Glutamylation of Npm2 and Nap1 acidic disordered regions increases DNA mimicry and histone chaperone efficiency.

Histone chaperones-structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)-protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.

Federal and State Policy Issues Affecting Lesbian, Gay, Bisexual, Transgender, and Queer Older Adults.

Anti-lesbian, gay, bisexual, transgender, and queer (LGBTQ) + discrimination is widespread, harming the health of LGBTQ + people and constituting a barrier to care. This contributes to higher rates of poverty among LGBTQ + people, especially among people of color, and lower insurance coverage rates. The Affordable Care Act's expansion of insurance access has reduced uninsurance rates among LGBT people and people living with human immunodeficienc virus (HIV). Systemic improvements in culturally responsive health care have occurred over the past decade, including increased collection and use of sexual orientation and gender identity data to improve quality of care. As older LGBTQ + people enter elder service systems, reforms are needed to ensure equitable access.

A Peer-to-Peer Collaborative Learning Approach for the Implementation of Evidence-Informed Interventions to Improve HIV-Related Health Outcomes.

The nationwide scale-up of evidence-based and evidence-informed interventions has been widely recognized as a crucial step in ending the HIV epidemic. Although the successful delivery of interventions may involve intensive expert training, technical assistance (TA), and dedicated funding, most organizations attempt to replicate interventions without access to focused expert guidance. Thus, there is a grave need for initiatives that meaningfully address HIV health disparities while addressing these inherent limitations. Here, the Health Resources and Services Administration HIV/AIDS Bureau (HRSA HAB) initiative Using Evidence-Informed Interventions to Improve HIV Health Outcomes among People Living with HIV (E2i) piloted an alternative approach to implementation that de-emphasized expert training to naturalistically simulate the experience of future HIV service organizations with limited access to TA. The E2i approach combined the HAB-adapted Institute for Healthcare Improvement's Breakthrough Series Collaborative Learning Model with HRSA HAB's Implementation Science Framework, to create an innovative multi-tiered system of peer-to-peer learning that was piloted across 11 evidence-informed interventions at 25 Ryan White HIV/AIDS Program sites. Four key types of peer-to-peer learning exchanges (i.e., intervention, site, staff role, and organization specific) took place at biannual peer learning sessions, while quarterly intervention cohort calls and E2i monthly calls with site staff occurred during the action periods between learning sessions. Peer-to-peer learning fostered both experiential learning and community building and allowed site staff to formulate robust site-specific action plans for rapid cycle testing between learning sessions. Strategies that increase the effectiveness of interventions while decreasing TA could provide a blueprint for the rapid uptake and integration of HIV interventions nationwide.

Assessing the Impact of the 340B Drug Pricing Program: A Scoping Review of the Empirical, Peer-Reviewed Literature.

Policy Points The 340B Drug Pricing Program accounts for roughly 1 out of every 100 dollars spent in the $4.3 trillion US health care industry. Decisions affecting the program will have wide-ranging consequences throughout the US safety net. Our scoping review provides a roadmap of the questions being asked about the 340B program and an initial synthesis of the answers. The highest-quality evidence indicates that nonprofit, disproportionate share hospitals may be using the 340B program in margin-motivated ways, with inconsistent evidence for increased safety net engagement; however, this finding is not consistent across other hospital types and public health clinics, which face different incentive structures and reporting requirements. CONTEXT: Despite remarkable growth and relevance of the 340B Drug Pricing Program to current health care practice and policy debate, academic literature examining 340B has lagged. The objectives of this scoping review were to summarize i) common research questions published about 340B, ii) what is empirically known about 340B and its implications, and iii) remaining knowledge gaps, all organized in a way that is informative to practitioners, researchers, and decision makers. METHODS: We conducted a scoping review of the peer-reviewed, empirical 340B literature (database inception to March 2023). We categorized studies by suitability of their design for internal validity, type of covered entity studied, and motivation-by-scope category. FINDINGS: The final yield included 44 peer-reviewed, empirical studies published between 2003 and 2023. We identified 15 frequently asked research questions in the literature, across 6 categories of inquiry-motivation (margin or mission) and scope (external, covered entity, and care delivery interface). Literature with greatest internal validity leaned toward evidence of margin-motivated behavior at the external environment and covered entity levels, with inconsistent findings supporting mission-motivated behavior at these levels; this was particularly the case among participating disproportionate share hospitals (DSHs). However, included case studies were unanimous in demonstrating positive effects of the 340B program for carrying out a provider's safety net mission. CONCLUSIONS: In our scoping review of the 340B program, the highest-quality evidence indicates nonprofit, DSHs may be using the 340B program in margin-motivated ways, with inconsistent evidence for increased safety net engagement; however, this finding is not consistent across other hospital types and public health clinics, which face different incentive structures and reporting requirements. Future studies should examine heterogeneity by covered entity types (i.e., hospitals vs. public health clinics), characteristics, and time period of 340B enrollment. Our findings provide additional context to current health policy discussion regarding the 340B program.

