Azithromycin therapy in infants hospitalized for respiratory syncytial virus bronchiolitis: Airway matrix metalloproteinase-9 levels and subsequent recurrent wheeze.

BACKGROUND: Early life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits. OBJECTIVE: To investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW). METHODS: A total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months. RESULTS: Upper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively). CONCLUSION: Azithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV. TRIAL REGISTRATION: This study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).

The inorganic NItrate and eXercise performance in Heart Failure (iNIX-HF) phase II clinical trial: Rationale and study design.

Background: Heart failure (HF) is a debilitating and often fatal disease that affects millions of people worldwide. Diminished nitric oxide synthesis, signaling, and bioavailability are believed to contribute to poor skeletal muscle function and aerobic capacity. The aim of this clinical trial (iNIX-HF) is to determine the acute and longer-term effectiveness of inorganic nitrate supplementation on exercise performance in patients with HF with reduced ejection fraction (HFrEF). Methods: This clinical trial is a double-blind, placebo-controlled, randomized, parallel-arm design study in which patients with HFrEF (n = 75) are randomized to receive 10 mmol potassium nitrate (KNO3) or a placebo capsule daily for 6 wk. Primary outcome measures are muscle power determined by isokinetic dynamometry and peak aerobic capacity (VO2peak) determined during an incremental treadmill exercise test. Endpoints include the acute effects of a single dose of KNO3 and longer-term effects of 6 wk of KNO3. The study is adequately powered to detect expected increases in these outcomes at P < 0.05 with 1-ß>0.80. Discussion: The iNIX-HF phase II clinical trial will evaluate the effectiveness of inorganic nitrate supplements as a new treatment to ameliorate poor exercise capacity in HFrEF. This study also will provide critical preliminary data for a future 'pivotal', phase III, multi-center trial of the effectiveness of nitrate supplements not only for improving exercise performance, but also for improving symptoms and decreasing other major cardiovascular endpoints. The potential public health impact of identifying a new, relatively inexpensive, safe, and effective treatment that improves overall exercise performance in patients with HFrEF is significant.

Parents, but not their children, demonstrate greater delay discounting with resource scarcity.

BACKGROUND: Individuals with obesity tend to discount the future (delay discounting), focusing on immediate gratification. Delay discounting is reliably related to indicators of economic scarcity (i.e., insufficient resources), including lower income and decreased educational attainment in adults. It is unclear whether the impact of these factors experienced by parents also influence child delay discounting between the ages of 8 and 12-years in families with obesity. METHODS: The relationship between indices of family income and delay discounting was studied in 452 families with parents and 6-12-year-old children with obesity. Differences in the relationships between parent economic, educational and Medicaid status, and parent and child delay discounting were tested. RESULTS: Results showed lower parent income (p = 0.019) and Medicaid status (p = 0.021) were differentially related to greater parent but not child delay discounting among systematic responders. CONCLUSIONS: These data suggest differences in how indicators of scarcity influence delay discounting for parents and children, indicating that adults with scarce resources may be shaped to focus on immediate needs instead of long-term goals. It is possible that parents can reduce the impact of economic scarcity on their children during preadolescent years. These findings suggest a need for policy change to alleviate the burden of scarce conditions and intervention to modify delay discounting rate and to improve health-related choices and to address weight disparities.

Relationships examined: Parent and child readiness to change and sociodemographic characteristics in family based weight loss treatment.

