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All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies.

Planting trees is widely regarded as an important part of climate change mitigation and adaptation efforts. As a result, large-scale tree planting projects have been initiated around the world. However, a number of these initiatives have unintentionally opened up risks to native forests and biodiversity while increasing exotic tree cover. Using the Aotearoa New Zealand One Billion Trees programme as a case study we reflect on what trees are being incentivised by these projects and the downstream impacts of how these projects are realised. We suggest ten recommendations for how these initiatives could be adapted to avoid perverse outcomes for native species while jointly achieving our carbon and biodiversity goals: (1) Diversify strategies—protect first, restore second, plant third; (2) Consider net change in trees—do not just count trees planted; (3) Consider the co-benefits of carbon and biodiversity from the outset; (4) Consider the broader landscape; (5) Consider the carbon and biodiversity benefits of soil; (6) Consider the importance of existing carbon stocks; (7) Consider potential impacts to non-tree ecosystems; (8) Consider the longevity of the future forest; (9) Support landowners in planting and maintaining native trees; (10) Remember that climate goals cannot be achieved by planting trees alone. We believe these recommendations are critical for improving the outcomes of the One Billion Trees programme in Aotearoa New Zealand, while providing important insights relevant to other tree planting initiatives around the world.

PURPOSE Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants < 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database ( ClinOmics ), containing all genomic variants, and clinical annotation including survival data. CONCLUSION This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.

As we reflect on the disruptive impact that the pandemic has inflicted upon our personal and professional lives, I marvel at the resilience of our Motion Imaging Technology Council’s determination to continue addressing the rapidly evolving digital imaging technology challenges that are confronting filmmakers. Since its formation in 2002 as the ASC Technology Committee, our agenda over the years has consistently identified the critical technology developments driving the evolution of digital production workflows. The unique nature of our mission has always been the fusion of a solid scientific and engineering knowledge base with a laser focus on how these technologies can best benefit the cinematographer’s ability to utilize them to enhance their creative vision.

Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n=52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/ml•hr (110%); Clearance was 4.6 L/hr/m(2) (90%); half-life was 25 hours (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters were predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n=132 patients) demonstrated substantial variability. The median (CV%) AUC was 78ng/ml•hr (98%); clearance was 17.2L/hr/m(2) (67%); half-life was 14.6 hours (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. CONCLUSION: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.

Research has shown that having meaningful occupations and active, valued social roles is important in successfully transitioning into retirement. Golf is often associated with retirees and studies ...

Purpose: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. Patients and Methods: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. Results: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. Conclusions: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity. See related commentary by Schulte and Eggert, p. 3507

Background Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate linking an antimitotic agent (DM1) to an anti-CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities. Methods Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m2 per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21-day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56-positive cell counts, and tumor CD56 expression were assessed. Results Sixty-two patients enrolled. The median age was 14.3 years (range, 2.8-29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose-limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non-dose-limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response. Conclusions Lorvotuzumab mertansine (110 mg/m2 ) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.

Historical temperature measurements are the basis of global climate datasets like HadCRUT4. This dataset contains many missing values, particularly for periods before the mid-twentieth century, although recent years are also incomplete. Here we demonstrate that artificial intelligence can skilfully fill these observational gaps when combined with numerical climate model data. We show that recently developed image inpainting techniques perform accurate monthly reconstructions via transfer learning using either 20CR (Twentieth-Century Reanalysis) or the CMIP5 (Coupled Model Intercomparison Project Phase 5) experiments. The resulting global annual mean temperature time series exhibit high Pearson correlation coefficients (≥0.9941) and low root mean squared errors (≤0.0547 °C) as compared with the original data. These techniques also provide advantages relative to state-of-the-art kriging interpolation and principal component analysis-based infilling. When applied to HadCRUT4, our method restores a missing spatial pattern of the documented El Niño from July 1877. With respect to the global mean temperature time series, a HadCRUT4 reconstruction by our method points to a cooler nineteenth century, a less apparent hiatus in the twenty-first century, an even warmer 2016 being the warmest year on record and a stronger global trend between 1850 and 2018 relative to previous estimates. We propose image inpainting as an approach to reconstruct missing climate information and thereby reduce uncertainties and biases in climate records.From:Kadow, C., Hall, D.M. & Ulbrich, U. Artificial intelligence reconstructs missing climate information. Nature Geoscience 13, 408–413 (2020). https://doi.org/10.1038/s41561-020-0582-5The presentation will tell from the journey of changing an image AI to a climate research application.

