Semipermeable species boundaries create opportunities for gene flow and adaptive potential.

Hybridisation and gene flow can have both deleterious and adaptive consequences for natural populations and species. To better understand the extent of hybridisation in nature and the balance between its beneficial and deleterious outcomes in a changing environment, information on naturally hybridising nonmodel organisms is needed. This requires the characterisation of the structure and extent of natural hybrid zones. Here, we study natural populations of five keystone mound-building wood ant species in the Formica rufa group across Finland. No genomic studies across the species group exist, and the extent of hybridisation and genomic differentiation in sympatry is unknown. Combining genome-wide and morphological data, we demonstrate more extensive hybridisation than was previously detected between all five species in Finland. Specifically, we reveal a mosaic hybrid zone between Formica aquilonia, F. rufa and F. polyctena, comprising further generation hybrid populations. Despite this, we find that F. rufa, F. aquilonia, F. lugubris and F. pratensis form distinct gene pools in Finland. We also find that hybrids occupy warmer microhabitats than the nonadmixed populations of cold-adapted F. aquilonia, and suggest that warm winters and springs, in particular, may benefit hybrids over F. aquilonia, the most abundant F. rufa group species in Finland. In summary, our results indicate that extensive hybridisation may create adaptive potential that could promote wood ant persistence in a changing climate. Additionally, they highlight the potentially significant ecological and evolutionary consequences of extensive mosaic hybrid zones, within which independent hybrid populations face an array of ecological and intrinsic selection pressures.

Reconstructing 3D Face of Infants in Social Interactions Using Morphable Models of Non-Infants.

3D morphable models (3DMMs) simultaneously reconstruct facial morphology, expression and pose from 2D images, and thus could be an invaluable tool for capturing and characterizing the face and facial behavior in early childhood. However, 3DMM fitting on infants is a largely unexplored problem. All publicly available 3DMMs are developed for adults, and it is unclear if and to what extent they can be used on videos of infants. In this paper, we compare five state-of-the-art 3DMM fitting methods on data from naturalistic infant-caregiver interactions. Results suggest that it is possible to produce consistent and subject-specific reconstructions of 3D shape identity from multiple frames, but not from a single frame. Qualitative evaluation highlights that facial regions with high texture variation, such as eyes, brows and mouth, are captured with higher accuracy compared to the rest of the face. Thus, even though a 3DMM developed for adults has significant limitations when reconstructing the morphology of the entire facial region of infants, applications that involve analysis of facial behavior can be feasible. Our encouraging results, combined with the unique ability of 3DMMs to disentangle two major sources of noise for expression analysis (i.e., identity bias and pose variations), motivate future research on using 3DMMs to measure the facial behavior of infants.

Infants later diagnosed with autism have lower canonical babbling ratios in the first year of life.

BACKGROUND: Canonical babbling-producing syllables with a mature consonant, full vowel, and smooth transition-is an important developmental milestone that typically occurs in the first year of life. Some studies indicate delayed or reduced canonical babbling in infants at high familial likelihood for autism spectrum disorder (ASD) or who later receive an ASD diagnosis, but evidence is mixed. More refined characterization of babbling in the first year of life in infants with high likelihood for ASD is needed. METHODS: Vocalizations produced at 6 and 12 months by infants (n = 267) taking part in a longitudinal study were coded for canonical and non-canonical syllables. Infants were categorized as low familial likelihood (LL), high familial likelihood diagnosed with ASD at 24 months (HL-ASD) or not diagnosed (HL-Neg). Language delay was assessed based on 24-month expressive and receptive language scores. Canonical babble ratio (CBR) was calculated by dividing the number of canonical syllables by the number of total syllables. Generalized linear (mixed) models were used to assess the relationship between group membership and CBR, controlling for site, sex, and maternal education. Logistic regression was used to assess whether canonical babbling ratios at 6 and 12 months predict 24-month diagnostic outcome. RESULTS: No diagnostic group differences in CBR were detected at 6 months, but HL-ASD infants produced significantly lower CBR than both the HL-Neg and LL groups at 12 months. HL-Neg infants with language delay also showed reduced CBR at 12 months. Neither 6- nor 12-month CBR was significant predictors of 24-month diagnostic outcome (ASD versus no ASD) in logistic regression. LIMITATIONS: Small numbers of vocalizations produced by infants at 6 months may limit the reliability of CBR estimates. It is not known if results generalize to infants who are not at high familial likelihood, or infants from more diverse racial and socioeconomic backgrounds. CONCLUSIONS: Lower canonical babbling ratios are apparent by the end of the first year of life in ASD regardless of later language delay, but are also observed for infants with later language delay without ASD. Canonical babbling may lack specificity as an early marker when used on its own.

