Gestational dating by metabolic profile at birth: a California cohort study.

BackgroundAccurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications.ObjectiveWe sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group.Study designWe evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11-20 weeks' gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions.ResultsAlong with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset.ConclusionWhen considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care

Primary antifungal prophylaxis for cryptococcal disease in HIV‐positive people

Background Cryptococcal disease remains one of the main causes of death in HIV‐positive people who have low cluster of differentiation 4 (CD4) cell counts. Currently, the World Health Organization (WHO) recommends screening HIV‐positive people with low CD4 counts for cryptococcal antigenaemia (CrAg), and treating those who are CrAg‐positive. This Cochrane Review examined the effects of an approach where those with low CD4 counts received regular prophylactic antifungals, such as fluconazole. Objectives To assess the efficacy and safety of antifungal drugs for the primary prevention of cryptococcal disease in adults and children who are HIV‐positive. Search methods We searched the CENTRAL, MEDLINE PubMed, Embase OVID, CINAHL EBSCOHost, WHO International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, conference proceedings for the International AIDS Society (IAS) and Conference on Retroviruses and Opportunistic Infections (CROI), and reference lists of relevant articles up to 31 August 2017. Selection criteria Randomized controlled trials of adults and children, who are HIV‐positive with low CD4 counts, without a current or prior diagnosis of cryptococcal disease that compared any antifungal drug taken as primary prophylaxis to placebo or standard care. Data collection and analysis Two review authors independently assessed eligibility and risk of bias, and extracted and analysed data. The primary outcome was all‐cause mortality. We summarized all outcomes using risk ratios (RR) with 95% confidence intervals (CI). Where appropriate, we pooled data in meta‐analyses. We assessed the certainty of the evidence using the GRADE approach. Main results Nine trials, enrolling 5426 participants, met the inclusion criteria of this review. Six trials administered fluconazole, while three trials administered itraconazole. Antifungal prophylaxis may make little or no difference to all‐cause mortality (RR 1.07, 95% CI 0.80 to 1.43; 6 trials, 3220 participants; low‐certainty evidence). For cryptococcal specific outcomes, prophylaxis probably reduces the risk of developing cryptococcal disease (RR 0.29, 95% CI 0.17 to 0.49; 7 trials, 5000 participants; moderate‐certainty evidence), and probably reduces deaths due to cryptococcal disease (RR 0.29, 95% CI 0.11 to 0.72; 5 trials, 3813 participants; moderate‐certainty evidence). Fluconazole prophylaxis may make no clear difference to the risk of developing clinically resistant Candida disease (RR 0.93, 95% CI 0.56 to 1.56; 3 trials, 1198 participants; low‐certainty evidence); however, there may be an increased detection of fluconazole‐resistant Candida isolates from surveillance cultures (RR 1.25, 95% CI 1.00 to 1.55; 3 trials, 539 participants; low‐certainty evidence). Antifungal prophylaxis was generally well‐tolerated with probably no clear difference in the risk of discontinuation of antifungal prophylaxis compared with placebo (RR 1.01, 95% CI 0.91 to 1.13; 4 trials, 2317 participants; moderate‐certainty evidence). Antifungal prophylaxis may also make no difference to the risk of having any adverse event (RR 1.07, 95% CI 0.88 to 1.30; 4 trials, 2317 participants; low‐certainty evidence), or a serious adverse event (RR 1.08, 95% CI 0.83 to 1.41; 4 trials, 888 participants; low‐certainty evidence) when compared to placebo or standard care. Authors' conclusions Antifungal prophylaxis reduced the risk of developing and dying from cryptococcal disease. Therefore, where CrAG screening is not available, antifungal prophylaxis may be used in patients with low CD4 counts at diagnosis and who are at risk of developing cryptococcal disease

Economic compensation interventions to increase uptake of voluntary medical male circumcision for HIV prevention: A systematic review and meta-analysis.