The St Andrews team would like to thank the Leverhulme Trust (RPG-2016-047) for financial support. Computational resources have been provided by the Consortium des Équipements de Calcul Intensif (CÉCI), funded by the Fonds de la Recherche Scientifiques de Belgique (F. R. S.-FNRS) under Grant No. 2.5020.11, as well as the Tier-1 supercomputer of the Fédération Wallonie-Bruxelles, infrastructure funded by the Walloon Region under the grant agreement n1117545. We acknowledge support from the European Union's Horizon 2020 research and innovation programme under the ITN TADFlife (GA 812872). Y.O. acknowledges funding by the Fonds de la Recherche Scientifique-FNRS under Grant no. F.4534.21 (MIS-IMAGINE). D. B. is a FNRS Research Director. EZ-C is a Royal Society Leverhulme Trust Senior Research fellow (SRF\R1\201089). In this work we present a new multi-resonance thermally activated delayed fluorescence (MR-TADF) emitter paradigm, demonstrating that the structure need not require the presence of acceptor atoms. Based on an in silico design, the compound DiICzMes4 possesses a red-shifted emission, enhanced photoluminescence quantum yield, and smaller singlet-triplet energy gap, ΔEST, than the parent indolocarbazole that induces MR-TADF properties. Coupled cluster calculations accurately predict the magnitude of the ΔEST when the optimized singlet and triplet geometries are used. Slow yet optically detectable reverse intersystem crossing contributes to low efficiency in organic light-emitting diodes using DiICzMes4 as the emitter. However, when used as a terminal emitter in combination with a TADF assistant dopant within a hyperfluorescence device architecture, maximum external quantum efficiencies of up to 16.5% were achieved at CIE (0.15, 0.11). This represents one of the bluest hyperfluorescent devices reported to date. Simultaneously, recognising that MR-TADF emitters do not require acceptor atoms reveals an unexplored frontier in materials design, where yet greater performance may yet be discovered. Publisher PDF

Background The extent to which smoking and drinking in a local community is associated with nutrition and Z-scores of infants from spontaneous preterm deliveries, is uncertain. Aim To investigate associations of different levels of maternal smoking and drinking in spontaneous preterm birth with infant birthweight Z-scores. Methods Information, including gestational age (determined by earliest ultrasound), maternal arm circumference (measured at enrolment), smoking-drinking data (obtained up to 4 occasions), birthweight data (obtained from medical records) and birthweight Z-scores (calculated from INTERGROWTH- 21st study), collected over a period of nine years was used to compare 407 spontaneous preterm births with 3 493 spontaneous term births Analyses of variance, correlations and multiple regression were performed in STATISTICA. Results Women with spontaneous preterm birth, had significantly lower gravidity and smaller arm circumference when compared to women with spontaneous birth at term. Women with spontaneous preterm birth drank more and heavier during pregnancy, and more smoked. Gestational age at birth was significantly longer in heavy-smokers-heavy-drinkers compared to heavy-smokers-no-drinkers (7.1 days) and in no-smokers-heavy-drinkers when compared to no-smokers-no-drinkers (11.2 days). Birthweight was significantly lower in low-smokers-heavy-drinkers when compared to low-smokers-no-drinkers (240g) and in heavy-smokers-low-drinkers when compared to no-smokers-low-drinkers (273g). Birthweight Z-scores were significantly lower in low-smokers-heavy-drinkers when compared to low-smokers-low-drinkers and low-smokers-no-drinkers; and, also significantly lower in heavy-smokers-low-drinkers when compared to low-smokers-low-drinkers and no-smokers-low-drinkers. Conclusion Alcohol aggravates the detrimental effect of smoking on birthweight and birthweight Z-scores but seems to counteract the negative association of smoking with gestational age.

