Factors associated with falls in older adults: A secondary analysis of a 12-month randomized controlled trial.

PURPOSE: While identifying older adults at risk for falls is important, fall prediction models have had limited success, in part because of a poor understanding of which physical function measures to include. The purpose of this secondary analysis was to determine physical function measures that are associated with future falls in older adults. METHODS: In a 12-month trial comparing Vitamin D3 supplementation versus placebo on neuromuscular function, 124 older adults completed physical function measures at baseline, including the Short Physical Performance Battery (SPPB), Timed Up and Go, tests of leg strength and power, standing balance on a force plate with firm and foam surfaces, and walking over an instrumented walkway. Falls were recorded with monthly diaries over 12 months and categorized as no falls vs. one or more falls. Univariate and multivariable logistic regression adjusting for demographics, treatment assignment, depression, and prescription medications were conducted to examine the association between each physical function measure and future falls. Models were additionally adjusted for fall history. RESULTS: 61 participants sustained one or more falls. In univariate analysis, white race, depression, fall history, SPPB, and postural stability on foam were significantly associated with future falls. In multivariable analysis, fall history (OR (95% CI): 3.20 (1.42-7.43)), SPPB (0.80 (0.62-1.01)), and postural stability on foam (3.01 (1.18, 8.45)) were each significantly associated with future falls. After adjusting for fall history, only postural stability on foam was significantly associated with falls. CONCLUSIONS: When developing fall prediction models, fall history, the SPPB, and postural stability when standing on foam should be considered.

Efficacy of Control-IQ Technology in a General Endocrine Clinic.

OBJECTIVE: Recent advances in technology have allowed for the expanded use of hybrid closed-loop insulin pump therapy and automated insulin delivery systems for the management of diabetes mellitus. We assessed the outcomes of introducing Tandem t:slim X2 with the Control-IQ technology in a general endocrine clinic. METHODS: Data from 66 adults with type 1 (n = 61) and type 2 (n = 5) diabetes mellitus were aggregated for analysis. Patients were either transitioned from traditional insulin pump therapy or multiple daily injection therapy to Tandem t:slim X2 with the Control-IQ technology from January 2020 to June 2021. The assessed clinical end points included changes in time below range, time above range, and time in target range. Changes in hemoglobin A1C before and after Control-IQ technology implementation were noted. The primary outcome was a change in time in target range with the Control-IQ technology. RESULTS: There was a significant increase in time in target range when comparing pre- and post-Control-IQ technology (49.5% vs 63.3%, P < .0003) values. There was a reduction in time above range (46.8% vs 34.9%, P < .0013), a decrease in time below range (4.0% vs 1.7%, P = .017), and a decrease in hemoglobin A1C after transitioning to the Control-IQ technology (7.7% [61 mmol/mol] vs 7.1% [54 mmol/mol], P < .017). The patient dropout rate was low (7%). CONCLUSION: The Control-IQ technology system was effective in reducing hyperglycemia while increasing time in target range and decreasing hypoglycemia. This technology is a useful and effective addition to the growing number of automated insulin delivery systems. The clinical outcomes mirror the results found in the key adult pivotal trials.

Gradient and Acceleration of Decline in Physical and Cognitive Functions in Older Adults: A Disparity Analysis.

