Although health care systems aspire to deliver equitable care, practical tools that empower the health care workforce to weave equity throughout quality improvement (QI) processes are lacking. In this article, we report findings from context of use interviews that informed the development of a user-centered tool to support equity-focused QI.Semistructured interviews were conducted from February to April of 2019. Participants included 14 medical center administrators, departmental or service line leaders, and clinical staff involved in direct patient care from three Veterans Affairs (VA) Medical Centers within a single region. Interviews covered existing practices for monitoring health care quality  and explored how equity data might fit into current processes. Themes extracted through rapid qualitative analysis were used to draft initial functional requirements for a tool to support equity-focused QI.Although the potential value of examining disparities in health care quality was clearly recognized, the data necessary for examining disparities were lacking for most quality measures. Interviewees also desired guidance on how inequities could be addressed through QI. The ways in which QI initiatives were selected, carried out, and supported also had important design implications for tools to support equity-focused QI.The themes identified in this work guided the development of a national VA Primary Care Equity Dashboard to support equity-focused QI within VA. Understanding the ways in which QI was carried out across multiple levels of the organization provided a successful foundation upon which to build functional tools to support thoughtful engagement around equity in clinical settings. Quality monitoring tools  designed to highlight disparities in quality metrics have started to emerge.34There is no shortage of blueprints, roadmaps, and calls to action that provide guidance on how to address inequities from within the health care system.34 Practical tools that empower QI teams to weave equity throughout their work have yet to be developed, and current quality monitoring practices continue to lack an explicit focus on equity.36 To facilitate a true paradigm shift in the way QI is conducted, it is necessary to understand the current workflow and environmental constraints in which QI teams operate, and identify multiple points in the QI process when equity should be considered.While these dashboards reflect health care systems' recognition and commitment to reducing health care disparities, they are only a first step toward fully integrating equity into quality improvement (QI) initiatives.Toward this end, we sought to understand the context for integrating equity into the current VA QI process. This work was the foundation for a broader initiative to develop a multifaceted user-centered tool that would both highlight health care inequities within VA Medical Centers (VAMCs) and empower members of the health care workforce to approach QI through an equity lens.37 UCD places end users at the center of an iterative process that seeks to understand the responsibilities and requirements of users before designing the tool rather than designing the tool and subsequently trying to obtain user buy-in.38In this article, we focus on the first stage of a user-centered design (UCD) process to support equity-focused QI in VA. UCD aims to create tools that are usable and useful by applying human factor knowledge and usability methods to improve the likelihood of adoption and sustained use.39The UCD process starts with seeking an in-depth understanding of the realities and constraints of the context in which end users will interact with the tool, such as their priorities, tasks, workflow, and resources . The nex40 and were contacted by interviewers by email. Most interviewees were familiar with the interviewers through their shared place of employment.Our population of interest included members of the VA health care workforce who are directly involved in prioritizing, directing, or conducting QI initiatives in VA primary care settings in one regional VA network. To understand how priorities are set at multiple levels of the organization, we interviewed medical center administrators, departmental or service line leaders, and clinical staff involved in direct patient care. All interviewees were in roles where they interacted with QI data in some capacity. Interviewees were identified using purposeful samplingSemistructured interviews were conducted in-person or by telephone, with email follow-up for clarification or additional questions as needed. Interviews lasted ∼30 min and were conducted from February to April of 2019. Interviewers included the three co-authors, working alone or in pairs. All interviewers were experienced in conducting semistructured interviews and were trained in the social sciences . Most interviewees were interviewed individually apart from one instance in which two people were interviewed together.Interviews were designed to understand existing practices for monitoring health care quality  and explore how equity data might fit into current QI processes. Interviewees were asked to identify high-priority quality measures, describe who was involved in tracking quality data and how measures were tracked, and report whether disparities by race and ethnicity, gender, or geography were being monitored. Questions also asked about past or ongoing QI initiatives, whether such initiatives were explicitly focused on disparities, and how information about disparities, if made available, would likely be utilized in future QI efforts.41 Interviewers summarized key points from each interview into an excel spreadsheet. Interviewers then reviewed the summaries after every two to three interviews and identified areas to probe further in subsequent interviews. The process continued until saturation was reached.42 Interview summaries were then used to draft an initial set of interface design and functional requirements for developing a tool to support equity-focused QI.Themes were extracted through rapid qualitative analysis.We conducted a total of 13 interview with 14 respondents  from three VA medical facilities of varying complexity within a single region . InterviInterviewees described typical processes for planning and carrying out QI, including how priorities are set, who is involved, how data are used to inform interventions and track progress, if/how equity is incorporated into current workflow, and what resources exist to support initiatives. Below we summarize insights that emerged from these interviews, organized into themes related to QI priorities, tasks and workflows, and resources.Given the VA's hierarchical structure, most strategic priorities discussed by interviewees were top-down in nature. Priorities set by VA Central Office become national priorities, which influence regional network annual plans, which in turn influence priorities and QI goals at individual facilities. Interviewees conveyed that the formula used to rank individual VA facilities in terms of quality  prompted local leaders to strive for overall improvement relative to other VAMCs. Described by one chief of staff, “We are looking to be at the top of quality indicators. It is a ranked system, so you want to achieve the highest ranking possible.”Acknowledging the influence of national quality priorities, respondents noted that priorities also emerged from the bottom-up based on local needs. Another chief of staff described planning for “reactive” initiatives in response to things that go wrong, while many department leaders and front-line providers reported identifying areas for improvement based on trends observed in the local patient population.Even though disparities were not routinely examined or prioritized in practice, respondents generally acknowledged that stratifying quality measures by demographic groups could be useful. One provider felt that having race, gender, and regional information about patients could be helpful in targeting efforts to reduce readmission rates for ambulatory sensitive conditions. A primary care chief shared that examining quality measures by race could help raise provider awareness about things like racial bias. A chief of staff remarked, “I would love to see all demographic data for Veterans be integrated into all data registries to be used by folks in innovative ways.” They further acknowledged that where people live and how much money people make, characteristics that are not widely available in existing VA data sources, have a huge influence on health.Data are needed at multiple levels of aggregation throughout the QI process. Medical center administrators rely on aggregated data when reviewing quality at the facility level and setting improvement priorities. As potential issues are flagged, data are examined at more granular levels to pinpoint specific clinical settings in which quality lags.The concept of “drilling down” from highly aggregated reports to team- and patient-level data was a common theme across interviewees. One primary care chief detailed a typical process of presenting aggregated data to providers followed by generating and distributing provider or team-specific reports of patients who were not meeting the measure. The purpose of drilling down to “patient outlier” reports was at least threefold: investigate why patients may not be meeting the quality measure, inform clinical interventions, and support proactive outreach.Regardless of the level at which priorities are set or quality issues are identified, implementing improvement practices is typically delegated to members of the clinical workforce. When medical center leadership prioritized quality measures, for example, it was common practice to task frontline staff members in the form of committees, workgroups, or individuals  with reviewing data and carrying out improvement strategies. An associate chief nurse noted that high-priority performance measures were “funneled down to nurse managers and nurses in each unit.” Those nurses then conducted locally tailored projects to investigate and address root causes of quality issues within their clinical settings.Even though those involved in direct patient care were tapped to assist with addressing quality issues, providers without a designated QI role expressed that they lack adequate time to do anything other than see patients. When asked about the extent to which quality measures are used in their own practice, one physician answered, “Not much. We are overwhelmed with data. We need protected time to do anything other than clinical work.” Another described, “I don't use tools directly because I don't have bandwidth to do it. Everyone agrees it's something we should do, but you've got to find the best way to work it into the process.”Interviewees explained that examining disparities in quality measures was rare. Most respondents (12 of 14) said that they do not routinely see facility or service line-level quality reports stratified by race and ethnicity, gender, geographic location, or other disparity-related variables. Although some respondents had seen reports stratified by race, such reports were not standard. One chief of staff explained, “Measures are not usually broken down that way. You may be able to drill down to those factors, but I am not sure how easy it would be.”3Demographic characteristics were also rarely and inconsistently included in patient-level reports. Some interviewees shared that binary gender, geographic region , and age were sometimes included, although this was highly dependent on the data source. Race and ethnicity were nearly always omitted from patient-level reports. Instances in which race and ethnicity had been included were in reference to a past QI initiative that explicitly focused on addressing racial disparities in hypertension.Interviewees widely agreed that they would benefit from expert recommendations on interpreting equity data, designing equity-focused projects, and using evidence-based interventions to reduce disparities. Generic or universal improvement strategies will be the default without support from health equity experts. When referring to an example of an improvement initiative inspired by data showing that blood pressure control targets were lower for Black Veterans, a respondent shared that, “We targeted our QI effort toward the entire population of outliers because we felt these interventions could help everyone.” QI teams may opt for generic or universally applied approaches that are seen as valuable due to their feasibility or broad reach, with the assumption that minoritized patient groups will see the same benefit from these interventions as the majority.This UCD-driven, qualitative inquiry into current VA QI practices provided several critical insights regarding what will be needed to fully weave equity into the QI culture within the VA and the context in which a health equity-focused QI tool would be used. The themes we identified have several implications for designing tools that make equity a core consideration throughout all stages of QI.43First, equity