Effects of the COVID-19 Pandemic on Pediatric and Adolescent ASCVD Risk Factors.

PURPOSE OF REVIEW: In this review, we provide insight into and raise awareness of the impact of the COVID-19 pandemic on the prevalence of acquired atherosclerotic cardiovascular disease (ASCVD) risk factors in adolescents. We highlight data that could be used to guide the response to a future pandemic with the goal of reducing premature cardiovascular disease (CVD)-related morbidity and premature mortality. RECENT FINDINGS: During the global COVID-19 pandemic, many individuals, including youth, voluntarily or were mandated to alter the usual lifestyle in order to limit exposure and reduce the spread of the virus. Some of these changes resulted in unintended consequences, particularly acquisition of risk factors such as excessive weight gain, insulin resistance/diabetes, and dyslipidemia, commonly associated with ASCVD. A study from China examined changes in the prevalence of obesity and found a 2.4% rise attributable to the pandemic. Adequate daily physical activity plays an important role in ASCVD risk reduction. A systematic review and meta-analysis showed a 20% (90% CI, -34 to -4%) reduction in physical activity from before vs. during the COVID-19 pandemic. Another study of patients with type 2 diabetes found the mean HbA1c was significantly elevated during the COVID-19 pandemic (7.53 ± 1.02% in 2020) compared with the previous 2 years. In addition, there has been an alarming rise of childhood mental health concerns and suicide during the pandemic. Early identification and optimum management of CVD risk factors play an important role helping prevent future cardiovascular disease. Following the rapid spread of the virus, the World Health Organization (WHO) officially declared COVID-19 a global pandemic on March 11th, 2020. In an attempt to avoid infection and reduce the spread of the virus, many alterations in lifestyle were adopted on an international scale. While necessary, these modifications resulted in many adverse unintended health consequences in children and adolescents. This paper reviews the impact of the pandemic and the associated lifestyle changes on the prevalence of acquired atherosclerotic cardiovascular disease (ASCVD) risk factors in youth. In addition to providing insight, we hope to raise awareness of the pandemic's impact, and highlight specific data that could be used to guide the response to a future pandemic.

Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia.

OBJECTIVES: To evaluate the lipid-altering efficacy and safety of ezetimibe monotherapy in young children with heterozygous familial hypercholesterolemia (HeFH) or nonfamilial hypercholesterolemia (nonFH). STUDY DESIGN: One hundred thirty-eight children 6-10 years of age with diagnosed HeFH or clinically important nonFH (low-density lipoprotein cholesterol [LDL-C] ≥ 160 mg/dL [4.1 mmol/L]) were enrolled into a multicenter, 12-week, randomized, double-blind, placebo-controlled study. Following screening/drug washout and a 5-week single-blind placebo-run-in with diet stabilization, subjects were randomized 2:1 to daily ezetimibe 10 mg (n = 93) or placebo (n = 45) for 12 weeks. Lipid-altering efficacy and safety were assessed in all treated patients. RESULTS: Overall, mean age was 8.3 years, 57% were girls, 80% were white, mean baseline LDL-C was 228 mg/dL (5.9 mmol/L), and 91% had HeFH. After 12 weeks, ezetimibe significantly reduced LDL-C by 27% after adjustment for placebo (P < .001) and produced significant reductions in total cholesterol (21%), nonhigh-density lipoprotein cholesterol (26%), and apolipoprotein B (20%) (P < .001 for all). LDL-C lowering response in sex, race, baseline lipids, and HeFH/nonFH subgroups was generally consistent with overall study results. Ezetimibe was well tolerated, with a safety profile similar to studies in older children, adolescents, and adults. CONCLUSIONS: Ezetimibe monotherapy produced clinically relevant reductions in LDL-C and other key lipid variables in young children with primary HeFH or clinically important nonFH, with a favorable safety/tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00867165.

Metabolic assessment of menstruating and nonmenstruating normal weight adolescents.