BACKGROUND: Substantive previous work has shown that both gait speed and global cognition decline as people age. Rates of their decline, as opposed to cross-sectional measurements, could be more informative of future functional status and other clinical outcomes because they more accurately represent deteriorating systems. Additionally, understanding the sex and racial disparity in the speed of deterioration, if any, is also important as ethnic minorities are at an increased risk of mobility disability and dementia. METHOD: Data from 2 large longitudinal intervention studies were integrated. Rates of decline were derived from individual-level measures of gait speed of 400-m walk and scores on the Modified Mini Mental State Examination (3MSE). We also assessed age-associated declines and accelerations in changes across the ages represented in the studies (age range 53-90). RESULTS: The mean rate of decline in 400-m gait speed across individuals was 0.03 m/s per year, and multivariable analysis showed a significant acceleration in decline of -0.0013 m/s/y2 (p < .001). Both race and sex moderated the rate of decline. For global cognition, the mean rate of decline was 0.05 of a point per year on the 3MSE scale, and acceleration in the rate of decline was significant (-0.017 point/y2, p < .001), but neither sex nor race moderated the decline. CONCLUSION: Rate of decline in physical but not cognitive function appears moderated by sex and race. This finding, as well as rates and accelerations of decline estimated herein, could inform future intervention studies. CLINICAL TRIALS REGISTRATION NUMBER: NCT00017953 (Look AHEAD); NCT01410097 (Look AHEAD ancillary); NCT00116194 (LIFE).

Real-World Efficacy of the Hybrid Closed-Loop System.

BACKGROUND: Hybrid closed-loop (HCL) insulin pump therapy (Medtronic 670G) is an emerging technology that is growing in use worldwide. Initial clinical trials demonstrated the effectiveness of HCL in reducing hypoglycemia and improving glucose control; however, these subjects were intensely monitored and supervised. There has been concern regarding the ability of patients to remain in auto mode. We aimed to assess HCL when used in a typical outpatient endocrine clinic. METHODS: We initially analyzed data from 80 individuals with type 1 diabetes managed in an endocrine clinic by a single certified diabetes educator (CDE). We then included our other providers and had 230 subjects by the end of the study. Patients were either transitioned from traditional insulin pump or multiple daily insulin injection therapy (MDI) to HCL. Patients initiated to HCL pump therapy from July 2017 through February 2020 were studied. Endpoints of change in time in hypoglycemic/hyperglycemic range and time in target range were analyzed. The primary outcome was a change in percent time in the target range during manual mode compared with auto mode. RESULTS: There was an 18.2% increase in average time in target range when comparing manual mode to auto mode (59.3% vs 70.1%, P < .0001). Average time in hyperglycemic range was significantly reduced by 26.7% (39.0% vs 28.6%, P < .0001) but without increasing average time in hypoglycemic range (1.7% vs 1.3%, P = 0.95). CONCLUSIONS: HCL was effective in reducing hyperglycemia and increasing time in the target range but did not increase hypoglycemia. These data suggest HCL will improve the metrics of glucose control.

Predicting Future Mobility Limitation in Older Adults: A Machine Learning Analysis of Health ABC Study Data.

BACKGROUND: Mobility limitation in older adults is common and associated with poor health outcomes and loss of independence. Identification of at-risk individuals remains challenging because of time-consuming clinical assessments and limitations of statistical models for dynamic outcomes over time. Therefore, we aimed to develop machine learning models for predicting future mobility limitation in older adults using repeated measures data. METHODS: We used annual assessments over 9 years of follow-up from the Health, Aging, and Body Composition study to model mobility limitation, defined as self-report of any difficulty walking a quarter mile or climbing 10 steps. We considered 46 predictors, including demographics, lifestyle, chronic conditions, and physical function. With a split sample approach, we developed mixed models (generalized linear and Binary Mixed Model forest) using (a) all 46 predictors, (b) a variable selection algorithm, and (c) the top 5 most important predictors. Age was included in all models. Performance was evaluated using area under the receiver operating curve in 2 internal validation data sets. RESULTS: Area under the receiver operating curve ranged from 0.80 to 0.84 for the models. The most important predictors of mobility limitation were ease of getting up from a chair, gait speed, self-reported health status, body mass index, and depression. CONCLUSIONS: Machine learning models using repeated measures had good performance for identifying older adults at risk of developing mobility limitation. Future studies should evaluate the utility and efficiency of the prediction models as a tool in clinical settings for identifying at-risk older adults who may benefit from interventions aimed to prevent or delay mobility limitation.

Use of the Molecular Adsorbent Recirculating System in Acute Liver Failure: Results of a Multicenter Propensity Score-Matched Study.

