Circulating trace elements for the prediction of preeclampsia and small for gestational age babies.

INTRODUCTION: Poor gestational outcomes due to placental insufficiency can have lifelong consequences for mother and child. OBJECTIVE: There is a need for better methods of diagnosis, and elemental metabolomics may provide a means to determine the risk of gestational disorders. METHODS: This study used blood plasma samples collected at 36 weeks' gestation from women who later developed preeclampsia (n = 38), or small-for-gestational age babies (n = 91), along with matched controls (n = 193). Multi-element analysis was conducted by inductively coupled plasma mass spectrometer (ICP-MS), allowing simultaneous measurement of 28 elements. RESULTS: Women who later developed PE, exhibited significantly increased concentrations of K, Rb and Ba. For SGA pregnancies, there was a significant increase in Cu and a decrease in As concentrations. Despite significant differences in single elements, the elemental profile of groups indicated no clustering of control, PE, or SGA samples. Positive predicative values correctly identified approximately 60% of SGA and 70% of PE samples. CONCLUSION: This is the first-time elemental metabolomics has been used to predict SGA and PE at 36 weeks. Though significant changes were identified, routine clinical use may be limited but may contribute to a multi marker test. Future analysis should include other biomarkers, metabolic data or clinical measurements made throughout gestation.

ErbB1-dependent signalling and vesicular trafficking in primary afferent nociceptors associated with hypersensitivity in neuropathic pain.

Effective analgesic treatment for neuropathic pain remains an unmet need, so previous evidence that epidermal growth factor receptor inhibitors (EGFRIs) provide unexpected rapid pain relief in a clinical setting points to a novel therapeutic opportunity. The present study utilises rodent models to address the cellular and molecular basis for the findings, focusing on primary sensory neurons because clinical pain relief is provided not only by small molecule EGFRIs, but also by the anti-EGFR antibodies cetuximab and panitumumab, which are unlikely to access the central nervous system in therapeutic concentrations. We report robust, rapid and dose-dependent analgesic effects of EGFRIs in two neuropathic pain models, matched by evidence with highly selective antibodies that expression of the EGFR (ErbB1 protein) is limited to small nociceptive afferent neurons. As other ErbB family members can heterodimerise with ErbB1, we investigated their distribution, showing consistent co-expression of ErbB2 but not ErbB3 or ErbB4, with ErbB1 in cell bodies of nociceptors, as well as providing evidence for direct molecular interaction of ErbB1 with ErbB2 in situ. Co-administration of selective ErbB1 and ErbB2 inhibitors produced clear evidence of greater-than-additive, synergistic analgesia; highlighting the prospect of a unique new combination therapy in which enhanced efficacy could be accompanied by minimisation of side-effects. Peripheral (intraplantar) administration of EGF elicited hypersensitivity only following nerve injury and this was reversed by local co-administration of selective inhibitors of either ErbB1 or ErbB2. Investigating how ErbB1 is activated in neuropathic pain, we found evidence for a role of Src tyrosine kinase, which can be activated by signals from inflammatory mediators, chemokines and cytokines during neuroinflammation. Considering downstream consequences of ErbB1 activation in neuropathic pain, we found direct recruitment to ErbB1 of an adapter for PI 3-kinase and Akt signalling together with clear Akt activation and robust analgesia from selective Akt inhibitors. The known Akt target and regulator of vesicular trafficking, AS160 was strongly phosphorylated at a perinuclear location during neuropathic pain in an ErbB1-, ErbB2- and Akt-dependent manner, corresponding to clustering and translocation of an AS160-partner, the vesicular chaperone, LRP1. Exploring whether neuronal ion channels that could contribute to hyperexcitability might be transported by this vesicular trafficking pathway we were able to identify Nav1.9, (Nav1.8) and Cav1.2 moving towards the plasma membrane or into proximal axonal locations - a process prevented by ErbB1 or Akt inhibitors. Overall these findings newly reveal both upstream and downstream signals to explain how ErbB1 can act as a signalling hub in neuropathic pain models and identify the trafficking of key ion channels to neuronal subcellular locations likely to contribute to hyperexcitability. The new concept of combined treatment with ErbB1 plus ErbB2 blockers is mechanistically validated as a promising strategy for the relief of neuropathic pain.

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

Prolonged Analgesia by Spinal Cord Stimulation Following a Spinal Injury Associated With Activation of Adult Neural Progenitors.

