Human distal airways contain a multipotent secretory cell that can regenerate alveoli.

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.

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).

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.

The Lung Allograft Microbiome Associates with Pepsin, Inflammation, and Primary Graft Dysfunction.

Rationale: Primary graft dysfunction (PGD) is the principal cause of early morbidity and mortality after lung transplantation. The lung microbiome has been implicated in later transplantation outcomes but has not been investigated in PGD. Objectives: To define the peritransplant bacterial lung microbiome and relationship to host response and PGD. Methods: This was a single-center prospective cohort study. Airway lavage samples from donor lungs before organ procurement and recipient allografts immediately after implantation underwent bacterial 16S ribosomal ribonucleic acid gene sequencing. Recipient allograft samples were analyzed for cytokines by multiplex array and pepsin by ELISA. Measurements and Main Results: We enrolled 139 transplant subjects and obtained donor lung (n = 109) and recipient allograft (n = 136) samples. Severe PGD (persistent grade 3) developed in 15 subjects over the first 72 hours, and 40 remained without PGD (persistent grade 0). The microbiome of donor lungs differed from healthy lungs, and recipient allograft microbiomes differed from donor lungs. Development of severe PGD was associated with enrichment in the immediate postimplantation lung of oropharyngeal anaerobic taxa, particularly Prevotella. Elevated pepsin, a gastric biomarker, and a hyperinflammatory cytokine profile were present in recipient allografts in severe PGD and strongly correlated with microbiome composition. Together, immediate postimplantation allograft Prevotella/Streptococcus ratio, pepsin, and indicator cytokines were associated with development of severe PGD during the 72-hour post-transplantation period (area under the curve = 0.81). Conclusions: Lung allografts that develop PGD have a microbiome enriched in anaerobic oropharyngeal taxa, elevated gastric pepsin, and hyperinflammatory phenotype. These findings suggest a possible role for peritransplant aspiration in PGD, a potentially actionable mechanism that warrants further investigation.

Mobile health technology to improve emergent frailty after lung transplantation.

We evaluated the feasibility, safety, and efficacy of a mHealth-supported physical rehabilitation intervention to treat frailty in a pilot study of 18 lung transplant recipients. Frail recipients were defined by a short physical performance battery (SPPB score ≤7). The primary intervention modality was Aidcube, a customizable rehabilitation mHealth platform. Our primary aims included tolerability, feasibility, and acceptability of use of the platform, and secondary outcomes were changes in SPPB and in scores of physical activity, and disability measured using the Duke Activity Status Index (DASI) and Lung Transplant-Value Life Activities (LT-VLA). Notably, no adverse events were reported. Subjects reported the app was easy to use, usability improved over time, and the app enhanced motivation to engage in rehabilitation. Comments highlighted the complexities of immediate post-transplant rehabilitation, including functional decline, pain, tremor, and fatigue. At the end of the intervention, SPPB scores improved a median of 5 points from a baseline of 4. Physical activity and patient-reported disability also improved. The DASI improved from 4.5 to 19.8 and LT-VLA score improved from 2 to 0.59 at closeout. Overall, utilization of a mHealth rehabilitation platform was safe and well received. Remote rehabilitation was associated with improvements in frailty, physical activity and disability. Future studies should evaluate mHealth treatment modalities in larger-scale randomized trials of lung transplant recipients.

Postreperfusion plasma endothelial activation markers are associated with acute kidney injury after lung transplantation.

Acute kidney injury (AKI) is common after lung transplantation, but molecular markers remain poorly studied. The endothelial activation markers soluble thrombomodulin (sTM), protein C, and plasminogen activator inhibitor-1 (PAI-1) are implicated in kidney microcirculatory injury in animal models of AKI. We tested the association of 6-hour postreperfusion plasma levels of these markers with posttransplant AKI severity in patients enrolled in the Lung Transplant Outcomes Group prospective cohort study at the University of Pennsylvania during two eras: 2004-06 (n = 61) and 2013-15 (n = 67). We defined AKI stage through postoperative day 5 using Kidney Disease Improving Global Outcomes creatinine criteria. We used multivariable ordinal logistic regression to determine the association of each biomarker with AKI, adjusted for primary graft dysfunction and extracorporeal life support. AKI occurred in 57 (45%) patients across both eras: 28 (22%) stage 1, 29 (23%) stage 2-3. Higher sTM and lower protein C plasma levels were associated with AKI stage in each era and remained so in multivariable models utilizing both eras (sTM: OR 1.76 [95% CI 1.19-2.60] per standard deviation, P = .005; protein C: OR 0.54 [1.19-2.60], P = .003). We conclude that 6-hour postreperfusion plasma sTM and protein C levels are associated with early postlung transplant AKI severity.