OBJECTIVES: The molecular adsorbent recirculating system removes water-soluble and albumin-bound toxins and may be beneficial for acute liver failure patients. We compared the rates of 21-day transplant-free survival in acute liver failure patients receiving molecular adsorbent recirculating system therapy and patients receiving standard medical therapy. DESIGN: Propensity score-matched retrospective cohort analysis. SETTING: Tertiary North American liver transplant centers. PATIENTS: Acute liver failure patients receiving molecular adsorbent recirculating system at three transplantation centers (n = 104; January 2009-2019) and controls from the U.S. Acute Liver Failure Study Group registry. INTERVENTIONS: Molecular adsorbent recirculating system treatment versus standard medical therapy (control). MEASUREMENTS AND MAIN RESULTS: One-hundred four molecular adsorbent recirculating system patients were propensity score-matched (4:1) to 416 controls. Using multivariable conditional logistic regression adjusting for acute liver failure etiology (acetaminophen: n = 248; vs nonacetaminophen: n = 272), age, vasopressor support, international normalized ratio, King's College Criteria, and propensity score (main model), molecular adsorbent recirculating system was significantly associated with increased 21-day transplant-free survival (odds ratio, 1.90; 95% CI, 1.07-3.39; p = 0.030). This association remained significant in several sensitivity analyses, including adjustment for acute liver failure etiology and propensity score alone ("model 2"; molecular adsorbent recirculating system odds ratio, 1.86; 95% CI, 1.05-3.31; p = 0.033), and further adjustment of the "main model" for mechanical ventilation, and grade 3/4 hepatic encephalopathy ("model 3"; molecular adsorbent recirculating system odds ratio, 1.91; 95% CI, 1.07-3.41; p = 0.029). In acetaminophen-acute liver failure (n = 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in mean arterial pressure (92.0 vs 78.0 mm Hg), creatinine (77.0 vs 128.2 µmol/L), lactate (2.3 vs 4.3 mmol/L), and ammonia (98.0 vs 136.0 µmol/L; p ≤ 0.002 for all). In nonacetaminophen acute liver failure (n = 53), molecular adsorbent recirculating system was associated with significant improvements in bilirubin (205.2 vs 251.4 µmol/L), creatinine (83.1 vs 133.5 µmol/L), and ammonia (111.5 vs 140.0 µmol/L; p ≤ 0.022 for all). CONCLUSIONS: Treatment with molecular adsorbent recirculating system is associated with increased 21-day transplant-free survival in acute liver failure and improves biochemical variables and hemodynamics, particularly in acetaminophen-acute liver failure.

A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure.

BACKGROUND & AIMS: Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. METHODS: We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. RESULTS: Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. CONCLUSIONS: Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. LAY SUMMARY: While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.

Clinical and Neurologic Outcomes in Acetaminophen-Induced Acute Liver Failure: A 21-Year Multicenter Cohort Study.

BACKGROUND & AIMS: Acetaminophen (APAP)-induced acute liver failure (ALF) is a rare disease associated with high mortality rates. This study aimed to evaluate changes in interventions, psychosocial profile, and clinical outcomes over a 21-year period using data from the ALF Study Group registry. METHODS: A retrospective review of this prospective, multicenter cohort study of all APAP-ALF patients enrolled during the study period (1998-2018) was completed. Primary outcomes evaluated were the 21-day transplant-free survival (TFS) and neurologic complications. Covariates evaluated included enrollment cohort (early, 1998-2007; recent, 2008-2018), intentionality, psychiatric comorbidity, and use of organ support including continuous renal replacement therapy (CRRT). RESULTS: Of 1190 APAP-ALF patients, recent cohort patients (n = 608) had significantly improved TFS (recent, 69.8% vs early, 61.7%; P = .005). Recent cohort patients were more likely to receive CRRT (22.2% vs 7.6%; P < .001), and less likely to develop intracranial hypertension (29.9% vs 51.5%; P < .001) or die by day 21 from cerebral edema (4.5% vs 11.6%; P < .001). Grouped by TFS status (non-TFS, n = 365 vs TFS, n = 704), there were no differences in psychiatric comorbidity (51.5% vs 55.0%; P = .28) or intentionality (intentional, 39.7% vs 41.6%; P = .58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy, King's College criteria, and MELD score, the use of CRRT (odds ratio, 1.62; P = .023) was associated with significantly increased TFS (c-statistic, 0.86). In a second model adjusting for the same covariates, recent enrollment was associated significantly with TFS (odds ratio, 1.42; P = .034; c-statistic, 0.86). CONCLUSIONS: TFS in APAP-ALF has improved in recent years and rates of intracranial hypertension/cerebral edema have decreased, possibly related to increased CRRT use.