OBJECTIVES: Responses of spinal progenitors to spinal cord stimulation (SCS) following spinal cord injury (SCI) in rats were assessed to reveal their potential contribution to SCS-induced analgesia. METHODS: Spinal epidural electrodes were implanted in rats at T12 rostral to a quadrant dorsal horn injury at T13. Further groups additionally received either a microlesion to the dorsolateral funiculus (DLF) or gabapentin (10 mg/kg). SCS was performed at 25 Hz for 10 minutes on day 4 (early SCS) and at 10 Hz for 10 minutes on day 8 (late SCS) after injury. Paw withdrawal threshold (PWT) was measured before injury, 30 minutes before or after SCS, and before cull on day 14, followed by immunostaining assessment. RESULTS: Paw withdrawal thresholds in uninjured animals (51.0 ± 4.0 g) were markedly reduced after SCI (17.3 ± 2.2 g). This was significantly increased by early SCS (38.5 ± 5.2 g, P < 0.01) and further enhanced by late SCS (50.9 ± 1.9 g, P < 0.01) over 6 days. Numbers of neural progenitors expressing nestin, Sox2, and doublecortin (DCX) in the spinal dorsal horn were increased 6 days after SCS by 6-fold, 2-fold, and 2.5-fold, respectively (P < 0.05 to 0.01). The elevated PWT evoked by SCS was abolished by DLF microlesions (48.9 ± 2.6 g vs. 19.0 ± 3.9 g, P < 0.01) and the number of nestin-positive cells was reduced to the level without SCS (P < 0.05). Gabapentin enhanced late SCS-induced analgesia from 37.0 ± 3.9 g to 54.0 ± 0.8 g (P < 0.01) and increased gamma-aminobutyric acid (GABA)-ergic neuronal marker vesicular GABA transporter-positive newborn cells 2-fold (P < 0.01). CONCLUSIONS: Spinal progenitor cells appear to be activated by SCS via descending pathways, which may be enhanced by gabapentin and potentially contributes to relief of SCI-induced neuropathic pain.

Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial.

OBJECTIVE: Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. METHODS: In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. RESULTS: The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). CONCLUSIONS: This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

Validation of verbal autopsy methods using hospital medical records: a case study in Vietnam.

BACKGROUND: Information on causes of death (COD) is crucial for measuring the health outcomes of populations and progress towards the Sustainable Development Goals. In many countries such as Vietnam where the civil registration and vital statistics (CRVS) system is dysfunctional, information on vital events will continue to rely on verbal autopsy (VA) methods. This study assesses the validity of VA methods used in Vietnam, and provides recommendations on methods for implementing VA validation studies in Vietnam. METHODS: This validation study was conducted on a sample of 670 deaths from a recent VA study in Quang Ninh province. The study covered 116 cases from this sample, which met three inclusion criteria: a) the death occurred within 30 days of discharge after last hospitalisation, and b) medical records (MRs) for the deceased were available from respective hospitals, and c) the medical record mentioned that the patient was terminally ill at discharge. For each death, the underlying cause of death (UCOD) identified from MRs was compared to the UCOD from VA. The validity of VA diagnoses for major causes of death was measured using sensitivity, specificity and positive predictive value (PPV). RESULTS: The sensitivity of VA was at least 75% in identifying some leading CODs such as stroke, road traffic accidents and several site-specific cancers. However, sensitivity was less than 50% for other important causes including ischemic heart disease, chronic obstructive pulmonary diseases, and diabetes. Overall, there was 57% agreement between UCOD from VA and MR, which increased to 76% when multiple causes from VA were compared to UCOD from MR. CONCLUSIONS: Our findings suggest that VA is a valid method to ascertain UCOD in contexts such as Vietnam. Furthermore, within cultural contexts in which patients prefer to die at home instead of a healthcare facility, using the available MRs as the gold standard may be meaningful to the extent that recall bias from the interval between last hospital discharge and death can be minimized. Therefore, future studies should evaluate validity of MRs as a gold standard for VA studies in contexts similar to the Vietnamese context.

A Developmental Cascade Model of Behavioral Sleep Problems and Emotional and Attentional Self-Regulation Across Early Childhood.

This article documents the longitudinal and reciprocal relations among behavioral sleep problems and emotional and attentional self-regulation in a population sample of 4,109 children participating in Growing Up in Australia: The Longitudinal Study of Australian Children (LSAC)-Infant Cohort. Maternal reports of children's sleep problems and self-regulation were collected at five time-points from infancy to 8-9 years of age. Longitudinal structural equation modeling supported a developmental cascade model in which sleep problems have a persistent negative effect on emotional regulation, which in turn contributes to ongoing sleep problems and poorer attentional regulation in children over time. Findings suggest that sleep behaviors are a key target for interventions that aim to improve children's self-regulatory capacities.