Effect of ARTEMIS (DCLRE1C) deficiency and microinjection timing on editing efficiency during somatic cell nuclear transfer and in vitro fertilization using the CRISPR/Cas9 system.

The ability to efficiently introduce site-specific genetic modifications to the mammalian genome has been dramatically improved with the use of the CRISPR/Cas9 system. CRISPR/Cas9 is a powerful tool used to generate genetic modifications by causing double-strand breaks (DSBs) in DNA. Artemis (ART; also known as DCLRE1C), is a nuclear protein and is essential for DSB end joining in DNA repair via the canonical non-homologous end joining (c-NHEJ) pathway. In this work, we tested whether ART deficiency affects DNA repair following CRISPR/Cas9 induced DSBs in somatic cells. We also demonstrated the effect of microinjection timing on embryo developmental ability and gene targeting efficiency of CRISPR/Cas9 system to disrupt the interleukin 2 receptor subunit gamma (IL2RG) locus using porcine in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT) derived embryos. In comparison to non-injected controls, CRISPR/Cas9 injection of IVF derived zygotes at 4 h and 8 h after fertilization did not impact cleavage and blastocyst rate. Gene modification rate was observed to be higher, 53.3% (9/16) in blastocysts injected 4 h post-fertilization as compared to 11.1% (1/9) in blastocysts injected 8 h post-fertilization. Microinjection 8 h after chemical activation of SCNT derived embryos decreased blastocyst development rate compared to non-injected controls but showed a higher gene modification efficiency of 66.7% as compared to 25% in the 4 h post-activation injection group. Furthermore, we observed that male ART-/- and ART+/- porcine fetal fibroblast (pFF) cells showed lower modification rates (2.5% and 1.9%, respectively) as compared to the ART intact cell line (8.3%). Interestingly, the female ART-/- and ART+/- pFF cells had modification rates (4.2% and 10.1%, respectively) similar to those seen in the ART intact cells. This study demonstrates the complex effect of various parameters such as microinjection timing and ART deficiency on gene editing efficiency in in vitro derived porcine embryos.

Atypicalities of Gesture Form and Function in Autistic Adults.

While well-represented on clinical measures, co-speech gesture production has never been formally studied in autistic adults. Twenty-one verbally fluent autistic adults and 21 typically developing controls engaged in a controlled conversational task. Group differences were observed in both semantic/pragmatic and motoric features of spontaneously produced co-speech gestures. Autistic adults prioritized different functions of co-speech gesture. Specifically, they used gesture more than controls to facilitate conversational turn-taking, demonstrating a novel nonverbal strategy for regulating conversational dynamics. Autistic adults were more likely to gesture unilaterally than bilaterally, a motoric feature of gesture that was individually associated with autism symptoms. Co-speech gestures may provide a link between nonverbal communication symptoms and known differences in motor performance in autism.

Language delay aggregates in toddler siblings of children with autism spectrum disorder.

BACKGROUND: Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype. METHODS: We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample. RESULTS: Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n = 235) versus LR-noASD group (n = 115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition. CONCLUSIONS: Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms.

Hydraulic fracturing volume is associated with induced earthquake productivity in the Duvernay play.

