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Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

OBJECTIVES: To explore the prevalence of poor sleep quality in couples undergoing fertility treatment and study possible associations.PARTICIPANTS: 163 women and 132 partners receiving in vitro (IVF) or intracytoplasmic sperm injection (ICSI) fertility treatment.SETTING: Three public Danish fertility clinics.DESIGN AND MEASUREMENTS: Participants completed the Pittsburgh Sleep Quality Index (PSQI) at three time-points as part of a larger RCT. Additional data from patient records and questionnaires were included to evaluate possible associations with treatment protocol type, psychological distress, and pregnancy outcome.RESULTS: Mean PSQI global scores before treatment were 8.1 (standard deviation = 2.3), with 91% of participants having PSQI scores > 5, indicating poor sleep quality. Scores did not differ between women and their partners and did not change during treatment. Statistically significant associations were found between sleep quality and depressive symptoms and state anxiety (p < .001). No difference in PSQI scores was found between protocol types. While there was a trend towards higher clinical pregnancy rates among women with good sleep quality (PSQI ≤ 5 = 72.7%, PSQI 6-10 = 52.6% and PSQI ≥ 11 = 42.3%), the differences did not reach statistical significance (p = .10-.21).CONCLUSIONS: Poor sleep quality is a prevalent problem among couples undergoing fertility treatment and is associated with psychological distress and possibly with pregnancy outcomes. Success rates after fertility treatment remain moderate, and poor sleep quality, a potentially modifiable factor, could be relevant to screen for and treat among couples undergoing fertility treatment. The high prevalence of poor sleep quality calls for further investigation.

Accurate prediction of the pKa’s of protein residues is crucial to many applications in biological simulation and drug discov-ery. Here we present the use of free energy perturbation (FEP) calculations for the prediction of single protein residue pKa values. We begin with an initial set of 191 residues with experimentally determined pKa values. To isolate sampling limita-tions from force field inaccuracies, we develop an algorithm to classify residues whose environments are significantly affect-ed by crystal packing effects. We then report an approach to identify buried histidines that require significant sampling be-yond what is achieved in typical FEP calculations. We therefore define a clean dataset not requiring algorithms capable of predicting major conformational changes on which other pKa prediction methods can be tested. On this data set, we report an RMSE of 0.76 pKa units for 35 ASP residues, 0.51 pKa units for 44 GLU residues, and 0.67 pKa units for 76 HIS resi-dues.

Introduction Emerging evidence links abnormal myocardial blood flow reserve (MBFR), a marker of coronary microvascular dysfunction (CMD), and heart failure with preserved ejection fraction (HFpEF). However, the relationship between CMD and diastolic dysfunction (DD) in patients with OSA remains unclear. We analyzed the relationship between OSA, abnormal MBFR and markers of DD in a patient cohort. Methods Using healthcare records, we generated a cross-sectional database of 231 individuals who had sleep testing, echocardiogram(s), and cardiac PET stress test. Abnormal MBFR was defined as the stress-to-rest ratio of myocardial blood flow < 2.0. We created DD score with a point each given to a) left atrial volume index (LAVI) ≥34, b)average E/e’ ratio>14/lateral e’>10/medial e’>7, and in a subgroup of 122 individuals with available data we added c)tricuspid regurgitation jet (TR) velocity > 2.7m/s. Higher scores suggest greater likelihood of DD. Models were adjusted for demographics and cardiometabolic risk factors. Results The mean (SD) age and BMI was 60(11) years and 39.5(8.7) kg/m2; 61% were female. Eighty-four participants had severe OSA (apnea-hypopnea index ≥ 30/hr). Compared to non-severe OSA, severe OSA was associated with 2-fold odds of abnormal MBFR (adjusted OR [aOR) 2.1, 95%CI:1.1–4.0). However, there was no association with abnormal LAVI, abnormal E/e’ (average E/e’>14 vs. < 9), or elevated TR velocity. In the adjusted model, abnormal MBFR was associated with abnormal E/e’ (aOR 4.4 [95% CI: 1.6-11.8]) and elevated TR velocity (aOR: 3.7 [95%CI: 1.3-10.9]). Abnormal MBFR was associated with increase in DD score (range 0–2; aOR per-unit increase = 1.7 [95% CI: 1.0-3.0]. In the subset with data on TR velocity, abnormal MBFR was associated with a three-fold increase in the odds of a unit increase in DD score (range 0–3; aOR 3.3 [95% CI: 1.5,7.4]). The association between abnormal MBFR and DD was present regardless of OSA severity. Severe OSA was not associated with DD. Conclusion Abnormal MBFR/CMD may be implicated in the development of DD and HFpEF in patients with OSA. MBFR assessment may be useful in HFpEF risk stratification in non-severe OSA. Larger studies are required to determine the role of CMD in the development of DD/HFpEF in OSA. Support (if any)

