High Isoniazid Exposures When Administered with Rifapentine Once Weekly for Latent Tuberculosis in Individuals with Human Immunodeficiency Virus.

Isoniazid pharmacokinetics are not yet well-described during once weekly, high-dose administrations with rifapentine (3HP) for latent tuberculosis infection (LTBI). Fewer data describe 3HP with dolutegravir-based antiretroviral therapy for the treatment of human immunodeficiency virus (HIV). The only prior report of 3HP with dolutegravir reported elevated isoniazid exposures. We measured the plasma isoniazid levels in 30 adults receiving 3HP and dolutegravir for the treatment of LTBI and HIV. The patients were genotyped to determine NAT2 acetylator status, and a population PK model was estimated by nonlinear mixed-effects modeling. The results were compared to previously reported data describing 3HP with dolutegravir, 3HP alone, and isoniazid with neither dolutegravir nor rifapentine. The isoniazid concentrations were adequately described by a one compartment model with a transit compartment absorption process. The isoniazid clearance for slow (8.33 L/h) and intermediate (12 L/h) acetylators were similar to previously reported values. Rapid acetylators (N = 4) had clearance similar to those of intermediate acetylators and much slower than typically reported, but the small sample size was limiting. The absorption rate was lower than usual, likely due to the coadministration with food, and it was faster among individuals with a low body weight. Low-body weight participants were also observed to have greater oral bioavailability. The isoniazid exposures were consistent with, or greater than, the previously reported "elevated" concentrations among individuals receiving 3HP and dolutegravir. The concentrations were substantially greater than those presented in previous reports among individuals receiving 3HP or isoniazid without rifapentine or dolutegravir. We discuss the implications of these findings and the possibility of a drug-drug interaction that is mediated by cellular transport. (This study has been registered at ClinicalTrials.gov under identifier NCT03435146 and has South African National Clinical Trial Registration no. DOH-27-1217-5770.).

Optimal BIS reference functions for closed-loop induction of anesthesia with propofol.

During closed-loop induction of anesthesia a closed-loop system will typically administer propofol to bring a patient to a target depth of hypnosis, or reference point, as quickly as possible while minimizing overshoot. Infusion rates are modified in response to patient feedback to maintain the patient at the reference point. In many cases, rapid inductions may be ideal. In some populations and contexts, however, slower inductions may be preferable and result in better patient outcomes. We introduce a framework for explicitly defining and optimizing clinical outcomes of interest during closed-loop inductions. The central innovation is to replace the traditional fixed reference point with a parametric, time-varying reference function. The parameters of the reference function are then selected to minimize an objective function that encapsulates a clinical goal for the population. We consider as objectives 1) combinations of over- and under-shoot of the target depth of hypnosis, 2) time to stably reach the target, and 3) the amount of propofol administered. By incorporating population variability in the objective function, the resulting reference function defines an optimal dosing protocol for a specific outcome in the target population. We illustrate this approach by simulating closed-loop inductions for a constructed population of synthetic patients. The population is split into training and test sets that are used to identify and evaluate optimal reference functions, respectively. Reference function performance is compared to a standard approach of targeting a fixed reference point, corresponding to a rapid-induction strategy. The outcome of interest was almost always minimized in the test set by use of a reference function with less variability between patients. Our simulations suggest that reference functions can be an effective method of achieving clinical goals when induction speed is not the only priority.

The development of a current events and dialogue forum at a large U.S. academic medical center.

