Insulin-Like Growth Factor 1 in the Preterm Rabbit Pup: Characterization of Cerebrovascular Maturation following Administration of Recombinant Human Insulin-Like Growth Factor 1/Insulin-Like Growth Factor 1-Binding Protein 3.

Following preterm birth, serum levels of insulin-like growth factor 1 (IGF-1) decrease compared to corresponding in utero levels. A recent clinical trial indicated that supplementation with recombinant human (rh) IGF-1/rhIGF-binding protein 3 (rhIGF-1/rhIGFBP-3) prevents severe intraventricular hemorrhage (IVH) in extremely preterm infants. In a preterm rabbit pup model, we characterized endogenous serum and hepatic IGF-1, along with brain distribution of IGF-1 and IGF-1 receptor (IGF1R). We then evaluated the effects of rhIGF-1/rhIGFBP-3 on gene expression of regulators of cerebrovascular maturation and structure. Similar to preterm infants, serum IGF-1 concentrations decreased rapidly after preterm birth in the rabbit pup. Administration of rhIGF-1/rhIGFBP-3 restored in utero serum levels but was rapidly eliminated. Immunolabeled IGF1R was widely distributed in multiple brain regions, displaying an abundant density in the choroid plexus and sub-ependymal germinal zones. Increased IGF-1 immunoreactivity, distributed as IGF1R, was detected 4 h after rhIGF-1/rhIGFBP-3 administration. The rhIGF-1/rhIGFBP-3 treatment led to upregulation of choroid plexus genes involved in vascular maturation and structure, with corresponding protein translation for most of these genes. The preterm rabbit pup model is well suited for evaluation of IGF-1-based prevention of IVH. Administration of rhIGF-1/rhIGFBP-3 affects cerebrovascular maturation, suggesting a role for it in preventing preterm IVH.

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial.

OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784.

Lipoprotein-associated phospholipase A2, a novel cardiovascular inflammatory marker, in HIV-infected patients.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging biomarker of cardiovascular disease. This study was conducted to describe the distribution of Lp-PLA2 in a cohort of human immunodeficiency virus (HIV)-infected adults and to determine associations between Lp-PLA2, cardiometabolic risk factors, and subclinical atherosclerosis in this population. METHODS: Lp-PLA2 was assessed in 341 (25% women, 52% white, 74% on highly active antiretroviral therapy [HAART]) participants of a cohort with detailed characterization of atherogenic risk factors, including surrogate markers of carotid and coronary atherosclerosis. RESULTS: Mean Lp-PLA2 mass was 313 ± 105 ng/mL and activity 173 ± 49 nmol/minute/mL. Seventy-five percent of participants had abnormal Lp-PLA2. Those in the highest Framingham Risk Score tertile had significantly higher Lp-PLA2 activity. Participants with abnormal carotid intima-media thickness (cIMT) had higher Lp-PLA2 mass and activity. Those with coronary artery calcium (CAC) scores >100 had significantly higher Lp-PLA2 mass than those with lower or nondetectable calcium. Those on HAART and protease inhibitor (PI)-based treatment had significantly higher Lp-PLA2 mass and activity than those who were treatment-naive or not on PIs. In multivariate regression, HAART and PI use were positively associated with Lp-PLA2 activity and mass after adjusting for age, race, sex, low-density and high-density lipoprotein cholesterol levels, triglyceride level, and smoking. Adding Lp-PLA2 activity tertiles to the model improved the predictive value for abnormal common cIMT, but not internal cIMT or CAC score. CONCLUSIONS: Lp-PLA2 is highly abnormal in HIV-infected patients and is associated with several cardiovascular and HIV treatment-specific risk factors. Lp-PLA2 may be used as an additional and more vascular specific biomarker for cardiovascular risk stratification in HIV-positive patients.

Urinary eicosanoid metabolites in HIV-infected women with central obesity switching to raltegravir: an analysis from the women, integrase, and fat accumulation trial.

