Stillbirth risk across pregnancy by size for gestational age in Western Cape Province, South Africa: Application of the fetuses-at-risk approach using perinatal audit data

Background. There is little published work on the risk of stillbirth across pregnancy for small-for-gestational-age (SGA) and large-for-gestational (LGA) pregnancies in low-resource settings.Objectives. To compare stillbirth risk across pregnancy between SGA and appropriate-for-gestational-age (AGA) pregnancies in Western Cape Province, South Africa (SA).Methods. A retrospective audit of perinatal mortality data using data from the SA Perinatal Problem Identification Program was conducted. All audited stillbirths with information on size for gestational age (N=677) in the Western Cape between October 2013 and August 2015 were included in the study. The Western Cape has antenatal care (ANC) appointments at booking and at 20, 26, 32, 34, 36, 38 and 41 (if required) weeks’ gestation. A fetuses-at-risk approach was adopted to examine stillbirth risk (28 - 42 weeks’ gestation, ≥1 000 g) across gestation by size for gestational age (SGA <10th centile Theron growth curves, LGA >90th centile). Stillbirth risk was compared between SGA/LGA and AGA pregnancies.Results. SGA pregnancies were at an increased risk of stillbirth compared with AGA pregnancies between 30 and 40 weeks’ gestation, with the relative risk (RR) ranging from 3.5 (95% confidence interval (CI) 1.6 - 7.6) at 30 weeks’ gestation to 15.3 (95% CI 8.8 - 26.4) at 33 weeks’ gestation (p<0.001). The risk for LGA babies increased by at least 3.5-fold in the later stages of pregnancy (from 37 weeks) (p<0.001). At 38  weeks, the greatest increased risk was seen for LGA pregnancies (RR 6.6, 95% CI 3.1 - 14.2; p<0.001).Conclusions. There is an increased risk of stillbirth for SGA pregnancies, specifically between 33 and 40 weeks’ gestation, despite fortnightly ANC visits during this time. LGA pregnancies are at an increased risk of stillbirth after 37 weeks’ gestation. This high-risk period highlights potential issues with the detection of fetuses at risk of stillbirth even when ANC is frequent.

The Relationship of Upwelling to Mussel Production in the Rias on the Western Coast of Spain

We have calculated an upwelling index for each month over a 17-year period (1969-1985) for a point off the western coast of Spain. We interpret April through September values of the index to indicate the flux of nitrate-rich water in the Spanish Rias. The index representing the 6-month upwelling series has been correlated with an index representing the conditions of mussels grown during that season on rafts in Ria de Arosa. Two seasons represent extreme upwelling conditions over the 17-year sampling period: 1977 when the upwelling index was the highest, and 1983 when it was the lowest. A comparison of the condition of mussels during these years showed that meat content was double in 1977. We suggest, by this study, that long range forecasts of synoptic scale weather patterns could be used to predict the potential nutritional value of mussels harvested in the rias of Spain

Targeted Molecular Iron Oxide Contrast Agents for Imaging Atherosclerotic Plaque.

Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits1. To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo. Aim: To develop a range of MRI contrast agents based on superparamagnetic iron oxide nanoparticles (SPIONs), and test them in a murine model of advanced atherosclerosis. Methods: Nanoparticles of four core sizes were synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1-octadecene) (PMAO), poly(ethyleneimine) (PEI) or alendronate, then characterised for core size, hydrodynamic size, surface potential and relaxivity. On the basis of these results, one candidate was selected for further studies. In vivo studies using 10 nm PMAO-coated SPIONs were performed in ApoE -/- mice fed a western diet and instrumented with a perivascular cuff on the left carotid artery. Control ApoE -/- mice were fed a normal chow diet and were not instrumented. Mice were scanned on a 3T MR scanner (Philips Achieva) with the novel SPION contrast agent, and an elastin-targeted gadolinium agent that was shown previously to enable visualisation of plaque burden. Histological analysis was undertaken to confirm imaging findings through staining for macrophages, CX3CL1, elastin, tropoelastin, and iron. Results: The lead SPION agent consisted of a 10 nm iron oxide core with poly(maleicanhydride-alt-1-octadecene), (-36.21 mV, r2 18.806 mmol-1/s-1). The irregular faceting of the iron oxide core resulted in high relaxivity and the PMAO provided a foundation for further functionalisation on surface -COOH groups. The properties of the contrast agent, including the negative surface charge and hydrodynamic size, were designed to maximise circulation time and evade rapid clearance through the renal system or phagocytosis. In vitro testing showed that the SPION agent was non-toxic. In vivo results show that the novel contrast agent accumulates in similar vascular regions to a gadolinium-based contrast agent (Gd-ESMA) targeted to elastin, which accumulates in plaque. There was a significant difference in SPION signal between the instrumented and the contralateral non-instrumented vessels in diseased mice (p = 0.0411, student's t-test), and between the instrumented diseased vessel and control vessels (p = 0.0043, 0.0022, student's t-test). There was no significant difference between the uptake of either contrast agent between stable and vulnerable plaques (p = 0.3225, student's t-test). Histological verification was used to identify plaques, and Berlin Blue staining confirmed the presence of nanoparticle deposits within vulnerable plaques and co-localisation with macrophages. Conclusion: This work presents a new MRI contrast agent for atherosclerosis which uses an under-explored surface ligand, demonstrating promising properties for in vivo behaviour, is still in circulation 24 hours post-injection with limited liver uptake, and shows good accumulation in a murine plaque model

