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BACKGROUND: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. OBJECTIVE: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. DESIGN: Propensity score-weighted population-based cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. MEASUREMENTS: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). RESULTS: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n = 747 018), ART-conceived singleton infants (n = 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n = 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n = 13 574). LIMITATIONS: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. CONCLUSION: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.
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Infertilidade Masculina , Anormalidades Urogenitais , Feminino , Humanos , Lactente , Masculino , Gravidez , Austrália , Estudos de Coortes , Resultado da Gravidez , Sêmen , Recém-Nascido , Pré-EscolarRESUMO
This study aimed to determine whether a correlation exists between residual dentin thickness and quantitative light-induced fluorescence (QLF) values and, if so, to analyze its tendencies. Forty extracted sound human molars were assigned to filled and unfilled groups. The teeth were submerged in a mold with clear acrylic resin. Red utility wax was inserted into the pulp chamber space in the filled group to simulate vital pulp. The specimen was sectioned longitudinally to observe the inside of the pulp space. The samples were cut horizontally from the highest point of the pulp space 2 mm apart. QLF images were then taken of 2 mm, 1 mm, and 0.5 mm samples using the QLF-D Biluminator™ 2 + system. Three operators independently evaluated the QLF images, and the statistical analysis was conducted using one-way analysis of variance, Pearson correlation coefficients, and intraclass correlation coefficients. In the filled group, the mean ΔF values for residual dentin thicknesses of 2 mm, 1 mm, and 0.5 mm were - 3.22, - 7.84, and - 11.52, respectively. In the unfilled group, the mean ΔF values were 0, - 6.90, and - 10.14, respectively. A positive correlation was found between residual dentin thickness and ΔF values (P < 0.05). The intraclass correlation coefficients for observations made by the three operators for the filled and unfilled groups were 0.831 and 0.917, respectively (P < 0.05). In conclusion, residual dentin thickness and ΔF values were significantly correlated and had a highly positive correlation regardless of the QLF device operator.
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STUDY QUESTION: In a country with supportive funding for medically assisted reproduction (MAR) technologies, what is the proportion of MAR births over-time? SUMMARY ANSWER: In 2017, 6.7% of births were conceived by MAR (4.8% ART and 1.9% ovulation induction (OI)/IUI) with a 55% increase in ART births and a stable contribution from OI/IUI births over the past decade. WHAT IS KNOWN ALREADY: There is considerable global variation in utilization rates of ART despite a similar infertility prevalence worldwide. While the overall contribution of ART to national births is known in many countries because of ART registries, very little is known about the contribution of OI/IUI treatment or the socio-demographic characteristics of the parents. Australia provides supportive public funding for all forms of MAR with no restrictions based on male or female age, and thus provides a unique setting to investigate the contribution of MAR to national births as well as the socio-demographic characteristics of parents across the different types of MAR births. STUDY DESIGN, SIZE, DURATION: This is a novel population-based birth cohort study of 898â084 births using linked ART registry data and administrative data including birth registrations, medical services, pharmaceuticals, hospital admissions and deaths. Birth (a live or still birth of at least one baby of ≥400 g birthweight or ≥20 weeks' gestation) was the unit of analysis in this study. Multiple births were considered as one birth in our analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included a total of 898â084 births (606â488 mothers) in New South Wales and the Australian Capital Territory, Australia 2009-2017. We calculated the prevalence of all categories of MAR-conceived births over the study period. Generalized estimating equations were used to examine the association between parental characteristics (parent's age, parity, socio-economic status, maternal country of birth, remoteness of mother's dwelling, pre-existing medical conditions, smoking, etc.) and ART and OI/IUI births relative to naturally conceived births. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of MAR births increased from 5.1% of all births in 2009 to 6.7% in 2017, representing a 30% increase over the decade. The proportion of OI/IUI births remained stable at around 2% of all births, representing 32% of all MAR births. Over the study period, ART births conceived by frozen embryo-transfer increased nearly 3-fold. OI/IUI births conceived using clomiphene citrate decreased by 39%, while OI/IUI births conceived using letrozole increased 56-fold. Overall, there was a 55% increase over the study period in the number of ART-conceived births, rising to 56% of births to mothers aged 40 years and older. In 2017, almost one in six births (17.6%) to mothers aged 40 years and over were conceived using ART treatment. Conversely, the proportion of OI/IUI births was similar across different mother's age groups and remained stable over the study period. ART children, but not OI/IUI children, were more likely to have parents who were socio-economically advantaged compared to naturally conceived children. For example, compared to naturally conceived births, ART births were 16% less likely to be born to mothers who live in the disadvantaged neighbourhoods after accounting for other covariates (adjusted relative risk (aRR): 0.84 [95% CI: 0.81-0.88]). ART- or OI/IUI-conceived children were 25% less likely to be born to immigrant mothers than births after natural conception (aRR: 0.75 [0.74-0.77]). LIMITATIONS, REASONS FOR CAUTION: The social inequalities that we observed between the parents of children born using ART and naturally conceived children may not directly reflect disparities in accessing fertility care for individuals seeking treatment. WIDER IMPLICATIONS OF THE FINDINGS: With the ubiquitous decline in fertility rates around the world and the increasing trend to delay childbearing, this population-based study enhances our understanding of the contribution of different types of MARs to population profiles among births in high-income countries. The parental socio-demographic characteristics of MAR-conceived children differ significantly from naturally conceived children and this highlights the importance of accounting for such differences in studies investigating the health and development of MAR-conceived children. STUDY FUNDING/COMPETING INTEREST(S): This study was funded through Australian National Health and Medical Research Council (NHMRC) grant: APP1127437. G.M.C. is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproduction Database with funding support from the Fertility Society of Australia and New Zealand. C.V. is an employee of The University of New South Wales (UNSW), Director of Clinical Research of IVFAustralia, Member of the Board of the Fertility Society of Australia and New Zealand, and Member of Research Committee of School of Women's and Children's Health, UNSW. C.V. reports grants from Australian National Health and Medical Research Council (NHMRC), and Merck KGaA. C.V. reports consulting fees, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript, writing or educational events or attending meeting or travel from Merck, Merck Sparpe & Dohme, Ferring, Gedon-Richter and Besins outside this submitted work. C.V. reported stock or stock options from Virtus Health Limited outside this submitted work. R.J.N. is an employee of The University of Adelaide, and Chair DSMC for natural therapies trial of The University of Hong Kong. R.J.N. reports grants from NHMRC. R.J.N. reports lecture fees and support for attending or travelling for lecture from Merck Serono which is outside this submitted work. L.R.J. is an employee of The UNSW and Foundation Director of the Centre for Big Data Research in Health at UNSW Sydney. L.R.J. reports grants from NHMRC. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
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Saúde da Criança , Saúde da Mulher , Adulto , Austrália/epidemiologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Gravidez , Técnicas de Reprodução AssistidaRESUMO
PURPOSE: To describe vitamin A deficiency using multimodal functional visual assessments and imaging. METHODS/CASE: A 50-year-old female with past medical history significant for Roux-en-Y gastric bypass surgery complained of nyctalopia and "yellowing" of vision. RESULTS: Vitamin A levels were noted to be < 0.06 mg/L (normal 0.3-0.12 mg/L). Fundus examination was notable for peripheral yellow punctate lesions, superior arcuate defects on HVF 30-2 testing, an indistinct ellipsoid zone on SD-OCT, and absent rod responses and severely reduced amplitudes for the cone photoreceptors on full-field ERG. These findings resolved with initiation of parenteral vitamin A supplementation. CONCLUSION: This report documents an example of vitamin A deficiency in the developed world. We aim to provide a comprehensive description of clinical examination and multimodal imaging findings before and after vitamin supplementation for vitamin A deficiency.