Global aging has proceeded at an unprecedented and accelerating rate. The aging of the population creates both opportunities and challenges for older adults, their families, and society in general. Importantly, there is substantial variation in the effects of and response to global aging both within and across nations depending, in part, on prevailing cultural expectations and values, political and economic imperatives, and social and demographic characteristics. Thus, while some regions and countries have responded with innovative policies and programs to better enable the growing cohort of older adults to remain active and engaged in the community, other regions and countries have struggled with their response or barely begun to plan for the rising population of older adults. This symposium assembles editors at five leading gerontology journals to demonstrate the role that peer-reviewed scholarship can play in disseminating knowledge that informs gerontological research, policy, and practice internationally. Editors include: Edward Alan Miller, PhD, FGSA, Journal of Aging & Social Policy; Jeffrey Burr, PhD, FGSA, Research on Aging; Julie Robison, PhD, FGSA,, Journal of Applied Gerontology; Sandra Torres, PhD, FGSA, Ageing & Society; and Julie Hicks Patrick, PhD, FGSA, International Journal of Aging & Human Development. Each presenter will review the scope, content, and focus of their journals and the role and opportunities for international scholarship.

This symposium reports evaluation findings from the Right Care, Right Place, Right Time (R3) program. The initiative is designed to integrate housing, health, and supportive care to residents of affordable senior housing using a wellness team (nurse and social worker). The embedded team works directly with residents to address health-related, educational, and informational needs and access to services - focusing on proactive outreach and prevention, coordination with providers, constant contact with residents, and targeting high-risk residents. The initiative aims to create a replicable, scalable, and sustainable model of housing with supportive services that enables independent living while reducing health care costs. Two wellness teams served approximately 400 participants at seven Boston-area buildings. The R3 program was implemented in two phases. The 18-month pre-intervention period was January 2016-March 2017, while the 18-month Phase 1 intervention period was July 2017-December 2018. The 21-month Phase 2 implementation period (known R32), which introduced a targeting strategy to identify high risk residents, was January 2019-September 2020. Evaluation activities included quantitative and qualitative components. Program participants and non-participants at intervention and comparison sites were surveyed on program-related experiences. Program, housing, and community partners were interviewed. Key performance indicators were tracked. Medicare claims data were analyzed using comparison groups. Focus groups were completed with payers, housing providers, and community stakeholders. The purpose of this symposium is to identify the experiences of program participants and key stakeholders with the R3 program, and to assess program impact. Edward Miller and Marc Cohen will serve as chair and co-chair, respectively.

There has been a long-standing interest in developing housing models that integrate the supportive services that older people need to remain at home as long as possible. This approach has boomed for better-off people who can afford the cost of private-pay independent living and assisted living environments. For those with fewer resources, however, options are limited, given that they are largely dependent on public financing. This study focuses on how to develop sustainable models of housing with services for low-income older people. Using data from 31 key informant interviews and three focus groups, it reports and analyzes expert perspectives on how programs such as R3 can achieve financial sustainability. Four major themes emerged: (1) funding as the key to sustaining housing with services; (2) funding housing with services through participating health plans; (3) other potential funding sources for housing with services; and (4) gaining buy-in for housing with services.