needs to be incorporated into quality monitoring practices at the national level, given that what is prioritized in national quality monitoring practices heavily influences regional and local priorities. Because the VA's current quality ranking system does not include equity as an explicit element, regional and local efforts to improve quality rankings rarely focus explicitly on reducing inequities as opposed to elevating quality overall. For equity to be fully integrated throughout VA's QI culture, methods that monitor and rank facilities in terms of quality need to incorporate measures of variability in performance across historically marginalized or minoritized Veteran populations.43–47 Applying such methods at a national level would also provide guidance to VA in terms of which facilities to engage in equity-focused improvement initiatives and how to prioritize patients from marginalized populations to close quality gaps.Including indicators that convey how consistently each facility delivers high-quality care regardless of patient demographic characteristics would not only demonstrate VA's commitment to equity as one of the pillars of health care quality but would also provide facilities with equity-specific targets to strive toward when considering local QI priorities. Applying analytic methods that decompose disparities into within and between facility components could further inform efforts to identify the largest and most persistent disparities affecting the VA patient populations.Second, building equity into multiple levels of infrastructure will be needed to keep equity top of mind throughout the QI process. National, regional, and local decision support tools need to include the capability to stratify and compare quality measures by demographic groups defined by race/ethnicity, gender, and other proxy markers for historical, social, and economic disadvantage. Disaggregating data in regional and local quality reporting tools would facilitate the consideration of equity-related issues when developing regional and local priorities and performance plans. Given that responsibility for exploring causes of quality issues and carrying out improvement initiatives is often delegated to local people or teams within specific clinical areas, such teams also need to be equipped with the data and protected time required to investigate and intervene on root causes of inequities.Demographic characteristics and indicators of social determinants of health that are available in the electronic health record should be included in all patient-level quality reports. The inclusion of this information would facilitate in-depth exploration into potential root causes of quality issues that may be disproportionately affecting the health care of certain patient subgroups versus those that are common across all patients. Including patient demographic information would also facilitate efficient outreach to populations that are experiencing disparate care and may need tailored improvement interventions.Third, the practice of delegating responsibility for improving quality to individual teams and providers poses potential barriers to incorporating equity into the QI process. For example, a common scenario is that a quality gap is identified at a facility level, and then teams and providers are called upon to help improve that quality measure for their individual patients. They may be provided with clinical reminders or lists of patients who have not received the recommended level of care, and then tasked with addressing the quality issue for their patients. Our findings showed that providers involved in direct care of patients often do not have the protected time to investigate or address quality issues at a population level.Furthermore, disparities are system-level issues caused by multiple factors, many of which are outside the scope of what individual providers or teams can address within their regular work. Considering system-level policies, practices, and potential biases as possible root causes of disparities should be part of the conversation when designing equity-focused improvement initiatives. The dominant model of delegating the responsibility for improving quality to individual teams and providers is not conducive to engaging the workforce in the collective action and system changes needed to address disparities in quality.48–52 To demonstrate that it is possible to reduce disparities when equity is an explicit consideration of QI, members of the health care workforce should also be trained on promising practices for reducing disparities.Finally, systems for providing equity training and resources will be essential to advancing equity-focused improvement initiatives. Training and support should emphasize the bigger goals of the QI initiative and how individuals can contribute to positive change. To foster a sense of urgency to act on disparities within our personal spheres of influence, members of the health care workforce should be given opportunities to learn about social and structural determinants of health equity and the ways in which health care policies have caused and perpetuate inequities.53 Teams should also be encouraged to partner with clinical staff who work with marginalized Veterans and engage Veterans from marginalized groups when designing equity-focused QI to assure that new initiatives benefit the target group, are designed to be sustained and spread, and do not have unintended negative consequences.54–56 Making publicly available toolkits, tailored patient educational materials, and other equity-oriented resources easily accessible could also help jump start new equity-focused improvement initiatives.Such promising practices include developing interventions with multiple targets for change , leveraging community health workers or peers, culturally tailoring interventions to the needs and preferences of marginalized groups, and empowering nurses to lead QI initiatives.The themes identified in this work guided our initial development of tools and processes to support equity-focused QI within VA. Understanding the overall ways in which QI was carried out across multiple levels of the organization helped us to distinguish two categories of users with differing needs: (1) decision-makers who set QI priorities and (2) frontline staff who design, implement, and evaluate interventions. We chose to focus initially on the second set of users, given that this group plays an essential role in the success of many improvement initiatives, yet expressed not having adequate time or infrastructure to support QI activities.37 we developed a national VA Primary Care Equity Dashboard (PCED) to meet the needs of QI champions working in VA Primary Care settings as they plan, design, implement, and evaluate equity-focused QI projects in their local VAMCs. Hosted on the VHA Office of Health Equity SharePoint site, the PCED contains a series of reports that show both quality and equity in select outpatient measures tracked by the VA Office of Reporting, Analytics, Performance, Improvement, and Deployment.57Continuing with the steps of the UCD process,Importantly, the PCED shows how individual VAMCs compare to the national average on each measure overall and by subgroups defined by racial/ethnic group, gender/sex, rural/urban residence, and neighborhood poverty level. The PCED also includes patient-level reports that contain patient demographic variables as well as clinical information about patients who have not yet received the recommended level of quality for a particular measure. To assist end users with planning initiatives, the PCED also contains a curated library of relevant evidence-based equity-focused resources, and additional guidance on how to use the PCED is available on the PCED SharePoint Site.58 the PCED now has over 1600 users spanning all 23 Veterans Integrated Service Networks and VA Central Office. Case studies based on the PCED have been featured in a course sponsored by VHA Office of Patient Centered Care and Cultural Transformation on social and structural determinants of health, and projects inspired and supported by the PCED have been presented as Health Equity Safety stories to the VA Governance Board. Based on the initial uptake of the PCED and early success stories, the PCED provides a successful model for how to build functional tools that support thoughtful engagement around equity in clinical settings.First released on a national scale in February 2021,


Myeloid cells  are bone marrow-derived cells of the innate immune system and function as the first responders during acute infectious and sterile inflammatory insults. However, when their responses are not tightly regulated, the activity of these innate immune cells can have detrimental effects on tissue integrity and trigger chronic inflammatory conditions.The advent of omics and spatial technologies complemented by the work carried out within international consortia, such as the Human Cell Atlas  and the ex vivo models to validate both their causative role to disease and the effects of the disease microenvironment on their biological functions in perturbation experiments. Moreover, additional single-cell transcriptomics, epigenetics and proteomics datasets on myeloid cells can now be fully integrated with single-cell atlases  are dysregulated in chronic human inflammatory diseases and b) may have predictive value in distinguishing disease phenotypes. Our collection includes 4 primary research articles that touch on the heterogeneity and functionalities of myeloid cells in severe burn, chronic obstructive pulmonary disease (COPD), sepsis and Huang et al. analyzed the transcriptional landscape of circulating neutrophils from early-stage severe burn patients and discovered distinct subgroups with functional differences. The authors described the upregulated degranulation and metabolic dysregulation and observed time-dependent patterns of activation, suggesting a role for neutrophils in early stages of severe burn. These findings are in line with Velásquez et al. who followed up the frequencies and gene expression profiles of blood CD15+ cells to distinguish systemic inflammatory response syndrome from sepsis patients in the intensive care unit. The presence of immature neutrophil populations  defined the clinical picture in sepsis patients, a finding that was reflected by the elevation of azurophilic, specific and gelatinase-containing granule gene expression. Together, the data speak for the significance of neutrophil gene signatures as predictive biomarkers in systemic inflammatory diseases.Circulating neutrophils are an understudied immune population despite their high abundance in the peripheral blood and their involvement in systemic diseases, such as sepsis and severe burns. Magoulopoulou et al. and Baßler et al. contributed two exciting stories about the transcriptional remodeling of these myeloid cells in infection and COPD. Using spatial transcriptomics technologies and a 33-gene set, Magoulopoulou et al. demonstrated that inflammatory macrophages are located at subcellular distance to Mycobacterium tuberculosis bacilli, reminiscent of infected populations, whereas non-infected cells were enriched in antigen presentation and T cell-related transcripts at later time points. The results reveal differences in spatial distribution between infected macrophage populations and T cells, as well as time-dependent induction of antigen presentation and adaptive immunity programs in tuberculosis. Lastly, Bassler et al. assessed the population structure of alveolar macrophages in COPD, a progressive obstructive and inflammatory condition of the small airways, with single-cell transcriptomics. They showed that macrophages from COPD patients decrease antigen presentation capacity and chemotaxis, accumulate cholesteryl esters and undergo mitochondrial dysfunction, reminiscent of impaired immune activation. Cell-cell communication analysis predicted that TGF-β is a major upstream regulator of transcriptional changes. Both articles highlight the high degree of macrophage plasticity in infection and chronic inflammatory diseases and suggest that further work is required to better understand the relationship between their functions and the exact localization in their microenvironment.Lung macrophage populations play a pivotal role in mounting immune responses against invading pathogens and irritants, such as cigarette smoke. In our collection, In conclusion, our Research Topic aimed to shed light on the transcriptomic diversity of myeloid populations and provide evidence of gene expression profiles that may serve as biomarkers for human inflammatory diseases. Indeed, the included work studied the functions of blood neutrophil subgroups and their gene signatures in severe burn and sepsis, while making a case about the relevance of tissue localization in shaping macrophage responses in tuberculosis and the complex transcriptional remodeling in macrophages from human restrictive lung disease.TSK wrote the editorial. All authors contributed to the article and approved the submitted version.


