Theropod Fauna from Southern Australia Indicates High Polar Diversity and Climate-Driven Dinosaur Provinciality

The Early Cretaceous fauna of Victoria, Australia, provides unique data on the composition of high latitude southern hemisphere dinosaurs. We describe and review theropod dinosaur postcranial remains from the Aptian–Albian Otway and Strzelecki groups, based on at least 37 isolated bones, and more than 90 teeth from the Flat Rocks locality. Several specimens of medium- and large-bodied individuals (estimated up to ∼8.5 metres long) represent allosauroids. Tyrannosauroids are represented by elements indicating medium body sizes (∼3 metres long), likely including the holotype femur of Timimus hermani, and a single cervical vertebra represents a juvenile spinosaurid. Single specimens representing medium- and small-bodied theropods may be referrable to Ceratosauria, Ornithomimosauria, a basal coelurosaur, and at least three taxa within Maniraptora. Thus, nine theropod taxa may have been present. Alternatively, four distinct dorsal vertebrae indicate a minimum of four taxa. However, because most taxa are known from single bones, it is likely that small-bodied theropod diversity remains underestimated. The high abundance of allosauroids and basal coelurosaurs (including tyrannosauroids and possibly ornithomimosaurs), and the relative rarity of ceratosaurs, is strikingly dissimilar to penecontemporaneous dinosaur faunas of Africa and South America, which represent an arid, lower-latitude biome. Similarities between dinosaur faunas of Victoria and the northern continents concern the proportional representatation of higher clades, and may result from the prevailing temperate–polar climate of Australia, especially at high latitudes in Victoria, which is similar to the predominant warm–temperate climate of Laurasia, but distinct from the arid climate zone that covered extensive areas of Gondwana. Most dinosaur groups probably attained a near-cosmopolitan distribution in the Jurassic, prior to fragmentation of the Pangaean supercontinent, and some aspects of the hallmark ‘Gondwanan’ fauna of South America and Africa may therefore reflect climate-driven provinciality, not vicariant evolution driven by continental fragmentation. However, vicariance may still be detected at lower phylogenetic levels

Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in Preterm Infants

© 2017, The Author(s). Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200CCloseSPigtSPiA and g.-181ACloseSPigtSPiC) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies

High-quality health systems in the Sustainable Development Goals era: time for a revolution.

