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1.
Nature ; 594(7862): 265-270, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34040261

RESUMO

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine1,2. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes3. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation4,5. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.


Assuntos
Blockchain , Tomada de Decisão Clínica/métodos , Confidencialidade , Conjuntos de Dados como Assunto , Aprendizado de Máquina , Medicina de Precisão/métodos , COVID-19/diagnóstico , COVID-19/epidemiologia , Surtos de Doenças , Feminino , Humanos , Leucemia/diagnóstico , Leucemia/patologia , Leucócitos/patologia , Pneumopatias/diagnóstico , Aprendizado de Máquina/tendências , Masculino , Software , Tuberculose/diagnóstico
2.
Hum Mol Genet ; 32(10): 1741-1752, 2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-36715614

RESUMO

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable-similar to those of higher risk of coronary artery disease and type 2 diabetes-and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.


Assuntos
Diabetes Mellitus Tipo 2 , Doença de Huntington , Humanos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/genética , Valores de Referência , Proteína Huntingtina/genética , Doença de Huntington/patologia , Lipoproteínas , Lipoproteínas LDL/genética , Expansão das Repetições de Trinucleotídeos/genética
3.
Mol Psychiatry ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811690

RESUMO

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.

4.
Med J Malaysia ; 79(Suppl 1): 110-116, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38555894

RESUMO

INTRODUCTION: Cleaners perform a vital role in environmental health by keeping the place clean, but they are also exposed to various hazards. Yet, there is a lack of effective and accessible occupational safety standard measures, thus making this to be difficult to monitor the long-term health effects of cleaners. This study aims to determine the respirable dust exposure on respiratory symptoms among cleaners in a public university in Selangor. MATERIALS AND METHODS: A cross-sectional study was carried out among 51 cleaners. The respondents' background information and respiratory symptoms were gathered using a series of standardised questionnaires validated by the American Thoracic Society (ATS-DLD-78-A). The 8- hour respirable dust exposure to cleaners was measured using an air sampling pump (Gillian & Sensodyne Gil Air 3). RESULTS: The mean of respirable dust was lower than permissible exposure limit with 0.63±0.57mg/m3. The respiratory symptoms among the cleaners showed no significant association between cough, phlegm, and breathing difficulties with working tenure. Meanwhile, wheezing and coughing with phlegm have an almost significant association with working tenure among cleaners with (Χ2=1.00, p=0.08) and (Χ2=1.00, p=0.07) respectively. Exposure to respirable dust has exhibited 6 times the prevalence of coughing with phlegm among cleaners (PR=6.28, 95% CI: 0.44, 89.38). CONCLUSION: The findings of this study demonstrated that the cleaners were significantly affected by the respirable dust. The cleaners' working environment has caused them to be exposed to respirable dust.


Assuntos
Poluentes Ocupacionais do Ar , Pneumopatias , Exposição Ocupacional , Humanos , Exposição Ocupacional/efeitos adversos , Poluentes Ocupacionais do Ar/análise , Estudos Transversais , Malásia/epidemiologia , Universidades , Tosse/epidemiologia , Tosse/etiologia , Poeira/análise
5.
Hum Brain Mapp ; 44(7): 2701-2711, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36852616

RESUMO

Visual impairment and retinal neurodegeneration are intrinsically connected and both have been associated with cognitive impairment and brain atrophy, but the underlying mechanisms remain unclear. To investigate whether transneuronal degeneration is implicated, we systematically assessed the relation between visual function and retinal, visual pathway, hippocampal and brain degeneration. We analyzed baseline data from 3316 eligible Rhineland Study participants with visual acuity (VA), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) data available. Regional volumes, cortical volume, and fractional anisotropy (FA) were derived from T1-weighted and diffusion-weighted 3 T MRI scans. Statistical analyses were performed using multivariable linear regression and structural equation modeling. VA and ganglion cell layer (GCL) thinning were both associated with global brain atrophy (SD effect size [95% CI] -0.090 [-0.118 to -0.062] and 0.066 [0.053-0.080], respectively), and hippocampal atrophy (-0.029 [-0.055 to -0.003] and 0.114 [0.087-0.141], respectively). The effect of VA on whole brain and hippocampal volume was partly mediated by retinal neurodegeneration. Similarly, the effect of retinal neurodegeneration on brain and hippocampal atrophy was mediated through intermediate visual tracts, accounting for 5.2%-23.9% of the effect. Visual impairment and retinal neurodegeneration were robustly associated with worse brain atrophy, FA, and hippocampal atrophy, partly mediated through disintegration of intermediate visual tracts. Our findings support the use of OCT-derived retinal measures as markers of neurodegeneration, and indicate that both general and transneuronal neurodegeneration along the visual pathway, partly reflecting visual impairment, account for the association between retinal neurodegeneration and brain atrophy.


Assuntos
Encéfalo , Retina , Humanos , Retina/patologia , Encéfalo/patologia , Imageamento por Ressonância Magnética , Transtornos da Visão , Atrofia/patologia
6.
Psychol Med ; 53(4): 1611-1619, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-34412712

RESUMO

BACKGROUND: Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. METHODS: Analyses were based on the data of 2956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. RESULTS: Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. CONCLUSIONS: There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.