Elevated Serum Liver-Type Fatty Acid Binding Protein Levels in Non-acetaminophen Acute Liver Failure Patients with Organ Dysfunction.

BACKGROUND: Liver-type fatty acid binding protein (FABP1) has previously been demonstrated to improve prognostic discrimination in acetaminophen (APAP)-induced ALF but has not been investigated in other etiologies of ALF. AIM: To determine whether FABP1 levels (early: admission or late: days 3-5) are associated with 21-day transplant-free survival in non-APAP ALF. METHODS: FABP1 was measured in serum samples from 384 ALF patients (n = 88 transplant-free survivors (TFS), n = 296 died/LT-NTFS) using solid-phase enzyme-linked immunosorbent assay and analyzed with US ALFSG registry data. RESULTS: Of 384 ALF patients (autoimmune hepatitis n = 125, drug-induced liver injury n = 141, Hepatitis B n = 118), 177 (46%) patients received LT. Early FABP1 levels were significantly higher in ALF patients requiring vasopressor support (203.4 vs. 76.3 ng/mL) and renal replacement therapy (203.4 vs. 78.8 ng/mL; p < 0.001 for both). Late FABP1 levels were significantly higher in patients requiring mechanical ventilation (77.5 vs. 53.3 ng/mL), vasopressor support (116.4 vs. 53.3 ng/mL) and in patients with grade 3/4 hepatic encephalopathy (71.4 vs. 51.4 ng/mL; p = 0.03 for all). Late FABP1 levels were significantly lower in TFS patients (TFS 54 vs. NTFS 66 ng/mL; p = 0.049) but not admission (TFS 96 vs. NTFS 87 ng/mL; p = 0.67). After adjusting for significant covariates, serum FABP1 did not discriminate significantly between TFS and patients who died/received LT at day 21 either on admission (p = 0.29) or late (days 3-5, p = 0.087) time points. CONCLUSION: In this first report of FABP1 in non-APAP ALF, FABP1 levels at late time points (days 3-5) were significantly lower in ALF patients who were alive without transplant at day 21 but not after adjusting for covariates reflecting severity of illness. Higher FABP1 levels were associated with the presence of increased organ failure.

Longitudinal partially ordered data analysis for preclinical sarcopenia.

Sarcopenia is a geriatric syndrome characterized by significant loss of muscle mass. Based on a commonly used definition of the condition that involves three measurements, different subclinical and clinical states of sarcopenia are formed. These states constitute a partially ordered set (poset). This article focuses on the analysis of longitudinal poset in the context of sarcopenia. We propose an extension of the generalized linear mixed model and a recoding scheme for poset analysis such that two submodels-one for ordered categories and one for nominal categories-that include common random effects can be jointly estimated. The new poset model postulates random effects conceptualized as latent variables that represent an underlying construct of interest, that is, susceptibility to sarcopenia over time. We demonstrate how information can be gleaned from nominal sarcopenic states for strengthening statistical inference on a person's susceptibility to sarcopenia.

Impact of structured interdisciplinary bedside rounding on patient outcomes at a large academic health centre.

