiosarcoma. Finding the appropriate dosing strategy and sequencing of eBAT administration, in combination with other therapeutics, are among important factors for future directions. Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may have a role in reducing toxicity in comparative oncologic trials in dogs. Pseudomonas aeruginosa exotoxin A (PE) or diphtheria toxin (DT), both of which have similar mechanisms of cytotoxicity [Immunotoxins are mostly defined as bioengineered hybrid molecules consisting of an immune system ligand , linked to a potent toxin, designed to specifically kill designated target cells . In thistoxicity ,3. The ctoxicity . It has toxicity ,5. LTTs toxicity . Advancetoxicity .Pseudomonas exotoxin as a toxin. Moxe is a chimeric molecule composed of a single-chain fragment variable (scFv) antibody moiety, which recognizes the CD22 receptor on B cells, fused with truncated PE, which triggers cell death [Monospecific immunotoxins have successfully reached the market. Though currently discontinued, denileukin diftitox (Ontak) received FDA approval for the treatment of cutaneous T cell lymphoma in 1999 . Ontak wll death . Moxe wall death .The binding moiety of a targeted toxin binds to determinants expressed on cancer cells and/or the tumor microenvironment and is largely responsible for its specificity. Investigators have reported certain disadvantages in selecting ligands or antibodies that bind a single target determinant. For example, targeting CD19 in B cell malignancies with CD19-directed blinatumomab resulted in the downregulation of CD19 in clinical studies . A potenMost successful LTT clinical applications relate to targeting liquid tumors. A sizable challenge will be successfully targeting solid tumors. Tumor antigens can be highly evasive due to modulation or shedding, and solid tumors have a highly developed vasculature that promotes growth. In this instance, bispecific targeting may be even more important. EGFR and ErbB-2 are prominent cancer markers. In early studies, investigators developed bispecific LTTs to target solid tumors . scFv2 is a well-established marker that serves as a valuable target for antibodies, EGFR inhibitors, and targeted toxins. EGFR targeting is advantageous because it is a viable target for multiple tumors with diverse histological and developmental origins, including carcinomas, sarcomas, and brain tumors . EGFR inThough less toxic than conventional chemotherapies, EGFR-targeting therapeutics still have notable adverse effects. The ubiquity of EGFR expression in both tumors and healthy tissue renders off-target toxicity an issue with anti-EGFR therapeutics. Though EGFR can be expressed in mutant form or overexpressed in tumors of the mammary glands, lungs, pancreas, intestines, and central nervous system, EGFR can also be found in both healthy tissue and tumors in the wild type form at normal levels . MoreoveSolid tumors require new blood vessels to grow . VasculaUrokinase plasminogen activating receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-linked receptor that binds urokinase in order to induce the proteolytic reorganization of tissue via phospholipase-C. uPAR is a key receptor involved in cancer signaling pathways that promotes tumor growth and metastasis . ThroughIn order to take collective advantage of vascular targeting, EGFR targeting, and simultaneous bispecific targeting, we fashioned a hybrid molecule consisting of human EGF, human ATF, and truncated PE . To enhaIn the following sections, we review some of our work detailing how eBAT works against various cancers both in vitro and in vivo. eBAT was first reported by our group as being active against human glioblastoma, a tumor with historically poor treatment prognosis and high EGFR and uPAR expression. eBAT was highly active against human glioblastoma cell lines in vitro, including the U87 and U118 cell lines. Based on the aggressive tumorgenicity of U87 in rat glioma models, U87 was transfected with a luciferase gene for the purpose of real-time bioluminescent imaging . From ouU87 proved more tumorigenic in nude rats than in nude mice. Thus, rats were chosen for their increased size, and intracranial tumors were established using U87 cells expressing the luciferase reporter gene (U87-luc). Treatment was administered via a catheter and convection-enhanced delivery (CED). Microinfusion pumps with a hollow fiber (HF) catheter delivered the drug to the same coordinates as the tumor. Treatment resulted in significant tumor reductions in rat brain tumors, with some rats surviving tumor-free for up to 130 days upon the conclusion of treatment . Both ineBAT was studied in two carcinoma models using the UMSCC-11B human head and neck squamous cell carcinoma (HNSCC) cell line and the triple-negative breast cancer cell line MBA-MB-231 ,39. FlowA recent area of study for eBAT is in human sarcomas, a group of rare and aggressive tumors that originate from the mesenchyme . ConsistCancer stem cells (CSCs) represent the progenitor fraction of cancer cells that are chemotherapy and radiation resistant. Tumor spheroid assays are one way of studying CSCs in vitro. Studies by Pilbeam et al. showed that eBAT effectively reduced the number of cells in non-adherent spheroid cancer cell cultures of human RH30 sarcoma cells . This haRecently, eBAT was found to be effective against adult rhabdomyosarcoma and human osteosarcoma in vitro . Flow cyHaving established its efficacy in small animal rodent models, we sought to validate the drug’s usefulness in large animals. We investigated the hypothesis of whether or not bispecific targeting would benefit the efficacy of targeted toxins against hemangiosarcoma (HSA). HSA was chosen for a variety of reasons. HSA is an aggressive and incurable cancer derived from blood vessel forming cells that are highly resistant to chemotherapy and are host to a subpopulation of CSCs that further amplify drug resistance. The co-expression of EGFR and uPAR by HSA cells supported the clinical use of eBAT. Through in vitro studies, we observed that eBAT bound and killed canine tumor cells at picomolar concentrations . In the Canine sarcomas can be useful models for human sarcomas . The eBAFor the first time, eBAT was found to be effective in non-xenografted large animal sarcomas in a study design similar to a human clinical trial ,47. eBATAn important finding related to the canine eBAT studies is the reduced toxicity attributed to the addition of the uPAR targeting ligand to the bispecific molecule. Interestingly, in the clinical canine trials, none of the eBAT-treated dogs experienced signs of capillary leak syndrome, the toxicity which is of the greatest concern for LTTs ,51. FurtPseudomonas-based Moxe in leukemia clinical trials in which anti-drug antibodies were detected in 84% of evaluable patients after two drug treatment cycles [Few LTTs delivering bacterial toxin payloads have made it to FDA-approved status. The road to approval is difficult and there are many barriers that eBAT must overcome before it can reach human clinical trials. Though the current in vivo data in small and large animals are promising, the appropriate timing, dosage, and delivery of the treatment in humans remain to be determined. We expect future pharmacokinetic studies of the metabolism of eBAT in dogs to help us optimize the appropriate dosing and schedule of eBAT in human patients. The development of an immunogenic response to the LTT is also a consideration. On the basis of response criteria, physicians may decide that patients are ineligible to repeat cycles of LTT therapy due to the development of antitoxin antibodies after their first cycle. Interestingly, in a recent report, Kreitman et al. reported on t cycles . AntibodIt is also worth mentioning that other bispecific ErbB targeting agents have already undergone clinical evaluation. LY3164530 is a bispecific antibody that targets mesenchymal-epithelial transition factor (MET) and EGFR for treating advanced and metastatic cancer that recently underwent phase I trials . Though Pseudomonas reagents, we believe that the bispecific LTT eBAT has a promising clinical future.In conclusion, eBAT has several advantages and disadvantages . eBAT ha


