MEASURING LOW BIRTHWEIGHT AND PRETERM BIRTH IN RURAL NEPAL: VALIDATING MATERNAL REPORTS, EXPLORING MATERNAL COMPREHENSION AND TESTING NEW METHODS FOR MULTIPLE IMPUTATION AND ADJUSTMENT

Between 2011 and 2016, neonatal mortality in Nepal fell from 33 to 21 deaths per 1000 live births. With global resources allocated to scale-up interventions to meet the Sustainable Development Goals, tracking coverage of interventions and estimating the population in need are essential. Maternal reports collected as part of national surveys are often the only source of child health information available to generate nationally-representative coverage indicators in low-income countries. This research examines the validity of indicators calculated from maternal reports and explores possible strategies to improve these estimates in data collection and in analysis. Nested in a large community-based randomized trial in rural Nepal, this thesis aims to address the three following research questions: 1. Are the low birthweight (LBW) and preterm birth indicators valid when calculated from maternal reports? 2. What are possible reasons for poor validity in these indicators? 3. How valid are new methods to adjust LBW calculated from recall data? We interviewed mothers from the trial one to 24 months after birth about their child’s health in the first week of life and compared reports to data collected prospectively in the trial to assess validity of their responses. We conducted focus groups with study staff and in-depth interviews with mothers who provided discordant responses to explore maternal understanding of questions. We then applied previously developed methods to multiply impute and adjust the LBW indicator to our dataset in a validation exercise. Indicators generated from maternal reports underestimated the burden of LBW and preterm births in this study setting. The LBW indicator using reported birthweight in grams had low individual-level accuracy (AUC 0.69, 95% CI 0.67 to 0.72) and high population-level bias (IF 0.62, 95% CI 0.52 to 0.72). LBW using reported birth size and the preterm birth indicator had lower individual-level accuracy and higher population-level bias up to 24 months following birth. Challenges related to translations of questions and possible cultural-specific perceptions about birth size may have contributed to the poor validity of these indicators. Visual aids of newborns of varying sizes may help to scale relative birth size questions and facilitate more accurate maternal reports in different settings. In an analysis where patterns in missingness and heaping were simulated, new methods to multiply impute missing birthweights and adjust the LBW indicator performed better than previous methods

Miro, MCU, and calcium: Bridging our understanding of mitochondrial movement in axons

Neurons are extremely polarized structures with long axons and dendrites, which require proper distribution of mitochondria and maintenance of mitochondrial dynamics for neuronal functions and survival. Indeed, recent studies show that various neurological disorders are linked to mitochondrial transport in neurons. Mitochondrial anterograde transport is believed to deliver metabolic energy to synaptic terminals where energy demands are high, while mitochondrial retrograde transport is required to repair or remove damaged mitochondria in axons. It has been suggested that Ca2+ plays a key role in regulating mitochondrial transport by altering the configuration of mitochondrial protein, miro. However, molecular mechanisms that regulate mitochondrial transport in neurons still are not well characterized. In this review, we will discuss the roles of miro in mitochondrial transport and how the recently identified components of the mitochondrial calcium uniporter add to our current model of mitochondrial mobility regulation.open2

Measuring the Effects of Massage on Exercise Performance and Cardiopulmonary Response in Children With and Without Heart Disease: A Pilot Study

Background: Congenital heart disease, a common and serious birth defect, affects 8 per 1000 live born infants. Decreased exercise capacity and development of obesity is common in this population. These children may benefit from therapies, such as massage therapy, that could enhance cardiovascular and skeletal muscle function when they exercise. Purpose: A pilot study conducted at the pediatric cardiology clinic of the Mattel Children’s Hospital of the University of California–Los Angeles examined the safety and feasibility of measuring the effects of pre-exercise massage on exercise performance and cardiopulmonary response in children with and without heart disease. Participants and Methods: Sixteen children (mean age: 9.2 ± 2.2 years) participated in the study. Ten participants had various forms of heart disease, and six children were healthy. A female certified massage therapist with specialized training in pediatric massage provided a 30-minute massage to the participants. Using a standard protocol, each participant underwent two exercise tests: one test with and one without pre-exercise massage. Heart rate, blood pressure, and oxygen uptake (VO2) were measured in the participants. Results: All recruited participants completed the study. No adverse events occurred during any of the exercise tests or massage sessions. Measurements during exercise with or without a preceding massage were compared, and the pre-exercise massage condition yielded a significantly higher heart rate and higher minute ventilation. Measurements during exercise in children with heart disease and in healthy participants showed no significant differences in peak heart rate, blood pressure, peak VO2, peak work rate, minute ventilation, or respiratory quotient. Conclusions: In this study, peak heart rate, peak VO2, and peak minute ventilation were higher when children received a massage before exercise testing. Larger studies will be needed to investigate the strength of this finding. Future studies should include measurements of anxiety and psychological factors in addition to cardiopulmonary measures

Transition Analysis for the HIFiRE-5 Vehicle

The Hypersonic International Flight Research and Experimentation (HIFiRE) 5 flight experiment by Air Force Research Laboratories and Australian Defense Science and Technology Organization is designed to provide in-flight boundary-layer transition data for a canonical 3D configuration at hypersonic Mach numbers. This paper outlines the progress, to date, on boundary layer stability analysis for the HIFiRE-5 flight configuration, as well as for selected test conditions from the wind tunnel experiments supporting the flight test. At flow conditions corresponding to the end of the test window, rather large values of linear amplification factor are predicted for both second mode (N>40) and crossflow (N>20) instabilities, strongly supporting the feasibility of first in-flight measurements of natural transition on a fully three-dimensional hypersonic configuration. Additional results highlight the rich mixture of instability mechanisms relevant to a large segment of the flight trajectory, as well as the effects of angle of attack and yaw angle on the predicted transition fronts for ground facility experiments at Mach 6