Acute aortic valve insufficiency (AAVI) is a pathologic medical condition that has a presentation on a spectrum of severity and is attributable to numerous etiologies. Most often, it is caused by infective endocarditis, which depending on the patient’s clinical status may require treatment with either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). This case presents a patient with acute aortic valve insufficiency secondary to infective endocarditis, requiring intervention. Further, it also provides real-time use of the general guidelines used in the determination of SAVR vs. TAVR candidacy. This case will further help providers in the cardiology realm to identify this presentation and increase comfort in referring to existing guidelines, as well as highlight where the current guidelines appear limited. Acute aortic valve insufficiency (AAVI), often linked to infective endocarditis, poses a critical health risk that may potentiate urgent treatment. While some patients respond well to medical treatment, many require surgery to restore valve function and prevent complications. Aortic valve replacement (AVR) emerges as the preferred surgical solution for those with AAVI due to endocarditis, offering two main options: transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). The choice between these approaches depends on individual patient factors such as the severity of valve dysfunction, infection extent, comorbidities, and the patient's overall health. The decision of whether to proceed with surgery and, if so, when to perform AVR in AAVI cases remains a matter of ongoing debate -3. In thA 48-year-old gentleman with a past medical history of obstructive sleep apnea and polysubstance use (including intravenous cocaine and methamphetamine) presented to the emergency department with progressive shortness of breath and fatigue. Associated symptoms included dyspnea on exertion, orthopnea, and abdominal and lower extremity swelling. Of note, the patient’s previous medical care was in Mexico, where he was diagnosed with congestive heart failure and treated with antibiotics for presumed valvular disease without a specified timeline. His home medications included metoprolol tartrate, spironolactone, and atorvastatin. The patient was hemodynamically stable with notable exam findings including diffuse lung crackles bilaterally, 5/6 diastolic heart murmur, and mild pitting edema of both lower extremities. Chest x-ray revealed cardiomegaly and pulmonary vascular congestion Figure . He was The cardiothoracic surgery service was consulted for evaluation and consideration of the patient's eligibility for aortic valve replacement given his entire clinical picture and history of polysubstance abuse . Due to the patient’s preference to not be on lifelong warfarin and the associated valve sound from having a mechanical valve, the patient elected for the placement of a bioprosthetic valve. The patient was aware of the valve’s efficacy being limited to 10-15 years and that it may require redoing SAVR. On the ninth hospital day, surgical bioprosthetic aortic valve replacement was performed with initial annular enlargement of the aortic root that would permit the largest possible prosthesis to facilitate future valve management in the setting of a narrow sinotubular junction (STJ). Of note, intraoperative findings included infective destruction of the left and non-coronary leaflets with stringy vegetation and a lack of annular involvement or root abscess. After valve placement, supravalvular stenosis was noted intraoperatively and attributed to the patch aortotomy closure, which was resolved with subsequent vertical division of the STJ and the original patch was followed with augmentation that involved further aortic root reconstruction. Due to concern for bacterial seeding from the vegetation noted intraoperatively, the patient was placed on a course of vancomycin and cefepime for a total of six weeks. Ultimately, intraoperative bacterial, anaerobic, acid-fast bacillus, and fungal cultures did not grow any organisms. Pathologic examination of the explanted aortic valve leaflets found calcific degeneration and focal acute inflammation without any fungal forms identified on the silver stain. His follow-up TTE demonstrated normal ejection fraction and normally functioning aortic valve prosthesis.The presented case emphasizes the importance of in-depth evaluation and serves as another data point to contribute to the body of literature surrounding the use of SAVR in acute aortic regurgitation secondary to infective endocarditis; the patient’s symptomatic progression, history of intravenous drug use with previous endocarditis, and mild left ventricular hypertrophy directed the treating team toward a diagnosis of recurrent endocarditis of the aortic valve. Although no organisms were identified on the work-up, this was likely attributable to numerous previous rounds of antibiotics. Due to his worsening heart failure symptoms and echocardiogram findings of severe aortic regurgitation, the cardiology service recommended valvular intervention and presented both TAVR and SAVR to the patient as potential options noting that bioprosthetic SAVR would be preferable in the absence of other significant comorbidities. He underwent the procedure without complications, and the follow-up examination showed marked improvement in both clinical and echocardiographic findings. In this patient subset with acute aortic insufficiency, it is imperative to immediately risk stratify the patient's condition to elucidate whether or not the condition warrants urgent intervention. The European Society of Cardiology (ESC) is one of the only prominent organizations that provide guidelines on the appropriateness of surgical intervention in the setting of endocarditis with aortic regurgitation. Namely, the patient is a candidate for early surgical intervention-defined as within 48 hours of diagnosis, if the patient meets any of the following criteria: Hemodynamic instability due to severe aortic regurgitation, severe left ventricular dysfunction with an ejection fraction less than 30%, large mobile vegetations greater than one centimeter in size, persistent bacteremia or fever despite appropriate antibiotic therapy, and evidence of perivalvular extension of infection in the form of abscess, fistula, or pseudoaneurysm -3. HowevThe timing of AVR in patients with AAVI secondary to endocarditis is controversial, and there is no clear consensus on the optimal timing of surgery. The 2020 ACC/AHA guidelines for managing patients with valvular heart disease only broadly state that surgery should not be delayed, especially if there is hypotension, pulmonary edema, or evidence of low flow . AdditioThe present literature is still deciphering which patient populations benefit more from TAVR versus SAVR. Generally, these cases are evaluated on a case-by-case basis with particular evaluative emphasis on high-risk surgical patients, those with limited surgical options, hemodynamic instability, and valvular anatomy. Though, in some reviews, there is anecdotal evidence and some expert opinion that points to SAVR as the preferred option for this patient subset as it allows for complete removal of the infected valve and surrounding tissue as well as easier access to other affected cardiac structures. There is additionally a seemingly lower risk of 30-day mortality, stroke, and aortic valve reoperation in the SAVR group compared to those undergoing TAVR ,6. It shThe presented case describes a clinical scenario that would benefit from more specific guidelines regarding when to perform surgery as well as to determine whether TAVR or SAVR is more appropriate for this specific patient population. Though the patient was deemed a surgical candidate due to presumed endocarditis with severe acute aortic regurgitation with refractory pulmonary edema, there was no clear consensus guidance on whether TAVR or SAVR was preferred. This case is limited by only being one data point, but it highlights the need for future research to be performed in order to draw more robust conclusions for patients with acute aortic valve insufficiency secondary to infective endocarditis; specifically, more research should be performed to determine if earlier intervention yields better outcomes in this patient subset, as well as which type of intervention produces the best long-term outcomes. More generally, this research should serve to aid in refining current guidelines on when to perform SAVR or TAVR, or the superiority of one over the other.


