Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients.

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.

Comparing Public Perceptions of Child and Adult Grief Responses to Familial Incarceration.

Children of incarcerated parents may grieve this loss, yet perceptions of their grief are understudied. Using vignettes varying by age (adult/child) and grief response (prolonged/resilient), we examined differences between perceptions of adults and children grieving parental incarceration. Participants rated grief response appropriateness, comfort providing support, and grief therapy recommendations for the grieving person in the vignette. Participants perceived resilience as more appropriate than prolonged grief [F (1, 224) = 9.02, p = .003, η2 = .04]. Age did not predict outcomes. Recommending grief therapy was higher for prolonged grief, yet 53% of participants with resilient vignettes recommended the person should seek grief therapy, which is concerning given possible iatrogenic effects. Thus, laypeople may have stigma toward individuals grieving parental incarceration, regardless of age.

Prolonged Grief Disorder, but Not Death From COVID-19, Elicits Public Stigma: A Vignette-Based Experiment.

We investigated the effects of cause of death (COVID-19 with an underlying medical condition vs. without) and prolonged grief disorder status (PGD present or absent) on participants' reported public stigma towards the bereaved. Participants (N = 304, 66% women; Mage = 39.39 years) were randomly assigned to read one of four vignettes describing a bereaved man. Participants completed stigma measures assessing negative attributions, desired social distance, and emotional reactions. Participants reported significantly stronger stigmatizing responses towards an individual with PGD (vs. without PGD) across all stigma measures. There was no significant difference in stigma based on cause of death; however, stigma was reported regardless of cause of death. There was no significant interaction between cause of death and PGD on stigma. This study supports the robust finding of public stigma being reported toward an individual with PGD, suggesting these individuals are at risk of public stigma and not receiving adequate bereavement support.

The Effects of Positive Psychological Factors on the Mental Wellbeing of Medical Students.

Objective A well-established association exists between academic performance and levels of depression and anxiety among medical students. However, the effects of positive psychological factors on symptoms of depression and anxiety and academic performance have not been adequately studied. This study explores the relationship between the above variables and identifies positive psychological factors that can promote medical student wellbeing. Methods Medical students were surveyed at four time points during their first two years of medical education using Qualtrics. The surveys used a five-point Likert scale to assess students' levels of loneliness, religiosity, engaged living, life fulfillment, resilience, psychological wellbeing, and symptoms of depression and anxiety. Academic performance was measured using students' Comprehensive Basic Science Examination scores. Linear mixed effect models with maximum likelihood estimation were used to investigate the relationship between positive psychological factors and scores on depression and anxiety as well as the relationship between demographic and psychological factors and exam scores. Results Seventy-two students completed the study. A significant positive correlation was observed between loneliness and symptoms of depression and anxiety, while the same symptoms had significant negative correlations with engaged living. None of the positive psychological factors were significantly predictive of exam scores. Conclusion Our findings suggest that medical students who develop meaningful relationships and live engaged lives are less likely to develop symptoms of depression and anxiety. Our study lays the groundwork for future research focusing on identifying and implementing pre-clinical curriculum changes aiming to improve medical students' mental health.

Eighteen-year outcome of anterior cruciate ligament reconstruction with patellar tendon or hamstring autograft.

PURPOSE: To evaluate patient reported outcomes and radiographic arthritic changes of transtibial anterior cruciate ligament reconstruction (ACLR) with either bone-patellar tendon-bone (BPTB) or hamstrings (HS) auto-grafts at a minimum of 15-year follow-up. METHODS: Ninety-four patients (51 of the HS group, 43 of BPTB group) who were operated between the years 2000 to 2005 in two tertiary referral hospitals were contacted and invited to a retrospective evaluation. The interview included subjective outcomes using the Lysholm knee scoring questionnaire, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Tegner activity level scale, Visual Analogue Scale (VAS) for pain and patients' satisfaction scale. Knee examination included measurements of motion and stability. Knee radiographs were evaluated for osteoarthritic changes according to the Kellgren-Lawrence (KL) score. RESULTS: The average evaluation time from surgery was 18.6 years. Subjectively, there was no significant difference between groups except for a better post-operative level of activity and satisfaction in the HS group. Objectively, there was no significant difference between groups in knee stability and range of motion. Most patients had grade KL ≤ 1 radiographic osteoarthritits changes and there was no significant difference between groups. Recurrent complete tear of the reconstructed graft occurred in 3 patients of each group. In both groups 84% had no further surgery while the indications for further surgery were mostly a meniscal tear or tibial hardware removal. CONCLUSIONS: Very long-term outcomes and clinical stability of transtibial HS or BPTB graft ACL reconstruction are good with low rate of graft failure and radiographic osteoarthritis.