Training Health Center Staff in the Provision of Culturally Responsive Care for Sexual and Gender Minority Patients: Results of a Randomized Controlled Trial.

Purpose: The study was designed to evaluate whether an educational intervention to train the health center (HC) staff to optimize care for sexual and gender minority (SGM) patients could improve documentation of sexual orientation and gender identity (SOGI) and increase preventive screenings. Methods: Twelve HCs were matched and randomized to either receive a tailored, multicomponent educational intervention or a 1-hour prerecorded webinar. Documentation of SGM status and clinical testing was measured through analysis of data that HCs report annually. Nonparametric statistics were used to assess associations between baseline HC characteristics and outcome measures. Results: The HCs were geographically, racially, and ethnically diverse. In all but one HC, <10% of the patients were identified as SGM. Intervention HCs underwent between 3 and 10 trainings, which were highly acceptable. In 2018, 9 of 12 HCs documented SO and 11 of 12 documented GI for at least 50% of their patients. Five of 6 intervention HCs increased SO documentation by 2020, compared to 3 of 6 control HCs (nonsignificant, NS). Five intervention HCs increased GI documentation, although generally by less than 10%, compared to 2 of the controls (NS). Intervention HCs tended to increase documentation of preventive services more than control HCs, but the changes were NS. Conclusions: An educational intervention designed to train the HC staff to provide culturally responsive services for SGM patients was found to be acceptable, with favorable, but nonsignificant changes. Further refinement of the intervention using a larger sample of HCs might demonstrate the effectiveness of this approach. Clinical trial registration #: NCT03554785.

Scoping Literature Review: Experiences of Sexual and Gender Minority Older Adults, With Diagnoses of Dementia, Who Use Residential Long-Term Services and Supports.

The number of sexual and gender minority (SGM) older adults utilizing residential long-term supports and services (LTSS) will increase in the forthcoming decades. Paradoxically, while requiring more LTSS services than their non-SGM counterparts, SGM older adults are less likely to access these services, partly due to fears of discrimination. Furthermore, SGM older adults living with Alzheimer's disease and related dementias (AD/ADRD) present unique challenges and opportunities for LTSS facilities. This article provides a scoping review on the intersection between experiences of SGM older adults with AD/ADRD who use residential LTSS. This review identified three themes: (1) the experiences of discrimination among SGM residents in LTSS facilities, (2) the need for comprehensive staff training in residential LTSS to ensure proper care of SGM populations, and (3) the crucial role of inclusive facility policies. As the number of SGM older adults is expected to increase, further research is necessary.

Glutamylation of Npm2 and Nap1 acidic disordered regions increases DNA charge mimicry to enhance chaperone efficiency.

Histone chaperones-structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)-protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that, to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model.

Introduction: Diabetes mellitus (DM) impairs fracture healing and is associated with susceptibility to infection, which further inhibits fracture healing. While intermittent parathyroid hormone (1-34) (iPTH) effectively improves fracture healing, it is unknown whether infection-associated impaired fracture healing can be rescued with PTH (teriparatide). Methods: A chronic diet-induced type 2 diabetic mouse model was used to yield mice with decreased glucose tolerance and increased blood glucose levels compared to lean-fed controls. Methicillin-resistant Staphylococcus aureus (MRSA) was inoculated in a surgical tibia fracture model to simulate infected fracture, after which mice were treated with a combination of antibiotics and adjunctive teriparatide treatment. Fracture healing was assessed by Radiographic Union Scale in Tibial Fractures (RUST), micro-computed tomography (µCT), biomechanical testing, and histology. Results: RUST score was significantly poorer in diabetic mice compared to their lean nondiabetic counterparts. There were concomitant reductions in micro-computed tomography (µCT) parameters of callus architecture including bone volume/total volume, trabecular thickness, and total mineral density in type 2 diabetes mellitus (T2DM) mice. Biomechanicaltesting of fractured femora demonstrated diminished torsional rigidity, stiffness, and toughness to max torque. Adjuvant teriparatide treatment with systemic antibiotic therapy improved numerous parameters of bone microarchitecture bone volume, increased connectivity density, and increased trabecular number in both the lean and T2DM group. Despite the observation that poor fracture healing in T2DM mice was further impaired by MRSA infection, adjuvant iPTH treatment significantly improved fracture healing compared to antibiotic treatment alone in infected T2DM fractures. Discussion: Our results suggest that teriparatide may constitute a viable adjuvant therapeutic agent to improve bony union and bone microarchitecture to prevent the development of septic nonunion under diabetic conditions.

Lessons Learned from the U.S. Public Health Response to the 2022 mpox Outbreak.