Involving certified peer specialists in all phases of intervention development and research is a high priority to advance peer-delivered services. Certified peer specialists are individuals with a lived experience of a mental illness, and they are trained and accredited to provide Medicaid reimbursable mental health services. Community-engaged research can facilitate the development and implementation of peer-delivered interventions; however, little is known about the processes. We present our application of community-engaged research to inform the development and implementation of a peer-delivered mobile health  intervention for adults with serious mental illness.The aim of this study was to present a framework that can be used as a guide for researchers and certified peer specialists to develop and implement peer-delivered mHealth interventions in community settings.Informed by principles of community-engaged research, we developed the Academic Researchers-Certified Peer Specialists mHealth Research Continuum. Principles of community-engaged research included in the Continuum include the following: (1) develop a clear understanding of the purpose, goal, and population involved in community change; (2) become knowledgeable about all aspects of the community; (3) interact and establish relationships with the community; (4) encourage community self-determination; (5) partner with the community; (6) respect community diversity and culture; (7) activate community assets and develop capacity; (8) maintain flexibility; and (9) commit to long-term collaboration.Overall, 4 certified peer specialists participated in all phases of intervention development and research. Individuals who participated in the Academic Researchers-Certified Peer Specialists’ mHealth Research Continuum collaborated on 5 studies advancing peers’ roles in services delivery using mHealth and secured grant funding from a foundation to sustain their study. The Academic Researchers-Certified Peer Specialists’ mHealth Research Continuum has created a rare environment of inclusion by combining scientific expertise and certified peer specialists’ expertise to achieve a shared vision.This study delineates a process by which academic researchers and certified peer specialists participated in community-engaged research to develop and implement peer-delivered mHealth interventions in community settings. Consumers diagnosed with a serious mental illness (SMI) have been long-established advocates for transparency and full partnerships with providers in treatment settings . These pCommunity engagement is defined as “the process of working collaboratively with and through groups of people affiliated by geographic proximity, special interest, or similar situations to address issues affecting the well-being of those people” . A systeand the populations’ interests. Certified peer specialists, unlike most researchers, have unique expertise and insight into the mental health care system as they have a lived experience utilizing this system for their personal health care needs [In developing peer-delivered interventions, certified peer specialists represent both interventionists’ re needs . Certifire needs . For exare needs . As suchInformed by community-engaged research principles, we delineate a process by which certified peer specialists were included as full partners in the development of a peer-delivered mHealth for adults with SMI. The goal of this report is to present a framework that can be used as a guide for researchers and certified peer specialists to develop and implement peer-delivered mHealth interventions in community settings.Aligned with the first principle of community-engaged research, academic researchers developed a clear understanding of the social problem experienced by consumers with SMI that certified peer specialists wanted to address . To begiAligned with the principle of self-determination in community engagement, academic researchers worked with the community’s goal  to addreReaching Across: Mental Health Clients Helping Each Other [Aligned with the principle of community engagement to become knowledgeable about the community , academich Other ), and unNext, researchers identified certified peer specialists’ assets. For example, certification as a peer specialist in Massachusetts requires active participation in treatment; completion of an 80-hour training including classes, small group activities, and homework on fundamentals of peer support; cross-cultural partnering; use of first-person, nonclinical language; and passing score on a written examination. Certified peer specialists are then accredited to provide Medicaid reimbursable services in 34 states [In addition, certified peer specialists are a trained workforce with professional practice standards that could guide intervention development. Professional practice standards include (1) not forcing people to participate in services, (2) sharing stories of recovery, (3) not judging others, (4) embracing diversity, (5) educating and advocating for others, (6) addressing difficult issues, (7) learning from people they support and those supported learn from them, (8) embracing equality, 9) using a strengths-based approach, (10) setting clear expectations, and (11) focusing on the person and encouraging them to achieve what they want in life [ using a Finally, nearly all certified peer specialists in the national online survey owned a smartphone , and everyone indicated that smartphones and tablets could enhance the services they deliver . They reNext, academic researchers had the opportunity to informally speak with a certified peer specialist who provided services in the Massachusetts area. The purpose of this conversation was to learn more about certified peer specialists. This in-person conversation lasted approximately 30 min. As a result of this informal discussion, academic researchers advanced their knowledge of certified peer specialists beyond written material of peers’ beliefs, values, culture, and history and identified potential power differentials that may impact the relationship. For example, academic researchers learned that peers may be skeptical of people involved in the mental health care system and research—potentially due to historical, structural oppression, and stigma . As suchwith certified peer specialists. Then, in an open discussion, academic researchers and certified peer specialists elaborated on these principles and offered examples of how each principle would apply to the partnership. In As academic researchers moved toward formalizing the partnership , principles of fairness, empowerment, inclusion, and self-determination -15 were Aligned with the principle of community-engaged research to establish an authentic relationship with the certified peer specialists’ community , academiFairnessResource sharing: financial incentives, offering transportation assistance, and food; and resource allocation: equitable pay for certified peer specialistEmpowermentPeer training in the research capacity building and de-emphasized that researchers were the experts; rather, both groups brought their unique expertise to the teamInclusionFull inclusion on research teams and equal credit for mobile health intervention development as evidence by peer-reviewed publications and national presentations with peers as authors or co-presentersSelf-determinationAcademic researchers worked with the community’s goal and modified the intervention to include peer support in addition to medical and psychiatric self-management skills training and refocused the intervention from the medical model to the recovery model of services deliveryCertified peer specialists did not assist in selecting this intervention to adapt. I-IMR is an evidence-based approach consisting of an individually tailored program addressing physical and mental health self-management in adults with SMI aged over 50 years. The academic researchers selected an intervention for older adults with SMI, as older adults with SMI are more likely to have multiple comorbidities  and, thuThe academic researchers adapted I-IMR for in-person delivery by a certified peer specialist. To support fidelity, we included the use of guided eModules  and a smartphone app designed to complement in-person eModule sessions.The eModules were designed to be reviewed on a tablet side-by-side with a certified peer specialist and a consumer with SMI during weekly 1-hour in-person sessions in a community setting. Each eModule includes videos and experiential learning tasks on psychoeducation and coping skills training. Academic researchers worked with certified peer specialists and filmed peer-led self-management videos on personal recovery stories (unscripted) that were included in the eModules. eModule sessions include (1) Identifying Your Individual Recovery and Wellness Goals: Setting recovery and health goals and strategies to achieve goals and orientation to the smartphone app; (2) Psychoeducation: Psychoeducation on SMI and medical illness; (3) Stress Vulnerability and Illness: Causes of mental illness and factors that influence its course; (4) Building Social Supports and Recovery and Wellness: How to build social supports; (5) Medication Adherence Strategies: Behavioral tailoring and motivational techniques for medication adherence; (6) Psychiatric and Medical Relapse Prevention: Identify warning signs and develop a relapse prevention plan; (7) Coping with Psychiatric Symptoms and Health-related Stress and Solving Problems: Establish a method managing symptoms; (8) Coping with Stress, Chronic Pain, and Medical Symptoms: Identifying stressors that exacerbate symptoms and strategies to cope with stress; (9) Medication Misuse: Addressing medication misuse and the effects on symptoms and functioning; and (10) A Guide to Navigating the Mental Health and Medical Health