The association of post-lung transplant acute kidney injury with mortality is independent of primary graft dysfunction: A cohort study.

BACKGROUND: Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality. METHODS: We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders. RESULTS: Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality. CONCLUSIONS: Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD.

Frailty phenotypes and mortality after lung transplantation: A prospective cohort study.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation.

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion.

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant.

Longitudinal Prediction of Quality-of-Life Scores and Locomotion in Individuals With Traumatic Spinal Cord Injury.

OBJECTIVES: To examine (1) differences in quality-of-life scores for groups based on transitions in locomotion status at 1, 5, and 10 years postdischarge in a sample of people with spinal cord injury (SCI); and (2) whether demographic factors and transitions in locomotion status can predict quality-of-life measures at these time points. DESIGN: Retrospective case study of the National SCI Database. SETTING: Model SCI Systems Centers. PARTICIPANTS: Individuals with SCI (N=10,190) from 21 SCI Model Systems Centers, identified through the National SCI Model Systems Centers database between the years 1985 and 2012. Subjects had FIM (locomotion mode) data at discharge and at least 1 of the following: 1, 5, or 10 years postdischarge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM-locomotion mode; Severity of Depression Scale; Satisfaction With Life Scale; and Craig Handicap Assessment and Reporting Technique. RESULTS: Participants who transitioned from ambulation to wheelchair use reported lower participation and life satisfaction, and higher depression levels (P<.05) than those who maintained their ambulatory status. Participants who transitioned from ambulation to wheelchair use reported higher depression levels (P<.05) and no difference for participation (P>.05) or life satisfaction (P>.05) compared with those who transitioned from wheelchair to ambulation. Demographic factors and locomotion transitions predicted quality-of-life scores at all time points (P<.05). CONCLUSIONS: The results of this study indicate that transitioning from ambulation to wheelchair use can negatively impact psychosocial health 10 years after SCI. Clinicians should be aware of this when deciding on ambulation training. Further work to characterize who may be at risk for these transitions is needed.

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation.

RATIONALE: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Differences between manufacturers in reported power wheelchair repairs and adverse consequences among people with spinal cord injury.

OBJECTIVE: To compare the frequency of power wheelchair (PWC) repairs and consequences experienced over a 6-month period by individuals with spinal cord injury (SCI) who use a PWC ≥40h/wk, based on manufacturer, seating functions, Healthcare Common Procedure Coding System (HCPCS) group, and model, and over time. DESIGN: Convenience observational sample survey. SETTING: Spinal Cord Injury Model System centers. PARTICIPANTS: Individuals with SCI (N=945) who use a PWC ≥40h/wk. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Number of required wheelchair repairs and resulting consequences (ie, being stranded, missing work/school, or missing a medical appointment). RESULTS: Rates of required repairs (47.6%-63.3%) and consequences (26.7%-40.7%) were high across manufacturers. Differences between manufacturers were found among PWCs without seating functions (P<.001-.008) and among group 2 wheelchairs (P=.007). Across the 10 most prescribed wheelchairs in this study, 54.5% to 73.9% of users required 1 or more repairs over a 6-month period. Increases in the number of repairs were also found for several PWC manufacturers with time. Differences were found in participant age, working status, years since injury, and presence of seating functions between manufacturers. CONCLUSIONS: The differences found in the number of repairs reported by survey respondents based on PWC manufacturer and the increases in repairs over time require further evaluation.

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.

Evacuation preparedness in full-time wheelchair users with spinal cord injury.

