Pregnancy-induced severe hypertriglyceridemia effectively treated with therapeutic plasmapheresis.

INTRODUCTION: Hypertriglyceridemia is associated with significant morbidity during pregnancy. Hypertriglyceridemia-induced pancreatitis (HTGP) is associated with genetically determined dyslipidemia or a secondary condition such as diabetes, alcohol, pregnancy, or medication use. The lack of data on the safety of drugs to be used to decrease triglyceride levels during pregnancy dictates that other strategies must be chosen. PATIENT AND METHODS: We describe a case of a pregnant woman with severe hypertriglyceridemia treated with two different techniques of plasmapheresis (Dual Filtration apheresis and Centrifugal Plasma Separation). RESULTS: The patient could be treated throughout the pregnancy, with good control of the triglycerides, and a healthy baby was born. CONCLUSION: Hypertriglyceridemia is a major issue during pregnancy. The use of plasmapheresis is a safe and efficient tool in that clinical scenario.

The predictive value of the sFlt-1/PlGF ratio in suspected preeclampsia in a New Zealand population: A prospective cohort study.

BACKGROUND: Internationally, placental growth factor (PlGF)-based tests are used as prognostic markers in suspected preeclampsia. However, Ministry of Health guidelines do not currently endorse PlGF-based tests in New Zealand (NZ). AIMS: To investigate the predictive value of soluble fms-like tyrosine kinase 1 (sFlt-1)/PlGF ratio in suspected preeclampsia in a NZ population. MATERIALS AND METHODS: A prospective cohort study of singleton pregnancies at 20+0 -36+6 weeks gestation with suspected preeclampsia as defined by Society of Obstetric Medicine Australia and NZ (SOMANZ) criteria. PRIMARY OBJECTIVE: to evaluate a sFlt-1/PlGF ratio >38 at ≤35+0 weeks gestation to predict birth ≤14 days. SECONDARY OBJECTIVES: to assess a sFlt-1/PlGF ratio cut-off of 38 at ≤37+0 weeks gestation, to rule out preeclampsia ≤1 week, rule in preeclampsia ≤4 weeks, and to predict perinatal outcome. Clinicians were blinded to sFlt-1/PlGF ratio results. RESULTS: Included were 222 participants, 19.4% Maori and 10.4% Pasifika. A sFlt-1/PlGF >38 predicted birth ≤14 days, positive predictive value (PPV) 51.4% (95% CI, 39.6-63.0) and negative predictive value (NPV) 95.9% (95% CI, 91.4-98.1), median (interquartile range) days to birth 14 (2-27) vs 49 (33-70), P < 0.000. A sFlt-1/PlGF cut-off of 38 ruled out preeclampsia ≤1 week (NPV 96.2% (95% CI, 92.3-98.2)) and ruled in preeclampsia ≤4 weeks (PPV 75.0% (95% CI, 65.0-82.9)). A sFlt-1/PlGF >38 was associated with greater perinatal morbidity. CONCLUSIONS: The predictive value of the sFlt-1/PlGF ratio in NZ is comparable to that reported in international trials. Used in clinical practice the sFlt-1/PlGF ratio may aid risk stratification in suspected preeclampsia, directing limited resources to those pregnancies at highest risk.

Tighter or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity: A stepped-wedge, cluster-randomised trial.