In mid-2022, an mpox outbreak occurred in the United States and more than 100 countries, disproportionately affecting men who have sex with men (MSM). Initially, the U.S. public health system failed to deploy tests, treatment, and vaccines effectively. Key federal policy changes in August 2022, along with risk reduction among many MSM, led to a steady reduction in new diagnoses by December 2022. Mpox outbreaks occurred among MSM in Chicago and France in May 2023, and vaccination rates remain low. This perspective analyzes the U.S. response to the 2022 outbreak, and it identifies the lessons learned that may guide mpox management moving forward.

FDA's 2023 Policy Update-Promoting Safety and Inclusivity in Blood Donation.

This Viewpoint discusses the US Food and Drug Administration's 2023 policy update to its blood donation guidelines for men who have sex with men.

"Going Back in the Closet": Addressing Discrimination Against Sexual and Gender Minority Residents in Long-Term Services and Supports by Providing Culturally Responsive Care.

Sexual and gender minority (SGM) older adults face discrimination in long-term services and supports (LTSS). Yet, SGM older adults use LTSS disproportionately higher relative to their non-SGM counterparts. The discrimination is compounded by existing disparities, resulting in worse health outcomes and well-being for SGM older adults. Guided by socioecological model, we posit that training LTSS staff in SGM responsive care and implementing SGM anti-discrimination policies will be needed to improve care. Considering accessibility and turnover challenges, training should be online, interactive, and easily accessible. Studies that assess interventions for SGM responsive care are needed to guide policy and practice.

The rate and predictors of healing of repaired lesser tuberosity osteotomy in reverse total shoulder arthroplasty.

Background: Evidence is building that a functional subscapularis improves function-specifically internal rotation tasks-following reverse total shoulder arthroplasty (rTSA). However, the optimal method for subscapularis repair during rTSA remains unknown with variable healing rates reported. This study aims to investigate the rate of and predictors for healing a lesser tuberosity osteotomy (LTO) following rTSA. Methods: Following local institutional review board approval, patients with at least one-year follow-up for rTSA managed with an LTO and subsequent repair between March, 2017 and March, 2020 were retrospectively identified. Shoulders were selected for LTO repair based upon preoperative imaging and intraoperative assessment of subscapularis quality. All patients were implanted with a system consisting of a 150° or 155° (constrained) humeral neck-shaft angle and 2.5 to 4.5 millimeters (mm) of glenoid lateralization (Trabecular Metal Reverse Shoulder System; Zimmer Biomet, Warsaw, IN, USA). At a minimum of six months, radiographs were reviewed for an assessment of LTO healing by three independent reviewers. Healing was classified as displaced, fibrous union, or ossified union. For assessing predictors, the repair was considered intact if the LTO fragment was not displaced (fibrous union or ossified union). Results: Sixty-five rTSA with LTO repair were performed in 64 patients. These patients had an average age of 67.2 years (range, 31-81) and 36 (55.4%; 36/65) were female. At an average follow-up of 15.2 months (range, 8-38), 50 cases (76.9%; 50/65) were classified as having an ossified union. The radiographic healing could not be assessed in a single case. Of the 14 cases without ossific union, 8 (12.3%; 8/65) were displaced and 6 (9.2%; 6/65) were classified as a fibrous union. In logistic regression, only combined humeral liner height predicted LTO displacement (odds ratio = 1.4 [95% confidence interval = 1.1-1.8]; P = .01). Humeral loosening was not found in any cases following LTO. Conclusion: This analysis demonstrates that radiographic healing of LTO repair is more favorable than published rates of healing after subscapularis tenotomy or peel in the setting of rTSA. Subscapularis management with LTO provides the ability to monitor repair integrity with plain radiographs and a predictable radiographic healing rate. The integrity of subscapularis repair may be influenced by the use of thicker humeral liners. Further investigation is needed to determine the functional impact of a healed subscapularis following rTSA.

Prevalence of Self-Reported Kidney Disease in Older Adults by Sexual Orientation: Behavioral Risk Factor Surveillance System Analysis (2014-2019).