care System: Accessing mental health and medical health services and making informed decisions.informal relationship with 2 certified peer specialists and 2 consumers with SMI. We consulted with these individuals, but they were not part of the scientific team meetings. Our process included asking a clinical social worker to talk to certified peer specialists and consumers with SMI to get their opinions on the features of the smartphone app, but not the content of the intervention. The scientific team consisted of clinical social workers, physicians, and engineers [The smartphone app was designed to assist in the transfer of self-management skills from in-person sessions with certified peer specialists to real-world environments. As we were developing the smartphone app, we had an ngineers . The appOnce we developed these products (app and eModules), we used a scientific approach to allow peers and consumers to evaluate our study and be involved in early technology development. Academic researchers used an adaptive systems engineering approach  to conduDuring this process, certified peer specialists provided their expertise on the needs of the community and contributed to the context of unhealthy behaviors and poor management of mental and physical health conditions. For example, academic researchers learned that healthy eating is a challenge for individuals with SMI as they may face difficulties with affording healthy foods on a limited income or due to unemployment or underemployment, or they may lack cooking skills or skills to determine healthy eating, lack a reliable place to cook, or they may eat junk food as a means to feel better in the short term. As part of this process, certified peer specialists also identified barriers and facilitators to mHealth implementation and made recommendations to ease intervention uptake. For example, certified peer specialists informed academic researchers that the app should not only be available on a smartphone but also on a tablet because older adults with SMI who wear glasses may experience difficulty reading the small text on the smartphone .At this time, we learned of the need to consider certified peer specialists’ preferences and philosophy of services delivery, social and environmental contexts, and perspectives of feasibility and acceptability from certified peer specialists and consumers with SMI. We needed certified peer specialists to have a more substantive and egalitarian role in the technology development process; we needed to establish a formal partnership and to include certified peer specialists and consumers with SMI in the expert team meetings to move this program of research forward.Consumer Engagement Liaison for the Department of Mental Health in the state of Massachusetts. As the Consumer Engagement Liaison  understood the needs of the local community, the Liaison advocated for academic researcher inclusion in the certified peer specialists’ network within the public mental health service system . This community gatekeeper model allowed ease of access and the opportunity to develop a trusting relationship between academic researchers and certified peer specialists.Aligned with community-engaged research principles, academic researchers partnered with the certified peer specialist community . We engaConsumer Engagement Liaison, we convened a meeting with certified peer specialists, social workers, disability rights advocates, health services researchers, primary care providers, and the Massachusetts Department of Mental Health. We discussed consumers’ needs with SMI. Together, we established a need for an effective, easily accessible self-management intervention for adults with SMI. Academic researchers presented the adapted version of I-IMR, including the eModules and the smartphone app, newly renamed as PeerTECH. After this initial meeting, a formal research partnership developed with the joint goal of assessing PeerTECH’s feasibility, acceptability, and effectiveness. Overall, 4 certified peer specialists, 2 social workers, 1 disability rights advocate, 3 health services researchers, 2 primary care providers, and 1 individual with the Massachusetts Department of Mental Health participated in all phases of intervention development and research.With the assistance of the Throughout this process, academic researchers respected certified peer specialists’ diversity and culture . We heldAligned with the principle of community-engaged research to develop community capacity, academic researchers worked with certified peer specialists to develop peers research capacity . To prepOnce trained, certified peer specialists directed scientific efforts related to the following: (1) text message dose; (2) recruitment—deciding on the location, identifying and hiring, training certified peer specialists using academic profiling, and implementation; (3) identifying outcomes of interest; (4) modified research questions (see below for detailed description); (5) resource allocation—defining equitable pay for certified peer specialists, caseload, and hours required; (6) interpretation of the findings; and (7) dissemination.The peer direct service team met weekly with the peer supervisor  to discuss services delivery, training needs, and modifications to PeerTECH intervention delivery and management procedures. The peer supervisor directed issues to academic researchers weekly during the collaborative research team meetings. Issues brought forth by the peer supervisor included transportation for certified peer specialists, developing a program for matching peers with consumers, and technology training for certified peer specialists. Pragmatic considerations in community-engaged research included flexibility and resource sharing, for example, during training, we included providing financial incentives to certified peer specialists, flexibility with starting times and overestimating timeline, and offering transportation assistance and food.We included reciprocal capacity building and co-learning in our application of community-engaged research. On the basis of certified peer specialists’ expertise, peers advocated to examine additional outcomes and also identified potential mechanisms of action. Specifically, peers identified important outcomes including social support, hope, and empowerment. As such, we examined these outcomes. Peers also suggested that without having hope, how is managing ones’ mental and physical health possible? Thus, we defined hope as a mechanism of action on the self-management of medical and psychiatric skill development. As such, academic researchers and certified peer specialists also modified the existing research questions. The original research question included the following: “to what extent does PeerTECH impact self-management skill development?” This research question was modified to examine “to what extent does PeerTECH impact self-management skill development, hope, empowerment, and social support?”Certified peer specialists worked alongside academic researchers and identified research sites and acceptable screening tools and assisted in hiring, training, and managing peers. The academic researchers-certified peer specialists’ mHealth research group allowed reciprocal capacity building and learning. For example, researchers learned peer history and services delivery practice standards, peer support, and mutuality. The major change this made to the research included modifying the intervention to include peer support in addition to medical and psychiatric self-management skills training, refocusing the intervention from the medical model to the recovery model of services delivery, and the inclusion of consumer-reported measures. In practice of cultural humility , we de-The academic researchers-certified peer specialists’ mHealth research group led the effort to examine the feasibility, acceptability, and preliminary effectiveness of PeerTECH with adults with SMI in a pre-post pilot study. Our study design and findings have been reported elsewhere . PeerTECAt the pilot study’s conclusion, we conducted a focus group with 3 certified peer specialists involved with PeerTECH and 8 individual interviews with adults with SMI . Both grAligned with the community-engaged research principle of activating community assets , academiAligned with the principle of community-engaged research to commit to long-term collaboration , academiIndividuals in the academic researchers-certified peer specialist mHealth research group have collaborated on 5 studies over 1 year to advance the role of peers in services delivery using mHealth. We anticipate this group to be long-term as it has secured grant funding from a private foundation to sustain their study. Consistent with principles of community engagement, this approach to community-engaged research has created a rare environment of inclusion through the combination of scientific expertise and certified peer specialists’ expertise , we incorporated peers in all aspects of research and mHealth intervention development. In our framework, peers were equal partners in helping define the problem, creating mHealth intervention content, identifying outcomes of interest, modifying research questions, and identifying research sites, and they also assisted researchers in hiring, training, and managing peers. Finally, peers also guided our dissemination efforts. Our framework can be used as a guide for researchers and certified peer specialists to develop and implement peer-delivered mHealth interventions in community settings.This is the first report of a community-engaged research framework that includes certified peer specialists in all stages of research and mHealth intervention development. Unlike the recent models of mHealth community-engaged research that focus on only mHealth intervention development and implementation is a complex scientific process that incorporates multiple disciplines with their own distinctive cultures and expertise . Promoti