BACKGROUND: Family based treatment is an effective, multipronged approach to address obesity as it plagues families. OBJECTIVE: To investigate the relationships among sociodemographic characteristics (e.g., education and income), body mass index (BMI) and race/ethnicity with readiness to change for parents enrolled in the Primary care pediatrics, Learning, Activity and Nutrition (PLAN) study. METHODS: Multivariate linear regressions tested two hypotheses: (1) White parents will have higher levels of baseline readiness to change, when compared to Black parents; (2) parents with higher income and education will have higher levels of readiness to change at baseline. RESULTS: A positive relationship exists between baseline parent BMI and readiness to change (Pearson correlation, 0.09, p < 0.05); statistically significant relationships exist between parent education level (-0.14, p < 0.05), income (0.04, p < 0.05) and readiness to change. Additionally, a statistically significant relationship exists, with both White (ß, -0.10, p < 0.05), and Other, non-Hispanic (-0.10, p < 0.05) parents exhibiting lower readiness to change than Black, non-Hispanic parents. Child data did not indicate significant relationships between race/ethnicity and readiness to change. CONCLUSIONS: Results demonstrate that investigators should consider sociodemographic characteristic factors and different levels of readiness to change in participants enrolling in obesity interventions.

Family-Based Behavioral Treatment for Childhood Obesity Implemented in Pediatric Primary Care: A Randomized Clinical Trial.

Importance: Intensive behavioral interventions for childhood overweight and obesity are recommended by national guidelines, but are currently offered primarily in specialty clinics. Evidence is lacking on their effectiveness in pediatric primary care settings. Objective: To evaluate the effects of family-based treatment for overweight or obesity implemented in pediatric primary care on children and their parents and siblings. Design, Setting, and Participants: This randomized clinical trial in 4 US settings enrolled 452 children aged 6 to 12 years with overweight or obesity, their parents, and 106 siblings. Participants were assigned to undergo family-based treatment or usual care and were followed up for 24 months. The trial was conducted from November 2017 through August 2021. Interventions: Family-based treatment used a variety of behavioral techniques to develop healthy eating, physical activity, and parenting behaviors within families. The treatment goal was 26 sessions over a 24-month period with a coach trained in behavior change methods; the number of sessions was individualized based on family progress. Main Outcomes and Measures: The primary outcome was the child's change from baseline to 24 months in the percentage above the median body mass index (BMI) in the general US population normalized for age and sex. Secondary outcomes were the changes in this measure for siblings and in BMI for parents. Results: Among 452 enrolled child-parent dyads, 226 were randomized to undergo family-based treatment and 226 to undergo usual care (child mean [SD] age, 9.8 [1.9] years; 53% female; mean percentage above median BMI, 59.4% [n = 27.0]; 153 [27.2%] were Black and 258 [57.1%] were White); 106 siblings were included. At 24 months, children receiving family-based treatment had better weight outcomes than those receiving usual care based on the difference in change in percentage above median BMI (-6.21% [95% CI, -10.14% to -2.29%]). Longitudinal growth models found that children, parents, and siblings undergoing family-based treatment all had outcomes superior to usual care that were evident at 6 months and maintained through 24 months (0- to 24-month changes in percentage above median BMI for family-based treatment and usual care were 0.00% [95% CI, -2.20% to 2.20%] vs 6.48% [95% CI, 4.35%-8.61%] for children; -1.05% [95% CI, -3.79% to 1.69%] vs 2.92% [95% CI, 0.58%-5.26%] for parents; and 0.03% [95% CI, -3.03% to 3.10%] vs 5.35% [95% CI, 2.70%-8.00%] for siblings). Conclusions and Relevance: Family-based treatment for childhood overweight and obesity was successfully implemented in pediatric primary care settings and led to improved weight outcomes over 24 months for children and parents. Siblings who were not directly treated also had improved weight outcomes, suggesting that this treatment may offer a novel approach for families with multiple children. Trial Registration: ClinicalTrials.gov Identifier: NCT02873715.

Effect of excessive gestational weight gain on insulin sensitivity and insulin kinetics in women with overweight/obesity.