The American Rescue Plan Act (ARPA) includes a one year 10 percentage point increase in the Federal Medical Assistance Percentage for Medicaid-funded home and community-based services (HCBS). The goal is to strengthen state efforts to help older adults and people with disabilities live safely in their homes and communities rather than in institutional settings during the COVID-19 pandemic. This presentation provides a detailed description and analysis of this provision, including issues state governments need to consider when expending the additional federal revenue provided. It also draws lessons from the Affordable Care Act’s Balancing Incentive Program to suggest insights for the potential of ARPA to promote further growth in Medicaid HCBS programs. The presentation concludes by highlighting the importance of instituting strategies and processes for maximizing enhanced federal matching funds under ARPA in preparation for subsequent availability of substantial additional federal resources targeting Medicaid HCBS under other proposed initiatives.

Activity-based protein profiling (ABPP) is a versatile strategy for enabling identification and characterization of new functional protein sites and discovery of lead compounds for therapeutic development. Yet, the vast majority of ABPP methods applied for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to the cancer-driver protein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new hyperreactive, ligandable methionine residues, including an allosteric M169 site that is proximal to an activating T172 phosphorylation site. With this information in hand, we designed and synthesized a new methionine-targeting covalent ligand library based on oxaziridine fragments bearing a diverse array of heterocyclic, heteroatom, and stereochemically-rich substituents. ABPP screening of this focused library against a clickable broad-spectrum ReACT probe identified 1oxF11 as a covalent modifier of the CDK4/Cyclin-D1 heterodimer at the M169 site. This compound inhibited CDK4 kinase activity in a dose-dependent manner on purified protein and in live cells. Further biochemical analyses with a phospho-specific CDK4 antibody revealed crosstalk between M169 oxidation and T172 phosphorylation upon 1oxF11 treatment, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression at the S-phase checkpoint. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

The race variable in research has been the topic of debate in both research and clinical realms. The tension surrounding the discourse of the use of race in research stem from the difficulties in defining race, the limitations of the variable, and the implications for health and racial equity. In this review, we dissect the challenges faced when incorporating race into research and offer a guide for incorporating race in research in a manner that promotes racial and health equity.

Specialty drugs are expensive, but spending on specialty drugs is difficult to measure because of proprietary rebate payments by manufacturers to insurers, pharmacy benefit managers, and state Medi...

Recently, Peeva and the second author constructed irreducible projective varieties with regularity much larger than their degree, yielding counterexamples to the Eisenbud-Goto Conjecture. Their construction involved two new ideas: Rees-like algebras and step-by-step homogenization. Yet, all of these varieties are singular and the nature of the geometry of these projective varieties was left open. The purpose of this paper is to study the singularities inherent in this process. We compute the codimension of the singular locus of an arbitrary Rees-like algebra over a polynomial ring. We then show that the relative size of the singular locus can increase under step-by-step homogenization. To address this defect, we construct a new process, we call prime standardization, which plays a similar role as step-by-step homogenization but also preserves the codimension of the singular locus. This is derived from ideas of Ananyan and Hochster and we use this to study the regularity of certain smooth hyperplane sections of Rees-like algebras, showing that they all satisfy the Eisenbud-Goto Conjecture, as expected. On a more qualitative note, while Rees-like algebras are almost never Cohen-Macaulay and never normal, we characterize when they are seminormal, weakly normal, and, in positive characteristic, F-split. Finally, we construct a finite free resolution of the canonical module of a Rees-like Algebra over the presenting polynomial ring showing that it is always Cohen-Macaulay and has a surprising self-dual structure., Comment: 31 pages

Our multi-institutional university consortium implemented a gastroschisis pathway in 2015 to standardize and improve care by promoting avoidance of routine intubation and paralysis during silo placement, expeditious abdominal wall closure, discontinuation of antibiotics/narcotics within 48 h of closure, and early initiation/advancement of feeds.Adherence to the gastroschisis pathway was prospectively monitored. Outcomes for the contemporary cohort (2015-2018) were compared with a historical cohort (2007-2012).Good adherence to the pathway was observed for 70 cases of inborn uncomplicated gastroschisis. The contemporary cohort had significantly lower median mechanical ventilator days (2 versus 5; p 0.01) and antibiotic days (5.5 versus 9; p 0.01) as well as earlier days to initiation of feeds (12 versus 15; p 0.01). However, no differences were observed in length of stay (28 versus 29 days; p = 0.70). A skin closure technique was performed in 66% of the patients, of which 46% were performed at bedside without intubation, the assistance of an operating-room team, or general anesthesia.In this study, adherence to a clinical pathway for gastroschisis across different facilities was feasible and led to reduction in exposure to mechanical ventilation and antibiotics. The adoption of a bedside skin closure technique appears to facilitate compliance with the pathway.Level II/III TYPE OF STUDY: Prospective comparative study with historical cohort.