As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular , large molecular , and protein-bound ones (indoxyl sulfate,  Patients with impaired renal function, or chronic kidney disease (CKD), exhibit a high cardiovascular risk , which iMuch has been learned from the pathophysiologic studies involving VC. Uremic toxins play a particularly critical role in the process of uremic VC, and targeted removal of these toxins may be an important approach for managing uremic VC. However, the existing literature fails to emphasize the multifaceted role of uremic toxin removal through the gastrointestinal route. In the following sections, we will provide an overview of the relationship between uremic toxins and VC; the plausible options for mitigating the adverse influences posed by uremic toxins; and, most importantly, the under-recognized role of gastrointestinal tract-based elimination of these toxins.Generations of work have provided us with a deeper insight into how VC spawns and grows in the uremic environment. The prior theory of passive mineral deposition surrounding necrotic cores in the layers of the vascular wall has now been replaced by an active cell-mediated theory of osteoid matrix deposition, performed mainly by the phenotypically transformed vascular smooth muscle cells (VSMCs) . A simplAmong the pathogenesis of VC, uremic toxins expectedly assume importance over time as CKD progresses. A majority of the uremic toxins exhibit adverse vascular effects, ranging from atherosclerosis, vascular inflammation, to VC. Clinical studies consistently show that levels of multiple uremic toxins closely correlate with the severity of uremic VC. Large cohort studies have shown that higher serum phosphate levels are independently associated with an increased mortality and accelerated progression of VC among CKD patients , while aAs proposed by the European Uremic Toxin (EUTox) workgroup , candidaThese are prototypic, including urea, creatinine, calcium, inorganic phosphate, and polyamines , althougExperimentally, a myriad of evidence indicates that the retention of small molecular uremic toxins, such as inorganic phosphate, precipitates VC. The model of phosphate-induced osteoblastic trans-differentiation of VSMCs has assumed widespread popularity as an experimental approach for studying VC . MechaniThese large molecules are more difficult to tackle compared with small molecular ones, because of the inefficient removal using conventional dialysis modalities. The terminology of these molecules can be diverse, ranging from middle molecules , large mSimilarly, several studies have demonstrated that TNF-α and interferon-γ exposure induced VSMC calcification in cell models, and this process was reversible upon anti-inflammatory treatments . These ip-cresyl sulfate (pCS) [p-cresol, which is processed to pCS through detoxification in liver as well as colonic mucosa. Dietary tryptophan, on the other hand, is converted to indole by colonic microbes, which is further metabolized by liver into IS. Both IS and pCS act as typical uremic toxins by showing direct cytotoxic effects to hepatic cells, myocardium, and renal tubular cells, in animal experiments and human studies [These are among the most influential factors that contribute to adverse influences including several prototypes such as IS and te (pCS) . Dietary studies .3K/Akt pathway upregulation [Their crucial role in the pathogenesis of VC is increasingly recognized . Aside fgulation . Specifigulation . In addigulation . It is agulation . In lighA summary of the pathogenic connection between uremic toxins and uremic VC is shown in Judging from the importance of uremic toxins to cause uremic VC, it is tempting to devise treatments against VC by lowering these toxins . There hArtificial kidneys aiming to remove circulatory uremic toxins are the cornerstones for this toxin-directed approach. Conventional dialytic modalities efficiently extract small molecules like inorganic phosphate and uric acid . However2 [Dietary manipulation is an alternative approach to reduce uremic toxins . Several2 . A subst2 .Treatments delivered through the gastrointestinal tract are now gaining attention in modern research to manage toxin-related complications. Indeed, the importance of a kidney-gut axis has been upheld in recent years. Progressive renal function impairment is frequently accompanied by a deranged gastrointestinal bacterial homeostasis (dysbiosis), owing to uremia-induced gastrointestinal motility and permeability changes via the direct effect of uremic toxins and/or their metabolites on colonic microenvironment . Gut dysApart from microbiota modulation, there are other plausible interventions aiming to reduce uremic toxins through the gastrointestinal route. The concept of “gastrointestinal decontamination” has been embraced by the healthcare community for treating poisoning for decades. Through the timely removal of harmful substances and the prevention of gastrointestinal toxin absorption, gastrointestinal decontamination assists in optimizing patient outcomes. Recently, this approach is further adopted from diverse fields, for example, the use of non-absorbable antibiotics to exert gastrointestinal decontamination on attenuating intestinal inflammation and reducing the risk of graft-versus-host disease in patients undergoing hematopoietic stem cell transplantation  and seleTight control of the serum phosphate level reduces VC through the reduction of secondary hyperparathyroidism, calcium phosphate product, and active mineralization protein deposition in vascular cells . In addiEach class of these phosphate binders has their strengths and drawbacks   and tenapanor  stand at the forefront of this approach . AlthougIt should be emphasized that uremia is a state of calcium overload . Prior sMagnesium has gradually been recognized for its potent inhibitory effects on the calcification process involving vasculature. Epidemiological studies have consistently revealed that serum magnesium levels inversely correlate with the presence, the severity, and the rate of progression of VC in patients with CKD and ESRD . In animConsequently, gastrointestinal toxin decontamination based on magnesium administration may theoretically bear both local and systemic benefits in terms of vasculo-protection.Oral charcoal-based removal of protein-bound uremic toxin may be a useful choice to counteract VC. In vitro studies already support the feasibility of this approach . ResearcPreliminary studies revealed that microbiota modulation through manipulating dietary composition might attenuate the extent of atherogenesis in animal models . The useThe pathogenesis of uremic VC, from the current understanding, includes VSMC phenotypic switch upon noxious metabolic stimuli; rising oxidative stress; a pro-inflammatory environment; the declined anti-calcific factors; and, most importantly, the adverse influences posed by various uremic toxins. Small- and large-size uremic toxins as well as protein-bound ones each predispose CKD or ESRD patients to develop uremic VC. Interventions aimed to neutralize uremic toxins have since been embraced as potential therapeutic options for uremic VC. The gastrointestinal tract serves as both a source of uremic toxin generation and the route of treatment delivery. The concept of gastrointestinal decontamination through the elimination or the prevention of toxin absorption within the gut can be an integrative approach for ameliorating VC. Administration in combinations to target uremic toxins is expected to counteract VC from different dimensions and act synergistically. The quest for an optimal VC management strategy in CKD and ESRD is still underway . Hopeful