OBJECTIVE: Obesity increases the risk for pregnancy complications and maternal hyperglycemia. The Institute of Medicine developed guidelines for gestational weight gain (GWG) targets for women with overweight/obesity, but it is unclear whether exceeding these targets has adverse effects on maternal glucose metabolism. METHODS: Insulin sensitivity (assessed using the Matsuda Insulin Sensitivity Index), ß-cell function (assessed as insulin secretion rate in relation to plasma glucose), and plasma insulin clearance rate were evaluated using a frequently sampled oral glucose tolerance test at 15 and 35 weeks of gestation in 184 socioeconomically disadvantaged African American women with overweight/obesity. RESULTS: Insulin sensitivity decreased, whereas ß-cell function and insulin clearance increased from 15 to 35 weeks of gestation in the entire group. Compared with women who achieved the recommended GWG, excessive GWG was associated with a greater decrease in insulin sensitivity between 15 and 35 weeks. ß-cell function and plasma insulin clearance were not affected by excessive GWG. CONCLUSIONS: These data demonstrate that gaining more weight during pregnancy than recommended by the Institute of Medicine is associated with functional effects on glucose metabolism.

SARS-CoV-2 active infection prevalence and seroprevalence in the adult population of St. Louis County.

BACKGROUND: The true prevalence of COVID-19 is difficult to estimate due to the absence of random population-based testing. To estimate current and past COVID-19 infection prevalence in a large urban area, we conducted a population-based survey in St. Louis County, Missouri. METHODS: The population-based survey of active infection (PCR) and seroprevalence (IgG antibodies) of adults (≥18 years) was conducted through random-digit dialing and targeted sampling of St. Louis County residents with oversampling of Black residents. Infection prevalence of residents was estimated using design-based and raking weighting. RESULTS: Between August 17 and October 24, 2020, 1245 residents completed a survey and underwent PCR testing; 1073 residents completed a survey and underwent PCR and IgG testing or self-reported results. Weighted prevalence estimates of residents with active infection were 1.9% (95% CI, 0.4%-3.3%) and 5.6% were ever infected (95% CI, 3.3%-8.0%). Overall infection hospitalization and fatality ratios were 4.9% and 1.4%, respectively. CONCLUSIONS: Through October 2020, the percentage of residents that had ever been infected was relatively low. A markedly higher percentage of Black and other minorities compared to White residents were infected with COVID-19. The St. Louis region remained highly vulnerable to widespread infection in late 2020.

Azithromycin to Prevent Recurrent Wheeze Following Severe Respiratory Syncytial Virus Bronchiolitis.

BACKGROUND: Early-life severe respiratory syncytial virus (RSV) bronchiolitis is a risk factor for childhood asthma. Because azithromycin may attenuate airway inflammation during RSV bronchiolitis, we evaluated whether it would reduce the occurrence of post-RSV recurrent wheeze. METHODS: We prospectively enrolled 200 otherwise healthy 1- to 18-month-old children hospitalized with RSV bronchiolitis in this single-center, double-blind, placebo-controlled study and randomly assigned them to receive oral azithromycin (10 mg/kg daily for 7 days, followed by 5 mg/kg daily for 7 days) or placebo. Randomization was stratified by recent open-label antibiotic use. The primary outcome was the occurrence of recurrent wheeze, defined as a third episode of post-RSV wheeze over the following 2 to 4 years. RESULTS: As an indication of the biologic activity of azithromycin, nasal wash interleukin-8 levels, at day 14 after randomization, were lower among azithromycin-treated participants (P<0.01). Despite evidence of biologic activity, azithromycin did not reduce the risk of post-RSV recurrent wheeze (47% in the azithromycin group vs. 36% in the placebo group; adjusted hazard ratio, 1.45; 95% confidence interval [CI], 0.92 to 2.29; P=0.11). Azithromycin also did not modify the risk of recurrent wheeze among participants already receiving other antibiotic treatment at the time of enrollment (hazard ratio, 0.94; 95% CI, 0.43 to 2.07). There was a potential signal among antibiotic-naïve participants who received azithromycin to have an increased risk of recurrent wheeze (hazard ratio, 1.79; 95% CI, 1.03 to 3.1). CONCLUSIONS: Azithromycin therapy for 14 days during acute severe RSV bronchiolitis did not reduce recurrent wheeze occurrence over the following 2 to 4 years. Our data suggest no benefit of azithromycin administration with the goal of preventing recurrent wheeze in later life. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02911935.).