BACKGROUND: Treatment for gestational diabetes mellitus (GDM) aims to reduce maternal hyperglycaemia. The TARGET Trial assessed whether tighter compared with less tight glycaemic control reduced maternal and perinatal morbidity. METHODS AND FINDINGS: In this stepped-wedge, cluster-randomised trial, identification number ACTRN12615000282583, 10 hospitals in New Zealand were randomised to 1 of 5 implementation dates. The trial was registered before the first participant was enrolled. All hospitals initially used less tight targets (fasting plasma glucose (FPG) <5.5 mmol/L (<99 mg/dL), 1-hour <8.0 mmol/L (<144 mg/dL), 2 hour postprandial <7.0 mmol/L (<126 mg/dL)) and every 4 months, 2 hospitals moved to use tighter targets (FPG ≤5.0 mmol/L (≤90 mg/dL), 1-hour ≤7.4 mmol/L (≤133 mg/dL), 2 hour postprandial ≤6.7 mmol/L) (≤121 mg/dL). Women with GDM, blinded to the targets in use, were eligible. The primary outcome was large for gestational age. Secondary outcomes assessed maternal and infant health. Analyses were by intention to treat. Between May 2015 and November 2017, data were collected from 1,100 women with GDM (1,108 infants); 598 women (602 infants) used the tighter targets and 502 women (506 infants) used the less tight targets. The rate of large for gestational age was similar between the treatment target groups (88/599, 14.7% versus 76/502, 15.1%; adjusted relative risk [adjRR] 0.96, 95% confidence interval [CI] 0.66 to 1.40, P = 0.839). The composite serious health outcome for the infant of perinatal death, birth trauma, or shoulder dystocia was apparently reduced in the tighter group when adjusted for gestational age at diagnosis of GDM, BMI, ethnicity, and history of GDM compared with the less tight group (8/599, 1.3% versus 13/505, 2.6%, adjRR 0.23, 95% CI 0.06 to 0.88, P = 0.032). No differences were seen for the other infant secondary outcomes apart from a shorter stay in intensive care (P = 0.041). Secondary outcomes for the woman showed an apparent increase for the composite serious health outcome that included major haemorrhage, coagulopathy, embolism, and obstetric complications in the tighter group (35/595, 5.9% versus 15/501, 3.0%, adjRR 2.29, 95% CI 1.14 to 4.59, P = 0.020). There were no differences between the target groups in the risk for pre-eclampsia, induction of labour, or cesarean birth, but more women using tighter targets required pharmacological treatment (404/595, 67.9% versus 293/501, 58.5%, adjRR 1.20, 95% CI 1.00 to 1.44, P = 0.047). The main study limitation is that the treatment targets used may vary to those in use in some countries. CONCLUSIONS: Tighter glycaemic targets in women with GDM compared to less tight targets did not reduce the risk of a large for gestational age infant, but did reduce serious infant morbidity, although serious maternal morbidity was increased. These findings can be used to aid decisions on the glycaemic targets women with GDM should use. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583.

Nanoscale Pattern Extraction from Relative Positions of Sparse 3D Localizations.

Inferring the organization of fluorescently labeled nanosized structures from single molecule localization microscopy (SMLM) data, typically obscured by stochastic noise and background, remains challenging. To overcome this, we developed a method to extract high-resolution ordered features from SMLM data that requires only a low fraction of targets to be localized with high precision. First, experimentally measured localizations are analyzed to produce relative position distributions (RPDs). Next, model RPDs are constructed using hypotheses of how the molecule is organized. Finally, a statistical comparison is used to select the most likely model. This approach allows pattern recognition at sub-1% detection efficiencies for target molecules, in large and heterogeneous samples and in 2D and 3D data sets. As a proof-of-concept, we infer ultrastructure of Nup107 within the nuclear pore, DNA origami structures, and α-actinin-2 within the cardiomyocyte Z-disc and assess the quality of images of centrioles to improve the averaged single-particle reconstruction.

ADIPS 2020 guideline for pre-existing diabetes and pregnancy.

This is the full version of the Australasian Diabetes in Pregnancy Society (ADIPS) 2020 guideline for pre-existing diabetes and pregnancy. The guideline encompasses the management of women with pre-existing type 1 diabetes and type 2 diabetes in relation to pregnancy, including preconception, antepartum, intrapartum and postpartum care. The management of women with monogenic diabetes or cystic fibrosis-related diabetes in relation to pregnancy is also discussed.

Antenatal models of care for women with gestational diabetes mellitus: Vignettes from an international meeting.

