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Background: Over 214 million students globally have been affected by school closures during the COVID-19 pandemic. To address knowledge gaps on transmission of SARS-CoV-2 delta (B.1.617.2) and omicron (B.1.1.529) variants in educational settings we examined virus transmission in schools and early childhood education and care settings (ECECs) in New South Wales (NSW), Australia in relation to mitigation measures, including COVID-19 vaccination. Methods: Secondary transmission from children and adults with laboratory-confirmed SARS-CoV-2 infection who attended a school (n = 3170) or ECECs (n = 5800) while infectious was investigated over two periods: 1) June 16 to September 18, 2021 (delta outbreak), and; 2) October 18 to December 18, 2021 (delta and omicron; schools only). Close contacts of cases underwent 14 days quarantine and SARS-CoV-2 nucleic acid testing. Secondary attack rates (SARs) were calculated and compared with state-wide notification data, school attendance, and vaccination status. Findings: 1187 schools and 300 ECECs had students (n = 1349) or staff (n = 440) attend while infectious. Of 24,277 contacts investigated, most (91.8%; 22,297/24,277) were tested and 912 secondary cases identified. The secondary attack rate (SAR) was 5.9% in 139 ECECs and 3.5% in 312 schools. The risk of becoming a secondary case was higher in unvaccinated school staff (OR 4.7; 95% CI: 1.7-13.3), particularly ECEC staff (OR 9.0; 95% CI: 3.6-22.7) and unvaccinated school students than in vaccinated school staff. SARs were similar for delta (4.9%) and omicron BA.1 (4.1%) in the unvaccinated and higher compared with vaccinated contacts (0.9% and 3.4%, respectively). Increasing school attendance rates raised case incursions and secondary case numbers, but not community-wide infection rates. Interpretation: Vaccination reduced SARS-CoV-2 transmission rates in schools, although less so for omicron than delta variants. Despite higher community-based transmission rates, in-school transmission remained low and stable with high attendance, suggesting that community restrictions, rather than school closures, best mitigated COVID-19 impacts. Funding: NSW Government Department of Health.
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Serological assays for SARS-CoV-2 infection are now widely available for use in diagnostic laboratories. Limited data are available on the performance characteristics in different settings, and at time periods remote from the initial infection. Validation of the Abbott (Architect SARS-CoV-2 IgG), DiaSorin (Liaison SARS-CoV-2 S1/S2 IgG) and Roche (Cobas Elecsys Anti-SARS-CoV-2) assays was undertaken utilising 217 serum samples from 131 participants up to 7 months following COVID-19 infection. The Abbott and DiaSorin assays were implemented into routine laboratory workflow, with outcomes reported for 2764 clinical specimens. Sensitivity and specificity were concordant with the range reported by the manufacturers for all assays. Sensitivity across the convalescent period was highest for the Roche at 95.2-100% (95% CI 81.0-100%), then the DiaSorin at 88.1-100% (95% CI 76.0-100%), followed by the Abbott 68.2-100% (95% CI 53.4-100%). Sensitivity of the Abbott assay fell from approximately 5 months; on this assay paired serum samples for 45 participants showed a significant drop in the signal-to-cut-off ratio and 10 sero-reversion events. When used in clinical practice, all samples testing positive by both DiaSorin and Abbott assays were confirmed as true positive results. In this low prevalence setting, despite high laboratory specificity, the positive predictive value of a single positive assay was low. Comprehensive validation of serological assays is necessary to determine the optimal assay for each diagnostic setting. In this low prevalence setting we found implementation of two assays with different antibody targets maximised sensitivity and specificity, with confirmatory testing necessary for any sample which was positive in only one assay.
