Projected impact of anti-obesity pharmacotherapy use on racial and ethnic disparities in adolescent obesity.

BACKGROUND: Paediatric obesity disproportionately impacts individuals from minoritized racial and ethnic backgrounds. Recent guidelines support use of anti-obesity pharmacotherapy for adolescents with obesity, but the potential impact on disparities in obesity prevalence has not been evaluated. OBJECTIVES: To model changes in obesity prevalence with increasing utilization of anti-obesity pharmacotherapy among adolescents. METHODS: Data representative of American adolescents ages 12-17 years were obtained from the National Health and Nutrition Examination Survey, cycles 2011 through pre-pandemic 2020. A body mass index (BMI) reduction of 16.7% was applied to each participant based on clinical trial results of weekly subcutaneous semaglutide 2.4 mg among adolescents. Utilization disparities were based on utilization of the same medication class among adults. Obesity prevalence was calculated assuming utilization of 10%-100%, stratified by race and ethnicity. RESULTS: Among 4442 adolescents representing 26 247 384 American adolescents, projected overall obesity prevalence decreased from 22.2% to 8.4% with 100% utilization. However, disparities increased relative to Non-Hispanic White youth, with prevalence among Non-Hispanic Black and Mexican American youth ranging from 40%-60% higher to 90%-120% higher, respectively. CONCLUSIONS: Increasing utilization of anti-obesity pharmacotherapy may widen relative disparities in obesity, particularly if utilization is unequal. Advocacy for equitable access is needed to minimize worsening of obesity-related disparities.

A Multisite Retrospective Review of Direct Oral Anticoagulants Compared to Warfarin in Adult Fontan Patients.

PURPOSE: Direct oral anticoagulants (DOACs) are not recommended in adult Fontan patients (Level of Evidence C). We hypothesized that DOACs are comparable to warfarin and do not increase thrombotic and embolic complications (TEs) or clinically significant bleeds. METHODS: We reviewed the medical records of adult Fontan patients on DOACs or warfarin at three major medical centers. We identified 130 patients: 48 on DOACs and 107 on warfarin. In total, they were treated for 810 months on DOACs and 5637 months on warfarin. RESULTS: The incidence of TEs in patients on DOACs compared to those on warfarin was not increased in a statistically significant way (hazard ratio [HR] 1.7 and p value 0.431). Similarly, the incidence of nonmajor and major bleeds in patients on DOACs compared to those on warfarin was also not increased in a statistically significant way (HR for nonmajor bleeds in DOAC patients was 2.8 with a p value of 0.167 and the HR for major bleeds was 2.0 with a p value 0.267). In multivariate analysis, congestive heart failure (CHF) was a risk factor for TEs across both groups (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.3-17.6) and bleed history was a risk factor for clinically significant bleeds (OR = 6.8, 95% CI = 2.7-17.2). CONCLUSION: In this small, retrospective multicenter study, the use of DOACs did not increase the risk of TEs or clinically significant bleeds compared to warfarin in a statistically significant way.

ROBOTIC PARAGANGLIOMA RESECTION IN A PREGNANT PATIENT.

OBJECTIVE: Functional paragangliomas in pregnancy are rare; however, if not recognized and treated early, they can be life-threatening. New treatment approaches with robotic resection are promising. METHODS: We present a case of a pregnant female with a paraganglioma which was successfully resected during the second trimester using Da Vinci Xi robotic system. Paraganglioma was diagnosed with plasma and urinary catecholamines and metanephrines, a contrast computed tomography (CT) scan, and confirmed with surgical pathology. RESULTS: The patient was initially seen in the emergency room prior to the index pregnancy for nausea, vomiting, and intermittent, left lower quadrant abdominal pain, episodic sweating, palpitations, and anxiety. CT scan of the abdomen and pelvis showed a 4.8 × 4.3 cm heterogeneously enhancing mass in the left retroperitoneum adjacent to the aorta just below the left adrenal gland. She had normal plasma metanephrines but elevated plasma normetanephrines of 7.12 nmol/L (normal, <0.89 nmol/L). Twenty-four-hour urine norepinephrine and catecholamines were elevated to 604 µg (normal, <90 µg/24 hours) and 610 µg (normal, <115 µg/24 hours), respectively. Chromogranin A was elevated to 940 ng/mL (normal, 0 to 95 ng/mL). Paraganglioma was suspected. Doxazosin was started for blood pressure control. The patient became pregnant unexpectedly shortly after. She was managed by a multidisciplinary team. At 18 weeks of pregnancy, she underwent a transabdominal robotic resection of the left retroperitoneal paraganglioma with an excellent outcome. CONCLUSION: Functional paragangliomas in pregnancy are rare but must be recognized and treated early to reduce maternal and fetal complications. An innovative robotic approach should be considered and explored.