BACKGROUND: Gestational diabetes (GDM) is one of the commonest pregnancy complications and is placing an increasing burden on diabetes and obstetric resources. AIMS: To describe different antenatal models of care that have developed to address the increasing proportion of pregnancies complicated by GDM. MATERIALS AND METHODS: Narrative review with thematic analysis from 15 volunteer antenatal diabetes in pregnancy services from Australia and New Zealand identified through a national diabetes organisation. Main outcomes were approaches to patient education, medical nutrition therapy (MNT), ongoing management and escalation of therapy for women with GDM. RESULTS: All clinics provided at least one group education and one MNT session within 1-2 weeks of GDM diagnosis. Women from culturally and linguistically diverse communities usually required 1:1 education. Ongoing management of women with GDM was through either all women being seen in the GDM clinic, a step-up approach (ongoing management by the primary antenatal team with diabetes team referral if self-blood glucose monitoring (SBGM) or insulin therapy dosage criteria are reached) or step-down approach (ongoing management by the diabetes team with step-down to the primary antenatal team if SBGM criteria are reached). Telehealth was used to reduce the burden of clinic attendance, particularly in rural areas. CONCLUSIONS: Increasing numbers, earlier diagnoses, the need to provide care to women in rural, remote areas, and cultural/language differences, have generated a range of different antenatal models of care, allowed better workload accommodation and probably reduced costs. Randomised controlled trials of different models of care, with associated health economic analyses, are urgently needed.

Persistent Replication of a Chikungunya Virus Replicon in Human Cells Is Associated with Presence of Stable Cytoplasmic Granules Containing Nonstructural Protein 3.

Chikungunya virus (CHIKV), a mosquito-borne human pathogen, causes a disabling disease characterized by severe joint pain that can persist for weeks, months, or even years in patients. The nonstructural protein 3 (nsP3) plays essential roles during acute infection, but little is known about the function of nsP3 during chronic disease. Here, we used subdiffraction multicolor microscopy for spatial and temporal analysis of CHIKV nsP3 within human cells that persistently replicate replicon RNA. Round cytoplasmic granules of various sizes (i) contained nsP3 and stress granule assembly factors 1 and 2 (G3BP1/2), (ii) were next to double-stranded RNA foci and nsP1-positive structures, and (iii) were close to the nuclear membrane and the nuclear pore complex protein Nup98. Analysis of protein turnover and mobility by live-cell microscopy revealed that the granules could persist for hours to days, accumulated newly synthesized protein, and moved through the cytoplasm at various speeds. The granules also had a static internal architecture and were stable in cell lysates. Refractory cells that had cleared the noncytotoxic replicon regained the ability to respond to arsenite-induced stress. In summary, nsP3 can form uniquely stable granular structures that persist long-term within the host cell. This continued presence of viral and cellular protein complexes has implications for the study of the pathogenic consequences of lingering CHIKV infection and the development of strategies to mitigate the burden of chronic musculoskeletal disease brought about by a medically important arthropod-borne virus (arbovirus).IMPORTANCE Chikungunya virus (CHIKV) is a reemerging alphavirus transmitted by mosquitos and causes transient sickness but also chronic disease affecting muscles and joints. No approved vaccines or antivirals are available. Thus, a better understanding of the viral life cycle and the role of viral proteins can aid in identifying new therapeutic targets. Advances in microscopy and development of noncytotoxic replicons (A. Utt, P. K. Das, M. Varjak, V. Lulla, A. Lulla, A. Merits, J Virol 89:3145-3162, 2015, https://doi.org/10.1128/JVI.03213-14) have allowed researchers to study viral proteins within controlled laboratory environments over extended durations. Here we established human cells that stably replicate replicon RNA and express tagged nonstructural protein 3 (nsP3). The ability to track nsP3 within the host cell and during persistent replication can benefit fundamental research efforts to better understand long-term consequences of the persistence of viral protein complexes and thereby provide the foundation for new therapeutic targets to control CHIKV infection and treat chronic disease symptoms.

Tight or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity? (TARGET): study protocol for a stepped wedge randomised trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is strongly associated with significant adverse maternal and perinatal health outcomes that have lifelong consequences. Treatment for women with GDM aims to normalise maternal blood glucose concentrations to reduce these adverse health risks. Target recommendations for glycaemic control in women with GDM vary amongst international organisations. All their recommendations rely on consensus, as there have been no published randomised trials that compare different intensities of glucose control in women with GDM. The TARGET Trial aims to determine whether tighter targets for glycaemic control in women with GDM compared with less tight targets, reduce maternal and perinatal morbidity without adverse health consequences. METHODS/DESIGN: Using a stepped wedge, cluster randomised trial the 10 participating hospitals will be randomised to the timing of the change from the less tight to the tighter glycaemic target period. During the less tight target period, all health professionals at the hospital will aim to use the less tight glycaemic targets for treatment of women with GDM (fasting plasma glucose < 5.5 mmol/L; 1 h postprandial < 8.0 mmol/L; 2 h postprandial < 7.0 mmol/L). During the tighter target period all health professionals at the hospital will aim to use the tighter glycaemic targets for treatment of women with GDM (fasting plasma glucose ≤5.0 mmol/L, 1 h postprandial ≤7.4 mmol/L; 2 h postprandial ≤6.7 mmol/L). The primary study outcome is large for gestational age infant (birth weight > 90th centile). A sample size of 1080 participants will detect a treatment difference of 6% in the proportion of large for gestational age babies from 13% with less tight glycaemic targets to 7% with tighter targets, assuming an intra-cluster correlation coefficient of 0.05. DISCUSSION: The TARGET Trial will provide high-level evidence of direct relevance for clinical practice. If tighter treatment targets for women with GDM clearly result in significantly fewer large for gestational age infants and less adverse maternal and perinatal outcomes then they should be recommended for women with GDM. This would be of great importance to these women, their children, health services and communities. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN 12615000282583 .

Evaluation of the NZ guidelines for screening for persistent postpartum hyperglycaemia following gestational diabetes.

BACKGROUND: Recent New Zealand guidelines recommend annual glycated haemoglobin (HbA1c) measurements from three months postpartum, replacing the glucose tolerance test (GTT) at six weeks, to screen for persistent hyperglycaemia following gestational diabetes. Data suggest that this screening approach may miss cases of type 2 diabetes, but are they detected at subsequent screening and will screening rates improve? AIMS: Our aim was to evaluate the effectiveness of HbA1c monitoring in improving screening rates following gestational diabetes and in detecting postpartum hyperglycaemia. MATERIALS AND METHODS: During 2015 in Christchurch, all women with gestational diabetes were offered HbA1c and GTT measurements at three months postpartum and subsequent annual HbA1c measurements were recommended. Data from electronic hospital records were collected for a minimum 18 months postpartum. RESULTS: Of the cohort of 333 women, 218 (65%) completed both HbA1c and GTT at three months postpartum, 74 (22%) HbA1c only, 16 (5%) GTT only, 25 (8%) no screening; 184 (55%) had subsequent HbA1c tests. Diabetes was detected by GTT in five (2%) women and by HbA1c in only one out of five (20%); the disagreement between tests resolved in three out of four (75%) women with subsequent testing. Prediabetes was detected by GTT in 30 (14%) women; however, HbA1c only detected five out of 30 (17%) and subsequent HbA1c testing identified a further two out of 30 with prediabetes. CONCLUSIONS: HbA1c measurement at three months postpartum had a good uptake. However, most cases of diabetes were identified by subsequent HbA1c testing, the uptake of which was suboptimal. The importance of annual HbA1c monitoring following gestational diabetes needs greater emphasis.

Antenatal haemoglobin A1c centiles: does one size fit all?

BACKGROUND: In New Zealand, haemoglobin A1c measurements are routinely offered at booking, preferably before 20 weeks gestation, to detect pre-existing hyperglycaemia. A haemoglobin A1c <5.9% (41 mmol/mol) is considered normal based on the reference range for the non-pregnant population. AIMS: To determine pregnancy-specific haemoglobin A1c centiles by gestation and ethnicity. MATERIALS AND METHODS: This is a population-based observational study of pregnancies uncomplicated by diabetes (pre-existing or gestational) with ≥1 haemoglobin A1c measurement. Haemoglobin A1c centiles were calculated from data extracted from electronic laboratory and clinical records for pregnancies during 2008-2010. RESULTS: Included were 6800 pregnancies, European 80% (5462), Maori 6% (415), Pacific Islander 3% (196) and 11% (727) 'Others' (mostly Asian). Haemoglobin A1c levels fell with increasing gestation, reaching a nadir at 24 weeks, a trend verified by longitudinal data from 112 women. The 97.5th centile for haemoglobin A1c in European women was 5.76% (39.5 mmol/mol) at 8+0  weeks, 5.70% (38.8 mmol/mol) at 16+0  weeks, and 5.65% (38.3 mmol/mol) at 24+0  weeks. Non-European women had both higher plasma glucose levels (although within the range considered normal) and higher mean haemoglobin A1c levels compared with Europeans; mean (SD) difference in haemoglobin A1c in Maori +0.13% (0.05) (+1.4 mmol/mol (0.5)), Pacific +0.20% (0.03) (+2.2 mmol/mol (0.3)), 'Others' +0.10% (0.03) (+1.1 mmol/mol (0.3)). CONCLUSIONS: The New Zealand haemoglobin A1c cut-point ≥5.9% (41 mmol/mol) for identifying hyperglycaemia in early pregnancy is greater than the 97.5th centile in European and 'Other' women. Utilising population haemoglobin A1c centiles adjusted by gestation may thus better guide management decisions.

Is There a Role for HbA1c in Pregnancy?

Outside pregnancy, HbA1c analysis is used for monitoring, screening for and diagnosing diabetes and prediabetes. During pregnancy, the role for HbA1c analysis is not yet established. Physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised. Other factors that influence HbA1c are also important to consider, particularly since emerging data suggest that, in early pregnancy, HbA1c elevations close to the reference range may both identify women with underlying hyperglycaemia and be associated with adverse pregnancy outcomes. In later pregnancy, HbA1c analysis is less useful than an oral glucose tolerance test (OGTT) at detecting gestational diabetes. Postpartum, HbA1c analysis detects fewer women with abnormal glucose tolerance than an OGTT, but the ease of testing may improve follow-up rates and combining HbA1c analysis with fasting plasma glucose or waist circumference may improve detection rates. This article discusses the relevance of HbA1c testing at different stages of pregnancy.

Histone deacetylase 3 indirectly modulates tubulin acetylation.

Histone deacetylase 3 (HDAC3), a member of the Class I subfamily of HDACs, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterized, but its cytoplasmic roles are still not elucidated fully. We found that blocking HDAC3 activity using MI192, a compound specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 h treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behaviour of microtubules in live cells. siRNA-mediated knockdown (KD) of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3-silencing mediator of retinoic and thyroid receptors (SMRT)-deacetylase-activating domain (DAD) complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation.

New Zealand National GDM Guidelines: an alternative view of some good practice points.

The New Zealand Gestational Diabetes Mellitus (GDM) Guidelines, commissioned by the Ministry of Health, contains many good points, but several recommendations are creating controversy. This opinion piece discusses an alternative approach to early pregnancy screening for diabetes. We suggest that it is reasonable to refer women with an HbA1c ≥41 mmol/mol (5.9%) for further management, rather than the recommended referral threshold of ≥50 mmol/mol (6.7%). We also suggest that, for subsequent screening for GDM at 24-28 weeks' gestation, a 75 g oral glucose tolerance test should be offered rather than a 50 g glucose challenge test.

The Role of Implicit and Explicit Beliefs in Grave-Good Practices: Evidence for Intuitive Afterlife Reasoning.

The practice of burying objects with the dead is often claimed as some of the earliest evidence for religion, on the assumption that such "grave goods" were intended for the decedents' use in the afterlife. However, this assumption is largely speculative, as the underlying motivations for grave-good practices across time and place remain little understood. In the present work, we asked if explicit and implicit religious beliefs (particularly those concerning the continuity of personal consciousness after death) motivate contemporary grave-good practices. Across three studies, and comparing participants from the United States and NZ, we measured grave-good deposition at actual or hypothetical funerals, finding that jewelry, photographs, and other items with sentimental, emotional, and relationship value were common. In addition, intuitive afterlife reasoning (as measured by people's attributions of mental states to the dead) motivated grave-good decision-making for about half (Study 2) or more (Study 3) people, including afterlife nonbelievers ("extinctivists"), while those who held explicit (i.e., stated) afterlife beliefs were more likely to participate in the practice. The decision to leave grave goods was also associated with magical contagion beliefs and a need for personal comfort, while other motivations, such as social signaling, were less common. Our results suggest that "afterlife use" is a common motivation for grave-good practices, and that humans possess evolutionarily early intuitions about postdeath consciousness.

Longitudinal analysis of sentiment and emotion in news media headlines using automated labelling with Transformer language models.

This work describes a chronological (2000-2019) analysis of sentiment and emotion in 23 million headlines from 47 news media outlets popular in the United States. We use Transformer language models fine-tuned for detection of sentiment (positive, negative) and Ekman's six basic emotions (anger, disgust, fear, joy, sadness, surprise) plus neutral to automatically label the headlines. Results show an increase of sentiment negativity in headlines across written news media since the year 2000. Headlines from right-leaning news media have been, on average, consistently more negative than headlines from left-leaning outlets over the entire studied time period. The chronological analysis of headlines emotionality shows a growing proportion of headlines denoting anger, fear, disgust and sadness and a decrease in the prevalence of emotionally neutral headlines across the studied outlets over the 2000-2019 interval. The prevalence of headlines denoting anger appears to be higher, on average, in right-leaning news outlets than in left-leaning news media.

RNA-Seq analysis of a Pax3-expressing myoblast clone in-vitro and effect of culture surface stiffness on differentiation.

Skeletal muscle satellite cells cultured on soft surfaces (12 kPa) show improved differentiation than cells cultured on stiff surfaces (approximately 100 kPa). To better understand the reasons for this, we performed an RNA-Seq analysis for a single satellite cell clone (C1F) derived from the H2kb-tsA58 immortomouse, which differentiates into myotubes under tightly regulated conditions (withdrawal of É£-interferon, 37 °C). The largest change in overall gene expression occurred at day 1, as cells switched from proliferation to differentiation. Surprisingly, further analysis showed that proliferating C1F cells express Pax3 and not Pax7, confirmed by immunostaining, yet their subsequent differentiation into myotubes is normal, and enhanced on softer surfaces, as evidenced by significantly higher expression levels of myogenic regulatory factors, sarcomeric genes, enhanced fusion and improved myofibrillogenesis. Levels of mRNA encoding extracellular matrix structural constituents and related genes were consistently upregulated on hard surfaces, suggesting that a consequence of differentiating satellite cells on hard surfaces is that they attempt to manipulate their niche prior to differentiating. This comprehensive RNA-Seq dataset will be a useful resource for understanding Pax3 expressing cells.

Customised birthweight centiles are useful for identifying small-for-gestational-age babies in women with type 2 diabetes.

BACKGROUND: Customised birthweight centiles identify small-for-gestational-age (SGA) babies at increased risk of morbidity more accurately than population centiles, but they have not been validated in obese populations. AIMS: To compare the rates of SGA by population and customised birthweight centiles in babies of women with type 2 diabetes and examine perinatal outcomes in customised SGA infants. METHODS: Data were from a previous retrospective cohort study detailing pregnancy outcomes in 212 women with type 2 diabetes. Customised and population birthweight centiles were calculated; pregnancy details and neonatal outcomes were compared between groups that delivered infants who were SGA (birthweight < 10th customised centile) and appropriate weight for gestational age (AGA) (birthweight 10-90th customised centile). RESULTS: Fifteen (7%) babies were SGA by population centiles and 32 (15%) by customised centiles. Two babies of Indian women were reclassified from SGA to AGA by customised centiles. Nineteen babies were reclassified from AGA to SGA by customised centiles; of these, 15 (79%) were born to Polynesian women, five (26%) were born less than 32 weeks and two (11%) were stillborn. Customised SGA infants, compared with AGA infants, were more likely to be born preterm (19 (59%) vs 20 (16%), P < 0.001) and more likely to be stillborn (4 (13%) vs 0 P = 0.001). After excluding still births, admission to the neonatal unit was also more common (19 of 28 (68%) vs 43 of 127 (34%), P < 0.001). CONCLUSIONS: In our population more babies were classified as SGA by customised compared with population centiles. These customised SGA babies have high rates of morbidity.

Prediabetes in pregnancy, can early intervention improve outcomes? A feasibility study for a parallel randomised clinical trial.

OBJECTIVE: Measurement of glycated haemoglobin (HbA1c) in early pregnancy is routine in New Zealand to identify women with diabetes and prediabetes. However, the benefit of early intervention in women with prediabetes is inconclusive. Our aim was to test the feasibility of a two-arm parallel randomised controlled trial of standard care versus early intervention in pregnancies complicated by prediabetes. SETTING: Two tertiary referral centres in New Zealand. PARTICIPANTS: Women <14 weeks' gestation and HbA1c ≥5.9%-6.4% (41-46 mmol/mol) measured at booking, without pre-existing diabetes. INTERVENTIONS: Randomisation was done by remote web-based allocation into one of two groups. Women in the early intervention group attended an antenatal diabetes clinic, commenced daily home blood glucose monitoring, and medication was prescribed if lifestyle measures failed to maintain target blood glucose levels. Controls received lifestyle education, continued standard care with their midwife and/or obstetrician, and were asked to perform a 75 g oral glucose tolerance test at 24 weeks' gestation with a referral to clinic if this test was positive. Both groups received lifestyle questionnaires at recruitment and in late pregnancy. OUTCOME MEASURES: Recruitment rate, adherence to protocol and validation of potential primary outcomes. RESULTS: Recruitment rates were lower than expected, especially in Maori and Pacific women. Non-adherence to allocated treatment protocol was significant, 42% (95% CI 24% to 61%) in the early intervention group and 30% (95% CI 16% to 51%) in controls. Caesarean section and pre-eclampsia were signalled as potential primary outcomes, due to both the high observed incidence in the control group and ease of measurement. CONCLUSIONS: For a future definitive trial, extending the gestation of eligibility and stepped-wedge cluster randomisation may overcome the identified feasibility issues. Consistent with published observational data, pre-eclampsia and emergency caesarean section could be included as primary outcome measures, both of which have a significant impact on maternal and neonatal morbidity and healthcare costs. TRIAL REGISTRATION NUMBER: ACTRN12615000904572; Pre-results.

A1603P and K1617del, Mutations in ß-Cardiac Myosin Heavy Chain that Cause Laing Early-Onset Distal Myopathy, Affect Secondary Structure and Filament Formation In Vitro and In Vivo.

Over 20 mutations in ß-cardiac myosin heavy chain (ß-MHC), expressed in cardiac and slow muscle fibers, cause Laing early-onset distal myopathy (MPD-1), a skeletal muscle myopathy. Most of these mutations are in the coiled-coil tail and commonly involve a mutation to a proline or a single-residue deletion, both of which are predicted to strongly affect the secondary structure of the coiled coil. To test this, we characterized the effects of two MPD-1 causing mutations: A1603P and K1617del in vitro and in cells. Both mutations affected secondary structure, decreasing the helical content of 15 heptad and light meromyosin constructs. Both mutations also severely disrupted the ability of glutathione S-transferase-light meromyosin fusion proteins to form minifilaments in vitro, as demonstrated by negative stain electron microscopy. Mutant eGFP-tagged ß-MHC accumulated abnormally into the M-line of sarcomeres in cultured skeletal muscle myotubes. Incorporation of eGFP-tagged ß-MHC into sarcomeres in adult rat cardiomyocytes was reduced. Molecular dynamics simulations using a composite structure of part of the coiled coil demonstrated that both mutations affected the structure, with the mutation to proline (A1603P) having a smaller effect compared to K1617del. Taken together, it seems likely that the MPD-1 mutations destabilize the coiled coil, resulting in aberrant myosin packing in thick filaments in muscle sarcomeres, providing a potential mechanism for the disease.