A sharp increase in the frequency of earthquakes near Fox Creek, Alberta, began in December 2013 in response to hydraulic fracturing. Using a hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We show that induced earthquakes are associated with completions that used larger injection volumes (104 to 105 cubic meters) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have an insignificant association with seismic response. Further findings suggest that geological factors play a prominent role in seismic productivity, as evidenced by spatial correlations. Together, volume and geological factors account for ~96% of the variability in the induced earthquake rate near Fox Creek. This result is quantified by a seismogenic index-modified frequency-magnitude distribution, providing a framework to forecast induced seismicity.

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism.

BACKGROUND: We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. METHODS: A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. RESULTS: Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen's d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. CONCLUSIONS: This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Neural correlates of naturalistic social cognition: brain-behavior relationships in healthy adults.

Being able to infer the thoughts, feelings and intentions of those around us is indispensable in order to function in a social world. Despite growing interest in social cognition and its neural underpinnings, the factors that contribute to successful mental state attribution remain unclear. Current knowledge is limited because the most widely used tasks suffer from two main constraints: (i) They fail to capture individual variability due to ceiling effects and (ii) they use highly simplistic, often artificial stimuli inapt to mirror real-world socio-cognitive demands. In the present study, we address these problems by employing complex depictions of naturalistic social interactions that vary in both valence (positive vs negative) and ambiguity (high vs low). Thirty-eight healthy participants (20 female) made mental state judgments while brain responses were obtained using functional magnetic resonance imaging (fMRI). Accuracy varied based on valence and ambiguity conditions and women were more accurate than men with highly ambiguous social stimuli. Activity of the orbitofrontal cortex predicted performance in the high ambiguity condition. The results shed light on subtle differences in mentalizing abilities and associated neural activity.

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation.

Oocyte and preimplantation embryo development entail dynamic changes in chromatin structure and gene expression, which are regulated by a number of maternal and zygotic epigenetic factors. Histone deacetylases (HDACs), which tighten chromatin structure, repress transcription and gene expression by removing acetyl groups from histone or non-histone proteins. HDAC1 and HDAC2 are two highly homologous Class I HDACs and display compensatory or specific roles in different cell types or in response to different stimuli and signaling pathways. We summarize here the current knowledge about the functions of HDAC1 and HDAC2 in regulating histone modifications, transcription, DNA methylation, chromosome segregation, and cell cycle during oocyte and preimplantation embryo development. What emerges from these studies is that although HDAC1 and HDAC2 are highly homologous, HDAC2 is more critical than HDAC1 for oocyte development and reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development.

The effect of co-administration of intravenous calcium chloride and oxytocin on maternal hemodynamics and uterine tone following cesarean delivery: a double-blinded, randomized, placebo-controlled trial.

BACKGROUND: Oxytocin administration to prevent uterine atony following cesarean delivery is associated with adverse effects including hypotension, tachycardia, and nausea. Calcium chloride increases mean arterial pressure, systemic vascular resistance, and uterine smooth muscle contractility. This study evaluated whether the co-administration of calcium chloride with oxytocin following cesarean delivery could alter maternal hemodynamics. Secondary outcomes included uterine tone and blood loss. METHODS: Sixty healthy parturients with singleton, term, vertex pregnancies undergoing elective cesarean delivery under spinal anesthesia were randomized to one of three study solutions given intravenously immediately after umbilical cord clamping: (1) placebo, oxytocin 5U alone; (2) CA-200, oxytocin 5U+calcium chloride 200mg; or (3) CA-400, oxytocin 5U+calcium chloride 400mg. Blood pressure, heart rate, uterine tone, vasopressor or alternate uterotonic use and the incidence of nausea or vomiting were recorded. Baseline and intraoperative plasma concentration of ionized calcium and hematocrit were measured. RESULTS: Plasma concentration of ionized calcium was elevated in both study groups compared with placebo (P=0.001). Blood pressure decreased and heart rate increased in all groups (P <0.0001), with no differences between groups. No differences were observed between groups in uterine tone, vasopressor use, hematocrit change, estimated blood loss, incision-to-delivery interval, delivery-to-skin closure interval, total intravenous fluid administered or incidence of nausea. CONCLUSIONS: The decrease in blood pressure associated with oxytocin administration following cesarean delivery was not attenuated with co-administration of calcium chloride at the doses evaluated. Vasopressor use, uterine tone, and blood loss were also unaffected.