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Anticorpos Antivirais/análise , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Anticorpos Antivirais/sangue , Humanos , Laboratórios , Estudos Longitudinais , SARS-CoV-2 , Sensibilidade e EspecificidadeRESUMO
Objectives: Current events with the recent COVID-19 outbreak are necessitating steep learning curves for the NHS workforce. Ultrasound, although not used in the diagnosis of COVID-19 may be utilised by practitioners at the point of care (POC) or on the intensive care units (ITUs) where rapid assessment of the lung condition may be required. The aim of this article was to review current literature surrounding the use of lung ultrasound in relation to COVID-19 and provide Sonographers with a quick and digestible reference guide for lung pathologies. Key findings: Ultrasound is being used in Italy and China to help review lung condition during the COVID-19 outbreak however not strictly as a diagnostic tool as Computed Tomography (CT) of the chest and chest radiographs are currently gold standard. Ultrasound is highly sensitive in the detection of multiple lung pathologies which can be demonstrated in conjunction with COVID-19 however to date there are no specific, nor pathognomonic findings which relate to COVID-19 on ultrasound. Conclusion: Lung ultrasound is highly sensitive and can quickly and accurately review lung condition creating potential to assess for changes or resolution over time, especially in the ITU and POC setting. However it should not be used as a diagnostic tool for COVID-19 due to low specificity in relation to the virus. Implications for practice: The adoption of lung ultrasound to monitor lung condition during the COVID-19 outbreak may reduce the need for serial exposure to ionising radiation on the wards and in turn reduce the number of radiographers required to attend infected wards and bays, protecting both patients and the workforce.
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Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Cuidados Críticos/métodos , Pulmão/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Sistemas Automatizados de Assistência Junto ao Leito , Ultrassonografia/métodos , COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMO
Studies have identified that there are many barriers to treatment of mental health illnesses in military populations, including the negative-associated stigma. One such barrier includes perceptions of weakness, leading to concerns about leadership and competency and being seen as malingering. Furthermore, similarities can be seen in civilian health professionals, where concerns of negative perceptions can limit reporting and treatment of mental health illnesses. Despite the frequency of stressful events, military and health professionals do not become immune to stress and are often ill prepared to cope with acute stressors that can often build on each other until emotional exhaustion and/or crisis point. Even with targeted internal programmes, the stigma of seeking mental health assistance in the military and medicine is poor and is believed to contribute to poor outcomes, such as the potential of increased suicide prevalence.
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Transtornos Mentais/terapia , Serviços de Saúde Mental , Militares/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Estigma Social , Humanos , Liderança , Saúde Mental , Medicina MilitarRESUMO
Essentials FcγRIIa mediates life-threatening heparin-induced thrombocytopenia (HIT). Most anti-platelet factor (PF)4-heparin IgGs are not pathogenic so diagnosis of HIT is challenging. Dimeric rsFcγRIIa was used to quantify receptor-binding activity of anti-PF4-heparin antibodies. Dimeric rsFcγRIIa binding specifically correlated with occurrence of HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a major and potentially fatal consequence of antibodies produced against platelet factor 4 (PF4)-heparin complexes following heparin exposure. Not all anti-PF4-heparin antibodies are pathogenic, so overdiagnosis can occur, with resulting inappropriate use of alternative anticoagulation therapies that have associated risks of bleeding. However, definitive platelet functional assays are not widely available for routine analysis. Objectives To assess the utility of dimeric recombinant soluble FcγRIIa (rsFcγRIIa) ectodomains for detecting HIT antibodies. Patients/Methods Plasma from 27 suspected HIT patients were tested for pathogenic anti-PF4-heparin antibodies by binding of a novel dimeric FcγRIIa ectodomain probe. Plasmas were also tested by the use of PF4-heparin IgG ELISA, the HemosIL AcuStar HIT IgG-specific assay, and a serotonin release assay (SRA). Results The dimeric rsFcγRIIa test produced no false positives and excluded four samples that were positive by IgG ELISA. In this small patient cohort, the novel assay correctly assigned 93% of the suspected HIT patients, with two of the HIT patients being scored as false negatives. The improved discrimination of the novel assay over the IgG ELISA, which scored four false positives, supports the mechanistic interpretation that binding of dimeric rsFcγRIIa detects pairs of closely spaced IgG antibodies in PF4-heparin immune complexes. Conclusions This study found the cell-free, function-based dimeric rsFcγRIIa assay to be convenient, simple, and potentially predictive of HIT. The assay had improved specificity over the IgG ELISA, and correlated strongly with the AcuStar HIT IgG-specific assay, warranting further evaluation of its potential to identify HIT in larger patient cohorts.