BackgroundEconomic compensation interventions may help support higher voluntary medical male circumcision (VMMC) coverage in priority sub-Saharan African countries. To inform World Health Organization guidelines, we conducted a systematic review of economic compensation interventions to increase VMMC uptake.MethodsEconomic compensation interventions were defined as providing money or in-kind compensation, reimbursement for associated costs (e.g. travel, lost wages), or lottery entry. We searched five electronic databases and four scientific conferences for studies examining the impact of such interventions on VMMC uptake, HIV testing and safer-sex/risk-reduction counseling uptake within VMMC, community expectations about compensation, and potential coercion. We screened citations, extracted data, and assessed risk of bias in duplicate. We conducted random-effects meta-analysis. We also reviewed studies examining acceptability, values/preferences, costs, and feasibility.ResultsOf 2484 citations identified, five randomized controlled trials (RCTs) and three non-randomized controlled trials met our eligibility criteria. Studies took place in Kenya, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. Meta-analysis of four RCTs showed significant impact of any economic compensation on VMMC uptake (relative risk: 5.23, 95% CI: 3.13 to 8.76). RCTs of food/transport vouchers and conditional cash transfers generally showed increases in VMMC uptake, but lotteries, subsidized VMMC, and receiving a gift appeared somewhat less effective. Three non-randomized trials showed mixed impact. Six additional studies suggested economic compensation interventions were generally acceptable, valued for addressing key barriers, and motivating to men. However, some participants felt they were insufficiently motivating or necessary; one study suggested they might raise community suspicions. One study from South Africa found a program cost of US$91 per additional circumcision and US$450-$1350 per HIV infection averted.ConclusionsEconomic compensation interventions, particularly transport/food vouchers, positively impacted VMMC uptake among adult men and were generally acceptable to potential clients. Carefully selected economic interventions may be a useful targeted strategy to enhance VMMC coverage

Service delivery interventions to increase uptake of voluntary medical male circumcision for HIV prevention: A systematic review.

BackgroundVoluntary medical male circumcision (VMMC) remains an essential component of combination HIV prevention services, particularly in priority countries in sub-Saharan Africa. As VMMC programs seek to maximize impact and efficiency, and to support World Health Organization guidance, specific uptake-enhancing strategies are critical to identify.MethodsWe systematically reviewed the literature to evaluate the impact of service delivery interventions (e.g., facility layout, service co-location, mobile outreach) on VMMC uptake among adolescent and adult men. For the main effectiveness review, we searched for publications or conference abstracts that measured VMMC uptake or uptake of HIV testing or risk reduction counselling within VMMC services. We synthesized data by coding categories and outcomes. We also reviewed studies assessing acceptability, values/preferences, costs, and feasibility.ResultsFour randomized controlled trials and five observational studies were included in the effectiveness review. Studies took place in South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. They assessed a range of service delivery innovations, including community-, school-, and facility-based interventions. Overall, interventions increased VMMC uptake; some successfully improved uptake among age-specific subpopulations, but urban-rural stratification showed no clear trends. Interventions that increased adult men's uptake included mobile services (compared to static facilities), home-based testing with active referral follow-up, and facility-based HIV testing with enhanced comprehensive sexual education. Six acceptability studies suggested interventions were generally perceived to help men choose to get circumcised. Eleven cost studies suggested interventions create economies-of-scale and efficiencies. Three studies suggested such interventions were feasible, improving facility preparedness, service quality and quantity, and efficiencies.ConclusionsInnovative changes in male-centered VMMC services can improve adult men's and adolescent boys' VMMC uptake. Limited evidence on interventions that enhance access and acceptability show promising results, but evidence gaps persist due to inconsistent intervention definition and delivery, due in part to contextual relevance and limited age disaggregation

Dyslipidemia and Adherence to the Mediterranean Diet in Croatian HIV-Infected Patients during the First Year of Highly Active Antiretroviral Therapy