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Doenças Retinianas , Deficiência de Vitamina A , Documentação , Eletrorretinografia/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Imagem Multimodal , Doenças Retinianas/diagnóstico , Doenças Retinianas/etiologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Vitamina A/uso terapêutico , Deficiência de Vitamina A/diagnóstico , Deficiência de Vitamina A/tratamento farmacológicoRESUMO
PURPOSE: To describe cases of unilateral cone-rod dysfunction presenting in two middle-aged females. METHODS: This case series highlights two middle-aged female patients with progressive visual decline in one eye. Fundus photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), multi-focal electroretinogram (mfERG), full-field electroretinogram(ffERG), and genetic testing were obtained. RESULTS: In the first patient, mfERG showed an extinguished response and ffERG demonstrated markedly reduced a-wave and b-wave amplitudes (more pronounced under photopic conditions) in the right eye. SD-OCT showed attenuation of the ellipsoid zone of the right eye. Similar findings were appreciated in the second patient. Genetic testing in the first patient identified three heterozygous variants in PRPH2, RCBTB1, and USH2A. The second patient was found to have heterozygous variants in BBS1 and ABCA4. CONCLUSION: These two cases add to the literature of case reports of unilateral cone-rod and rod-cone dystrophies. However, the underlying etiology of the unilateral pattern of cone-rod dysfunction and the significance of the heterozygous mutations found in both cases remains uncertain.
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Distrofias de Cones e Bastonetes , Eletrorretinografia , Adulto , Pessoa de Meia-Idade , Humanos , Feminino , Tomografia de Coerência Óptica/métodos , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras de Vertebrados , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Associadas aos Microtúbulos , Fatores de Troca do Nucleotídeo GuaninaRESUMO
Chimeric antigen receptors (CARs) are fusion proteins that contain antigen-recognition domains and T cell signaling domains. Signaling lymphocytic-activation molecule F7 (SLAMF7) is a promising target for CAR T cell therapies of the plasma cell malignancy multiple myeloma (MM) because SLAMF7 is expressed by MM but not normal nonhematopoietic cells. We designed CARs targeting SLAMF7. We transduced human T cells with anti-SLAMF7 CARs containing either CD28 or 4-1BB costimulatory domains. T cells expressing CD28-containing CARs or 4-1BB-containing CARs recognized SLAMF7 in vitro. SLAMF7-specific cytokine release was higher for T cells expressing CARs with CD28 versus 4-1BB domains. In murine solid tumor and disseminated tumor models, anti-tumor activity of T cells was superior with CD28-containing CARs versus 4-1BB-containing CARs. Because of SLAMF7 expression on some normal leukocytes, especially natural killer cells that control certain viral infections, the inclusion of a suicide gene with an anti-SLAMF7 CAR is prudent. We designed a construct with a CD28-containing anti-SLAMF7 CAR and a suicide gene. The suicide gene encoded a dimerization domain fused to a caspase-9 domain. T cells expressing the anti-SLAMF7 CAR plus suicide-gene construct specifically recognized SLAMF7 in vitro and eliminated tumors from mice. T cells expressing this construct were eliminated on demand by administering the dimerizing agent AP1903 (rimiducid).
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Expressão Gênica , Genes Transgênicos Suicidas/genética , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/métodos , Camundongos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: In the general population, varenicline is consistently shown to be more efficacious for smoking cessation than nicotine replacement therapy (NRT). Current clinical guidelines for the management of smoking during pregnancy recommend against the use of varenicline, whilst supporting the use of NRT. However, little is known about the comparative effectiveness of these smoking cessation therapies among pregnant women. AIMS AND METHODS: Routinely-collected records of all births in two Australian States during 2011 and 2012 were used to create a population-based cohort of women who smoked during the first half of pregnancy. Pharmaceutical dispensing data were used to identify varenicline and nicotine patch dispensings in the first half of pregnancy. Propensity score matching was used to account for the potentially different distribution of confounding factors between the treatment groups. The outcome was defined as smoking abstinence during the second half of pregnancy. RESULTS: After propensity score-matching, our cohort comprised 60 women who used varenicline and 60 who used nicotine patches during the first half of pregnancy. More varenicline users (33.3%, 95% CI: 21.7%-46.7%) quit smoking than nicotine patch users (13.3%, 95% CI: 5.9%-24.6%). The adjusted rate difference was 24.2% (95% CI: 10.2%-38.2%) and the adjusted relative risk was 2.8 (95% CI: 1.4-5.7). CONCLUSIONS: Varenicline was almost three times more effective than nicotine patches in assisting pregnant women to quit smoking. Further studies are needed to corroborate our results. Together with data on the safety of varenicline during pregnancy, evidence regarding the relative benefit of varenicline and NRT during pregnancy important for informing clinical decisions for pregnant smokers. IMPLICATIONS: This study is the first to measure the comparative effectiveness of varenicline and nicotine patches during pregnancy - women using varenicline were almost three times as likely to quit smoking than those using nicotine patches. This study addressed a clinically important question using an observational study, noting that there is an absence of evidence from randomized controlled trials because of the ethical issues associated with including pregnant women in clinical trials of medicines of unknown safety.