BACKGROUND: Effective communication between healthcare providers and patients and their family members is an integral part of daily care and discharge planning for hospitalised patients. Several studies suggest that team-based care is associated with improved length of stay (LOS), but the data on readmissions are conflicting. Our study evaluated the impact of structured interdisciplinary bedside rounding (SIBR) on outcomes related to readmissions and LOS. METHODS: The SIBR team consisted of a physician and/or advanced practice provider, bedside nurse, pharmacist, social worker and bridge nurse navigator. Outcomes were compared in patients admitted to a hospital medicine unit using SIBR (n=1451) and a similar control unit (n=770) during the period of October 2016 to September 2017. Multivariable negative binomial regression analysis was used to compare LOS and logistic regression analysis was used to calculate 30-day and 7-day readmission in patients admitted to SIBR and control units, adjusting for covariates. RESULTS: Patients admitted to SIBR and control units were generally similar (p≥0.05) with respect to demographic and clinical characteristics. Unadjusted readmission rates in SIBR patients were lower than in control patients at both 30 days (16.6% vs 20.3%, p=0.03) and 7 days (6.3% vs 9.0%, p=0.02) after discharge, while LOS was similar. After adjusting for covariates, SIBR was not significantly related to the odds of 30-day readmission (OR 0.81, p=0.07) but was lower for 7-day readmission (OR 0.70, p=0.03); LOS was similar in both groups (p=0.58). CONCLUSION: SIBR did not reduce LOS and 30-day readmissions but had a significant impact on 7-day readmissions.

Food Insecurity Is Associated with an Increased Prevalence of Comorbid Medical Conditions in Obese Adults: NHANES 2007-2014.

BACKGROUND: Numerous studies have examined if food insecurity (FI) leads to increased weight gain, but little is known about how FI affects obese participants. OBJECTIVE: Our objective was to determine if obese, food-insecure adults are more likely to have medical comorbidities than obese, food-secure adults. DESIGN: We conducted a cross-sectional study using the 2007-2014 National Health and Nutrition Examination Survey (NHANES). PARTICIPANTS: All obese participants (≥ 20 years) in NHANES were eligible. Participants who were pregnant or missing FI data were excluded. MAIN MEASURES: The primary exposure was household FI, and the primary outcome was the total number of obesity-related comorbidities. Secondary outcomes evaluated the association between FI and individual comorbidities. Propensity score weighting was used to improve covariate balance. We used negative binomial regression to test the association between FI and the total number of comorbidities. We used logistic regression to test the association between FI and individual comorbidities. KEY RESULTS: Of the 9203 obese participants, 15.6% were food insecure. FI (ß = 0.09, 95% CI: 0.02, 0.15; p = 0.01) and very low food security (ß = 0.17, 95% CI: 0.07, 0.28; p = 0.003) were associated with an increased number of comorbidities. In secondary analyses, FI was associated with increased odds of coronary artery disease (OR: 1.5, 95% CI: 1.1, 2.0) and asthma (OR: 1.3, 95% CI: 1.1, 1.6). Very low food security was associated with increased odds of coronary artery disease, diabetes, and asthma. CONCLUSION: Obese adults living in food-insecure households were more likely to have an increased number of comorbid conditions than obese adults living in food-secure households. Clinicians should be aware of the association between FI and comorbid medical conditions when treating patients with obesity.

Predicting in-hospital mortality in pneumonia-associated septic shock patients using a classification and regression tree: a nested cohort study.

