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1.
Nature ; 587(7835): 650-656, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33149304

RESUMO

G-protein-coupled receptors (GPCRs) are membrane proteins that modulate physiology across human tissues in response to extracellular signals. GPCR-mediated signalling can differ because of changes in the sequence1,2 or expression3 of the receptors, leading to signalling bias when comparing diverse physiological systems4. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms with different patterns of expression across different tissues. Here we integrate data from human tissue-level transcriptomes, GPCR sequences and structures, proteomics, single-cell transcriptomics, population-wide genetic association studies and pharmacological experiments. We show how a single GPCR gene can diversify into several isoforms with distinct signalling properties, and how unique isoform combinations expressed in different tissues can generate distinct signalling states. Depending on their structural changes and expression patterns, some of the detected isoforms may influence cellular responses to drugs and represent new targets for developing drugs with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling that considers how combinatorial expression of isoforms in a particular cell type, tissue or organism collectively influences receptor signalling and drug responses.

3.
PLoS Genet ; 16(10): e1009173, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33108368

RESUMO

In the frigid, oxygen-rich Southern Ocean (SO), Antarctic icefishes (Channichthyidae; Notothenioidei) evolved the ability to survive without producing erythrocytes and hemoglobin, the oxygen-transport system of virtually all vertebrates. Here, we integrate paleoclimate records with an extensive phylogenomic dataset of notothenioid fishes to understand the evolution of trait loss associated with climate change. In contrast to buoyancy adaptations in this clade, we find relaxed selection on the genetic regions controlling erythropoiesis evolved only after sustained cooling in the SO. This pattern is seen not only within icefishes but also occurred independently in other high-latitude notothenioids. We show that one species of the red-blooded dragonfish clade evolved a spherocytic anemia that phenocopies human patients with this disease via orthologous mutations. The genomic imprint of SO climate change is biased toward erythrocyte-associated conserved noncoding elements (CNEs) rather than to coding regions, which are largely preserved through pleiotropy. The drift in CNEs is specifically enriched near genes that are preferentially expressed late in erythropoiesis. Furthermore, we find that the hematopoietic marrow of icefish species retained proerythroblasts, which indicates that early erythroid development remains intact. Our results provide a framework for understanding the interactions between development and the genome in shaping the response of species to climate change.


Assuntos
Mudança Climática , Eritrócitos/metabolismo , Evolução Molecular , Peixes/genética , Animais , Regiões Antárticas , Peixes/metabolismo , Genoma/genética , Oceanos e Mares , Oxigênio/metabolismo
4.
Q J Nucl Med Mol Imaging ; 64(4): 338-345, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33026211

RESUMO

Copper-64 is a very attractive radioisotope with unique nuclear properties that allow using it as both a diagnostic and therapeutic agent, thus providing an almost ideal example of a theranostic radionuclide. A characteristic of Cu-64 stems from the intrinsic biological nature of copper ions that play a fundamental role in a large number of cellular processes. Cu-64 is a radionuclide that reflects the natural biochemical pathways of Cu-64 ions, therefore, can be exploited for the detection and therapy of certain malignancies and metabolic diseases. Beside these applications of Cu-64 ions, this radionuclide can be also used for radiolabelling bifunctional chelators carrying a variety of pharmacophores for targeting different biological substrates. These include peptide-based substrates and immunoconjugates as well as small-molecule bioactive moieties. Fueled by the growing interest of Member States (MS) belonging to the International Atomic Energy Agency (IAEA) community, a dedicated Coordinated Research Project (CRP) was initiated in 2016, which recruited thirteen participating MS from four continents. Research activities and collaborations between the participating countries allowed for collection of an impressive series of results, particularly on the production, preclinical evaluation and, in a few cases, clinical evaluation of various 64Cu-radiopharmaceuticals that may have potential impact on future development of the field. Since this CRP was finalized at the beginning of 2020, this short review summarizes outcomes, outputs and results of this project with the purpose to propagate to other MS and to the whole scientific community, some of the most recent achievements on this novel class of theranostic 64Cu-pharmaceuticals.