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m(2) completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus -0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥ 50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study.

Burden of Treatments for Respiratory Complications in Extremely Premature Infants: Interviews with Caregivers.

Introduction: Extremely premature (EP) infants (<28 weeks gestational age) with respiratory conditions after discharge from the neonatal intensive care unit (NICU) impose a significant burden on caregivers. This study explored caregiver burden post-NICU discharge and perceptions of meaningful change in infant chronic respiratory morbidity. Methods: Adult primary caregivers of EP infants 3-14 months corrected age were recruited through patient advocacy organizations or hospital centers in the USA, Northern Ireland, Germany, and Japan and interviewed by phone. Interviews explored caregiver experiences with infants with respiratory conditions, associated treatment burden, and meaningful change in infant respiratory morbidity as measured by treatment use. Qualitative analysis of interview data was performed using MAXQDA software. Sociodemographic data were summarized using descriptive statistics. Results: Forty-five caregivers (95.6% female) of EP infants were interviewed. Respiratory morbidities post-NICU discharge included coughing (78%), breathing difficulties (76%), wheezing (58%), and bronchopulmonary dysplasia/chronic lung disease of prematurity (56%). Respiratory medications were required by 87% of infants, 80% used home respiratory technology support (e.g., supplemental oxygen), 38% were re-hospitalized, and 33% had emergency department visits. Caregivers considered visits to the emergency department to be the most burdensome treatment requirement they experienced, and reduction in the number of emergency department visits was considered the most meaningful change in treatment use. Conclusion: These findings underscore the significant burden faced by caregivers of EP infants with respiratory morbidities. Development of treatments for respiratory complications should take into consideration the concerns and preferences of caregivers in order to provide a meaningful benefit.

Development of the PREMature Infant Index (PREMII™), a clinician-reported outcome measure assessing functional status of extremely preterm infants.

BACKGROUND: Comprehensive measures to evaluate the effectiveness of medical interventions in extremely preterm infants are lacking. Although length of stay is used as an indicator of overall health among preterm infants in clinical studies, it is confounded by nonmedical factors (e.g. parental readiness and availability of home nursing support). OBJECTIVES: To develop the PREMature Infant Index (PREMII™), an electronic content-valid clinician-reported outcome measure for assessing functional status of extremely preterm infants (<28 weeks gestational age) serially over time in the neonatal intensive care unit. We report the development stages of the PREMII, including suggestions for scoring. METHODS: We developed the PREMII according to US Food and Drug Administration regulatory standards. Development included five stages: (1) literature review, (2) clinical expert interviews, (3) Delphi panel survey, (4) development of items/levels, and (5) cognitive interviews/usability testing. Scoring approaches were explored via an online clinician survey. RESULTS: Key factors reflective of functional status were identified by physicians and nurses during development of the PREMII, as were levels within each factor to assess functional status. The resulting PREMII evaluates eight infant health factors: respiratory support, oxygen administration, apnea, bradycardia, desaturation, thermoregulation, feeding, and weight gain, each scored with three to six gradations. Factor levels are standardized on a 0-100 scale; resultant scores are 0-100. No usability issues were identified. The online clinician survey identified optimal scoring methods to capture functional status at a given time point. CONCLUSIONS: Our findings support the content validity and usability of the PREMII as a multifunction outcome measure to assess functional status over time in extremely preterm infants. Psychometric validation is ongoing.

Prevalence of chronic respiratory morbidity, length of stay, inpatient readmissions, and costs among extremely preterm infants with bronchopulmonary dysplasia.