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Anticoagulantes/efeitos adversos , Autoanticorpos/imunologia , Heparina/efeitos adversos , Imunoensaio/métodos , Epitopos Imunodominantes , Fator Plaquetário 4/imunologia , Receptores de IgG/imunologia , Trombocitopenia/diagnóstico , Anticoagulantes/imunologia , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Heparina/imunologia , Humanos , Valor Preditivo dos Testes , Domínios Proteicos , Receptores de IgG/metabolismo , Reprodutibilidade dos Testes , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologiaRESUMO
BACKGROUND: The aim of the current study was to identify functional predictors of perceived impact of childhood disability among families of children with neurodevelopmental disorders and disabilities. We first examined the relationship between sub-domains of adaptive and problematic behaviour and perceived family impact. Second, we examined whether the same sub-domains would emerge as significant after controlling for the impact of child diagnosis, including autism spectrum disorder, cerebral palsy and intellectual disability. METHOD: Caregivers of 216 children and adolescents (M = 8.17 years) with neurodevelopmental disorder and disability completed measures of children's practical, conceptual and social skills (i.e. adaptive behaviour), behaviour problems and positive and negative family impact. RESULTS: Indices of child adaptive and problematic behaviour were only significantly associated with perceived negative family impact. Children's practical and social skills, as well as emotional symptoms, emerged as significant predictors of perceived negative family impact, with emotional symptoms accounting for greatest variance. Including diagnosis in our statistical models did not explain additional variance above and beyond these particular sub-domains of child functioning. CONCLUSIONS: The study findings suggest that it is not children's most impaired domains of functioning that are perceived as significantly impactful by the family. The findings highlight the importance of devoting consideration to the ways in which the functional limitations experienced by children with chronic developmental health conditions similarly impact family life and well-being, regardless of disorder designation.
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Adaptação Psicológica , Sintomas Afetivos/psicologia , Crianças com Deficiência/psicologia , Família/psicologia , Transtornos do Neurodesenvolvimento/psicologia , Comportamento Problema/psicologia , Habilidades Sociais , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Anemia , Leucopenia , Trombocitopenia , Animais , Plaquetas , Camundongos , Transdução de SinaisRESUMO
The significant role of platelets in the protection of tumour cells from immune attack and shear forces and the promotion of tumour cell extravasation from the bloodstream in the process of haematogenous metastasis have been extensively studied. The role of platelets, and in particular platelet membranes, in the promotion of a more metastatic phenotype in tumour cells is a more recent and, therefore, less well-recognised area of research. This review article summarises studies that have focused on the impact of tumour cell interactions with platelets and platelet membranes on tumour cell behaviour in vitro and in vivo. Furthermore, the gene expression changes that occur within tumour cells following contact with platelet membranes are also extensively reviewed. Overall, the interaction of platelet membranes with tumour cells results in a more invasive phenotype and the promotion of epithelial to mesenchymal transition with our own genetic studies revealing that matrix metalloproteinase-1, plasminogen activator inhibitor-1 and interleukin-8 are globally upregulated in a range of tumour cell lines.