E.Z.-C. thanks the Leverhulme Trust (No. RPG-2016-047) and the University of St Andrews for support. The authors are grateful to the EPSRC for financial support (grants EP/ P007805/1, EP/P010482/1, EP/L017008/1, EP/J01771X, and EP/J00916). M.M. thanks the Innovation Programme H2020-MSCA-IF-2014-659237 for financial support. W.L. thanks the China Scholarship Council (grant number 201708060003). V.L. thanks the F.R.S.-FNRS for his Research Associate position. Computational resources have been provided by the Consortium des É quipements de Calcul Intensif (CÉ CI), funded by the Fonds de la Recherche Scientifiques de Belgique (F.R.S.FNRS) under Grant No. 2.5020.11, GEQ U.G006.15, 1610468, and RW/GEQ. (2016). D.B. is an FNRS Research Director. Herein, we report the use of spiro-configured fluorene-xanthene scaffolds as a novel, promising, and effective strategy in thermally activated delayed fluorescence (TADF) emitter design to attain high photoluminescence quantum yields (ΦPL), short delayed luminescence lifetime, high external quantum efficiency (EQE), and minimum efficiency roll-off characteristics in organic light-emitting diodes (OLEDs). The optoelectronic and electroluminescence properties of SFX (spiro-(fluorene-9,9′-xanthene))-based emitters (SFX-PO-DPA, SFX-PO-DPA-Me, and SFX-PO-DPA-OMe) were investigated both theoretically and experimentally. All three emitters exhibited sky blue to green emission enabled by a Herzberg–Teller mechanism in the excited state. They possess short excited-state delayed lifetimes (

The development of multiple resonance thermally activated delayed fluorescence (MR-TADF) materials possessing narrow emission spectra has attracted significant attention as emitters for high colour purity organic light emitting diodes (OLEDs). In this work, a simple design strategy is introduced to construct an MR-TADF emitter, DDiKTa, through dimerization of the known MR-TADF emitter DiKTa. This design permits concentration quenching to be largely suppressed, which is a known weakness of previously reported MR-TADF emitters. OLEDs based on DDiKTa show an EQEmax of 19% at a doping concentration of 9 wt%. The electroluminescence spectrum is red-shifted into the green, producing a rare example of a green-emitting MR-TADF OLED.

Background Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown. Methods We evaluated children with osteosarcoma (OS) on two Children’s Oncology Group trials with higher dose doxorubicin (375–600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected. Results All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P Z-scores (P Z-scores were significantly smaller for girls (P P = 0.06). Girls had significantly smaller LV end-diastolic dimension Z-scores normalized to BSA (P Conclusions Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity. Trial registrations ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.

Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

Introduction Shock index (SI) is a predictor of hemodynamic compromise in obstetric patients. The SI threshold for action is not well understood. We aimed to evaluate SI thresholds as predictors of outcomes in obstetric patients. Material and methods We undertook a prospective cohort study at three South African hospitals of women with postpartum hemorrhage (n = 283) or maternal sepsis (n = 126). The “first” and “worst” SI following diagnosis were recorded. SI was compared with conventional vital signs as predictors of outcomes. The performance of SI

Pregnancy-related acute kidney injury (AKI) is a rare but serious complication in high-income settings and remains an important cause of maternal and foetal morbidity and mortality in low- and middle-income settings. Hypertensive disorders of pregnancy are the leading cause of pregnancy-related AKI worldwide. In this article, we outline the epidemiology, aetiology, recognition, investigation and management of pregnancy-related AKI. Difficulties in the definition of AKI, approaches to determine the cause of AKI in diagnostically challenging circumstances and diagnosis of new renal disease in pregnancy are discussed.

Objective To investigate the outcomes of critically ill obstetric patients managed in a obstetric critical care unit in South Africa. Methods Patients with severe maternal morbidity managed in the labor ward of Tygerberg Hospital were studied over three months before the establishment of the obstetrician-led obstetric critical care unit. One year later, patients managed in the obstetric critical care unit were studied using the same methods. The primary outcome measures were maternal morbidity and mortality. Results In the before-obstetric critical care unit prospective audit 63 patients met criteria for obstetric critical care. During the second period 60 patients were admitted to the obstetric critical care unit. There were no significant differences between the groups in baseline characteristics, admission indications or Acute Physiology and Chronic Health Evaluation scores. Continuous positive airway pressure ( p Conclusion The establishment of an obstetrician-led obstetric critical care unit facilitated a decrease in maternal mortality. Trial registration: Not applicable.