OBJECTIVE: Resumption of menses (ROM) is a key indicator of recovery in AN, but patients may remain amenorrheic despite weight restoration. The objective of this study is to better understand the mechanism of amenorrhea in patients with eating disorders. METHOD: A retrospective chart review was conducted of 382 normal weight adolescents with a history of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, who had been referred for indirect calorimetry tests. Resting energy expenditure (REE) was compared between amenorrheic (n = 60) and regularly menstruating females (n = 121). RESULTS: Participants with amenorrhea had a mean REE of 1,103 kcal/24 h (79% predicted), whereas participants who were menstruating regularly had a mean REE of 1,217 kcal/24 h (85% predicted; p = 0.001). The amenorrheic group was found to be at a lower mean body weight (53.7 +/- 5.6 kg vs. 57.5 +/- 7.4 kg; p < or = 0.001), at a lower percent ideal body weight (98.5 +/- 8.3% vs. 102.8 +/- 10.2%; p = 0.005), and at a lower BMI (20.5 +/- 1.7 vs. 21.5 +/- 2.2; p = 0.002). DISCUSSION: This study highlights that amenorrheic participants with a history of eating disorders who are at normal body weight are hypometabolic, suggesting an adaptive response to dietary restriction.

Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing.

Despite compliance with lifestyle recommendations, some children and adolescents with high-risk hyperlipidemia will require lipid-lowering drug therapy, particularly those with familial hypercholesterolemia. The purpose of this statement is to examine new evidence on the association of lipid abnormalities with early atherosclerosis, discuss challenges with previous guidelines, and highlight results of clinical trials with statin therapy in children and adolescents with familial hypercholesterolemia or severe hypercholesterolemia. Recommendations are provided to guide decision-making with regard to patient selection, initiation, monitoring, and maintenance of drug therapy.

Treatment goal weight in adolescents with anorexia nervosa: use of BMI percentiles.

OBJECTIVE: There is a lack of consensus as to how to determine treatment goal weight in the growing adolescent with anorexia nervosa (AN). Resumption of menses (ROM) is an indicator of biological health and weight at ROM can be used as a treatment goal weight. This study determined the BMI percentile for age at which ROM occurs. METHOD: A secondary analysis of a prospective cohort study examining 56 adolescent females with AN, aged 12-19 years, followed every 3 months until ROM. BMI percentiles for age and gender at ROM were determined using the nutrition module of Epi Info 2002. RESULTS: At 1-year follow-up, 36 participants (64.3%) resumed menses and 20 (35.7%) remained amenorrheic. Mean BMI percentile at ROM was 27.1 (95% CI = 20.0-34.2). Fifty percent of participants who resumed menses, did so at a BMI percentile between the 14th and 39th percentile. CONCLUSION: A BMI percentile range of 14th-39th percentile can be used to assign a treatment goal weight, with adjustments for prior weight, stage of pubertal development, and anticipated growth.

Assessment and Management of Hypotension in the Elderly Patient.

INTRODUCTION: Elderly patients often present to the emergency department (ED) with nonspecific signs of infection and excessive fluid loss, with limited research into their management. The purpose of this audit was to assess the initial management of hypotensive elderly patients in the ED: observations within 15 min, fluid challenge within 1 h, time to assessment by a physician, and initial management of septic shock. SUBJECTS AND METHODS: Online patient systems were reviewed to find 40 patients >65 years old who were hypotensive (systolic blood pressure <100 mmHg or diastolic blood pressure <60 mmHg) in the ED between 1st October 2015 and 16th November 2015. This data were used to perform a retrospective audit to assess their management. RESULTS: Forty hypotensive patients were identified with an average age of 79.6, with 55% being male. Eighty-three percent had their observations recorded within 15 min of presentation, 35% had their observations repeated within 1 h, and 35% were fluid challenged within 1 h. Nearly 60% patients were reviewed within 1 h by a physician. About 33% patients were in septic shock with 41% receiving IVF within 1 h, and all 40 patient receiving antibiotics. DISCUSSION: The majority of patients had their observations performed within 15 min; however, a smaller percentage was fluid challenged within 1 h with their observations rechecked. Despite a sepsis pathway, hypotensive patients were still not receiving fluids within the hour. CONCLUSION: Developing a fast-track protocol for hypotensive elderly patients in the ED could improve initial rehydration management and ensure observations are reported in a timely manner.

Supersize teens: the metabolic syndrome.