Hospitalization for Lactic Acidosis Among Patients With Reduced Kidney Function Treated With Metformin or Sulfonylureas.

OBJECTIVE: To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function. RESEARCH DESIGN AND METHODS: This retrospective cohort combined data from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylureas were followed from development of reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or serum creatinine ≥1.4 mg/dL [female] or 1.5 mg/dL [male]) through hospitalization for lactic acidosis, death, loss to follow-up, or study end. Lactic acidosis hospitalization was defined as a composite of primary discharge diagnosis or laboratory-confirmed lactic acidosis (lactic acid ≥2.5 mmol/L and either arterial blood pH <7.35 or serum bicarbonate ≤19 mmol/L within 24 h of admission). We report the cause-specific hazard of lactic acidosis hospitalization between metformin and sulfonylureas from a propensity score-matched weighted cohort and conduct an additional competing risks analysis to account for treatment change and death. RESULTS: The weighted cohort included 24,542 metformin users and 24,662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8 mL/min/1.73 m2). There were 4.18 (95% CI 3.63, 4.81) vs. 3.69 (3.19, 4.27) lactic acidosis hospitalizations per 1,000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio [aHR] 1.21 [95% CI 0.99, 1.50]). Results were consistent for both primary discharge diagnosis (aHR 1.11 [0.87, 1.44]) and laboratory-confirmed lactic acidosis (1.25 [0.92, 1.70]). CONCLUSIONS: Among veterans with diabetes who developed reduced kidney function, occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those patients who continued sulfonylureas.

Respiratory syncytial virus hospitalisation trends in children with haemodynamically significant heart disease, 1997-2012.

OBJECTIVE: The aim of the study was to evaluate the trends in respiratory syncytial virus-related hospitalisations and associated outcomes in children with haemodynamically significant heart disease in the United States of America. Study design The Kids' Inpatient Databases (1997-2012) were used to estimate the incidence of respiratory syncytial virus hospitalisation among children ⩽24 months with or without haemodynamically significant heart disease. Weighted multivariable logistic regression and chi-square tests were used to evaluate the trends over time and factors associated with hospitalisation, comparing eras before and after publication of the 2003 American Academy of Pediatrics palivizumab immunoprophylaxis guidelines. Secondary outcomes included in-hospital mortality, morbidity, length of stay, and cost. RESULTS: Overall, 549,265 respiratory syncytial virus-related hospitalisations were evaluated, including 2518 (0.5%) in children with haemodynamically significant heart disease. The incidence of respiratory syncytial virus hospitalisation in children with haemodynamically significant heart disease decreased by 36% when comparing pre- and post-palivizumab guideline eras versus an 8% decline in children without haemodynamically significant heart disease (p<0.001). Children with haemodynamically significant heart disease had higher rates of respiratory syncytial virus-associated mortality (4.9 versus 0.1%, p<0.001) and morbidity (31.5 versus 3.5%, p<0.001) and longer hospital length of stay (17.9 versus 3.9 days, p<0.001) compared with children without haemodynamically significant heart disease. The mean cost of respiratory syncytial virus hospitalisation in 2009 was $58,166 (95% CI:$46,017, $70,315). CONCLUSIONS: These data provide stakeholders with a means to evaluate the cost-utility of various immunoprophylaxis strategies.

Post-market surveillance to detect adverse events associated with Melody® valve implantation.

OBJECTIVE: The aim of this study was to describe previously unrecognised or under-recognised adverse events associated with Melody® valve implantation. BACKGROUND: In rare diseases and conditions, it is typically not feasible to conduct large-scale safety trials before drug or device approval. Therefore, post-market surveillance mechanisms are necessary to detect rare but potentially serious adverse events. METHODS: We reviewed the United States Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database and conducted a structured literature review to evaluate adverse events associated with on- and off-label Melody® valve implantation. Adverse events were compared with those described in the prospective Investigational Device Exemption and Post-Market Approval Melody® transcatheter pulmonary valve trials. RESULTS: We identified 631 adverse events associated with "on-label" Melody® valve implants and 84 adverse events associated with "off-label" implants. The most frequent "on-label" adverse events were similar to those described in the prospective trials including stent fracture (n=210) and endocarditis (n=104). Previously unrecognised or under-recognised adverse events included stent fragment embolisation (n=5), device erosion (n=4), immediate post-implant severe valvar insufficiency (n=2), and late coronary compression (n=2 cases at 5 days and 3 months after implantation). Under-recognised adverse events associated with off-label implantation included early valve failure due to insufficiency when implanted in the tricuspid position (n=7) and embolisation with percutaneous implantation in the mitral position (n=5). CONCLUSION: Post-market passive surveillance does not demonstrate a high frequency of previously unrecognised serious adverse events with "on-label" Melody® valve implantation. Further study is needed to evaluate safety of "off-label" uses.

