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.

Oral combined hydrochlorothiazide and lisinopril vs nifedipine for postpartum hypertension: a comparative-effectiveness pilot randomized controlled trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors and diuretics may be underutilized for postpartum hypertension because of their teratogenicity during pregnancy. OBJECTIVE: We evaluated whether combined oral hydrochlorothiazide and lisinopril therapy produced superior short-term blood pressure control when compared with nifedipine among postpartum individuals with hypertension requiring pharmacologic treatment. STUDY DESIGN: We performed a pilot randomized controlled trial (October 2021 to June 2022) that included individuals with chronic hypertension or hypertensive disorders of pregnancy with 2 systolic blood pressure measurements ≥150 mm Hg and/or diastolic blood pressure measurements ≥100 mm Hg within 72 hours after delivery. Participants were randomized to receive either combined hydrochlorothiazide and lisinopril therapy or nifedipine therapy after stratifying the participants by diagnosis (chronic hypertension vs hypertensive disorders of pregnancy). The primary outcome was stage 2 hypertension (systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg) determined using a home blood pressure monitor on days 7 to 10 after delivery or at readmission to the hospital for blood pressure control. The secondary outcomes included severe maternal morbidity (any of the following: intensive care unit admission; hemolysis, elevated liver enzymes, low platelet count syndrome; eclampsia; stroke; cardiomyopathy; or maternal death), need for intravenous medications after randomization, hospital length of stay, blood pressure during first clinic visit, medication compliance, and adverse events. A pilot trial with 70 individuals was planned given the limited available data on combined hydrochlorothiazide and lisinopril therapy use in postpartum care. We calculated relative risks and 95% credible intervals in an intention-to-treat analysis. Finally, we conducted a preplanned Bayesian analysis to estimate the probability of benefit or harm with a neutral informative prior. RESULTS: Of 111 eligible individuals, 70 (63%) agreed and were randomized (31 in the hydrochlorothiazide and lisinopril group and 36 in the nifedipine group; 3 withdrew consent after randomization), and the characteristics were similar at baseline between the groups. The primary outcome was unavailable for 9 (12.8%) participants. The primary outcome occurred in 27% of participants in the hydrochlorothiazide and lisinopril group and in 43% of the participants in the nifedipine group (posterior adjusted relative risk, 0.74; 95% credible interval, 0.40-1.31). Bayesian analysis indicated an 85% posterior probability of a reduction in the primary outcome with combined hydrochlorothiazide and lisinopril therapy relative to nifedipine treatment. No differences were noted in the secondary outcomes or adverse medication events. CONCLUSION: The results of the pilot trial suggest a high probability that combined hydrochlorothiazide and lisinopril therapy produces superior short-term BP control when compared with nifedipine. These findings should be confirmed in a larger trial.

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.

Management of Hypertension in Children and Adolescents.

Hypertension in children and adolescents is becoming a greater problem in the developed world. Although traditionally thought of as usually secondary to renal, vascular, or endocrine causes, primary hypertension is becoming the most common form seen in childhood. This changing epidemiology is related to the recent obesity epidemic. The evaluation of high blood pressure in children is more involved than in adults and is aimed both at identifying secondary causes and to identify other co-morbidities of cardiovascular risk. Treatment of hypertension in childhood and adolescence is aimed at reducing cardiovascular risk. While there are a growing number of antihypertensive agents with FDA labeling for children, there remain far fewer options than for adults. This paper reviews the epidemiology, definitions, evaluations, and management of elevated blood pressure in children and adolescents.

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.

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.

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.

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.

N-of-1 Trials as a Decision Support Tool in Clinical Practice: A Protocol for a Systematic Literature Review and Narrative Synthesis.

The n-of-1 trial can utilized in clinical practice as a decision support tool, which may improve patient outcomes by providing both the patient and the clinician with objective evidence to inform personalized treatment decisions. As its use broadens, it will be important to study whether the added time and effort of an n-of-1 trial results in measurable improvements in important patient outcomes compared to usual clinical practice. Parallel-group randomized clinical trials testing the n-of-1 approach versus usual care have been undertaken in a number of medical settings. A systematic review will be performed according to PRISMA guidelines, using MEDLINE, Embase, Cochrane, CINAHL, PsycINFO, Scopus, and Web of Science to search for randomized clinical trials in humans, without date or language restriction. Reports from the gray literature and ongoing studies in trial registries will be included. Articles will be screened by two independent reviewers with a third reviewer consulted to adjudicate disagreement. The quality of included studies will be assessed using the Cochrane Collaboration's tool for assessing risk of bias. A narrative synthesis will explore the differing methodological approaches of the included studies. The protocol will be registered in the PROSPERO registry, and the results of the review will be published in a peer-reviewed journal. To our knowledge, this systematic review will be the first to comprehensively assess the existing research on randomized trials testing the n-of-1 trial approach in clinical practice.

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.

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.

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.

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.

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.

Cefepime-induced neurotoxicity in a pediatric patient on chronic hemodialysis: a case report.

Impaired renal function increases the risk for cefepime-induced neurotoxicity. Symptoms include disorientation, myoclonus, status epilepticus, ataxia, gait disturbance, coma, and death. A high index of suspicion and early recognition of symptoms can minimize the risk of progression of symptoms to permanent neurologic impairment or death.

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.

Is one measurement enough to evaluate blood pressure among adolescents? A blood pressure screening experience in more than 9000 children with a subset comparison of auscultatory to mercury measurements.

Evaluation of blood pressure is recommended in all children older than 3 years. Auscultatory devices are the recommended method to assess blood pressure in pediatrics, but automated oscillometric devices are increasingly common. A retrospective analysis of our school-based blood pressure screening was performed to determine if multiple oscillometric blood pressure measurements are needed to approach true blood pressure. All children had 4 oscillometric measurements of blood pressures and a random subset of 287 had an additional auscultatory measurement. Among 9870 participants, we observed a nonlinear decrease in blood pressure over time. The largest decrease in systolic blood pressure was between first and second (-3.8 mm Hg) and in diastolic from second to third (-3.3 mm Hg) measurement. For systolic blood pressure, the second oscillometric measurement, the average of second to third and the average of first to third were statistically similar to a single auscultatory measurement. We conclude that assessment of blood pressure using oscillometric devices should include at least 3 measurements in the same sitting to avoid inaccurate assessment.

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.