Severe maternal morbidity in Scotland.

Using a cohort study design, we analysed 17 diagnoses and 9 interventions (including critical care admission) as a composite measure of severe maternal morbidity for pregnancies recorded over 14 years in Scotland. There were 762,918 pregnancies, of which 7947 (10 in 1000 pregnancies) recorded 9345 severe maternal morbidity events, 2802 episodes of puerperal sepsis being the most common (30%). Severe maternal morbidity incidence increased from 9 in 1000 pregnancies in 2012 to 17 in 1000 pregnancies in 2018, due in part to puerperal sepsis recording. The odds ratio (95%CI) for severe maternal morbidity was higher for: older women, for instance 1.22 (1.13-1.33) for women aged 35-39 years and 1.44 (1.27-1.63) for women aged > 40 years compared with those aged 25-29 years; obese women, for instance 1.13 (1.06-1.21) for BMI 30-40 kg.m-2 and 1.32 (1.15-1.51) for BMI > 40 kg.m-2 compared with BMI 18.5-24.9 kg.m-2 ; multiple pregnancy, 2.39 (2.09-2.74); and previous caesarean delivery, 1.52 (1.40-1.65). The median (IQR [range]) hospital stay was 3 (2-5 [1-8]) days with severe maternal morbidity and 2 (1-3 [1-5]) days without. Forty-one women died during pregnancy or up to 42 days after delivery, representing mortality rates per 100,000 pregnancies of about 365 with severe maternal morbidity and 1.6 without. There were 1449 women admitted to critical care, 807 (58%) for mechanical ventilation or support of at least two organs. We recorded an incidence of severe maternal morbidity higher than previously published, possibly because sepsis was coded inaccurately in our databases. Further research may determine the value of this composite measure of severe maternal morbidity.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

BACKGROUND: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. INTERPRETATION: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. FUNDING: Gilead Sciences.

Are Anesthesia and Surgery during Infancy Associated with Decreased White Matter Integrity and Volume during Childhood?

BACKGROUND: Anesthetics have neurotoxic effects in neonatal animals. Relevant human evidence is limited. We sought such evidence in a structural neuroimaging study. METHODS: Two groups of children underwent structural magnetic resonance imaging: patients who, during infancy, had one of four operations commonly performed in otherwise healthy children and comparable, nonexposed control subjects. Total and regional brain tissue composition and volume, as well as regional indicators of white matter integrity (fractional anisotropy and mean diffusivity), were analyzed. RESULTS: Analyses included 17 patients, without potential confounding central nervous system problems or risk factors, who had general anesthesia and surgery during infancy and 17 control subjects (age ranges, 12.3 to 15.2 yr and 12.6 to 15.1 yr, respectively). Whole brain white matter volume, as a percentage of total intracranial volume, was lower for the exposed than the nonexposed group, 37.3 ± 0.4% and 38.9 ± 0.4% (least squares mean ± SE), respectively, a difference of 1.5 percentage points (95% CI, 0.3 to 2.8; P = 0.016). Corresponding decreases were statistically significant for parietal and occipital lobes, infratentorium, and brainstem separately. White matter integrity was lower for the exposed than the nonexposed group in superior cerebellar peduncle, cerebral peduncle, external capsule, cingulum (cingulate gyrus), and fornix (cres) and/or stria terminalis. The groups did not differ in total intracranial, gray matter, and cerebrospinal fluid volumes. CONCLUSIONS: Children who had anesthesia and surgery during infancy showed broadly distributed, decreased white matter integrity and volume. Although the findings may be related to anesthesia and surgery during infancy, other explanations are possible.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

Are anesthesia and surgery during infancy associated with altered academic performance during childhood?