Skeletal muscle is a target tissue of GH. Based on its anabolic properties, it is widely accepted that GH enhances muscle performance in sports. Athletic performance depends on muscle strength and the energy required to power muscle function. The energy required to power muscle function is derived from a continuum of anaerobic and aerobic sources. Molecular and functional studies provide evidence that in muscle GH stimulates the anaerobic and suppresses the aerobic energy system, in turn affecting power-based functional measures in a time-dependent manner. In recreational athletes, GH improves anaerobic capacity but has not been proven to significantly enhance muscle strength, power, or maximum rate of oxygen consumption. GH appears likely to selectively benefit sprint events and not physical performance that depends on strength and endurance. Arch Endocrinol Metab. 2019;63(6):576-81 The use of substances to gain competitive advantage in sports is probably as old as sports.It is not known when athletes first started to use growth hormone (GH). It was promoted as a performance enhancing agent in the first edition of The Underground Steroid Handbook in 1981. This was well before the first human trials of reporting the benefits of GH in adults with GH deficiency. By then, GH had become widely known in competitive sport as a “doping agent” often used in combination with testosterone or other androgenic anabolic steroids.The appeal of GH stems from its anabolic and lipolytic properties that increase muscle mass and reduce fat mass respectively. Evidence that GH is widely abused is evident from the number of website hits for GH supply, by customs and police drug seizures and by increasing media reports of prosecution of high-profile athletes . Fifty pAbuse of GH can start at a young age. A survey of 10th grade boys in the US indicated that 5% had taken GH, with more than half using GH in conjunction with steroids . Doses uDue to its health risks to athletes and its potential to enhance sports performance – in addition to violating the spirit of sport – GH was listed in 2008 in the List of Prohibited Substances (http://www.wada-ama.org/rtecontent/document/2008_List_En.pdf) by the World Anti-Doping Code at all times, both in- and out-of-competition. What then is the evidence that GH enhances sporting performance? This review will cover information on the effects of GH on muscle function, on substrate and energy metabolism and examine evidence whether GH benefits different forms of physical outcome measures in recreational athletes.Muscle function is regulated by many factors including genes, nutrition, lifestyle and hormones such as GH, thyroid hormones, testosterone and glucocorticoids. The stimulation of muscle protein anabolism and growth by GH has led to widespread expectation that it improves muscle strength and power. Skeletal muscles are specialized contractile tissues that control posture and physical activity while serving an important role in energy metabolism. Muscle function is dependent on the composition and strength of fibre types that require energy to drive and sustain contractile work.Muscle function is most commonly measured as strength and power . StrengtSkeletal muscle is composed of fibres that are made up of different proteins with distinct properties. Actin and myosin are functional contractile proteins, whereas tropomyosin and troponin are structural proteins that keep the contractile proteins in proper alignment giving fibres elasticity and extensibility. Myosin protein consists of two heavy chain and four light chains. Muscle fibres are classified by myosin heavy chain (MHC) isoforms mainly into two types. Type I fibres, also known as slow twitch fibres, contain an abundance of mitochondria and rely on aerobic or oxidative pathways for energy production. These fibres determine the endurance capacity of muscle. In contrast, type II fibres, also known as fast twitch fibres, generate energy from anaerobic or glycolytic pathways due to their low mitochondrial content. These fibres have high contractile force, but easy fatigability from limited energy supply. They subserve high intensity activities such as sprinting and weight lifting. There are few small human studies investigating the GH regulation of muscle fibre composition. These studies do not provide sufficient evidence supporting a role of GH in the regulation of type I or II fibres in human skeletal muscle .The contractile function of skeletal muscle relies on a constant supply of chemical energy. During muscle contraction, chemical energy is converted to mechanical energy that leads to movement.Many factors regulate energy synthesis from substrate utilization in exercising including nutrition, metabolic hormones and the level of exercise. Whole body lipolysis during resting condition  and exerIn summary, GH effects on substrate metabolism are tissue specific. Evidence suggests that GH may promote non-oxidative or anaerobic substrate metabolism in skeletal muscle for ATP synthesis, findings contrary to its effects on whole body metabolism.Muscle strength is commonly assessed by measuring the force or torque produced during an isometric or isokinetic contraction. Isometric strength is the MVC that can be developed against an immovable object without a change in joint angle, whilst isokinetic strength is a measure of torque/force through a range of motion in which limb is moving at a constant velocity . This foThere is strong evidence that long-term replacement of GH normalizes muscle strength in adults with GH deficiency in whom isometric and isokinetic muscle strength are reduced . Only a Muscle power is defined as work performed per unit of time and is expressed in joules per second or watts. It is described in terms of aerobic and anaerobic power, depending on which energy source is predominantly utilized to do the work. Thus, muscle power can be assessed by measuring aerobic exercise capacity and anaerobic exercise capacity.2 max) in L/min or ml/kg/min or maximal aerobic power output in watts or kilojoules during an incremental exercise test on a cycle ergometer or a treadmill . Compared to baseline, men who guessed incorrectly had significantly improved self-assessed scores for all categories and also increased measured performance for VO2 max and strength. For women, there were no significantly greater outcomes for those who guessed incorrectly compared to correctly. In short, athletes who believed they were on active treatment not only had a perceived improvement on performance, but also in measured physical performance. The effect was greater in men. This study showed that a placebo effect may contribute to perceived and actual performance-enhancing effects of GH, particularly in men (A placebo effect refers to a favorable outcome arising purely from the belief that one has received a beneficial treatment . In theiy in men . HoweverThe collective published information on the performance outcomes of GH treatment are limited by the dose and duration of treatment and evaluation . These sThere has been high expectation that GH enhances physical performance based on its anabolic and lipolytic actions. Physical performance in sports is a complex entity influenced by muscle size, contractile strength and the energy source required to support the duration of physical activity which in turn determines anaerobic and aerobic capacity. In fit people, GH in doses used in ethically-supervised studies does not affect muscle strength or aerobic capacity but improves anaerobic capacity. The evidence suggests that GH is unlikely to benefit power or endurance sports but likely to benefit sprint events.


Psychosis spectrum disorder (PSD) affects 1% of the world population and results in a lifetime of chronic disability, causing devastating personal and economic consequences. Developing new treatments for PSD remains a challenge, particularly those that target its core cognitive deficits. A key barrier to progress is the tenuous link between the basic neurobiological understanding of PSD and its clinical phenomenology. In this perspective, we focus on a key opportunity that combines innovations in non-invasive human neuroimaging with basic insights into thalamic regulation of functional cortical connectivity. The thalamus is an evolutionary conserved region that forms forebrain-wide functional loops critical for the transmission of external inputs as well as the construction and update of internal models. We discuss our perspective across four lines of evidence: First, we articulate how PSD symptomatology may arise from a faulty network organization at the macroscopic circuit level with the thalamus playing a central coordinating role. Second, we discuss how recent animal work has mechanistically clarified the properties of thalamic circuits relevant to regulating cortical dynamics and cognitive function more generally. Third, we present human neuroimaging evidence in support of thalamic alterations in PSD, and propose that a similar “thalamocortical dysconnectivity” seen in pharmacological imaging  in healthy individuals may link this circuit phenotype to the common set of symptoms in idiopathic and drug-induced psychosis. Lastly, we synthesize animal and human work, and lay out a translational path for biomarker and therapeutic development. Patientoimaging . IdentifLike all mammalian counterparts, the human forebrain is organized into loops connecting the cortex, thalamus and basal ganglia . BroadlyIn addition to its unique anatomical features, converging lines of evidence suggest that the thalamus is prominently altered in patients with PSD and schizophrenia in particular, thus supporting the idea that it may not only be a target of intervention, but also a viable biomarker of specific symptoms associated with PSD . InteresHere we discuss a framework that considers the critical role of the thalamus in the neurobiology of PSD. We structure this piece into four sections. First, we outline our central hypothesis related to thalamocortical dysconnectivity and PSD symptomatology, with an overarching framing that PSD fundamentally affects computations supporting cognitive control and reasoning . Second,functional dysconnectivity underlies the debilitating, complex and highly heterogeneous symptoms seen in PSD patients. These symptoms include formal thought disorder, delusional beliefs, hallucinations, affective disturbances, and executive deficits . We suggest that all of these symptoms are to some extent cognitive in nature, and are linked to perturbations in coordinated activity patterns across higher-order associative circuits. Within this framework, associative thalamic circuits play an essential regulatory role, offering a window into PSD etiology and perhaps even rational correction.A major idea in this piece is that PSD is a syndrome associated with perturbation in processing across distributed large-scale neural systems, which preferentially and severely impacts forebrain associative systems. This It is important to recognize that the clinical reality of PSD is heterogeneity; the symptoms outlined above are variable in onset, severity, prevalence, and treatment response across individual patients. Therefore, it is likely impossible to define this syndrome by a single neurobiological “cause.” Instead, we suggest that the core deficits across the spectrum of psychotic illness are related to appropriately organizing information flow across levels of reasoning hierarchy . In otheThe key aspect of the framework that we offer here, is that the associative thalamus provides a functional bridge across these specialized frontal areas, allowing their interactions to be both dynamically efficient and highly flexible, depending on the behavioral context . TherefoAs noted, the thalamus is a centrally-located structure in the mammalian forebrain, which is traditionally divided into individual nuclei based on Nissl staining and gross connectivity . There aGiven the lack of local excitatory recurrence in the thalamic nuclei, the functionality of thalamic projection neurons is anchored in their long-range input-output connectivity patterns . ArguablRecent studies outside of primary sensory thalamic areas have challenged the relay view, and ascribed a critical functional role for the thalamus in cognitive computations. For instance, studies in associative thalamic structures like the mediodorsal thalamus and pulvinar have shown that these nuclei may have convergent inputs from multiple cortical areas and that, in contrast to primary relay nuclei, they can integrate and transform these inputs into novel representations, including temporal context , confideConsistent with this revised model of the thalamus , work inSimilar to the pulvinar, the mediodorsal thalamus establishes widespread connections across multiple cortical areas . HoweverIn summary, the fact that associative thalamic structures provide a mechanism for regulating associative cortical computations in a precise manner, and in turn coordinate activity across large-scale cortical networks is consistent with our overall thesis that associative thalamic structures could be leveraged to identify and target cognitive control deficits in PSD.Advancing research in the field of PSD will require innovation in non-invasive neuroimaging which will provide the opportunity to link observed neural changes to the diversity of symptoms in this syndrome. More specifically, progress will be accelerated by neuroimaging signals that can be optimized for risk prediction, diagnostics, treatment development and prognosis. Here we argue that