Exploring contextual factors influencing the implementation of evidence-based care for hypertension in Rwanda: a cross-sectional study using the COACH questionnaire.

IMPORTANCE: Hypertension is the largest contributor to the Global Burden of Disease. In Rwanda, as in most low-income and middle-income countries, an increasing prevalence of hypertension and its associated morbidity and mortality is causing major healthcare and economic impact. Understanding healthcare systems context in hypertension care is necessary. OBJECTIVE: To study the hypertension healthcare context as perceived by healthcare providers using the Context Assessment for Community Health (COACH) tool. DESIGN: A cross-sectional cohort responded to the COACH questionnaire and a survey about hypertension training. SETTING: Three tertiary care hospitals in Rwanda. PARTICIPANTS: Healthcare professionals (n=223). PRIMARY OUTCOMES AND MEASURES: The COACH tool consists of 49 items with eight subscales: resources, community engagement, commitment to work, informal payment, leadership, work culture, monitoring services for action (5-point Likert Scale) and sources of knowledge (on a 0-1 scale). Four questions surveyed training on hypertension. RESULTS: Responders (n=223, 75% women; 56% aged 20-35 years) included nurses (n=142, 64%, midwives (n=42, 19%), primary care physicians (n=28, 13%) and physician specialists (n=11, 5%)). The subscales commitment to work, leadership, work culture and informal payment scored between 4.7 and 4.1 and the community engagement, monitoring services for action and organizational resources scored between 3.1 and 3.5. Sources of knowledge had a mean score of 0.6±0.3. While 73% reported having attended a didactic hypertension seminar in the past year, only 28% had received long-term training and 51% had <3-year experience working with hypertension care delivery. The majority (99%) indicated a need for additional training in hypertension care. CONCLUSIONS: There is a need for increased and continuous training in Rwanda. Healthcare responders stated a commitment to work and reported supportive leadership, while acknowledging limited resources and no monitoring systems. The COACH tool provides contextual guidance to develop training strategies prior to the implementation of a sustainable hypertension care programme.

Implementing family-based behavioral treatment in the pediatric primary care setting: Design of the PLAN study.

Family-based behavioral treatment (FBT) is an evidence-based treatment for pediatric obesity. FBT has primarily been implemented in specialty clinics, with highly trained interventionists. The goal of this study is to assess effectiveness of FBT implemented in pediatric primary care settings using newly trained interventionists who might implement FBT in pediatric practices. The goal is to randomize 528 families with a child with overweight/obesity (≥85th BMI percentile) and parent with overweight/obesity (BMI ≥ 25) across four sites (Buffalo and Rochester, New York; Columbus, Ohio; St. Louis, Missouri) to FBT or usual care and obtain assessments at 6-month intervals over 24 months of treatment. FBT is implemented using a mastery model, which provides quantity of treatment tailored to family progress and following the United States Preventive Services Task Force recommendations for effective dose and duration of treatment. The primary outcome of the trial is change in relative weight for children, and secondarily, for parents and siblings who are overweight/obese. Between group differences in the tendency to prefer small immediate rewards over larger, delayed rewards (delay discounting) and how this is related to treatment outcome is also evaluated. Challenges in translation of group-based interventions to individualized treatments in primary care settings, and in study implementation that arose due to the COVID-19 pandemic are discussed. It is hypothesized that the FBT intervention will be associated with better changes in relative weight for children, parents, and siblings than usual care. The results of this study can inform future dissemination and implementation of FBT into primary care settings.

A multi-center trial of exercise and testosterone therapy in women after hip fracture: Design, methods and impact of the COVID-19 pandemic.