Objective: To evaluate the prevalence of chronic respiratory morbidity (CRM) in preterm infants (born ≤28 weeks gestational age (GA)) and compare healthcare resource utilization and costs among infants with/without CRM, and with/without bronchopulmonary dysplasia (BPD).Methods: Commercial claims data from the Truven MarketScan database were retrospectively analyzed. Included infants were born ≤28 weeks GA and admitted to a neonatal intensive care unit (January 2009-June 2016). Continuous insurance eligibility was required from birth through 1 year (CRM/no CRM cohorts) or ≥3 months (BPD/no BPD cohorts) CA or death.Results: CRM analysis included 1782 infants; 29.0% had CRM. BPD analysis included 2805 infants; 61.1% had BPD. The mean birth hospital length of stay was longer in infants with CRM versus those with no CRM (p < 0.0001). In infants with CRM or BPD, hospital readmission rates were significantly increased versus those without (both p < 0.0001). Total health care costs were significantly higher in infants with CRM (p = 0.0488) and BPD (p < 0.0001) versus those without. After birth hospitalization, outpatient visits and hospital readmissions accounted for most of the costs for the CRM and BPD cohorts.Conclusion: CRM and BPD following extremely preterm birth impose a significant health care burden.

Development of a severity scale to assess chronic lung disease after extremely preterm birth.

OBJECTIVE: Chronic lung disease of prematurity (CLDP) is a frequent complication of prematurity. We aimed to identify what clinicians believe are the most important factors determining the severity of CLDP in extremely preterm infants (<28 weeks gestational age) after discharge from the neonatal intensive care unit (NICU) through 12 months corrected age (CA), and to evaluate how these factors should be weighted for scoring, to develop a CLDP severity scale. STUDY DESIGN: Clinicians completed a three-round online survey utilizing Delphi methodology. Clinicians rated the importance of various factors used to evaluate the severity of CLDP, from 0 (not at all important) to 10 (very important) for the period between discharge home from the NICU and 12 months CA. Fourteen factors were considered in Round 1; 13 in Rounds 2 and 3. The relative importance of factors was explored via a set of 16 single-profile tasks (i.e., hypothetical patient profiles with varying CLDP severity levels). RESULTS: Overall, 91 clinicians from 11 countries who were experienced in treating prematurity-related lung diseases completed Round 1; 88 completed Rounds 2 and 3. Based on Round 3, the most important factors in determining CLDP severity were mechanical ventilation (mean absolute importance rating, 8.89), supplemental oxygen ≥2 L/min (8.49), rehospitalizations (7.65), and supplemental oxygen <2 L/min (7.56). Single-profile tasks showed that supplemental oxygen had the greatest impact on profile classification. CONCLUSION: The most important factors for clinicians assigning CLDP severity during infancy were mechanical ventilation, supplemental oxygen ≥2 L/min, and respiratory-related rehospitalizations.

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start.

Health Care Burden of Bronchopulmonary Dysplasia Among Extremely Preterm Infants.

Background: Infants born extremely preterm are at high risk of developing bronchopulmonary dysplasia (BPD). This study aimed to assess the incremental health care burden of BPD and associated comorbidities among extremely preterm infants in the United States. Methods: Health service claims in the Premier Perspective database were retrospectively analyzed for infants born at ≤28 weeks gestation who were admitted to neonatal intensive care during birth hospitalization and survived to a postmenstrual age of ≥36 weeks. Gestational age (GA) at birth and BPD status of infants was determined based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes recorded in the database. Results: Of the 12,017 infants included, 4,904 (40.8%) had BPD. BPD increased with decreasing GA: 67.4% of infants born at <24 weeks GA had BPD vs. 28.7% of those born at 27-28 weeks. Infants with BPD had significantly longer hospital stays following birth than those without (mean [standard deviation (SD)] 102 [34] vs. 83 [24] days, respectively, P < 0.001), and incurred higher total charges (mean [SD] $799,499 [$535,528] vs. $588,949 [$377,137], respectively, P < 0.001). Mean total charges incurred during index hospitalization decreased as GA at birth increased, with GA having a bigger effect than presence or absence of BPD. During their first year, infants with BPD had a higher in-hospital late mortality rate than those without (1.9 vs. 0.6%), and were more likely to have two or more hospital encounters following birth hospitalization (58.0 vs. 48.2%). Among infants who had two or more encounters after discharge, those with BPD experienced a higher percentage of pulmonary symptoms than those without (46.3 vs. 38.9%). Comparison with infants who did not have BPD, retinopathy of prematurity, or intraventricular hemorrhage showed that BPD is the main complication contributing to increased length of stay, costs, in-hospital mortality, and additional health care encounters. Conclusion: BPD is a key contributor to the large health care burden associated with extremely preterm birth. However, GA at birth has a bigger effect on health care costs for extremely preterm infants than the presence of BPD.