Congenital Heart Disease in Premature Infants 25-32 Weeks' Gestational Age.

OBJECTIVE: To determine the birth prevalence of congenital heart defects (CHDs) across the spectrum of common defects in very/extremely premature infants and to compare mortality rates between premature infants with and without CHDs. STUDY DESIGN: The Kids' Inpatient Databases (2003-2012) were used to estimate the birth prevalence of CHDs (excluding patent ductus arteriosus) in very/extremely premature infants born between 25 and 32 weeks' gestational age. Birth prevalence was compared with term infants for a subset of "severe" defects expected to be near universally diagnosed in the neonatal period. Weighted multivariable logistic regression was used to calculate aORs of mortality comparing very and extremely premature infants with vs without CHDs. RESULTS: We identified 249 011 very/extremely premature infants, including 28 806 with CHDs. The overall birth prevalence of CHDs was 116 per 1000 very/extremely premature births. Severe CHDs had significantly higher birth prevalence in very/extremely premature infants when compared with term infants (7.4 per 1000 very/premature births vs 1.5 per 1000 term births; P < .001). Very/extremely premature infants with severe CHDs had an overall 26.3% in-hospital mortality and a 7.5-fold increased adjusted odds of death compared with those without CHDs. Mortality varied widely by defect in very/extremely premature infants, ranging from 12% for interrupted aortic arch to 67% for truncus arteriosus. CONCLUSIONS: Given the increased birth prevalence of severe CHDs in very/extremely premature infants, and significantly higher mortality, there is justification for intensive interventions aimed at decreasing the likelihood of premature delivery for patients where CHD is diagnosed in utero.

Systematic Review of the Impact of Transition Interventions for Adolescents With Chronic Illness on Transfer From Pediatric to Adult Healthcare.

Transfer from pediatric to adult care is a critical component of a high-quality transition experience for adolescents and young adults (AYA) with chronic illness. To examine the current evidence regarding the effect of transition interventions on care transfer, we performed a systematic review of studies that evaluated the effect of transition interventions on the specific health services outcome of transfer. The Medline, CINAHL, and PsycINFO databases were searched for studies that evaluated 1) a discrete transition intervention for AYA, 2) included a comparison group, and 3) reported on the outcome of transfer from pediatric to adult healthcare. References were screened and reviewed separately by authors, and relevant study details were abstracted during the review process. Five studies from five different countries were included in the final analysis. All five studies were conducted in specialty care clinics, with three interventions involving a nurse practitioner or systems navigator and two interventions involving physicians. Four studies were retrospective observational studies, and one was a pilot randomized controlled trial. Three of the five studies found that the transition intervention was associated with increased rates of transfer while the other two showed no statistically significant effects. Overall, evaluation of transfer appears to be hindered by methodological challenges. Establishing clearer definitions and metrics of transfer and creating the infrastructure needed to monitor the transfer of patients more consistently are important goals.

Treatment of supraventricular tachycardia in infants: Analysis of a large multicenter database.

OBJECTIVE: Supraventricular tachycardia (SVT) is the most common arrhythmia in infants. Infants are typically treated with antiarrhythmic medications, but there is a lack of evidence guiding management, thus exposing infants to risks of both inadequate therapy and medication adverse events. We used data from a large clinical database to better understand current practices in SVT management, safety of commonly used medications, and outcomes of hospitalized infants treated for SVT. METHODS: This retrospective data analysis included all infants discharged from Pediatrix Medical Group neonatal intensive care units between 1998 and 2012 with a diagnosis of SVT who were treated with antiarrhythmic medications. We categorized infants by the presence of congenital heart disease other than patent ductus arteriosus. Medications were categorized as abortive, acute, or secondary prevention therapies. We used descriptive statistics to describe medication use, adverse events, and outcomes including SVT recurrence and mortality. RESULTS: A total of 2848 infants with SVT were identified, of whom 367 (13%) had congenital heart disease. Overall, SVT in-hospital recurrence was high (13%), and almost one fifth of our cohort (18%) experienced an adverse event. Mortality was 2% in the overall cohort and 6% in the congenital heart disease group (p<0.001). Adenosine was the most commonly used abortive therapy, but there was significant practice variation in therapies used for acute treatment and secondary prevention of SVT. CONCLUSION AND PRACTICE IMPLICATION: Significant variation in SVT treatment and suboptimal outcomes warrant future clinical trials to determine best practices in treating SVT in infants.

Comparative effectiveness of digoxin and propranolol for supraventricular tachycardia in infants.