BACKGROUND: Up to 75% of hip fracture patients never recover to their pre-fracture functional status. Supervised exercise that includes strength training can improve functional recovery after hip fracture. The role of testosterone replacement for augmenting the effects of exercise in older women after hip fracture is unknown. METHODS: The Starting Testosterone and Exercise after Hip Injury (STEP-HI) Study is a 6-month Phase 3 multicenter randomized placebo-controlled trial designed to compare supervised exercise (EX) plus 1% testosterone topical gel, with EX plus placebo gel, and with enhanced usual care (EUC). Female hip fracture patients age ≥ 65 years are being recruited from clinical centers across the United States. Participants are community dwelling and enrolled within 24 weeks after surgical repair of the fracture. The EX intervention is a center-based program of progressive resistance training. The EUC group receives a home exercise program and health education. Participants receive dietary counseling, calcium and vitamin D. The primary outcome is the Six Minute Walk Distance. Secondary outcomes include physical performance measures, self-reported function and quality of life, and dual energy x-ray absorptiometry measures of body composition and bone mineral density. RESULTS: Enrollment, interventions, and follow-up are ongoing. We describe the impact of the coronavirus disease 2019 pandemic on the trial, including modifications made to allow continuation of the interventions and outcome data collection using remote video and audio technology. CONCLUSIONS: Results from the STEP-HI study are expected to have important clinical and public health implications for management of the growing population of hip fracture patients.

Lung function trajectories and bronchial hyperresponsiveness during childhood following severe RSV bronchiolitis in infancy.

BACKGROUND: Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis. METHODS: In a prospective cohort of 206 children with their first episode of RSV-confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5-16 years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12 years of age, respectively. Longitudinal changes in FEV1 , FVC, and FEV1 /FVC z-scores and methacholine PC20 were analyzed. RESULTS: 55% of the study cohort (N = 122) were male, and 55% were Caucasian. During follow-up, longitudinal changes in z-scores for pre- and post-bronchodilator FEV1 (P < .0001) FVC (P < .0001) and FEV1 /FVC (P < .0001 for pre- and 0.007 for post-bronchodilator) from age 5 to 10-16 years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC20 geometric mean increased from 0.28 mg/mL at 7 years to 0.53 mg/mL at 12 years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P = .0003). CONCLUSIONS: Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre- and post-bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post-bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.

Impaired tumor necrosis factor-α secretion by CD4 T cells during respiratory syncytial virus bronchiolitis associated with recurrent wheeze.

BACKGROUND: Infants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro-stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life. METHODS: We obtained peripheral blood from 166 infants hospitalized with their first episode of RSV-confirmed bronchiolitis. Granzyme B (GZB) expression, and interleukin-10, interferon-γ, tumor necrosis factor-α (TNF-α), IL-4, and IL-5 production by in vitro anti-CD3/CD28- and anti-CD3/CD46-activated CD4+ T cells, and percentage of peripheral Treg (CD4+CD25hi Foxp3hi ) cells were measured by flow cytometry. Wheezing was assessed every 6 months. Recurrent wheezing was defined as three or more episodes following the initial RSV bronchiolitis. RESULTS: Sixty-seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25hi Foxp3hi ) cells was not significantly different between the wheezing groups. Decreased TNF-α production from anti-CD3/CD28- and anti-CD3/CD46- activated CD4+ T cells was observed in the recurrent wheezers, compared with nonwheezers (p = .048 and .03, respectively). There were no significant differences in the GZB+ CD4+ T cells and production of other inflammatory cytokines between these groups. CONCLUSIONS: We demonstrated lower TNF-α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently developed recurrent wheezing, compared with children with no subsequent wheeze. These findings support the role of CD4+ T cell immunity in the development of subsequent wheezing in these children.

A Pragmatic Trial of Symptom-Based Inhaled Corticosteroid Use in African-American Children with Mild Asthma.