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Plaquetas/patologia , Comunicação Celular/fisiologia , Neoplasias/sangue , Neoplasias/patologia , Animais , Membrana Celular/fisiologia , Humanos , Metástase NeoplásicaRESUMO
BACKGROUND: Podoconiosis affects an estimated 3 million people in Ethiopia with a further 19 million at risk. Volcanic soil and pathogens enter skin breaches in the feet causing inflammation, lymphoedema and hyperkeratosis. There is no robust evidence on optimal podoconiosis skincare regimens to improve skin barrier function (SBF). OBJECTIVES: To evaluate the effectiveness of a new, low-cost, evidence-based intervention to improve SBF in the lower limbs of those with podoconiosis. METHODS: A randomized controlled trial (NCT02839772) was conducted over 3 months in two podoconiosis clinics (n = 193). The intervention comprised 2% (v/v) glycerine added to a reduced volume of soaking water. The control group received the current skincare regimen. Primary outcome measures were transepidermal water loss (TEWL) and stratum corneum hydration (SCH) at four specific sites on the lower limbs. RESULTS: Improvement in SBF was observed in both groups across all measurement sites and time points, although this was significantly greater in the experimental group. TEWL reduced in both groups at all sites. For example, on top of the foot the estimated group difference in TEWL at visit 4 was 1·751 [standard error (SE) = 0·0390] in favour of the experimental group [t = 3·15, degrees of freedom (df) = 189·58, P = 0·002, 95% confidence interval (CI) 0·066-2·85], indicating a greater reduction in TEWL in the experimental group. Similarly, at the same site the estimated group difference in SCH at visit 4 was -2·041 (SE = 0·572) in favour of the experimental group (t = -3·56, df = 186·74, P < 0·001, 95% CI -3·16 to -0·91), indicating a greater increase in SCH in the experimental group. There were also significantly greater reductions in odour, number of wounds and largest foot circumference in the experimental vs. the control group. CONCLUSIONS: The addition of 2% (v/v) glycerol to a reduced volume (83% reduction) of soaking water significantly improved SBF.
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Elefantíase/terapia , Higiene , Higiene da Pele/métodos , Emolientes/administração & dosagem , Etiópia , Glicerol/administração & dosagem , Humanos , Perna (Membro) , Solventes/administração & dosagem , Resultado do Tratamento , Perda Insensível de Água/fisiologiaRESUMO
Essentials Dimeric high-affinity collagen receptor glycoprotein VI (GPVI) is present on resting platelets. Spatio-temporal organization of platelet GPVI-dimers was evaluated using advanced microscopy. Upon platelet adhesion to collagenous substrates, GPVI-dimers coalesce to form clusters. Clustering of GPVI-dimers may increase avidity and facilitate platelet activation SUMMARY: Background Platelet glycoprotein VI (GPVI) binding to subendothelial collagen exposed upon blood vessel injury initiates thrombus formation. Dimeric GPVI has high affinity for collagen, and occurs constitutively on resting platelets. Objective To identify higher-order oligomerization (clustering) of pre-existing GPVI dimers upon interaction with collagen as a mechanism to initiate GPVI-mediated signaling. Methods GPVI was located by use of fluorophore-conjugated GPVI dimer-specific Fab (antigen-binding fragment). The tested substrates include Horm collagen I fibers, soluble collagen III, GPVI-specific collagen peptides, and fibrinogen. GPVI dimer clusters on the platelet surface interacting with these substrates were visualized with complementary imaging techniques: total internal reflection fluorescence microscopy to monitor real-time interactions, and direct stochastic optical reconstruction microscopy (dSTORM), providing relative quantification of GPVI cluster size and density. Confocal microscopy was used to locate GPVI dimer clusters, glycoprotein Ib, integrin α2 ß1 , and phosphotyrosine. Results Upon platelet adhesion to all collagenous substrates, GPVI dimers coalesced to form clusters; notably clusters formed along the fibers of Horm collagen. dSTORM revealed that GPVI density within clusters depended on the substrate, collagen III being the most effective. Clusters on fibrinogen-adhered platelets were much smaller and more numerous; whether these are pre-existing oligomers of GPVI dimers or fibrinogen-induced is not clear. Some GPVI dimer clusters colocalized with areas of phosphotyrosine, indicative of signaling activity. Integrin α2 ß1 was localized to collagen fibers close to GPVI dimer clusters. GPVI clustering depends on a dynamic actin cytoskeleton. Conclusions Platelet adhesion to collagen induces GPVI dimer clustering. GPVI clustering increases both avidity for collagen and the proximity of GPVI-associated signaling molecules, which may be crucial for the initiation and persistence of signaling.
