Re-examining the factor structure of the Insomnia Severity Index (ISI) and defining the meaningful within-individual change (MWIC) for subjects with insomnia disorder in two phase III clinical trials of the efficacy of lemborexant.

BACKGROUND: The Insomnia Severity Index (ISI) is a widely used measure of insomnia severity. Various ISI research findings suggest different factor solutions and meaningful within-individual change (MWIC) to detect treatment response in patients with insomnia. This study examined an ISI factor solution and psychometric indices to define MWIC in a robust patient sample from clinical trial settings. METHODS: We endeavored to improve upon previous validation of ISI by examining structural components of confirmatory factor analysis (CFA) models using two large, placebo-controlled clinical trials of lemborexant for insomnia. Using the best-fitting two-factor solution, we evaluated anchor-based, distribution-based and receiver operating characteristic (ROC) curve methods to derive an estimate of the MWIC. RESULTS: The model structure for the 7-item scale proposed in other research did not fit the observed data from our two lemborexant clinical trials (N = 1956) as well as a two-factor solution based on 6 items did. Using triangulation of anchor-based, distribution-based, and ROC methods, we determined that a 5-point reduction using 6 items best represented a clinically meaningful improvement in individuals with insomnia in our patient sample. CONCLUSIONS: A 6-item two-factor scale had better psychometric properties than the 7-item scale in this patient sample. On the 6-item scale, a reduction of 5 points in the ISI total score represented the MWIC. Generalizability of the proposed MWIC may be limited to patient populations with similar demographic and clinical characteristics.

Psychometric evaluation of the patient-reported experience of cognitive impairment in schizophrenia (PRECIS) scale.

BACKGROUND: Cognitive impairment associated with schizophrenia (CIAS) represents a distinct, persistent, and core group of schizophrenia symptoms. Cognitive symptoms have been shown to have an impact on quality of life. There are several published CIAS measures, but none based on direct patient self-report. It is important to capture the patient's perspective to supplement performancebased outcome measures of cognition to provide a complete picture of the patient's experience. This paper describes additional validation work on the Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) instrument. METHODS: Data from two large, international, pharmaceutical clinical trials in medically and psychiatrically stable English-speaking patients with schizophrenia and 88 healthy controls were analyzed. An exploratory factor analysis (EFA) was conducted in one trial (n = 215), using the original 35-item PRECIS. The factor structure suggested by EFA was further evaluated using item response theory (IRT; Samejima's graded response model), and tested using confirmatory factor analysis (CFA). Both EFA and CFA results were tested in a second trial with similar inclusion/exclusion characteristics (n = 410). Additional statistical properties were evaluated in healthy controls. RESULTS: EFA suggested that the best solution after item reduction suggested a factor structure of 6 factors based on 26 items (memory, communication, self-control, executive function, attention, sharpness of thought), supporting a total score, with an additional 2-item bother score (28 items in all). IRT analysis indicated the items were well-ordered within each domain. The CFA demonstrated excellent model fit, accounting for 69% of the variance. The statistical properties of the 28-item version of the PRECIS were confirmed in the second trial. Evidence for internal consistency and test-retest reliability was robust. Known-groups validity was supported by comparison of healthy controls with patients with schizophrenia. Correlations indicated moderate associations between PRECIS and functioning instruments like the Schizophrenia Cognition Rating Scale (SCoRS), but weak correlations with performance-based outcomes like MATRICS Consensus Cognitive Battery (MCCB). DISCUSSION: Using two clinical trial samples, we identified a robust factor structure for the PRECIS and were able to replicate it in the second sample. Evaluation of the meaningful score difference (MSD) should be repeated in future studies, as these samples did not show enough change for it to be evaluated. CONCLUSIONS: This analysis provides strong evidence for the reliability and validity of the PRECIS, a 28-item, patient-reported instrument to assess cognitive impairment associated with schizophrenia. The correlation with functioning and the weak correlation with performance on cognitive tasks suggests that patient reports of cognitive impairment measure a unique aspect of patient experience.

Characterizing health-related quality of life and identifying disease predictors among patients suspected of having long COVID: an analysis of COMET-ICE clinical trial data.