Interaction of daptomycin with two recombinant thromboplastin reagents leads to falsely prolonged patient prothrombin time/International Normalized Ratio results.

A cluster of patients experiencing elevations of International Normalized Ratio without clinical bleeding in temporal association with daptomycin therapy was identified during postmarketing safety surveillance. A common element was the thromboplastin reagent used for the laboratory assay. The present study evaluated the effect of daptomycin on measured prothrombin time using commercially available thromboplastin reagent kits commonly used in the United States. Thirty reagent kits were obtained. Daptomycin was added to pooled normal human plasma samples to achieve final concentrations of 0-200 microg/ml. Quality control ranges were established for each reagent kit using normal and abnormal control plasmas. Triplicate assays of the prothrombin time were performed on the daptomycin-spiked plasma samples using each of the 30 kits. The activated partial thromboplastin time and thrombin time were also assessed. Statistical comparisons of interest were performed using analysis of variance with the Bonferroni t-test for multiple comparisons; alpha = 0.05 was used. Addition of daptomycin to human plasma samples dose-dependently prolonged measured prothrombin times when two recombinant thromboplastin reagents were utilized. The findings were statistically and clinically significant. No clinically meaningful effect was observed with the other reagents. The activated partial thromboplastin time and thrombin time were not affected. Prolonged International Normalized Ratio patient values were an artifact caused by the interaction of daptomycin with the in-vitro prothrombin time test reagent; an in-vivo anticoagulant effect was not observed. Healthcare providers should consider a possible drug-laboratory test interaction if prolonged prothrombin time or elevated International Normalized Ratio values are observed in patients receiving daptomycin.

Metabolic syndrome and subclinical atherosclerosis in patients infected with HIV.

BACKGROUND: The present study examines the association between carotid and coronary atherosclerosis and metabolic syndrome in human immunodeficiency virus (HIV)-infected adults. METHODS: We measured the common and internal carotid intima-media thickness (c-IMT) using B-mode ultrasonography, and we measured coronary artery calcium (CAC) using high-resolution, electrocardiographic, synchronized, computed tomography, for 314 HIV-infected men and women. Metabolic syndrome was defined by National Cholesterol Education Program/Adult Treatment Panel III criteria. We compared the c-IMT measurements and CAC scores of patients with metabolic syndrome with the scores of those without metabolic syndrome using a Wilcoxon test for continuous variables and a chi2 test for categorical variables. To examine the association between surrogate markers and metabolic syndrome, we used logistic regression analysis. RESULTS: Participants with metabolic syndrome were more likely to have a common c-IMT measurement >0.8 mm than were those without metabolic syndrome (17% vs.7%; P=.009), but both groups were equally likely to have an internal c-IMT measurement >1.0 mm (20% vs. 13%; P=.15). Any positive CAC score was more likely to occur for participants with metabolic syndrome (80.3% vs. 46.7%; P<.0001). In a multivariate model adjusted for sex, age, ethnicity, and smoking status, participants with metabolic syndrome were more likely than those without metabolic syndrome to have an abnormal common c-IMT measurement (odds ratio [OR], 2.9; P=.020) and detectable CAC scores (OR, 4.9; P<.0001) but not a higher internal c-IMT measurement (OR, 1.6; P=.255). CONCLUSION: Our study demonstrates that HIV-infected individuals with metabolic syndrome may be at increased risk for subclinical atherosclerosis and supports screening for metabolic syndrome among HIV-infected patients at risk for cardiovascular disease.

