Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.

SUPPORT: SUrvey of Parental Leave POlicies of RadiaTion Oncology Programs and Residency Applicants.

Purpose: Recruitment to radiation oncology training programs has recently declined, and gender inequities persist in radiation oncology. Policies that promote inclusivity, such as the updated American College of Graduate Medical Education parental leave policy establishing minimum parental leave requirements, may support recruitment to radiation oncology. Methods and Materials: We surveyed 2021-2022 radiation oncology residency applicants and program directors (PDs) about program-specific parental leave policies, transparency of parental leave information during the residency application and interview process, and perceptions of the effect of parenthood on residency training, career advancement, and well-being. Results: Of 89 radiation oncology PDs, 29 (33%) completed the survey. Of 154 residency applicants (current fourth-year medical students, international applicants, or postdoctoral fellows) surveyed, 62 (40%) completed the survey. Most applicants planned to start a family during residency (53%) and reported perceived flexibility to start a family influenced their decision to pursue radiation oncology over other career specialties (55%). Many applicants viewed time in residency (nonresearch, 22%), in research (33%), and as early career faculty (24%) as the best time to start a family. A small number of applicants used program-specific parental leave policy information in determining their rank list (11%), and many applicants sought information regarding fertility health care benefits (55%). Many applicants obtained parental leave information verbally, despite expressing a preference for objective means (slide deck, 63%; website, 50%; or handout, 42%) of information sharing. PDs were all supportive of a 6-week maternity leave policy (100% agree or strongly agree with the policy) and did not feel parental leave would negatively affect a resident's ability to pursue an academic (100%) or private practice career (100%). Conclusions: Many radiation oncology residency applicants plan to start families during training, seek and value program-specific parental leave information and health benefits, and prefer objective means of information sharing. These findings likely reflect those who have strong views of parental leave policies.

Virtual Radiation Oncology Clerkship During the COVID-19 Pandemic and Beyond.

PURPOSE: We evaluated the impact of a virtual radiation oncology clerkship. METHODS AND MATERIALS: We developed a 2-week virtual radiation oncology clerkship that launched on April 27, 2020. Clerkship components included a virtual clinic with radiation oncology faculty and residents, didactic lectures, student talks, and supplemental sessions such as tumor boards and chart rounds. Medical students completed pre- and post-clerkship self-assessments. Faculty and resident participants also completed surveys on their experience with virtual lectures and clinics. Pre- and post-clerkship results were compared using a 2-sided paired t test. An analysis of variance model was used to analyze the clerkship components. RESULTS: Twenty-six medical students, including 4 visiting students, enrolled over 2 clerkship periods (4 weeks). All students completed the pre- and post-clerkship self-assessments and agreed that the clerkship improved their understanding of radiation oncology. Compared with 3 (11.5%) students who agreed that they understood the daily responsibilities of a radiation oncologist before the clerkship, 22 (84.6%) students agreed and 3 (11.5%) strongly agreed that they understood the daily responsibilities of a radiation oncologist after the clerkship (P < .0001). Although 15 students (57.7%) reported an increased interest in radiation oncology because of the clerkship, the mean level of interest in radiation oncology as a career remained the same, with pre- and post-clerkship scores of 3.0 (±0.9) and 3.0 (±1.1) on a 5-point scale, respectively (P = .7). Students found virtual clinic and didactic lectures to be the most valuable components of the clerkship. Most respondents agreed (30.8%) or strongly agreed (65.4%) to recommend the clerkship to their classmates. CONCLUSIONS: Our virtual clerkship was effective in increasing medical student interest in and knowledge about radiation oncology. These data will help optimize a new paradigm of virtual radiation oncology education for medical students during COVID-19 and beyond.

Continuing Medical Student Education During the Coronavirus Disease 2019 (COVID-19) Pandemic: Development of a Virtual Radiation Oncology Clerkship.

PURPOSE: Our institution cancelled all in-person clerkships owing to the coronavirus disease 2019 pandemic. In response, we designed a virtual radiation oncology medical student clerkship. METHODS AND MATERIALS: We convened an advisory panel to design a virtual clerkship curriculum. We implemented clerkship activities using a cloud-based learning management system, video web conferencing systems, and a telemedicine portal. Students completed assessments pre- and postclerkship to provide data to improve future versions of the clerkship. RESULTS: The virtual clerkship spans 2 weeks and is graded pass or fail. Students attend interactive didactic sessions during the first week and participate in virtual clinic and give talks to the department during the second week. Didactic sessions include lectures, case-based discussions, treatment planning seminars, and material adapted from the Radiation Oncology Education Collaborative Study Group curriculum. Students also attend virtual departmental quality assurance rounds, cancer center seminars, and multidisciplinary tumor boards. The enrollment cap was met during the first virtual clerkship period (April 27 through May 8, 2020), with a total of 12 students enrolling. CONCLUSIONS: Our virtual clerkship can increase student exposure and engagement in radiation oncology. Data on clerkship outcomes are forthcoming.