Introduction: Long COVID affects health-related quality of life (HRQoL). Here, we investigate the extent to which symptoms experienced during the acute phase of COVID-19 are significant predictors of the presence of long COVID at 12 weeks. Methods: Post-hoc analysis of COMET-ICE trial data, which assessed sotrovimab vs. placebo for treatment of mild-to-moderate COVID-19 among high-risk patients. Patient-reported outcome measures were completed during the trial, including the inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus), the 12-Item Short Form (SF-12) Hybrid questionnaire, and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH). COVID-19 symptoms and impacts (measured by the FLU-PRO Plus) and HRQoL (measured by SF-12 Hybrid and WPAI:GH) were compared between the acute phase (Days 1-21 and 29) and long-COVID phase (at Week 12) among patients with and without long COVID based on COMET-ICE data. Subgroups experiencing long COVID were derived using "All," "Returning," and "Persisting" symptomatic definitions. Long-COVID predictors were identified using a multivariate logistic regression model; odds ratios (ORs) and 95% CIs were calculated. Results: Long-COVID subgroups had significantly higher baseline scores for most FLU-PRO Plus domains and Total Score compared with the non-long-COVID group. WPAI:GH and SF-12 Hybrid scores generally showed significantly more impairment for the long-COVID subgroups at baseline and Week 12 vs. the non-long-COVID group. In the univariate analyses, all FLU-PRO Plus domains were significant predictors of long COVID (all p < 0.05), with the exception of the Sense domain. Older age increased the risk of long COVID (OR 1.02, 95% CI 1.00-1.04, p < 0.05). Non-White patients were significantly less likely to have long COVID by the Returning and Persisting definitions vs. White patients (all p < 0.05). In the multivariate analysis, higher scores for the Nose domain (ORs 3.39-5.60, all p < 0.01) and having COPD (ORs 3.75-6.34, all p < 0.05) were significant long-COVID predictors. Conclusion: Patients who progressed to long COVID had higher symptom severity during the acute disease phase and showed significantly greater negative impact on HRQoL over an extended time period from initial infection through at least the subsequent 3 months. The FLU-PRO Plus Nose domain and having COPD were significant predictors of long COVID.

Assessing the Clinical Meaningfulness of the Alzheimer's Disease Composite Score (ADCOMS) Tool.

INTRODUCTION: The Alzheimer's Disease Composite Score (ADCOMS) is a tool developed to detect clinical progression and measure treatment effect in patients in early stages of Alzheimer's disease (AD). The psychometric properties of the ADCOMS have been established; however, the threshold for clinical meaningfulness has yet to be identified. METHODS: Anchor-based, distribution-based, and ROC curve analyses were used to estimate clinically meaningful thresholds for change in ADCOMS for patients with mild cognitive impairment (MCI) and AD dementia. This study included data from three sources: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the National Alzheimer's Coordinating Center (NACC), and a legacy dataset that included data from four sources: the placebo group from three MCI trials and an earlier data cut from ADNI. Results were stratified by disease severity (MCI vs. dementia) and APOE ε4 carrier status. RESULTS: A total of 5355 participants were included in the analysis. The ADCOMS was able to detect change for MCI and dementia patients who experienced a meaningful decline in cognition (as defined by the Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB]) between baseline and month 12. The following ADCOMS cut-offs were proposed: 0.05 for MCI and 0.10 for dementia. CONCLUSIONS: The ADCOMS was previously established as a valid and reliable tool for use in clinical trials for MCI due to AD and dementia populations. By defining thresholds for clinically meaningful change of ADCOMS, this work is an important step in interpreting clinical findings and estimates of treatment effects in early stage AD trials.

Poor Graft and Patient Survival After Liver Transplantation in Sarcoidosis.

GOALS AND BACKGROUND: There are limited data on post-liver transplantation (LT) outcomes of patients with sarcoidosis. STUDY: We examined the clinical characteristics and post-LT outcomes of patients with sarcoidosis using the United Network for Organ Sharing database from 1985 to 2016 and compared them to patients (entire cohort as well as age, gender, and year of LT-matched counterparts) with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). For the matched design, a conditional logistic regression was used for categorical variables and marginal generalized estimating equation regression models for continuous variables. Survival functions were constructed using the Kaplan-Meier estimator. RESULTS: A total of 206 patients with sarcoidosis, transplanted during the study period, were compared with 3933 patients with PBC and 5323 with PSC. In total, 197 patients with sarcoidosis were compared with 576 with PBC and 576 with PSC in the 1:3 matched analysis. The sarcoidosis group had a higher proportion of blacks (53.3%) and a higher prevalence of obesity and type II diabetes mellitus. The graft and patient survival for sarcoidosis patients were lower when compared with unmatched PBC and PSC patients. The results remained unchanged in the matched analysis. At 5-year, patient survival was ~15% lower for the sarcoidosis group when compared with PBC and PSC. In multivariate analysis using matched data, hazard ratios (HRs) for graft (HR=1.68, 95% confidence interval=1.03-2.75, P=0.04), and patient (HR=2.01, confidence interval=1.22-3.34, P<0.01) survival were higher for sarcoidosis. CONCLUSIONS: Patients who underwent LT for sarcoidosis had a lower graft and patient survival when compared with those with PBC or PSC. That being said, 66% of patients survived 5 years after transplantation, suggesting that LT is an acceptable option in this population.