the thalamus presents a uniquely powerful opportunity for PSD neuroimaging biomarker development which may be linked to specific symptoms.via functional magnetic resonance imaging sensitive to blood-oxygen-level-dependent (BOLD) signal changes. It is now widely accepted that BOLD fMRI signal exhibits spatiotemporal coherence in humans. These relationships can be quantified using statistical association   , which iformance . This apformance  or subcoformance , with informance . Therefovia whole-brain neuroimaging segmentation tools that leverage high-resolution structural scans  . These tAs noted, the thalamus is composed of multiple nuclei that form different types of input and output connections with cortex and striatum, in turn forming functional loops. In the context of understanding neural disruptions in PSD it is particularly important to distinguish between sensory and associative thalamus, which form distinct large-scale connection patterns onto cortex in the service of two fundamentally different types of operations: primary sensory relays from the environment versus coordination and regulation of association cortex in the service of cognitive function. Therefore, one strong prediction would be that the association thalamic connectivity may be preferentially affected by PSD – a syndrome that corrupts computations relevant for cognitive control. Consistent with this notion, the mediodorsal thalamus appears to drive the main observation of neural dysconnectivity in schizophrenia; recent studies have found reduced connectivity between higher-order thalamus and dorsal striatum, suggesting altered prefrontal cortico-striato-thalamo-cortical functional connectivity . This obStudies have concluded that, although PSD has a strong heritable component, there is considerable heterogeneity in the types of genetic changes underlying this syndrome . This haKetamine is a non-competitive NMDA receptor antagonist that rapidly and transiently induces symptoms seen in PSD when administered at subanesthetic doses, predominantly impacting executive function . A workiLysergic acid diethylamide (LSD) is a psychedelic substance, which activates serotonin 5HT2A receptors and induces symptoms of PSD with a dominant effect on perception and thought organization . As withTetrahydrocannabinol is a compound that activates endogenous endocannabinoid receptors, which are known to modulate E/I balance across cortical circuitry . AdminisCollectively, these human neuroimaging studies highlight the value of using pharmacology as a tool to perturb the brain in a manner that reproduces core symptoms of PSD. A major conclusion of these studies is that thalamocortical dysconnectivity may be an obligatory intermediate phenotype when mimicking PSD behavior. If true, this supports an etiological role of these circuits in psychosis. Future studies can exploit the individual differences within and across these manipulations in order to make even more precise mechanistic discoveries at the neural systems level. It is worth noting that the speed of these interventions provides therapeutic hope. For example, the fact that, under some conditions, certain individuals can experience well-formed delusions indicates that this feature of PSD may not require years of aberrant neural processing in order to form , but ratAs described above, pharmacological neuroimaging can reveal how a molecular perturbation produces systems-level effects in brain-wide neural dynamics, which in turn correlate with evoked symptoms. Such experimental studies highlight the explanatory gaps across levels of analysis–from receptors to circuit, and behavior–that need to be bridged to have a mechanistic understanding of how disease processes and therapeutics impact system-level brain function and in turn relate to symptoms. One approach to integrate findings across levels is through computational modeling of neural systems. Computational models of thalamic and cortical circuits offer opportunities to study the impact of hypothesized molecular alterations on neural dynamics and cognitive function relevant to PSD and other neuropsychiatric disorders.why” questions regarding thalamocortical organization , or more recently non-invasive ultrasound, has been useful in a number of clinical applications. Could a similar approach be useful in targeting treatment resistant PSD? This question is quite pertinent as ∼30% of patients continue to experience debilitating symptoms despite treatment with clozapine as their last resort antipsychotic agent .As highlighted throughout this perspective, the thalamus occupies a central location not only in forebrain structural organization but its functional one as well. This conclusion is supported by both invasive recordings in non-human animals and neuroimaging studies in humans. The animal studies provide mechanistic insight that is hard to obtain from human studies, whereas the human studies provide direct relevance to cognitive operations that are difficult to implement in animals. Therefore, the combination of these approaches is necessary and jointly support the idea that associative thalamic structures are engaged in regulating the interactions within and across associative cortical areas, and that perturbations within these areas lead to a host of abnormalities characteristic of PSD.This mesoscopic-to-macroscopic level of description is critical for bridging the findings at the molecular and cellular level with PSD symptoms, and ultimately develop the next generation diagnostics and therapeutics. Consistent with this notion, a recent circuit study on mice identified two distinct cell types in the mediodorsal thalamus that either enhance or suppress task-relevant prefrontal activity patterns . The keyThe studies above highlight an important idea; translational progress may be best achieved when it focuses on evolutionarily conserved areas between the human brain and its non-human counterparts. It is no secret that the human cortex is one of the most fascinating pieces of machinery nature has generated over the last 4 billion years of evolution on this planet. However, its unique expansion poses a challenge, insofar that many of its divisions are difficult to map on species normally studied in the laboratory (including macaque monkeys). The thalamus may provide unique translational opportunities in that domain; there are far fewer disputes about homology across divisions of the thalamus between species (even with mice) compared to, say, areas of frontal cortex .That said, we should mention that the mechanistic accessibility that rodents provide needs to be augmented by the cognitive complexity that non-human primate models afford. These organisms, which can perform much higher level cognitive functions including well-parametrized versions of cognitive tasks used in PSD clinical practice , are indSimilar to non-human primates, our view is that computational models will play essential bridging roles across levels of analysis in the quest for next generation PSD diagnostics and therapeutics. In addition to biophysically constrained models, which provide a link from molecules to circuit function , recent The thalamus has emerged as a critical node in large-scale functional forebrain organization. Its continued exploration may offer mechanistic insights into how the brain implements cognitive operations whose perturbation, we have argued, form the basis of most PSD symptoms. Given the recent advances in targeting the thalamus through DBS and focused ultrasound, this new understanding may tell us where in the thalamus to target and when in the illness to do so.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.AA and MH conceptualized and wrote the manuscript. Both authors contributed to the article and approved the submitted version.


Nonlinear careers through academia are increasingly common, but funding agencies and search committees penalize these paths. Why do scientists stray from the beaten path, how do they contribute to science, and how do we level the playing field? Those who follow non-linear career trajectories often face disadvantages in academia. This Perspective looks at why individuals might choose non-linear careers and how these benefit diversity in science. The institutional structure of an academic career discourages following a nonlinear career trajectory. Most critically, time and age restrictions for early-career funding can systematically disadvantage those who have taken nonlinear career paths. We are a group of early-stage investigators working in the United States who have taken nonlinear paths through our academic careers: a high school dropout who restarted her education after having children; an immigrant scientist who left academia to work as a consultant and financial analyst for an extended period and then returned; a mother who started her family during her PhD and left academia when the career became incompatible with parenthood, only to return later; and a first-generation college student from a low socioeconomic background who worked full time throughout her education. Here, we argue that those with more diverse career histories benefit the scientific community. We propose better practices for targeting funding to early-career scientists without creating obstacles for those who have taken nonlinear career paths.Obtaining funding to support a lab is critical for establishing an early-stage investigator’s career. In recognition of the fact that early-stage investigators may not be able to compete effectively against established investigators, many funders specifically target early-stage investigators, aiming to kickstart their careers. To equalize the playing field, these funders have eligibility criteria. For instance, the largest funder of STEM research in the world, the US National Institutes of Health (NIH) , restricLimitations relative to absolute age, time from doctoral degree, and/or duration of postdoctoral training arbitrarily select against early-stage investigators who have taken nonlinear or nontraditional career paths. To illustrate this, we have depicted our own career paths against the “model” linear career path . Taking The reasons that a scientist may take a less straightforward path through their career are generally tied to socioeconomic inequality, elitism, and exclusion of minority populations, caregivers, and women . ExaminiEconomic factors strongly intersect with parenthood, which may also lead to a slower academic career. The low compensation at early stages of academia poses an obstacle for many caregivers, and parenthood can result in a substantial slowing of productivity given that many universities do not offer infrastructure for daycare and other child support . This leWe believe that people who have had nonlinear career trajectories bring unique and beneficial qualities to academia. Despite their background or the life events that might have made their course less straightforward, these scientists persisted. Overcoming challenges and failure is an integral part of the academic path. Resilience requires motivational intensity and persistence, traits that are inarguably important for a successful academic career. We need to recognize that scientists with nonlinear career histories have developed a level of motivational intensity that is predictive of success in academia. The scientific community should embrace such resilience. In addition, job skills from working in other sectors are valuable and round out a faculty member’s abilities to run a lab . We planTo improve opportunities for career advancement and funding for people who have taken nonlinear paths, we suggest several practices that could be implemented. First, funding agencies should be intentional about their goals when setting age requirements for opportunities. In general, for faculty-level funding, the clock should start from the time that the first tenure-track-equivalent faculty position began and not from the end of the PhD or start of the post-doctoral period. Funding should not include an age cap. Agencies should recognize that many case-by-case discussions will be needed and assign resources accordingly, rather than imposing inflexible criteria. One size does not fit all.Second, funding agencies and hiring committees in the US should standardize the ability to justify periods of low productivity or career breaks. Policies of various European funding agencies that extend eligibility based on a calculated time period worked, accounting explicitly for part-time work, family/caregiving leave, and periods employed outside of the field, may provide inspiration .Third, hiring and funding groups should consider alternative strategies for gathering key career productivity information into CVs and bio-sketches  to makeIn summary, those who have taken nonlinear paths through their academic careers are currently disadvantaged by limits to funding eligibility and negative bias for their choices. Because nonlinear paths are more likely to be taken by women, caregivers, and those from underrepresented or low socioeconomic backgrounds, many funding eligibility requirements are in conflict with the goals of the scientific community to improve representation of people from a wide variety of backgrounds in the sciences. We believe that people who have taken nonlinear paths enrich the scientific community, bringing creativity and resourcefulness as well as job skills and life experiences that benefit the lab. Academic scientists who have taken nonlinear paths through their careers deserve equitable chances at funding opportunities and career advancement.