OBJECTIVE: To analyze and evaluate the efficacy of evacuation plans described by individuals with spinal cord injury (SCI). DESIGN: Descriptive study from a convenience sample. SETTING: Outpatient population center in Pittsburgh, PA, USA. METHODS: Twenty-one individuals with SCI who previously indicated that they had a plan of evacuation from either their homes, places of work, or towns/cities were contacted via telephone and asked to describe their evacuation plans. The number of critical elements (scale of 0-10 with 10 indicating a more thorough plan) and assistive technology (AT) devices were recorded. OUTCOME MEASURES: The number of critical elements (scale of 0-10 with 10 indicating a more thorough plan) and AT devices were recorded. RESULTS: Median home and town/city evacuation scores were both 3.00 (ranges: 1.0-4.0 and 0.0-8.0, respectively). Median evacuation scores of individuals with paraplegia were higher in home (P = 0.05, r = 0.44) and town/city (P = 0.045, r = 0.63) than individuals with tetraplegia. Median evacuation scores of subjects who were employed were higher in home (P = 0.036, r = 0.47) and town/city (P = 0.064, r = 0.59) than unemployed. CONCLUSION: Low scores indicate that individuals with SCI who believe that they have plans are not adequately prepared for an emergency evacuation. Interventions are needed to improve evacuation readiness and lack of preparedness in a catastrophe should be considered by emergency personnel when responding.

Criterion validity and accuracy of global positioning satellite and data logging devices for wheelchair tennis court movement.

PURPOSE: To compare the criterion validity and accuracy of a 1 Hz non-differential global positioning system (GPS) and data logger device (DL) for the measurement of wheelchair tennis court movement variables. METHODS: Initial validation of the DL device was performed. GPS and DL were fitted to the wheelchair and used to record distance (m) and speed (m/second) during (a) tennis field (b) linear track, and (c) match-play test scenarios. Fifteen participants were monitored at the Wheelchair British Tennis Open. RESULTS: Data logging validation showed underestimations for distance in right (DLR) and left (DLL) logging devices at speeds >2.5 m/second. In tennis-field tests, GPS underestimated distance in five drills. DLL was lower than both (a) criterion and (b) DLR in drills moving forward. Reversing drill direction showed that DLR was lower than (a) criterion and (b) DLL. GPS values for distance and average speed for match play were significantly lower than equivalent values obtained by DL (distance: 2816 (844) vs. 3952 (1109) m, P = 0.0001; average speed: 0.7 (0.2) vs. 1.0 (0.2) m/second, P = 0.0001). Higher peak speeds were observed in DL (3.4 (0.4) vs. 3.1 (0.5) m/second, P = 0.004) during tennis match play. CONCLUSIONS: Sampling frequencies of 1 Hz are too low to accurately measure distance and speed during wheelchair tennis. GPS units with a higher sampling rate should be advocated in further studies. Modifications to existing DL devices may be required to increase measurement precision. Further research into the validity of movement devices during match play will further inform the demands and movement patterns associated with wheelchair tennis.

Rehabilitation Characteristics and Outcomes for Lung Transplantation for COVID-19: A Case Series.

OBJECTIVE: Severe coronavirus disease 2019 (COVID-19) can result in irreversible lung damage, with some individuals requiring lung transplantation. The purpose of this case series is to describe the initial experience with the rehabilitation and functional outcomes of 9 patients receiving a lung transplant for COVID-19. METHODS: Nine individuals, ranging in age from 37 to 68 years, received bilateral orthotopic lung transplantation (BOLT) for COVID-19 between December 2020 and July 2021. Rehabilitation was provided before and after the transplant, including in-hospital rehabilitation, postacute care inpatient rehabilitation, and outpatient rehabilitation. RESULTS: Progress with mobility was limited in the pretransplant phase despite rehabilitation efforts. Following transplantation, 2 individuals expired before resuming rehabilitation, and 2 others had complications that delayed their progress. The remaining 5 experienced clinically important improvements in mobility and walking capacities. CONCLUSION: Considerable rehabilitation resources are required to care for individuals both before and after BOLT for COVID-19. Rehabilitation can have a profound impact on both functional and clinical outcomes for this unique patient population. IMPACT: There is limited literature on the rehabilitation efforts and outcomes for patients who received BOLT for COVID-19. Occupational therapists and physical therapists play an important role during the pretransplant and posttransplant recovery process for this novel patient population. LAY SUMMARY: Patients with a bilateral orthotopic lung transplant due to COVID-19 require a unique rehabilitation process. They have significant difficulties with activities of daily living and functional mobility across the pretransplant and posttransplant continuum of care, but progressive gains in functional performance may be possible with a comprehensive multidisciplinary rehabilitation program.

Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation.

Background: Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk time period. Methods: We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We derived a model in 270 patients using NONMEM (version 7.5.1) and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and multivariable analysis was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of mean prediction error (PE). Results: We developed a one-compartment base model with a fixed rate absorption constant. Significant covariates in multivariable analysis were postoperative day, hematocrit, transplant type, CYP3A5 genotype, total body weight, and time-varying postoperative day, hematocrit, and CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR -29.3%-70.53%). Conclusion: Postoperative day was the strongest predictor of tacrolimus exposure in the early post-lung transplant period. Future multicenter studies employing intensive sampling to examine a broad set of variables related to critical illness physiology are needed to understand determinants of clearance, volume of distribution and absorption in this population.

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.

Manual wheelchair skills capacity predicts quality of life and community integration in persons with spinal cord injury.

OBJECTIVES: To determine wheelchair (WC) skills success rates for manual WC users with spinal cord injury (SCI), to determine subject characteristics associated with the lowest success rates of WC skills, and to characterize the relationship between WC skills and measures of community integration and quality of life (QOL). DESIGN: Cross-sectional multisite study. SETTING: Six Spinal Cord Injury Model Systems (SCIMS) centers. PARTICIPANTS: Individuals with SCI (N=214) who were at least 11 months postinjury, treated at an SCIMS center, and who used a manual WC as their primary means of mobility. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Wheelchair Skills Test (WST) and questionnaires of demographics and characteristics, QOL, and community participation. RESULTS: Of the 31 skills in the WST assessed, success rates ranged from 19.6% to 100%. Eight skills had success rates of ≤75%: folding/unfolding the WC (71.5%), ascending (19.6%) and descending (47.2%) a 15-cm curb, ascending (23.2%) and descending (26.5%) stairs, transferring from ground to WC (40.6%), turning 180° in wheelie position (55.2%), and holding a 30-second stationary wheelie (59.9%). Male sex, paraplegia, employed status, lower education, younger age at injury, and white race were among the participant characteristics bivariately associated with higher success rates of several WC skills. After controlling for covariates, higher success rates of several WC skills and a higher total WST score predicted better self-perceived health, higher life satisfaction, and more community participation. CONCLUSIONS: For people with SCI who use a manual WC as their primary means of mobility, their ability to perform manual WC skills is associated with higher community participation and life satisfaction. Factors contributing to low success rates need to be investigated, and interventions to improve these rates are needed.

The relationship between quality of life and change in mobility 1 year postinjury in individuals with spinal cord injury.

OBJECTIVE: To examine quality-of-life (QOL) factors and change in mobility in individuals with traumatic spinal cord injury (SCI) 1 year after injury. DESIGN: Retrospective case study of National SCI Database data. SETTING: SCI Model Systems (SCIMS) sites (N=18). PARTICIPANTS: Subjects (N=1826; age >18y) who presented to an SCIMS site after traumatic SCI between June 2004 and July 2009 and returned for 1-year follow-up. All subjects had FIM mobility data for both assessments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Assessment of impairment based on Lower-Extremity Motor Score. Assessment of QOL based on Craig Handicap Assessment and Reporting Technique, Patient Health Questionnaire, Satisfaction With Life Scale, Self-perceived Health Status, and pain severity scores. RESULTS: Of the sample, 55 individuals transitioned from walking to wheelchair use within 1 year of discharge. This group had the highest number of individuals from minority groups (52.8%) and the lowest employment rate (7.3%). Compared with individuals who transitioned from wheelchair use to walking or maintained wheelchair use or ambulation, the walking-to-wheelchair transition group had significantly lower QOL scores (P<.01), including higher depression (P<.01) and higher pain severity (P<.001). CONCLUSIONS: Individuals with SCI who transitioned from walking at discharge to wheelchair use within 1 year had low QOL factors, including high pain and depression scores. Rehabilitation professionals should consider encouraging marginal ambulators to work toward functional independence from a wheelchair, rather than primary ambulation during acute inpatient rehabilitation.