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Plaquetas/metabolismo , Colágeno/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Actinas/metabolismo , Vasos Sanguíneos/lesões , Adesão Celular , Citoesqueleto/metabolismo , Humanos , Microscopia Confocal , Ativação Plaquetária , Adesividade Plaquetária , Multimerização Proteica , Transdução de SinaisRESUMO
HIV-positive patients are at increased risk for coronary artery disease (CAD); changes in platelet activation may play a role. This study was performed to determine if levels of soluble glycoprotein VI (sGPVI), a platelet-specific marker of activation, were different in HIV-positive patients compared with HIV-negative controls and further if levels were predictive of CAD in HIV. Twenty-four HIV-positive individuals (HIV cases) with CAD were compared with 46 age- and sex-matched HIV-positive controls without CAD and 41 HIV-negative controls (healthy controls). Platelet activation (represented by sGPVI level) was compared 12 months and 1 month prior to CAD diagnosis. sGPVI was quantified by ELISA. sGPVI levels were higher in HIV-positive subjects (combined) than healthy controls (122.5 ng/mL [interquartile ranges (IQR) 90.3-160.5] versus 84.7 ng/mL [IQR 48.6-119.5], p <0.001). Twelve months before the event, there was no difference in sGPVI between HIV cases and HIV controls (113.4 ng/mL [IQR 85.6-141.65] versus 128.0 ng/mL [IQR 96.6-179.4], p = 0.369). One month prior to the event, sGPVI was significantly lower in HIV cases compared with HIV controls (109.0 ng/mL [IQR 79.4-123.4] versus 133.9 ng/mL [IQR 112.7-171.9], p = 0.010). These results remained significant following adjustment for possible confounders. This work demonstrates that HIV infection is associated with higher sGPVI levels. A fall in sGPVI immediately prior to first coronary artery event may reflect a loss of negative-feedback mechanism and be an important pathological step in the development of symptomatic CAD, but further work is needed to confirm these findings and determine their clinical impact.
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Plaquetas/metabolismo , Doença da Artéria Coronariana/diagnóstico , Infecções por HIV/sangue , Ativação Plaquetária , Glicoproteínas da Membrana de Plaquetas/metabolismo , Idoso , Biomarcadores/sangue , Plaquetas/virologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/virologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de PlaquetasRESUMO
Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.
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Plaquetas/citologia , Oxigenação por Membrana Extracorpórea , Coração Auxiliar , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Glicoproteínas da Membrana de Plaquetas/química , Adolescente , Adulto , Idoso , Estenose da Valva Aórtica/fisiopatologia , Plaquetas/metabolismo , Estudos de Coortes , Feminino , Insuficiência Cardíaca/complicações , Hemorragia/complicações , Heparina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária , Estresse Mecânico , Trombose , Varfarina/uso terapêutico , Adulto Jovem , Fator de von Willebrand/químicaAssuntos
Plaquetas/citologia , Colágeno/metabolismo , Fator de von Willebrand/metabolismo , Plaquetas/metabolismo , Feminino , Heterozigoto , Humanos , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Domínios Proteicos , Adulto Jovem , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética , Fator de von Willebrand/química , Fator de von Willebrand/genéticaRESUMO
UNLABELLED: Essentials The platelet thrombin receptor, PAR4, is an emerging anti-thrombotic drug target. We examined the anti-platelet & anti-thrombotic effects of PAR4 inhibition in human blood. PAR4 inhibition impaired platelet procoagulant activity in isolated cells and during thrombosis. Our study shows PAR4 is required for platelet procoagulant function & thrombosis in human blood. SUMMARY: Background Thrombin-induced platelet activation is important for arterial thrombosis. Thrombin activates human platelets predominantly via protease-activated receptor (PAR)1 and PAR4. PAR1 has higher affinity for thrombin, and the first PAR1 antagonist, vorapaxar, was recently approved for use as an antiplatelet agent. However, vorapaxar is contraindicated in a significant number of patients, owing to adverse bleeding events. Consequently, there is renewed interest in the role of platelet PAR4 in the setting of thrombus formation. Objectives To determine the specific antiplatelet effects of inhibiting PAR4 function during thrombus formation in human whole blood. Methods and Results We developed a rabbit polyclonal antibody against the thrombin cleavage site of PAR4, and showed it to be a highly specific inhibitor of PAR4-mediated platelet function. This function-blocking