OBJECTIVES: Supraventricular tachycardia is the most common arrhythmia in infants, and antiarrhythmic medications are frequently used for prophylaxis. The optimal prophylactic antiarrhythmic medication is unknown, and prior randomized trials have been underpowered. We used data from a large clinical registry to compare efficacy and safety of digoxin and propranolol for infant supraventricular tachycardia prophylaxis. We hypothesized that supraventricular tachycardia recurrence is less common on digoxin when compared with propranolol. DESIGN: Retrospective cohort study. SETTING: Pediatrix Medical Group neonatal ICUs. PATIENTS: Infants discharged from 1998 to 2012 with supraventricular tachycardia who were treated with digoxin or propranolol. We excluded infants discharged before completing 2 days of therapy, those with Wolff-Parkinson-White syndrome, structural heart defects (except atrial/ventricular septal defects and patent ductus arteriosus), and those started on multidrug therapy. MEASUREMENTS AND MAIN RESULTS: We used Cox proportional hazards to evaluate supraventricular tachycardia recurrence, defined as need for adenosine or electrical cardioversion while exposed to digoxin versus propranolol, controlling for infant characteristics, inotropic support, supplemental oxygen, and presence of a central line. We identified 342 infants exposed to digoxin and 142 infants exposed to propranolol. The incidence rate of treatment failure was 6.7/1,000 infant-days of exposure to digoxin and 15.4/1,000 infant-days of exposure to propranolol. On multivariable analysis, treatment failure was higher on propranolol when compared with that on digoxin (hazard ratio, 1.97; 95% CI, 1.05-3.71). Hypotension was more frequent during exposure to digoxin versus propranolol (39.4 vs 11.1/1,000 infant-days; p < 0.001). There was no difference in frequency of other clinical adverse events. CONCLUSIONS: Digoxin was associated with fewer episodes of supraventricular tachycardia recurrence but more frequent hypotension in hospitalized infants relative to propranolol.

Anti-hypertensive drugs in children and adolescents.

Worldwide the prevalence of essential hypertension in children and adolescents continues to increase. Traditionally providers have used "off-label" drugs to treat pediatric hypertension, meaning that rigorous clinical trials of these drugs have not been specifically performed in pediatric patient populations. Consequently providers have extrapolated dosing, safety and efficacy from trials in adults. This practice is sub-optimal as children demonstrate unique differences in drug metabolism and response. Use of unstudied or understudied drugs increases risk of adverse events and/or can lead to sub-optimal efficacy. Recognizing these concerns, regulatory agencies have created financial incentives for industry to conduct pediatric clinical trials. These incentives, coupled with the emerging pediatric hypertension epidemic, have spurred over 30 clinical trials of anti-hypertensive drugs over the past 15 years and have resulted in labeling of 10 new drugs by the United States Food and Drug Administration for treatment of hypertension in children and adolescents. Unfortunately the financial incentive structures focus on newer drugs and drug classes. Consequently there is now a relative dearth of trial data for older but sometimes commonly prescribed pediatric antihypertensive drugs. This article reviews recent pediatric antihypertensive drug trials with a focus on trial design and endpoints, drug dosing, safety, efficacy and specific drug indications. We also review the available data and experience for some of the more commonly prescribed, but less well studied "older" pediatric antihypertensive drugs.

Tgfbeta signaling directly induces Arf promoter remodeling by a mechanism involving Smads 2/3 and p38 MAPK.

We have investigated how the Arf gene product, p19(Arf), is activated by Tgfß during mouse embryo development to better understand how this important tumor suppressor is controlled. Taking advantage of new mouse models, we provide genetic evidence that Arf lies downstream of Tgfß signaling in cells arising from the Wnt1-expressing neural crest and that the anti-proliferative effects of Tgfß depend on Arf in vivo. Tgfß1, -2, and -3 (but not BMP-2, another member of the Tgfß superfamily) induce p19(Arf) expression in wild type mouse embryo fibroblasts (MEFs), and they enhance Arf promoter activity in Arf(lacZ/lacZ) MEFs. Application of chemical inhibitors of Smad-dependent and -independent pathways show that SB431542, a Tgfß type I receptor (TßrI) inhibitor, and SB203580, a p38 MAPK inhibitor, impede Tgfß2 induction of Arf. Genetic studies confirm the findings; transient knockdown of Smad2, Smad3, or p38 MAPK blunt Tgfß2 effects, as does Cre recombinase treatment of Tgfbr2(fl/fl) MEFs to delete Tgfß receptor II. Chromatin immunoprecipitation reveals that Tgfß rapidly induces Smads 2/3 binding and histone H3 acetylation at genomic DNA proximal to Arf exon 1ß. This is followed by increased RNA polymerase II binding and progressively increased Arf primary and mature transcripts from 24 through 72 h, indicating that increased transcription contributes to p19(Arf) increase. Last, Arf induction by oncogenic Ras depends on p38 MAPK but is independent of TßrI activation of Smad 2. These findings add to our understanding of how developmental and tumorigenic signals control Arf expression in vivo and in cultured MEFs.