Tissue-resident innate immune cells exert a wide range of functions in both adult homeostasis and pathology. Our understanding of when and how these cellular networks are established has dramatically changed with the recognition that many lineages originate at least in part from fetal sources and self-maintain independently from hematopoietic stem cells. Indeed, fetal-derived immune cells are found in most organs and serous cavities of our body, where they reside throughout the entire lifespan. At the same time, there is a growing appreciation that pathologies manifesting in adulthood may be caused by adverse early life events, a concept known as “developmental origins of health and disease” (DOHaD). Yet, whether fetal-derived immune cells are mechanistically involved in DOHaD remains elusive. In this review, we summarize our knowledge of fetal hematopoiesis and its contribution to adult immune compartments, which results in a “layered immune system.” Based on their ontogeny, we argue that fetal-derived immune cells are prime transmitters of long-term consequences of prenatal adversities. In addition to increasing disease susceptibility, these may also directly cause inflammatory, degenerative, and metabolic disorders. We explore this notion for cells generated from erythro-myeloid progenitors (EMP) produced in the extra-embryonic yolk sac. Focusing on macrophages and mast cells, we present emerging evidence implicating them in lifelong disease by either somatic mutations or developmental programming events resulting from maternal and early environmental perturbations. It is now widely recognized that many non-communicable diseases have developmental origins, brought about by somatic mutations or environmental perturbations during gestation and in early life. Immune dysregulation is a common denominator in the etiology of these diseases, and can even directly cause pathology. Indeed, immune cells have many functions beyond protective immunity, for example in controlling tissue homeostasis. The first immune cells seed developing tissues during organogenesis, and unlike previously thought, appear fully functional already at these early stages. Moreover, we have recently come to realize that fetal-derived cells persist and self-maintain in adult tissues. This is true for macrophages and mast cells derived from erythro-myeloid progenitors (EMP) generated in the yolk sac (YS) before the emergence of hematopoietic stem cells (HSC). Their ontogeny and proliferative capacity make EMP-derived cells particularly vulnerable to early life perturbations and identify them as potential transmitters of long-term effects on health and disease.in vivo lineage and cause-consequence relationships between perturbation of immune development and pathology, we will primarily discuss experimental animal studies. However, where possible, we will also discuss relevant human data, especially those that benefitted from recent technological advancements such as single-cell RNA-sequencing. We will briefly summarize our current understanding of fetal hematopoiesis and its contribution to adult tissue-resident immune compartments/landscapes. Having established their normal developmental trajectories, we will then discuss a growing body of literature supporting the notion that mutations affecting EMP or exposure to adverse early life environments render macrophages and mast cells pathogenic in conditions as diverse as neurological or atopic disease and cancer.Here, we explore this notion, focusing on EMP and their cellular progeny. Because they allow establishing Traditionally, HSC found in the bone marrow (BM) have been regarded as the sole, lifelong source of all immune cells. This view has changed with the recognition that many lineages originate at least in part from fetal sources and self-maintain independently from HSC. Indeed, we now appreciate that fetal-derived cells comprise varying proportions of the resident immune compartments in most adult organs and serous cavities.de novo hematopoiesis is otherwise restricted to fetal stages. Fetal hematopoiesis occurs in several waves that differ in time and space but partially overlap , a second wave sometimes called transient or transient-definitive  . This soryocytes , and posryocytes . Primitifinitive . EMP arefinitive . In addi cells (This complex process generates what has been termed a “2) cells , this co2) cells .Similarly to mice, also human hematopoietic waves appear sequentially at distinct sites, with EMP-like cells in the YS that produce erythrocytes, as well as macrophages, megakaryocytes interpretation of in vivo data from single fate-mapping models, intermingling with in vitro assays that do not necessarily reflect in vivo lineage output, and not accounting for developmental events during embryogenesis-has stirred an ongoing debate about the exact nature and identity of hematopoietic progenitors, their emergence and their contribution to distinct cell types  and their production partially overlaps in space and time. Therefore, at present, no single fate-mapping model can unequivocally pinpoint distinct pre-HSC waves with precision, and conclusions on the origins of immune cells should be drawn with caution and from several ll types .ex vivo and progenitor transplantation assays that lymphoid potential precedes the onset of adult-type HSC-dependent hematopoiesis and that certain innate(-like) lymphocytes even remain of fetal origin throughout life , lymphoid tissue inducer (LTi), and natural killer (NK) cells first emerge independently of adult-type HSC , do not generate lymphocytes in vivo  has been put forward , and LMP in vivo .in vivo using additional, complementary approaches.The LMP controversy illustrates how difficult it often remains to assign the origin of fetal-derived immune cells to specific progenitors, even with genetic fate mapping. The models used often rely solely on the temporal distinction of waves, the resolution of which is insufficient for progenitors produced between E8.5 and E10.5. Whilst DETC and fetal LTi are likely not EMP-derived based on the absence of labeling in several models , it has Possibly the most heavily debated controversy concerns the precise origins of fetal-derived immune cells found in adult organs, in particular tissue-resident macrophages. While many scientists might dismiss this as a pure developmental biologists’ or even semantics problem, we believe it is essential to precisely dissect the ontogeny of those immune cells that remain lifelong within tissues, where they undergo continuous genetic and epigenetic changes that may eventually influence or perturb organ homeostasis. In an attempt to delineate different progenitor waves, the nomenclature of “early” and “late” EMP (or EMP1 and EMP2) has been introduced, which proposes that early EMP (produced at E7.5) belong to the primitive wave, while late EMP (starting at E8.5) express the transcription factor c-Myb and thus originate from the second, definitive wave of hematopoiesis . BecauseIn vivo, EMP heterogeneity and their actual lineage output would be dictated by stage-specific signals co-opting cell-autonomous transcriptional networks to meet the current demands for immune cells. Such a demand-driven model could easily be reconciled with existing experimental data: Macrophages are considered integral to organogenesis and thus, need to colonize tissues as they develop. At E7.5, YS EMP therefore primarily give rise to microglia, while at E10.5, they mainly produce macrophages for tissues that develop later during embryogenesis, e.g., the lung  and c-Myb expression is rather artificial and does not reflect the real-life scenario. Rather, early and late EMP might represent two extremes of the same wave, “captured” by different labeling approaches. We propose that EMP represent a continuous product of the YS hemogenic endothelium generated between E7.5 and E10.5, which intrinsically have the same differentiation potential, irrespective of their time of emergence. This is supported by clonogenic assays for EMP obtained from the YS at these different time points and fetal liver EMP at E12.5 . In vivothe lung . Althougthe lung . Rather To respond to these demands, EMP need to produce committed progenitors that can invade tissues via the circulation. This can occur via different routes, some of which involve migration to the fetal liver , where tIt is now firmly established that the likelihood of developing a non-communicable disease in adulthood is strongly influenced by environmental factors in early life, including the fetal period . This coin utero impact later-life health and disease by programming offspring immunity.Whilst similar considerations apply to environmental perturbations in the perinatal period, which is arguably important for shaping the immune system in response to microbial exposures and colonization, fetal development normally occurs in a tightly controlled intra-uterine environment and thus, represents a critical window of vulnerability. As outlined above, the fetal period also overlaps with key events of immune development, strongly suggesting that environmental insults experienced At least three requirements must be met for environmental perturbations during fetal development to have long-lasting effects that can persist into adulthood: Signals must (1) be conveyed to the developing fetus, either directly by crossing the placental barrier, or by eliciting an inflammatory