Affirming Care for LGBTQ+ Patients.

The lesbian, gay, bisexual, transgender, and queer(LGBTQ +) community is a marginalized minority group who continues to face and experience significant discrimination, prejudice, stigma, oppression, and abuse in various societal domains including health care. The older adult LGBTQ + community is an especially vulnerable group as they have unique minority stressors attributed to intersectional identities of age, ableism, ethnicity, and employment, among other factors. It is critical for health care providers to recognize and mitigate disproportionate care by engaging in strategies that promote inclusion and affirmation of their sexual orientation and gender identity. The biopsychosocial, cultural, and spiritual framework is a useful tool to care for this community in a holistic and compassionate way.

Disrespectful and inadequate palliative care to transgender persons.

OBJECTIVES: The purpose of this study was to describe disrespectful, inadequate, and abusive care to seriously ill patients who identify as transgender and their partners. METHODS: A cross-sectional mixed methods study was conducted. The sample included 865 nurses, physicians, social workers, and chaplains. Respondents were asked whether they had observed disrespectful, inadequate, or abusive care due to the patient being transgender and to describe such care. RESULTS: Of the 21.3% of participants who reported observing discriminatory care to a transgender patient, 85.3% had observed disrespectful care, 35.9% inadequate care, and 10.3% abusive care. Disrespectful care included insensitivity; rudeness, ridicule, and gossip by staff; not acknowledging or accepting the patient's gender identity or expression; privacy violations; misgendering; and using the incorrect name. Inadequate care included denying, delaying, or rushing care; ignorance of appropriate medical and other care; and marginalizing or ignoring the spouse/partner. SIGNIFICANCE OF RESULTS: These findings illustrate discrimination faced by seriously ill transgender patients and their spouse/partners. Providers who are disrespectful may also deliver inadequate care to transgender patients, which may result in mistrust of providers and the health-care system. Inadequate care due to a patient's or spouse's/partner's gender identity is particularly serious. Dismissing spouses/partners as decision-makers or conferring with biological family members against the patient's wishes may result in unwanted care and constitute a Health Insurance Portability and Accountability Act of 1996 (HIPAA) violation. Institutional policies and practices should be assessed to determine the degree to which they are affirming to both patients and staff, and revised if needed. Federal and state civil rights legislation protecting the LGBTQ+ community are needed, particularly given the rampant transphobic legislation and the majority of states lacking civil rights laws protecting LGBTQ+ people. Training healthcare professionals and staff to become competent and comfortable treating transgender patients is critical to providing optimal care for these seriously ill patients and their spouse/partner.

Imidazolone as an Amide Bioisostere in the Development of ß-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors.

B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

Disrespectful and inadequate palliative care to lesbian, gay, and bisexual patients.

OBJECTIVES: The study aims to describe inadequate, disrespectful, and abusive palliative and hospice care received by lesbian, gay, and bisexual (LGB) patients and their spouses/partners due to their sexual orientation or gender identity. METHODS: A national sample of 865 healthcare professionals recruited from palliative and hospice care professional organizations completed an online survey. Respondents were asked to describe their observations of inadequate, disrespectful, or abusive care to LGB patients and their spouses/partners. RESULTS: There were 15.6% who reported observing disrespectful care to LGB patients, 7.3% observed inadequate care, and 1.6% observed abusive care; 43% reported discriminatory care toward the spouses/partners. Disrespectful care to LGB patients included insensitive and judgmental attitudes and behaviors, gossip and ridicule, and disrespect of the spouse/partner. Inadequate care included denial of care; care that was delayed incomplete, or rushed; dismissive or antagonistic treatment; privacy and confidentiality violations; and dismissive treatment of the spouse/partner. SIGNIFICANCE OF RESULTS: These findings provide evidence of discrimination faced by LGB patients and partners while receiving care for serious illness. Hospice and palliative care programs should promote respectful, inclusive, and affirming care for the lesbian, gay, bisexual, transgender, and queer (LGBTQ) community, including policies and practices that are welcoming and supportive to both employees and patients. Staff at all levels should be trained to create safe and respectful environments for LGBTQ patients and their families.

Assessing and Addressing the Risk of Venous Thromboembolism Across the Spectrum of Gender Affirming Care: A Review.