Expectant management of appropriately selected cases of early pre-eclampsia in a dedicated, tertiary in-patient setting with frequent non-invasive maternal and fetal surveillance, prolongs pregnancy, improves perinatal outcome and mitigates the impact of maternal complications. As the rate of abruptio placentae in a large descriptive study performed nearly 20 years ago was 20%, a study to re-evaluate the rate of abruptio placentae and other maternal complications was performed.A retrospective study that included all women admitted for expectant management with stable early pre-eclampsia (≥24 and34 weeks' gestation) was performed at Tygerberg Hospital, a secondary and tertiary referral centre in South Africa over a period of 12 months.Abruptio placentae and other maternal complications.During the study period, 9137 women were delivered at the study institution. The data of 102 of 106 women admitted for expectant management of early pre-eclampsia were available. Thirty-four (33%) reached the elective delivery threshold of 34 weeks. Seventeen women (17%) experienced ≥1 complication. There were four cases (4%) each with abruptio placentae, HELLP syndrome and renal insufficiency. Three of the cases with abruptio placentae were asymptomatic, only being diagnosed at caesarean section for fetal distress. Nine women developed mild/moderate ascites. There were no admissions to the critical care unit and no deaths.Abruptio placentae occurred in 4% of women managed expectantly with early pre-eclampsia and was most often asymptomatic before delivery.

Herein, we report the use of spiro-configured fluorene-xanthene scaffolds as a novel, promising and effective strategy in thermally activated delayed fluorescence (TADF) emitter design to attain high photoluminescence quantum yields (PL), short delayed luminescence lifetime, high external quantum efficiency (EQE) and minimum efficiency roll-off characteristics in organic light-emitting diodes (OLEDs). The optoelectronic and electroluminescence properties of SFX-, spiro-(fluorene-9,9’-xanthene), based emitters (SFX-PO-DPA, SFX-PO-DPA-Me and SFX-PO-DPA-OMe) were investigated both theoretically and experimentally. All three emitters exhibited sky blue to green emission enabled by a Herzberg-Teller mechanism in the excited state. They possess short excited state delayed lifetimes (

Charge-coupled device (CCD)-based technologies exposed to high-energy radiation are susceptible to the formation of stable defects within the charge transfer channel that defer signal to subsequent pixels and limit the lifetime of the detector. Performance degradation due to these defects depends upon the interplay between the clock timings used to operate the device and the properties of defects introduced by irradiation. Characterization of both the type and number of post-irradiation defects makes it possible to minimize charge loss though the appropriate selection of clock timings for a given operating temperature. This technique has the potential to increase nominal mission lifetimes by several years for CCD-based instruments and is of particular significance to electron multiplying charge-coupled devices (EMCCDs) for photon counting applications where the effect of charge traps on low signal levels is expected to be most severe. We present a study of charge traps within CCDs, specifically within EMCCDs irradiated at room temperature to proton fluences up to and including 1.45 × 1010 p + / cm2 (74 MeV). Defects are characterized through the “single-trap pumping” technique, with clocking schemes specifically designed for the 2-phase pixel architecture of the EMCCD. Five dominant trap species are thought to be introduced by the irradiation, the Si-E center, Si-A center, double and single acceptor charge states of the silicon divacancy (VV − − , VV − ), and an as yet unidentified defect referred to here as the Si-U center (the “unknown” trap). Energy-level and cross-section values are presented that allow inference of the defect landscape for a range of proton fluences and operating temperatures. While the study focuses specifically on EMCCDs, in more general terms, the results for trap properties are interpreted as being applicable to all CCD types following irradiation and can serve as a foundation for future charge loss correction and optimization techniques.

This talk gives an overview of cutting-edge artificial intelligence applications and techniques for the earth-system sciences. We survey the most important recent contributions in areas including extreme weather, physics emulation, nowcasting, medium-range forecasting, uncertainty quantification, bias-correction, generative adversarial networks, data in-painting, network-HPC coupling, physics-informed neural nets, and geoengineering, amongst others. Then, we describe recent AI breakthroughs that have the potential to be of greatest benefit to the geosciences. We also discuss major open challenges in AI for science and their potential solutions. This talk is a living document, in that it is updated frequently, in order to accurately relect this rapidly changing field.

AimsPregnant women with diabetes often require preterm delivery. Antenatal betamethasone reduces perinatal morbidity and mortality, but induces hyperglycemia. The primary objective was to observe glucose excursions and determine the preliminary safety of a protocol for subcutaneous insulin following betamethasone administration in an antenatal ward.Material and MethodsThis retrospective study included all women with diabetes who received betamethasone due to anticipated preterm delivery. Glucose excursions were evaluated in the fasting state and 2-h postprandial. Blood glucose values ≥14mmol/L or ≤3.5mmol/L were regarded as unacceptable hyper- and hypoglycemia respectively. Events over the first 96 h were documented.ResultsThis study spanned 52 months and included fifty-nine women. Eleven episodes of defined hypoglycemia occurred in six women, all receiving insulin therapy, but none after a corrective dose of insulin. No serious hypoglycemic incident was reported. Seventeen women experienced hyperglycemic incidents almost entirely (47/56) within 48 h of betamethasone administration, most often postprandially (34/56) and in 85% of episodes, preceded by pre-prandial values >9 mmol/L (29/34). 14 (82.4%) of these women were receiving background insulin therapy. No case with gestational diabetes encountered defined hyperglycemia.ConclusionsThis small study demonstrated preliminary safety of the protocol. Enhanced surveillance is necessary for 72 h after initiation of betamethasone.