response at the fetal-maternal interface. Such signals must (2) be sensed by physiological systems equipped to respond to environmental stimuli, and (3) these systems must persist and undergo long-lasting imprinting or programming. This applies to the immune system , and in Programming of these immune cells might act on different levels and manifest in several ways that are non-mutually exclusive. Adverse environments could directly act on individual cells, modulating their effector functions, causing e.g., a long-lasting shift in the balance between type I and II immunity . AdverseThe DOHaD have been described half a century ago, directly linking prenatal nutrition to mental disorders . Before In light of the regulation of gene expression by metabolites and MIA, epigenetic regulation of gene expression is currently the proposed mechanism of adverse intergenerational effects . HoweverIn the healthy developing brain, microglia interact with neuronal progenitors and regulate their cell numbers . They arIn the adult brain, microglia actively contribute to learning and memory by surveying and modulating multiple synaptic structures , controlThis overwhelming collection of the homeostatic functions of microglia, their longevity, and their ability to acquire epigenetic memory  makes thAtopic diseases are caused by IgE-mediated allergic reactions that represent exaggerated immune responses to otherwise harmless substances like pollen, dander, and certain types of food. Mast cells are the central mediators of these responses . Upon thin utero by maternal IgE crossing the placental barrier mediate airway and skin inflammation upon postnatal re-exposure  . IBS is Similarly, in mice, early life stress potentiates mast cell- glia and -neuron interactions in the myenteric plexus in a histamine-dependent manner . While mMacrophages and mast cells densely populate the stroma of most solid tumors, where they can have either tumor-promoting or -suppressive functions. At present, this complexity represents a major hurdle for the clinical exploitation of these cells to diagnostic, prognostic or therapeutic benefit. Their impact on tumor growth can be different within distinct cellular neighborhoods  and thusin vivo models of maternal stress, as discussed above. Moreover, patients suffering from mast cell activation syndrome are also at a higher risk of developing solid tumors, including melanoma  is one example, which presents a remarkable diversity of phenotypes ranging from subtle skin lesions and mild neurological symptoms to life-threatening disseminated disease. Since the discovery of recurrent somatic mutations in the MAPK signaling pathway, particularly BRAFV600E , known tV600E , histiocV600E  as well V600E mutation into the EMP lineage (V600E+) developed behavioral deficits and displayed chronically activated microglia, which eventually resulted in paralysis and neurodegeneration. In contrast, BRAFV600E expression in all CD11c+ cells, i.e., dendritic cells and some tissue-resident macrophages, resulted in myeloid-cell tumors in the lung and spleen while targeting the whole hematopoietic system caused a leukemic phenotype and prenatal lethality  for NF1 in Schwann cells alone is not sufficient to induce neurofibromas (Neurofibromatosis type 1 (NF-1) is a common genetic disorder caused by loss-of-function mutations in the fibromas . Strikinfibromas . MechaniAlthough the tumor-promoting role for MC in neurofibroma has been demonstrated using BM transplantation into adult recipient mice, it is important to note that the onset for tumor development often is in childhood, and this is particularly true for plexiform neurofibroma . It is tDrosophila is a powerful tool to manipulate different cell types genetically and in a mosaic fashion, and there are some parallels to mammals concerning macrophage development  to characterize the combination of two distinct genetic alterations that result in tumorigenesis.Similar to mast cells, also macrophages seem to participate in intercellular complementation. This is the case for example in a sporadic colorectal tumor model where reciprocal BM chimera studies indicate that tumor-associated macrophages (TAMs) with a constitutively active cytoplasmic hematopoietic cell kinase promote tumorigenesis . Howeverelopment . Here, aCsf1rMeriCreMer or CreERTCx3cr1 models (In more general terms, the contribution of EMP-derived macrophages to the pre-metastatic niche can be studied in mice by genetically manipulating these cells using common fate-mapping drivers such as T models  in combiT models . In contT models  or persiT models . In summV600E mutation in the EMP lineage results in mutant microglia, thereby causing neurodegeneration (V12 - is sufficient to activate microglia and lead to photoreceptor degeneration (As described above, a BRAFneration . Similarneration . In contneration  or p53 (neration  is neuroneration  it may wneration  in the nneration .One overarching question remaining is why the animal kingdom relies on consecutive hematopoietic waves, with only the adult-type HSC remaining active later throughout life. We believe that evolution has selected for this layering to supply immune cells that meet the stage-specific demands of developing tissues.Drosophila, where they have prominent roles in development and immunity (At earlier stages, rather than providing protective immunity, these demands are likely homeostatic in nature. Indisputably, oxygen supply by YS-derived red blood cells is needed as soon as the heart starts beating, a time point at which the embryo proper is developmentally likely not equipped to give rise to HSC. This may be explained by the need for a state of physiological hypoxia in embryos, which is important for the proliferation and survival of hematopoietic precursors . Similarimmunity , similarimmunity . Beyond in utero priming, postnatal life. Infectious threats would arguably have to occur at frequencies high enough to impose a strong selection pressure for establishing immune cells this early. This might well be the case in nature and could explain why the developing fetus also invests energy in generating other, short-lived cell types such as granulocytes and NK cells, which will be replaced just a few days later.In addition to developmental functions, fetal immune cells might protect from infections occurring during pregnancy or, following At least longer-lived fetal immune cells might also undergo immune priming. Although it is the longstanding belief that the fetus is sterile, data is emerging that the human microbiome is seeded before birth and DNA of bacteria, fungi, and viruses has been detected in amniotic and meconium fluid . These sWhatever their physiological functions, the presence of fetal-derived, proliferating immune cells in virtually all adult tissues makes the organism vulnerable to developmental programming events during gestation, as well as the accumulation of somatic mutations. These perturbations may shift their functions from homeostasis- to inflammation-promoting. Using mice as model organisms and applying environmental challenges such as MIA, maternal obesity, or smoking, we may be able to establish cause-consequence relationships between developmental programming of EMP-derived cells and pathophysiology in the offspring, which cannot be deduced from epidemiology. Combining such models with the ever-growing toolbox to target developmentally distinct immune cell populations or their hematopoietic progenitors will allow us to dissect their precise roles in adult disease onset and progression. Delineating the basic mechanisms shaping the functions of EMP-derived cells might ultimately inform if and how we could reverse their programming toward restoring homeostasis. Finally, such mechanistic studies in animals can now be complemented with deep sequencing efforts of single human cells, where somatic mutations in nuclear or mitochondrial DNA might serve as a readout for cellular origin, thus allowing us to study immune cell origin not only in patients, e.g., after transplantation, but also in healthy subjects.RG and EM wrote the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


EngAGE is a technology-based program leveraging Alexa that encourages older adult (OA) activity and socialization from home while empowering caregivers to support them. EngAGE delivers daily, in-home, NIA Go4Life exercise routines with instructions, pictures and music via Alexa Echo Shows or Fire Tablets to OAs. Caregivers use EngAGE to view scheduled exercises, follow progress, and send encouraging messages that are read aloud to OAs by Alexa. We will discuss the strategic co-design of EngAGE with OAs and caregivers and the utilization and functional impact of EngAGE over a 12-week feasibility and usability study (n=10 OA + caregiver pairs). Preliminary analyses revealed improvement in upper  and lower  body strength. Discussion of focus group data will cover themes of perceived benefits, user experience, drivers/barriers to usage and desired features for EngAGE.