OBJECTIVE: Accumulating evidence demonstrates that gender affirming hormone therapy (GAHT) improves mental health outcomes in transgender persons. Data specific to the risks associated with GAHT for transgender persons continue to emerge, allowing for improvements in understanding, predicting, and mitigating adverse outcomes while informing discussion about desired effects. Of particular concern is the risk of venous thromboembolism (VTE) in the context of both longitudinal GAHT and the perioperative setting. Combining what is known about the risk of VTE in cisgender individuals on hormone therapy (HT) with the evidence for transgender persons receiving HT allows for an informed approach to assess underlying risk and improve care in the transgender community. OBSERVATIONS: Hormone formulation, dosing, route, and duration of therapy can impact thromboembolic risk, with transdermal estrogen formulations having the lowest risk. There are no existing risk scores for VTE that consider HT as a possible risk factor. Risk assessment for recurrent VTE and bleeding tendencies using current scores may be helpful when assessing individual risk. Gender affirming surgeries present unique perioperative concerns, and certain procedures include a high likelihood that patients will be on exogenous estrogens at the time of surgery, potentially increasing thromboembolic risk. CONCLUSIONS AND RELEVANCE: Withholding GAHT due to potential adverse events may cause negative impacts for individual patients. Providers should be knowledgeable about the management of HT in transgender individuals of all ages, as well as in the perioperative setting, to avoid periods in which transgender individuals are off GAHT. Treatment decisions for both anticoagulation and HT should be individualized and tailored to patients' overall goals and desired outcomes, given that the physical and mental health benefits of gender affirming care may outweigh the risk of VTE.

A Call for the Creation of LGBTQ+ Competencies for Hospice and Palliative Medicine (HPM) Fellowship Programs.

CONTEXT: LGBTQ+ people and their families have unique needs, concerns, and issues when navigating serious illness. OBJECTIVES: To develop curricular milestones and an educational framework for hospice and palliative medicine (HPM) fellowship programs to meet the needs of this community. METHODS: A working group has developed a plan for the inclusion of LGBTQ+ competencies in HPM fellowship programs, utilizing input from an AAHPM Special Interest Group (SIG) at a national meeting. DISCUSSION: Learning to provide culturally competent care is essential for all HPM providers. Our group recommends specific clinical training competencies with plans to pilot them in upcoming academic years. Creating curricular recommendations will help guide fellowship programs education in the care of LGBTQ+ patients with serious illness.

Project Respect: experiences of seriously ill LGBTQ+ patients and partners with their health care providers.

Discrimination against lesbian, gay, bisexual, transgender, and queer (LGBTQ+) persons in health care creates barriers to serious illness care, including patients avoiding or delaying necessary care, providers disrespecting wishes of surrogates, and adverse outcomes for patients and families. A cross-sectional mixed-methods study using an online survey was used to determine the extent to which LGBTQ+ patients and spouses, partners, and widows experienced disrespectful or inadequate care due to sexual orientation or gender identity. A total of 290 LGBTQ+ patients and partners reported high levels of disrespectful and inadequate care, including 35.2% stating their provider was insensitive to them because of their identity; 30% reporting their provider was unaware of LGBTQ+ health needs; 23.1% feeling judged; 20.7% experiencing rudeness; 20.3% stating providers did not use their correct pronouns; and 19.7% reporting their treatment decisions were disregarded. Black and Hispanic patients were 2-4 times more likely than non-Hispanic White patients to report discrimination. This study demonstrated high levels of disrespectful and inadequate care towards patients and partners due to being LGBTQ+, which was especially problematic for Black and Hispanic patients and those living in politically conservative regions. Recommendations include federal and state civil rights laws to prohibit LGBTQ+ discrimination and institutional practices to address discrimination, including cultural sensitivity training for staff.

BRET measurement on CCD camera-based microtiter plate readers.

NanoBRET assays, which utilize bioluminescence energy resonance transfer (BRET), have been widely adopted in drug discovery for measuring both protein-protein interactions and drug target engagement. While the EnVision and other traditional well-scanning plate readers that measure a single well at a time are satisfactory for signal detection for smaller experiments, it becomes challenging to scale these assays to applications that require higher throughput. To address this, we explored the adaptation of the ViewLux and FLIPR plate readers for measuring NanoBRET signal. These plate readers utilize charge-coupled device (CCD) cameras for detection, which enable imaging of the entire assay plate simultaneously. We used tool compounds to generate data from each plate reader and found that the image-based plate readers can be used to measure NanoBRET signals with high S/B and Z´, resulting in comparable IC50 values to those obtained from the EnVision, while requiring less time to complete reads. Consequently, utilization of image-based plate readers for NanoBRET measurement may enable applications that require faster reads, such as for high-throughput screening or kinetics studies.

Palliative care needs, concerns, and affirmative strategies for the LGBTQ population.