Diagnostic utility of microarray testing in pregnancy loss.

OBJECTIVES: To determine the frequency of clinically significant chromosomal abnormalities identified by chromosomal microarray in pregnancy losses at any gestational age and to compare microarray performance with that of traditional cytogenetic analysis when testing pregnancy losses. METHODS: Among 535 fetal demise specimens of any gestational age, clinical microarray-based comparative genomic hybridization (aCGH) was performed successfully on 515, and a subset of 107 specimens underwent additional single nucleotide polymorphism (SNP) analysis. RESULTS: Overall, clinically significant abnormalities were identified in 12.8% (64/499) of specimens referred with normal or unknown karyotypes. Detection rates were significantly higher with earlier gestational age. In the subset with normal karyotype, clinically significant abnormalities were identified in 6.9% (20/288). This detection rate did not vary significantly with gestational age, suggesting that, unlike aneuploidy, the contribution of submicroscopic chromosomal abnormalities to fetal demise does not vary with gestational age. In the 107 specimens that underwent aCGH and SNP analysis, seven cases (6.5%) had abnormalities of potential clinical significance detected by the SNP component, including female triploidy. aCGH failed to yield fetal results in 8.3%, which is an improvement over traditional cytogenetic analysis of fetal demise specimens. CONCLUSIONS: Both the provision of results in cases in which karyotype fails and the detection of abnormalities in the presence of a normal karyotype demonstrate the increased diagnostic utility of microarray in pregnancy loss. Thus, chromosomal microarray testing is a preferable, robust method of analyzing cases of pregnancy loss to better delineate possible genetic etiologies, regardless of gestational age.

Recommendations on vaccination for Asian small animal practitioners: a report of the WSAVA Vaccination Guidelines Group.

In 2012 and 2013, the World Small Animal Veterinary Association (WSAVA) Vaccination Guidelines Group (VGG) undertook fact-finding visits to several Asian countries, with a view to developing advice for small companion animal practitioners in Asia related to the administration of vaccines to dogs and cats. The VGG met with numerous first opinion practitioners, small animal association leaders, academic veterinarians, government regulators and industry representatives and gathered further information from a survey of almost 700 veterinarians in India, China, Japan and Thailand. Although there were substantial differences in the nature and magnitude of the challenges faced by veterinarians in each country, and also differences in the resources available to meet those challenges, overall, the VGG identified insufficient undergraduate and postgraduate training in small companion animal microbiology, immunology and vaccinology. In most of the countries, there has been little academic research into small animal infectious diseases. This, coupled with insufficient laboratory diagnostic support, has limited the growth of knowledge concerning the prevalence and circulating strains of key infectious agents in most of the countries visited. Asian practitioners continue to recognise clinical infections that are now considered uncommon or rare in western countries. In particular, canine rabies virus infection poses a continuing threat to animal and human health in this region. Both nationally manufactured and international dog and cat vaccines are variably available in the Asian countries, but the product ranges are small and dominated by multi-component vaccines with a licensed duration of immunity (DOI) of only 1 year, or no description of DOI. Asian practitioners are largely unaware of current global trends in small animal vaccinology or of the WSAVA vaccination guidelines. Consequently, most practitioners continue to deliver annual revaccination with both core and non-core vaccines to adult animals, with little understanding that "herd immunity" is more important than frequent revaccination of individual animals within the population. In this paper, the VGG presents the findings of this project and makes key recommendations for the Asian countries. The VGG recommends that (1) Asian veterinary schools review and increase as needed the amount of instruction in small animal vaccinology within their undergraduate curriculum and increase the availability of pertinent postgraduate education for practitioners; (2) national small animal veterinary associations, industry veterinarians and academic experts work together to improve the scientific evidence base concerning small animal infectious diseases and vaccination in their countries; (3) national small animal veterinary associations take leadership in providing advice to practitioners based on improved local knowledge and global vaccination guidelines; (4) licensing authorities use this enhanced evidence base to inform and support the registration of improved vaccine product ranges for use in their countries, ideally with DOI for core vaccines similar or equal to those of equivalent products available in western countries (i.e. 3 or 4 years). The VGG also endorses the efforts made by Asian governments, non-governmental organisations and veterinary practitioners in working towards the goal of global elimination of canine rabies virus infection. In this paper, the VGG offers both a current pragmatic and future aspirational approach to small animal vaccination in Asia. As part of this project, the VGG delivered continuing education to over 800 Asian practitioners at seven events in four countries. Accompanying this document is a list of 80 frequently asked questions (with answers) that arose during these discussions. The VGG believes that this information will be of particular value to Asian veterinarians as they move towards implementing global trends in small companion animal vaccinology.

BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos.

Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass, which gives rise to embryonic stem cells (ESCs). Here we report that BRD4 regulates expression of the pluripotency factor Nanog in mouse ESCs and preimplantation embryos, as well as in human ESCs and embryonic cancer stem cells. Inhibition of BRD4 function using a chemical inhibitor, small interfering RNAs, or a dominant-negative approach suppresses Nanog expression, and abolishes the self-renewal ability of ESCs. We also find that BRD4 associates with BRG1 (brahma-related gene 1, aka Smarca4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4)), a key regulator of ESC self-renewal and pluripotency, in the Nanog regulatory regions to regulate Nanog expression. Our study identifies Nanog as a novel BRD4 target gene, providing new insights for the biological function of BRD4 in stem cells and mouse embryos. Knowledge gained from these non-cancerous systems will facilitate future investigations of how Brd4 dysfunction leads to cancers.

Diferencias en calidad de vida asociado a la apariencia nasal en pacientes operados de rinoplastia comparado con grupo control: validez del instrumento rhinoplasty outcome evaluation / Evaluation of the rhinoplasty outcome evaluation among chilean participants

Background: The Rhinoplasty Outcome Evaluation (ROE) is an instrument to assess the cosmetic and functional aspects of the nose from the patient's perspective. Its construct validity in Chilean subjects has been published previously. Aim: To compare the ROE scores in different groups of participants. Material and Methods: The questionnaire was applied to patients waiting for a rhinoplasty, patients hospitalized for other causes and medical students. Results: The overall reliability of the scale was 84.8 percent. Significant differences between groups in the total scores of four out of six items were observed. Conclusions: The Spanish version of the ROE is adequate to evaluate the satisfaction with nasal appearance and function among Chilean individuals.

Objetivo: El Rhinoplasty Outcome Evaluation (ROE) es un instrumento específico para la evaluación cosmética y funcional de la nariz desde la perspectiva del paciente, desarrollado originalmente en inglés. El objetivo del presente estudio es comparar las distribuciones en distintas poblaciones. Material y Método: El instrumento validado en español chileno ROE fue sometido a prueba para evaluar su validez de criterio comparando los resultados de la escala en pacientes programados que deseaban someterse a rinoplastía versus 2 grupos control: 1) Pacientes hospitalizados por otras causas y 2) Estudiantes de medicina. La validez de constructo ya ha sido publicada por los creadores de la escala. Para la comparación de variables se utilizaron las pruebas t de Student, ANOVA, Wilcoxon, Kruskall Wallis, prueba exacta de Fisher o χ² según correspondiera. Para todas las pruebas se utilizó un nivel alfa de 5 por ciento. Resultados: Se aplicó la encuesta a 45 pacientes. La edad promedio de la muestra fue de 35,4 años. La confiabilidad de la escala fue de 84,78 por ciento. Se observaron diferencias estadísticamente significativas en el puntaje total (p = 0,0047) en 4 de los 6 ítems. Conclusión: Los resultados preliminares de nuestro estudio sugieren que la versión en Español del Rhinoplasty Outcomes Evaluation es útil para evaluar la satisfacción con la apariencia nasal en chilenos.

