Prevalence of and Factors Associated with Financial Toxicity After Pancreatectomy and Gastrectomy.

BACKGROUND: Financial toxicity (FT) refers to the adverse impact of cancer treatment costs on patients' experiences, potentially leading to poor adherence to treatment and outcomes. However, the prevalence of FT among patients undergoing major upper gastrointestinal cancer operations, as well as factors associated with FT, remain unclear. METHODS: We conducted a cross-sectional study by sending the Comprehensive Score for financial Toxicity (COST) survey and Surgery-Q (a survey specifically developed for this study) to patients who underwent gastrectomy or pancreatectomy for malignant disease at our institution in 2019-2021. RESULTS: We sent the surveys to 627 patients and received responses from 101 (16%) patients. The FT prevalence (COST score <26) was 48 (48%). Patients likely to experience FT were younger than 50 years of age, of non-White race, earned an annual income <$75,000, and had credit scores <740 (all p < 0.05). Additionally, longer hospital stay (p = 0.041), extended time off work for surgery (p = 0.011), and extended time off work for caregivers (p = 0.005) were associated with FT. Procedure type was not associated with FT; however, patients who underwent minimally invasive surgery (MIS) had a lower FT probability (p = 0.042). In a multivariable analysis, age <50 years (p = 0.031) and credit score <740 (p < 0.001) were associated with high FT risk, while MIS was associated with low FT risk (p = 0.024). CONCLUSIONS: Patients with upper gastrointestinal cancer have a major risk of FT. In addition to predicting the FT risk before surgery, facilitating quicker functional recovery with the appropriate use of MIS is considered important to reducing the FT risk.

N-of-1 trials: The epitome of personalized medicine?

Observational studies are notoriously susceptible to bias, and parallel-group randomized trials are important to identify the best overall treatment for eligible patients. Yet, such trials can be expected to be a misleading indicator of the best treatment for some subgroups or individual patients. In selected circumstances, patients can be treated in n-of-1 trials to address the inherent heterogeneity of treatment response in clinical populations. Such trials help to accomplish the ultimate goal of all biomedical research, to optimize the care of individual patients.

Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity.

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data. METHODS: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients. RESULTS: With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long-term survival. CONCLUSIONS: These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.

N-of-1 Trials vs. Usual Care in Children With Hypertension: A Pilot Randomized Clinical Trial.

BACKGROUND: Blood pressure (BP) is often inadequately controlled in children treated for hypertension, and personalized (n-of-1) trials show promise for tailoring treatment choices. We assessed whether patients whose treatment choices are informed by an n-of-1 trial have improved BP control compared to usual care. METHODS: A randomized clinical trial was conducted in a pediatric hypertension clinic in Houston from April 2018 to September 2020. Hypertensive adolescents and young adults 10-22 years old were randomized 1:1 to a strategy of n-of-1 trial using ambulatory BP monitoring to inform treatment choice or usual care, with treatment selected by physician preference. The primary outcome was the proportion of patients with ambulatory BP control at 6 months in a Bayesian analysis. RESULTS: Among 49 participants (23 randomized to n-of-1 trials and 26 to usual care), mean age was 15.6 years. Using skeptical priors, we found a 69% probability that n-of-1 trials increased BP control at 6 months (Bayesian odds ratio (OR) 1.24 (95% credible interval (CrI) 0.51, 2.97), and 74% probability using neutral informed priors (OR 1.45 (95% CrI 0.48, 4.53)). Systolic BP was reduced in both groups, with a 93% probability of greater reduction in the n-of-1 trial group (mean difference between groups = -3.6 mm Hg (95% CrI -8.3, 1.28). There was no significant difference in side effect experience or caregiver satisfaction. CONCLUSIONS: Among hypertensive adolescents and young adults, n-of-1 trials with ambulatory BP monitoring likely increased the probability of BP control. A large trial is needed to assess their use in clinical practice. CLINICALTRIALS.GOV: NCT03461003. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; NCT03461003.

Antihypertensives in Children and Adolescents.