Karnofsky Performance Status Following Liver Transplantation in Patients With Multiple Organ Failures and Probable Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: Little is known about outcomes of patients who underwent liver transplantation for acute on chronic liver failure (ACLF) and multiple organ failures. We compared Karnofsky Performance Status (KPS) before and after liver transplantation among patients with different numbers of organ failures and probable ACLF. METHODS: We performed a retrospective cohort study of adults who underwent liver transplantation within 30 days of listing with the United Network for Organ Sharing (UNOS) network from January 1, 2006, through September 30, 2016. We determined the prevalence of organ failures using a modified version of the Chronic Liver Failure-Sequential Organ Failure Assessment scale and collected KPS scores at the time of transplantation and at intervals of 3 to 12 months after liver transplantation. Multivariate analyses were performed to adjust for confounders including UNOS region. RESULTS: At the time of liver transplantation, 2838 patients had no organ failure, 2944 had 1 to 2 organ failures, and 1342 patients had 3 or more organ failures. KPS scores following liver transplantation improved significantly in all groups; scores ranged from 81 in patients with no organ failure to 72 in patients with 5 to 6 organ failures. Excellent performance status (KPS score, ≥80) by 1 year after transplantation was achieved by 60% of patients with 5 to 6 organ failures, 64% to 66% of patients with 3 to 4 organ failures, and 70% to 71% of patients with 1 to 2 organ failures, compared with 72.5% of patients without organ failure. Patients with 1 to 4 organ failure were more likely to achieve KPS scores of 80 or more than patients without organ failure, after we adjusted for other covariates and UNOS region. In addition, black patients were less likely, and patients with alcoholic cirrhosis were more likely, to have KPS scores of 80 or more after liver transplantation. CONCLUSIONS: In a retrospective cohort study of patients with probable ACLF who underwent liver transplantation within 30 days of listing with the UNOS network, 60% to 66% of patients with 3 or more organ failures achieved excellent performance 3 to 12 months later.

Multiple Regional Listing Increases Liver Transplant Rates for Those With Model for End-stage Liver Disease Score <15.

BACKGROUND: Multiple listing (ML) at >1 transplant center is one mechanism to combat the geographic disparities in liver transplantation (LT) rates. The objective of our study was to determine the impact of multiple listing on LT rates. METHODS: We examined the United Network of Organ Sharing database from 2002 to 2016 after excluding those listed for multiple organs, hepatocellular carcinoma, or living donor LT. The waitlist mortality and LT rates for the ML groups and the single listed (SL) group were compared after stratifying patients by the Model for End-Stage Liver Disease (MELD) with a cutoff at 15 (<15 and ≥15). RESULTS: Of the 83 935 listed during the study period, 80 351 were listed in a single center (SL group), and 3584 were listed in >1 center (ML group). Of the ML groups, 2028 (2.4%) were listed at multiple donor service areas but within the same region (ML-SR) and 1556 (1.9%) listed in different regions (ML-DR). The median MELD at LT was 20, 21, and 24 for ML-DR, ML-SR, and SL groups, respectively (P = 0.001). Although the probability of receiving LT was significantly higher for the ML groups relative to the SL group for both MELD groups (<15 and ≥15), the impact was the highest for ML-DR group. At MELD score <15, the probability of LT was 72% for ML-DR, 38% for ML-SR, and 32% for SL groups. At MELD score ≥15, the probability of LT was 79% for ML-DR, 67% for ML-SR, and 61% for SL groups. CONCLUSIONS: Multiple listing appeared to considerably improve a patient's chance of receiving LT and survival with the highest benefit for those with low MELD scores (<15) listed at multiple regions.