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Nicotina , Abandono do Hábito de Fumar , Austrália/epidemiologia , Estudos de Coortes , Feminino , Humanos , Gravidez , Fumar , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/uso terapêuticoRESUMO
Human cytomegalovirus (HCMV) latency and reactivation rely on a complex interplay between cellular differentiation, cell signaling pathways, and viral gene functions. HCMV reactivation in dendritic cells (DCs) is triggered by IL-6 and extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase signaling. However, activation of the same pathway fails to reactivate HCMV in other myeloid cell types, despite this signaling axis being active in those cells. We hypothesized that IL-6-induced ERK activation initiates the changes in chromatin structure required for viral reactivation but that a concomitant signal is necessary to complete the changes in chromatin structure required for gene expression to occur. Using a differential phosphoproteomics approach in cells that do or do not support IL-6-induced viral reactivation, we identified the concomitant activation of an Src family kinase (SFK), hematopoietic cell kinase (HCK), specifically in DCs in response to IL-6. Pharmacological and genetic inhibition of HCK activity indicated that HCK is required for HCMV reactivation. Furthermore, the HCK/SFK activity was linked to recruitment of the monocytic leukemia zinc finger protein (MOZ) histone acetyltransferase to the viral promoter, which promoted histone acetylation after ERK-mediated histone phosphorylation. Importantly, pharmacological and genetic inhibition of MOZ activity prevented reactivation. These results provide an explanation for the selective activation of viral gene expression in DCs by IL-6, dependent on concomitant SFK and ERK signaling. They also reveal a previously unreported role for SFK activity in the regulation of chromatin structure at promoters in eukaryotic cells via MOZ histone acetyltransferase activity.
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Citomegalovirus/genética , Citomegalovirus/fisiologia , Histona Acetiltransferases/metabolismo , Regiões Promotoras Genéticas/genética , Ativação Viral/genética , Quinases da Família src/metabolismo , Células Cultivadas , Humanos , Dedos de ZincoRESUMO
BACKGROUND: Varenicline, bupropion and nicotine replacement therapy (NRT) are three effective pharmacotherapies for smoking cessation, but data about their safety in pregnancy are limited. We assessed the risk of adverse perinatal outcomes and major congenital anomalies associated with the use of these therapies in pregnancy in Australia. METHODS: Perinatal data for 1,017,731 deliveries (2004 to 2012) in New South Wales and Western Australia were linked to pharmaceutical dispensing, hospital admission and death records. We identified 97,875 women who smoked during pregnancy; of those, 233, 330 and 1057 were exposed to bupropion, NRT and varenicline in pregnancy, respectively. Propensity scores were used to match exposed women to those who were unexposed to any smoking therapy (1:10 ratio). Propensity scores and gestational age at exposure were used to match varenicline-exposed to NRT-exposed women (1:1 ratio). Time-dependent Cox proportional hazards models estimated hazard ratios (HR) with 95% confidence intervals (95% CI) for any adverse perinatal event (a composite of 10 unfavourable maternal and neonatal outcomes) and any major congenital anomaly. RESULTS: The risk of any adverse perinatal event was not significantly different between bupropion-exposed and unexposed women (39.2% versus 39.3%, HR 0.93, 95% CI 0.73-1.19) and between NRT-exposed and unexposed women (44.8% vs 46.3%, HR 1.02, 95% CI 0.84-1.23), but it was significantly lower in women exposed to varenicline (36.9% vs 40.1%, HR 0.86, 95% CI 0.77-0.97). Varenicline-exposed infants were less likely than unexposed infants to be born premature (6.5% vs 8.9%, HR 0.72, 95% CI 0.56-0.92), be small for gestational age (11.4% vs 15.4%, HR 0.68, 95% CI 0.56-0.83) and have severe neonatal complications (6.6% vs 8.2%, HR 0.74, 95% CI 0.57-0.96). Among infants exposed to varenicline in the first trimester, 2.9% had a major congenital anomaly (3.5% in unexposed infants, HR 0.91, 95% CI 0.72-1.15). Varenicline-exposed women were less likely than NRT-exposed women to have an adverse perinatal event (38.7% vs 51.4%, HR 0.58, 95% CI 0.33-1.05). CONCLUSIONS: Pregnancy exposure to smoking cessation pharmacotherapies does not appear to be associated with an increased risk of adverse birth outcomes. Lower risk of adverse birth outcomes in varenicline-exposed pregnancies is inconsistent with recommendations that NRT be used in preference to varenicline.