Advancing systematic-review methodology in exposure science for environmental health decision making.

Systematic review (SR) is a rigorous methodology applied to synthesize and evaluate a body of scientific evidence to answer a research or policy question. Effective use of systematic-review methodology enables use of research evidence by decision makers. In addition, as reliance on systematic reviews increases, the required standards for quality of evidence enhances the policy relevance of research. Authoritative guidance has been developed for use of SR to evaluate evidence in the fields of medicine, social science, environmental epidemiology, toxicology, as well as ecology and evolutionary biology. In these fields, SR is typically used to evaluate a cause-effect relationship, such as the effect of an intervention, procedure, therapy, or exposure on an outcome. However, SR is emerging to be a useful methodology to transparently review and integrate evidence for a wider range of scientifically informed decisions and actions across disciplines. As SR is being used more broadly, there is growing consensus for developing resources, guidelines, ontologies, and technology to make SR more efficient and transparent, especially for handling large amounts of diverse data being generated across multiple scientific disciplines. In this article, we advocate for advancing SR methodology as a best practice in the field of exposure science to synthesize exposure evidence and enhance the value of exposure studies. We discuss available standards and tools that can be applied and extended by exposure scientists and highlight early examples of SRs being developed to address exposure research questions. Finally, we invite the exposure science community to engage in further development of standards and guidance to grow application of SR in this field and expand the opportunities for exposure science to inform environment and public health decision making.

A Systematic Review and Meta-Analysis Investigating the Relationship between Exposures to Chemical and Non-Chemical Stressors during Prenatal Development and Childhood Externalizing Behaviors.

Childhood behavioral outcomes have been linked to low quality intrauterine environments caused by prenatal exposures to both chemical and non-chemical stressors. The effect(s) from the many stressors a child can be prenatally exposed to may be influenced by complex interactive relationships that are just beginning to be understood. Chemical stressors influence behavioral outcomes by affecting the monoamine oxidase A (MAOA) enzyme, which is involved in serotonin metabolism and the neuroendocrine response to stress. Non-chemical stressors, particularly those associated with violence, have been shown to influence and exacerbate the externalizing behavioral outcomes associated with low MAOA activity and slowed serotonin metabolism. The adverse developmental effects associated with high stress and maternal drug use during pregnancy are well documented. However, research examining the combined effects of other non-chemical and chemical stressors on development and childhood outcomes as a result of gestational exposures is scarce but is an expanding field. In this systematic review, we examined the extant literature to explore the interrelationships between exposures to chemical and non-chemical stressors (specifically stressful/traumatic experiences), MAOA characteristics, and childhood externalizing behaviors. We observed that exposures to chemical stressors (recreational drugs and environmental chemicals) are significantly related to externalizing behavioral outcomes in children. We also observed that existing literature examining the interactions between MAOA characteristics, exposures to chemical stressors, and traumatic experiences and their effects on behavioral outcomes is sparse. We propose that maternal stress and cortisol fluctuations during pregnancy may be an avenue to link these concepts. We recommend that future studies investigating childhood behaviors include chemical and non-chemical stressors as well as children's inherent genetic characteristics to gain a holistic understanding of the relationship between prenatal exposures and childhood behavioral outcomes.

Systematic review and meta-analyses of lead (Pb) concentrations in environmental media (soil, dust, water, food, and air) reported in the United States from 1996 to 2016.

Environmental lead (Pb) contamination is a persistent public health issue that prominently impacts communities across the United States. Multimedia Pb exposure assessments are utilized to provide a holistic evaluation of Pb exposure and inform the development of programs and regulations that are protective of human health. To conduct multimedia exposure assessments, robust, media-specific environmental Pb concentration data are necessary. To support this effort, systematic review and meta-analysis methods were used to conduct a comprehensive synthesis of research measuring Pb in multiple environmental media (soil, dust, water, food, and air) over a 20-year period within the United States. The breadth of the resulting database allowed for the evaluation of sample characteristics that can serve as indicators of environmental Pb contamination. Random effects models run on literature and national survey datasets generated overall mean estimates of Pb concentrations that can be used for multimedia Pb exposure modeling for general and high-exposure-risk populations. Results from our study highlighted several important trends: 1) The mean estimate of Pb in residential soils is three times higher for urbanized areas than non-urbanized areas; 2) The mean estimate of Pb in produce reported in the literature is approximately three orders of magnitude greater than commercially-sourced raw produce monitored in national surveys; 3) The mean estimate of Pb in soils from shooting ranges is two times greater than non-residential Pb contaminated Superfund sites reported in the literature; 4) Research reporting environmental Pb concentrations for school and daycare sites is very limited; 5) Inconsistent sample collection and reporting of results limited synthesis efforts; and 6) The U.S. EPA's Air Quality System was the most robust, publicly available national survey resource. Results from these analyses will inform future multimedia Pb exposure assessments and be useful in prioritizing future research and program development.