PURPOSE OF REVIEW: To review target organ outcomes and current pharmacologic treatment options for children and adolescents with hypertension. RECENT FINDINGS: There is an increased prevalence of pediatric hypertension. Following the 2017 AAP clinical practice guidelines, there is a growing body of literature illustrating the association between pediatric hypertension and end organ damage, though few studies looking at long-term outcomes. There is also new data to support the use of n-of-1 trials to identify the best antihypertensive therapy for an individual. Pediatric hypertension is increasing in prevalence and is associated with end organ damage. Treatment of hypertensive children has been shown to reverse end organ damage. Due to the lack of large, randomized trials assessing antihypertensive classes against one another, n-of-1 studies may serve as a viable and safe option to optimize patient care.

A scoping review of randomized trials assessing the impact of n-of-1 trials on clinical outcomes.

BACKGROUND: The single patient (n-of-1) trial can be used to resolve therapeutic uncertainty for the individual patient. Treatment alternatives are systematically tested against each other, generating patient-specific data used to inform an individualized treatment plan. We hypothesize that clinical decisions informed by n-of-1 trials improve patient outcomes compared to usual care. Our objective was to provide an overview of the clinical trial evidence on the effect of n-of-1 trials on clinical outcomes. METHODS: A systematic search of medical databases, trial registries, and gray literature was performed to identify trials assessing clinical outcomes in a group of patients undergoing an n-of-1 trial compared to those receiving usual care for any clinical condition. We abstracted elements related to study design and results and assessed risk of bias for both the overall randomized trials and the n-of-1 trials. The review was registered on PROSPERO. (CRD: 42020166490). FINDINGS: Twelve randomized trials of the n-of-1 approach were identified in conditions spanning chronic pain, osteoarthritis, chronic irreversible airflow limitation, attention-deficit hyperactivity disorder, hyperlipidemia, atrial fibrillation, statin intolerance, and hypertension. One trial showed a statistically significant benefit in the primary outcome. Only one reached the pre-specified sample size target. Secondary outcomes showed modest benefits, including decreasing medication use, fewer atrial fibrillation episodes, and improved patient satisfaction. INTERPRETATION: Very few trials have been undertaken to assess the effectiveness of n-of-1 trials in improving clinical outcomes, and most trials were underpowered for the primary outcome. Barriers to enrollment and retention in these trials should be explored, as well-powered randomized trials are needed to clarify the clinical impact of n-of-1 trials and assess their utility in clinical practice.

Personalized Trial Ethics and Institutional Review Board Submissions.

The ethical and regulatory oversight of any clinical activity related to human subjects is commonly determined based on its categorization as either clinical practice or research. Prominent bioethicists have criticized the traditional distinctions used to delineate these categories, calling them counterproductive and outmoded, and arguing that learning and clinical practice should be deliberately and appropriately integrated. Personalized trials represent a clinical activity with characteristics that overlap both categories, making ethical and regulatory oversight requirements less straightforward. When the primary intent of the personalized trial is to assist in the conduct of individualized patient care with an emphasis on protecting the clinical decision from the biases inherent in usual clinical practice, how should this activity be regulated? In this article, we will explore the ethical underpinnings of personalized trials and propose various approaches to meeting regulatory requirements. Instead of imposing standard research regulations on the conduct of all personalized trials, we recommend that personalized trialists and IRB panels should consider whether participation in a personalized trial results in any foreseeable incremental increase in risk to the participant compared with usual care. This approach may reduce regulatory barriers, which could promote more widespread uptake of personalized trials.

Treating Hypertension in Children With n-of-1 Trials.

OBJECTIVES: Clinicians prescribe antihypertensive medication to children with primary hypertension, but without data to define a particular choice as first-line therapy. A one-size-fits-all approach may not be appropriate for these patients. Our aim was to develop a personalized approach to hypertension treatment, using repeated ambulatory blood pressure monitoring (ABPM) in n-of-1 trials (single-patient randomized crossover trials). METHODS: Children undergoing hypertension management at a single pediatric referral center were offered participation in an n-of-1 trial with repeated ABPM to compare 3 commonly used medications. The medication producing the greatest blood pressure reduction, and without unacceptable side effects, was selected as the preferred therapy for the individual. RESULTS: Forty-two children agreed to participate; 7 were normotensive without medication; and 3 failed to complete one treatment cycle. Of the remaining 32 patients, lisinopril was preferred for 16, amlodipine for 8, hydrochlorothiazide for 4, and 4 had uncontrolled blood pressure on maximum doses of monotherapy. In conservative Bayesian analyses, the proportion of patients who preferred lisinopril was 49% (95% credible interval [CrI]: 32% to 69%), 24% (95% CrI: 12% to 41%) preferred amlodipine, and 12% (95% CrI: 4% to 26%) preferred hydrochlorothiazide. The preferred therapy for the majority (67%) of African American participants was lisinopril. Unacceptable side effects were reported in 24% of assessments for hydrochlorothiazide, 16% for lisinopril, and 13% for amlodipine. CONCLUSIONS: No single medication was preferred for more than half of hypertensive children. n of-1 trials with repeated ABPM may promote better informed and individualized decisions in pediatric hypertension management.