BACKGROUND: Symptom-based adjustment (SBA) of inhaled corticosteroids may be an alternative patient-centered approach in which day-to-day inhaled corticosteroid use is adjusted by symptoms and short-acting ß-agonist need. OBJECTIVE: To evaluate the effectiveness of SBA in the primary care setting. METHODS: We conducted a randomized, open-label, pragmatic equivalence trial in African-American children (6-17 years old) with mild asthma managed by 12 primary care providers (PCPs). A total of 206 participants were randomized to SBA (as-needed beclomethasone 80 µg with rescue short-acting ß-agonist) or provider-based guideline-directed adjustment (PBA): maintenance beclomethasone 80 µg/d (6-11 years old), 160 µg/d (12-17 years old), with subsequent guideline-based dose adjustment by PCPs. PCPs implemented both treatment assignments, with outcomes measured by blinded staff. All participants received symptom recognition and albuterol use education from peer educators. Primary outcome was change in asthma control (measured by Asthma Control Test [ACT]/childhood ACT [cACT]) over 12 months. RESULTS: Participants had adequately controlled asthma (mean ACT or cACT score = 21.6 ± 2.8) at baseline. After 1 year, there was no significant between-group difference in change in ACT scores (SBA - PBA): ACT: -0.88 (95% CI, -2.19 to 0.42), cACT: -0.73 (-2.09 to 0.62), or combined ACT and cACT (P = .10), and was within the predefined statistical clinical equivalence. The proportion with an exacerbation and measures of lung function were similar between groups. Compared with PBA, SBA led to less beclomethasone use (SBA: 526 µg/mo [95% CI, 412-639 µg] vs PBA: 1961 µg/mo [95% CI, 1681-2241]; P < .0001). More parents in the SBA arm felt they were managing their child's asthma. CONCLUSIONS: SBA in African-American children with mild asthma was similar to PBA in asthma control and events when implemented by PCPs with lower inhaled corticosteroid exposure.

Effect of Fresh vs Standard-issue Red Blood Cell Transfusions on Multiple Organ Dysfunction Syndrome in Critically Ill Pediatric Patients: A Randomized Clinical Trial.

Importance: The clinical consequences of red blood cell storage age for critically ill pediatric patients have not been examined in a large, randomized clinical trial. Objective: To determine if the transfusion of fresh red blood cells (stored ≤7 days) reduced new or progressive multiple organ dysfunction syndrome compared with the use of standard-issue red blood cells in critically ill children. Design, Setting, and Participants: The Age of Transfused Blood in Critically-Ill Children trial was an international, multicenter, blinded, randomized clinical trial, performed between February 2014 and November 2018 in 50 tertiary care centers. Pediatric patients between the ages of 3 days and 16 years were eligible if the first red blood cell transfusion was administered within 7 days of intensive care unit admission. A total of 15 568 patients were screened, and 13 308 were excluded. Interventions: Patients were randomized to receive either fresh or standard-issue red blood cells. A total of 1538 patients were randomized with 768 patients in the fresh red blood cell group and 770 in the standard-issue group. Main Outcomes and Measures: The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured for 28 days or to discharge or death. Results: Among 1538 patients who were randomized, 1461 patients (95%) were included in the primary analysis (median age, 1.8 years; 47.3% girls), in which there were 728 patients randomized to the fresh red blood cell group and 733 to the standard-issue group. The median storage duration was 5 days (interquartile range [IQR], 4-6 days) in the fresh group vs 18 days (IQR, 12-25 days) in the standard-issue group (P < .001). There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0% (95% CI, -2.0% to 6.1%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group (P = .34). Conclusions and Relevance: Among critically ill pediatric patients, the use of fresh red blood cells did not reduce the incidence of new or progressive multiple organ dysfunction syndrome (including mortality) compared with standard-issue red blood cells. Trial Registration: ClinicalTrials.gov Identifier: NCT01977547.

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

BACKGROUND: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. METHODS: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. RESULTS: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. CONCLUSIONS: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.

Clinical significance of the bronchodilator response in children with severe asthma.