5.
J Nucl Med ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067341

RESUMO

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising treatment for prostate cancer. We reported a ligand featuring two lysine-ureido-glutamate groups, 64Cu-CuSarbisPSMA previously. Here, we report the therapeutic potential of 67Cu-CuSarbisPSMA. Methods: Growth of PSMA-positive xenografts was evaluated following treatment with 67Cu-CuSarbisPSMA or 177Lu-LuPSMA I&T. Results: At 13 days post-injection, tumor growth was similarly inhibited by the two tracers in a dose-dependent manner. Survival was comparable after single (30 MBq) or fractionated administrations (2 x 15MBq, two weeks apart). Conclusion: 67Cu-CuSarbisPSMA is efficacious in a PSMA-expressing model of prostate cancer.

6.
PLoS One ; 15(10): e0240631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33057414

RESUMO

BACKGROUND: Improving access and quality in health care is a pressing issue worldwide and pay for performance (P4P) strategies have emerged as an alternative to enhance structure, process and outcomes in health. In 2011, Brazil adopted its first P4P scheme at national level, the National Programme for Improving Primary Care Access and Quality (PMAQ). The contribution of PMAQ in achieving the Sustainable Development Goals related to maternal and childcare remains under investigated in Brazil. OBJECTIVE: To estimate the association of PMAQ with the provision of maternal and childcare in Brazil, controlling for socioeconomic, geographic and family health team characteristics. METHOD: We used cross-sectional quantile regression (QR) models for two periods, corresponding to 33,368 Family Health Teams (FHTs) in the first cycle and 39,211 FHTs in the second cycle of PMAQ. FHTs were analysed using data from the Brazilian Ministry of Health (SIAB and CNES) and the Brazilian Institute for Geography and Statistics (IBGE). RESULTS: The average number of antenatal consultations per month were positively associated with PMAQ participating teams, with larger effect in the lower tail (10th and 25th quantiles) of the conditional distribution of the response variable. There was a positive association between PMAQ and the average number of consultations under 2 years old per month in the 10th and 25th quantiles, but a negative association in the upper tail (75th and 90th quantiles). For the average number of physician consultations for children under 1 year old per month, PMAQ participating teams were positively associated with the response variable in the lower tail, but different from the previous models, there is no clear evidence that the second cycle gives larger coefficients compared with first cycle. CONCLUSION: PMAQ has contributed to increase the provision of care to pregnant women and children under 2 years at primary healthcare level. Teams with lower average number of antenatal or child consultations benefited the most by participating in PMAQ, which suggests that PMAQ might motivate worse performing health providers to catch up.


Assuntos
Cuidado do Lactente/organização & administração , Programas Nacionais de Saúde/organização & administração , Cuidado Pré-Natal/organização & administração , Atenção Primária à Saúde/organização & administração , Reembolso de Incentivo , Brasil , Estudos Transversais , Feminino , Acesso aos Serviços de Saúde/economia , Acesso aos Serviços de Saúde/organização & administração , Humanos , Lactente , Cuidado do Lactente/economia , Recém-Nascido , Programas Nacionais de Saúde/economia , Gravidez , Cuidado Pré-Natal/economia , Atenção Primária à Saúde/economia , Avaliação de Programas e Projetos de Saúde , Qualidade da Assistência à Saúde
7.
AJR Am J Roentgenol ; 215(6): 1464-1473, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33084361

RESUMO

OBJECTIVE. This article reviews the use and current imaging techniques of cardiac CT angiography and cardiac MRI in the evaluation of commonly encountered pediatric cardiac processes that may present to the general radiologist. CONCLUSION. Imaging pediatric patients with acquired and congenital heart disease is an important skill for general radiologists. As survival rates increase and these patients enter adulthood, knowledge of pediatric acquired and congenital heart disease remains pertinent.