Risk of cardiovascular disease in a cohort of HIV-infected adults: a study using carotid intima-media thickness and coronary artery calcium score.

BACKGROUND: There is concern that human immunodeficiency virus (HIV) infection and the use of highly active antiretroviral therapy lead to accelerated atherosclerosis and increased risk of cardiovascular disease. We measured 2 surrogate markers of subclinical atherosclerosis, carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) scores, in HIV-infected adults. METHODS: A cross-sectional analysis of 242 men and 85 women with HIV infection was used. Carotid ultrasonography and coronary computed tomography were performed, and their associations with cardiovascular risk factors were examined. RESULTS: Among men, the mean (+/- standard deviation [SD]) common c-IMT was 0.62+/-0.2 mm, the mean (+/-SD) internal c-IMT was 0.76+/-0.5 mm, and 136 patients (56.1%) had detectable CAC. Among women, the mean (+/-SD) common c-IMT was 0.59+/-0.2 mm, the mean (+/-SD) internal c-IMT was 0.66+/-0.4 mm, and 40 patients (47.1%) had detectable CAC. Neither the c-IMT nor the CAC score differed by antiretroviral therapy class or individual medications for either sex. For men, age and waist circumference independently predicted common c-IMT; age, systolic blood pressure, and high-sensitivity C-reactive protein level independently predicted internal c-IMT; and age, apolipoprotein B level, and high-sensitivity C-reactive protein level independently predicted CAC score. For women, age and body mass index independently predicted common c-IMT; age independently predicted internal c-IMT; and age and glucose level independently predicted CAC score. CONCLUSIONS: Our participants had more abnormal surrogate markers than expected at a relatively young age, but those were not associated with use of highly active antiretroviral therapy or protease inhibitors. At present, the positive associations were primarily with traditional and novel cardiovascular risk factors. Some HIV-specific (not treatment-specific) factors were observed; they may become more evident with prolonged HIV infection and treatment.

Transmission of infectious diseases during commercial air travel.

Because of the increasing ease and affordability of air travel and mobility of people, airborne, food-borne, vector-borne, and zoonotic infectious diseases transmitted during commercial air travel are an important public health issue. Heightened fear of bioterrorism agents has caused health officials to re-examine the potential of these agents to be spread by air travel. The severe acute respiratory syndrome outbreak of 2002 showed how air travel can have an important role in the rapid spread of newly emerging infections and could potentially even start pandemics. In addition to the flight crew, public health officials and health care professionals have an important role in the management of infectious diseases transmitted on airlines and should be familiar with guidelines provided by local and international authorities.

Neonatal death: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.

More than 40% of all deaths in children under 5 years of age occur during the neonatal period: the first month of life. Immunization of pregnant women has proven beneficial to both mother and infant by decreasing morbidity and mortality. With an increasing number of immunization trials being conducted in pregnant women, as well as roll-out of recommended vaccines to pregnant women, there is a need to clarify details of a neonatal death. This manuscript defines levels of certainty of a neonatal death, related to the viability of the neonate, who confirmed the death, and the timing of the death during the neonatal period and in relation to immunization of the mother.

Neonatal infections: Case definition and guidelines for data collection, analysis, and presentation of immunisation safety data.

Maternal vaccination is an important area of research and requires appropriate and internationally comparable definitions and safety standards. The GAIA group, part of the Brighton Collaboration was created with the mandate of proposing standardised definitions applicable to maternal vaccine research. This study proposes international definitions for neonatal infections. The neonatal infections GAIA working group performed a literature review using Medline, EMBASE and the Cochrane collaboration and collected definitions in use in neonatal and public health networks. The common criteria derived from the extensive search formed the basis for a consensus process that resulted in three separate definitions for neonatal blood stream infections (BSI), meningitis and lower respiratory tract infections (LRTI). For each definition three levels of evidence are proposed to ensure the applicability of the definitions to different settings. Recommendations about data collection, analysis and presentation are presented and harmonized with the Brighton Collaboration and GAIA format and other existing international standards for study reporting.

