Small airway brush gene expression predicts chronic lung allograft dysfunction and mortality.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) limits survival following lung transplant, but substantial lung damage occurs before diagnosis by traditional methods. We hypothesized that small airway gene expression patterns could identify CLAD risk before spirometric diagnosis and predict subsequent graft failure. METHODS: Candidate genes from 4 rejection-associated transcript sets were assessed for associations with CLAD or graft failure in a derivation cohort of 156 small airway brushes from 45 CLAD cases and 37 time-matched controls with >1-year stable lung function. Candidate genes not associated with CLAD and time to graft failure were excluded, yielding the Airway Inflammation 2 (AI2) gene set. Area under the receiver operating curve (AUC) for CLAD and competing risks of death or graft failure were assessed in an independent validation cohort of 37 CLAD cases and 37 controls. RESULTS: Thirty-two candidate genes were associated with CLAD and graft failure, comprising the AI2 score, which clustered into 3 subcomponents. The AI2 score identified CLAD before its onset, in early and late post-CLAD brushes, as well as in the validation cohort (AUC 0.69-0.88). The AI2 score association with CLAD was independent of positive microbiology, CLAD stage, or CLAD subtype. However, transcripts most associated with CLAD evolved over time from CLAD onset. The AI2 score predicted time to graft failure and retransplant-free survival in both cohorts (p ≤ 0.03). CONCLUSIONS: This airway inflammation gene score is associated with CLAD development, graft failure, and death. Future studies defining the molecular heterogeneity of airway inflammation could lead to endotype-targeted therapies.

Storylines of family medicine II: foundational building blocks-context, community and health.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'II: foundational building blocks-context, community and health', authors address the following themes: 'Context-grounding family medicine in time, place and being', 'Recentring community', 'Community-oriented primary care', 'Embeddedness in practice', 'The meaning of health', 'Disease, illness and sickness-core concepts', 'The biopsychosocial model', 'The biopsychosocial approach' and 'Family medicine as social medicine.' May readers grasp new implications for medical education and practice in these essays.

Nurturing Empathy through Arts, Literature, and Role Play for Postgraduate Trainees of Ophthalmology.

Background and Purpose: Empathy is essential in patient-centered compassionate health care. Lack of formal training, workload, patient factors, and digitalization have been attributed to its regression. Empathy can be nurtured by educational interventions. A structured empathy education module for postgraduate trainees is not available in India. The aim for this research was to develop, deliver, and evaluate one for ophthalmology postgraduate trainees. Methodology: This interventional study was conducted in the tertiary ophthalmology department of Western India during 2022-2023. Four workshops comprising of interactive lectures, literature, creative arts, and role plays were delivered with trained facilitators. Data from surveys for trainee self-assessment, patient perception of trainee empathy, pre-post knowledge test, and trainee and facilitator feedback were collected and analyzed. Results: Seventy-nine ophthalmology postgraduate trainees participated in this intervention. Excessive workload and lack of training were shared as the barriers to empathetic care. Trainees showed improved knowledge, skills, and attitude in empathy after the workshops. The facilitators and trainees were satisfied with the learning goals, execution, utility, feasibility, and relevance of the workshops. Ninety-three percent trainees want this module to be a part of postgraduate curriculum. Conclusion: This study substantiates the use of structured interactive training for cultivating empathy in postgraduate trainees. Barriers against empathy were identified and can be mitigated by restorative measures. Literature, arts, and role plays are the effective education tools for empathy.

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.

A phase 3 study evaluating the lot consistency, immunogenicity, safety, and tolerability of a Clostridioides difficile vaccine in healthy adults 65 to 85 years of age.