Effect of Clinical and Attitudinal Characteristics on Obtaining Comprehensive Medication Reviews.

BACKGROUND: Comprehensive medication reviews (CMRs) consist of in-depth reviews of patients' medications to identify effectiveness or safety problems and often generate cost savings for individuals. Despite their advantages, CMRs are not widely obtained. Previous studies found that older age, female sex, and experience of side effects were associated with obtaining a medication review. OBJECTIVE: To quantify the association between attitudinal and clinical factors with intention and predict future behavior to obtain a CMR among Medicare Part D beneficiaries. METHODS: A sample of Medicare Part D beneficiaries from 1 health care plan (n = 660) completed a 14-item survey over the telephone assessing factors that were hypothesized to affect their intention and behavior to obtain a CMR. The survey collected medication use history and health care information with the medication user self-evaluation tool, health status, adherence, intention to obtain a CMR, and demographic characteristics. Subjects subsequently were informed that they could obtain a CMR from their pharmacies. Claims data were obtained that indicated which subjects received a CMR. Two dependent variables were predicted: intention to schedule a CMR using a multivariate linear regression model and receipt of a CMR using a logistic regression and including intention as a predictor variable. RESULTS: The mean age of participants was 76.6 (SD = 7.61) years; 71% were female; and participants took an average of 5.2 (SD = 3.18) medications. The intention to have a CMR was 2.85 (SD = 1.41) on a 5-point scale, and 5.6% of the participants actually had a CMR. Worrying about medications doing more harm than good, number of pharmacies where participants obtained their medications from, number of medications, and number of medical conditions predicted intention to obtain a CMR. Patients who perceived their health status to be poorer compared with others their age were more likely to have a CMR. Intention to obtain a CMR was not associated with receipt of a CMR. CONCLUSIONS: Stakeholders should target patients who perceive their health to be poor for a CMR, hence expanding the scope of CMRs and increasing the number of older adults benefiting from this service. DISCLOSURES: This study was funded by a grant from the Agency for Healthcare Research and Quality (1R18HS018353). Frank is an employee of Outcomes MTM. Pendergast has received grants from the NIH, NIA, and PICORI. Farris has received grants from NIH and speaker fees from Chulalongkorn University, Bangkok, Thailand, and the American College of Clinical Pharmacy. All other authors declare that they have no conflicts of interest. Study concept was developed by Farris, Pendergast, Chrischilles, and Doucette. Pendergast, Frank, Farris, and Aneese collected the data, with assistance from Chrischilles and Doucette. Data interpretation was performed by Farris, Marshall, Salgado, and Aneese, with assistance from the other authors. The manuscript was written by Farris, Salgado, and Aneese, with assistance from the other authors, and revised by Salgado and Marshall, assisted by the other authors.

Stimulating comprehensive medication reviews among Medicare Part D beneficiaries.

OBJECTIVES: To assess the impact of a patient engagement intervention utilizing the Medication User Self-Evaluation (MUSE) tool on the completion percentage of comprehensive medication reviews (CMRs) among Medicare Part D beneficiaries. STUDY DESIGN: A case-control study. METHODS: Beneficiaries from 2 Medicare Part D plans were randomly assigned to 3 study arms (1 control arm plus 2 intervention arms for 2011 and 2012, respectively). Each beneficiary who participated in the MUSE intervention met 3 inclusion criteria and was matched with a single control group beneficiary based on: gender; age (within 5-year interval); plan type (ie, Medicare Prescription Drug Plan, Medicare Advantage Prescription Drug Plan); number of unique prescriptions; pharmacy medication therapy management (MTM) training status; and time period (2011, 2012). The outcome of interest was whether or not the beneficiary received a CMR in the 6 months following the index date. Generalized estimating equation (GEE) models were used to compare CMR percentages over time and between MUSE intervention groups. This study used MTM service claims data. RESULTS: The final sample of 1015 beneficiaries received MUSE intervention, of which 1007 were successfully matched to a control beneficiary. The estimated odds of having a CMR among those who received the MUSE intervention were 2 times that of their counterparts (P = .0048) across both study years. CONCLUSIONS: Given the strong evidence found for a positive association between participation in a CMR and the MUSE intervention, Part D plans could use the MUSE to engage targeted beneficiaries in using pharmacist-provided MTM services.

Factors affecting Medicare Part D beneficiaries' decision to receive comprehensive medication reviews.