This study aimed to estimate the impact of sharing drug rebates at the point of sale on out-of-pocket spending by linking estimated rebates to administrative claims data for employer-sponsored insurance enrollees in 2018.We applied the drug rebate rate to the retail price of each brand name drug fill, allocated the reductions to out-of-pocket spending based on cost-sharing provisions, and aggregated each individual's out-of-pocket spending across drug fills. We assumed that generic drugs have no rebates for employer-sponsored insurance. We assessed the impact of sharing rebates at the point of sale on out-of-pocket spending overall, for the therapeutic classes and specific drugs with the highest average out-of-pocket spending per user, and by health plan type.Across 4 simulations with different assumptions about the degree of cross-fill effects, we found that 10.4% to 12.2% of enrollees in our sample would have realized savings on out-of-pocket spending if rebates were shared to the point of sale. Among those with savings, approximately half would save $50 or less, and 10% would save$500 annually. We calculated that a premium increase of $1.06 to $1.41 per member per month among the continuously enrolled, insured population would be sufficient to finance the out-of-pocket savings in our sample.Our study suggests that, for a small percentage of enrollees, sharing drug rebates at the point of sale would likely improve the affordability of high-priced brand name drugs, especially drugs that face significant competition.

The voluntary nature of the R3 program means that the experiences of residents who enroll in the program are critical to program success. Surveys were distributed to participants and non-participants in the intervention and control buildings during R32. Findings indicate that most enrollees are interacting with R32 staff; they trust them and feel that they provide important information; and they feel safer, less alone, and healthier because of their participation in the program. Roughly nine-in-ten are satisfied with the program and three in five would recommend it to a friend. Fully one-third believe that the program is helping them avoid medical emergencies necessitating a trip to the emergency room. When faced with a serious medical concern, residents in R32 buildings are far less likely to view calling 911 or going to the emergency room for treatment as a way to address their issue compared to individuals living in control buildings.

Housing with services programs have potential to benefit residents and operators of affordable senior housing communities. This study aimed to understand housing and community partner views on the benefits of the R3 program. Data derived from 31 interviews with R3 program managers and wellness team members, executives and direct service staff at the intervention sites, and community partners. Overwhelmingly positive overall assessments of the R3 program were reported. Concrete benefits to residents included receiving additional attention and support; connecting with family and health care resources; enhancing group programming; preventing ambulance transports; helping with transitions; and improving health and quality of life. Psychosocial benefits to residents included: empowering program participants; providing socio-emotional support; and alleviating psychosocial distress. Benefits to housing sites included augmenting staffing levels, skills, and capabilities; proactively tracking and responding to resident needs; lowering resident turnover; and learning from and adopting procedures and processes underlying the R3 philosophy.

The 2020 election of Joe Biden to the presidency has shifted the foundations of the American political system after four years of conservative policy leadership. Combined with a slim Democratic majority in Congress, the policies, priorities, and proposals of the Biden administration have important ramifications for all spheres of American life. Nowhere is this clearer than with older Americans who disproportionately supported Donald Trump’s reelection but are among those who benefit most with enactment of the Democratic party agenda. Between 2010 and 2050 the proportion of the U.S. population aged 65 years or older is projected to increase from 13% to 20%. Population aging creates opportunities and challenges for older adults, their families, and society in general. The Biden administration has chosen to meet these challenges, in part, by seeking to expand the social safety net. By contrast, the Trump administration largely supported Republican priorities to draw back on the federal government’s commitment to programs intended to support an aging population. This panel examines aging politics and policy during the first two years of the Biden administration. It reports on older adults’ voting patterns and the role of issue framing in limiting public support for proposals such as Medicare for All. It analyzes provisions in the American Rescue Plan Act and Build Back Better Bill to bolster formal care and services for older adults, as well as federal actions to support family caregivers. Edward Miller serves as panel chair; Janelle Fassi serves as co-chair and Marc Cohen as discussant.

