APOL1 genotype and patient outcomes in US and South African transplant recipients with HIV who received kidneys from donors with HIV

Lower kidney allograft survival has been demonstrated in kidney transplant recipients (KTR) without HIV whose donors have two apolipoprotein L1 (APOL1) renal risk variants (RRV). The effects of APOL1 RRV on kidney transplant outcomes in people with HIV (PWH) have not been fully assessed. To determine whether APOL1 renal risk variants (G1/G2) in donors or recipients are associated with outcomes of kidney transplantation in people with HIV (PWH)? Comparative analysis of kidney allograft outcomes in two of the largest longitudinal clinical studies examining transplantation outcomes in PWH. Two cohorts of HIV-positive KTR (R+) and their respective HIV-negative (D-) or HIV-positive (D+) kidney donors from the South African (SA) HIV+ to HIV+ transplantation clinical study and the United States of America (US) HOPE in Action Kidney transplantation clinical trial. All patients with genomic DNA available for APOL1 genotyping were included. APOL1 Genotype was determined using a probe-based assay. Time to first rejection, HIV-associated nephropathy, graft failure or death were compared by both donor and recipient APOL1 RRV status. Genomic DNA was available for 21 donors with HIV and 38 HIV D+/R+ recipients in the SA cohort, and 57 donors (40 D+ and 17 D-) and 119 recipients (49 HIV D+/R+ and 70 D-/R+) in the US cohort. Recipient outcomes were not associated with recipient APOL1 genotype. However, recipients whose donor carried one versus zero APOL1 RRV were significantly more likely to experience a negative composite outcome (p<0.02 for both cohorts independently), which led to an adjusted hazard ratio of a poor composite outcome of 2.9 (95% CI 1.1–7.4) and 10.1 (95% CI 2.4–42.7) in the SA and US cohorts, respectively. In two independent studies, the presence of one APOL1 RRV in a donor kidney led to significantly worse post-transplant outcomes while recipient APOL1 genotype was not associated with outcomes. Further research into the interaction between the allograft environment and donor APOL1 genotype in PWH is required. Do APOL1 renal risk variants (G1/G2) influence the outcomes of kidney transplantation in people with HIV (PWH)? In two of the largest cohorts of PWH who are also kidney transplant recipients, the presence of even one donor APOL1 renal risk variant was associated with an adjusted hazard ratio of a poor composite outcome of 10.1 (95%CI=2.4-42.7) and 2.9 (95%CI=1.1-7.4) in the US and SA cohorts, respectively. Recipient APOL1 genotype was not associated with graft outcomes. This may have implications for allocation of allograft kidneys in PWH, as well as informing the need for therapies targeting APOL1 gene expression in kidney transplant recipients

The Influence of Hospital Policies on Clinicians’ Decisions to Withhold or Withdraw Life-Sustaining Treatment

There is considerable variation in clinicians’ approaches to decisions to withhold or withdraw life sustaining treatment (LST) across US hospitals. These differences are not explained by patient preferences alone and are likely influenced by other factors (eg, hospital policies, hospital culture, state laws, medical society guidelines). How do hospital policies influence clinician approaches to decisions to withhold or withdraw LST among patients admitted to an ICU? We conducted semistructured interviews with ICU nurses and physicians at 3 geographically diverse hospital systems across the United States between July and October 2024. We asked clinicians about their experiences with, and perceptions of, hospital policies on withholding or withdrawing LST and the relationship between these policies and clinician decision-making in ethically challenging scenarios. We interviewed 10 nurses and 8 attending physicians with a median of 5 years (range, 2-36 years) in practice. Clinicians described limited awareness of, and familiarity with, their hospital’s policies that addressed withholding or withdrawing LST. Clinicians with knowledge of these policies could identify their location but described barriers to accessing them. Although clinicians perceived hospital policies as helpful in some ways (eg, legal protection, ethical guidance), they viewed them as neither acknowledging nor addressing sociodemographic disparities or clinician value judgments in LST decision-making. Perceptions varied about whether clinicians followed their own hospital policy guidance when making decisions to withhold or withdraw LST. Clinicians lack detailed understanding about their hospitals’ policies that address withholding or withdrawing LST and perceive these policies as having limited applicability to clinical practice. These findings suggest that hospital policies may have little influence on clinician behavior in addressing decisions to withhold or withdraw LST in ethically challenging scenarios

Surgical Stabilization of Fractures in Combat Trauma: External Fixation During the Global War on Terror