BACKGROUND: The Vanderbilt Community Circle (VC2) was designed to provide all faculty, staff, and students within the entire Vanderbilt University Medical Center community a dedicated venue to discuss current events and ongoing societal issues. APPROACH: During the 2017-18 academic year, four VC2 events were held on: "Race, identity, and conflict in America," "Gun violence in America," "Gender in the workplace," and "Immigration in America." Facilitators guided participants to share their views and perspectives on these matters with pre-developed open-ended questions. Attendees started discussions in small groups and then eventually combined into a large one. Pre- and post-event surveys were administered to measure the program's effectiveness. EVALUATION: One-hundred and twenty-four participants were included, 75 of whom completed both the pre- and post-event surveys. Sixty-four of the 75 (85%) agreed or strongly agreed that "multiple perspectives and opinions were represented" and 73% felt that their "own perspective was broadened on the issue." Most (89%) believed that the format and setting of the event was conducive to dialogue and discussion, and almost all (91%) reported that they would attend a similar event in the future. Groningen Reflection Ability Scale scores were high before (94 [25th-75th: 88-99]) and remained high after the events (93 [25th-75th: 88-93.3], p > 0.05). REFLECTION: We successfully implemented a medical center-wide, recurring current events and dialogue forum in hopes of increasing reflection, unity, and understanding across our own community.

Basal Insulin Degludec and Glycemic Control Compared to Aspart Via Insulin Pump in Type 1 Diabetes (BIGLEAP): A Single-Center, Open-Label, Randomized, Crossover Trial.

OBJECTIVE: We compared the efficacy of the second-generation basal insulin degludec (IDeg) to that of insulin aspart via pump using continuous glucose monitoring in patients with well-controlled type 1 diabetes. METHODS: In this 40-week, single-center, randomized, crossover-controlled trial, adults with well-controlled type 1 diabetes (hemoglobin A1C of <7.5% [<58 mmol/mol]) (N = 52) who were using an insulin pump and continuous glucose monitoring were randomized to 1 of 2 treatments for a 20-week period: a single daily injection of IDeg with bolus aspart via pump or a continuous subcutaneous insulin infusion (CSII) with aspart, followed by crossover to the other treatment. The primary endpoint was time in range (70-180 mg/dL) during the final 2 weeks of each treatment period. RESULTS: Fifty-two patients were randomized and completed both treatment periods. The time in range for IDeg and CSII was 71.5% and 70.9%, respectively (P = .553). The time in level 1 hypoglycemia for the 24-hour period with IDeg and CSII was 2.19% and 1.75%, respectively (P = .065). The time in level 2 hypoglycemia for the 24-hour period with IDeg and CSII was 0.355% and 0.271%, respectively (P = .212), and the nocturnal period was 0.330% and 0.381%, respectively (P = .639). The mean standard deviation of blood glucose levels for the 24-hour period for IDeg and CSII was 52.4 mg/dL and 51.0 mg/dL, respectively (P = .294). The final hemoglobin A1C level for each treatment was 7.04% (53 mmol/mol) with IDeg, and 6.95% (52 mmol/mol) with CSII (P = .288). Adverse events were similar between treatments. CONCLUSION: We observed similar glycemic control between IDeg and insulin aspart via CSII for basal insulin coverage in patients with well-controlled type 1 diabetes.

Psychopharmaceutical Prescription Monitoring for Children in the Child Welfare System.

OBJECTIVE: Children in the child welfare system are more likely to receive psychotropic medication prescriptions than children in the general population. The authors used prescription- and administrative-level data to quantify variability in prescribing practices among prescribers for the child welfare population in a southern U.S. state. METHODS: Using administrative- and prescription-level child data and Administration on Children, Youth and Families guidelines, the authors defined the primary outcome, potentially inappropriate psychotropic prescriptions (i.e., red-flagged prescriptions). A hierarchical-logistic regression model was fit to account for case complexity and estimate the adjusted probability of a prescription being red-flagged. A funnel plot was used to visualize standardized prescribing rates for every prescriber and identify outlying prescribers. RESULTS: From May 2016 to September 2017, 506 prescribers issued 64,923 prescriptions for 4,093 children with a median (interquartile range) age of 14 (10-16) years. Most prescribers (76.9%) issued at least one red-flagged prescription, 1,263 (30.9%) children received at least one red-flagged prescription, and 14,806 (22.8%) prescriptions were red-flagged. The standardized prescribing rate for each prescriber was compared with a benchmark of 22.8%, defined a priori as the proportion of red-flagged prescriptions in the overall sample. Forty-seven prescribers (9%) prescribed red-flagged prescriptions between two and three standard deviations above the benchmark, and 72 prescribers (14%) more than three standard deviations above the benchmark. CONCLUSIONS: It is vital to monitor psychotropic prescriptions for children in the child welfare system. Quantifying variability in prescribing practices among prescribers for these children might be used to guide oversight.

Incidence and neighborhood-level determinants of child welfare involvement.

BACKGROUND: Child maltreatment is a global public health issue that has been linked with multiple negative health and life outcomes. OBJECTIVE: This study evaluates the association between children placed in out-of-home care and neighborhood-level factors using eight years of administrative data. PARTICIPANTS AND SETTING: Between 2011-2018, 33,890 unique instances of child welfare involvement were captured in a department of child and family services database in a southern state in the United States. METHODS: Removal addresses were geocoded and linked to the U.S. Census Bureau's American Community Survey to obtain census tract socioeconomic factors. Incidence overall and stratified by individual and neighborhood-level factors was computed. Rate ratios, relative indexes of inequality, and concentration curves quantified disparities in incidence of child welfare involvement by neighborhood-level factors. RESULTS: Incidence of children less than 19 years old placed into out-of-home care was 255 per 100,000 person-years (95 % CI: 252, 258). At the individual level, incidence was highest among children <5 and 15-17 years old, comparable between male and female children, and higher among Black children. At the neighborhood level, incidence was highest in census tracts with lower median household incomes, higher percentages of households below poverty or of female-headed or single-parent households, higher unemployment rates, and fewer residents with some college education or health insurance. CONCLUSIONS: Incidence of children placed into out-of-home care is disproportionally higher for those who live in disadvantaged communities. Understanding neighborhood-level risk factors that may be linked to child welfare involvement can help inform policy and target prevention efforts.

Prevalence and Course of Frailty in Survivors of Critical Illness.

OBJECTIVES: Little is known about frailty that develops following critical illness. We sought to describe the prevalence of newly acquired frailty, its clinical course, and the co-occurrence of frailty with disability and cognitive impairment in survivors of critical illness. DESIGN: Longitudinal prospective cohort study. SETTING: Medical and surgical ICUs at five U.S. centers. PATIENTS: Adult patients treated for respiratory failure and/or shock. MEASUREMENTS AND MAIN RESULTS: We measured frailty with the Clinical Frailty Scale at baseline (i.e., study enrollment) and at 3 and 12 months postdischarge. We constructed alluvial diagrams to describe the course of frailty and Venn diagrams to describe the overlap of frailty with disability in activities of daily living and cognitive impairment. We included 567 participants a median (interquartile range) of 61 years old (51-70 yr old) with a high severity of illness (Acute Physiology and Chronic Health Evaluation II of 23). Frailty (Clinical Frailty Scale scores ≥ 5) was present in 135 of 567 (24%) at baseline, 239 of 530 (45%) at 3 months, and 163 of 445 (37%) at 12 months. Of those with frailty at 3- or 12-month follow-up, 61% were not frail at baseline. Transition to a worse frailty state occurred in 242 of 530 of patients (46%) between baseline and 3 months and in 179 of 445 of patients (40%) between baseline and 12 months. There were 376 patients with frailty, disability, or cognitive impairment at 3-month follow-up. Of these, 53 (14%) had frailty alone. At 12 months, 276 patients had frailty, disability, or cognitive impairment, 37 (13%) of whom had frailty alone. CONCLUSIONS: Frailty is common among survivors of critical illness. In the majority, frailty is newly acquired. Roughly one in seven had frailty without co-occurring disability or cognitive impairment. Studies to understand outcomes of frailty that develops as the result of a critical illness and to identify modifiable risk factors for this potentially reversible syndrome are needed.

A randomized trial of a specialist palliative care intervention for patients undergoing surgery for cancer: rationale and design of the Surgery for Cancer with Option of Palliative Care Expert (SCOPE) Trial.