Infectious Risks of Air Travel.

Infectious diseases are still among the leading causes of death worldwide due to their persistence, emergence, and reemergence. As the recent Ebola virus disease and MERS-CoV outbreaks demonstrate, the modern epidemics and large-scale infectious outbreaks emerge and spread quickly. Air transportation is a major vehicle for the rapid spread and dissemination of communicable diseases, and there have been a number of reported outbreaks of serious airborne diseases aboard commercial flights including tuberculosis, severe acute respiratory syndrome, influenza, smallpox, and measles, to name a few. In 2014 alone, over 3.3 billion passengers (a number equivalent to 42% of the world population) and 50 million metric tons of cargo traveled by air from 41,000 airports and 50,000 routes worldwide, and significant growth is anticipated, with passenger numbers expected to reach 5.9 billion by 2030. Given the increasing numbers of travelers, the risk of infectious disease transmission during air travel is a significant concern, and this chapter focuses on the current knowledge about transmission of infectious diseases in the context of both transmissions within the aircraft passenger cabin and commercial aircraft serving as vehicles of worldwide infection spread.

Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat.

BACKGROUND: Tesamorelin, a synthetic analog of human growth hormone-releasing factor, decreases visceral adipose tissue (VAT) in human immunodeficiency virus (HIV)-infected patients with lipodystrophy. OBJECTIVES: 1) To evaluate the utility of patient characteristics and validated disease-risk scores, namely indicator variables for the metabolic syndrome defined by the International Diabetes Federation (MetS-IDF) or the National Cholesterol Education Program (MetS-NCEP) and the Framingham Risk Score (FRS), as predictors of VAT reduction during tesamorelin therapy at 3 and 6 months, and 2) To explore the characteristics of patients who reached a threshold of VAT <140 cm2, a level associated with lower risk of adverse health outcomes, after 6 months of treatment with tesamorelin. METHODS: Data were analyzed from two Phase 3 studies in which HIV-infected patients with excess abdominal fat were randomized in a 2:1 ratio to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) subcutaneously daily for 6 months, using ANOVA and ANCOVA models. RESULTS: Metabolic syndrome (MetS-IDF or MetS-NCEP) and FRS were significantly associated with VAT at baseline. Presence of metabolic syndrome ([MetS-NCEP), triglyceride levels >1.7 mmol/L, and white race had a significant impact on likelihood of response to tesamorelin after 6 months of therapy (interaction p-values 0.054, 0.063, and 0.025, respectively). No predictive factors were identified at 3 months. The odds of a VAT reduction to <140 cm2 for subjects treated with tesamorelin was 3.9 times greater than that of subjects randomized to placebo after controlling for study, gender, baseline body mass index (BMI) and baseline VAT (95% confidence interval [CI] 2.03; 7.44). CONCLUSIONS: Individuals with baseline MetS-NCEP, elevated triglyceride levels, or white race were most likely to experience reductions in VAT after 6 months of tesamorelin treatment. The odds of response of VAT <140 cm2 was 3.9 times greater for tesamorelin-treated patients than that of patients receiving placebo.

Switch to Raltegravir From Protease Inhibitor or Nonnucleoside Reverse-Transcriptase Inhibitor Does not Reduce Visceral Fat In Human Immunodeficiency Virus-Infected Women With Central Adiposity.

Human immunodeficiency virus-infected women with central adiposity switched to raltegravir-based antiretroviral therapy immediately or after 24 weeks. No statistically significant changes in computed tomography-quantified visceral adipose tissue (VAT) or subcutaneous fat were observed, although 48 weeks of raltegravir was associated with a 6.4% VAT decline. Raltegravir for 24 weeks was associated with improvements in lipids.