BACKGROUND: A toxoid-based Clostridioides difficile vaccine is currently in development. Here, we report lot-to-lot consistency, immunogenicity, safety, and tolerability of 3 C difficile vaccine doses in healthy older adults. METHODS: This phase 3, placebo-controlled study randomized (1:1:1:1) healthy adults 65 to 85 years of age to 1 of 3 C difficile vaccine lots or placebo. Participants received C difficile vaccine (200 µg total toxoid) or placebo (Months 0, 1, 6). The primary immunogenicity objective was lot-to-lot consistency (2-sided 95 % CIs within 0.5 and 2 for comparisons of geometric mean concentration [GMC] ratios) for toxins A- and B-specific neutralizing antibody levels 1 month after Dose 3. Safety outcomes included local reactions and systemic events ≤7 days after vaccination, adverse events (AEs), and serious AEs (SAEs). RESULTS: Of 1317 enrolled participants, 1218 completed the study. C difficile vaccine immunogenicity was consistent across lots, with neutralizing antibody responses 1 month after Dose 3 for both toxin A (GMC [95 % CI]: lot 1, 878.8 [786.3, 982.2]; lot 2, 873.0 [779.2, 978.1]; lot 3, 872.9 [782.6, 973.5]) and toxin B (lot 1, 5823.9 [5041.0, 6728.4]; lot 2, 5462.8 [4733.4, 6304.7]; lot 3, 5426.0 [4724.4, 6231.8]). Two-sided 95 % CIs for GMC ratios were within 0.5 and 2 for toxins A and B, indicating lot-to-lot consistency was achieved. C difficile vaccine was well tolerated, with similar rates of local reactions and systemic events among vaccine lots. AE and SAE rates were similar across C difficile vaccine (36.5 % and 4.5 %, respectively) and placebo (35.3 % and 6 %). CONCLUSIONS: Three doses (Months 0,1,6) of toxoid-based C difficile vaccine induced robust neutralizing antibody responses and were well tolerated in healthy participants 65 to 85 years of age. Lot-to-lot consistency was excellent, indicating the manufacturing process for this C difficile vaccine formulation was well controlled. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03579459.

Time Spent Outdoors Partly Accounts for the Effect of Education on Myopia.

Purpose: The purpose of this study was to investigate if education contributes to the risk of myopia because educational activities typically occur indoors or because of other factors, such as prolonged near viewing. Methods: This was a two-sample Mendelian randomization study. Participants were from the UK Biobank, Avon Longitudinal Study of Parents and Children, and Generation R. Genetic variants associated with years spent in education or time spent outdoors were used as instrumental variables. The main outcome measures were: (1) spherical equivalent refractive error attained by adulthood, and (2) risk of an early age-of-onset of spectacle wear (EAOSW), defined as an age-of-onset of 15 years or below. Results: Time spent outdoors was found to have a small genetic component (heritability 9.8%) that tracked from childhood to adulthood. A polygenic score for time outdoors was associated with children's time outdoors; a polygenic score for years spent in education was inversely associated with children's time outdoors. Accounting for the relationship between time spent outdoors and myopia in a multivariable Mendelian randomization analysis reduced the size of the causal effect of more years in education on myopia to -0.17 diopters (D) per additional year of formal education (95% confidence interval [CI] = -0.32 to -0.01) compared with the estimate from a univariable Mendelian randomization analysis of -0.27 D per year (95% CI = -0.41 to -0.13). Comparable results were obtained for the outcome EAOSW. Conclusions: Accounting for the effects of time outdoors reduced the estimated causal effect of education on myopia by 40%. These results suggest about half of the relationship between education and myopia may be mediated by children not being outdoors during schooling.

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.

Relational care and epistemic injustice.

The philosophical underpinnings of primary care have been examined from several perspectives in recent years. In two previous articles, we have argued that a relational view of autonomy is better matched to the primary care setting than others, and that view is mainly formed from the descriptors of its practice. Here we develop that analysis further, linking it to other relevant theory: the experience of human suffering and epistemic injustice. We argue that relational care is fundamental to ameliorating epistemic injustice and that relationships are integral to ethical practice, rather than being distinct. We propose that personalised care as described in the NHS Long Term Plan is not possible without addressing epistemic injustice and therefore without reconsidering our existing normative ethical frameworks.

Feedback that Lands: Exploring How Residents Receive and Judge Feedback During Entrustable Professional Activities.

Introduction: Receiving feedback from different types of assessors (e.g., senior residents, staff supervisors) may impact trainees' perceptions of the quantity and quality of data during entrustable professional activity (EPA) assessments. We evaluated the quality of EPA feedback provided by different assessors (senior residents, chief medical residents/subspecialty residents, and staff) and explored residents' judgements of the value of this feedback. Methods: From a database of 2228 EPAs, we calculated the frequency of contribution from three assessor groups. We appraised the quality of 60 procedure-related EPAs completed between July 2019 and March 2020 using a modified Completed Clinical Evaluation Report Rating (CCERR) tool. Next, we asked 15 internal medicine residents to sort randomly selected EPAs according to their judgements of value, as an elicitation exercise before a semi-structured interview. Interviews explored participants' perceptions of quality of written feedback and helpful assessors. Results: Residents completed over 60% of EPA assessments. We found no difference in modified-CCERR scores between the three groups. When judging EPA feedback value, residents described a process of weighted deliberation, considering perceived assessor characteristics (e.g., credibility, experience with EPA system), actionable written comments, and their own self-assessment. Discussion: Like other recent studies, we found that residents contributed most to procedure-related EPA assessments. To the established list of factors influencing residents' judgements of feedback value, we add assessors' adherence to, and their shared experiences of being assessed within, EPA assessment systems. We focus on the implications for how assessors and leaders can build credibility in themselves and in the practices of EPA assessments.