With obesity and type 2 diabetes on the rise in children and adolescents, there has been recent interest in the study of the metabolic (insulin resistance) syndrome in this population. Characteristics of the syndrome include impaired glucose tolerance, hypertension, dyslipidemia, and abdominal obesity. These features are known to cluster and convey increased cardiovascular risk over time. Screening of children and adolescents is important to the goal of prevention, and therapeutic lifestyle modification is the primary treatment modality. When this fails, pharmacotherapy aimed at the individual risk factors may be indicated.

Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial.

Osteopenia is a serious medical complication of anorexia nervosa, with no known effective treatment. We conducted a double-blinded, randomized trial comparing alendronate (10 mg daily) with placebo in 32 adolescents with anorexia nervosa (mean age, 16.9 +/- 1.9 yr). All subjects received 1200 mg elemental calcium and 400 IU vitamin D daily and received the same multidisciplinary treatment for their eating disorder. Bone mineral densities (BMDs) of the lumbar spine and femoral neck were measured by dual energy x-ray absorptiometry at baseline and after 1 yr of treatment. Twenty-nine subjects completed the study. Femoral neck and lumbar spine BMDs increased 4.4 +/- 6.4% and 3.5 +/- 4.6% in the alendronate group compared with increases of 2.3 +/- 6.9% and 2.2 + 6.1% in the control group (P = 0.41, femoral neck; P = 0.53, lumbar spine). From baseline to follow-up, BMD increased significantly at the femoral neck (P = 0.02) and lumbar spine (P = 0.02) in those receiving alendronate, but did not increase in those assigned placebo (P = 0.22, femoral neck; P = 0.18, lumbar spine). At follow-up, body weight was the most important determinant of BMD. BMD was significantly higher in subjects who were weight-restored compared with those who remained at low weight (P = 0.002, femoral neck; P = 0.04, lumbar spine). After controlling for body weight, treatment group assignment still had an independent effect at the femoral neck. We conclude that in adolescents with anorexia nervosa, weight restoration is the most important determinant of BMD, but treatment with alendronate did increase the BMD of the lumbar spine and femoral neck within the group receiving alendronate, but not compared with placebo in the primary analysis. Until additional studies have demonstrated efficacy and long-term safety, the use of alendronate in this population should be confined to controlled clinical trials.

Phase I trial of preoperative doxorubicin-based concurrent chemoradiation and surgical resection for localized extremity and body wall soft tissue sarcomas.

PURPOSE: The primary objective of this phase I trial was to define the maximum-tolerated dose of continuous-infusion doxorubicin administered with standard preoperative radiation for patients with localized, potentially resectable soft tissue sarcomas of the extremities or body wall. PATIENTS AND METHODS: Twenty-seven patients with radiographically resectable intermediate- or high-grade soft tissue sarcomas were treated. Preoperative external-beam radiation was administered in 25 2-Gy fractions (total dose, 50 Gy). Concurrent continuous-infusion doxorubicin was administered by an initial bolus (4 mg/m(2)) and subsequent 4-day continuous infusion (12.5, 15.0, 17.5, or 20.0 mg/m(2)/wk). Radiographic restaging was performed 4 to 7 weeks after chemoradiation, and patients with localized disease underwent surgical resection. RESULTS: Chemoradiation was completed as an outpatient procedure in 25 patients (93%). The maximum-tolerated dose of continuous-infusion doxorubicin combined with standard preoperative radiation was 17.5 mg/m(2)/wk; at this dose level, seven (30%) of 23 patients had grade 3 dermatologic toxicity. Macroscopically complete resection (R0 or R1) was performed in all 26 patients who underwent surgery. Among 22 patients who were treated with doxorubicin 17.5/mg/m(2)/wk with concurrent radiation and subsequent surgery, 11 patients (50%) had 90% or greater tumor necrosis, including two patients who had complete pathologic responses. CONCLUSION: Preoperative doxorubicin-based chemoradiation appears safe and feasible. The maximum-tolerated dose of continuous-infusion doxorubicin with standard preoperative radiation was 17.5 mg/m(2)/wk. Pathologic response rates with this regimen are encouraging.

Evidence that transfer of functional p53 protein results in increased apoptosis in prostate cancer.