The Lesbian, Gay, Bisexual, Transgender, and Queer/Questioning population, also known as sexual and gender minorities, are an incredibly marginalized and vulnerable population that have been disproportionately affected by the provision, delivery, and optimal access to high-quality medical care including palliative, hospice, and end-of-life care. The long-standing and unique experiences shaped by positive and negative historical events have led to a better understanding of significant barriers and gaps in equitable healthcare for this population. The intersection of both internal and external stressors as well as minority identities in the context of discriminatory political and societal infrastructures have resulted in variable health outcomes that continues to be plagued by economic barriers, oppressive legislative policies, and undesirable societal practices. It could not be more urgent and timely to call upon the government and healthcare systems at large to execute reforms in policies and regulations, engage in cultural competency training, and promote cultural shifts in beliefs, attitudes, and practices that will ultimately recognize, prioritize, and address the needs of this population. After all, health care access is a universal right regardless of personal, social, political, and economic determinants of comprehensive medical care.

Structures and mechanism of human glycosyltransferase ß1,3-N-acetylglucosaminyltransferase 2 (B3GNT2), an important player in immune homeostasis.

ß1,3-N-acetylglucosaminyltransferases (B3GNTs) are Golgi-resident glycosyltransferases involved in the biosynthesis of poly-N-acetyl-lactosamine chains. They catalyze the addition of the N-acetylglucosamine to the N-acetyl-lactosamine repeat as a key step of the chain elongation process. Poly-N-acetyl-lactosamine is involved in the immune system in many ways. Particularly, its long chain has been demonstrated to suppress excessive immune responses. Among the characterized B3GNTs, B3GNT2 is the major poly-N-acetyl-lactosamine synthase, and deletion of its coding gene dramatically reduced the cell surface poly-N-acetyl-lactosamine and led to hypersensitive and hyperresponsive immunocytes. Despite the extensive functional studies, no structural information is available to understand the molecular mechanism of B3GNT2, as well as other B3GNTs. Here we present the structural and kinetic studies of the human B3GNT2. Five crystal structures of B3GNT2 have been determined in the unliganded, donor substrate-bound, acceptor substrate-bound, and product(s)-bound states at resolutions ranging from 1.85 to 2.35 Å. Kinetic study shows that the transglycosylation reaction follows a sequential mechanism. Critical residues involved in recognition of both donor and acceptor substrates as well as catalysis are identified. Mutations of these invariant residues impair B3GNT2 activity in cell assays. Structural comparison with other glycosyltransferases such as mouse Fringe reveals a novel N-terminal helical domain of B3GNTs that may stabilize the catalytic domain and distinguish among different acceptor substrates.

Experiences of Lesbian, Gay, Bisexual, and Transgender Patients and Families in Hospice and Palliative Care: Perspectives of the Palliative Care Team.

Background: Lesbian, gay, bisexual, and transgender (LGBT) patients fear being open about their identities, not receiving equal or safe treatment, and having their family and surrogates disrespected or ignored by providers. Objective: To examine inadequate, disrespectful, and abusive care to patients and family due to sexual orientation or gender identity. Design: A cross-sectional study using an online survey. Setting/Subjects: Home and residential hospice, inpatient palliative care service, and other inpatient and outpatient settings. Subjects were 865 hospice and palliative care providers, including physicians, social workers, nurses, and chaplains. Measurements: Inadequate, disrespectful, or abusive care to LGBT patients and discriminatory treatment of family and surrogates were measured. Results: Among respondents, 53.6% thought that lesbian, gay, or bisexual (LGB) patients were more likely than non-LGB patients to experience discrimination at their institution; 23.7% observed discriminatory care; 64.3% reported that transgender patients were more likely than nontransgender patients to experience discrimination; 21.3% observed discrimination to transgender patients; 15% observed the spouse/partner of LGBT patients having their treatment decisions disregarded or minimized; and 14.3% observed the spouse/partner or surrogate being treated disrespectfully. Conclusions: These findings provide strong evidence that LGBT patients and their families are more likely to receive discriminatory care as compared with those who are not LGBT. Disrespectful care can negatively impact the trust patients have in providers and institutions, and lead to delaying or avoiding care, or not disclosing relevant information. Partners/spouses and surrogates may be treated disrespectfully, have their treatment decisions ignored or minimized, be denied or have limited access to the patient, and be denied private time. Advocacy and staff training should address barriers to delivering respectful and nondiscriminatory care.

A "Click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation.

Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs. We demonstrate the utility of this approach with the bromodomain and extraterminal domain-4 (BRD4) ligand JQ-1 (3) and ligase binders targeting cereblon (CRBN) and Von Hippel-Lindau (VHL) proteins. An AlphaScreen proximity assay was used to determine the ability of PROTACs to form the ternary ligase-PROTAC-target protein complex and a MSD assay to measure cellular degradation of the target protein promoted by PROTACs.