This chapter discusses horticulture and wool farming in the 1950s and 1960s. Increase in wheat acreage created transport, storage and distribution problems. During the Korean War, the wool tonnage purchased by the USA from New Zealand increased fivefold and prices tripled. The organisation set up in the 1940s to handle wool surpluses finished and a national scheme replaced it with the objective to offer ‘greater resistance to any downward trend’. Synthetic fibres began to compete with wool sales. Wool reform debate demonstrated the difficulties in modernising farming. Proposals for compulsory acquisition were rejected. But Government removed from the Legislation provision for agreement by growers before powers of acquisition could be used.

In the late 1940s, there were ample markets for produce and full employment; New Zealand was prosperous because the UK had contracted to buy from New Zealand all of its exportable surplus food and new contracts were agreed at ‘substantially increased prices’. When its first year ended, Federated Farmers main produce sections had been constituted—dairy, meat and wool, and agriculture. The essence of Federated Farmers was coping with an extremely diverse range of issues that impacted on agricultural economics and food policy. That was possible because the produce sections dealt with the more immediate problems associated with their particular produce. Federated Farmers’ influence on Government policy is demonstrated for 1947 by the diversity of issues influencing agricultural economics and food policy.

The Government asked whether Producer Boards should be abolished—was their mixture of regulatory and commercial activities still appropriate? The dairy industry was evolving towards merging the Dairy Board and Dairy Companies into a single company, Fonterra. The Treasury thought producer control of marketing gave only minor benefits. Marketing by a single organisation stifled the innovation and efficiency gains from competition. Producer Boards had wide-ranging regulatory functions but separating regulatory and commercial roles was an underlying principle of contemporaneous public-sector reform. Treasury considered that regulatory functions should be administered by Government. Accountability to farmers needed to be enhanced. The reviews and consultations produced the Meat Board and Wool Board Acts in 1997. Those redefined the objectives of the Boards and increased their accountability.

This chapter analyses meat and dairy farming in the 1950s and 1960s. Federated Farmers was shocked when the Government did not ask the Federation’s consent to use surpluses built up from finance stabilisation policies during wartime. Farmers pressed for full dairy farming costs to be recognised, but the Government did not want to continue linking its ‘guaranteed price’ for dairy produce with farm costs. Prices paid to farmers would depend largely on overseas realisations for their produce. The 1960s were marked for the dairy industry by many attempts by Federated Farmers to bring to the attention of Government the relatively low incomes of dairyfarmers and to seek relief. Farmers encouraged also schemes to eradicate bovine tuberculosis, brucellosis and leptospirosis.

World recession hit the export industries. The Government granted $71 million to establish stabilisation funds for farming and to hold farm costs. Special measures were introduced for agricultural servicing industries and tax advantages encouraged development of the cooperative movement in farming. Responses to the Government’s assistance demonstrate the perception of farming subsidies by others. The Federation proposed measures to control the Government’s economic policy and the Federation was invited, unusually, to attend the Cabinet Economic Committee. The Government adopted many points made by the Federation. A new Prime Minister, Robert Muldoon, emphasised the need to increase farming exports; ‘Supplementary Minimum Prices’ (SMPs) were introduced to meet farmers’ living expenses, operating expenditure and new development. Farming was now a highly-subsidised industry.

New Zealand realised its entrenched relationship with Britain would no longer provide sufficient overseas income, but market diversification was hindered by trade barriers, including barriers in New Zealand, itself, which imposed restrictions on imports. UK bulk purchase agreements ended in 1954, but those had made farmers lose touch with modern marketing requirements for other countries. Farmers recognised early the importance of establishing relations with US farming organisations if trading with the US was to be developed. New Zealand’s dependence on the USA for security discouraged trading links with China. But, eventually, a New Zealand trade mission to China identified that import of milk solids would be needed in China. China would eventually replace the UK as New Zealand’s main agricultural trading partner.