Kidney Transplantation is the preferred treatment for most patients with end-stage renal disease (ESRD) . DespiteBiomarkers are biomolecules found in body fluids or tissues. Traditional monitoring after renal transplantation includes the continuous measurement of serum creatinine (Scr), estimated glomerular filtration rate (eGFR), blood concentration of immunosuppressive drugs, donor specific antibody (DSA) monitoring, virus quantity detection, and so on. However, they often reflect advanced tissue damage and have limited ability to accurately detect SCR. Recent advances in high-throughput molecular biotechnologies and bioinformatics have now made it possible to in-depth analysis of kidney allograft rejection and response to treatment. Accordingly, new biomarkers can be identified and validated by non-invasive or minimal-invasive approaches. And the discovery of novel biomarkers as reported in this collection raised new hope for early detection and development of promising new treatment approaches.Li et al. include LASSO, random forest, and support vector machines. Six hub genes  were identified as potential predictors of acute kidney injury. These genes can be used as a new tool for early diagnosis of AKI.Most transplanted kidneys come from deceased donors and inevitably experience ischemia reperfusion injury, which may lead to AKI and affect the recovery of renal function after surgery. Three machine learning algorithms used the study by Raïch-Regué et al. used immunohistochemistry to show that p-S6RP in the peritubular capillary endothelia was associated with circulating human leukocyte antigens (HLA)-DSA in transplanted kidney tissue biopsies and first suggested that it could be used as a sensitive alternative biomarker for HLA-DSA to diagnose ABMR when DSA was not available or not yet detected. Renal operational tolerance, defined as the condition in which a SOT recipient retains stable graft function and lacks histological signs of rejection, after at least 1 year of immunosuppressant discontinuation  can be used to distinguish the origin of cfDNA, so that donor derived cell free DNA (dd-cfDNA) can be widely used to detect the early graft function status  and T cell-mediated rejection (TCMR) can significantly lead to deterioration of graft function and eventually graft loss. Currently, complement activation in the form of C4d deposits in peritubular capillaries (PTC) is used as an ABMR marker  is that it can identify different immune cells in the graft kidney, which is of great significance to explore the changes both in number and function of macrophages , T cellsIn conclusion, identification of earlier diagnostic biomarkers will not only allows designing individualized therapy for timely therapeutic intervention, but also further advance understanding of pathgeneisis of kidney allograft rejection. The field has been evolving rapidly; substantial prograss has been made over the last decade. It is conceivable that as the number of clinical studies using omics and other innovative approaches continues to increase, biomarkers with high sensitivity and specificity will be identified and vlidatated in the next few years, thus guiding the development of early preventive treatment strategies for clinical applications.XD wrote and revised the editorial. XH and ZZ revised the editorial. All authors reviewed the manuscripts submitted to the Research Topic and the final version of this editorial. All authors contributed to the article and approved the submitted version.


While several meta-analyses and reviews have summarized the evidence of in utero cannabis exposure on adverse obstetric outcomes  and long-term offspring development, there has not been a focus on in utero cannabis exposure and risk for structural birth defects.Cannabis use among pregnant women has increased over time. Therefore, there is a great public health need to understand the consequences of in utero cannabis exposure and structural birth defects.We conducted a systematic review using PRISMA guidelines to evaluate the association between We identified 20 articles to include in our review and focused on interpreting findings from the 12 that adjusted for potential confounders. We report findings by seven organ systems. Within the 12 articles, four reported on cardiac malformations, three reported on central nervous system malformations, one reported on eye malformations, three reported on gastrointestinal malformations, one reported on genitourinary malformations, one reported on musculoskeletal malformations, and two reported on orofacial malformations.in utero cannabis exposure and birth defects reported in more than two articles were mixed . Findings for associations between in utero cannabis exposure and birth defects reported in two articles  or in a single article  suggested that cannabis exposure was not associated with these types of malformations, but strong conclusions cannot be drawn from such sparce research. We review the limitations and gaps in the existing literature and call for more research to rigorously evaluate associations between in utero cannabis exposure and structural birth defects.Findings on associations between identifier CRD42022308130. Several meta-analyses and reviews have summarized the evidence of in utero cannabis exposure on adverse obstetric outcomes  and long-term offspring development  AND (Cannabis OR Marijuana) AND .” The inclusion criteria were English-language articles and epidemiological studies. Animal studies and review articles were excluded as the focus of our review was strictly on human outcomes.Web of Science and PubMed databases were searched for English language articles published before February 1, 2022 utilizing the following key words: “ malformations, and results were conflicting  the four articles reporting on adjusted associations with cardiac malformations  in addition to self-reported cannabis use would reduce measurement error related to regnancy ].in utero cannabis exposure is vital for individuals to make informed choices about cannabis use in pregnancy, as well as for families and providers caring for infants exposed to cannabis in utero.Importantly, no single study can implement all of these recommendations, particularly given common obstacles faced by researchers, such as funding limitations restricting the scope of studies, challenges enrolling participants, difficulty obtaining biological samples, and loss to follow-up. However, future research should try to incorporate as many of these recommendations as possible to reduce biases and maximize the overall quality of the studies. Rigorous, high-quality information on the potential consequences of


The utilization of biomaterials in tissue engineering systems provides a valuable platform for controllably directing the fates of SSPCs with physical signals as a tool for mechanobiology investigations and as a template for guiding skeletal tissue regeneration. It is paramount to study this mechanobiology and account for these mechanics-mediated behaviors to develop next-generation tissue engineering therapies that synergistically combine physical and chemical signals to direct cell fate. Ultimately, taking advantage of the evolved mechanobiology of SSPCs with customizable biomaterial constructs presents a powerful method to predictably guide bone and skeletal organ regeneration.Skeletal stem and progenitor cells (SSPCs) are the multi-potent, self-renewing cell lineages that form the hematopoietic environment and adventitial structures of the skeletal tissues. Skeletal tissues are responsible for a diverse range of physiological functions because of the extensive differentiation potential of SSPCs. The differentiation fates of SSPCs are shaped by the physical properties of their surrounding microenvironment and the mechanical loading forces exerted on them within the skeletal system. In this context, the present review first highlights important biomolecules involved with the mechanobiology of how SSPCs sense and transduce these physical signals. The review then shifts focus towards how the static and dynamic physical properties of microenvironments direct the biological fates of SSPCs, specifically within biomaterial and tissue engineering systems. Biomaterial constructs possess designable, quantifiable physical properties that enable the growth of cells in controlled physical environments both  Skeletal stem and progenitor cells are the multipotent, self-renewing cell lineages found in the bone marrow stroma that are broadly responsible for the repair, regeneration, and remodeling of skeletal tissue and cartilage . SSPCs hThe versatile range of functions that SSPCs possess results from their high sensitivity to the specific chemical and physical microenvironment in which they develop . The phyMechanobiology is a rapidly emerging field concerned with how cells sense, process, and respond to mechanical information resulting from the extracellular environment . It has bona fide skeletal stem or progenitor cell due to different reported detection methods, isolation, and functional evaluation  is a non-receptor protein tyrosine kinase found within the cytosol that is referred to as protein-tyrosine kinase-2 (PTK2) in humans . FAK is GTPases are a class of proteins that hydrolyze GTP to GDP and transduce signals by cycling between GTP-bound active states and GDP-bound inactive states . Rho-famYes-activated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are homologous transcriptional co-activator proteins that influence the expression of genes controlling cell differential fate in SSPCs . More spThe Piezo1/2 ion channels similarly play an important role in the mechanism of mechanotransduction in SSPCs. These transmembrane proteins are composed of numerous transmembrane domains and large extracellular domains, forming a mechanically sensitive complex . When suIn the context of SSPCs and bone differentiation, the Piezo1/2 mechanism of mechanotransduction has significant implications. Mechanical forces exerted on skeletal stem cells through physical activity or external loading influence their fate determination and lineage commitment. Activation of Piezo1/2 channels in response to these forces leads to an increase in intracellular calcium levels, initiating a series of molecular events that regulate osteogenic differentiation . This caStatic biomaterial strategies in this context are defined to be biomaterial systems with fixed physical properties that do not inherently change over most periods of time. Such is often the case with non-active biomaterial constructs, whose properties are determined strictly by their material properties and method of fabrication. For example, titanium dental implants have the fixed material properties of titanium but can be 3D-printed with different structures and surface topologies to affect osseointegration differently . These sBiomaterial constructs are typically two-dimensional  or three-dimensional  but can also be effectively unidimensional (1D) in the case of single nanofibers  Figure . The dimPorosity is typically associated with 3D biomaterial scaffolds and refers to the average volume of void space (pores) in a given bulk volume of the scaffold. The pores are oftentimes size-controlled with modern porous scaffold fabrication techniques . HistoriSSPCs are most abundantly observed in the bone marrow located in the trabecular bone, which is extremely porous with an average porosity of 79.3%, indicating this evolved design plays a role in the biology of SSPCs . Scaffolin-vivo and in-vitro , biomaterials promoting chondrogenesis typically have a Young’s Modulus in the range of cartilage tissue (500–2000 kPa or 0.5–2 MPa), and biomaterials promoting osteogenesis typically have a Young’s Modulus above these ranges . UltimatDynamic strategies in this context are defined to be biomaterial systems with the capacity for inducible changes in their physical properties that effectively change the microenvironment or exert dynamic forces over short periods of time. This requires active biomaterials that can change their physical properties in