Child Adult Relationship Enhancement in Primary Care (PriCARE): study design/protocol for a randomized trial of a primary care-based group parenting intervention to prevent child maltreatment.

BACKGROUND: Child maltreatment (CM) is a pervasive public health problem and there is a critical need for brief, effective, scalable prevention programs. Problematic parent-child relationships lie at the heart of CM. Parents who maltreat their children are more likely to have punitive parenting styles characterized by high rates of negative interaction and ineffective discipline strategies with over-reliance on punishment. Thus, parenting interventions that strengthen parent-child relationships, teach positive discipline techniques, decrease harsh parenting, and decrease child behavioral problems hold promise as CM prevention strategies. Challenges in engaging parents, particularly low-income and minority parents, and a lack of knowledge regarding effective implementation strategies, however, have greatly limited the reach and impact of parenting interventions. Child Adult Relationship Enhancement in Primary Care (PriCARE)/Criando Niños con CARIÑO is a 6-session group parenting intervention that holds promise in addressing these challenges because PriCARE/CARIÑO was (1) developed and iteratively adapted with input from racially and ethnically diverse families, including low-income families and (2) designed specifically for implementation in primary care with inclusion of strategies to align with usual care workflow to increase uptake and retention. METHODS: This study is a multicenter randomized controlled trial with two parallel arms. Children, 2-6 years old with Medicaid/CHIP/no insurance, and their English- and Spanish-speaking caregivers recruited from pediatric primary care clinics in Philadelphia and North Carolina will be enrolled. Caregivers assigned to the intervention regimen will attend PriCARE/CARIÑO and receive usual care. Caregivers assigned to the control regimen will receive usual care only. The primary outcome is occurrence of an investigation for CM by child protective services during the 48 months following completion of the intervention. In addition, scores for CM risk, child behavior problems, harsh and neglectful parenting behaviors, caregiver stress, and caregiver-child interactions will be assessed as secondary outcome measures and for investigation of possible mechanisms of intervention-induced change. We will also identify PriCARE/CARIÑO implementation factors that may be barriers and facilitators to intervention referrals, enrollment, and attendance. DISCUSSION: By evaluating proximal outcomes in addition to the distal outcome of CM, this study, the largest CM prevention trial with individual randomization, will help elucidate mechanisms of change and advance the science of CM prevention. This study will also gather critical information on factors influencing successful implementation and how to optimize intervention referrals, enrollment, and attendance to inform future dissemination and practical applications. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov (NCT05233150) on February 1, 2022, prior to enrolling subjects.

Medically tailored meals for food insecurity and type 2 diabetes: Protocol for the Food as Medicine for Diabetes (FAME-D) trial.

BACKGROUND: Food insecurity is associated with worse glycemic management for individuals with type 2 diabetes mellitus (T2DM), but whether medically tailored meals (MTM), a food insecurity intervention, can improve glycemic management is unclear. OBJECTIVE: To describe the protocol for a trial assessing whether an MTM plus lifestyle intervention improves hemoglobin A1c (HbA1c) and participant-reported outcomes, relative to a food subsidy (money that can be spent on foods participants choose), for adults with both T2DM and food insecurity. METHODS: The Food as Medicine for Diabetes (FAME-D) randomized clinical trial (goal n = 200) is a pragmatic trial with an active comparator. Participants, who will have T2DM and report food insecurity, will be randomly assigned to a 6-month MTM plus telephone-delivered lifestyle change intervention, or a 6-month food subsidy ($40/month). The primary outcome is HbA1c at 6 months. Secondary outcomes include HbA1c at 12 months to assess whether the intervention effect (if any) is sustained, along with weight, food insecurity, diabetes distress, and health-related quality of life. Qualitative analyses of semi-structured interviews will help understand why, how, and under what circumstances the intervention achieved its observed results. CONCLUSION: Results from FAME-D will help inform clinical management of food insecurity when it co-occurs with T2DM. Further, results may be useful as healthcare payors are considering coverage for MTM interventions. CLINICALTRIALS: gov: NCT04828785.

Sustainable and equivalent improvements in symptoms and functional well-being following viral cure from ledipasvir/sofosbuvir versus elbasvir/grazoprevir for chronic hepatitis C infection: Findings from the randomized PRIORITIZE trial.

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

Biodistribution of Biomimetic Drug Carriers, Mononuclear Cells, and Extracellular Vesicles, in Nonhuman Primates.