Network inefficiencies in autism spectrum disorder at 24 months.

Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral symptoms that emerge during the first years of life. Associated with these symptoms are differences in the structure of a wide array of brain regions, and in the connectivity between these regions. However, the use of cohorts with large age variability and participants past the generally recognized age of onset of the defining behaviors means that many of the reported abnormalities may be a result of cascade effects of developmentally earlier deviations. This study assessed differences in connectivity in ASD at the age at which the defining behaviors first become clear. There were 113 24-month-old participants at high risk for ASD, 31 of whom were classified as ASD, and 23 typically developing 24-month-old participants at low risk for ASD. Utilizing diffusion data to obtain measures of the length and strength of connections between anatomical regions, we performed an analysis of network efficiency. Our results showed significantly decreased local and global efficiency over temporal, parietal and occipital lobes in high-risk infants classified as ASD, relative to both low- and high-risk infants not classified as ASD. The frontal lobes showed only a reduction in global efficiency in Broca's area. In addition, these same regions showed an inverse relation between efficiency and symptom severity across the high-risk infants. The results suggest delay or deficits in infants with ASD in the optimization of both local and global aspects of network structure in regions involved in processing auditory and visual stimuli, language and nonlinguistic social stimuli.

Birthing in the Barkly: births to Barkly women in 2010.

INTRODUCTION: A 2007 review of maternity services in Australia's Northern Territory (NT) noted the dissatisfaction of women in the Barkly region where the birthing service closed in 2006. The review recommended improved integration of maternity services, a consumer focus, and a pilot study of birthing in Tennant Creek Hospital (TCH) in the Barkly region. Barkly region is sparsely populated, with 5700 people in 320,000 km². The town of Tennant Creek with 3100 population is the only centre of more than 1000 people. In the Barkly region, 64% of the population and 74% of birthing women are Aboriginal. Current NT Department of Health (NT DoH) policy requires all women to give birth in a town with facilities for operative delivery. For most Barkly women this means travelling 500 km to Alice Springs with limited support for travel and accommodation. Emergency air evacuation is arranged for all women who enter labour or give birth while in the Barkly region, whether at TCH or elsewhere. This project was a collaboration between Anyinginyi Health Aboriginal Corporation and NT DoH to examine clinical data to inform a discussion of re-introducing birthing to TCH. METHODS: Women who were resident in the Barkly region and gave birth in NT in 2010 were identified from the NT Midwives Data Collection. Women who gave birth in Central Australia were managed at Alice Springs Hospital (ASH), either for the birth or afterwards. Antenatal, birthing, postnatal and neonatal data were extracted from ASH records. RESULTS: In total 99 women were identified as residents in the Barkly region from all those who gave birth in 2010. Of these, 83 gave birth in Central Australia, and their records were reviewed for this study, showing that 69 (83%) were Aboriginal; 42 were resident in Tennant Creek; and 29% were aged under 20 years with one under 16 years. Regarding delivery, 53 (64%) women had an unassisted vaginal birth; of 18 women who had had a previous caesarean section, 5 (28%) had a vaginal birth; of the 25 women who had had a normal vaginal birth previously and had no indications for obstetric consultation at the time of labour, three underwent emergency caesarean section. There were 86 infants, all liveborn; 16% were preterm; 21% were of low birth weight; and 6% weighed more than 4.5 kg. Six women gave birth in the Barkly region, two at TCH and four in health centres in remote townships. These mothers and babies were evacuated immediately following birth to ASH, irrespective of indications for referral. Eleven women were evacuated to ASH in labour and six of these were preterm. CONCLUSION: Opportunities exist to improve maternity care through improved collaboration, even when women cannot give birth in or near their home community due to the absence of birthing services. The remote location of the Barkly region presents challenges to providing maternity care that addresses medical, cultural, psychological and social needs of the childbearing population. Because of this, every opportunity should be taken to optimise maternity care by improvements in continuity of care and carer, improved communication between service providers, and the use of evidence-based guidelines.

AKT is a therapeutic target in myeloproliferative neoplasms.

The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.