BACKGROUND: Pneumonia complicated by septic shock is associated with significant morbidity and mortality. Classification and regression tree methodology is an intuitive method for predicting clinical outcomes using binary splits. We aimed to improve the prediction of in-hospital mortality in patients with pneumonia and septic shock using decision tree analysis. METHODS: Classification and regression tree models were applied to all patients with pneumonia-associated septic shock in the international, multicenter Cooperative Antimicrobial Therapy of Septic Shock database between 1996 and 2015. The association between clinical factors (time to appropriate antimicrobial therapy, severity of illness) and in-hospital mortality was evaluated. Accuracy in predicting clinical outcomes, sensitivity, specificity, and area under receiver operating curve of the final model was evaluated in training (n = 2111) and testing datasets (n = 2111). RESULTS: The study cohort contained 4222 patients, and in-hospital mortality was 51%. The mean time from onset of shock to administration of appropriate antimicrobials was significantly higher for patients who died (17.2 h) compared to those who survived (5.0 h). In the training dataset (n = 2111), a tree model using Acute Physiology and Chronic Health Evaluation II Score, lactate, age, and time to appropriate antimicrobial therapy yielded accuracy of 73% and area under the receiver operating curve 0.75. The testing dataset (n = 2111) had accuracy of 69% and area under the receiver operating curve 0.72. CONCLUSIONS: Overall mortality (51%) in patients with pneumonia complicated by septic shock is high. Increased time to administration of antimicrobial therapy, Acute Physiology and Chronic Health Evaluation II Score, serum lactate, and age were associated with increased in-hospital mortality. Classification and regression tree methodology offers a simple prognostic model with good performance in predicting in-hospital mortality.

The association between FABP7 serum levels with survival and neurological complications in acetaminophen-induced acute liver failure: a nested case-control study.

BACKGROUND: Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality due to intracranial hypertension (ICH), a result of cerebral edema (CE) and astrocyte swelling. Brain-type fatty acid-binding protein (FABP7) is a small (15 kDa) cytoplasmic protein abundantly expressed in astrocytes. The aim of this study was to determine whether serum FABP7 levels early (day 1) or late (days 3-5) level were associated with 21-day mortality and/or the presence of ICH/CE in APAP-ALF patients. METHODS: Serum samples from 198 APAP-ALF patients (nested case-control study with 99 survivors and 99 non-survivors) were analyzed by ELISA methods and assessed with clinical data from the US Acute Liver Failure Study Group (ALFSG) Registry (1998-2014). RESULTS: APAP-ALF survivors had significantly lower serum FABP7 levels on admission (147.9 vs. 316.5 ng/ml, p = 0.0002) and late (87.3 vs. 286.2 ng/ml, p < 0.0001) compared with non-survivors. However, a significant association between 21-day mortality and increased serum FABP7 early [log FABP7 odds ratio (OR) 1.16, p = 0.32] and late (log FABP7 ~ OR 1.34, p = 0.21) was not detected after adjusting for significant covariates (MELD, vasopressor use). Areas under the receiver-operating curve for early and late multivariable models were 0.760 and 0.892, respectively. In a second analysis, patients were grouped based on the presence (n = 46) or absence (n = 104) of ICH/CE. A significant difference in FABP7 levels between patients with or without ICH/CE at early (259.7 vs. 228.2 ng/ml, p = 0.61) and late (223.8 vs. 192.0 ng/ml, p = 0.19) time points was not identified. CONCLUSION: Serum FABP7 levels were significantly elevated at early and late time points in APAP-ALF non-survivors compared to survivors. However, significant differences in FABP7 levels by 21-day mortality were not ascertained after adjusting for significant covariates (reflecting severity of illness). Our study suggests that FABP7 may not discriminate between patients with or without intracranial complications.

Methods for Analysis of Pre-Post Data in Clinical Research: A Comparison of Five Common Methods.

Often repeated measures data are summarized into pre-post-treatment measurements. Various methods exist in the literature for estimating and testing treatment effect, including ANOVA, analysis of covariance (ANCOVA), and linear mixed modeling (LMM). Under the first two methods, outcomes can either be modeled as the post treatment measurement (ANOVA-POST or ANCOVA-POST), or a change score between pre and post measurements (ANOVA-CHANGE, ANCOVA-CHANGE). In LMM, the outcome is modeled as a vector of responses with or without Kenward-Rogers adjustment. We consider five methods common in the literature, and discuss them in terms of supporting simulations and theoretical derivations of variance. Consistent with existing literature, our results demonstrate that each method leads to unbiased treatment effect estimates, and based on precision of estimates, 95% coverage probability, and power, ANCOVA modeling of either change scores or post-treatment score as the outcome, prove to be the most effective. We further demonstrate each method in terms of a real data example to exemplify comparisons in real clinical context.