response to chemical or physical stimuli, such as a piezoelectric material that elongates in an electric field to exert an increased surface tension force along an anchored cell. Additionally, inherently dynamic properties like viscoelasticity are also relevant because they determine how cells physically remodel the microenvironment in time. This can also involve artificial systems that are not necessarily biomaterial in nature but serve the purpose of simulating a dynamic environment . Such dynamic strategies are much more limited in the literature but are nonetheless important because they provide an informative basis for how SSPCs respond to acute microenvironment changes and forces, such as those experienced in physical exercise. SSPCs live in a highly dynamic environment and are known to remodel skeletal tissue in response to dynamic forces ; mechanoin-vitro systems that use the aid of powered machines  or utilities  to exert dynamic forces on cultured cells. These devices are oftentimes used to study the behavior of different cells in response to varied magnitudes and exposures to mechanical loading forces, usually compressive or shear forces  that continues to increase as long as the applied stress force is greater than the biomaterial viscous force . Moreovein-vivo, in-vitro, and with SSPC spheroids arriving at the common conclusion that fast stress relaxing viscoelastic biomaterials promote SSPC proliferation, migration, differential fate towards osteogenesis, and fusion with surrounding tissues in-vivo, and mature bone formation urethane or poly(lactide-co-caprolactone), have been demonstrated to promote chondrogenesis with SSPCs . CartilaGrowth factors, such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF), facilitate cell proliferation, differentiation, and extracellular matrix synthesis . Meanwhiin-vitro  . Note thin-vivo. An active biomaterial scaffold would be ideal for this task because they are 3D and usually implantable, but few constructs have been synthesized that can reversibly impose mechanical loading in-vivo to external stimuli on demand. Developing an active biomaterial tool to quantitatively investigate dynamic mechanobiology for SSPCs in a complex in-vivo environment would help quantify the desirable dynamic properties and mechanical loading forces necessary for a healthy skeletal microenvironment. It would be a useful tool to investigate how fluid flow through porous environments, in response to mechanical compression, mediates nutrient exchange and influences SSPC fate with shear stress in-vivo. Finally, it would help inform a new class of regenerative engineering strategies that utilize dynamics and statics to modulate SSPC mechanobiology for tissue repair and regeneration.Among the important physical strategies for producing desirable SSPC regenerative outcomes, the studies presented on active biomaterials and mechanical loading systems suggest that dynamic physical environments and mechanical loading are universally advantageous strategies for promoting angiogenesis, migration, proliferation, and differentiation . This isEqually crucial to developing new biomaterial constructs and tools is paramount mapping out the intricate molecular mechanisms by which SSPC mechanotransduction occurs in both static and dynamic microenvironments. Significant progress has been made on this in the past two decades with the emergence of novel tools and methods in molecular biology for studying proteomics and gene expression, but there is still ambiguity with the role of even the most well-studied central biomolecules in mechanotransduction. As previously mentioned, there is a history of controversy and debate as to whether YAP nuclear translocation promotes or inhibits osteogenesis . Most rein-vitro and in-vivo, and evaluating their phenotypic outcomes has shed some perspective on how native skeletal tissues and biological materials reproducibly guide SSPC fate. Furthermore, this has led to an increased understanding of the molecular mechanisms by which skeletal organs and cells transduce mechanical stimuli. These mechanical stimuli derive from the physical properties of the microenvironment, which can be broadly categorized as static or dynamic. These properties all work in conjunction to control SSPC behavior and therefore it is paramount to consider how different combinations of all the static and dynamic physical properties in a microenvironment dictate SSPC outcomes when engineering novel strategies to regenerate skeletal tissues with precision and predictability. There are still many questions and challenges ahead in this interdisciplinary collaboration to understand and engineer the SSPC physicochemical microenvironment, but significant progress has been established in just the past decade and the field only continues to grow.Next-generation tissue engineering strategies require an understanding of the underlying mechanobiology by which biomaterial and microenvironment physical properties influence SSPC behavior. Culturing SSPCs in artificial biomaterial microenvironments with known physical properties, both


Exposure to natural vegetation  is related to beneficial outcomes, including higher positive and lower negative affect, in individuals with and those without mental health concerns. Researchers have yet to examine dynamic associations between greenspace exposure and affect within individuals over time. Smartphone-based ecological momentary assessment (EMA) and passive sensors  allow for frequent sampling of data that may reveal potential moment-to-moment mechanisms through which greenspace exposure impacts mental health.In this study, we examined associations between greenspace exposure and affect (both self-reported and inferred through speech) in people with and those without schizophrenia spectrum disorder (SSD) at the daily level using smartphones.Twenty people with SSD and 14 healthy controls reported on their current affect 3 times per day over 7 days using smartphone-based EMA. Affect expressed through speech was labeled from ambient audio data collected via the phone’s microphone using Linguistic Inquiry and Word Count (LIWC). Greenspace exposure, defined as the normalized difference vegetation index (NDVI), was quantified based on continuous geo-location data collected from the phone’s GPS.P=.04) and fewer anger words (P=.04) than controls. Groups did not significantly differ in mean EMA-reported positive or negative affect, LIWC total word count, or NDVI exposure. Greater greenspace exposure showed small to moderate associations with lower EMA-reported negative affect across groups. In controls, greenspace exposure on a given day was associated with significantly lower EMA-reported anxiety on that day  but significantly higher use of negative affect words . There were no significant associations between greenspace exposure and affect at the daily level among participants with SSD.Overall, people with SSD used significantly more positive affect words (Our findings speak to the utility of passive and active smartphone assessments for identifying potential mechanisms through which greenspace exposure influences mental health. We identified preliminary evidence that greenspace exposure could be associated with improved mental health by reducing experiences of negative affect. Future directions will focus on furthering our understanding of the relationship between greenspace exposure and affect on individuals with and those without SSD. The potential health benefits of spending time in nature have been of interest to researchers and health professionals for centuries. Research has shown that viewing pictures and videos of nature was associated with higher self-reported positive affect and lower negative affect and physiological markers of stress  than viewing urban areas . ContinuGreenspace refers to grass, trees, and other vegetation in a given area. Exposure to greenspace can be defined in a number of ways, but generally refers to the amount of contact or access that individuals have to natural, outdoor environments such as parks, forests, or gardens ,10. SeveExposure to greenspace has been linked to improved mental health . In a reStudies among those diagnosed with mental illness, including people with schizophrenia spectrum disorder (SSD), may provide further insight regarding the mechanisms through which greenspace exposure impacts mental health and well-being . There iOnly 2 studies have directly examined the relationship between greenspace exposure and the incidence of serious mental illness, with mixed results. In one study, more greenspace exposure during the first decade of life was associated with a lower incidence of psychosis in adulthood . In contAmbulatory assessments supported by mobile technologies may help clarify the relationship between greenspace exposure and mental health in those with and without mental illness. The ubiquity of smartphones has allowed for the feasible use of ecological momentary assessment (EMA), or the experience sampling method, to actively collect data on individual experiences and behaviors repeatedly over days, weeks, or months in the context of daily life. Furthermore, data can be collected passively and semicontinuously using smartphone sensors, supplementing EMA surveys . Among tThe combination of passive and active smartphone data can provide a comprehensive understanding of potential correlates of greenspace exposure, ultimately informing our understanding of the impact of greenspace on mental health and well-being. In one recent ambulatory study among people with SSD , greenspIn this study, we examined daily associations between greenspace exposure and affect in people with SSD and a comparison group with no known mental illness using smartphones. We measured affect using both active and passive data streams , and measured greenspace exposure using NDVI values spatially joined with GPS-based geo-location. Given the exploratory nature of the work, and limited sample size, we primarily aimed to assess the utility of using smartphone-based active and passive measures to understand associations between greenspace and its affect in daily life. Specifically, we hypothesized that controls would have significantly greater mean NDVI throughout the study than people with SSD. Additionally, we predicted that within groups, greater exposure to greenspace on a given day would be associated with (1) higher ratings of positive affect (happiness) and lower ratings of negative affect (anxiety and sadness), and (2) greater use of positive affect words and lower use of negative affect words on that same day.This study involves a secondary analysis of data collected as part of another study. Methods are described in detail in the primary outcomes paper.Twenty people with SSD and 15 controls (no psychiatric diagnosis) were recruited from the San Francisco Bay Area in 2016. Community-based participants with SSD were recruited via outpatient clinician referrals and brochures or flyers posted in local clinics. Control participants were recruited via community flyers and public advertisements on websites typically used to recruit for psychological research studies. SSD participants were eligible for the study if they met “Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition” criteria for a diagnosis of SSD using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition . ControlPotential participants completed a brief phone screening prior to being invited to participate in the study. Participants came into the laboratory for a visit where they met with a trained research assistant and completed informed verbal and written consent. Once inclusion or exclusion criteria were confirmed, participants completed an in-clinic assessment. The research assistant then provided the participant with an Android smartphone and trained them on how to use the Ethica Data app . At the Participants were asked to respond to prompts from the Ethica app 3 times per day for a period of 7 days. Surveys were administered a minimum of 90 minutes apart throughout each day at randomized time points within the