SIGNIFICANCE STATEMENT: Studies discusses CKD disparities by age, race and ethnicity, and socioeconomics. However, despite well-documented disparities in CKD risk factors in LGBT+ adults, limited literature addresses CKD prevalence in this population. This analysis uses Behavioral Risk Factor Surveillance System (2014-2019) data to compare self-reported kidney disease prevalence in LGBT+ older adults (older than 50 years) with their heterosexual peers. Our findings indicate that LGBT+ older adults have higher rates of self-reported kidney disease and a higher incidence of CKD risks including smoking, activity limitations, adverse health outcomes, and limited access to health care, housing, and employment. These results support increasing access to screening for CKD risk factors, providing culturally responsive health care, and addressing societal drivers of vulnerability in older LGBT+ adults. BACKGROUND: Existing research documents disparities in CKD by age, race and ethnicity, and access to health care. However, research on CKD in lesbian, gay, bisexual, and trans (LGBT+) older adults, despite their higher rates of diabetes, heart disease, smoking, and alcohol use, is limited. METHODS: Pooled data from the Behavioral Risk Factor Surveillance System (2014-2019) for 22,114 LGBT+ adults and 748,963 heterosexuals aged 50 and older were used to estimate the prevalence of self-reported kidney disease. Logistic regressions were used to compare older adults by sexual orientation. RESULTS: Older LGBT+ men (adjusted odds ratio=1.3; 95% confidence interval [CI], 1.09-1.54) were more likely than their heterosexual counterparts to report kidney disease, after controlling for sociodemographic factors, health behaviors, access to health care, and self-reported coronary heart disease, HIV, and diabetes; LGBT+ men and women also reported higher incidences of known risk factors for CKD. For example, both LGBT+ men (odds ratio [OR]=1.39; [95% CI], 1.26-1.54) and LGBT+ women (OR=1.39; [95% CI], 1.25-1.55) were more likely to be smokers and have a higher incidence of activity limitations, adverse health outcomes, and limited access to health care, housing, and employment. CONCLUSION: These results support increasing access to screenings for CKD risk factors, providing preventative education and culturally responsive and affirming care, and addressing other societal drivers of vulnerability in older LGBT+ adults. The findings also support the value of interventions that address the interaction between CKD risk factors and the social marginalization that older LGBT+ adults experience.

Spatial genetic structure of European wild boar, with inferences on late-Pleistocene and Holocene demographic history.

European wildlife has been subjected to intensifying levels of anthropogenic impact throughout the Holocene, yet the main genetic partitioning of many species is thought to still reflect the late-Pleistocene glacial refugia. We analyzed 26,342 nuclear SNPs of 464 wild boar (Sus scrofa) across the European continent to infer demographic history and reassess the genetic consequences of natural and anthropogenic forces. We found that population fragmentation, inbreeding and recent hybridization with domestic pigs have caused the spatial genetic structure to be heterogeneous at the local scale. Underlying local anthropogenic signatures, we found a deep genetic structure in the form of an arch-shaped cline extending from the Dinaric Alps, via Southeastern Europe and the Baltic states, to Western Europe and, finally, to the genetically diverged Iberian peninsula. These findings indicate that, despite considerable anthropogenic influence, the deeper, natural continental structure is still intact. Regarding the glacial refugia, our findings show a weaker signal than generally assumed, but are nevertheless suggestive of two main recolonization routes, with important roles for Southern France and the Balkans. Our results highlight the importance of applying genomic resources and framing genetic results within a species' demographic history and geographic distribution for a better understanding of the complex mixture of underlying processes.

Recruiting, Facilitating, and Retaining a Youth Community Advisory Board to Inform an HIV Prevention Research Project with Sexual and Gender Minority Youth.

Sexual and gender minority (SGM) youth are at disproportionate risk of acquiring HIV, and as such, SGM youth should be meaningfully engaged in research aimed at developing effective, tailored HIV interventions. Youth Community Advisory Boards (YCABs) are an important element of community-engaged research and support the development of community-informed interventions. This article describes recruitment, facilitation, and retention of a YCAB composed of SGM youth in Greater Boston, to inform a national HIV prevention research project. These lessons can serve as a guide to future researchers who want to form YCABs as part of community-engaged research.

HIV Care Continuum Interventions for Transgender Women: A Topical Review.

Transgender women experience a disproportionate prevalence of HIV and barriers to linkage to care, retention in care, medication adherence, and viral suppression. As part of a national cooperative agreement funded by the Health Resources and Services Administration's HIV/AIDS Bureau, we searched the literature from January 1, 2010, through June 1, 2020, for English-language articles on interventions designed to improve at least 1 HIV care continuum outcome or address 1 barrier to achieving HIV care continuum outcomes among transgender women diagnosed with HIV in the United States. To be included, articles needed to identify transgender women as a priority population for the intervention. We found 22 interventions, of which 15 reported quantitative or qualitative outcomes and 7 reported study protocols. Recent interventions have incorporated a range of strategies that show promise for addressing pervasive structural and individual barriers rooted in societal and cultural stigma and discrimination against transgender people. Cross-cutting themes found among the interventions included meaningful community participation in the design and implementation of the interventions; culturally affirming programs that serve as a gateway to HIV care and combine gender-affirming care and social services with HIV care; interventions to improve behavioral health outcomes; peer-led counseling, education, and navigation; and technology-based interventions to increase access to care management and online social support. Ongoing studies will further elucidate the efficacy and effectiveness of these interventions, with the goal of reducing disparities in the HIV care continuum and bringing us closer to ending the HIV epidemic among transgender women in the United States.