8.
Alzheimers Dement (Amst) ; 12(1): e12097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32999915

RESUMO

Introduction: We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aß) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET). Methods: In 72 individuals from the Insight 46 study, CSF Aß40, Aß42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays, and inter-platform Pearson correlations were derived. Logistic regressions and receiver-operating characteristic analysis generated CSF cut-points optimizing concordance with 18F-florbetapir amyloid PET status (n = 63). Results: Measurements of CSF Aß, p-tau181, and their ratios correlated well across platforms (r 0.84-.94, P < .0001); those of t-tau and t-tau/Aß42 correlated moderately (r 0.57-0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.110 for Lumipulse Aß42/Aß40, 0.087 for MSD Aß42/Aß40, and 25.3 for Lumipulse Aß42/p-tau181. Discussion: The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.

11.
Development ; 147(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958507

RESUMO

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a 'big data' resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32977705

RESUMO

Introduction: As of January 2020, 115,600 refugees remain in Greece; most are Afghani, Iraqi or Syrian nationals. This qualitative research study explores the views of key stakeholders providing healthcare for refugees in Greece between 2015 and 2018. The focus was on identifying key barriers and facilitators to healthcare access for refugees in Greece. Methods: 16 interviewees from humanitarian and international organisations operating in Greece were identified through purposive and snowball sampling. Semi-structured interviews were conducted between March and April 2018. Data were analysed using the Framework Method. Results: Key themes affecting healthcare access included the influence of socio-cultural factors (healthcare expectations, language, gender) and the ability of the Greek health system to respond to existing and evolving demands; these included Greece's ongoing economic crisis, human resource shortages, weak primary healthcare system, legal barriers and logistics. The evolution of the humanitarian response from emergency to sustained changes to EU funding, coordination and comprehensiveness of services affected healthcare access for refugees. Conclusion: The most noted barriers cited by humanitarian stakeholders to healthcare access for refugees in Greece were socio-cultural and language differences between refugees and healthcare providers and poor coordination among stakeholders. Policies and interventions which address these could improve healthcare access for refugees in Greece with coordination led by the EU.


Assuntos
Pessoal de Saúde/psicologia , Acesso aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde , Refugiados/psicologia , Altruísmo , Feminino , Grécia , Humanos , Entrevistas como Assunto , Masculino , Organizações , Pesquisa Qualitativa , Refugiados/estatística & dados numéricos , Participação dos Interessados , Síria/etnologia
13.
Global Health ; 16(1): 91, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32993694

RESUMO

BACKGROUND: In the UK, according to the 1967 Abortion Act, all abortions must be approved by two doctors, reported to the Department of Health and Social Care (DHSC), and be performed by doctors within licensed premises. Removing abortion from the criminal framework could permit new service delivery models. We explore service delivery models in primary care settings that can improve accessibility without negatively impacting the safety and efficiency of abortion services. Novel service delivery models are common in low-and-middle income countries (LMICs) due to resource constraints, and services are sometimes provided by trained, mid-level providers via "task-shifting". The aim of this study is to explore the quality of early abortion services provided in primary care of LMICs and explore the potential benefits of extending their application to the UK context. METHODS: We searched MEDLINE, EMBASE, Global Health, Maternity and Infant Care, CINAHL, and HMIC for studies published from September 1994 to February 2020, with search terms "nurses", "midwives", "general physicians", "early medical/surgical abortion". We included studies that examined the quality of abortion care in primary care settings of low-and-middle-income countries (LMICs), and excluded studies in countries where abortion is illegal, and those of services provided by independent NGOs. We conducted a thematic analysis and narrative synthesis to identify indicators of quality care at structural, process and outcome levels of the Donabedian model. RESULTS: A total of 21 indicators under 8 subthemes were identified to examine the quality of service provision: law and policy, infrastructure, technical competency, information provision, client-provider interactions, ancillary services, complete abortions, client satisfaction. Our analysis suggests that structural, process and outcome indicators follow a mediation pathway of the Donabedian model. This review showed that providing early medical abortion in primary care services is safe and feasible and "task-shifting" to mid-level providers can effectively replace doctors in providing abortion. CONCLUSION: The way services are organised in LMICs, using a task-shifted and decentralised model, results in high quality services that should be considered for adoption in the UK. Collaboration with professional medical bodies and governmental departments is necessary to expand services from secondary to primary care.