Discovery of novel drug delivery systems to the brain remains a key task for successful treatment of neurodegenerative disorders. Herein, the biodistribution of immunocyte-based carriers, peripheral blood mononuclear cells (PBMCs), and monocyte-derived EVs are investigated in adult rhesus macaques using longitudinal PET/MRI imaging. 64 Cu-labeled drug carriers are introduced via different routes of administration: intraperitoneal (IP), intravenous (IV), or intrathecal (IT) injection. Whole body PET/MRI (or PET/CT) images are acquired at 1, 24, and 48 h post injection of 64 Cu-labeled drug carriers, and standardized uptake values (SUVmean and SUVmax ) in the main organs are estimated. The brain retention for both types of carriers increases based on route of administration: IP < IV < IT. Importantly, a single IT injection of PBMCs produces higher brain retention compared to IT injection of EVs. In contrast, EVs show superior brain accumulation compared to the cells when administered via IP and IV routes, respectively. Finally, a comprehensive chemistry panel of blood samples demonstrates no cytotoxic effects of either carrier. Overall, living cells and EVs have a great potential to be used for drug delivery to the brain. When identifying the ideal drug carrier, the route of administration could make big differences in CNS drug delivery.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.

BACKGROUND & AIMS: The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. METHODS: PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. RESULTS: Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). CONCLUSIONS: The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.

The Type and Amount of Dietary Fat Affect Plasma Factor VIIc, Fibrinogen, and PAI-1 in Healthy Individuals and Individuals at High Cardiovascular Disease Risk: 2 Randomized Controlled Trials.

BACKGROUND: Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) are cardiovascular disease (CVD) risk factors and are modulated, in part, by fat type and amount. OBJECTIVE: We evaluated fat type and amount on the primary outcomes: factor VIIc, fibrinogen, and PAI-1. METHODS: In the Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Trial, 2 controlled crossover feeding studies evaluated substituting carbohydrate or MUFAs for SFAs. Study 1: healthy participants (n = 103) were provided with (8 wk) an average American diet [AAD; designed to provide 37% of energy (%E) as fat, 16% SFA], a Step 1 diet (30%E fat, 9% SFA), and a diet low in SFA (Low-Sat; 26%E fat, 5% SFA). Study 2: participants (n = 85) at risk for CVD and metabolic syndrome (MetSyn) were provided with (7 wk) an AAD, a step 1 diet, and a high-MUFA diet (designed to provide 37%E fat, 8% SFA, 22% MUFA). RESULTS: Study 1: compared with AAD, the Step 1 and Low-Sat diets decreased mean factor VIIc by 1.8% and 2.6% (overall P = 0.0001), increased mean fibrinogen by 1.2% and 2.8% (P = 0.0141), and increased mean square root PAI-1 by 0.0% and 6.0% (P = 0.0037), respectively. Study 2: compared with AAD, the Step 1 and high-MUFA diets decreased mean factor VIIc by 4.1% and 3.2% (overall P < 0.0001), increased mean fibrinogen by 3.9% and 1.5% (P = 0.0083), and increased mean square-root PAI-1 by 2.0% and 5.8% (P = 0.1319), respectively. CONCLUSIONS: Replacing SFA with carbohydrate decreased factor VIIc and increased fibrinogen in healthy and metabolically unhealthy individuals and also increased PAI-1 in healthy subjects. Replacing SFA with MUFA decreased factor VIIc and increased fibrinogen but less than carbohydrate. Our results indicate an uncertain effect of replacing SFA with carbohydrate or MUFA on cardiometabolic risk because of small changes in hemostatic factors and directionally different responses to decreasing SFA. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT00000538?term=NCT00000538&rank=1 as NCT00000538.

Development and Reporting of Prediction Models: Guidance for Authors From Editors of Respiratory, Sleep, and Critical Care Journals.

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.

Incidence and risk factors of non-device-associated pneumonia in an acute-care hospital.