Digits: Two Reports on New Units of Scholarly Publication

The Digits team (Matt Burton, Matthew J. Lavin, Jessica Otis, and Scott B. Weingart) convened around the question of how we might share, preserve, and legitimize scholarship freed from the affordances of print. For the A.W. Mellon-funded Digits Planning Grant (2016-2018), the PIs had three goals: - Investigate the use of software containers for research in the sciences, social sciences, and humanities. - Assess the infrastructural needs of digital humanists around publishing and preserving web-centric scholarship. - Gather a team of experts to guide the above activities and plan how they might inform a beneficial intervention into the scholarly ecosystem. Through our investigation into the scholarly uses of containers, we discovered that the technical infrastructure needed to connect containers with digital publications is underdeveloped. We see potential for container technologies to facilitate existing digital scholarly publications and afford new forms of computational scholarship, but this process would first require a series of infrastructural bridges. The digital scholarship needs assessment we conducted, as well as our advisory board meetings, made it clear that a targeted technological intervention alone would not be enough to welcome web-first publications into the scholarly ecosystem; in-tandem cultural and institutional changes are also necessary

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage.

A defective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome

Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin

Dysfunctional elastin turnover plays a major role in the progression of atherosclerotic plaques. Failure of tropoelastin cross-linking into mature elastin leads to the accumulation of tropoelastin within the growing plaque, increasing its instability. Here we present Gd4-TESMA, an MRI contrast agent specifically designed for molecular imaging of tropoelastin within plaques. Gd4-TESMA is a tetrameric probe composed of a tropoelastin-binding peptide (the VVGS-peptide) conjugated with four Gd(III)-DOTA-monoamide chelates. It shows a relaxivity per molecule of 34.0 ± 0.8 mM-1 s-1 (20 MHz, 298 K, pH 7.2), a good binding affinity to tropoelastin (KD = 41 ± 12 μM), and a serum half-life longer than 2 h. Gd4-TESMA accumulates specifically in atherosclerotic plaques in the ApoE-/- murine model of plaque progression, with 2 h persistence of contrast enhancement. As compared to the monomeric counterpart (Gd-TESMA), the tetrameric Gd4-TESMA probe shows a clear advantage regarding both sensitivity and imaging time window, allowing for a better characterization of atherosclerotic plaques

Applying the international classification of diseases to perinatal mortality data, South Africa

OBJECTIVE : To examine the feasibility of applying the International Classification of Diseases-perinatal mortality (ICD-PM) coding to an existing data set in the classification of perinatal deaths. METHODS : One author, a researcher with a non-clinical public health background, applied the ICD-PM coding system to South Africa’s national perinatal mortality audit system, the Perinatal Problem Identification Program. The database for this study included all perinatal deaths (n = 26 810), defined as either stillbirths (of birth weight > 1000 g and after 28 weeks of gestation) or early neonatal deaths (age 0–7 days), that occurred between 1 October 2013 and 31 December 2016. A clinical obstetrician verified the coding. FINDINGS : The South African classification system does not include the timing of death; however, under the ICD-PM system, deaths could be classified as antepartum (n = 15 619; 58.2%), intrapartum (n = 3725; 14.0%) or neonatal (n = 7466; 27.8%). Further, the South African classification system linked a maternal condition to only 40.3% (10 802/26 810) of all perinatal deaths; this proportion increased to 68.9% (18 467/26 810) under the ICD-PM system. CONCLUSION : The main benefit of using the clinically relevant and user-friendly ICD-PM system was an enhanced understanding of the data, in terms of both timing of death and maternal conditions. We have also demonstrated that it is feasible to convert an existing perinatal mortality classification system to one which is globally comparable and can inform policy-makers internationally.http://www.who.int/bulletin/enam2019Afrikaan