Executive summary: Although health outcomes have improved in low-income and middle-income countries (LMICs) in the past several decades, a new reality is at hand. Changing health needs, growing public expectations, and ambitious new health goals are raising the bar for health systems to produce better health outcomes and greater social value. But staying on current trajectory will not suffice to meet these demands. What is needed are high-quality health systems that optimise health care in each given context by consistently delivering care that improves or maintains health, by being valued and trusted by all people, and by responding to changing population needs. Quality should not be the purview of the elite or an aspiration for some distant future; it should be the DNA of all health systems. Furthermore, the human right to health is meaningless without good quality care because health systems cannot improve health without it. We propose that health systems be judged primarily on their impacts, including better health and its equitable distribution; on the confidence of people in their health system; and on their economic benefit, and processes of care, consisting of competent care and positive user experience. The foundations of high-quality health systems include the population and their health needs and expectations, governance of the health sector and partnerships across sectors, platforms for care delivery, workforce numbers and skills, and tools and resources, from medicines to data. In addition to strong foundations, health systems need to develop the capacity to measure and use data to learn. High-quality health systems should be informed by four values: they are for people, and they are equitable, resilient, and efficient. For this Commission, we examined the literature, analysed surveys, and did qualitative and quantitative research to evaluate the quality of care available to people in LMICs across a range of health needs included in the Sustainable Development Goals (SDGs). We explored the ethical dimensions of high-quality care in resource-constrained settings and reviewed available measures and improvement approaches. We reached five conclusions: The care that people receive is often inadequate, and poor-quality care is common across conditions and countries, with the most vulnerable populations faring the worst Data from a range of countries and conditions show systematic deficits in quality of care. In LMICs, mothers and children receive less than half of recommended clinical actions in a typical preventive or curative visit, less than half of suspected cases of tuberculosis are correctly managed, and fewer than one in ten people diagnosed with major depressive disorder receive minimally adequate treatment. Diagnoses are frequently incorrect for serious conditions, such as pneumonia, myocardial infarction, and newborn asphyxia. Care can be too slow for conditions that require timely action, reducing chances of survival. At the system level, we found major gaps in safety, prevention, integration, and continuity, reflected by poor patient retention and insufficient coordination across platforms of care. One in three people across LMICs cited negative experiences with their health system in the areas of attention, respect, communication, and length of visit (visits of 5 min are common); on the extreme end of these experiences were disrespectful treatment and abuse. Quality of care is worst for vulnerable groups, including the poor, the less educated, adolescents, those with stigmatised conditions, and those at the edges of health systems, such as people in prisons. Universal health coverage (UHC) can be a starting point for improving the quality of health systems. Improving quality should be a core component of UHC initiatives, alongside expanding coverage and financial protection. Governments should start by establishing a national quality guarantee for health services, specifying the level of competence and user experience that people can expect. To ensure that all people will benefit from improved services, expansion should prioritise the poor and their health needs from the start. Progress on UHC should be measured through effective (quality-corrected) coverage. High-quality health systems could save over 8 million lives each year in LMICs More than 8 million people per year in LMICs die from conditions that should be treatable by the health system. In 2015 alone, these deaths resulted in US$6 trillion in economic losses. Poor-quality care is now a bigger barrier to reducing mortality than insufficient access. 60% of deaths from conditions amenable to health care are due to poor-quality care, whereas the remaining deaths result from non-utilisation of the health system. High-quality health systems could prevent 2·5 million deaths from cardiovascular disease, 1 million newborn deaths, 900 000 deaths from tuberculosis, and half of all maternal deaths each year. Quality of care will become an even larger driver of population health as utilisation of health systems increases and as the burden of disease shifts to more complex conditions. The high mortality rates in LMICs for treatable causes, such as injuries and surgical conditions, maternal and newborn complications, cardiovascular disease, and vaccine preventable diseases, illustrate the breadth and depth of the health-care quality challenge. Poor-quality care can lead to other adverse outcomes, including unnecessary health-related suffering, persistent symptoms, loss of function, and a lack of trust and confidence in health systems. Waste of resources and catastrophic expenditures are economic side effects of poor-quality health systems. As a result of this, only one-quarter of people in LMICs believe that their health systems work well. Health systems should measure and report what matters most to people, such as competent care, user experience, health outcomes, and confidence in the system Measurement is key to accountability and improvement, but available measures do not capture many of the processes and outcomes that matter most to people. At the same time, data systems generate many metrics that produce inadequate insight at a substantial cost in funds and health workers' time. For example, although inputs such as medicines and equipment are commonly counted in surveys, these are weakly related to the quality of care that people receive. Indicators such as proportion of births with skilled attendants do not reflect quality of childbirth care and might lead to false complacency about progress in maternal and newborn health. This Commission calls for fewer, but better, measures of health system quality to be generated and used at national and subnational levels. Countries should report health system performance to the public annually by use of a dashboard of key metrics (eg, health outcomes, people's confidence in the system, system competence, and user experience) along with measures of financial protection and equity. Robust vital registries and trustworthy routine health information systems are prerequisites for good performance assessment. Countries need agile new surveys and real-time measures of health facilities and populations that reflect the health systems of today and not those of the past. To generate and interpret data, countries need to invest in national institutions and professionals with strong quantitative and analytical skills. Global development partners can support the generation and testing of public goods for health system measurement (civil and vital registries, routine data systems, and routine health system surveys) and promote national and regional institutions and the training and mentoring of scientists. New research is crucial for the transformation of low-quality health systems to high-quality ones Data on care quality in LMICs do not reflect the current disease burden. In many of these countries, we know little about quality of care for respiratory diseases, cancer, mental health, injuries, and surgery, as well as the care of adolescents and elderly people. There are vast blind spots in areas such as user experience, system competence, confidence in the system, and the wellbeing of people, including patient-reported outcomes. Measuring the quality of the health system as a whole and across the care continuum is essential, but not done. Filling in these gaps will require not only better routine health information systems for monitoring, but also new research, as proposed in the research agenda of this Commission. For example, research will be needed to rigorously evaluate the effects and costs of recommended improvement approaches on health, patient experience, and financial protection. Implementation science studies can help discern the contextual factors that promote or hinder reform. New data collection and research should be explicitly designed to build national and regional research capacity. Improving quality of care will require system-wide action To address the scale and range of quality deficits we documented in this Commission, reforming the foundations of the health system is required. Because health systems are complex adaptive systems that function at multiple interconnected levels, fixes at the micro-level (ie, health-care provider or clinic) alone are unlikely to alter the underlying performance of the whole system. However, we found that interventions aimed at changing provider behaviour dominate the improvement field, even though many of these interventions have a modest effect on provider performance and are difficult to scale and sustain over time. Achieving high-quality health systems requires expanding the space for improvement to structural reforms that act on the foundations of the system. This Commission endorses four universal actions to raise quality across the health system. First, health system leaders need to govern for quality by adopting a shared vision of quality care, a clear quality strategy, strong regulation, and continuous learning. Ministries of health cannot accomplish this alone and need to partner with the private sector, civil society, and sectors outside of health care, such as education, infrastructure, communication, and transport. Second, countries should redesign service delivery to maximise health outcomes rather than geographical access to services alone. Primary care could tackle a greater range of low-acuity conditions, whereas hospitals or specialised health centres should provide care for conditions, such as births, that need advanced clinical expertise or have the risk of unexpected complications. Third, countries should transform the health workforce by adopting competency-based clinical education, introducing training in ethics and respectful care, and better supporting and respecting all workers to deliver the best care possible. Fourth, governments and civil society should ignite demand for quality in the population to empower people to hold systems accountable and actively seek high-quality care. Additional targeted actions in areas such as health financing, management, district-level learning, and others can complement these efforts. What works in one setting might not work elsewhere, and improvement efforts should be adapted for local context and monitored. Funders should align their support with system-wide strategies rather than contribute to the proliferation of micro-level efforts. In this Commission, we assert that providing health services without guaranteeing a minimum level of quality is ineffective, wasteful, and unethical. Moving to a high-quality health system—one that improves health and generates confidence and economic benefits—is primarily a political, not technical, decision. National governments need to invest in high-quality health systems for their own people and make such systems accountable to people through legislation, education about rights, regulation, transparency, and greater public participation. Countries will know that they are on the way towards a high-quality, accountable health system when health workers and policymakers choose to receive health care in their own public institutions.Fil: Kruk, Margaret E.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Gage, Anna D.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Arsenault, Catherine. Harvard University. Harvard School of Public Health; Estados UnidosFil: Jordan, Keely. New York College of Global Public Health; Estados UnidosFil: Leslie, Hannah H.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Roder DeWan, Sanam. Harvard University. Harvard School of Public Health; Estados UnidosFil: Adeyi, Olusoji. Banco Mundial; Estados UnidosFil: Barker, Pierre. Institute For Healthcare Improvement; Estados UnidosFil: Daelmans, Bernadette. Organizacion Mundial de la Salud; SuizaFil: Doubova, Svetlana V.. Instituto Mexicano del Seguro Social; MéxicoFil: English, Mike. KEMRI - Wellcome Trust; KeniaFil: Garcia Elorrio, Ezequiel. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guanais, Frederico. Banco Interamericano de Desarrollo; Estados UnidosFil: Gureje, Oye. University Of Ibadan; NigeriaFil: Hirschhorn, Lisa R.. Northwestern University; Estados UnidosFil: Jiang, Lixin. National Center For Cardiovascular Diseases; ChinaFil: Kelley, Edward. Organizacion Mundial de la Salud; SuizaFil: Lemango, Ephrem Tekle. Federal Ministry of Health; EtiopíaFil: Liljestrand, Jerker. Bill and Melinda Gates Foundation; Estados UnidosFil: Malata, Address. Malawi University Of Science And Technology; MalauiFil: Marchant, Tanya. London School of Hygiene & Tropical Medicine; Reino UnidoFil: Matsoso, Malebona Precious. National Department of Health of the Republic of South Africa; SudáfricaFil: Meara, John G.. Harvard Medical School; Estados UnidosFil: Mohanan, Manoj. University of Duke; Estados UnidosFil: Ndiaye, Youssoupha. Ministry of Health and Social Action of the Republic of Senegal; SenegalFil: Norheim, Ole F.. University of Bergen; NoruegaFil: Reddy, K. Srinath. Public Health Foundation of India; IndiaFil: Rowe, Alexander K.. Centers for Disease Control and Prevention; Estados UnidosFil: Salomon, Joshua A.. Stanford University School Of Medicine; Estados UnidosFil: Thapa, Gagan. Legislature Parliament Of Nepal; NepalFil: Twum Danso, Nana A. Y.. Maza; GhanaFil: Pate, Muhammad. Big Win Philanthropy; Reino Unid