When undertaking quality improvement (QI) initiatives, one of the greatest burdens is repeated data collection. Intensive care registries, such as those commonly used in high-income countries (HICs), have enabled systematic capture of routine information needed to measure intensive care unit (ICU) performance . Once coPoor quality of care has resulted in an estimated additional five million deaths, and six trillion US dollars in economic losses worldwide , 5. In SCritical care is expensive and complex. Many barriers impede the optimal care of critically ill patients, especially in resource-restricted settings . Basic eThe ability to continually evaluate care and empower stakeholders to identify priorities for improvement is a crucial but missing component of QI , 8. In lMany of the basic principles of ‘good quality’ critical care that have proved successful in HICs may be directly applicable to resource-limited settings. Often, however, practices are poorly implemented. To date, in LMICs, QI initiatives have had limited success in achieving sustained change or have proven difficult to scale . QualitySupported by a Wellcome Innovations Flagship Programme grant, our group of multidisciplinary healthcare professionals predominantly based in Asia, is establishing a locally led collaborative network: Collaboration for Research, Implementation and Training in intensive CARE in ASIA (CRIT CARE ASIA). The collaboration will improve patient outcomes using near real-time high-quality data to drive improvement and strengthen the health system through a system of audit and feedback. Delivered over 3 years and extendable beyond this period, the programme will establish an Asian ICU network across 42 units in nine countries and implement a setting-adapted electronic cloud-based registry co-designed and developed by clinicians in the region Fig. . Using tInitiating, maintaining or advancing a local improvement programme consumes large amounts of time and energy . Establilearning by doing model, whereby members of the network will be supported to interact with data generated through the registry and identify problems and possible solutions. Qualitative approaches, including ‘real-time evaluations’, from disciplines including anthropology and business, which lend themselves to rapid evaluation of complex health systems, will be utilised [To improve quality of care, it is necessary to locate the gap in care and to identify and understand its underlying determinants. Utilising mixed-methods, the network will encourage a utilised . FindingThe greatest challenge lies with information governance aspects of data curation and sharing. The diverse project team will use their extensive LMIC experience to overcome barriers to data sharing. International research partnerships can disproportionately advantage high-income countries and institutions . With thThe network will enable the implementation and evaluation of innovative LMIC technologies and provide opportunity for data linkage with the registry . The ICU


Characteristics of the neighbourhood environment, including population density, social fragmentation, and trust, have been linked to mental health outcomes. Using a longitudinal population-based cohort, we explored the relationship between objective and subjective neighbourhood characteristics and the odds of suicidal thoughts and attempts.We conducted a longitudinal study of 20764 participants living in Stockholm County who participated in the Stockholm Public Health Survey. We used multilevel modelling to examine if suicidal thoughts and attempts were associated with neighbourhood characteristics, independent of individual associations. We included objective and subjective measures to explore if there was a different relationship between these measures of the neighbourhood environment and suicidality.Associations between neighbourhood factors and suicidality were predominantly explained by individual characteristics, with the exception of neighbourhood-level deprivation and average residential trust. Each unit increase of deprivation was linked to increased odds of suicidal thoughts  and attempts . Decreasing residential trust was associated with increased odds of suicide attempts . There was no evidence that neighbourhood-level fragmentation or average trust in public and political institutions had an independent effect on suicidality once individual and sociodemographic factors were accounted for.This study showed that much of the neighbourhood-level variation in suicidal thoughts and attempts could be explained by compositional factors, including sociodemographic clustering within neighbourhoods. The independent effect of neighbourhood-level deprivation and average residential trust provide evidence that the neighbourhood context may exert an independent effect on suicidality beyond the impact of individual characteristics. We excluded individuals who did not have record of their neighbourhood at baseline, did not answer questions on trust in 2002, or did not respond to the suicide questionnaire in at least one of the follow-up waves of SPHC. This study was covered under the ethical permissions from the Regional Ethical Review Committee in Stockholm (Dnr 2010/1185-31/5).n = 771).Our primary outcomes were suicidal thoughts and attempts, assessed using a self-report questionnaire administered in 2002 (baseline), 2006, 2010, and 2014. Participants were asked [translated] ‘Have you ever been in the situation that you seriously considered taking your own life, maybe even planned how you would do it?’ and ‘Have you ever made an attempt to take your life?’ Individuals who responded ‘Yes, in the last week’ or ‘Yes, in the last year’ were coded as having suicidal thoughts or suicide attempts during follow-up in order to ensure the suicidal thought and suicide attempts occurred after the baseline measure. Those who reported suicidal thoughts or attempts at baseline were excluded  ‘no trust whatsoever’ to (5) ‘considerable trust.’ ‘No opinion’ was considered an equivocal response and coded as the middle response option. We summed the scores from these nine questions and rescaled them to create an ‘average trust in public and political institutions’ score between 1 and 45 .We used data from the Integrated Database for Health Insurance and Labour Market Studies (LISA) to calculate individual-level fragmentation and deprivation. Individual-level fragmentation was measured using relationship status, moving in the past year, and lone dwelling. Individual-level deprivation was measured using income quintile, education level, and employment status.n = 115).We had complete data on both individual-level objective measures  for all those who had a valid address at cohort entry, however, we excluded individuals who did not have subjective measures at baseline (n = 18).We obtained Small Area Market Statistics (SAMS) from Statistics Sweden to estimate neighbourhood exposures. SAMS use administrative boundaries to delineate socioeconomically homogenous areas containing between 1000 and 2000 individuals  to quintile 5 (very high trust).Objective neighbourhood characteristics were generated for each neighbourhood that contained at least one SPHC participant at baseline. These were obtained through record linkage with the LISA and the Total Population Register (RTB).Using methods similar to previous research , occupational classification. We included educational attainment and residential moves using information from the LISA; and region of birth, income, and population density from the RTB.We explored missingness within the cohort to determine if complete case analysis was appropriate. We then generated descriptive statistics of the sample. Next, using multilevel logistic regression, we investigated the association between neighbourhood characteristics at baseline and suicidality during follow-up. Individuals (level 1) were nested within neighbourhoods (level 2). We fitted a random intercept at the neighbourhood level to account for this higher-level clustering. We fitted random intercept Weibull models with normally distributed random effects to allow the baseline odds to vary across neighbourhoods. The null model, without fixed effects, was fitted to quantify the variation in the baseline odds for suicidality attributable to neighbourhood random effects. We then ran unadjusted and adjusted models and reported odds ratios (OR) with 95% confidence intervals (95% CI).There were 20 764 individuals, from 889 neighbourhoods in Stockholm County . The medWe examined the full cohort and determined that the proportion of missing data was low across study variables. The highest proportion