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Agonistas Nicotínicos/uso terapêutico , Abandono do Hábito de Fumar/métodos , Adulto , Estudos de Coortes , Feminino , Humanos , Gravidez , Fatores de RiscoRESUMO
OBJECTIVES: To prepare more accurate population-based Australian birthweight centile charts by using the most recent population data available and by excluding pre-term deliveries by obstetric intervention of small for gestational age babies. DESIGN: Population-based retrospective observational study. SETTING: Australian Institute of Health and Welfare National Perinatal Data Collection. PARTICIPANTS: All singleton births in Australia of 23-42 completed weeks' gestation and with spontaneous onset of labour, 2004-2013. Births initiated by obstetric intervention were excluded to minimise the influence of decisions to deliver small for gestational age babies before term. MAIN OUTCOME MEASURES: Birthweight centile curves, by gestational age and sex. RESULTS: Gestational age, birthweight, sex, and labour onset data were available for 2 807 051 singleton live births; onset of labour was spontaneous for 1 582 137 births (56.4%). At pre-term gestational ages, the 10th centile was higher than the corresponding centile in previous Australian birthweight charts based upon all births. CONCLUSION: Current birthweight centile charts probably underestimate the incidence of intra-uterine growth restriction because obstetric interventions for delivering pre-term small for gestational age babies depress the curves at earlier gestational ages. Our curves circumvent this problem by excluding intervention-initiated births; they also incorporate more recent population data. These updated centile curves could facilitate more accurate diagnosis of small for gestational age babies in Australia.
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Peso ao Nascer , Retardo do Crescimento Fetal/epidemiologia , Recém-Nascido Pequeno para a Idade Gestacional , Austrália/epidemiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez , Valores de Referência , Estudos RetrospectivosRESUMO
The paclitaxel protein-bound particles for injectable suspension (marketed under the brand name Abraxane®) contains nanosized complexes of paclitaxel and albumin. The molecular interaction between paclitaxel and albumin within the higher-order nanostructure is analytically challenging to assess, as is any correlation of differences to differences in therapeutic effect. However, because the higher-order nanostructures may affect the paclitaxel release, a suitable in vitro assay to detect potential differences in paclitaxel release between comparator lots and products is desirable. Herein, solution NMR spectroscopy with a T2-filtering technique was developed to detect paclitaxel signal while suppressing albumin signals to follow the released paclitaxel in the NMR tube upon dilution. The non-invasive nature of NMR allows for precise measurement of a full range of dilution-induced drug release percentage from 14 to 92% without any sample extraction. The critical concentration of the drug product (DP) at 50% of release was 0.63 ± 0.04 mg/mL in PBS buffer. In addition, 2D diffusion ordered NMR spectroscopy (DOSY) results revealed that the released paclitaxel experiencing slightly slowed diffusion rates than free paclitaxel, which was attributed to paclitaxel in equilibrium with albumin-bound states. Collectively, the dilution-based NMR method offered an analytical approach to investigate physicochemical attributes of complex injectable products with minimal needed sample preparation and perturbation to nanoparticle formulation.