anti-PAR4 antibody was used to probe for PAR4-dependent platelet functions in human isolated platelets in the absence and presence of concomitant PAR1 inhibition. The anti-PAR4 antibody alone was sufficient to abolish the sustained elevation of cytosolic calcium level and consequent phosphatidylserine exposure induced by thrombin, but did not significantly inhibit integrin αII b ß3 activation, α-granule secretion, or aggregation. In accord with these in vitro experiments on isolated platelets, selective inhibition of PAR4, but not of PAR1, impaired thrombin activity (fluorescence resonance energy transfer-based thrombin sensor) and fibrin formation (anti-fibrin antibody) in an ex vivo whole blood flow thrombosis assay. Conclusions These findings demonstrate that PAR4 is required for platelet procoagulant function during thrombus formation in human blood, and suggest PAR4 inhibition as a potential target for the prevention of arterial thrombosis.
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Plaquetas/citologia , Agregação Plaquetária , Receptores de Trombina/antagonistas & inibidores , Trombose/metabolismo , Adulto , Animais , Anticorpos/química , Cálcio/metabolismo , Citosol/metabolismo , Feminino , Fibrina/química , Transferência Ressonante de Energia de Fluorescência , Voluntários Saudáveis , Humanos , Lactonas/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Selectina-P/metabolismo , Fosfatidilserinas/química , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/uso terapêutico , Piridinas/uso terapêutico , Receptor PAR-1/metabolismo , Transdução de Sinais , Trombina/química , Adulto JovemRESUMO
Simple, quality-assured, child-friendly formulations of existing first-line anti-tuberculosis (TB) drugs in the correct dosages are now becoming available. Efforts are currently underway by the TB Alliance, the World Health Organization (WHO), and its partners to make appropriate medicines available to treat children diagnosed with TB. The functioning of the current market and the distribution pathways in pediatric TB drugs now require characterization and understanding in order to develop appropriate strategies for delivery of these and other future pediatric TB medicines. The Stop TB Partnership's Global Drug Facility (GDF) plays a major role in supplying pediatric TB medications worldwide. GDF is considered to be the largest procurer of pediatric TB treatment and the largest supplier to national TB programs of quality pediatric drugs. Between 2007 and 2013, the GDF delivered more than 580, 000 treatments to children in over 50 countries, 14 of which are among the 22 high TB burden countries. We analyzed this data set in the context of WHO estimates of pediatric TB as well as other available information to assess the functioning of the current market, lessons learnt from the GDF experience in the market, and opportunities for future products.
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Antituberculosos/provisão & distribuição , Farmácias/provisão & distribuição , Tuberculose/tratamento farmacológico , Criança , Humanos , Cooperação Internacional , Marketing , Organização Mundial da SaúdeRESUMO
BACKGROUND: Effective parental management of childhood eczema requires education and support to reduce disease severity and improve the child's quality of life. Self-efficacy is a key factor influencing effective chronic disease management, yet there are no published scales to measure parental self-efficacy in managing childhood eczema. The Parental Self-Efficacy with Eczema Care Index (PASECI) was designed to measure parental self-efficacy in managing childhood eczema as a pre- and postintervention tool in the evaluation of a structured Eczema Education Programme (EEP). OBJECTIVES: To develop and test the validity, reliability and sensitivity of a new outcome measure (PASECI) designed to assess parental self-efficacy in managing their child's eczema to determine pre- vs. postintervention changes in educational intervention evaluation studies. METHODS: PASECI was developed from the literature, expert consultation and piloting of a 40-item prototype. The final 29-item scale is arranged in four subscales. Parents of children with eczema aged 0-16 years (n = 242) attending the EEP were assessed at 1 week pre-EEP and 4 weeks postintervention. Cronbach's α and factor analyses were undertaken. RESULTS: PASECI has face, content and construct validity. It is reliable, with high item internal consistency (α > 0·87 in all domains). Factor analysis revealed four viable domains. It was sensitive to change for postintervention measures using sign tests (P < 0·001). CONCLUSIONS: PASECI is a useful, valid, reliable and sensitive evaluative outcome measure of self-efficacy in parents managing childhood eczema.