Indigenous Cases of Leprosy (Hansen's Disease) in Southern Mississippi.

Hansen's disease or leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. In the U.S., leprosy is mainly reported in immigrants, but indigenous leprosy cases have been also reported in this country, especially in semitropical southern states (i.e., Texas, Louisiana). The objective of this series of cases is to describe indigenous leprosy cases reported in southern Mississippi (MS) during the period 2012-2014. Information was collected from medical records at Hattiesburg Clinic and the MS Department of Health. Four cases were reported during the period of study (3 Caucasian males, 1 African-American woman). Non of visited endemic leprosy country. The age ranged from 60 to 83 years (median: 75.5 years). Of the four cases, three presented with a slowly progressive erythematous rash disseminated mainly on the thorax and abdomen, with a lesser degree on the extremities. The time between onset of rash until the diagnosis ranged from 5 to 16 months (median: 7 months). Only one case had direct contact with armadillos (blood exposure). Non of these patients had a history of immunosuppression. The most common symptoms were neuropathic pain (n=2), generalized pruritus (n=2) and loss of sensation in extremities (n=2). One case had severe peripheral neuropathy with muscle weakness, atrophy in left arm, and wasting on left hand. Skin biopsies showed diffuse granulomatous infiltrate with foamy histiocytes along with acid fast bacilli by Fite stain. By Ridley-Jopling classification system, three cases were diagnosis as lepromatous leprosy, and one, borderline lepromatous. Treatment included clofazimine, dapsone and rifampin that was offered free of charge by the National Hansen's Diseases Program, Baton Rouge, L.A. One patient did not tolerate therapy. In conclusion, a slowly progressive disseminated erythematous skin rash on the trunk should raise suspicion for leprosy in the elderly population in south MS.

High-resolution microarray in the assessment of fetal anomalies detected by ultrasound.

AIMS: The main aim of this study was to determine the feasibility of using high-resolution microarray to assist with prenatal diagnosis of ultrasound-detected fetal abnormality and to describe the frequency of abnormal results in different categories of fetal anomalies. METHODS: Prospective cross-sectional study was conducted on women diagnosed with a fetal anomaly (ies) between February 2009 and December 2011 who were offered testing by microarray analysis (Affymetrix 2.7M SNP) and fluorescent in situ hybridisation (FISH) instead of standard karyotyping. Fetal anomalies were categorised according to organ system involvement. RESULTS: One hundred and eighteen women consented to testing with microarray. Eleven of one hundred eighteen (9.3%) cases had aneuploidy detected by FISH. Of the remaining 107, 23 (21.5%) had an abnormality detected on microarray, only three of which would have been detected using the combination of six-probe FISH and banded karyotype. The maximum expected yield for six-probe FISH and karyotype was thus 14/118 (11.8%), compared to 34/118 (28.8%), P < 0.0001. Of the 23 abnormalities detected with microarray, 10 (43%) were pathogenic, six (26%) were long continuous stretches of homozygosity and seven (30%) were of uncertain significance. The maximum yield was in cases with cardiovascular (100%); multiple (40%); central nervous system (CNS) (25%) and skeletal (9%) abnormalities. CONCLUSION: This study has confirmed the feasibility of translation of microarray into clinical practice. 11.8% (14/118) of the cases would have a genetic basis of an abnormality with a FISH and banded karyotype. This figure is approximately tripled to 28.8% (34/118) if we offer FISH and microarray. High yield for imbalances are multiple, cardiovascular, CNS and skeletal abnormalities.

Parents perception and experience of transitioning to adulthood for their child diagnosed with an intellectual disability.

Definitions of adulthood for people with intellectual disability are often complicated, with milestones being markedly different for this population. This is then associated with difficulties for both the people with intellectual disability and their parents, who are closely involved in this transitional period. This paper aims to report on parents' perception and experience of adulthood for their son or daughter with an Intellectual Disability (ID). Qualitative data were collected through 30 - 60-minute phone interviews with eight parents of a person with an intellectual disability aged 15 or older (mean parent age = 60; mean child age = 23). Thematic analysis found that Perception of Adulthood encompassed themes of Independence and Normality. Experiences of Adulthood were categorised under Government Services, Responsibility and Social Supports. Findings of this research provide information for the growing literature around adulthood for people with intellectual disability, as well as how to amend policies and procedures for services that cater to people with intellectual disability and their parents during this transition.