BACKGROUND: Although studies in neonatal animals show that anesthetics have neurotoxic effects, relevant human evidence is limited. We examined whether children who had surgery during infancy showed deficits in academic achievement. METHODS: We attempted to contact parents of 577 children who, during infancy, had one of three operations typically performed in otherwise healthy children. We compared scores on academic achievement tests with population norms. RESULTS: Composite scores were available for 287 patients. The mean normal curve equivalent score was 43.0±22.4 (mean±SD), lower than the expected normative value of 50, P<0.0001 by one-sample Student t test; and 35 (12%) had scores below the 5th percentile, more than expected, P<0.00001 by binomial test. Of 133 patients who consented to participate so that their scores could be examined in relation to their medical records, the mean score was 45.9±22.9, P=0.0411; and 15 (11%) scored below the 5th percentile, P=0.0039. Of 58 patients whose medical records showed no central nervous system problems/potential risk factors during infancy, 8 (14%) scored below the 5th percentile, P=0.008; however, the mean score, 47.6±23.4, was not significantly lower than expected, P=0.441. Duration of anesthesia and surgery correlated negatively with scores (r=-0.34, N=58, P=0.0101). CONCLUSIONS: Although the findings are consistent with possible adverse effects of anesthesia and surgery during infancy on subsequent academic achievement, other explanations are possible and further investigations are needed.

Australian lungfish (Neoceratodus forsteri): a missing link in the evolution of complementary side biases for predator avoidance and prey capture.

Side biases in behavior, reflecting lateral specializations of the brain, are widespread amongst vertebrates. We studied laterality in the Australian lungfish (Neoceratodus forsteri) to gain insight into the evolution of the complementary specializations of predator avoidance (right hemisphere) and foraging behavior (left hemisphere). Because N. forsteri is the closest extant ancestor of the first land-dwelling vertebrates, knowledge of laterality in this species should provide a missing link in the transition from fish to tetrapods. Predator escape responses were elicited by generating pressure waves and a significant bias for C-start responses to the left side was found. This bias was unaffected by activity levels that change according to a diurnal cycle: activity is higher in the dark phase than the light phase. A complementary bias to turn to the right side was found during feeding behavior. This pattern of opposite-side specializations matches that known for fish, anurans, reptiles, birds and, as some evidence indicates, also mammals. Hence, we conclude that it is a homologous pattern of lateralization that evolved in early aquatic vertebrates and was retained as they made the transition to land-dwelling tetrapods.

Anatomy and cytology of the thymus in juvenile Australian lungfish, Neoceratodus forsteri.

The anatomy, histology and ultrastructure of the thymus of a dipnoan, the Australian lungfish, Neoceratodus forsteri, was studied by light and transmission electron microscopy. The thymic tissue showed clear demarcation into a cortex and medulla with ample vascularization. Large cells including foamy and giant multinucleated cells with periodic acid Schiff/Alcian blue positive staining properties were localized mainly in the medulla. The major cellular components were epithelial cells and lymphoid cells. The epithelial cells were classified by location and ultrastructure into six sub-populations: capsular cells, cortical and medullary reticular cells, perivascular endothelial cells, intermediate cells, nurse-like cells and Hassall-like corpuscles. Myoid cells were found mainly in the cortico-medullary boundary and medulla. Macrophages and secretory-like cells were also present. These findings will provide a base of knowledge about the cellular immune system of lungfish.

Thyroid hormone deiodinases revisited: insights from lungfish: a review.

In vertebrates, hormones released from the thyroid gland travel in the circulation to target tissues where they may be processed by deiodinating enzymes into more active or inactive iodothyronines. In mammals, there are three deiodinating enzymes described. Type1 (D1), which primarily occurs in the liver, converts reverse T3 into T2 for clearance. It also converts T4 into T3. This production of T3 is believed to contribute to the bulk of circulating T3 in mammals. The type2 (D2) enzyme may be found in many other tissues where it converts T4 to T3, which is then transferred to the receptors in the nucleus of the same cell, i.e. does not contribute to the circulating T3. The type3 (D3) enzyme converts T3 into T2. The expression of the genes for these three enzymes and/or the activity of the enzymes have been studied in several non-mammalian groups of vertebrates. From agnathans to birds, D2 and D3 appear to occur universally, with the possible exception of squamate reptiles (lack D2?). D1 has not been found in amphibians, lungfish or agnathans. All three enzymes are selenoproteins, in which a selenocysteine is found in the active centre. The nucleotide code for translation of a selenocysteine is UGA, which under normal circumstances is a stop codon. In order for UGA to code for selenocysteine, there must be a SECIS element in the 3'UTR of the mRNA. Any disruption of the SECIS will result in a truncated protein in the region of its active centre. It is suggested that such alternative splicing may be a mode of altering the expression of deiodinases in particular tissues to change the response of such tissues to thyroid hormones under differing circumstances such as stages of development.

The seasonal reproductive cycle of a marsupial, Antechinus stuartii: effects of oral administration of melatonin.