was 5.3% missing in occupational position, with all other variables having between 0.0% and 2.0% missing , low trust , and very low trust  compared to those with high levels of trust . Each unThere was some evidence for similar patterns of increasing odds of suicide attempts by individual-level factors. There was evidence for increased odds of suicide attempts with decreasing individual-level trust in residential area  and average trust in public and political institutions  (online Supplementary Table S3). Individual-level fragmentation and deprivation scores were also associated with suicide attempts. For each unit increase in fragmentation, the odds of suicide attempts were 1.18 (95% CI 1.07–1.31), following adjustment for covariates. Compared to the lowest level of individual deprivation, individuals experiencing medium or high deprivation had elevated odds of suicide attempts  At the neighbourhood level, the unadjusted estimate for trust in residential area suggested a 13% increase in the odds of suicidal thoughts with each unit decrease (95% CI 10–17) (online Supplementary Table S4), but once fully adjusted for individual-level trust and sociodemographic factors, the association was null  . A weakeIn contrast, objectively measured neighbourhood deprivation was found to be associated with an association with suicidal thoughts following individual adjustment  and when fully adjusted for individual-level factors and sociodemographic factors . Neighbourhood fragmentation suggested an association between higher levels of fragmentation and suicidal thoughts in the unadjusted estimate , which persisted when adjusted for individual measures of fragmentation , but attenuated once sociodemographic factors were taken into account .These patterns were broadly consistent with those for suicide attempts. Lower neighbourhood-level mean trust in residential areas corresponded to increased odds of suicide attempts, even following adjustment , driven by high odds in the neighbourhoods with the lowest scores . The fully adjusted estimates did not show an association between neighbourhood-level average trust in public and political institutions score and suicide attempts, echoing what was found for suicidal thoughts.Objectively measured neighbourhood-level deprivation was found to be related to increased suicide attempts following adjustment for individual-level deprivation and sociodemographic factors . Neighbourhood-level fragmentation was associated with increased odds of suicide attempts in the unadjusted  and in the individually adjusted estimate , but these elevated odds were attenuated when fully adjusted  (online Supplementary Table S5) At the individual level, both objective (high deprivation and fragmentation) and subjective  were associated with increased odds of suicidal thoughts and attempts.At the neighbourhood level, higher levels of deprivation were associated with increased odds of suicidal thoughts and attempts. Decreasing average trust in residential area was associated with increased odds of suicide attempts, although this was not found for suicidal thoughts. Neighbourhood-level fragmentation and average trust in public and political institutions were not associated with increased odds of suicidality once individual characteristics were considered.There are several limitations that must be noted, including cohort response rates and limited information for calculating social fragmentation. Among those selected for the survey, the response rates in 2002, 2006, and 2010 were 62, 61, and 56%, respectively  % of persons who have moved in the last year, (2) % unmarried persons, (3) % single person households, and (4) % of persons in private rented accommodations Congdon, . We did A key strength of this analysis was the rich data available in the Stockholm Public Health Cohort and linked Swedish registers. We were able to combine self-report responses from the cohort study with register information to generate detailed estimates of exposures, outcomes, and confounders. Further, we were able to calculate area-level exposures on small, demographically homogenous areas (SAMS), which reduced the risk of exposure misclassification. Previous research on the appropriate scale for area-based analysis must balance size and power, as smaller areas tend to be more homogeneous but often lack the power to detect an effect. This has been demonstrated in a previous study, which found that the association between suicide rates and area deprivation disappeared when moving from smaller areas (wards) to larger areas   with subjective  at the neighbourhood-level, we found differing patterns of association with suicidal thoughts and attempts. One objective measure, neighbourhood-level deprivation, was linked to both suicidal thoughts and attempts, but the other objective measure, neighbourhood-level fragmentation, was not associated with suicidality. Similarly, one subjective measure, neighbourhood-level residential trust, was found to be associated with suicide attempts, but the other subjective measure  was not associated with suicidal thoughts or attempts. This varies from a previous cross-sectional study of adolescents, which found an association between perceived neighbourhood characteristics and suicidal thoughts and behaviours, but no evidence for a link between objective measures and suicidality (Allen & Goldman-Mellor, The unadjusted models suggested that some of the variance in odds of suicidal thoughts and attempts may be explained by neighbourhood factors, including neighbourhood-level residential trust, trust in public and political institutions, fragmentation, and deprivation. However, once individual scores and sociodemographic characteristics were considered only neighbourhood-level deprivation and residential trust remained associated with suicidality. Specifically, increasing neighbourhood-level deprivation was associated with increased odds of suicidal thoughts and attempts, while decreasing residential trust was associated with increased odds of suicide attempts.The complete attenuation of the association with other neighbourhood characteristics, including neighbourhood-level fragmentation and trust in public and political institutions supports a composition rather than contextual explanation for the results. The multilevel design of this study has enabled us to begin to disentangle the contextual and compositional effects, and these findings suggest that observed neighbourhood variation in suicidality may be largely attributed to the compositional characteristics of the people living within the neighbourhood. Residential segregation by socioeconomic status is persistent in many cities, leading to clustering of individuals with similar socioeconomic status in neighbourhood areas (Pickett & Wilkinson, In contrast, the associations between neighbourhood-level deprivation and average residential trust following adjustment for individual and demographic factors, provide evidence for contextual effects, where area-level factors conferred additional risk beyond individual and compositional explanations. Neighbourhood-level deprivation was linked to both increased suicidal thoughts and attempts, while residential trust remained associated with elevated odds of suicide attempts, following adjustment for individual and demographic characteristics.Living in neighbourhoods characterised by high levels of deprivation and distrust of neighbours may be linked to suicidal thoughts and attempts through entrapment or defeat, consistent with the arrested flight (Gilbert & Allan, These results suggest that multifaceted suicide prevention activities which target high-risk individuals clustering within neighbourhoods as well as high-risk neighbourhoods, characterised by high deprivation and distrust could be useful in reducing suicidal thoughts and attempts. Before such public mental health interventions could be implemented, further understanding of the underlying mechanisms which drive the contextual effects are warranted, as is further evidence for effective area-based suicide prevention interventions.Our findings show that while much of the neighbourhood variation in suicidal thoughts and attempts can be attributed to compositional characteristics of the area, neighbourhood-level deprivation and residential trust may confer additional risk. These findings support both compositional and contextual explanations for area-level variation in suicidality. These results suggest that multifaceted suicide prevention programmes which target both high-risk individuals and high-risk neighbourhoods could be beneficial in reducing rates of suicidal thoughts and attempts.