Elevated FABP1 serum levels are associated with poorer survival in acetaminophen-induced acute liver failure.

Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Serum liver-type fatty acid binding protein (FABP1) early (day 1) or late (day 3-5) levels are associated with 21-day mortality in the absence of liver transplant. Serum samples from 198 APAP-ALF patients (nested case-control study with 99 survivors, 99 nonsurvivors) were analyzed by enzyme-linked immunosorbent assay with clinical data from the US Acute Liver Failure Study Group registry (1998-2014). APAP-ALF survivors had significantly lower serum FABP1 levels early (238.6 versus 690.8 ng/mL, P < 0.0001) and late (148.4 versus 612.3 ng/mL, P < 0.0001) compared with nonsurvivors. FABP1 > 350 ng/mL was associated with significantly higher risk of death at early (P = 0.0004) and late (P < 0.0001) time points. Increased serum FABP1 early (log FABP1 odds ratio = 1.31, P = 0.027) and late (log FABP1 odds ratio = 1.50, P = 0.005) were associated with significantly increased 21-day mortality after adjusting for significant covariates (Model for End-Stage Liver Disease, vasopressor use). Areas under the receiver operating characteristic curve for early and late multivariable models were 0.778 and 0.907, respectively. The area under the receiver operating characteristic curve of the King's College criteria (early, 0.552 alone, 0.711 with FABP1; late, 0.604 alone, 0.797 with FABP1) and the Acute Liver Failure Study Group prognostic index (early, 0.686 alone, 0.766 with FABP1; late, 0.711 alone, 0.815 with FABP1) significantly improved with the addition of FABP1 (P < 0.002 for all). CONCLUSION: In patients with APAP-ALF, FABP1 may have good potential to discriminate survivors from nonsurvivors and may improve models currently used in clinical practice; validation of FABP1 as a clinical prediction tool in APAP-ALF warrants further investigation. (Hepatology 2017;65:938-949).

Quantitative analysis of mitochondrial morphology and membrane potential in living cells using high-content imaging, machine learning, and morphological binning.

Understanding the processes of mitochondrial dynamics (fission, fusion, biogenesis, and mitophagy) has been hampered by the lack of automated, deterministic methods to measure mitochondrial morphology from microscopic images. A method to quantify mitochondrial morphology and function is presented here using a commercially available automated high-content wide-field fluorescent microscopy platform and R programming-language-based semi-automated data analysis to achieve high throughput morphological categorization (puncta, rod, network, and large & round) and quantification of mitochondrial membrane potential. In conjunction with cellular respirometry to measure mitochondrial respiratory capacity, this method detected that increasing concentrations of toxicants known to directly or indirectly affect mitochondria (t-butyl hydroperoxide [TBHP], rotenone, antimycin A, oligomycin, ouabain, and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone [FCCP]), decreased mitochondrial networked areas in cultured 661w cells to 0.60-0.80 at concentrations that inhibited respiratory capacity to 0.20-0.70 (fold change compared to vehicle). Concomitantly, mitochondrial swelling was increased from 1.4- to 2.3-fold of vehicle as indicated by changes in large & round areas in response to TBHP, oligomycin, or ouabain. Finally, the automated identification of mitochondrial location enabled accurate quantification of mitochondrial membrane potential by measuring intramitochondrial tetramethylrhodamine methyl ester (TMRM) fluorescence intensity. Administration of FCCP depolarized and administration of oligomycin hyperpolarized mitochondria, as evidenced by changes in intramitochondrial TMRM fluorescence intensities to 0.33- or 5.25-fold of vehicle control values, respectively. In summary, this high-content imaging method accurately quantified mitochondrial morphology and membrane potential in hundreds of thousands of cells on a per-cell basis, with sufficient throughput for pharmacological or toxicological evaluation.