DNA Barcode Sequence Identification Incorporating Taxonomic Hierarchy and within Taxon Variability

For DNA barcoding to succeed as a scientific endeavor an accurate and expeditious query sequence identification method is needed. Although a global multiple–sequence alignment can be generated for some barcoding markers (e.g. COI, rbcL), not all barcoding markers are as structurally conserved (e.g. matK). Thus, algorithms that depend on global multiple–sequence alignments are not universally applicable. Some sequence identification methods that use local pairwise alignments (e.g. BLAST) are unable to accurately differentiate between highly similar sequences and are not designed to cope with hierarchic phylogenetic relationships or within taxon variability. Here, I present a novel alignment–free sequence identification algorithm–BRONX–that accounts for observed within taxon variability and hierarchic relationships among taxa. BRONX identifies short variable segments and corresponding invariant flanking regions in reference sequences. These flanking regions are used to score variable regions in the query sequence without the production of a global multiple–sequence alignment. By incorporating observed within taxon variability into the scoring procedure, misidentifications arising from shared alleles/haplotypes are minimized. An explicit treatment of more inclusive terminals allows for separate identifications to be made for each taxonomic level and/or for user–defined terminals. BRONX performs better than all other methods when there is imperfect overlap between query and reference sequences (e.g. mini–barcode queries against a full–length barcode database). BRONX consistently produced better identifications at the genus–level for all query types

Basal cell carcinoma: a paradigm for targeted therapies

INTRODUCTION: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012. AREAS COVERED: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials. EXPERT OPINION: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary