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Patterns of prescription medicine dispensing before and during pregnancy in New Zealand, 2005–2015
Describes prescription medicine dispensing before and during pregnancy in New Zealand, 2005-2015. Identifies the proportion of pregnancies during which at least one prescription medicine was dispensed, the number of different medicines used and the most commonly dispensed medicine groups both during pregnancy and in the 270 days before conception. Assesses dispensing during pregnancy by several maternal characteristics. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Journal Article
Small for Gestational Age Coded Diagnoses in Aotearoa New Zealand's Administrative Health Datasets: A Validation Study
Background and Aims Inaccurate coding of small for gestational age (SGA) infants in routinely collected health data has implications for research based on those data. We aimed to estimate the sensitivity and specificity of coded SGA diagnoses in New Zealand's routinely collected hospitalisation and mortality data, and determine whether sensitivity and specificity varied by infant, pregnancy, and maternal characteristics. Methods We estimated birthweight centiles of live and stillborn infants delivered in New Zealand between 2005 and 2020 using the Fenton Population Reference Calculator and the GROW Customised Bulk Centile Calculator (New Zealand version); values of the relevant variables (including gestational age, birthweight, infant sex, and others) were sourced from routinely collected national health data. We compared the SGA status derived from the calculators with coded SGA diagnoses (ICD‐10‐AM P051) in hospitalisation and mortality data. We estimated sensitivity and specificity ratios comparing coded diagnoses with each of the birthweight calculators using a generalised linear model, adjusting for infant, pregnancy, and maternal characteristics. Results This analysis included 887,871 infants, with 15,850 (1.8%) having a coded SGA diagnosis. By contrast, the number and proportion of babies classified as SGA using the Fenton and GROW calculators were 80,541 (9.1%) and 138,866 (15.6%), respectively. Overall, compared with the Fenton calculator, the sensitivity of coded SGA diagnoses was 13.1% (specificity 99.3%). Compared with the GROW calculator, the sensitivity was 9.8% (specificity 99.7%). Conclusion In New Zealand, population‐level research involving SGA diagnoses should derive birthweight centiles using an appropriate calculator instead of using ICD‐10‐AM coded diagnoses. Summary Study Question What is the sensitivity and specificity of coded ICD‐10‐AM small for gestational age (SGA) diagnoses in New Zealand's routinely collected hospitalisation and mortality data? Do sensitivity and specificity vary by infant, pregnancy, and maternal characteristics? What Is Already Known In data obtained from administrative health datasets, the proportion of births with coded SGA diagnoses is much less than expected. What This Study Adds Coded ICD‐10‐AM SGA diagnoses recorded in New Zealand's national health datasets have very poor sensitivity yet high specificity when compared with two different birthweight centile calculators. Researchers utilising these datasets should not rely on coded diagnoses, and instead should ascertain SGA status from recorded birthweight and gestational age.
Journal Article
The tree of life
This is a film about the conflict between nature and grace, the agonizing mystery of God, and the meaning of life itself. The death of his brother forces Jack O'Brien to confront his past, which is dominated by his difficult relationship with his father. Jack's father was a stern authoritarian whose no-nonsense demeanor masked a host of unfulfilled dreams. His mother was a gentle, kind woman who often allowed her own needs and desires to give way to those of her husband and children. As Jack's memories come flooding back--of the course of a Texas summer in the 1950s--viewers observe Jack's evolving relationship with his parents, his younger brother, and God, while adult Jack questions the meanings of life, love, and family.
DVD
Impact of Community Based Peer Support in Type 2 Diabetes: A Cluster Randomised Controlled Trial of Individual and/or Group Approaches
Diabetes peer support, where one person with diabetes helps guide and support others, has been proposed as a way to improve diabetes management. We have tested whether different diabetes peer support strategies can improve metabolic and/or psychological outcomes.
People with type 2 diabetes (n = 1,299) were invited to participate as either 'peer' or 'peer support facilitator' (PSF) in a 2x2 factorial randomised cluster controlled trial across rural communities (130 clusters) in England. Peer support was delivered over 8-12 months by trained PSFs, supported by monthly meetings with a diabetes educator. Primary end point was HbA1c. Secondary outcomes included quality of life, diabetes distress, blood pressure, waist, total cholesterol and weight. Outcome assessors and investigators were masked to arm allocation. Main factors were 1:1 or group intervention. Analysis was by intention-to-treat adjusting for baseline.
The 4 arms were well matched (Group n = 330, 1:1(individual) n = 325, combined n = 322, control n = 322); 1035 (79·7%) completed the mid-point postal questionnaire and 1064 (81·9%) had a final HbA1c. A limitation was that although 92.6% PSFs and peers were in telephone contact, only 61.4% of intervention participants attended a face to face session. Mean baseline HbA1c was 57 mmol/mol (7·4%), with no significant change across arms. Follow up systolic blood pressure was 2·3 mm Hg (0.6 to 4.0) lower among those allocated group peer-support and 3·0 mm Hg (1.1 to 5.0) lower if the group support was attended at least once. There was no impact on other outcomes by intention to treat or significant differences between arms in self-reported adherence or medication.
Group diabetes peer support over 8-12 months was associated with a small improvement in blood pressure but no other significant outcomes. Long term benefits should be investigated.
ISRCTN.com ISRCTN6696362166963621.
Journal Article
Activity of botulinum neurotoxin X and its structure when shielded by a non-toxic non-hemagglutinin protein
Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex and the crystal structure of the isolated NTNH protein. Unexpectedly, the BoNT/X complex is stable and protease-resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents very weak ganglioside binding and exposed hydrophobic surfaces.
Botulinum neurotoxins (BoNTs) are a family of protein toxins produced by clostridial bacteria that cause muscle paralysis, and exhibit structural and functional diversity within the BoNTs family. Here, the authors report the cryo-EM structure complex of a newly identified serotype BoNT/X with their partner protein NTNH/X and reveal the complex’s pH-dependent stability and receptor-binding properties.
Journal Article
Engineering an Effective Human SNAP-23 Cleaving Botulinum Neurotoxin A Variant
Botulinum neurotoxin (BoNT) serotype A inhibits neurotransmitter release by cleaving SNAP-25 and represents an established pharmaceutical for treating medical conditions caused by hyperactivity of cholinergic nerves. Oversecretion from non-neuronal cells is often also the cause of diseases. Notably, excessive release of inflammatory messengers is thought to contribute to diseases such as chronic obstructive pulmonary disease, asthma, diabetes etc. The expansion of its application to these medical conditions is prevented because the major non-neuronal SNAP-25 isoform responsible for exocytosis, SNAP-23, is, in humans, virtually resistant to BoNT/A. Based on previous structural data and mutagenesis studies of SNAP-23 we optimized substrate binding pockets of the enzymatic domain for interaction with SNAP-23. Systematic mutagenesis and rational design yielded the mutations E148Y, K166F, S254A, and G305D, each of which individually increased the activity of LC/A against SNAP-23 between 3- to 23-fold. The assembled quadruple mutant showed approximately 2000-fold increased catalytic activity against human SNAP-23 in in vitro cleavage assays. A comparable increase in activity was recorded for the full-length BoNT/A quadruple mutant tested in cultivated primary neurons transduced with a fluorescently tagged-SNAP-23 encoding gene. Equipped with a suitable targeting domain this quadruple mutant promises to complete successfully tests in cells of the immune system.
Journal Article
A comparison of biological activity of commercially available purified native botulinum neurotoxin serotypes A1 to F1 in vitro, ex vivo, and in vivo
Botulinum neurotoxin (BoNT) is a major therapeutic agent. Of seven native BoNT serotypes (A to G), only A and B are currently used in the clinic. Here we compared the potency of commercially available purified native serotypes A1 to F1 across in vitro, ex vivo, and in vivo assays. BoNT potency in vitro was assessed in rat primary cells (target protein cleavage and neurotransmitter release assays) in supraspinal, spinal, and sensory systems. BoNT potency ex vivo was measured in the mouse phrenic nerve hemidiaphragm (PNHD) assay, measuring muscle contractility. In vivo, BoNT‐induced muscle relaxation in mice and rats was assessed in the Digit Abduction Score (DAS) test, while effects on body weight (BW) gain were used to assess tolerability. In all assays, all BoNT serotypes were potent toxins, except serotype D1 in vivo which failed to produce significant muscle flaccidity in mice and rats. In rats, all serotypes were well‐tolerated, whereas in mice, reductions in BW were detected at high doses. Serotype A1 was the most potent serotype across in vitro, ex vivo, and in vivo assays. The rank order of potency of the serotypes revealed differences among assays. For example, species‐specificity was seen for serotype B1, and to a lesser extent for serotype C1. Serotypes F1 and C1, not currently in the clinic, showed preference for sensory over motor models and therefore could be considered for development in conditions involving the somatosensory system.
Journal Article
P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination
The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in motor coordination defects, but activators of Rac in the cerebellum are unknown. P-Rex family guanine-nucleotide exchange factors activate Rac. We show here that, whereas P-Rex1 expression within the brain is widespread, P-Rex2 is specifically expressed in the Purkinje neurons of the cerebellum. We have generated P-Rex2⁻/⁻ and P-Rex1⁻/⁻/P-Rex2⁻/⁻ mice, analyzed their Purkinje cell morphology, and assessed their motor functions in behavior tests. The main dendrite is thinned in Purkinje cells of P-Rex2⁻/⁻ pups and dendrite structure appears disordered in Purkinje cells of adult P-Rex2⁻/⁻ and P-Rex1⁻/⁻/P-Rex2⁻/⁻ mice. P-Rex2⁻/⁻ mice show a mild motor coordination defect that progressively worsens with age and is more pronounced in females than in males. P-Rex1⁻/⁻/P-Rex2⁻/⁻ mice are ataxic, with reduced basic motor activity and abnormal posture and gait, as well as impaired motor coordination even at a young age. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function.
Journal Article