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Albuminas/química , Composição de Medicamentos/métodos , Espectroscopia de Ressonância Magnética/métodos , Nanopartículas/química , Paclitaxel/administração & dosagem , Difusão , Paclitaxel/química , Tamanho da Partícula , Padrões de Referência , Solubilidade , SuspensõesRESUMO
BACKGROUND: Maternity populations are becoming increasingly multiethnic. Conflicting findings exist regarding the risk of adverse perinatal outcomes among immigrant mothers from different world regions and which growth charts are most appropriate for identifying the risk of adverse outcomes. OBJECTIVE: To evaluate whether infant mortality and morbidity, and the categorisation of infants as small for gestational age or large for gestational age (SGA or LGA) vary by maternal country of birth, and to assess whether the choice of growth chart alters the risk of adverse outcomes in infants categorised as SGA and LGA. METHODS: A population cohort of 601 299 singleton infants born in Australia to immigrant mothers was compared with 1.7 million infants born to Australian-born mothers, 2004-2013. Infants were categorised as SGA and LGA according to a descriptive Australian population-based birthweight chart (Australia-2012 reference) and the prescriptive INTERGROWTH-21st growth standard. Propensity score reweighting was used for the analysis. RESULTS: Compared to Australian-born infants, infants of mothers from Africa, Philippines, India, other Asia countries, and the Middle East had between 15.4% and 48.1% elevated risk for stillbirth, preterm delivery, or low Apgar score. The association between SGA and LGA and perinatal mortality varied markedly by growth chart and country of birth. Notably, SGA infants from African-born mothers had a relative risk of perinatal mortality of 6.1 (95% CI 4.3, 6.7) and 17.3 (95% CI 12.0, 25.0) by the descriptive and prescriptive charts, respectively. LGA infants born to Australian-born mothers were associated with a 10% elevated risk of perinatal mortality by the descriptive chart compared to a 15% risk reduction by the prescriptive chart. CONCLUSIONS: Country-of-birth-specific variations are becoming increasingly important for providing ethnically appropriate and safe maternity care. Our findings highlight significant variations in risk of adverse perinatal outcomes in immigrant subgroups, and demonstrate how the choice of growth chart alters the quantification of risk associated with being born SGA or LGA.
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Emigrantes e Imigrantes , Gráficos de Crescimento , Disparidades nos Níveis de Saúde , Recém-Nascido Pequeno para a Idade Gestacional , Mortalidade Perinatal/etnologia , Adulto , Austrália/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de RiscoAssuntos
Vitamina D , Humanos , Vitamina D/administração & dosagem , Administração Oral , Toxidermias/etiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Vitaminas/administração & dosagem , Vitaminas/efeitos adversos , Relação Dose-Resposta a DrogaRESUMO
The in vitro drug release in an aqueous medium is a critical performance metric for a sustained release drug product. During long-term release studies, drugs may degrade in the release medium, and such degradation can lead to errors in drug release quantitation. Using dexamethasone as a model drug and LC-MS/MS methods employing dexamethasone-d4 as an internal standard, this study identified that dexamethasone can degrade into 13 major degradation products in phosphate buffered saline (PBS) as a function of time, temperature (25, 37, and 45°C), and light exposure. A putative scheme for dexamethasone degradation pathways in PBS has been proposed. In proof-of-concept studies, the analytical method was used to quantitate dexamethasone and its degradation products during in vitro release studies with sustained release dexamethasone-poly(D,L-lactide-co-glycolide) (PLGA) implants incubated in phosphate buffer saline (PBS). Further, mathematical approaches were developed to estimate drug release from implants after accounting for drug degradation in PBS. The LC-MS/MS analytical method and the mathematical approaches developed could be used for assessing the stability and/or release of dexamethasone during manufacturing, storage, and use of various dosage forms.
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Anti-Inflamatórios/farmacocinética , Dexametasona/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Água/metabolismo , Anti-Inflamatórios/administração & dosagem , Cromatografia Líquida/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Dexametasona/administração & dosagem , Implantes de Medicamento , Liberação Controlada de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Espectrometria de Massas em Tandem/métodosRESUMO
PURPOSE: The main purpose of this study was to evaluate qualitative (Q1) and quantitative (Q2) equivalent oleaginous ophthalmic ointments of tobramycin (TOB) with different physicochemical properties and identify critical process/quality attributes using various in vitro methods of characterization. METHODS: Various sources of petrolatum and TOB, and two mixing methods were employed to generate Q1/Q2 equivalent ointments. Characterization studies included content uniformity, microscopy, modulated temperature differential scanning calorimetry (MTDSC), gas chromatography-mass spectrometry (GC/MS), thermogravimetric analysis (TGA) and rheology. RESULTS: The particle size distribution of TOB influenced the content uniformity of ointments. Differences in the MTDSC endothermic and exothermic peaks of TOB suggested the presence of different polymorphic forms. GC/MS revealed variations in the composition and distribution of linear and branched hydrocarbons of petrolatums. Differences were also observed in the TGA derivative weight loss peaks demonstrating differences in the composition of petrolatum that may be the source of the observed variations in the rheological parameters of the ointments. CONCLUSIONS: Source and composition of the petrolatum played a more critical role in determining the rheological properties compared to the method of preparation. Results demonstrated the impact of the source of TOB, excipients and manufacturing processes on the quality attributes of TOB ophthalmic ointments.
