Effect of Lung Transplantation on Health-Related Quality of Life in the Era of the Lung Allocation Score: A U.S. Prospective Cohort Study.

Under the U.S. Lung Allocation Score (LAS) system, older and sicker patients are prioritized for lung transplantation (LT). The impact of these changes on health-related quality of life (HRQL) after transplant has not been determined. In a single-center prospective cohort study from 2010 to 2016, we assessed HRQL before and repeatedly after LT for up to 3 years using the SF12-Physical and Mental Health, the respiratory-specific Airway Questionnaire 20-Revised, and the Euroqol 5D/Visual Analog Scale utility measures by multivariate linear mixed models jointly modeled with death. We also tested changes in LT-Valued Life Activities disability, BMI, allograft function, and 6-min walk test exercise capacity as predictors of HRQL change. Among 211 initial participants (92% of those eligible), LT improved HRQL by all 5 measures (p < 0.05) and all but SF12-Mental Health improved by threefold or greater than the minimally clinically important difference. Compared to younger participants, those aged ≥65 improved less in SF12-Physical and Mental Health (p < 0.01). Improvements in disability accounted for much of the HRQL improvement. In the LAS era, LT affords meaningful and durable HRQL improvements, mediated by amelioration of disability. Identifying factors limiting HRQL improvement in selected subgroups, especially those aged ≥65, are needed to maximize the net benefits of LT.

Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation.

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.

Gene set enrichment analysis identifies key innate immune pathways in primary graft dysfunction after lung transplantation.

We hypothesized alterations in gene expression could identify important pathways involved in transplant lung injury. Broncho alveolar lavage fluid (BALF) was sampled from donors prior to procurement and in recipients within an hour of reperfusion as part of the NIAID Clinical Trials in Organ Transplantation Study. Twenty-three patients with Grade 3 primary graft dysfunction (PGD) were frequency matched with controls based on donor age and recipient diagnosis. RNA was analyzed using the Human Gene 1.0 ST array. Normalized mRNA expression was transformed and differences between donor and postreperfusion values were ranked then tested using Gene Set Enrichment Analysis. Three-hundred sixty-two gene sets were upregulated, with eight meeting significance (familywise-error rate, FWER p-value <0.05), including the NOD-like receptor inflammasome (NLR; p < 0.001), toll-like receptors (TLR; p < 0.001), IL-1 receptor (p = 0.001), myeloid differentiation primary response gene 88 (p = 0.001), NFkB activation by nontypeable Haemophilus influenzae (p = 0.001), TLR4 (p = 0.008) and TLR 9 (p = 0.018). The top five ranked individual transcripts from these pathways based on rank metric score are predominantly present in the NLR and TLR pathways, including IL1ß (1.162), NLRP3 (1.135), IL1α (0.952), IL6 (0.931) and CCL4 (0.842). Gene set enrichment analyses implicate inflammasome-mediated and innate immune signaling pathways as key mediators of the development of PGD in lung transplant patients.

Early plasma soluble receptor for advanced glycation end-product levels are associated with bronchiolitis obliterans syndrome.

Early epithelial injury after lung transplantation may contribute to development of bronchiolitis obliterans syndrome (BOS). We evaluated the relationship between early postoperative soluble receptor for advanced glycation end-product (sRAGE) levels, a marker of type I alveolar cell injury and BOS. We performed a cohort study of 106 lung transplant recipients between 2002 and 2006 at the University of Pennsylvania with follow-up through 2010. Plasma sRAGE was measured 6 and 24 h after transplantation. Cox proportional hazards models were used to evaluate the association between sRAGE and time to BOS, defined according to ISHLT guidelines. Sixty (57%) subjects developed BOS. The average time to BOS was 3.4 years. sRAGE levels measured at 6 h (HR per SD of sRAGE: 1.69, 95% CI: 1.11, 2.57, p = 0.02) and 24 h (HR per SD of sRAGE: 1.74, 95% CI: 1.14, 2.65, p = 0.01) were associated with an increased hazard of BOS. Multivariable Cox regression indicated this relationship was independent of potential confounders. Elevated plasma sRAGE levels measured in the immediate postoperative period are associated with the development of BOS. Early epithelial injury after transplantation may contribute to the development of fibrosis in BOS.

Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures.

BACKGROUND AND STUDY AIMS: The accurate diagnosis of indeterminate pancreaticobiliary strictures presents a clinical dilemma. Probe-based confocal laser endomicroscopy (pCLE) offers real-time in vivo microscopic tissue examination that may increase sensitivity for the detection of malignancy. the objective of this study was to develop and validate a standard descriptive classification of pcle in the pancreaticobiliary system. PATIENTS AND METHODS: A total of 102 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) with pCLE to assess indeterminate pancreaticobiliary strictures were enrolled in a multicenter registry; 89 of these patients were evaluable. Information and data on the following were collected prospectively: clinical, ERCP, tissue sampling, pCLE, and follow-up. A uniform classification of pCLE findings ("Miami Classification") was developed, consisting of a set of image interpretation criteria. Thereafter, these criteria were tested through blinded consensus review of 112 randomized pCLE videos from 47 patients, and inter-observer variability was assessed in 42 patients . RESULTS: A consensus definition of the specific criteria of biliary and pancreatic pCLE findings for indeterminate strictures was developed. Single-image interpretation criteria did not have a high enough sensitivity for predicting malignancy. However, combining two or more criteria significantly increased the sensitivity and predictive values. The characteristics most suggestive of malignancy included the following: thick white bands (>20 µm), or thick dark bands (>40 µm), or dark clumps or epithelial structures. These provided sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 33%, 80%, and 80% compared with 48%, 100%, 100%, and 41% for standard tissue sampling methods. Inter-observer variability was moderate for most criteria. CONCLUSION: The Miami Classification enables a structured, uniform, and reproducible description of pancreaticobiliary pCLE. Combining individual characteristics improves the sensitivity for the detection of malignancy.

Burden, resilience and coping in caregivers of patients with interstitial lung disease.

RATIONALE: Prior work has described the experience of caregiving in idiopathic pulmonary fibrosis, but the effect on caregivers in interstitial lung disease (ILD) has not been explored. OBJECTIVES: Describe the burden, resilience, and health related quality of life (HRQoL) of caregivers of people with ILD. METHODS: In a mixed methods study, ILD caregivers completed questionnaires and participated in focus groups. A qualitative thematic analysis of the focus group transcripts was conducted. RESULTS: Thirty seven caregivers completed the survey, and 15 participated in the focus groups. 65% were female; the average age was 66 (SD = 13). The mean Short Form-36 role emotional and mental health scores were 18 (SD = 4) and 46 (SD = 7). The focus groups identified 4 major themes: emotional burden, changes in relationship, coping strategies, and unmet needs of caregivers. CONCLUSIONS: Caregiving for patients with ILD significantly impairs HRQoL, particularly, emotional health. Increasing resources could improve the caregiving experience in ILD.

Endoscopic retrograde cholangiopancreatography in the diagnosis and management of pancreatic diseases.

Endoscopic retrograde cholangiopancreatography (ERCP) has been used for diagnosis and treatment of pancreatic diseases for over 20 years. ERCP has been most intensely investigated for acute biliary pancreatitis. Randomized trials have proven that its use will decrease morbidity and have suggested a decrease in mortality for patients with severe gallstone pancreatitis. ERCP is also valuable in detecting and treating main pancreatic duct leaks with transpapillary stenting. Symptomatic pseudocysts, which may be seen in either acute or chronic pancreatitis, can be drained via the papilla or through creation of a cystogastrostomy or cystoduodenostomy with a needle-knife sphincterotome. Endoscopic treatment of patients with recurrent acute pancreatitis presumed due to pancreas divisum and sphincter of Oddi dysfunction remains controversial. Dominant pancreatic strictures or calculi in the setting of chronic pancreatitis may be treated with stenting and removal of calculi to improve abdominal pain. Finally, diagnosis of pancreatic cancer by brush cytology and palliative management of biliary obstruction with various plastic and expandable metal sents have simplified management of this difficult problem.