Survival Outcomes Are Not Affected When Liver Transplant Surgery Is Done at Night, During Weekends, or Summer Months.

BACKGROUND: It has been suggested that hospitalized patients may get suboptimal care in nights or on weekends or summer holidays due to sleep deprivation, physician fatigue, or reduced medical staffing. Our objective was to determine whether there were differences in outcomes when surgery was performed in the night (10 pm-6 am), on weekends (Saturday or Sunday), or during summer months (June-August). METHODS: We used United Network for Organ Sharing (UNOS) data sets of adults transplanted between February 27, 2002, and September 30, 2016. We estimated the start time of liver transplant surgery by utilizing the cross-clamp time and cold ischemia time (cross-clamp time + cold ischemia time - 2 h). The survival outcomes were estimated by Kaplan-Meier survival analysis. Patients with hepatocellular carcinoma (HCC) were analyzed separately. The independent effect of time of transplant on outcomes was analyzed after adjusting for common confounders, including Model for End-stage Liver Diseases scores and transplant center volume. RESULTS: During the study period, 4 434 (9.6%) were done in the night, 12 147 (26.4%) over weekends, and 11 976 (26%) during summer months. The graft and patient survival and complications were not influenced by the time of transplant for both HCC and non-HCC population. Cox regression analysis after adjusting for risk factors, including Model for End-stage Liver Diseases, donor risk index, and liver center volume, confirmed that there were no significant differences in outcomes. CONCLUSIONS: Our study showed that the time of transplant surgery whether done during nights, weekends, or summer months had no effect on graft or patient survival irrespective of center volume, patient, or donor risk factors.

Poor Survival After Retransplantation in NASH Cirrhosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) cirrhosis is a common indication for liver transplantation (LT) in the United States. There is a paucity of data on retransplantation (re-LT) in those who were initially transplanted for NASH. METHODS: We queried the United Network for Organ Sharing data sets from 2002 to 2016 to analyze the outcomes of adults with NASH (n = 128) and compared them with groups that received re-LT for cryptogenic cirrhosis (n = 189), alcoholic cirrhosis (n = 300) or autoimmune hepatitis cirrhosis (n = 118) after excluding multiple-organ re-LT and individuals with hepatocellular carcinoma. We estimated survival probabilities using a Kaplan-Meier estimator, and a relative risk of patient and graft mortality using proportional hazards regression. RESULTS: The NASH group was older and had a higher prevalence of obesity, type II diabetes mellitus, renal insufficiency, portal vein thrombosis, and poor performance status. The median interval between the first and the second LT was shorter in the NASH group (27 days). The graft and patient 5-year survival rates were lower for the NASH group after re-LT compared with the other 3 groups. After adjusting for demographic and disease complication factors, the factors that increased a risk of patient or graft failure were a poor performance status (hazard ratio [HR], 1.64; 1.19-2.26), Donor Risk Index (HR, 1.51; 1.08-2.12), and a high Model for End-stage Liver Disease score (HR, 1.02; 1.00-1.04). CONCLUSIONS: Despite the comparable outcomes reported for initial LT among the various etiologies, the outcome of re-LT is significantly worse for NASH cirrhosis.

Waiting List Mortality and Transplant Rates for NASH Cirrhosis When Compared With Cryptogenic, Alcoholic, or AIH Cirrhosis.

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) cirrhosis have excellent postliver transplant survival despite having many comorbidities. We hypothesized that this could be due to a selection bias. METHODS: We analyzed the United Network for Organ Sharing data from 2002 to 2016 and compared postliver transplant survival of NASH (n = 7935) patients with cryptogenic cirrhosis (CC) (n = 6087), alcoholic cirrhosis (AC) (n = 16 810), and autoimmune hepatitis cirrhosis (AIH) (n = 2734). RESULTS: By 3 years of listing, the cumulative incidence (CI) of death or deterioration was 29% for NASH, 28% for CC and AC, and 24% for AIH, but when adjusted for risk factors, the CI was similar for NASH and AIH. The factors that increased the risk of waiting list removal due to death/deterioration were poor performance status, encephalopathy, diabetes, high Model for End-stage Liver Disease, Hispanic race, older age and a low serum albumin. Most patients were transplanted within the first year (median, 2 months; interquartile range, 1-7 months) of listing and by 5 years, the unadjusted CI of transplantation was 54% for NASH, 52% for CC, 51% for AIH, and 48% for AC. The adjusted CI of transplantation within 2 months of listing was higher for AC (subhazard ratio [SHR], 1.17), AIH (SHR, 1.17), and CC (SHR, 1.13) when compared with NASH, but after 2 months, adjusted transplantation rates decreased in AC (SHR, 0.6), AIH (SHR, 0.78), and CC (SHR, 0.95). The negative predictors of receiving a transplant were dialysis, female sex, nonwhite race, high albumin, and creatinine. CONCLUSIONS: Patients with NASH cirrhosis are not disadvantaged by higher waitlist removal or lower transplantation rates.