Role 2 (R2) U.S. military treatment facilities (MTFs) provide forward damage control resuscitation and surgery. There are many configurations of R2 surgical teams, but each service defines external fixation (EF) as a requisite skill. To inform planning of potential future conflicts, this study describes EF utilization in recent past conflicts. The Department of Defense Trauma Registry (DoDTR) was retrospectively reviewed from 2003 to 2023. All combat casualties who underwent EF at U.S. MTFs were included. The primary outcome was the MTF level at which EF was performed. Secondary outcomes included the anatomic site of EF and population receiving EFs. Trends in these outcomes were evaluated across time and military operation. Six thousand one hundred eleven patients received 9,310 EFs; 2,600 were U.S. casualties, 1,630 foreign civilian, 275 North Atlantic Treaty Organization (NATO) military, and 1,605 non-NATO military. 19.5% of EFs were placed at R2, 67.6% at Role 3 (R3), 4.9% at Role 4 (R4), and 8.0% at R4-Continental US (R4C) MTFs. 78.0% of patients undergoing their first EF at R3 bypassed the R2. 67.5% of EFs were on the lower extremity and 19.4% were on the upper extremity. At both R2 and R3, the lower extremity was the predominant EF site (69.6% and 67.3% respectively). External pelvic fixation was rarely performed (0.3% and 0.1%). These results offer valuable insight into modern logistical concerns in the delivery of forward surgical care. First and foremost, it underscores the importance of maintaining EF capability in expeditionary surgical teams, especially at lower echelons of care. Given the increasing prevalence of EF at R2s and the logistical challenges of evacuation in future conflicts, consideration should be given to both sustaining orthopedic-trained surgeons in theater and ensuring all general surgeons have robust orthopedic capabilities

Sociodemographic Disparities in Decisions to Withhold or Withdraw Life-Sustaining Treatment

1. Participants will be able to identify sociodemographic disparities in decisions to withhold or withdraw life-sustaining treatment. 2. Participants will be able to apply practical steps to improve disparities in clinician decisions to withhold or withdraw life-sustaining treatment within their own institutions. Sociodemographic disparities in clinician decisions to withhold or withdraw life-sustaining treatment exist. This session will explore data identifying these disparities, discuss how hospital policies address these disparities, and explore steps to address these disparities. Completion of this session will well position hospice and palliative medicine clinicians to take practical steps to address these disparities within their individual institutions. Decisions to withhold or withdraw life-sustaining treatment (LST) for critically ill patients can be ethically controversial, especially when disagreements over these decisions exist among clinicians, patients, and surrogates. Sociodemographic disparities make this issue particularly fraught, especially in light of recent evidence that clinicians disproportionately make unilateral decisions to withhold LST for patients in certain vulnerable populations. For example, clinicians more often use unilateral do-not-resuscitate orders for Spanish-speaking patients and more often withhold extracorporeal life support for patients who are female, insured by Medicaid, or live in low-income neighborhoods. (1,2) To describe and explicate how United States hospital policies currently address decisions to withhold or withdraw LST in ethically controversial scenarios and explore how these policies ought to address these scenarios. Relying on our significant experience in clinical medical ethics and palliative medicine, this panel will be divided into three parts: each of the 2 panelists will speak for 9 minutes followed by a 7-minute question-answer period and discussion with the audience. This panel will first explore data identifying racial, ethnic, and socioeconomic disparities in clinician decisions to withhold or withdraw life-sustaining treatment. We will then discuss how hospital policies address these disparities. Last, we will explore steps to address sociodemographic disparities in clinician decisions to withhold or withdraw LST. This session will well position hospice and palliative medicine clinicians to be able to identify sociodemographic disparities that exist in clinician decisions to withhold or withdraw life-sustaining treatment and take practical steps to address these disparities within their institutions. 1. Mehta A.B., Taylor J.K., Day G., Lane T.C., Douglas I.S. Disparities in adult patient selection for extracorporeal membrane oxygenation in the United States: a population-level study. Ann Am Thorac Soc. 2023; 20: 1166-1174 2. Piscitello G.M., Tyker A., Schenker Y. et. al., Disparities in unilateral do not resuscitate order use during the COVID-19 pandemic. Crit Care Med. 2023; 51: 1012-102

'See something, say something': a qualitative study of neighborhood perceptions and brain health

Studies have shown the importance of neighborhood factors, such as residential segregation and green space, in associations with older adult brain health. In this qualitative study, we examine older adults' perceptions of their neighborhood, with a particular focus on residential diversity and segregation. We recruited participants from the longitudinal cohort at the UC Davis Alzheimer's Disease Research Center to participate in semi-structured interviews. Participants were interviewed and asked to describe features and perceptions of their neighborhood. Individual interviews lasted twenty-three minutes on average and were audio-taped, transcribed verbatim, and analyzed for recurring themes. A total of twenty-six participants were interviewed: 61.5% female, 50.0% non-Hispanic White and 50.0% Black/African American, mean age= 81.12, SD = 6.93 years.The most prominent themes were (1) Importance of public stores and similar third spaces; (2) Accessibility to green space, including parks and trees; (3) Staying active in the community, both physically and socially; (4) Neighborhood awareness and cohesion; and (5) Stereotypes, discrimination, and segregation. These findings highlight the social and built environment factors that are important to older adults and that may potentially affect brain health. Future research should examine how salient themes might differ depending on older adults' cognition