14.
BMC Health Serv Res ; 20(1): 873, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933503

RESUMO

BACKGROUND: Investing in human resources for health (HRH) is vital for achieving universal health care and the Sustainable Development Goals. The Programa Mais Médicos (PMM) (More Doctors Programme) provided 17,000 doctors, predominantly from Cuba, to work in Brazilian primary care. This study assesses whether PMM doctor allocation to municipalities was consistent with programme criteria and associated impacts on amenable mortality. METHODS: Difference-in-differences regression analysis, exploiting variation in PMM introduction across 5565 municipalities over the period 2008-2017, was employed to examine programme impacts on doctor density and mortality amenable to healthcare. Heterogeneity in effects was explored with respect to doctor allocation criteria and municipal doctor density prior to PMM introduction. RESULTS: After starting in 2013, PMM was associated with an increase in PMM-contracted primary care doctors of 15.1 per 100,000 population. However, largescale substitution of existing primary care doctors resulting in a net increase of only 5.7 per 100,000. Increases in both PMM and total primary care doctors were lower in priority municipalities due to lower allocation of PMM doctors and greater substitution effects. The PMM led to amenable mortality reductions of - 1.06 per 100,000 (95%CI: - 1.78 to - 0.34) annually - with greater benefits in municipalities prioritised for doctor allocation and where doctor density was low before programme implementation. CONCLUSIONS: PMM potential health benefits were undermined due to widespread allocation of doctors to non-priority areas and local substitution effects. Policies seeking to strengthen HRH should develop and implement needs-based criteria for resource allocation.

15.
BJGP Open ; 4(4)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32873539

RESUMO

BACKGROUND: Frequent paediatric attendances make up a large proportion of a GP's workload. Currently, there is no systematic review on frequent paediatric attendances in primary care. AIM: To identify the sociodemographic and clinical characteristics of children who attend primary care frequently. DESIGN & SETTING: A systematic review. METHOD: The electronic databases MEDLINE, Embase, and PsycINFO were searched up to January 2020, using terms relating to frequent attendance in primary care settings. Studies were eligible if they considered children frequently attending in primary care (aged 0-19 years). Relevant data were extracted and analysed by narrative synthesis. RESULTS: Six studies, of fair quality overall, were included in the review. Frequent attendance was associated with presence of psychosocial and mental health problems, younger age, school absence, presence of chronic conditions, and high level of anxiety in their parents. CONCLUSION: Various sociodemographic and medical characteristics of children were associated with frequent attendance in primary care. Research on interventions needs to account for the social context and community characteristics. Integrating GP services with mental health and social care could potentially provide a response to medical and psychosocial needs of frequently attending children and their families.

16.
Artigo em Inglês | PAHO-IRIS | ID: phr-52590

RESUMO

[Extract]. In 2015, the United Nations issued the Agenda for Sustainable Development Goals, which highlighted the need to ensure healthy lives and promote well-being for all across the lifespan. Goal 3 aims to make sure everyone has access to health and health coverage and, in 2019, the United Nations General Assembly adopted the political declaration of the highlevel meeting on universal health coverage reaffirming that “health is a precondition for and an outcome and indicator of the social, economic and environmental dimensions of sustainable development”. The High-Level Commission on Health Employment and Economic Growth identified that investments in the health and social workforce can spur inclusive economic growth. Achieving Goal 3 requires health services that are accessible (available and affordable), culturally acceptable and that provide quality care by well-trained health workers. The World Health Organization (WHO), however, estimates a worldwide projected shortfall of 18 million health workers by 2030, mostly in low- and lower-middle income countries. Countries at all levels of socioeconomic development face –to varying degrees– difficulties in employment, deployment, retention, and performance of their workforce due to chronic underinvestment in education and training of health workers and the mismatch between education and employment strategies in relation to health systems and population needs. [...]