Liver transplantation in patients with multiple organ failures: Feasibility and outcomes.

BACKGROUND & AIMS: Multiple organ failures (OFs) are common in patients with cirrhosis, but the independent effect of the number or type of OFs on liver transplantation (LT) outcomes is not well defined. METHOD: United Network for Organ Sharing data were analyzed from 2002 to 2016 for all adults listed for LT who received an LT within 30 days after listing. We estimated post-LT survival stratified by number and type of pre-transplant OFs before and after adjusting for confounding variables. RESULTS: During the study period, 4,714 (4.1%) patients died and 19,375 (16.6%) patients were transplanted within 30 days of listing. One or more OF were more common in those who were transplanted (57.4%) compared to those without LT (9.5%). The probability of staying alive more than 30 days on the waiting list without LT decreased with increasing number of OFs; while 90% were alive without OF, only 20% were alive with two OFs, and 2-8% with three or more OFs. The interval between listing and transplantation decreased with an increase in OFs, and the median time to transplant after listing was only 4-5 days with three or more OFs. Although the risk of post-LT mortality increased with increasing number of OFs, the 90-day patient survival was 90% and one-year survival was 81% in the presence of 5-6 OFs. The number of OFs was an independent predictor of survival, but the maximum difference in one-year graft or patient survival between those without OF and those with 5-6 OFs was only 9%. Additionally, the type of OF had minimal impact on outcomes. CONCLUSIONS: Liver transplantation is feasible with excellent outcomes, even in the presence of five or six OFs. LAY SUMMARY: Multiple organ failures, ranging from 1-6, are common in hospitalized patients with cirrhosis. The survival without liver transplant is dismal in the presence of three or more organ failures. Small retrospective studies have shown that liver transplant is feasible with good outcomes even in the presence of multiple organ failures. In this study, using a large national dataset, we show that survival chances for more than 30 days in those with three or more organ failures are less than 8%. However, if a liver transplant is performed quickly, the survival chances are very high with one-year survival ranging from 84% with three organ failures to 81% with 5-6 organ failures.

Karnofsky performance status before and after liver transplantation predicts graft and patient survival.

BACKGROUND & AIMS: The Karnofsky performance status (KPS) has been used for almost 70 years for clinical assessment of patients. Our objective was to determine whether KPS is an independent predictor of post-liver transplant (LT) survival after adjusting for known confounders. METHOD: Adult patients listed with the United Network for Organ Sharing (UNOS) from 2006 to 2016 were grouped into low (10-40%, n = 15,103), intermediate (50-70%, n = 22,183) and high (80-100%, n = 13,131) KPS groups based on KPS scores at the time of LT, after excluding those on ventilators or life support. We determined the trends in KPS before and after LT, and survival probabilities based on KPS. RESULTS: There was a decline in KPS scores between listing and LT and there was significant improvement after LT. The graft and patient survival differences were significantly lower (p <0.0001) in those with low KPS. After adjusting for other confounders, the hazard ratios for graft failure were 1.17 (1.12-1.22, p <0.01) for the intermediate and 1.38 (1.31-1.46, p <0.01) for the low group. Similarly, hazard ratios for patient failure were 1.18 (1.13-1.24, p <0.01) for the intermediate and 1.43 (1.35-1.52, p <0.01) for the low group. Other independent negative predictors for graft and patient survival were older age, Black ethnicity, presence of hepatic encephalopathy and donor risk index. Those who did not show significant improvements in post-LT KPS scores had poorer outcomes in all three KPS groups, but it was most obvious in the low KPS group with one-year patient survival of 33%. CONCLUSION: The KPS, before and after LT, is an independent predictor of graft and patient survival after adjusting for other important predictors of survival. LAY SUMMARY: The overall health of liver transplant recipients could be assessed by a simple clinical assessment tool called the Karnofsky performance status, which assesses an individual's overall functional status on an 11-point scale, in increments of 10, where a score of 0 is considered dead and 100 is considered perfect health. In this study, using a large dataset, we show that the performance status before and after liver transplant is a predictor of survival. More importantly, those who have low performance status before transplant and do not show an improvement in performance status between 3-12 months after liver transplant have very poor survival.