Measuring service quality and assessing its relationship to contraceptive discontinuation: A prospective cohort study in Pakistan and Uganda

Background: The quality of contraceptive counseling that women receive from their provider can influence their future contraceptive continuation. We examined (1) whether the quality of contraceptive service provision could be measured in a consistent way by using existing tools from 2 large-scale social franchises, and (2) whether facility quality measures based on these tools were consistently associated with contraceptive discontinuation.Methods: We linked existing, routinely collected facility audit data from social franchise clinics in Pakistan and Uganda with client data. Clients were women aged 15-49 who initiated a modern, reversible contraceptive method from a sampled clinic. Consented participants completed an exit interview and were contacted 3, 6, and 12 months later. We collapsed indicators into quality domains using theory-based categorization, created summative quality domain scores, and used Cox proportional hazards models to estimate the relationship between these quality domains and discontinuation while in need of contraception.Results: The 12-month all-modern method discontinuation rate was 12.5% among the 813 enrolled women in Pakistan and 5.1% among the 1,185 women in Uganda. We did not observe similar associations between facility-level quality measures and discontinuation across these 2 settings. In Pakistan, an increase in the structural privacy domain was associated with a 60% lower risk of discontinuation, adjusting for age and baseline method (PP=.005).Conclusions: We were not able to leverage existing, widely used quality measurement tools to create quality domains that were consistently associated with discontinuation in 2 study settings. Given the importance of contraceptive service quality and recent advances in indicator standardization in other areas, we recommend further effort to harmonize and simplify measurement tools to measure and improve contraceptive quality of care for all

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools

The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila. We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools. SIGNIFICANCE STATEMENT Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication

A Robust Determination of the Time Delay in 0957+561A,B and a Measurement of the Global Value of Hubble's Constant

Photometric monitoring of the gravitational lens system 0957+561A,B in the g and r bands with the Apache Point Observatory (APO) 3.5 m telescope during 1996 shows a sharp g band event in the trailing (B) image light curve at the precise time predicted from the observation of an event during 1995 in the leading (A) image with a delay of 415 days. This success confirms the "short delay," and the lack of any feature at a delay near 540 days rejects the "long delay" for this system, resolving a long-standing controversy. A series of statistical analyses of our light curve data yield a best fit delay of 417 +/- 3 days (95% confidence interval). Recent improvements in the modeling of the lens system (consisting of a galaxy and cluster) allow us to derive a value of the global (at z = 0.36) value of Hubble's constant H_0 using Refsdal's method, a simple and direct distance determination based on securely understood physics and geometry. The result is H_0 = 63 +/- 12 km/s/Mpc (for Omega = 1) where this 95% confidence interval is dominated by remaining lens model uncertainties.Comment: accepted by ApJ, AASTeX 4.0 preprint, 4 PostScript figure

KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline

Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality and reduction of elevated blood pressure (BP) remains an important intervention for slowing kidney disease progression. Over the past decade, the most appropriate BP target for initiation and titration of BP-lowering medications has been an area of intense research and debate within the clinical community. In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) in conjunction with several other professional societies released new hypertension guidelines based on data from a systematic review of clinical trials and observational data. While many of the recommendations in the ACC/AHA hypertension guideline are relevant to nephrology practice, BP targets and management strategies for patients receiving dialysis are not discussed. This Kidney Disease Outcomes Quality Initiative (KDOQI) commentary focuses largely on recommendations from the ACC/AHA hypertension guidelines that are pertinent to individuals at risk of chronic kidney disease or with non–dialysis-dependent chronic kidney disease. This KDOQI commentary also includes a brief discussion of the consensus statement regarding hypertension diagnosis and management for adults receiving maintenance dialysis published by the European Renal and Cardiovascular Medicine Working Group of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension. Overall, we support the vast majority of the ACC/AHA recommendations and highlight select areas in which best diagnosis and treatment options remain controversial

Intracellular interferons in fish : a unique means to combat viral infection

Peer reviewedPublisher PD

A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis

Introduction Rheumatoid arthritis (RA) is more common in females than males and sex steroid hormones may in part explain this difference. We conducted a case–control study nested within two prospective studies to determine the associations between plasma steroid hormones measured prior to RA onset and polymorphisms in the androgen receptor (AR), estrogen receptor 2 (ESR2), aromatase (CYP19) and progesterone receptor (PGR) genes and RA risk. Methods We genotyped AR, ESR2, CYP19, PGR SNPs and the AR CAG repeat in RA case–control studies nested within the Nurses\u27 Health Study (NHS), NHS II (449 RA cases, 449 controls) and the Women\u27s Health Study (72 cases, and 202 controls). All controls were matched on cohort, age, Caucasian race, menopausal status, and postmenopausal hormone use. We measured plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone binding globulin in 132 pre-RA samples and 396 matched controls in the NHS cohorts. We used conditional logistic regression models adjusted for potential confounders to assess RA risk. Results Mean age of RA diagnosis was 55 years in both cohorts; 58% of cases were rheumatoid factor positive at diagnosis. There was no significant association between plasma DHEAS, total testosterone, or calculated free testosterone and risk of future RA. There was no association between individual variants or haplotypes in any of the genes and RA or seropositive RA, nor any association for the AR CAG repeat. Conclusions Steroid hormone levels measured at a single time point prior to RA onset were not associated with RA risk in this study. Our findings do not suggest that androgens or the AR, ESR2, PGR, and CYP19 genes are important to RA risk in women