BACKGROUND: Our objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP). METHODS: We performed a cross-sectional analysis evaluating children ages 6 to 17 years with nonsevere asthma (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 µg of albuterol to determine reversibility (≥12% increase in FEV1 ). Participants were then given escalating doses up to 720 µg of albuterol to determine their maximum reversibility. RESULTS: We evaluated 230 children (n = 129 SA, n = 101 NSA) from five centers across the United States in the SARP I and II cohorts. SA (odds ratio [OR], 2.08, 95% confidence interval [CI], 1.05-4.13), second-hand smoke exposure (OR, 2.81, 95%CI, 1.23-6.43), and fractional exhaled nitric oxide (FeNO; OR, 1.97, 95%CI, 1.35-2.87) were associated with increased odds of airway reversibility after maximal bronchodilation, while higher prebronchodilator (BD) FEV1 % predicted (OR, 0.91, 95%CI, 0.88-0.94) was associated with decreased odds. In an analysis using the SARP III cohort (n = 186), blood neutrophils, immunoglobulin E (IgE), and FEV1 % predicted were significantly associated with BD reversibility. In addition, children with BD response have greater healthcare utilization. BD reversibility was associated with reduced lung function at enrollment and 1-year follow-up though less decline in lung function over 1 year compared to those without reversibility. CONCLUSIONS: Lung function, that is FEV1 % predicted, is a predictor of BD response in children with asthma. Additionally, smoke exposure, higher FeNO or IgE level, and low peripheral blood neutrophils are associated with a greater likelihood of BD reversibility. BD response can identify a phenotype of pediatric asthma associated with low lung function and poor asthma control.

Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach.

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.

The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. METHODS AND FINDINGS: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 µg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. CONCLUSIONS: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02899936.

Disseminating and implementing a lifestyle-based healthy weight program for mothers in a national organization: a study protocol for a cluster randomized trial.

BACKGROUND: Excessive weight gain among young adult women age 18-45 years is an alarming and overlooked trend that must be addressed to reverse the epidemics of obesity and chronic disease. During this vulnerable period, women tend to gain disproportionally large amounts of weight compared to men and to other life periods. Healthy Eating and Active Living Taught at Home (HEALTH) is a lifestyle modification intervention developed in partnership with Parents as Teachers (PAT), a national home visiting, community-based organization with significant reach in this population. HEALTH prevented weight gain, promoted sustained weight loss, and reduced waist circumference. PAT provides parent-child education and services free of charge to nearly 170,000 families through up to 25 free home visits per year until the child enters kindergarten. METHODS: This study extends effectiveness findings with a pragmatic cluster randomized controlled trial to evaluate dissemination and implementation (D&I) of HEALTH across three levels (mother, parent educator, PAT site). The trial will evaluate the effect of HEALTH and the HEALTH training curriculum (implementation strategy) on weight among mothers with overweight and obesity across the USA (N = 252 HEALTH; N = 252 usual care). Parent educators from 28 existing PAT sites (14 HEALTH, 14 usual care) will receive the HEALTH training curriculum through PAT National Center, using PAT's existing training infrastructure, as a continuing education opportunity. An extensive evaluation, guided by RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance), will determine implementation outcomes (acceptability, adoption, appropriateness, feasibility, fidelity, and adaptation) at the parent educator level. The Conceptual Framework for Implementation Research will characterize determinants that influence HEALTH D&I at three levels: mother, parent educator, and PAT site to enhance external validity (reach and maintenance). DISCUSSION: Embedding intervention content within existing delivery channels can help expand the reach of evidence-based interventions. Interventions, which have been adapted, can still be effective even if the effect is reduced and can still achieve population impact by reaching a broader set of the population. The current study will build on this to test not only the effectiveness of HEALTH in real-world PAT implementation nationwide, but also elements critical to D&I, implementation outcomes, and the context for implementation. TRIAL REGISTRATION: https://ClinicalTrials.gov , NCT03758638 . Registered 29 November 2018.