Stakeholder-driven transformative adaptation is needed for climate-smart nutrition security in sub-Saharan Africa.

Improving nutrition security in sub-Saharan Africa under increasing climate risks and population growth requires a strong and contextualized evidence base. Yet, to date, few studies have assessed climate-smart agriculture and nutrition security simultaneously. Here we use an integrated assessment framework (iFEED) to explore stakeholder-driven scenarios of food system transformation towards climate-smart nutrition security in Malawi, South Africa, Tanzania and Zambia. iFEED translates climate-food-emissions modelling into policy-relevant information using model output implication statements. Results show that diversifying agricultural production towards more micronutrient-rich foods is necessary to achieve an adequate population-level nutrient supply by mid-century. Agricultural areas must expand unless unprecedented rapid yield improvements are achieved. While these transformations are challenging to accomplish and often associated with increased greenhouse gas emissions, the alternative for a nutrition-secure future is to rely increasingly on imports, which would outsource emissions and be economically and politically challenging given the large import increases required.

'A problem shared is a problem halved': success of a statewide collaborative approach to fetal therapy. Outcomes of fetoscopic laser photocoagulation for twin-twin transfusion syndrome in Victoria.

AIMS: To evaluate the performance of a collaborative fetal therapy service for treatment for twin-twin transfusion syndrome (TTTS). METHODS: The Victorian Fetal Therapy Service (VFTS) was developed in 2006. It is a state-based three-centre collaborative service comprising a surgical team and clinical leadership group, designed to optimise access to, and performance of, fetoscopic procedures in Victoria. This is a prospective cohort study of VFTS patients referred for fetoscopic laser photocoagulation (FLP) for TTTS since 2006. RESULTS: Forty-nine consecutive women with advanced (stage 2-4) TTTS between 2006 and 2011 were included in this study. Overall survival was 67 of 98 (68%), and survival of ≥1 twin was seen in 42 of 49 pregnancies (86%). There was no difference in survival by disease stage at diagnosis (≥1 survivor: 66% (stage 2 or 3 TTTS) vs 77% (stage 4 TTTS), P = 0.44), nor by surgical era (≥1 survivor: 60% (2006-2008) vs 74% of cases (2009-2011), P = 0.21). The median gestation gained post-FLP was 10.5 weeks. CONCLUSION: These results are consistent with published series and confirm the success of a novel service delivery model for fetal therapy in Victoria. We suggest that collaborative models such as ours should be considered for fetal conditions where treatment is complex and the total number of cases is small to ensure a consistent approach to assessment, management and follow-up of patients and to optimise training and research opportunities.

Capturing epistemic reflexivity for teacher educators teaching about/to/for diversity in teacher education.

Internationally, there is a growing body of evidence which shows that newly graduated teachers do not feel prepared to teach the increasingly diverse student body in contemporary classrooms. However, to date, we have limited understanding of the ways in which teacher educators work with preservice teachers to enhance their knowledge about diversity and how to address the diverse needs of students in their classrooms. To further understand teacher educators' pedagogical decision making in the context of preparing preservice teachers for diverse classrooms, a way of capturing epistemic thinking in this space is required. The current study used the Epistemic Reflexivity Survey for Teacher Educators (ERS-TE) to explore the relationships between teacher educators' Epistemic Aims, Reliable epistemic processes (REPs), Criteria for Knowledge (Epistemic Ideals), Reflexivity (decision making) and Teaching Practices. Two hundred and eighty-six teacher educators across Australia and New Zealand completed the survey. Results indicated that epistemic aims related to understanding critical connections predicted engagement with reliable epistemic thinking processes, reflexivity, and teaching practices related to critical thinking and social justice. Findings are discussed in terms of implications for teacher educators' work with preservice teachers with respect to teaching about, to and for diversity.

In-Field Rainwater Harvesting Tillage in Semi-Arid Ecosystems: II Maize-Bean Intercrop Water and Radiation Use Efficiency.