OBJECTIVE: To update current estimates of non-device-associated pneumonia (ND pneumonia) rates and their frequency relative to ventilator associated pneumonia (VAP), and identify risk factors for ND pneumonia. DESIGN: Cohort study. SETTING: Academic teaching hospital. PATIENTS: All adult hospitalizations between 2013 and 2017 were included. Pneumonia (device associated and non-device associated) were captured through comprehensive, hospital-wide active surveillance using CDC definitions and methodology. RESULTS: From 2013 to 2017, there were 163,386 hospitalizations (97,485 unique patients) and 771 pneumonia cases (520 ND pneumonia and 191 VAP). The rate of ND pneumonia remained stable, with 4.15 and 4.54 ND pneumonia cases per 10,000 hospitalization days in 2013 and 2017 respectively (P = .65). In 2017, 74% of pneumonia cases were ND pneumonia. Male sex and increasing age we both associated with increased risk of ND pneumonia. Additionally, patients with chronic bronchitis or emphysema (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.40-3.06), congestive heart failure (HR, 1.48; 95% CI, 1.07-2.05), or paralysis (HR, 1.72; 95% CI, 1.09-2.73) were also at increased risk, as were those who were immunosuppressed (HR, 1.54; 95% CI, 1.18-2.00) or in the ICU (HR, 1.49; 95% CI, 1.06-2.09). We did not detect a change in ND pneumonia risk with use of chlorhexidine mouthwash, total parenteral nutrition, all medications of interest, and prior ventilation. CONCLUSION: The incidence rate of ND pneumonia did not change from 2013 to 2017, and 3 of 4 nosocomial pneumonia cases were non-device associated. Hospital infection prevention programs should consider expanding the scope of surveillance to include non-ventilated patients. Future research should continue to look for modifiable risk factors and should assess potential prevention strategies.

Medication Non-adherence in a Prospective, Multi-center Cohort Treated with Hepatitis C Direct-Acting Antivirals.

BACKGROUND: The prevalence and risk factors for non-adherence to direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) in clinical practice settings are under-studied. OBJECTIVES: (1) To quantify DAA non-adherence in the total cohort and among subgroups with and without mental health conditions, alcohol use, and substance use, and (2) to investigate patient- and treatment-level risk factor non-adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: A total of 1562 patients receiving DAAs between January 2016 and October 2017 at 11 US medical centers including academic and community practices. MAIN MEASURES: Self-reported medication non-adherence, defined as any missed doses in the past 7 days, surveyed early (T2: at 4 ± 2 weeks) and late in treatment (T3: 2-3 weeks prior to end of treatment). Non-adherence to post-treatment follow-up visits was defined as absence of lab results after DAA therapy completion. KEY RESULTS: Of 1447 patients, 162 (11%) reported non-adherence at T2 or T3. Medical records indicated 262 (17%) of the 1562 participants had not returned for post-treatment visits. At baseline, 37% of patients reported mental health conditions, 15% reported alcohol use, and 23% reported using substances in the previous year. Baseline characteristics associated with DAA non-adherence included alcohol use (OR 1.96), younger age (< 35 years vs. > 55 years: OR 3.40), non-white race (OR > 2.26), and DAA treatment cohort, but not substance use or mental health condition. Non-adherence to follow-up exhibited association with younger age and a higher baseline overall symptom burden. Among 1287 patients with evaluable sustained virologic response (SVR) data, 53 patients (4%) did not achieve SVR. The bivariate correlation between adherence and SVR was negligible (r = 0.01). CONCLUSIONS: DAA non-adherence was low and SVR rates were high. Mental health conditions, substance use, and alcohol use should not disqualify patients from DAA therapy. Patients with alcohol use disorder before DAA therapy initiation may benefit from targeted on-treatment support.

Probe Cocktail to Assess Transporter Function in Sandwich-Cultured Human Hepatocytes.

PURPOSE: Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH. METHODS: Rosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate. RESULTS: For rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive. CONCLUSIONS: These data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.

Incidence and risk factors of non-device-associated urinary tract infections in an acute-care hospital.

OBJECTIVE: To update current estimates of non-device-associated urinary tract infection (ND-UTI) rates and their frequency relative to catheter-associated UTIs (CA-UTIs) and to identify risk factors for ND-UTIs. DESIGN: Cohort study. SETTING: Academic teaching hospital. PATIENTS: All adult hospitalizations between 2013 and 2017 were included. UTIs (device and non-device associated) were captured through comprehensive, hospital-wide active surveillance using Centers for Disease Control and Prevention case definitions and methodology. RESULTS: From 2013 to 2017 there were 163,386 hospitalizations (97,485 unique patients) and 1,273 UTIs (715 ND-UTIs and 558 CA-UTIs). The rate of ND-UTIs remained stable, decreasing slightly from 6.14 to 5.57 ND-UTIs per 10,000 hospitalization days during the study period (P = .15). However, the proportion of UTIs that were non-device related increased from 52% to 72% (P < .0001). Female sex (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.50-2.50) and increasing age were associated with increased ND-UTI risk. Additionally, the following conditions were associated with increased risk: peptic ulcer disease (HR, 2.25; 95% CI, 1.04-4.86), immunosuppression (HR, 1.48; 95% CI, 1.15-1.91), trauma admissions (HR, 1.36; 95% CI, 1.02-1.81), total parenteral nutrition (HR, 1.99; 95% CI, 1.35-2.94) and opioid use (HR, 1.62; 95% CI, 1.10-2.32). Urinary retention (HR, 1.41; 95% CI, 0.96-2.07), suprapubic catheterization (HR, 2.28; 95% CI, 0.88-5.91), and nephrostomy tubes (HR, 2.02; 95% CI, 0.83-4.93) may also increase risk, but estimates were imprecise. CONCLUSION: Greater than 70% of UTIs are now non-device associated. Current targeted surveillance practices should be reconsidered in light of this changing landscape. We identified several modifiable risk factors for ND-UTIs, and future research should explore the impact of prevention strategies that target these factors.

Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.

BACKGROUND & AIMS: A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS: PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS: Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS: In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY: Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.

A comprehensive assessment of patient reported symptom burden, medical comorbidities, and functional well being in patients initiating direct acting antiviral therapy for chronic hepatitis C: Results from a large US multi-center observational study.

BACKGROUND: Symptom burden, medical comorbidities, and functional well-being of patients with chronic hepatitis C virus (HCV) initiating direct acting antiviral (DAA) therapy in real-world clinical settings are not known. We characterized these patient-reported outcomes (PROs) among HCV-infected patients and explored associations with sociodemographic, liver disease, and psychiatric/substance abuse variables. METHODS AND FINDINGS: PROP UP is a large US multicenter observational study that enrolled 1,600 patients with chronic HCV in 2016-2017. Data collected prior to initiating DAA therapy assessed the following PROs: number of medical comorbidities; neuropsychiatric, somatic, gastrointestinal symptoms (PROMIS surveys); overall symptom burden (Memorial Symptom Assessment Scale); and functional well-being (HCV-PRO). Candidate predictors included liver disease markers and patient-reported sociodemographic, psychiatric, and alcohol/drug use features. Predictive models were explored using a random selection of 700 participants; models were then validated with data from the remaining 900 participants. The cohort was 55% male, 39% non-white, 48% had cirrhosis (12% with advanced cirrhosis); 52% were disabled or unemployed; 63% were on public health insurance or uninsured; and over 40% had markers of psychiatric illness. The median number of medical comorbidities was 4 (range: 0-15), with sleep disorders, chronic pain, diabetes, joint pain and muscle aches being present in 20-50%. Fatigue, sleep disturbance, pain and neuropsychiatric symptoms were present in over 60% and gastrointestinal symptoms in 40-50%. In multivariable validation models, the strongest and most frequent predictors of worse PROs were disability, unemployment, and use of psychiatric medications, while liver markers generally were not. CONCLUSIONS: This large multi-center cohort study provides a comprehensive and contemporary assessment of the symptom burden and comorbid medical conditions in patients with HCV treated in real world settings. Pain, fatigue, and sleep disturbance were common and often severe. Sociodemographic and psychiatric markers were the most robust predictors of PROs. Future research that includes a rapidly changing population of HCV-infected individuals needs to evaluate how DAA therapy affects PROs and elucidate which symptoms resolve with viral eradication. TRIAL REGISTRATION: (Clinicaltrial.gov: NCT02601820).

Transporter-Mediated Alterations in Patients With NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate.

The expression of hepatic transporters, including organic anion transporting polypeptides (OATPs) and multidrug resistance-associated proteins (MRPs), is altered in nonalcoholic steatohepatitis (NASH); however, functional data in humans are lacking. In this study, 99m Tc-mebrofenin (MEB) was used to evaluate OATP1B1/1B3 and MRP2 function in NASH patients. Healthy subjects (n = 14) and NASH patients (n = 7) were administered MEB (∼2.5 mCi). A population pharmacokinetic model was developed to describe systemic and hepatic MEB disposition. Study subjects were genotyped for SLCO1B1 variants. NASH increased systemic and hepatic exposure (median ± 2 SE, healthy vs. NASH) to MEB (AUC0-300,blood : 1,780 ± 242 vs. 2,440 ± 775 µCi*min/L, P = 0.006; AUC0-180,liver : 277 ± 36.9 vs. 433 ± 40.3 kcounts*min/sec, P < 0.0001) due to decreased biliary clearance (0.035 ± 0.008 vs. 0.017 ± 0.002 L/min, P = 0.0005) and decreased Vcentral (11.1 ± 0.57 vs. 6.32 ± 1.02 L, P < 0.0001). MEB hepatic CLuptake was reduced in NASH and also in healthy subjects with SLCO1B1 *15/*15 and *1A/*15 genotypes. The pharmacokinetics of drugs that are OATP1B1/1B3 and MRP2 substrates may be substantially altered in NASH.