Assuntos
Cobertura Universal de Saúde , Pessoal de Saúde , Sistemas de Saúde , Mão de Obra em Saúde , Acesso Universal aos Serviços de Saúde , Infecções por Coronavirus
17.
Plant Cell ; 32(10): 3346-3369, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32769130

RESUMO

Arabinogalactan proteins (AGPs) are a family of plant extracellular proteoglycans involved in many physiological events. AGPs are often anchored to the extracellular side of the plasma membrane and are highly glycosylated with arabinogalactan (AG) polysaccharides, but the molecular function of this glycosylation remains largely unknown. The ß-linked glucuronic acid (GlcA) residues in AG polysaccharides have been shown in vitro to bind to calcium in a pH-dependent manner. Here, we used Arabidopsis (Arabidopsis thaliana) mutants in four AG ß-glucuronyltransferases (GlcAT14A, -B, -D, and -E) to understand the role of glucuronidation of AG. AG isolated from glcat14 triple mutants had a strong reduction in glucuronidation. AG from a glcat14a/b/d triple mutant had lower calcium binding capacity in vitro than AG from wild-type plants. Some mutants had multiple developmental defects such as reduced trichome branching. glcat14a/b/e triple mutant plants had severely limited seedling growth and were sterile, and the propagation of calcium waves was perturbed in roots. Several of the developmental phenotypes were suppressed by increasing the calcium concentration in the growth medium. Our results show that AG glucuronidation is crucial for multiple developmental processes in plants and suggest that a function of AGPs might be to bind and release cell-surface apoplastic calcium.

19.
Prehosp Emerg Care ; : 1-13, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32644857

RESUMO

BACKGROUND: Millions of patients receive medications in the Emergency Medical Services (EMS) setting annually, and dosing safety is critically important. The need for weight-based dosing in pediatric patients and variability in medication concentrations available in the EMS setting may require EMS providers to perform complex calculations to derive the appropriate dose to deliver. These factors can significantly increase the risk for harm when dose calculations are inaccurate or incorrect. METHODS: We conducted a scoping review of the EMS, interfacility transport and emergency medicine literature regarding pediatric medication dosing safety. A priori, the authors identified four research topics: (1) what are the greatest safety threats that result in significant dosing errors that potentially result in harm to patients, (2) what practices or technologies are known to enhance dosing safety, (3) can data from other settings be extrapolated to the EMS environment to inform dosing safety, and (4) what impact could standardization of medication formularies have on enhancing dosing safety. To address these topics, 17 PICO (Patient, Intervention, Comparison, Outcome) questions were developed and a literature search was performed. RESULTS: After applying exclusion criteria, 70 articles were reviewed. The methods for the investigation, findings from these articles and how they inform EMS medication dosing safety are summarized here. This review yielded 11 recommendations to improve safety of medication delivery in the EMS setting. CONCLUSION: These recommendations are summarized in the National Association of EMS Physicians® position statement: Medication Dosing Safety for Pediatric Patients in Emergency Medical Services.

20.
Hand (N Y) ; : 1558944719895786, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32698624

RESUMO

Background: The scratch collapse test (SCT) is a clinical examination maneuver that has been previously reported as a reliable and reproducible test to diagnose carpal tunnel syndrome (CTS). The initial study by Cheng et al in 2008 showed a simple test with high sensitivity. However, subsequent attempts to reproduce those findings have resulted in lower accuracy. Our goal was to evaluate the use of the SCT for patients presenting with symptoms of pain, numbness, or weakness in an upper extremity. Methods: Forty patients were referred to the electrodiagnostic (EDX) lab for evaluation of an upper extremity. One blinded examiner who was familiar with the maneuver performed the SCT on all 40 patients. Another physician or technician performed the nerve conduction study and electromyography. Patient history and accompanying physical examination findings were not revealed to the SCT examiner. Results: The relationship between the SCT performed by a blinded examiner and the EDX performed by blinded examiners was nonsignificant (P = .676) and showed a sensitivity of 0.48, specificity of 0.59, positive predictive value of 0.61, and negative predictive value of 0.45. Conclusion: Based on this study and previous findings by other authors, we would advise against the use of the SCT in CTS for important patient-care decisions, such as surgical decision-making, until future research is done. It is possible that the SCT, in combination with other physical examination maneuvers, could increase diagnostic accuracy and enhance patient management.

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