A Case of Hand-Foot-and-Mouth Disease in an Adult Male.

Hand-foot-and-mouth disease (HFMD) is commonly seen in infants and children; less frequently, it may be seen in adults as well. The disease is usually associated with viral infections, including many variants of enteroviruses and coxsackieviruses. We discuss the case of a 39-year-old male who presented with constitutional symptoms, fever, and lesions on his hands, feet, and mouth. His children, who had been recently diagnosed with HFMD, were likely the source of his infection. A comprehensive history and physical examination enabled us to identify the lesions, some of which were faint and difficult to visualize. Viral panel testing indicated positive results for human rhinovirus/enterovirus. Treatment and testing associated with the patient's condition were supportive, largely based on the history and physical findings which helped us narrow down our differential diagnoses. Complete resolution of the symptoms within one to two weeks is generally expected in these patients.

Decreased Lymphocytic Bronchitis Severity in the Era of Azithromycin Prophylaxis.

Large-airway lymphocytic inflammation (LB), assessed on endobronchial biopsies, has been associated with acute cellular rejection and chronic lung allograft dysfunction (CLAD). Azithromycin (AZI) prophylaxis has been used to prevent airway inflammation and subsequent CLAD, with inconsistent results. We hypothesized that AZI prophylaxis would be associated with reduced LB, changes in bronchoalveolar lavage (BAL) immune cell populations, and improved CLAD-free survival. Methods: We compared frequencies of LB from endobronchial biopsies before (N = 1856) and after (N = 975) protocolized initiation of AZI prophylaxis at our center. LB was classified as none, minimal, mild, or moderate by histopathologic analysis. LB grades were compared using ordinal mixed-model regression. Corresponding automated BAL leukocyte frequencies were compared using mixed-effects modeling. The effect of AZI prophylaxis on CLAD-free survival was assessed by a Cox proportional hazards model adjusted for age, sex, ethnicity, transplant indication, and cytomegalovirus serostatus. Results: Biopsies in the pre-AZI era had 2-fold increased odds (95% confidence interval, 1.5-2.7; P < 0.001) of higher LB grades. LB was associated with BAL neutrophilia in both eras. However, there was no difference in risk for CLAD or death between AZI eras (hazard ratio 1.3; 95% confidence interval, 0.7-2.0; P = 0.45). Conclusions: Decreased airway inflammation in the era of AZI prophylaxis may represent a direct effect of AZI therapy or reflect other practices or environmental changes. In this cohort, AZI prophylaxis was not associated with improved CLAD-free survival.

Dyspnoea in a patient with biopsy-proven pulmonary sarcoidosis: the challenges in diagnosing cardiac sarcoidosis.

A man in his 60s with biopsy-proven pulmonary sarcoidosis, not on treatment, presented with 6 weeks of dyspnea to the emergency department. ECG showed first-degree atrioventricular block and CT thorax demonstrated progressive pulmonary sarcoidosis with new multifocal consolidation. Antibiotics were initiated.A brain natriuretic peptide was elevated at 2024 ng/L and echocardiogram showed global left ventricular systolic dysfunction. Coronary angiogram revealed normal coronary arteries, and cardiac positron emission tomography and MRI demonstrated patterns compatible with cardiac sarcoidosis. The patient significantly improved with diuresis; he was started on prednisone, methotrexate and standard heart failure therapies.We outline the difficulties of attributing cardiac causes of dyspnoea in a patient with known pulmonary sarcoidosis given the rarity of cardiac involvement. We review proposed diagnostic criteria for cardiac sarcoidosis using enhanced imaging techniques without requiring invasive myocardial biopsy. This case discussion also highlights nuances in managing cardiac sarcoidosis based on the best available evidence and expert consensus.

Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 µg (RSV subgroups A and B, 60 µg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).

Design and implementation of a digital health home spirometry intervention for remote monitoring of lung transplant function.