PURPOSE: INGN 201 (Ad-p53) is a replication-defective adenoviral vector that encodes a wild-type p53 gene driven by the cytomegalovirus promoter. INGN 201 has been shown to have antitumoral activity against human prostate cancer cell lines. This study was undertaken to determine the safety of INGN 201 in patients with locally advanced prostate cancer, to assess transgene expression, and to evaluate antitumoral activity. EXPERIMENTAL DESIGN: Our study included patients with clinical stage T3, T1c-T2a with Gleason score 8-10 disease, or T2a-T2b with Gleason score 7 disease and a prostate-specific antigen level >10 ng/ml. INGN 201 was administered by intraprostatic injection under ultrasonographic guidance. One course of INGN 201 was defined as three separate INGN 201 administrations 2 weeks apart. Biopsies at baseline and 24 h after the first administration were assessed for p53 protein by immunohistochemical staining and for apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. RESULTS: A total of 38 courses of INGN 201 gene therapy were administered to 30 patients, of whom 26 underwent radical prostatectomy. There were no grade 3 or 4 adverse events related to INGN 201 administration. Of the 11 patients with negative baseline immunostaining for p53 protein, 10 had positive p53 immunostaining after the first administration of INGN 201, and 8 had an increase in apoptotic cells by terminal deoxynucleotidyl transferase-mediated nick end labeling staining. All 26 of the patients who underwent radical prostatectomy had significant residual viable prostate cancer, and 12 have experienced biochemical failure (median follow-up, 42 months). CONCLUSION: Intraprostatic INGN 201 gene therapy is safe and can reliably result in p53 protein production and apoptosis.

Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: Part I--correlating internal lung motion with skin fiducial motion.

PURPOSE: To measure the internal lung motion due to respiration using magnetic resonance images (MRIs); to evaluate the correlation between lung motion and skin surface motion and the reliability of tracking lung motion with external fiducials. METHODS AND MATERIALS: An MRI protocol using fast gradient-echo sequences was developed to acquire dynamic cine images of the thoracoabdominal region along the axial, sagittal, and coronal planes. The subjects (3 healthy volunteers and 4 lung cancer patients) were instructed to perform normal or altered breathing during MRI. Lung vessels identified on MRI were used as anatomic landmarks for internal lung structures. From sagittal cine MRI scans, the positions of the lung vessels and skin surface were tracked and their movements measured. Correlation between the movements of the external markers and internal structures was then calculated and analyzed. RESULTS: Lung vessel motion in the superior-inferior (SI) direction correlated best with mid-upper abdominal skin surface movement (correlation coefficient, 0.89 +/- 0.09 and 0.87 +/- 0.23 for volunteers and patients, respectively). The anterior-posterior (AP) vessel motion generally correlated poorly with the skin surface movement, with marker placement on the upper chest yielding the strongest results (correlation coefficient, 0.72 +/- 0.23 and 0.44 +/- 0.27 for volunteers and patients, respectively). The strength of the correlation depended on the locations of the tracked vessels, locations of the skin surface, and subjects' breathing patterns. The best correlation was seen between the motion of an abdominal fiducial and SI lung motion. Significant intersubject variability was also observed. CONCLUSION: Movement of an external fiducial may not correlate fully with, or predict, internal lung motion. Effective monitoring of respiration may have to rely on a combination of multiple fiducials and other physiologic parameters, such as lung volume and/or air flow.

Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: Part II-margin reduction of internal target volume.

PURPOSE: To analyze the relationship between lung motion and skin surface motion during respiration, determine the uncertainties and variability of such a relationship, and assess the potential of reducing internal target margin for gated radiotherapy. METHODS AND MATERIALS: Three healthy volunteers and four lung cancer patients were recruited in a prospective imaging study using MRI to track the internal lung and external skin motion during breathing. The relationship between the lung and skin motion was modeled using linear regression analysis. The slope of the linear fit and its confidence interval were analyzed for different lung locations, skin surface locations, and breathing patterns from separate imaging sessions. The margins of the internal target volume were calculated based on the residual lung motion during gating and its uncertainties from multiple treatment fractions for the gated treatment. RESULTS: The slope and confidence interval of the linear regression from the motion analysis were uniquely defined by the locations of the lung, skin surface, and breathing patterns. Statistically significant differences were observed among individuals and between different times of measurement. The normal free-breathing motion averaged from all volunteer and patient data was 13.4 +/- 7.4 mm along the superior-inferior (SI) direction and 6.9 +/- 2.6 mm along the anterior-posterior (AP) direction. With simulated respiratory gating, the average margin reduction was 5.5 +/- 4.8 mm and 1.6 +/- 1.0 mm, respectively, along the SI and AP directions (or 36% +/- 15% and 25% +/- 14%, respectively, relative to free-breathing motion). CONCLUSION: Because respiratory movement is rather complex, the relationship between the lung and skin surface motion is affected by many anatomic and physiologic factors. The reduction of internal target margin and efficacy of the free-breathing gating technique should be assessed for individual cases.