Macrophage and CD8 T cell discordance are associated with acute lung allograft dysfunction progression.

BACKGROUND: Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized that single cell investigation of bronchoalveolar lavage (BAL) cells at the time of ALAD would identify immune cells linked to progressive graft dysfunction. METHODS: We prospectively collected BAL from consenting lung transplant recipients for single cell RNA sequencing. ALAD was defined by a ≥10% decrease in FEV1 not caused by infection or acute rejection and samples were matched to BAL from recipients with stable lung function. We examined cell compositional and transcriptional differences across control, ALAD with decline, and ALAD with recovery groups. We also assessed cell-cell communication. RESULTS: BAL was assessed for 17 ALAD cases with subsequent decline (ALAD declined), 13 ALAD cases that resolved (ALAD recovered), and 15 cases with stable lung function. We observed broad differences in frequencies of the 26 unique cell populations across groups (p = 0.02). A CD8 T cell (p = 0.04) and a macrophage cluster (p = 0.01) best identified ALAD declined from the ALAD recovered and stable groups. This macrophage cluster was distinguished by an anti-inflammatory signature and the CD8 T cell cluster resembled a Tissue Resident Memory subset. Anti-inflammatory macrophages signaled to activated CD8 T cells via class I HLA, fibronectin, and galectin pathways (p < 0.05 for each). Recipients with discordance between these cells had a nearly 5-fold increased risk of severe graft dysfunction or death (HR 4.6, 95% CI 1.1-19.2, adjusted p = 0.03). We validated these key findings in 2 public lung transplant genomic datasets. CONCLUSIONS: BAL anti-inflammatory macrophages may protect against CLAD by suppressing CD8 T cells. These populations merit functional and longitudinal assessment in additional cohorts.

Provider beliefs and practices regarding the management of obesity in lung transplant recipients.

Obesity at the time of lung transplant is associated with decreased survival. How providers manage obesity after lung transplantation is unknown. We performed an international survey of lung transplant providers to assess beliefs and practices regarding post-transplant obesity management. Eighty-one providers initiated the survey and 73 (90%) completed the full survey. Respondents were primarily North American-based pulmonary physicians. Nearly all providers believe treating obesity improves quality of life (99%) and survival (95%) after lung transplantation, but that only 41% of patients attempting weight loss are successful. While respondents nearly always recommend diet (96%), exercise (92%), and dietician consultation (89%), they less frequently recommend prescription weight loss medications (29%) or bariatric surgery (11%). Lung transplant providers are motivated to treat obesity in transplant recipients. However, there is a gap between general obesity treatment guidelines and lung transplant practice. Additional training, education, and trials in this population could address this gap.

Investigating the Relationship Between Marital Status and Ethnicity on Neurocognitive Functioning in a Rural Older Population: A Project FRONTIER Study.

OBJECTIVES: Research indicates being married is related to better physical and psychological health. Little is known regarding the relationship between marital status and neurocognitive functioning and whether it differs based on ethnicity (Hispanic vs non-Hispanic). This is the first study to examine this relationship in a sample of aging adults in rural Texas. METHODS: Data from 1,864 participants (Mage = 59.68, standard deviation [SD]age = 12.21), who were mostly Hispanic (n = 1,053), women (n = 1,295), and married (n = 1,125) from Project Facing Rural Obstacles to Healthcare Now Through Intervention, Education, & Research were analyzed. Neuropsychological testing comprised Repeatable Battery for the Assessment of Neuropsychological Status, Trails Making Test, and Clock Drawing. Participants were dichotomized, married, and unmarried. RESULTS: There was a significant interaction between Hispanic identity and marital status on overall neurocognitive functioning (F(1, 1,480) = 4.79, p < .05, ηp2 = 0.003). For non-Hispanic individuals, married individuals had higher overall neurocognitive functioning compared to unmarried individuals, whereas neurocognitive functioning for Hispanic individuals did not significantly differ between married and unmarried individuals. There were significant main effects as married individuals (M = 84.95, SD = 15.56) had greater overall neurocognitive functioning than unmarried individuals (M = 83.47, SD = 15.86; F(1, 1,480) = 14.67, p < .001, ηp2 = 0.01), Hispanic individuals (M = 78.02, SD = 14.25) had lower overall neurocognitive functioning than non-Hispanic individuals (M = 91.43, SD = 15.07; F(1, 1,480) = 284.99, p < .001, ηp2 = 0.16). DISCUSSION: Hispanics living in rural areas experience additional stressors that could lead to worse neurocognitive functioning, which is supported by the Lifespan Biopsychosocial Model of Cumulative Vulnerability and Minority Health, which postulates that race/ethnicity/socioeconomic-status-related stressors exacerbate the impact of other life stressors. Reduction of stress on rural Hispanics should be a priority as it could positively affect their neurocognitive functioning.