Prevalence of Hypertension in Children.

In 2017, the American Academy of Pediatrics issued a new clinical practice guideline for defining hypertension in children as an update to the previous Fourth Report guidelines issued in 2004. Prevalence of confirmed pediatric hypertension in children has ranged from 2% to 4% based on previous guidelines yet it is unknown what the prevalence is under the new guideline. We estimated the prevalence of elevated blood pressure, stage 1, and stage 2 hypertension by the new American Academy of Pediatrics guideline in our school-based blood pressure screening program. New prevalence estimates were compared with Fourth Report prevalence estimates in the same population by sex, age, and height factors. In 22 224 students aged 10 to 17 years screened in school as part of the Houston Pediatric and Hypertension Program at the University of Texas McGovern Medical School, the prevalence of elevated blood pressure (previously called prehypertension) increased from 14.8% by Fourth Report to 16.3% by the new American Academy of Pediatrics guideline. This increase in elevated blood pressure resulted from differential classification changes in younger and older children. Prevalence of confirmed hypertension remains at 2% to 4% in this population, however shorter children <13 years old and taller, older children 13+ years old are systematically more likely to be diagnosed with hypertension by new guidelines.

Varying blood pressure in children: a diagnostic quandary interpreting the Fourth Report.

Fourth Report guidelines on pediatric blood pressure (BP) are not clear when defining hypertension in children as "an average systolic BP and/or diastolic BP ≥ 95th percentile for gender, age, and height on ≥ 3 occasions." We aimed to determine the prevalence of pediatric hypertension in a screening population based on two different guideline interpretations. Prevalence of hypertension among 2094 students at four Houston area schools was calculated based on the summation or sustained model definition from Fourth Report guidelines. Summation hypertension definition required the single average of the BPs recorded across three visits to be elevated. Sustained hypertension definition required BP at each of three visits to be elevated. Hypertension prevalence by the summation method was 7%, whereas sustained prevalence was only 3.3%. Nearly a quarter of students had varying BP and were not classifiable by the sustained method but most would be classified as normal or prehypertensive by the summation method. The prevalence of hypertension among adolescents doubled depending on the interpretation of Fourth Report guidelines. Although methods in research studies can be clearly examined on publication of results, it is unknown which interpretation method is being used in clinical practice.

Office blood pressure measurement alone often misclassifies treatment status in children with primary hypertension.

OBJECTIVE: Clinicians frequently rely on office blood pressure (BP) measurements alone to assess hypertension control, despite widespread acceptance of 24-h ambulatory blood pressure monitoring (ABPM) as the reference standard in the initial diagnosis of hypertension. This study was designed to investigate how often the hypertensive status differed between concurrent office BP versus ABPM measurements, and whether any patient-specific characteristics predict the risk for misclassification by office BP. PARTICIPANTS AND METHODS: This study evaluated 42 children with primary hypertension who underwent repeated ambulatory monitoring (190 total recordings) with concurrent office BP measurement as part of their participation in n-of-1 trials. RESULTS: In nearly 40% of the visits, the treatment status by office measurement was opposite to the status by ambulatory monitoring. Office BP underestimated the ambulatory hypertensive status (masked uncontrolled hypertension) in 25% of visits and overestimated ambulatory BP (white coat effect) in 14% of visits. The difference between office BP and ambulatory monitoring was consistent within patients across repeated visits. Patients whose office measurement underestimated or overestimated the ambulatory BP at the first visit were more likely to show persistent discrepancy at subsequent visits. CONCLUSION: The underuse of ambulatory monitoring in management decisions of children treated for primary hypertension may result in systematic misclassification of hypertension control.