Simulation-Based Training in Cardiac Surgery.

BACKGROUND: Operating room surgical training has significant limitations. This study hypothesized that some skills could be learned efficiently and safely by using simulation with component task training, deliberate practice, progressive complexity, and experienced coaching to produce safer cardiac surgeons. METHODS: Training modules included cardiopulmonary bypass, coronary artery bypass grafting, aortic valve replacement, massive air embolism, acute intraoperative aortic dissection, and sudden deterioration in cardiac function. Using deliberate practice, first-year cardiothoracic surgical residents at eight institutions were trained and evaluated on component tasks for each module and later on full cardiac operations. Evaluations were based on five-point Likert-scale tools indexed by module, session, task items, and repetitions. Statistical analyses relied on generalized linear model estimation and corresponding confidence intervals. RESULTS: The 27 residents who participated demonstrated improvement with practice repetitions resulting in excellent final scores per module (mean ± two SEs): cardiopulmonary bypass, 4.80 ± 0.12; coronary artery bypass grafting, 4.41 ± 0.19; aortic valve replacement, 4.51 ± 0.20; massive air embolism, 0.68 ± 0.14; acute intraoperative aortic dissection, 4.52 ± 0.17; and sudden deterioration in cardiac function, 4.76 ± 0.16. The transient detrimental effect of time away from training was also evident. CONCLUSIONS: Overall performance in component tasks and complete cardiac surgical procedures improved during simulation-based training. Simulation-based training imparts skill sets for management of adverse events and can help produce safer surgeons.

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. METHODS: Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. RESULTS: Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. CONCLUSIONS: Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.

An experimental approach to evaluate the impact of impaired transport function on hepatobiliary drug disposition using Mrp2-deficient TR- rat sandwich-cultured hepatocytes in combination with Bcrp knockdown.

Breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) are members of the ATP binding cassette (ABC) transporter family located in the canalicular membrane of hepatocytes that mediate biliary excretion of many drugs and endogenous compounds. BCRP and MRP2 have overlapping substrate profiles. Predicting drug disposition in the setting of altered transport function has important clinical significance. This investigation was designed to establish an in vitro model system to evaluate the impact of impaired Mrp2 and Bcrp function on hepatobiliary drug disposition. To achieve Bcrp knockdown by RNA interference (RNAi), sandwich-cultured hepatocytes (SCH) from Mrp2-deficient (TR(-)) and wild-type (WT) rats were infected with adenoviral vectors to express shRNA targeting Bcrp (Ad-siBcrp) at multiplicity of infection (MOI) of 1-10. MOI of 5 was identified as optimal. At MOI of 5, viral infection as well as WT or TR(-) status was statistically significant predictors of the rosuvastatin (RSV) biliary excretion index (BEI), consistent with the known role of Bcrp and Mrp2 in the biliary excretion of RSV in vivo in rats. Relative to WT rat SCH, marginal mean BEI (%) of RSV in TR(-) rat SCH decreased by 28.6 (95% CI: 5.8-51.3). Ad-siBcrp decreased marginal mean BEI (%) of RSV by 13.3 (7.5-9.1) relative to SCH infected with adenoviral vectors expressing a nontargeting shRNA (Ad-siNT). The BEI of RSV was almost ablated in TR(-) rat SCH with Bcrp knockdown (5.9 ± 3.0%) compared to Ad-siNT-infected WT rat SCH (45.4 ± 6.6%). These results demonstrated the feasibility of Bcrp knockdown in TR(-) rat SCH as an in vitro system to assess the impact of impaired Bcrp and Mrp2 function. At MOI of 5, viral infection had minimal effects on RSV total accumulation, but significantly decreased marginal mean taurocholate total accumulation (pmol/mg of protein) and BEI (%) by 9.9 (7.0-12.8) and 7.5 (3.7-11.3), respectively, relative to noninfected SCH. These findings may be due to off-target effects on hepatic bile acid transporters, even though no changes in protein expression levels of the hepatic bile acid transporters were observed. This study established a strategy for optimization of the knockdown system, and demonstrated the potential use of RNAi in SCH as an in vitro tool to predict altered hepatobiliary drug disposition when canalicular transporters are impaired.