windows of 10 AM-1 PM, 2-5 PM, and 5-8 PM. Participants were asked a variety of questions related to emotional experience and social context. Questions pertaining to emotional experience included a 6-point  scale for happiness, sadness, and anxiety  minus the visible (VIS) radiation and the NIR radiation plus the VIS radiation emitted:Satellites above the earth’s surface calculate NDVI values from the VIS and NIR light reflected by vegetation. Sparse vegetation reflects more VIS light and less infrared light, while dense vegetation absorbs most of the VIS light and thus reflects a large portion of the NIR light. The resulting calculated NDVI is a number that ranges from –1 to 1 where negative values represent water and values closer to 1 represent the highest levels of vegetation density. We excluded negative values from the analyses given limited data linking exposure to bodies of water and health outcomes. Geo-location data derived from smartphone sensors can be used to calculate NDVI values based on time spent in various locations, providing a fine-grained assessment of greenspace exposure within individuals as they go about their daily lives . Geo-locStudy phones were also programmed to semirandomly record 5-minute intervals of ambient audio for every 30 minutes throughout the study period. This method has shown evidence of acceptability and feasibility in SSD . ParticiWe limited audio transcription to only those instances in which the user was engaged in an interpersonal exchange. We defined social interactions as reciprocal, tangible user speech containing content intended for the purpose of communication with another human. A new social interaction was coded at times when a participant engaged in conversation with a different person or after a lapse in speech for twenty seconds or longer. Given this definition, we excluded speech that (1) did not involve the participant, (2) was directed toward animals or pets, (3) was directed toward infants, (4) involved singing (either to or without music), or (5) was designated as self-talk. Unintelligible speech was also omitted.Audio recordings were imported into Audacity (The Audacity Team) , a free,The study underwent a full review by the Boston University Charles River Campus Institutional Review Board (Protocol #: 4394). All participants provided informed consent before study participation, completed baseline questionnaires, and installed the Ethica platform on provisioned devices.A raster file of NDVI data (ranging from –1 to 1) for the San Francisco Bay area was extracted from the USGS Landsat8 Collection 1 Tier 1 TOA Reflectance from Google Earth Engine. This image was optimized to include the date of participant involvement in the study as well as least amount of cloud coverage. GPS data were preprocessed to exclude network-passive and GPS-passive coordinates. Since we did not obtain information on the participants’ addresses we manually tagged “home” by taking the most frequent GPS coordinate pair between 9 PM and 6 AM . These cSpeech transcriptions were analyzed using Linguistic Inquiry and Word Count (LIWC) . LIWC isP values less than .05 were considered statistically significant.We examined all data for assumptions of planned statistical analyses . We aggregated repeated assessments of affect on the daily level to create a mean value for each variable. Rating of positive and negative affect, as well as ambient audio variables, were not normally distributed. As such, we examined group differences for demographic, NDVI, affect experience, and LIWC metrics using Wilcoxon Rank Sum tests. We conducted Spearman correlations to examine associations between NDVI, EMA-reported affect, and speech-based word counts and categories. We examined group differences in variables  and ambulatory data . In addition, we ran bivariate correlations to evaluate how relevant demographic variables  were associated with NDVI. Given the exploratory nature of the analyses, we considered Spearman correlation magnitudes of 0.30 or greater (moderate effect) as meaningful signals. We followed up bivariate correlations that were at least moderate in magnitude with multilevel models conducted using Mplus (Muthen and Muthen). Two-level models were conducted to examine relationships between EMA-reported affect and NDVI within subjects at the daily level. All models involved individual-level clustering and person mean-centered NDVI values to examine deviations in the means at the individual level. We present standardized estimates of coefficients in the results. Two-tailed P=.06) or negative affect (P=.16), or LIWC total word count (P=.09). People with SSD used significantly more positive affect words (P=.04) and fewer anger words (P=.04) than controls. Groups did not significantly differ in overall NDVI exposure throughout the duration of the study ; there were no significant associations between daily greenspace exposure and EMA-reported happiness  or sadness  in controls. Among people with SSD, there were no significant associations between greenspace exposure and EMA-reported affect at the daily level, including anxiety , happiness , or sadness .In both groups, there were small to moderate associations between greater average greenspace exposure and lower average EMA-reported negative affect (sadness and anxiety) across the study , but not with positive affect words spoken . At the daily level, greater NDVI was associated with a significantly higher proportion of anger words , but not sadness words , spoken. In people with SSD, there was a moderate association between greater overall greenspace exposure and a lower proportion of negative affect words spoken, including anxious and anger words specifically  or negative affect  words spoken in SSD participants were not statistically significant. At the daily level, greater NDVI was not associated with the proportion of anger words  or sadness words  spoken.In controls, overall greenspace exposure was generally unrelated to affect expression in speech see . At the ally see . The daiIn this study, we examined the association between greenspace exposure and affect among people with and without SSD. We incorporated active (EMA) and passive (audio samples of speech and GPS geo-location) smartphone measures of both greenspace and affect experience and expression. In both groups, greater greenspace exposure showed small to moderate associations with lower EMA-reported negative affect, while greenspace was unrelated to positive affect.Participants with SSD who were exposed to greater levels of greenspace reported lower anxiety and sadness throughout the study. They also demonstrated a lower proportion of negative affect words spoken. Thus, for people with a serious mental illness, exposure to greenspace may be beneficial to well-being. Though, as noted, these associations were relatively small and were not present at the daily level. As such, there may not be a dynamic association between greenspace exposure and affect, at least over a relatively brief period of time. Instead, lower negative affect and greenspace exposure may covary at the between-person level .Controls with greater exposure to greenspace throughout the study similarly experienced a lower negative affect on average. Furthermore, momentary analyses demonstrated that controls reported lower anxiety on days with higher greenspace exposure. Thus, evidence of covariation between changes in greenspace exposure and affect experience was more robust in controls than participants with SSD. It could be that controls were more likely to experience benefits of greenspace exposure than those with SSD, or that the groups differed in the types of greenspace, or the ways in which they interacted with these spaces, leading to differential outcomes. Future research can address these questions by characterizing the quality of greenspace exposure using supplemental methods .Interestingly, controls spoke a greater proportion of negative affect words on days in which they had greater greenspace exposure. Although this association between greenspace exposure and negative affect expression was contrary to our hypothesis, it is common to see discrepancies between affect experience and expression . That isRelatedly, it is important to note the limitations in inferring emotion from speech using the LIWC; this method identifies the content of speech but does not consider the context in which those words are spoken. Without additional context, types of words used may not accurately represent the situation, or could even represent the opposite situation . The person speaking could also be reflecting on things other than their own affect . Future research should focus on independent and interacting relationships between experienced and expressed affect of greenspace exposure.While some results were in line with our hypotheses, larger samples may be necessary to identify small to moderate associations between greenspace exposure and affect in participants with SSD at the daily level. Additionally, groups did not differ in overall greenspace exposure across the study, which may be due quality not quantity of the greenspace exposure. For example, a park in the middle of a noisy, busy city might have different restorative benefits than a quiet, state park in the suburbs.Our work contributes to a growing literature that aims to characterize the influence of greenspace on well-being. Similar to previous work, we did find that greater greenspace exposure was associated with lower anxiety in the general population ,38. HoweA primary limitation of this study is the small sample size, potentially limiting the power to detect modest relationships between greenspace exposure and affect in daily life. We also did not incorporate additional confounds  that could influence the interpretation of the results, and will be a point of focus in future work. Although our design does provide rich, temporally dense data, it may be important to measure greenspace and affect over a longer period of time to detect dynamic associations. There are also limitations in the use of GPS-derived geo-location as a marker of NDVI . We also did not gather data related to subjective experience of greenspace exposure, which could serve to improve understanding of the degree to which participants valued or enjoyed such exposure, or their perception of degree of “greenness” of their environment. It is also important to note that not all greenspace is created equal; more objective and subjective information on the context surrounding greenspace exposure  could provide more robust modeling of associations with affect.More work is required to further understand the relationship between greenspace exposure and affect in those with and without SSD. Additional EMA questions could provide details on the participants’ surroundings  to fully understand their greenspace exposure. More questions related to affect experiences and mood could also help identify nuanced relationships between well-being and greenspace exposure. In future work, we can also test the momentary relationship between greenspace exposure and affect at a more temporally fine-grained level of analysis . Future directions can also harness other methods apart from LIWC to gather more rich information from speech. Some of these data science approaches include using machine learning algorithms to detect the affect of speech .Overall, our collection of both the active and passive smartphone data allowed for the assessment of within-person fluctuations in affect and their associations with greenspace exposure on a daily level in people with and without SSD. In both groups, greater greenspace exposure was associated with lower EMA-reported negative affect, but not positive affect, across the study. Within groups, controls reported lower anxiety on days with higher greenspace exposure, and also spoke a greater proportion of negative affect words, while people with SSD did not show associations at the daily level. Future studies should focus on additional aspects of greenspace exposure, affect, and experience on a fine-grained, dynamic level.