Public stigma toward prolonged grief and COVID-19 bereavement: A vignette-based experiment.

We investigated the effects of cause of death and the presence of prolonged grief disorder (PGD) on eliciting public stigma toward the bereaved. Participants (N = 328, 76% female; Mage = 27.55 years) were randomly assigned to read one of four vignettes describing a bereaved man. Each vignette differed by his PGD status (PGD diagnosis or no PGD diagnosis) and his wife's cause of death (COVID-19 or brain hemorrhage). Participants completed public stigma measures assessing negative attributions, desired social distance, and emotional reactions. Bereavement with PGD (versus without PGD) elicited large and significantly stronger responses across all stigma measures. Both causes of death elicited public stigma. There was no interaction between cause of death and PGD on stigma. With increased PGD rates expected during the pandemic, the potential for public stigma and reduced social support for people bereaved via traumatic deaths and people with PGD requires mitigation.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Disturbed sleep after lung transplantation is associated with worse patient-reported outcomes and chronic lung allograft dysfunction.

Many lung transplant recipients fail to derive the expected improvements in functioning, HRQL, or long-term survival. Sleep may represent an important, albeit rarely examined, factor influencing lung transplant outcomes. Within a larger cohort study, 141 lung transplant recipients completed the Medical Outcomes Study (MOS) Sleep Scale along with a broader survey of patient-reported outcome (PRO) measures and frailty assessment. MOS Sleep yields the Sleep Problems Index (SPI); we also derived an insomnia-specific subscale. Potential perioperative predictors of disturbed sleep and time to chronic lung allograft dysfunction (CLAD) and death were derived from medical records. We investigated associations between perioperative predictors on SPI and Insomnia and associations between SPI and Insomnia on PROs and frailty by linear regressions, adjusting for age, sex, and lung function. We evaluated the associations between SPI and Insomnia on time to CLAD and death using Cox models, adjusting for age, sex, and transplant indication. Post-transplant hospital length of stay >30 days was associated with worse sleep by SPI and insomnia (SPI: p=0.01; Insomnia p=0.02). Worse sleep by SPI and insomnia was associated with worse depression, cognitive function, HRQL, physical disability, health utilities, and Fried Frailty Phenotype frailty (all p<0.01). Those in the worst quartile of SPI and insomnia exhibited increased risk of CLAD (HR 2.18; 95%CI: 1.22-3.89 ; p=0.01 for SPI and HR 1.96; 95%CI 1.09-3.53; p=0.03 for insomnia). Worsening in SPI but not insomnia was also associated with mortality (HR: 1.29; 95%CI: 1.05-1.58; p=0.01). Poor sleep after lung transplant may be a novel predictor of patient reported outcomes, frailty, CLAD, and death with potentially important screening and treatment implications.

MICB Genomic Variant Is Associated with NKG2D-mediated Acute Lung Injury and Death.

Rationale: Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. Objectives: To investigate the association of a common missense variant, MICBG406A, with ALI. Methods: We assessed MICBG406A genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction (N = 619) and acute respiratory distress syndrome (N = 1,376). Variant protein functional effects were determined in cultured and ex vivo human samples. Measurements and Main Results: Recipients of MICBG406A-homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among MICBG406A-homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with MICBG406A. Expression of missense variant protein MICBD136N in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICBD136N cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. Conclusions: These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach.

Prolonged Grief Disorder: Addressing Misconceptions With Evidence.

There are many misconceptions about Prolonged Grief Disorder (PGD). We show with data that PGD is a diagnosis that applies to a rare few of mourners who are at risk of significant distress and dysfunction. Those mourners who meet criteria for PGD have been shown to benefit from specialized, targeted treatment for it. The case against PGD is empirically unsubstantiated, and the need for scientific examination of effective treatments is warranted.

The Role of Palliative Care in Heart Failure, Part 3: Facilitators and Barriers to Cardiac Palliative Care Clinic Development.

Background: Patients with heart failure frequently have significant disease burden and complex psychosocial needs. The integration of palliative care into the management of these patients can decrease symptom burden throughout their course of illness. Therefore, in 2009, we established a cardiac palliative care clinic colocated with heart failure providers in a large academic heart hospital. Objective: To better understand the facilitators and barriers to integrating palliative care into our heart failure management service. Design: Qualitative study using a semistructured interview guide. Setting, Subjects: Between October 2020 and January 2021, we invited all 25 primary cardiac providers at our academic medical center in the midwestern United States to participate in semistructured qualitative interviews to discuss their experiences with the cardiac palliative care clinic. Measurements: Interview transcripts were analyzed using a deductive-dominant thematic analysis approach to reveal emerging themes. Results: Providers noted that the integration of palliative care into the treatment of patients with heart failure was helped and hindered primarily by issues related to operations and communications. Operational themes about clinic proximity and the use of telehealth as well as communication themes around provider-provider communication and the understanding of palliative care were particularly salient. Conclusions: The facilitators and barriers identified have broad applicability that are independent of the etiological nature (e.g., cancer, pulmonary, neurological) of any specialty or palliative care clinic. Moreover, the strategies we used to implement improvements in our clinic may be of benefit to other practice models such as independent and embedded clinics.

The Role of Palliative Care in Heart Failure, Part 1: Referring Provider Perspectives About Opportunities in Advanced Cardiac Therapies.

Background: There are many ways that palliative care can support patients with heart failure, but the role of palliative care in supporting patients who are considering or are already using advanced cardiac therapies is less clear. Objective: To understand referring providers' perspectives about the role of palliative care in the treatment of patients with heart failure considering or using advanced cardiac therapies. Design: Qualitative study using a semistructured interview guide. Setting/Subjects: This study was conducted at an academic medical center in the United States with an integrated cardiac palliative care program. Interviews were conducted with cardiology providers, including cardiologists, cardiac surgeons, and nurse practitioners who care for patients with heart failure and who are considering or receiving advanced cardiac therapies. Measurements: Interview transcripts were analyzed deductively and inductively to reveal themes in providers' perspectives. Results: Five themes were identified about the role of palliative care when advanced therapies were considered or being used: (1) educating patients; (2) supporting goal-concordant care; (3) managing symptoms; (4) addressing psychosocial needs; and (5) managing end-of-life care. Providers suggested palliative care could be a facilitator of advanced therapies, rather than merely something to add to end-of-life care. Conclusions: Cardiology providers recognize the value of integrating palliative care across the heart failure disease trajectory to provide therapy options, support decision-making processes, and provide goal-concordant care for patients considering or receiving advanced therapies. Increasing awareness of opportunities to integrate palliative care throughout the treatment of these patients may help cardiology providers better coordinate with palliative care specialists to improve patient care.

The Role of Palliative Care in Heart Failure, Part 4: A Framework for Collaboration in Advance Care Planning.

Background: Palliative care integration into cardiology is growing, allowing primary cardiology care teams increasing opportunities to utilize palliative care to support processes such as advance care planning (ACP). Objective: The aim of the study is to understand perspectives of cardiac care team members about the involvement and impact of palliative care on ACP in heart failure. Design: A qualitative study using a semistructured interview guide was performed. Settings/Subjects: Interviews were conducted with cardiac care team members, including cardiologists, cardiac surgeons, and nurse practitioners, at a large academic medical center in the United States with an integrated cardiac palliative care team. Measurements: Deductive and inductive thematic analysis of interview transcripts enabled characterization of themes around the role of palliative care in ACP. Results: Two themes were identified with regard to providers' perspectives about ACP: (1) different levels of comfort with initiating and conducting ACP conversations and (2) different opinions about the desired role of palliative care in the ACP process. In exploring these themes, we characterized four distinct approaches to ACP with palliative care as a novel framework for planning consultation. Conclusions: The different approaches to ACP and the implications for how cardiac providers interact with the palliative care team present an important opportunity to guide ACP consultation in practice. Adoption of this framework may help cardiac providers enhance the process of care delivery and ACP in important ways that improve care for their patients.

CCR5 drives NK cell-associated airway damage in pulmonary ischemia-reperfusion injury.

Primary graft dysfunction (PGD) limits clinical benefit after lung transplantation, a life-prolonging therapy for patients with end-stage disease. PGD is the clinical syndrome resulting from pulmonary ischemia-reperfusion injury (IRI), driven by innate immune inflammation. We recently demonstrated a key role for NK cells in the airways of mouse models and human tissue samples of IRI. Here, we used 2 mouse models paired with human lung transplant samples to investigate the mechanisms whereby NK cells migrate to the airways to mediate lung injury. We demonstrate that chemokine receptor ligand transcripts and proteins are increased in mouse and human disease. CCR5 ligand transcripts were correlated with NK cell gene signatures independently of NK cell CCR5 ligand secretion. NK cells expressing CCR5 were increased in the lung and airways during IRI and had increased markers of tissue residency and maturation. Allosteric CCR5 drug blockade reduced the migration of NK cells to the site of injury. CCR5 blockade also blunted quantitative measures of experimental IRI. Additionally, in human lung transplant bronchoalveolar lavage samples, we found that CCR5 ligand was associated with increased patient morbidity and that the CCR5 receptor was increased in expression on human NK cells following PGD. These data support a potential mechanism for NK cell migration during lung injury and identify a plausible preventative treatment for PGD.