We investigated the association of adherence to the Mediterranean diet and other risk factors for dyslipidemia in HIV-infected Croatian patients during the first year of highly active antiretroviral therapy (HAART). Adherence to the Mediterranean diet was determined by a 150-item questionnaire; a 0 to 9-point diet scale was created that stratified respondents as having low adherence (<4 points) and moderate to high adherence (ł 4 points). We interviewed 117 participants between May 2004 and June 2005 and abstracted their serum lipid measurements taken during the first year of HAART. The values of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides increased most prominently in the first 3 to 6 months after initiation of HAART (average increase at 3 months: 25% for total cholesterol, 22% for LDL-cholesterol, 18% for HDL-cholesterol and 43% for triglycerides). A Mediterranean diet and physical activity had no effect on serum lipids. The mean total cholesterol was higher in participants receiving a combination of a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor compared to participants receiving a combination of nucleoside analogs with a non-nucleoside analog or a combination of nucleoside analogs and a protease inhibitor. Among individual drug treatments, indinavir/ritonavir had the most unfavorable lipid profile. We conclude that adherence to a Mediterranean diet does not influence serum lipid profiles during the first year of HAART

Isolation of galactosyltransferase from human milk and the determination of its N-terminal amino acid sequence

Galactosyltransferase (EC 2.4.1.22), purified to homogeneity from human milk by affinity chromatography, had an apparent molecular weight of 53,000 as determined by denaturing polyacrylamide gel electrophoresis. Subtration of the estimated contribution of the oligosaccharide portion of the molecule leaves a Mr of 47,000. An N-terminal amino acid sequence analysis of the isolated protein revealed a sequence similar to that found near the 5' end of a cDNA clone isolated by Shaper et al (11), which encodes a 35,500 molecular weight protein. Either the molecular weight of galactosyltransferase, has been overestimated, or a discrepancy exists between the actual molecular weight of galactosyltransferase and that predicted by the bovine cDNA clone isolated by Shaper et al (11).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26099/1/0000175.pd

Isolation of a cDNA coding for human galactosyltransferase

Human milk galactosyltransferase (EC 2.4.1.22) was purified to homogeneity using affinity chromatography. Edman degradation was used to determine the amino acid sequences of eight peptide fragments isolated from the purified enzyme. A 60-mer "optimal" oligonucleotide probe that corresponded to the amino acid sequence of one of the galactosyltransferase peptide fragments was constructed and used to screen a [lambda]gt10 cDNA library. Two hybridization-positive recombinant phages, each with a 1.7 Kbp insert, were detected among 3 x 106 recombinant [lambda]gt10 phages. Sequencing of one of the cDNA inserts revealed a 783 bp galactosyltransferase coding sequence. The remainder of the sequence corresponded to the 3'-region of the mRNA downstream from the termination codon.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26068/1/0000142.pd

Telomeric expression sites are highly conserved in trypanosoma brucei

Subtelomeric regions are often under-represented in genome sequences of eukaryotes. One of the best known examples of the use of telomere proximity for adaptive purposes are the bloodstream expression sites (BESs) of the African trypanosome Trypanosoma brucei. To enhance our understanding of BES structure and function in host adaptation and immune evasion, the BES repertoire from the Lister 427 strain of T. brucei were independently tagged and sequenced. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of expression site associated genes (ESAGs). The consequences of duplicated or missing ESAGs, including ESAG9, a newly named ESAG12, and additional variant surface glycoprotein genes (VSGs) were evaluated by functional assays after BESs were tagged with a drug-resistance gene. Phylogenetic analysis of constituent ESAG families suggests that BESs are sequence mosaics and that extensive recombination has shaped the evolution of the BES repertoire. This work opens important perspectives in understanding the molecular mechanisms of antigenic variation, a widely used strategy for immune evasion in pathogens, and telomere biology

Atypical disengagement from faces and its modulation by the control of eye fixation in children with Autism Spectrum Disorder

By using the gap overlap task, we investigated disengagement from faces and objects in children (9–17 years old) with and without autism spectrum disorder (ASD) and its neurophysiological correlates. In typically developing (TD) children, faces elicited larger gap effect, an index of attentional engagement, and larger saccade-related event-related potentials (ERPs), compared to objects. In children with ASD, by contrast, neither gap effect nor ERPs differ between faces and objects. Follow-up experiments demonstrated that instructed fixation on the eyes induces larger gap effect for faces in children with ASD, whereas instructed fixation on the mouth can disrupt larger gap effect in TD children. These results suggest a critical role of eye fixation on attentional engagement to faces in both groups

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one