Relatively few housing with services evaluations use rigorous designs when assessing program impacts on health services utilization. This study thus employed a pre/post difference-in-difference quasi-experimental design, including building-level comparisons using Medicare fee-for-service claims data across two stages of the R3 intervention. Intervention sites included seven buildings with roughly 1,200 individuals. Key outcomes included hospital admissions, 30-day hospital readmission, and emergency department admissions. Results indicate that adding the R3 intervention to low-income housing sites led to meaningful reductions in service utilization and costs when compared to buildings where the program was not operating. The introduction of risk-targeting in the second stage of the intervention further strengthened this effect. Findings demonstrate that residents of affordable senior housing communities, who tend to be in poorer health than their counterparts in the community, benefit from the R3 program and that additional investment in this type of initiative would benefit the health care system.

The R32 program seeks to ensure that individuals at high risk for adverse health outcomes are identified, engaged, and linked to needed services. The program pays particular attention to identifying individuals with risks related to mental health, memory, nutrition, food insecurity, and emergency department or inpatient hospitalizations. Key performance indicators were tracked, including the number and proportion of participants whose needs were addressed by R32. Results indicate that the program has succeeded in engaging the vast majority (>90%) of individuals with specific risk factors and connecting them with needed services. Viewed in the context of managed care plans, this level of performance is noteworthy and would earn the program a 5 Star rating – the highest rating available. Findings underscore the strong advantage offered by having a wellness nurse and wellness coordinator embedded on site in senior housing and using this platform to manage prevention and care services to residents.

On any given day 3.9% to 4.2% of the US population receives nursing home (NH) care. Given the critical role NHs play in caring for older adults, research has identified various demographic, biological, psychological, and social factors associated with NH utilization. Few studies, however, have explored religiosity as a predictor; none, longitudinally. This study thus aims to examine how one’s religiosity (organizational, non-organizational, intrinsic) affects NH use. A total of n=7,564 respondents (>51 years) from the 2006 wave of the Health and Retirement Study, with no prior NH use, were assessed every two years, until 2014. Hierarchical modeling techniques (i.e., Generalized Estimating Equations Multinomial Logistic Regression) were used to model the relationship between religiosity and subsequent NH use, while controlling for other factors. Results indicate that high levels of organizational religiosity (i.e., service attendance) is associated with higher rates of NH utilization (B= 0.13, p < 0.001). Conversely, they indicate that higher non-organizational religiosity (i.e., private prayer) is associated with a lower likelihood of NH care use (B= -0.03, p < 0.05). Sex and race served as moderators in these relationships. The association between higher levels of service attendance and higher rates of NH utilization may reflect the sharing of information about available resources such as long-term care through one’s social support networks, including congregations. In contrast, individuals who were more likely to pray on their own, may lack the social support provided by congregations, and as a result, experienced more limited knowledge transfer about available resources such as NHs.

CASE This is a case of a 44-year-old man with 10 years of history of painful callus-like swellings of bilateral index fingers. Sudden enlargement of the left index finger prompted biopsy, which revealed aggressive digital papillary adenocarcinoma (ADPA) that was treated with partial amputation. Biopsy of the contralateral finger revealed acanthotic skin with no evidence of malignancy. CONCLUSION Several case reports cite antecedent insult and chronic swelling before diagnosis. We describe a case of bilateral lesions with similar gross appearances, a long history of occupational repetitive trauma, and sudden enlargement of 1 lesion leading to the diagnosis of ADPA.

CASE Flexor digitorum profundus avulsions are common injuries that manifest as tendinous or bony avulsions from the distal phalanx. Rarely, additional fractures can occur in the distal phalanx. For such injuries, repair of the avulsion and fracture is recommended but difficult because of limited bone stock for fixation. CONCLUSION We present a case of a 28-year-old man with a combined flexor digitorum profundus bony avulsion and bony mallet finger, and describe a strategic fixation technique using an intramedullary suture anchor and dorsal button that provided stable fixation and resulted in excellent motion and function, with return to sport at 12 weeks.