The purpose of this study was to evaluate alternative management practices such as in-field rainwater harvesting (IRWH) and intercropping techniques through conducting on-farm demonstrations. Seven homestead gardens in Thaba Nchu rural communities in the central part of South Africa were selected as demonstration trials. Two tillage systems, conventional (CON) and IRWH, as the main plot, and three cropping systems as sub-plot (sole maize and beans and intercropping) were used to measure water use and radiation use parameters. The water productivity (WP) of various treatments was positively related to the radiation use efficiency (RUE), and the degree of associations varied for different tillage systems. The water use in IRWH was higher by 15.1%, 8.3%, and 10.1% over the CON for sole maize and beans and intercropping, respectively. Similarly, the intercropping system showed water use advantages over the solely growing crops by 5% and 8% for maize and by 16% and 12% for beans under IRWH and CON tillage, respectively. Maximum RUE was found for sole maize and beans under IRWH, higher by 13% and 55% compared to the CON tillage, respectively. The RUE under IRWH tillage was estimated to be 0.65 and 0.39 g DM MJ-1 in sole maize and intercropping, respectively. However, in sole and intercropped beans, the RUE showed higher values of 1.02 g DM MJ-1 and 0.73 g DM MJ-1, respectively. WP and RUE were associated with water deficits and proportional to lower radiation use. This relationship indicates that the intercepted radiation by plants for photosynthesis is directly related to the transpiration rate until radiation saturation occurs. Therefore, the higher water deficit and lesser efficiency in using the radiation available during the season can be improved by practicing IRWH techniques. Furthermore, in semi-arid areas, to enhance the efficiency of water and radiation usage in intercropping management, it is crucial to adjust plant population and sowing dates based on water availability and the onset of rainfall.

In-Field Rainwater Harvesting Tillage in Semi-Arid Ecosystems: I Maize-Bean Intercrop Performance and Productivity.

The purpose of this study was to monitor and compare the growth and productivity of maize/beans sole and inter-cropping systems under conventional (CON) and in-field rainwater harvesting (IRWH) tillage practices. During the typical drought conditions of the 2018/19 growing season, seven homestead gardens of smallholder farmers (four in Paradys and three in Morago villages) in the Thaba Nchu rural communities of South Africa were selected for on-farm demonstration trials. Two tillage systems CON and IRWH as the main plot and three cropping systems as sub-treatment (sole maize and beans and intercropping) were used to measure crop growth and productivity parameters. The results showed that IRWH tillage had significantly higher above-ground dry matter for both sole maize (29%) and intercropped maize (27%) compared to CON treatments. The grain yield under both tillage systems showed that IRWH-Sole >> IRWH-Ic >> CON-Sole >> CON-Ic, with values ranging from 878.2 kg ha-1 to 618 kg ha-1 (p ≤ 0.05). The low harvest index values (0.21-0.38) could have been due to the effect of the drought during the growing season. The results of precipitation use efficiency (PUE) showed that the IRWH tillage was more effective at converting rainwater into maize biomass and grain yield compared to CON tillage. However, the different cropping systems did not show a consistent trend in PUE. During the growing season, the PUE for AGDM varied for different tillage and cropping system treatments in Morago and Paradys. For maize, it ranged between 10.01-6.07 and 9.93-7.67 kg ha-1, while for beans, it ranged between 7.36-3.95 and 7.07-3.89 kg ha-1 mm-1. The PUE for grain yield showed similar trends with the significantly highest values of PUE under IRWH tillage systems for the Morago sites, but there were no significant differences at the Paradys site in both tillage and cropping systems. There is a critical need, therefore, to devise alternative techniques to promote an increase in smallholders' productivity based on an improved ability to capture and use resources more efficiently.

Agro-climatic sensitivity analysis for sustainable crop diversification; the case of Proso millet (Panicum miliaceum L.).

Current agricultural production depends on very limited species grown as monocultures that are highly vulnerable to climate change, presenting a threat to the sustainability of agri-food systems. However, many hundreds of neglected crop species have the potential to cater to the challenges of climate change by means of resilience to adverse climate conditions. Proso millet (Panicum miliaceum L.), one of the underutilised minor millets grown as a rainfed subsistence crop, was selected in this study as an exemplary climate-resilient crop. Using a previously calibrated version of the Agricultural Production Systems Simulator (APSIM), the sensitivity of the crop to changes in temperature and precipitation was studied using the protocol of the Coordinated Climate Crop Modelling Project (C3MP). The future (2040-2069) production was simulated using bias-corrected climate data from 20 general circulation models of the Coupled Model Intercomparison Project (CMIP5) under RCP4.5 and 8.5 scenarios. According to the C3MP analysis, we found a 1°C increment of temperature decreased the yield by 5-10% at zero rainfall change. However, Proso millet yields increased by 5% within a restricted climate change space of up to 2°C of warming with increased rainfall. Simulated future climate yields were lower than the simulated yields under the baseline climate of the 1980-2009 period (mean 1707 kg ha-1) under both RCP4.5 (-7.3%) and RCP8.5 (-16.6%) though these changes were not significantly (p > 0.05) different from the baseline yields. Proso millet is currently cultivated in limited areas of Sri Lanka, but our yield mapping shows the potential for expansion of the crop to new areas under both current and future climates. The results of the study, indicating minor impacts from projected climate change, reveal that Proso millet is an excellent candidate for low-input farming systems under changing climate. More generally, through this study, a framework that can be used to assess the climate sensitivity of underutilized crops was also developed.

Classifying external causes of injury: history, current approaches, and future directions.

The International Classification of Diseases (ICD) is used to categorize diseases, injuries, and external causes of injury, and it is a key epidemiologic tool enabling storage and retrieval of data from health and vital records to produce core international mortality and morbidity statistics. The ICD is updated periodically to ensure the classification system remains current, and work is now under way to develop the next revision, ICD-11. It has been almost 20 years since the last ICD edition was published and over 60 years since the last substantial structural revision of the external causes chapter. Revision of such a critical tool requires transparency and documentation to ensure that changes made to the classification system are recorded comprehensively for future reference. In this paper, the authors provide a history of the development of external causes classification and outline the external cause structure. They discuss approaches to manage ICD-10 deficiencies and outline the ICD-11 revision approach regarding the development of, rationale for, and implications of proposed changes to the chapter. Through improved capture of external cause concepts in ICD-11, a stronger evidence base will be available to inform injury prevention, treatment, rehabilitation, and policy initiatives to ultimately contribute to a reduction in injury morbidity and mortality.

5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail.

The 5-HT2AR (5-hydroxytryptamine-2A receptor) is a GPCR (G-protein-coupled receptor) that is implicated in the actions of hallucinogens and represents a major target of atypical antipsychotic agents. In addition to its classical signalling though PLC (phospholipase C), the receptor can activate several other pathways, including ARF (ADP-ribosylation factor)-dependent activation of PLD (phospholipase D), which appears to be achieved through a mechanism independent of heterotrimeric G-proteins. In the present study we show that wild-type and inactive constructs of PLD1 (but not PLD2) respectively facilitate and inhibit ARF-dependent PLD signalling by the 5-HT2AR. Furthermore we demonstrate that PLD1 specifically co-immunoprecipitates with the receptor and binds to a distal site in GST (glutathione transferase) fusion protein constructs of its C-terminal tail which is distinct from the ARF-interaction site, thereby suggesting the existence of a functional ARF-PLD signalling complex directly associated with this receptor. This reveals the spatial co-ordination of an important GPCR, transducer and effector into a physical complex that is likely to reinforce the impact of receptor activation on a heterotrimeric G-protein-independent signalling pathway. Signalling of this receptor through such non-canonical pathways may be important to its role in particular disorders.

Feasibility of implementing magnesium sulphate for neuroprotection in a tertiary obstetric unit.

BACKGROUND: It is important to establish whether research recommendations regarding magnesium sulphate for neuroprotection can be readily translated into clinical practice and achieve the dual objectives of good coverage of the target group, while minimising unnecessary or prolonged exposure to treatment. METHODS: This retrospective cohort study included all women admitted to a tertiary obstetric centre at 23-32 weeks gestation in the first 12 months following implementation of the guideline 'Magnesium sulphate for the prevention of cerebral palsy'. We determined the number triaged to receive magnesium sulphate, the proportion of infants who received magnesium sulphate prior to delivery and the total number of doses administered. RESULTS: A total of 330 women were admitted at a mean gestational age of 28.2 weeks, and 132/330 (40%) were prescribed magnesium sulphate, of whom 123/132 (93%) delivered. 142/191 (74%) infants born at <32 weeks' gestation received magnesium sulphate prior to delivery, with no significant differences seen by plurality or gestational age. Of the 145 doses administered, only 13 women received more than one dose, and only nine of 145 (7%) doses proved to be unnecessary. The median treatment duration was 3 h 58 min. The infusion was discontinued as result of side effects in 2% of women. CONCLUSION: Research recommendations regarding administration of magnesium sulphate with neuroprotective intent can be successfully translated into clinical practice. Appropriate triaging of women at high risk of imminent preterm birth is feasible, enabling a high level of magnesium sulphate coverage for infants that deliver prior to 32 weeks gestation, with minimal toxicity and a low rate of unnecessary maternal exposure.