Assuntos
Antibacterianos/administração & dosagem , Tobramicina/administração & dosagem , Administração Oftálmica , Antibacterianos/química , Composição de Medicamentos , Pomadas , Tamanho da Partícula , Vaselina/química , Reologia , Tobramicina/químicaRESUMO
OBJECTIVE: Ovarian cancer is the most lethal gynaecologic cancer. Disease prevention may be the only method to reduce the incidence of ovarian cancer. The Society of Gynecologic Oncology advised that salpingectomies may be an appropriate and feasible strategy for ovarian cancer risk reduction. This study conducted an economic evaluation from a societal perspective of bilateral salpingectomies versus conventional sterilization techniques in the prevention of ovarian cancer. STUDY DESIGN: We performed a micro-cost analysis comparing laparoscopic tubal coagulation, tubal clips and bilateral salpingectomies at the Michael Garron Hospital, formerly the Toronto East General Hospital, from 2015 to 2016. A Markov model was used in the cost-effectiveness and cost-utility analyses on these surgical procedures in ovarian cancer prevention. Costs were derived for the number ovarian cancer cases observed per sterilization method, cancer treatment, and associated procedural costs over each cancer patient's lifetime. The number of bilateral salpingectomies required to prevent an additional ovarian cancer case with the recommended treatment was also estimated. RESULTS: Bilateral salpingectomies performed at the Michael Garron Hospital generated savings of $7823 per life-year gained (95% CI $3248-$10 190; incremental cost [ΔC] -$907, incremental effect [ΔE] 0.11 life-years gained) compared with tubal clips and savings of $6315 per life-year gained (95% CI -$6360 to $9342; ΔC -$755, ΔE 0.11 life-years gained) compared with tubal coagulation. Most importantly, for every 150 bilateral salpingectomies performed, one case of ovarian cancer may be prevented. CONCLUSION: Laparoscopic bilateral salpingectomy is the dominant, cost-effective surgical strategy when compared to tubal clips and tubal coagulation to prevent ovarian cancer. Laparoscopic bilateral salpingectomies reduce costs and enhance quality-adjusted life-years relative to the two alternative treatments.
Assuntos
Serviços de Planejamento Familiar/normas , Neoplasias Ovarianas/prevenção & controle , Procedimentos Cirúrgicos Profiláticos/economia , Salpingectomia/economia , Esterilização Tubária/economia , Análise Custo-Benefício , Feminino , Humanos , Modelos Econômicos , Neoplasias Ovarianas/economia , Gravidez , Gravidez Ectópica/economia , Gravidez Ectópica/etiologia , Esterilização Tubária/efeitos adversos , Esterilização Tubária/métodosRESUMO
Investments in community-based HIV prevention programs in Ontario over the past two and a half decades are assumed to have had an impact on the HIV epidemic, but they have never been systematically evaluated. To help close this knowledge gap, we conducted a macro-level evaluation of investment in Ontario HIV prevention programs from the payer perspective. Our results showed that, from 1987 to 2011, province-wide community-based programs helped to avert a total of 16,672 HIV infections, saving Ontario's health care system approximately $6.5 billion Canadian dollars (range 4.8-7.5B). We also showed that these community-based HIV programs were cost-saving: from 2005 to 2011, every dollar invested in these programs saved about $5. This study is an important first step in understanding the impact of investing in community-based HIV prevention programs in Ontario and recognizing the impact that these programs have had in reducing HIV infections and health care costs.