Race and Obesity in Adolescent Hypertension.

BACKGROUND AND OBJECTIVES: The overall prevalence of essential hypertension in adolescents may be growing. Differences in blood pressure (BP) are well established in adults, but are less clear in adolescents. We hypothesize that the prevalence of hypertension differs by race/ethnicity among adolescents at school-based screenings. METHODS: We performed school-based BP screening in over 20 000 adolescents from 2000 to 2015. Race/ethnicity was self-reported. Height and weight were measured to determine BMI, and BP status was confirmed on 3 occasions to diagnose sustained hypertension according to Fourth Working Group Report criteria. RESULTS: We successfully screened 21 062 adolescents aged 10 to 19 years (mean, 13.8 years). The final prevalence of sustained hypertension in all subjects was 2.7%. Obesity rates were highest among African American (3.1%) and Hispanic (2.7%) adolescents. The highest rate of hypertension was seen in Hispanic (3.1%), followed by African American (2.7%), white (2.6%), and Asian (1.7%) adolescents (P = .019). However, obese white adolescents had the highest prevalence of sustained hypertension (7.4%) compared with obese African American adolescents (4.5%, P < .001). At lower BMI percentiles (<60th percentile), Hispanic adolescents actually had the lowest predicted prevalence of hypertension among the 4 groups. CONCLUSIONS: The prevalence of hypertension varies among different race/ethnicities. Although obesity remains the strongest predictor of early hypertension, the strength of this relationship is intensified in Hispanic and white adolescents, whereas it is lessened in African American adolescents.

Randomized n-of-1 Trials: Quality Improvement, Research, or Both?

The regulatory demarcations between clinical research and quality improvement (QI) are ambiguous and controversial. Some projects that were undertaken as a form of QI were deemed by regulatory agencies to be research and thus to require institutional review board approval. In the era of personalized medicine, some physicians may ask some patients to participate in n-of-1 trials in an effort to personalize and optimize each patient's medical treatment. Should such activities be considered research, QI, or just excellent personalized medicine? Experts in research, research regulation, and bioethics analyze these issues.

Comparative effectiveness of antihypertensive treatment for older children with primary hypertension: study protocol for a series of n-of-1 randomized trials.

BACKGROUND: Children are increasingly being diagnosed with primary hypertension. The absence of comparative effectiveness research of antihypertensive medications in children has contributed to considerable differences in prescribing practices among physicians treating children with primary hypertension. Even if parallel-group trials had established a best overall choice for most of these children, the best medication for an individual may differ from the best overall medication. METHODS/DESIGN: This project consists of a series of systematically administered n-of-1 trials among older children to verify the need for ongoing antihypertensive treatment and, if so, to identify the preferred single drug therapy from among the three major classes of drugs commonly used for primary hypertension (angiotensin-converting enzyme inhibitors, calcium channel blockers, and diuretics). We will determine whether one of these is the preferred therapy for the great majority of patients. The "preferred" therapy is the drug which produces normal ambulatory blood pressure, with the greatest reduction in blood pressure without unacceptable side effects. We will recruit 50 patients from the Houston Pediatric and Adolescent Hypertension Program clinic. For each patient, the three drugs will be prescribed in random order and each drug will be taken for 2 weeks. The effectiveness of each therapy will be measured with 24-h ambulatory blood pressure monitoring, and tolerability will be assessed using a side effect questionnaire. Participants will rotate through treatment periods, repeating drugs and adjusting doses until the preferred therapy is identified. In assessing whether one of the medications is most effective for the majority of subjects, the primary outcome will be the percentage of participants for whom each drug is selected as the preferred therapy. We hypothesize that no drug will be selected for the great majority of the subjects, a finding that would support consideration of clinical use of n-of-1 trials. Secondary analyses will explore whether patient characteristics predict which medication will be selected as a preferred drug. DISCUSSION: This study will help optimize care of participating patients and provide evidence regarding the usefulness of n-of-1 trials in identifying appropriate treatment for children with hypertension and potentially other disorders. TRIAL REGISTRATION: Clinicaltrials.gov NCT02412761 (registered 4/8/2015).

Unique Study Designs in Nephrology: N-of-1 Trials and Other Designs.