Mental and physical health-related quality of life in patients with hepatitis C is related to baseline comorbidities and improves only marginally with hepatitis C cure.

The objective of the study was to analyze the relationship between patient characteristics and the health-related quality of life (HRQoL) among patients with hepatitis C at the start of treatment, 2-12 weeks of treatment and ≥3 months post treatment using Short-Form 36 (SF-36). The eight domains and two composite scores of SF-36 were analyzed using 236 individuals. Compared to US general population norms, on average, the physical health scores were significantly lower for the studied hepatitis C population, while the differences related to mental health were between zero and small. For a physical health composite score, the treatment effect was between medium and large (0.70, 0.66, and 0.64 at the baseline and follow-ups), and for a mental health composite score it was close to zero. After controlling for demographic factors, the mixed-effects models demonstrated that HRQoL significantly improved only for general health during the treatment and vitality during post treatment. The strongest predictor of HRQoL at the two follow-up periods was HRQoL at baseline of the same domain. The ordinal logistic regressions showed that at the baseline, the strongest negative predictors of HRQoL in most of the domains were hypertension, diabetes, high BMI, high number of comorbidities including pulmonary comorbidities, low hemoglobin, and public health insurance. Considering that the improvement in HRQoL sustained after treatment only for a mental (vitality) domain, the main determinants of quality of life of the patients with hepatitis C were comorbidities.

Liver Transplantation in Cryptogenic Cirrhosis: Outcome Comparisons Between NASH, Alcoholic, and AIH Cirrhosis.

BACKGROUND: The outcomes of liver transplantation (LT) in patients with cryptogenic cirrhosis (CC) have not been adequately examined except for small case series. We believe that patients currently listed as CC have truly cryptogenic liver disease and may have different post-LT outcomes compared with nonalcoholic steatohepatitis (NASH). METHODS: We compared the post-LT outcomes of adults with CC (n = 3241) and compared them with cirrhosis from NASH (n = 4089), alcoholic cirrhosis (AC) (n = 7837), and autoimmune hepatitis (AIH) (n = 1435) using the United Network for Organ Sharing database from 2002 to 2016. We excluded those who had multiorgan transplantation and hepatocellular carcinoma. In addition to the well-known predictors of liver transplant outcomes, we analyzed the impact of Karnofsky Performance Status score at LT on immediate and late outcomes. RESULTS: There were significant differences in clinical characteristics between the groups. Despite these differences in clinical characteristics and risk factors, CC had similar graft and patient survival to NASH, AC, and AIH when assessed by Kaplan-Meier survival. Multivariate Cox regression analysis showed that graft and patient survival was similar in all 4 groups after adjusting for other confounders. Hispanics had a 24% lower risk of death (hazard ratio, 0.76) compared with whites in these combined cohorts after adjusting for all risk factors. In addition to other known risk factors, Karnofsky Performance Status score of 30% or less was associated with a 33% increase in risk of death (hazard ratio, 1.33) on multivariate analysis. CONCLUSION: Patients with CC had similar graft and patient survival when compared with NASH, AC, and AIH cirrhosis.

Is cryptogenic cirrhosis different from NASH cirrhosis?