Antechinus stuartii is a small marsupial with a brief, highly synchronised mating period believed to be controlled by the rate of change of photoperiod. Two experiments were performed to explore aspects of photoperiodic control of the seasonal cycle. In the first experiment the pineal hormone, melatonin, administered in the drinking water from the winter solstice, changed the normal response of A. stuartii to increasing rate of change of photoperiod. Melatonin administration shifted the induction of estrus in the females from the first week of August (controls) to an earlier time of mid-July and the consequent pouch changes associated with pregnancy and pseudo-pregnancy were also shifted by the same length of time. Post-mating decline and consequent death of males were also accelerated. In the second experiment melatonin was administered from the autumnal equinox, and this experimental protocol resulted in a desynchronisation of reproductive events. Melatonin administration desynchronised the female reproductive cycle, such that the mating period was extended to eight weeks, instead of the two weeks displayed by control females. Pouch changes and birth of young reflected this desynchronisation. Melatonin administration in males resulted in desynchronisation of reproductive parameters. While the normal yearly reproductive cycle was approximated in these males, the high syncronisation of reproductive maturation and male mortality events observed in control males, was not evident in melatonin-treated males. These results indicate that the pineal gland by way of the hormone melatonin is important in the synchronisation of the unusual life history of this marsupial mammal.

Short-term risk forecasts of heavy rainfall.

Methodologies for risk forecasts of severe weather hardly exist on the scale of nowcasting (0-3 hours). Here we discuss short-term risk forecasts of heavy precipitation associated with local thunderstorms. We use COTREC/RainCast: a procedure to extrapolate radar images into the near future. An error density function is defined using the estimated error of location of the extrapolated radar patterns. The radar forecast is folded ("smeared") with the density function, leading to a probability distribution of radar intensities. An algorithm to convert the radar intensities into values of precipitation intensity provides the desired probability (or risk) of heavy rainfall at any position within the considered window in space and time. We discuss, as an example, a flood event from summer 2000.

Evidence for lamprey GnRH-I and -III-like molecules in the brains of the southern hemisphere lampreys Geotria australis and Mordacia mordax.

The present study has characterized gonadotropic releasing hormone (GnRH)-like molecules in the brains of representatives of the two southern hemisphere families of lampreys, Geotriidae and Mordaciidae. Chromatographic and immunocytochemical evidence showed that the brains of Geotria australis and Mordacia mordax contain two forms of GnRH-like molecules. These two forms correspond to lamprey GnRH-I and -III, which were first sequenced from the brain of the anadromous sea lamprey Petromyzon marinus, a representative of the family Petromyzontidae that is found only in the northern hemisphere. In chromatographic studies (HPLC) using lamprey GnRH-I and -III antiserum, two early eluting GnRH forms coeluted with synthetic lamprey GnRH-I and -III standards. Our studies thus indicate that, despite their apparently long period of separation, the three families of extant lampreys have each retained both of the lamprey GnRH (-I and -III forms) molecules. Moreover, immunocytochemical localization of lamprey GnRH indicated that the pattern of its distribution in the adult brain of at least one of these southern hemisphere lampreys (G. australis) is similar to that previously described for P. marinus. Distribution of GnRH in the brain of larval G. australis was not as extensive as that in larval P. marinus, which may account for the later gonadal development in the former species. The fact that lamprey GnRH-I and -III are the dominant GnRH forms in all three families of lampreys implies that these neurohormones have an ancient origin.

Deciphering the origin of Met-enkephalin and Leu-enkephalin in Lobe-finned fish: cloning of australian lungfish proenkephalin.

The previous detection of Met-enkephalin and Leu-enkephalin in the CNS of the Australian lungfish, Neoceratodus forsteri, in a molar ratio comparable to mammals suggested that the lungfish proenkephalin precursor should contain the sequences of both Met-enkephalin and Leu-enkephalin as seen for mammalian proenkephalin. However, the cloning of a full-length proenkephalin cDNA from the CNS of the Australian lungfish indicates that the organization of this precursor is more similar to amphibian proenkephalin than mammalian proenkephalin. The Australian lungfish cDNA is 1284 nucleotides in length and the open reading frame (267 amino acids) contains seven opioid sequences (GenBank #AF232671). There are five copies of the Met-enkephalin sequence flanked by sets of paired basic amino acid proteolytic cleavage sites and two C-terminally extended forms of Met-enkephalin: YGGFMRSL and YGGFMGY. As seen for amphibians, no Leu-enkephalin sequence was detected in the Australian lungfish proenkephalin cDNA. The fact that Leu-enkephalin has been identified by radioimmunoassay and HPLC analysis in the CNS of the Australian lungfish indicates that a Leu-enkephalin-coding gene, distinct from proenkephalin, must be expressed in lungfish. Potential candidates may include a prodynorphin- or other opioid-like gene. Furthermore, the absence of a Leu-enkephalin sequence in lungfish and amphibian proenkephalin would suggest that the mutations that yielded this opioid sequence in tetrapod proenkephalin occurred at some point in the radiation of the amniote vertebrates.