BACKGROUND: In medical oncology settings, early specialist palliative care interventions have demonstrated improvements in patient quality of life and survival compared with usual oncologic care. However, the effect of early specialist palliative care interventions in surgical oncology settings is not well studied. METHODS: The Surgery for Cancer with Option for Palliative Care Expert (SCOPE) Trial is a single-center, prospective, single-blind, randomized controlled trial of a specialist palliative care intervention for cancer patients undergoing non-palliative surgery. It will enroll 236 patients scheduled for major abdominal operations for malignancy, who will be randomized 1:1 at enrollment to receive usual care (control arm) or specialist palliative care consultation (intervention arm). Intervention arm patients will receive consultations from a palliative care specialist (physician or nurse practitioner) preoperatively and postoperatively. The primary outcome is physical and functional wellbeing at 90 days postoperatively. Secondary outcomes are quality of life at 90 days postoperatively, posttraumatic stress disorder symptoms at 180 days postoperatively, days alive at home without an emergency room visit in the first 90 postoperative days, and overall survival at 1 year postoperatively. Participants will be followed for 3 years after surgery for exploratory analyses of their ongoing quality of life, healthcare utilization, and mortality. DISCUSSION: SCOPE is an ongoing randomized controlled trial evaluating specialist palliative care interventions for cancer patients undergoing non-palliative oncologic surgery. Findings from the study will inform ways to identify and improve care of surgical patients who will likely benefit from specialist palliative care services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03436290 First Registered: 16 February 2018 Enrollment Began: 1 March 2018 Last Update: 20 December 2018.

The Costs of Applying to Residency: One Institution's Efforts to Increase Transparency.

OBJECTIVES: To provide students at our own institution with more accurate and granular data regarding the costs associated with applying for residency. METHODS: We created an electronic survey with >28 different fields delineating the costs associated with applying for residency. Demographic data, costs broken down by type of expenditure, and how these costs were financed were measured. Each year, graduating students at our institution took the survey in 2015, 2016, 2017, and 2018 before The Match. We then created a dynamic, user-friendly, and interactive Web-based application to display these data numerically and graphically for students to use while planning and preparing for The Match. RESULTS: There was a response rate of 48.9% (194/397). Overall, students completed an away rotation at a median of 1.0 (interquartile range [IQR] 0-2.0) programs and spent $1000 (IQR $292-$1606) per away rotation. They applied to a median of 30.0 (IQR 20.0-47.8) categorical programs and attended 12.0 (IQR 10.0-16.0) interviews. The cost per interview was $282 (IQR $192-$407). The total expenditures for preparing for residency were $4992 (IQR $3034-$8,274). These numbers varied significantly by intended specialty. Differences were noted between our data and those from both a regional and recent national cohort. CONCLUSIONS: The costs associated with applying for residency are relatively unknown and can be significant for some. Institutionally led efforts may allow students to more appropriately plan and budget for The Match. Other institutions may benefit from a similar program.

Fundamental Curriculum Change with 1-Year Pre-Clerkship Phase and Effect on Stress Associated with Residency Specialty Selection.

Vanderbilt University School of Medicine recently changed from 2 pre-clerkship years (Traditional curriculum) to a 1.5-year pre-clerkship phase for one class (Hybrid curriculum) to a 1-year pre-clerkship phase (Curriculum 2.0). This study investigated the relationship between shortened pre-clerkship training and stress associated with selecting a residency field. The surveyed graduating medical student population included one cohort from the Traditional and Hybrid curricula, and the first two cohorts from Curriculum 2.0. The authors modeled recollected stress levels using a Zero-Inflated Linear Mixed Model with additional covariate and random effects adjustments. Specialty decision-related stress levels increased in the Hybrid curriculum by 10.208 points [p = 0.0115, 95% CI 2.293, 18.122] on a 0-100 point scale. Curriculum 2.0 students had an insignificant increase in stress of 4.062 points [p = 0.304, 95% CI - 3.690, 11.814] relative to the Traditional curriculum. Time since starting medical school and time when a specialty was chosen were the largest factors associated with stress. While this study only evaluated a single facet of the potential downstream effects of curricular change, these data should inspire confidence for reform efforts as a significant increase in specialty decision-related stress present in Hybrid curriculum resolved in both cohorts of Curriculum 2.0.