Hypophosphatemia during nutritional rehabilitation in anorexia nervosa: implications for refeeding and monitoring.

PURPOSE: To determine the incidence of hypophosphatemia in adolescents with anorexia nervosa (AN) hospitalized for nutritional rehabilitation and to examine factors predisposing to its development. METHODS: A retrospective chart review of 69 patients (66 female, 3 male) with AN consecutively admitted to an inpatient adolescent medical unit between July 1, 1998 and June 30, 2000. Mean age was 15.5 +/- 2.4 (range 8 to 22) years and mean % ideal body weight (IBW) was 72.7 +/- 7%. Serum phosphorus was measured daily for 1 week and then biweekly to weekly. Patients were started on 1200-1400 kcal/day and calories were increased by 200 kcal every 24-48 hours. RESULTS: Four (5.8%) patients developed moderate hypophosphatemia (<2.5 and > or = 1.0 mg/dl) and 15 (21.7%) had mild hypophosphatemia (<3.0 and > or = 2.5 mg/dl). Patients who developed moderate hypophosphatemia were significantly more malnourished than those who did not (p = 0.02). Phosphorus nadirs were directly proportional to % IBW (r = 0.3, p = 0.01). Over three-quarters of the patients (81%) reached their phosphorus nadir within the first week of hospitalization. The patient with the lowest phosphorus level experienced short runs of ventricular tachycardia. No other severe complications were seen. Overall, 19 (27.5%) patients required phosphorus supplementation. CONCLUSIONS: Phosphorus drops to its nadir during the first week of refeeding. We recommend daily monitoring of serum phosphorus with supplementation as needed during the first week of hospitalization, especially in those who are severely malnourished.

The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa.

INTRODUCTION: Osteopenia is a serious complication of anorexia nervosa (AN). Although in other states of estrogen deficiency, estrogen replacement therapy increases bone mass, its role in AN remains unresolved. STUDY OBJECTIVE: To study the effect of estrogen-progestin administration on bone mass in AN. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study of 50 adolescents with AN (mean age 16.8 +/- 2.3 yrs) was conducted in a tertiary referral center. MAIN OUTCOME MEASURES: Bone mineral density (BMD) of the lumbar spine and left hip were prospectively measured using dual-energy x-ray absorptiometry at baseline and annually. INTERVENTIONS: Twenty-two subjects received estrogen-progestin and 28 standard treatment (Rx) alone. Estrogen-progestin was administered daily as an oral contraceptive containing 20-35 mcg ethinyl estradiol. All subjects received calcium supplementation and the same medical, psychological, and nutritional intervention (standard Rx). Mean length of follow-up was 23.1 +/- 11.4 months. RESULTS: At presentation, patients were malnourished (79.5% +/- 7.6% IBW), hypoestrogenemic (estradiol 24.7 +/- 10.7 pg/mL), and had reduced bone mass (lumbar spine BMD -2.01 +/- 0.69 SD below the young adult reference mean). Ninety-two percent of subjects were osteopenic and 26% met WHO criteria for osteoporosis. Body weight, and no treatment group, was the major determinant of BMD. At one-year follow-up, there were no significant differences in absolute values or in net change of lumbar spine or femoral neck BMD between those who received estrogen-progestin and those who received standard Rx (80% power of finding a 3% difference in BMD at 1 yr). In those followed for 2-3 yrs, osteopenia was persistent and in some cases progressive. CONCLUSION: In our study population, estrogen-progestin did not significantly increase BMD compared with standard Rx. These results question the common practice of prescribing hormone replacement therapy to increase bone mass in AN.