Potentiation of warfarin anticoagulation associated with topical methyl salicylate.

OBJECTIVE: To report a case of international normalized ratio (INR) elevation resulting from the administration of topical methyl salicylate in a patient whose INR was previously stable while she received warfarin anticoagulation. CASE SUMMARY: A 22-year-old white woman presented with an INR of 12.2 after applying a topical pain-relieving gel to her knees daily for eight days. The potentiation of the warfarin anticoagulation was attributed to the low-dose methyl salicylate contained in the product. DISCUSSION: Methyl salicylate is systemically absorbed through the skin in measurable amounts, and may increase warfarin action by affecting vitamin K metabolism or by displacing warfarin from protein-binding sites. While several investigators have reported this interaction with use of high-dose methyl salicylate, this case indicates that a significant interaction can occur with the use of lower topical doses of methyl salicylate as well. CONCLUSIONS: Healthcare providers and patients taking warfarin must be aware of the potential hazard of using topical methyl salicylate in combination with warfarin.

Control of pulmonary surfactant secretion: an evolutionary perspective.

Pulmonary surfactant, a mixture consisting of phospholipids (PL) and proteins, is secreted by type II cells in the lungs of all air-breathing vertebrates. Virtually nothing is known about the factors that control the secretion of pulmonary surfactant in nonmammalian vertebrates. With the use of type II cell cultures from Australian lungfish, North American bullfrogs, and fat-tailed dunnarts, we describe the autonomic regulation of surfactant secretion among the vertebrates. ACh, but not epinephrine (Epi), stimulated total PL and disaturated PL (DSP) secretion from type II cells isolated from Australian lungfish. Both Epi and ACh stimulated PL and DSP secretion from type II cells of bullfrogs and fat-tailed dunnarts. Neither Epi nor ACh affected the secretion of cholesterol from type II cell cultures of bullfrogs or dunnarts. Pulmonary surfactant secretion may be predominantly controlled by the autonomic nervous system in nonmammalian vertebrates. The parasympathetic nervous system may predominate at lower body temperatures, stimulating surfactant secretion without elevating metabolic rate. Adrenergic influences on the surfactant system may have developed subsequent to the radiation of the tetrapods. Furthermore, ventilatory influences on the surfactant system may have arisen at the time of the evolution of the mammalian bronchoalveolar lung. Further studies using other carefully chosen species from each of the vertebrate groups are required to confirm this hypothesis.

Cranial neural crest cell migration in the Australian lungfish, Neoceratodus forsteri.

A crucial role for the cranial neural crest in head development has been established for both actinopterygian fishes and tetrapods. It has been claimed, however, that the neural crest is unimportant for head development in the Australian lungfish (Neoceratodus forsteri), a member of the group (Dipnoi) which is commonly considered to be the living sister group of the tetrapods. In the present study, we used scanning electron microscopy to study cranial neural crest development in the Australian lungfish. Our results, contrary to those of Kemp, show that cranial neural crest cells do emerge and migrate in the Australian lungfish in the same way as in other vertebrates, forming mandibular, hyoid, and branchial streams. The major difference is in the timing of the onset of cranial neural crest migration. It is delayed in the Australian lungfish in comparison with their living sister group the Lissamphibia. Furthermore, the delay in timing between the emergence of the hyoid and branchial crest streams is very long, indicating a steeper anterior-posterior gradient than in amphibians. We are now extending our work on lungfish head development to include experimental studies (ablation of selected streams of neural crest cells) and fate mapping (using fluoresent tracer dyes such as Dil) to document the normal fate as well as the role in head patterning of the cranial neural crest in the Australian lungfish.