SMAD4 Deficiency Promotes Pancreatic Cancer Progression and Confers Susceptibility to TGFβ Inhibition

The 5-year overall survival rate for pancreatic cancer remains ∼13%, underscoring the urgent need for improved treatment strategies. TGFβ is a promising target due to its significant involvement in the desmoplasia, immune suppression, and chemoresistance characteristics of pancreatic cancer. More than 300 clinical trials targeting TGFβ have been conducted in unselected patient cohorts; however, none of the therapies have gained FDA approval. Nevertheless, TGFβ blockade may hold promise for a subset of cancers with nonfunctional TGFβ signaling. More than 25% of pancreatic cancers carry mutations in SMAD4, a key component of canonical TGFβ signaling. In this study, we investigated the potential for stratifying patients based on SMAD4 mutational status to identify tumors susceptible to TGFβ inhibition. Analysis of SMAD4 expression in human pancreatic tumors revealed that SMAD4 mutation or loss is associated with worse disease-free survival. Intriguingly, intratumoral SMAD4 expression displayed heterogeneity among human pancreatic cancer samples. SMAD4-deficient genetically engineered mouse models and orthotopic SMAD4 knockout tumor models exhibited reduced survival, increased metastasis, and alterations in the tumor microenvironment compared with SMAD4 wild-type controls, consistent with gene and protein expression changes in the absence of functional SMAD4. Importantly, treating mice bearing SMAD4-deficient tumors with a blocking TGFβ antibody reduced tumor weight and improved survival. These findings suggest that genomic stratification by TGFβ axis alterations, such as SMAD4 mutations, may be a promising approach to identifying patients likely to benefit from a TGFβ inhibitor. Targeting TGFβ in pancreatic cancers that are deficient in canonical TGFβ signaling could provide a therapeutic strategy to enhance standard and immune therapy approaches for a substantial population of pancreatic cancer patients

Schisis-Like Presentations of Familial Exudative Vitreoretinopathy Caused by FZD4 Mutations

To describe a case series with schisis-like presentations of genetically confirmed familial exudative vitreoretinopathy (FEVR) caused by mutations. Retrospective case review of 4 patients with FEVR caused by mutations, analyzed by optical coherence tomography (OCT) for schisis-like characteristics. Three pediatric patients and 1 adult patient presented with unilateral, inner schisis in the retinal periphery. Overall, the schisis was characterized by thickening of the inner retinal layers and column-like structures affecting mostly the internal limiting membrane, nerve fiber layer, and ganglion cell layer, while mostly sparing the inner nuclear layer. Patients with genetically confirmed FEVR caused by mutations in can have a schisis-like presentation. This is a distinct entity from other retinal disorders that involve schisis. Since it can be hard to visualize clinically, peripheral OCT imaging should be performed during a retinal examination with the patient under anesthesia to fully evaluate these presenting characteristics

Patterns of Cannabis Use among Women With HIV in the United States

Cannabis legalization in the United States changed cannabis product potency and consumption modalities. Women with HIV are an aging population with prevalent cannabis use twice that of national estimates. Because cannabis use may confer both health benefits and risks, it is important to understand cannabis use patterns among women with HIV. This analysis characterized prevalence, frequencies, and modes (smoking, vaping, eating) of cannabis use among 1,246 women with HIV in the Women's Interagency HIV Study over 18 months (2018-2019). We compared participant characteristics using chi-square tests and Wilcoxon rank-sum tests. We illustrated flow between cannabis use frequency categories with a Sankey diagram. Median participant age was 52 years (interquartile range: 46, 58). 65% of participants identified as Black/African American; 50% had annual household incomes <$12,000. The period prevalence was 27% for any cannabis use and 15% for daily or more use. 50% reported varying use frequencies. Among women using cannabis, 96% reported smoking, 30% consumed edibles, and 18% vaped. Compared with women not using cannabis, greater proportions of women using cannabis reported alcohol (69% vs. 37%, p < 0.01), cigarette (61% vs. 29%, p < 0.01) and other drug use (16% vs. 4%, p < 0.01). Compared to those with no high potency use, a higher proportion of women using high potency products were in a state legalizing cannabis sales. Cannabis use among women with HIV is common and of variable frequency. Future work should characterize patterns of use, product choice motivations, and associated health impacts in the context of aging and HIV