BACKGROUND: We developed an automated, chat-based, digital health intervention using Bluetooth-enabled home spirometers to monitor for complications of lung transplantation in a real-world application. METHODS: A chat-based application prompted patients to perform home spirometry, enter their forced expiratory volume in 1 second (FEV1), answer symptom queries, and provided patient education. The program alerted patients and providers to substantial FEV1 decreases and concerning symptoms. Data was integrated into the electronic health record (EHR) system and dashboards were developed for program monitoring. RESULT: Between May 2020 and December 2021, 544 patients were invited to enroll, of whom 427 were invited remotely and 117 were enrolled in-person. 371 (68%) participated by submitting ≥1 FEV1 values. Overall engagement was high, with an average of 197 unique patients submitting FEV1 data per month. In-person enrollees submitted an average of 4.6 FEV1 values per month and responded to 55% of scheduled chats. Home and laboratory FEV1 values correlated closely (rho = 0.93). There was an average of 133 ± 59 FEV1 decline alerts and 59 ± 23 symptom alerts per month. 72% of patients accessed education modules, and the program had a high net promoter score (53) amongst users. CONCLUSIONS: We demonstrate that a novel, automated, chat-based, and EHR-integrated home spirometry intervention is well accepted, generates reliable assessments of graft function, and can deliver automated feedback and education resulting in moderately-high adherence rates. We found that in-person onboarding yields better engagement and adherence. Future work will aim to demonstrate the impact of remote care monitoring on early detection of lung transplant complications.

Development of the Lung Transplant Frailty Scale (LT-FS).

BACKGROUND: Existing measures of frailty developed in community dwelling older adults may misclassify frailty in lung transplant candidates. We aimed to develop a novel frailty scale for lung transplantation with improved performance characteristics. METHODS: We measured the short physical performance battery (SPPB), fried frailty phenotype (FFP), Body Composition, and serum Biomarkers representative of putative frailty mechanisms. We applied a 4-step established approach (identify frailty domain variable bivariate associations with the outcome of waitlist delisting or death; build models sequentially incorporating variables from each frailty domain cluster; retain variables that improved model performance ability by c-statistic or AIC) to develop 3 candidate "Lung Transplant Frailty Scale (LT-FS)" measures: 1 incorporating readily available clinical data; 1 adding muscle mass, and 1 adding muscle mass and research-grade Biomarkers. We compared construct and predictive validity of LT-FS models to the SPPB and FFP by ANOVA, ANCOVA, and Cox proportional-hazard modeling. RESULTS: In 342 lung transplant candidates, LT-FS models exhibited superior construct and predictive validity compared to the SPPB and FFP. The addition of muscle mass and Biomarkers improved model performance. Frailty by all measures was associated with waitlist disability, poorer HRQL, and waitlist delisting/death. LT-FS models exhibited stronger associations with waitlist delisting/death than SPPB or FFP (C-statistic range: 0.73-0.78 vs. 0.57 and 0.55 for SPPB and FFP, respectively). Compared to SPPB and FFP, LT-FS models were generally more strongly associated with delisting/death and improved delisting/death net reclassification, with greater improvements with increasing LT-FS model complexity (range: 0.11-0.34). For example, LT-FS-Body Composition hazard ratio for delisting/death: 6.0 (95%CI: 2.5, 14.2), SPPB HR: 2.5 (95%CI: 1.1, 5.8), FFP HR: 4.3 (95%CI: 1.8, 10.1). Pre-transplant LT-FS frailty, but not SPPB or FFP, was associated with mortality after transplant. CONCLUSIONS: The LT-FS is a disease-specific physical frailty measure with face and construct validity that has superior predictive validity over established measures.

Subphenotypes of frailty in lung transplant candidates.

Heterogeneous frailty pathobiology might explain the inconsistent associations observed between frailty and lung transplant outcomes. A Subphenotype analysis could refine frailty measurement. In a 3-center pilot cohort study, we measured frailty by the Short Physical Performance Battery, body composition, and serum biomarkers reflecting causes of frailty. We applied latent class modeling for these baseline data. Next, we tested class construct validity with disability, waitlist delisting/death, and early postoperative complications. Among 422 lung transplant candidates, 2 class model fit the best (P = .01). Compared with Subphenotype 1 (n = 333), Subphenotype 2 (n = 89) was characterized by systemic and innate inflammation (higher IL-6, CRP, PTX3, TNF-R1, and IL-1RA); mitochondrial stress (higher GDF-15 and FGF-21); sarcopenia; malnutrition; and lower hemoglobin and walk distance. Subphenotype 2 had a worse disability and higher risk of waitlist delisting or death (hazards ratio: 4.0; 95% confidence interval: 1.8-9.1). Of the total cohort, 257 underwent transplant (Subphenotype 1: 196; Subphenotype 2: 61). Subphenotype 2 had a higher need for take back to the operating room (48% vs 28%; P = .005) and longer posttransplant hospital length of stay (21 days [interquartile range: 14-33] vs 18 days [14-28]; P = .04). Subphenotype 2 trended toward fewer ventilator-free days, needing more postoperative extracorporeal membrane oxygenation and dialysis, and higher need for discharge to rehabilitation facilities (P ≤ .20). In this early phase study, we identified biological frailty Subphenotypes in lung transplant candidates. A hyperinflammatory, sarcopenic Subphenotype seems to be associated with worse clinical outcomes.