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Dermatite Atópica/terapia , Pais/psicologia , Autoeficácia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
Platelet cold agglutinins (PCA) cause pseudothrombocytopenia, spurious thrombocytopenia due to ex vivo platelet clumping, complicating clinical diagnosis, but mechanisms and consequences of PCA are not well defined. Here, we characterised an atypical immunoglobulin (Ig)M PCA in a 37-year-old woman with lifelong bleeding and chronic moderate thrombocytopenia, that induces activation and aggregation of autologous or allogeneic platelets via interaction with platelet glycoprotein (GP)VI. Patient temperature-dependent pseudothrombocytopenia was EDTA-independent, but was prevented by integrin αIIbß3 blockade. Unstimulated patient platelets revealed elevated levels of bound IgM, increased expression of activation markers (P-selectin and CD63), low GPVI levels and abnormally high thromboxane (TX)A2 production. Patient serum induced temperature- and αIIbß3-dependent decrease of platelet count in allogeneic donor citrated platelet-rich plasma (PRP), but not in PRP from Glanzmann's thrombasthenia or afibrinogenaemia patients. In allogeneic platelets, patient plasma induced shape change, P-selectin and CD63 expression, (14)C-serotonin release, and TXA2 production. Activation was not inhibited by aspirin, cangrelor or blocking anti-Fc receptor (FcγRIIA) antibody, but was abrogated by inhibitors of Src and Syk, and by a soluble GPVI-Fc fusion protein. GPVI-deficient platelets were not activated by patient plasma. These data provide the first evidence for an IgM PCA causing platelet activation/aggregation via GPVI. The PCA activity persisted over a five-year follow-up period, supporting a causative role in patient chronic thrombocytopenia and bleeding.
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Transtornos Hemorrágicos/imunologia , Imunoglobulina M/imunologia , Agregação Plaquetária/imunologia , Glicoproteínas da Membrana de Plaquetas/fisiologia , Trombocitopenia/imunologia , Adulto , Afibrinogenemia/sangue , Autoanticorpos/sangue , Biomarcadores/sangue , Temperatura Baixa/efeitos adversos , Crioglobulinas/farmacologia , Feminino , Humanos , Ativação Plaquetária/imunologia , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/fisiologia , Proteínas Tirosina Quinases/sangue , Trombastenia/sangue , Trombocitopenia/sangueRESUMO
Platelet activation is a frontline response to injury, not only essential for clot formation but also important for tissue repair. Indeed, the reparative influence of platelets has long been exploited therapeutically where application of platelet concentrates expedites wound recovery. Despite this, the mechanisms of platelet-triggered cytoprotection are poorly understood. Here, we show that activated platelets accumulate in the brain to exceptionally high levels following injury and release factors that potently protect neurons from apoptosis. Kinomic microarray and subsequent kinase inhibitor studies showed that platelet-based neuroprotection relies upon paracrine activation of the epidermal growth factor receptor (EGFR) and downstream DNA-dependent protein kinase (DNA-PK). This same anti-apoptotic cascade stimulated by activated platelets also provided chemo-resistance to several cancer cell types. Surprisingly, deep proteomic profiling of the platelet releasate failed to identify any known EGFR ligand, indicating that activated platelets release an atypical activator of the EGFR. This study is the first to formally associate platelet activation to EGFR/DNA-PK--an endogenous cytoprotective cascade.