Through the 1990s Federated Farmers campaigned to reduce farming costs by reforming coastal shipping and waterfront activities. The Government deregulated coastal shipping and initiated major reforms of the waterfront industry. Another major cost imposition on farming was union militancy in the meat freezing industry. The Government accepted the need to get away from traditionalism and protection and deregulated the industry. Also, unemployment weakened union power when two major meat-processing employers went into receivership. The average wage of the meat-processing worker decreased but productivity increased. The most effective change in waterfront and freezing works’ reform was achieved when Government introduced employment legislation making relations between employers and employees controlled by direct contracts and the right to strike was restricted.

Background. Six cell surface receptors, human epidermal growth factor receptor-2 (Her-2), platelet-derived growth factor receptor-β (PDGFR-β), insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR), c-Met, and vascular endothelial growth factor receptor-3 (VEGFR-3), previously demonstrated variable expression across varying patient-derived and standard osteosarcoma (OS) cell lines. The current study sought to validate previous expression patterns and evaluate whether these receptors offer prognostic and/or therapeutic value. Methods. Patient-derived OS cell lines (n = 52) were labeled with antibodies to Her-2, PDGFR-β, IGF-1R, IR, c-Met, and VEGFR-3. Expression was characterized using flow cytometry. The difference in geometric mean fluorescent intensity (geoMFIdiff = geoMFIpositive − geoMFInegative) was calculated for each receptor across all cell lines. Receptor expression was categorized as low (Q1), intermediate (Q2, Q3), or high (Q4). The event-free survival (EFS) and overall survival for the six cell surface receptors were estimated by the Kaplan–Meier method. Differences in hazard for EFS event and overall survival event for patients in each of the three expression levels in each of the six cell surface receptors were assessed using the log-rank test. Results. All 6 receptors were variably expressed in the majority of cell lines. IR and PDGFR-β expressions were found to be significant predictors for EFS amongst patients with nonmetastatic disease ( p = 0.02 and 0.01, respectively). The hazard ratio for EFS was significantly higher between high IR and intermediate IR expression (HR = 2.66, p = 0.02 ), as well as between high PDGFR-β and intermediate PDGFR-β expression (HR = 5.68, p = 0.002 ). Her-2, c-Met, IGF-1R, and VEGFR-3 were not found to be significant predictors for either EFS or overall survival. Conclusion. The six cell surface receptors demonstrated variable expression across the majority of patient-derived OS cell lines tested. Limited prognostic value was offered by IR and PDGFR-β expression within nonmetastatic patients. The remaining receptors do not provide clear prognostic utility. Nevertheless, their consistent, albeit variable, surface expression across a large panel of patient-derived OS cell lines maintains their potential use as future therapeutic targets.

Federated Farmers gestation is investigated noting that farming’s diverse aspects, together with farmers’ individualism and differing regional viewpoints, makes collective action difficult. In the early twentieth century, a Farmers’ Union, Sheepowners’ Federation and Fruitgrowers’ Federation Ltd were formed separately. The three organisations’ shared interests led to cooperative action in the 1930s. The need for strong representation was strengthened when New Zealand elected its first Labour Government, perceived to be biased against farmers. Farmers’ many shared perceptions led in 1941 to a loose federation with the leaders of the main organisations meeting regularly. That step was encouraged by seeing an urban trade unions’ federation successfully winning preferment for its policies from Government.

At the start of the 1960s, the New Zealand Finance Minister said ‘every effort must be made to diversify markets and persuade others to moderate agricultural protectionism’. Federated Farmers was sufficiently confident to propose a comprehensive policy for the New Zealand national economy. The Federation urged curbing inflation partly by a progressive reduction in protection to secondary industries. An Agricultural Development Conference identified the main needs to ensure increased production and the Government announced policy measures in line with the Federated Farmers’ proposals. How Federated Farmers achieved its objectives was described by the Federation’s Research Officer. In mid-1964, Federated Farmers decided it was again appropriate to request a mandatory levy on farm produce to fund the Federation’s activities, but, again, the request was refused.

Possible UK European Economic Community (EEC) membership was potentially catastrophic for New Zealand. But New Zealand worked to protect its vital interests rather than opposing UK membership. That approach was successful despite New Zealand’s import restrictions on British goods. Federated Farmers’ discussions with the EEC encouraged hopes of more outward EEC agricultural policies. New Zealand had to choose between shipping produce to the EEC and new markets, it fell 15% short of filling its EEC quota. The weakening trade relationship with the UK encouraged New Zealand to build trade partnerships in the Pacific and Asia recognising it would have to give up narrow, inward-looking, protectionist policies. Federated Farmers told the Pacific Basin Economic Council that trade expansion needed removal of market distortions.

The 1970s were marked by high inflation and global economic crises. Federated Farmers proposed a cost adjustment scheme to compensate farmers for inflation, but it was ill prepared. When the 1973 oil price crisis impacted on New Zealand’s major customers, the Federation secured major subsidisation from Governments to increase farm exports. The Federation also secured support for a levy to support its activities. When export lamb prices increased, the Government asked meat and wool farmers to voluntarily deposit, temporarily, $85 million of their increased income. The Government threatened to introduce a system of reference prices for export meat with payments above the reference price diverted from farmers to a ‘stabilisation’ fund. But violent opposition by farmers was threatened and the price reference scheme was abandoned.

Electron multiplying charge-coupled devices (EMCCDs) are a variant of standard CCD technology capable of single-optical photon counting at MHz pixel readout rates. For photon counting, thermal dark signal and clock-induced charge (CIC) are the dominant source of noise and must be minimized to reduce the likelihood of coincident events. Thermal dark signal is reduced to low levels through cooling or operation in inverted mode (pinning). However, mitigation of CIC requires precise tuning of both parallel and serial clock waveforms. Here, we present a detailed study of CIC within Teledyne-e2v EMCCDs with a goal of better understanding the physical mechanisms that dominate CIC production in both noninverted and inverted mode operations (IMO). Measurements are presented as a function of parallel and serial clock timings, clock amplitudes, and device temperature. The effects of radiation damage and annealing are also discussed. A widely accepted view is that CIC is signal generated through impact ionization of energetic holes as the clock phase is driven high. While this explanation holds for IMO, we propose that the majority of CIC generated in noninverted mode is in fact due to a secondary effect of light emission from hot carriers. The information from this study is then used to optimize CIC on Teledyne e2v CCD201s operating at 1-MHz pixel rate in NIMO. For the CCD201, we obtained total CIC levels as low as 6.9 × 10 − 4 e − / pix / frame with ≥90 % detective quantum efficiency. We conclude with proposals to further reduce CIC based upon modifications to clocking schemes and device architecture.

The chapter reviews relationships between New Zealand’s indigenous people, Māori, and farming. Before European colonisation, New Zealand was occupied by Māori with land used communally rather than owned individually. In 1840, ‘sovereignty’ passed to the UK through the Treaty of Waitangi with unclear consequences for Māori. A new court, the Native Land Court, impacted disastrously on Māori agriculture. In the 1920s, Government funded consolidating Māori land into economic farms. But only a small minority of Māori was supported. Later in the twentieth century Māori became increasingly urbanised and remained disadvantaged. The Waitangi Tribunal assessed Māori claims of Treaty breaches since 1840. Federated Farmers opposed the Waitangi Tribunal recommendation that privately owned farming land be returned to Māori. Eventually, Government purchased the farms at market value.

Federated Farmers found itself under pressure in the first decades of the twenty-first century, partly because the Producer Boards had converted to organisations, still levy funded, but more clearly focussed with an advocacy role. A young farmer perceived a lack of relevance among younger farmers. Membership halved. Farming was attacked as a major cause of environmental damage and that turned young people against farming. The Federation was living beyond its means. Rural militancy was increasing. That captured media attention but risked damaging farming’s image in urban communities. A significant criticism was that too often Federated Farmers adopted a position of opposition to Government. But other farm organisations saw Federated Farmers as an essential advocate for farmers.

Background Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy. Methods We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children’s Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided. Results We identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10–22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10–4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis. Conclusions These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.

SMILE (Solar Magnetosphere Ionosphere Link Explorer) is a collaborative mission between the European Space Agency and the Chinese Academy of Sciences that is scheduled to be launched in 2024 and will be placed in a highly elliptical, inclined, orbit. The on-board instrumentation will study interactions between the solar wind and the Earth’s magnetosphere-ionosphere system by imaging the soft X-ray emission that results from solar wind charge exchange whilst simultaneously collecting information about the northern aurora with a UV imager and investigating the solar wind and magnetosheath plasma and magnetospheric field conditions using a Light Ion Analyzer and a magnetometer.\ud \ud The SXI (Soft X-ray Imager) is a wide field ‘lobster-eye’ telescope that is equipped with two 4510 x 4510 pixel CCDs with 18 μm pixel pitch. It will image X-rays (300 eV-2000 eV) through focusing optics that consist of an array of Micro Pore plates.\ud \ud The predicted X-ray event rate is expected to be low and the instrument will operate in photon counting mode so the SXI is designed to maximize the useful information returned to earth by identifying and storing individual events on board the spacecraft before transmitting the relevant information back to earth. This study investigates the baseline methods that will be implemented on-board to isolate and extract these events from the images amongst a more complicated particle background. The detector response is modelled and verified with calibration data from the CCD270.\ud \ud The work presented here by the Centre for Electronic Imaging at the Open University demonstrates the proposed method for isolating individual soft X-rays from images taken using the SMILE SXI and subsequently sorting these X-rays into data packets suitable for transmitting to earth. Different methods are tested with simulated and real data to optimize the proportion of useful events transmitted.

THESEUS (Transient High Energy Sky & Early Universe Surveyor) is one of the three candidates for the M5 mission of the European Space Agency. The favoured mission will be announced in 2021 for an expected launch in 2032. THESEUS will be equipped with a Soft X-ray Imager (SXI) composed of a set of two telescopes using micro-pore optics offering an overall field of view of 0.5 sr (

The European Space Agency's Gaia spacecraft was launched in December 2013 and has been in orbit at the Earth-Sun Lagrange point 2 (L2) for over 6 years. The spacecraft measures the positions, distances, space motions and many other physical characteristics of around one billion stars in the Milky Way and beyond. It has a focal plane of 106 Charge-Coupled Devices (CCDs) which have all been performing well but have been measuring a small but quantifiable degradation in performance in time due to Non-Ionizing Energy Loss (NIEL) damage from interstellar radiation. This NIEL damage produces trap defects which can capture charge from signals and reduces the quality of the data. Gaia's original mission lifetime was planned to be around 5 years and the pre-flight testing and radiation damage analysis was tailored around those timescales as well as with the projected solar activity before launch. Closer to the time of launch and during Gaia's years of orbit, it has been noted that the solar activity was lower than what was initially predicted. From the previous analysis of in-flight data in 2016, it was calculated that Gaia was experiencing an order of magnitude less radiation damage than was predicted. \ud \ud This paper describes the analysis of charge calibration data and corresponding Charge Transfer Inefficiency (CTI) measurements from the in-flight CCDs, both near the beginning of the mission and after more than 5 years in orbit to quantify the radiation damage impact. These sets of results can be compared with those from the pre-flight tests which can be used to evaluate and understand the differences between the on-ground and in-flight results.

The strawberry blossom weevil (SBW), Anthonomus rubi, is a major pest in strawberry fields throughout Europe. Traps baited with aggregation pheromone are used for pest monitoring. However, a more effective lure is needed. For a number of pests, it has been shown that the attractiveness of a pheromone can be enhanced by host plant volatiles. The goal of this study was to explore floral volatile blends of different strawberry species (Fragaria x ananassa and Fragaria vesca) to identify compounds that might be used to improve the attractiveness of existing lures for SBW. Floral emissions of F. x a. varieties Sonata, Beltran, Korona, and of F. vesca, were collected by both solid-phase microextraction (SPME) and dynamic headspace sampling on Tenax. Analysis by gas chromatography/mass spectrometry showed the floral volatiles of F. x ananassa. and F. vesca were dominated by aromatic compounds and terpenoids, with 4-methoxybenzaldehyde (p-anisaldehyde) and α-muurolene the major compounds produced by the two species, respectively. Multi-dimensional scaling analyses separated the blends of the two species and explained differences between F. vesca genotypes and, to some degree, variation between F. x ananassa varieties In two-choice behavioral tests, SBW preferred odors of flowering strawberry plants to those of non-flowering plants, but weevils did not discriminate between odors from F. x ananassa and F. vesca flowering plants. Adding blends of six synthetic flower volatiles to non-flowering plants of both species increased the preference of SBW for these over the plants alone. When added individually to non-flowering plants, none of the components increased the preference of SBW, indicating a synergistic effect. However, SBW responded to 1,4-dimethoxybenzene, a major component of volatiles from F. viridis, previously found to synergize the attractiveness of the SBW aggregation pheromone in field studies.