Alternatives to the traditional parallel-group trial design may be required to answer clinical questions in special populations, rare conditions, or with limited resources. N-of-1 trials are a unique trial design which can inform personalized evidence-based decisions for the patient when data from traditional clinical trials are lacking or not generalizable. A concise overview of factorial design, cluster randomization, adaptive designs, crossover studies, and n-of-1 trials will be provided along with pertinent examples in nephrology. The indication for analysis strategies such as equivalence and noninferiority trials will be discussed, as well as analytic pitfalls.

Inpatient health care utilization in the United States among children, adolescents, and young adults with nephrotic syndrome.

BACKGROUND: Data describing inpatient health care utilization in children with nephrotic syndrome and related severe complications are limited. Our goals were to describe the charges, length of stay (LOS), and number of hospitalizations among children, adolescents, and young adults with nephrotic syndrome. STUDY DESIGN: A cross-sectional analysis of the Kids' Inpatient Database (KID) database from the Healthcare Cost and Utilization Project (HCUP). The HCUP-KID is an all-payer database of hospital discharges for children, adolescents, and young adults in the United States compiled every 3 years by the Agency for Healthcare Research and Quality. SETTING & PARTICIPANTS: HCUP-KID data were obtained for the 2006 and 2009 cohort years. We identified patients by searching discharges for nephrotic syndrome International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. PREDICTOR: Patient demographics, disease complications in children, adolescents, and young adults hospitalized with nephrotic syndrome. OUTCOME: Number of hospitalizations, mean charges, and LOS for children, adolescents, and young adults hospitalized with nephrotic syndrome. RESULTS: There were 6,308 hospitalization discharges in children, adolescents, and young adults with a primary or secondary diagnosis of nephrotic syndrome reported by 38 and 44 states in 2006 and 2009, respectively, representing an estimated 9,934 discharges nationally. Nephrotic syndrome resulted in an estimated 48,700 inpatient days and charges totaling $259 million. The mean charge per hospitalization was ∼$26,500 (SE, $1,100) and LOS was 5 days (SE, 0.1). 16% of discharges for nephrotic syndrome had a diagnosis code for at least one severe complication, including thromboembolism (3.6%), septicemia (3.8%), peritonitis (2.6%), pneumonia (5.4%), or diabetes (2.4%). Multivariable analysis showed age 15 years or older, race, higher socioeconomic status, acute renal failure, thromboembolic disease, hypertension, and infections predicted higher mean hospitalization charges. LIMITATIONS: The HCUP-KID database collects data on a hospitalization level. Consequently, health care utilization on an individual patient level or in the outpatient environment is not possible. CONCLUSIONS: We present a comprehensive description of inpatient health care utilization in children, adolescents, and young adults with nephrotic syndrome. The complications of nephrotic syndrome, including thromboembolism, infection, and hypertension, contribute significantly to these charges.

Long-term outcome of renal transplantation patients with Henoch-Schonlein purpura.

BACKGROUND AND OBJECTIVES: Although Henoch-Schönlein purpura (HSP) is the most common form of renal vasculitis in childhood, progression to ESRD is rare, and there are few data on outcomes of renal transplantation in patients with HSP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a matched retrospective cohort study of renal allografts using the United Network of Organ Sharing database (1987 to 2005). Of the 189,211 primary renal allografts, there were 339 with a diagnosis of HSP. The primary end point was allograft survival. RESULTS: Compared with the remainder of the database, the HSP population was younger (25 years versus 46 years), and had a higher proportion of women (47% versus 40%), live donors (50% versus 35%), and Caucasians (77% versus 60%). Controlling for age, gender, donor source, ethnicity, and year of transplantation, death-censored graft survival for patients with HSP was 80.0% at 5 years and 58.8% at 10 years compared with 79.0% at 5 years and 55.4% at 10 years in the non-HSP population. Among patients with reported causes of graft loss, failure from recurrent disease occurred in 13.6% of patients with HSP, compared with 6.6% in the non-HSP population. When analyzing allograft survival in recipients with HSP compared with those with IgA nephropathy, there was no difference in 10-year allograft survival (58.4% and 59.3%, respectively). CONCLUSIONS: These data indicate that although there is an increased risk of graft failure attributable to recurrent disease in patients with HSP, a diagnosis of HSP has little effect on overall renal allograft survival.