BACKGROUND & AIMS: We hypothesized that patients currently diagnosed with cryptogenic cirrhosis (CC) have truly 'cryptogenic' liver disease, which is unlikely to have evolved from NASH. The aim of this study is to characterize patients with CC, and compare their characteristics to patients with cirrhosis of other etiologies. METHODS: To investigate this, we compared the clinical characteristics of adults with CC (n = 7,999) to those with cirrhosis caused by non-alcoholic steatohepatitis (NASH) (n = 11,302), alcohol (n = 21,714) and autoimmune hepatitis (n = 3,447), using the UNOS database from 2002-16. We performed an age, gender and year of listing matched comparison of CC and NASH (n = 7,201 in each group), and also stratified patients by the presence of obesity or diabetes mellitus (DM). RESULTS: From 2002 to 2016, patients listed with a diagnosis of NASH increased from about 1% to 16% while CC decreased from 8% to 4%. A logistic regression model using the entire United Network for Organ Sharing data (n = 138,021) suggested that the strongest predictors of NASH were type 2 DM, obesity, age ≥60 years, female gender and white race. Type 2 DM was more common in patients with NASH (53%) than those with CC (29%), alcoholic cirrhosis (16%) and autoimmune hepatitis (16%), and obesity was more common in NASH (65.3%) compared to the other three groups (33-42%). There were more white individuals (82.3%) in the NASH group and a lower prevalence of black, Hispanic and Asian individuals, compared to the other three groups. Hepatocellular carcinoma was more commonly seen in NASH (19% vs. 9-13% in the other groups) and this is not influenced by obesity and type 2 DM. The differences between CC and NASH remained unchanged even when two groups were matched for age, gender and year of listing, or when stratified by the presence or absence of obesity or type 2DM. CONCLUSIONS: Based on risk perspectives, CC should not be equated with the term 'NASH cirrhosis'. LAY SUMMARY: We hypothesized that cryptogenic cirrhosis is a distinct condition from cirrhosis caused by non-alcoholic steatohepatitis (NASH). By comparing cryptogenic cirrhosis with cirrhosis of other causes, we found clear clinical differences. Therefore, cryptogenic cirrhosis should not be considered the same as NASH cirrhosis. Further investigations are required to identify unknown causes of cirrhosis.

Topical Timolol Maleate Treatment of Infantile Hemangiomas.

BACKGROUND: There has been a dramatic increase in the off-label use of ophthalmic timolol maleate, a ß-blocker used for infantile hemangioma (IH) treatment as a topical counterpart to oral propranolol. Its safety and efficacy in a pediatric population with IH have not been evaluated in a large cohort. Our goal was to retrospectively assess timolol's effectiveness, discern characteristics associated with response, and document reported adverse events. METHODS: A multicenter retrospective cohort study of 731 patients treated with topical timolol was completed at 9 centers. Inclusion required an IH suitable for timolol in the treating physician's judgment and access to clinical details including photographs. Logistic regression analysis and descriptive statistics were performed. Primary outcome measures were efficacy assessed by using visual analog scales for color and for size, extent, and volume from review of digital photographs taken as standard of care. RESULTS: Most IHs were localized (80.1%) and superficial (55.3%). Risk of disfigurement was the most common indication for therapy (74.3%). Duration of therapy (P < .0001), initial thinness (P = .008), and subtype (P = .031) were significant predictors of response. Best response occurred in superficial IHs <1 mm thick. Fifty-three (7.3%) required subsequent therapy with systemic ß-blocker. Adverse events were mild, occurring in 25 (3.4%) patients. No cardiovascular side effects were documented. CONCLUSIONS: Timolol seems to be a well-tolerated, safe treatment option with moderate to good effectiveness, demonstrating best response in thin, superficial IHs regardless of pretreatment size. Timolol can be recommended as an alternative to systemic ß-blockers and watchful waiting for many patients.

Mathematical Modeling of the Biomarker Milieu to Characterize Preterm Birth and Predict Adverse Neonatal Outcomes.

PROBLEM: To identify preterm neonates at risk for adverse neonatal outcomes. METHOD OF STUDY: A nested case-control study from the prospectively followed Boston Birth Cohort of mother-neonate pairs was performed. A classification model for preterm-born neonates was derived from 27 cord blood biomarkers using orthogonal projections to latent structures discriminant analysis. Predictive relationships were made between biomarkers and adverse outcomes using logistic regression. RESULTS: From 926 births (53% of which were preterm), using weighted values for 27 biomarkers, a score was created that classified 73% of preterm deliveries. Soluble TNF-R1, NT-3, MCP-1, BDNF, IL-4, MMP-9, TREM-1, TNF-α, IL-5 and IL-10 were most influential. Our model was more sensitive for birth <34 weeks (sensitivity 89.5%, specificity 76.9%). IL-10, TNF-α, BDNF, NT-3, MMP-9, sTNF-R1 and MCP-1 were significantly predictive of NEC, IVH, sepsis and infections. CONCLUSION: We developed a novel mathematical model of 27 biomarkers associated with adverse neonatal outcomes in neonates born preterm.