OBJECTIVES: To identify factors influencing Medicare Part D beneficiaries' decision to receive pharmacist-provided comprehensive medication reviews (CMRs) and to evaluate their experiences with pharmacist-provided CMRs. DESIGN: Cross-sectional descriptive study. SETTING: Beneficiaries living in Maryland or Minnesota, from November 2011 to January 2012. PARTICIPANTS: Medicare beneficiaries of two Medicare Part D plans who had completed a previous telephone interview for a larger project of medication therapy management quality improvement. INTERVENTION: Self-reported mail survey. MAIN OUTCOME MEASURES: Responses to survey items assessing beneficiaries' perceived importance of proposed factors affecting their decision to receive CMRs and items evaluating patients' experiences with pharmacist-provided CMRs if they had one in the previous year. RESULTS: The valid response rate was 33.4% (238 of 713). Among the proposed factors, "knowing the out-of-pocket cost" (4.12 ± 1.28 [mean ± SD]) and "conducting in the usual pharmacy" (4.01 ± 1.37) were most important in making a decision to get a CMR. Factors rated significantly more important by those who had versus had not received a CMR included "usual pharmacy," "receiving medication list," "physician's support," and "pharmacists discuss changes with physicians." About one-third (30.6%) of respondents reported having pharmacist-provided CMRs within the previous year. Most respondents believed that having CMRs was important for their health (90.6%) and were satisfied with the results of CMRs (94.7%). CONCLUSION: Patients preferred their usual pharmacy or convenient places to have a CMR. Also, a collaborative pharmacist-physician working relationship would be helpful in providing CMRs. Patients who received CMRs expressed a positive attitude toward and satisfaction with pharmacist-provided services.

Analysis of pharmacist-provided medication therapy management (MTM) services in community pharmacies over 7 years.

BACKGROUND: Although community pharmacists have historically been paid primarily for drug distribution and dispensing services, medication therapy management (MTM) services evolved in the 1990s as a means for pharmacists and other providers to assist physicians and patients in managing clinical, service, and cost outcomes of drug therapy. The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA 2003) and the subsequent implementation of Medicare Part D in January 2006 for the more than 20 million Medicare beneficiaries enrolled in the Part D benefit formalized MTM services for a subset of high-cost patients. Although Medicare Part D has provided a new opportunity for defining the value of pharmacist-provided MTM services in the health care system, few publications exist which quantify changes in the provision of pharmacist-provided MTM services over time. OBJECTIVES: To (a) describe the changes over a 7-year period in the primary types of MTM services provided by community pharmacies that have contracted with drug plan sponsors through an MTM administrative services company, and (b) quantify potential MTM-related cost savings based on pharmacists' self-assessments of the likely effects of their interventions on health care utilization. METHODS: Medication therapy management claims from a multistate MTM administrative services company were analyzed over the 7-year period from January 1, 2000, through December 31, 2006. Data extracted from each MTM claim included patient demographics (e.g., age and gender), the drug and type that triggered the intervention (e.g., drug therapeutic class and therapy type as either acute, intermittent, or chronic), and specific information about the service provided (e.g., Reason, Action, Result, and Estimated Cost Avoidance [ECA]). ECA values are derived from average national health care utilization costs, which are applied to pharmacist self-assessment of the "reasonable and foreseeable" outcome of the intervention. ECA values are updated annually for medical care inflation. RESULTS: From a database of nearly 100,000 MTM claims, a convenience sample of 50 plan sponsors was selected. After exclusion of claims with missing or potentially duplicate data, there were 76,148 claims for 23,798 patients from community pharmacy MTM providers in 47 states. Over the 7-year period from January 1, 2000, through December 31, 2006, the mean ([SD] median) pharmacy reimbursement was $8.44 ([$5.19] $7.00) per MTM service, and the mean ([SD] median) ECA was $93.78 ([$1,022.23] $5.00). During the 7-year period, pharmacist provided MTM interventions changed from primarily education and monitoring for new or changed prescription therapies to prescriber consultations regarding cost-efficacy management (Pearson chi-square P<0.001). Services also shifted from claims involving acute medications (e.g. penicillin antibiotics, macrolide antibiotics, and narcotic analgesics) to services involving chronic medications (e.g., lipid lowering agents, angiotensin-converting enzyme [ACE] inhibitors, and beta-blockers; P<0.001), resulting in significant changes in the therapeutic classes associated with MTM claims and an increase in the proportion of older patients served (P<0.001). These trends resulted in higher pharmacy reimbursements and greater ECA per claim over time (P<0.001). CONCLUSION: MTM interventions over a 7-year period evolved from primarily the provision of patient education involving acute medications towards consultation-type services for chronic medications. These changes were associated with increases in reimbursement amounts and pharmacist-estimated cost savings. It is uncertain if this shift in service type is a result of clinical need, documentation requirements, or reimbursement opportunities.