Thin layer chromatographic identification of some sympathomimetic amines.

Thin layer chromatographic behavior of some sympathomimetic amines in the presence of acids in neutral and organic solvent systems is reported. The sympathomimetic amines were dissolved in 0.1N HCl or ethanol and treated with bromocresol green or p-nitrobenzoyl chloride reagents on fiber sheets or precoated glass plates. Two-, 3-, and 4-, component solvent systems were tested. Benzene-ethyl acetate gave 2 spots for each amine standard; the more polar spots were satisfactorily separated. Amines in pharmaccuticals were not separated by any solvent system tested.

Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea.

OBJECTIVE: Patients referred for chronic diarrhea frequently undergo endoscopic evaluation. There are limited data on the role for colonoscopy with biopsy and ileoscopy for patients with chronic diarrhea. METHODS: We reviewed the charts of 228 patients with chronic diarrhea evaluated by colonoscopy between November 1995 and March 1998. Chronic diarrhea was defined as loose, frequent bowel movements for a minimum of 4 wk. Patients were excluded if biopsies were not performed in normal colons, if they had undergone previous bowel surgery, a history of inflammatory bowel disease, HIV, or an inadequate colonoscopy. RESULTS: One hundred sixty-eight patients were included in the analysis, of whom 142 (85%) had ileoscopy. Colonoscopy and biopsy yielded a specific histological diagnosis in 52 (31%) patients. These included Crohn's disease (9), ulcerative colitis (7), lymphocytic colitis (10), collagenous colitis (3), ischemic colitis (3), infectious colitis (6), and miscellaneous diseases (14). Ileoscopy yielded significant findings in 3% of patients (four with Crohn's disease and one with infection). CONCLUSIONS: Colonoscopy and biopsy is useful in the investigation of patients with chronic diarrhea yielding a histological diagnosis in 31% of patients without a previous diagnosis. Ileoscopy complemented colonoscopy findings in a minority of patients with chronic diarrhea and was essential for a diagnosis in only two patients.

Members of the Sp transcription factor family regulate rat calmodulin gene expression.

We have previously demonstrated that insulin positively regulates transcription of the rat calmodulin (CaM) I gene and that both basal and insulin stimulation of this gene are critically dependent on Sp1. Furthermore, a 392 bp CaM promoter was stimulated by insulin equal to the full promoter but lost activity with deletion of any of the three Sp1 sites (Solomon SS, Palazzolo MR, Takahashi T, Raghow R. Endocrinology 1997;138:5052-5054). Herein we document that Sp1 preferentially binds to the upstream sites Sp1(2) and Sp1(3) but not Sp1(1). Furthermore, gel-mobility super-shift assays demonstrate that both Sp1 and Sp3 protein are found in these complexes. When pPac-Spl, pPac-Sp3, pPac-USp3, and pPac-Sp4 were cotransfected with rCaM 1-392 promoter into Drosophila SL2 cells and challenged with 10,000 microU/mL insulin, we discovered that (1) Sp1 enhanced both basal and insulin-stimulated CaM I gene expression; (2) USp3, a "long" form of the Sp3 molecule, had a stimulatory effect on CaM I gene expression; (3) Sp1 or USp3 is involved in mediating insulin-stimulation of the CaM I gene in SL2 cells; and (4) Sp3, a "short" form of the Sp3 molecule, and Sp4 inhibited Spl-stimulated and insulin-stimulated Sp1-mediated CaM I gene expression. Together these data corroborate and extend our previous observations on Sp1 and elucidate that other members of the Sp family of transcription factors may also be involved in regulating the activity of the CaM promoter.