Assuntos
Movimentos Oculares , Esquizofrenia , Humanos , Esquizofrenia/genética , Endofenótipos , Estudo de Associação Genômica Ampla , Estudos de Coortes , Fatores de Risco
7.
Med J Malaysia ; 78(2): 225-233, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36988535

RESUMO

INTRODUCTION: Dementia is a global challenge for healthcare systems, including Malaysia. Despite evidence-based Clinical Practice Guidelines (CPG) for dementia management in primary care, detection is poor. Improving detection rates requires understanding current practice and influencing factors. This study aims to assess the practice of cognitive evaluation among primary care practitioners (PCPs) and its associated factors, as well as its correlation with their knowledge and attitudes towards early dementia diagnosis. MATERIALS AND METHODS: A cross-sectional study conducted online, using Google FormTM recruited 207 Medical Officers from 14 public primary health centres, with a response rate of 74%. The Knowledge, Attitude and Practice Questionnaire for Family Physicians (KAPQFP) was used to assess PCPs' knowledge, attitude and practice in dementia care. Items in each domain were scored on a 4-point Likert scale, with scores ranging from 1 to 4. Each domain's mean score was divided by 4 and converted to a scale of 100, with higher scores indicating better knowledge, attitude and practice. Bivariate analyses were conducted to determine the factors associated with cognitive evaluation practice. RESULTS: The overall mean practice score was 3.53±0.52 (88.3%), which is substantially higher than the mean score for perceived competency and knowledge of 2.46±0.51 (61.5%). The mean score for attitude towards dementia and collaboration with nurses and other healthcare professionals was 3.36±0.49 (84.0%) and 3.43±0.71 (85.8%), respectively. PCPs with prior dementia training showed better practice (p=0.006), as did PCPs with longer primary care work experience (p=0.038). A significant positive association was found between knowledge-practice ((rs=0.207, p=0.003), attitude towards dementia practice ((rs=0.478, p<0.001), and attitude towards collaboration with other healthcare professionals-practice (rs= 0.427, p<0.001). Limited time and inadequate knowledge regarding dementia diagnosis and cognitive evaluation tools were among the reasons cognitive evaluations were not performed. CONCLUSION: PCPs demonstrated better practice of cognitive evaluation, as compared to their knowledge and attitude. Given that their perceived competency and knowledge on dementia diagnosis is low and is positively associated with their practice, it is crucial to implement a comprehensive dementia training to enhance their knowledge and confidence on early detection of cognitive decline and cognitive evaluation in order to achieve better dementia detection in primary care.


Assuntos
Atitude do Pessoal de Saúde , Demência , Humanos , Estudos Transversais , Pessoal de Saúde , Demência/diagnóstico , Atenção Primária à Saúde
8.
Malays J Pathol ; 45(1): 135-138, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37119254

RESUMO

INTRODUCTION: Mixed warm and cold autoimmune haemolytic anaemia (AIHA) secondary to COVID-19 is rarely reported. CASE REPORT: We present a case of a 65-year-old Malay lady with no known medical illness, who was admitted for COVID-19 category 3 and mixed warm and cold AIHA. She presented with lethargy, productive cough and on and off fever. Blood investigations showed severe anaemia with spurious macrocytosis, increased lactate dehydrogenase (LDH) and total bilirubin with indirect bilirubin predominance. On full blood picture (FBP), there was normocytic normochromic anaemia with reticulocytosis, red blood cells clumping and NRBC's were seen. Both anti-IgG and anti-C3d were positive for monospecific Coombs test. For indirect Coombs test, auto-IgG and cold agglutinin were detected. DISCUSSION: These findings were consistent with mixed warm and cold AIHA. She was treated with intravenous methylprednisolone, before being changed to high dose oral prednisolone. A total of 3 units packed cells were transfused.


Assuntos
Anemia Hemolítica Autoimune , COVID-19 , Feminino , Humanos , Idoso , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/tratamento farmacológico , COVID-19/complicações , Prednisolona/uso terapêutico
9.
Med J Malaysia ; 77(2): 217-223, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35338630

RESUMO

INTRODUCTION: Oral health care is an important indicator of the overall wellbeing of pregnant women. Optimizing the utilisation of dental care during pregnancy goes a long way in ensuring an improved and optimal pregnancy outcome. OBJECTIVE: This study aimed to assess the practices of primary care doctors on oral health care in pregnancy and its association with the level of knowledge and attitude. MATERIALS AND METHODS: This cross-sectional study was conducted among primary care doctors in nine public health clinics in Petaling District. A self-administered questionnaire consisting of socio-demographic characteristics, knowledge, attitude, and practices related to oral health care in pregnancy was used. RESULTS: A total of 138 primary care doctors participated in this study with a response rate of 98.0%. Most primary care doctors frequently advised patients not to delay dental visits until after pregnancy (84.8%), advised patients to see dentists (69.7%), and referred patients to dentists during pregnancy (63.6%). However, only 18.9% perform assessments routinely to detect oral health issues. The median (IQR) score for knowledge was 17(4) (range score: 0-23) and attitude was 23(3) (range score: 6-30). Knowledge median score (p:0.026) and practices of referring patients to dentists (p:0.017) were significantly associated. There was a positive correlation between overall practices of primary care doctors and their age, years of experience, and knowledge. CONCLUSION: Most primary care doctors frequently advise and refer pregnant patients to see dentist. Primary care doctors with higher knowledge score, who were older and had more experience, had better overall practices on oral health care in pregnancy.


Assuntos
Atitude do Pessoal de Saúde , Saúde Bucal , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Gravidez , Resultado da Gravidez , Atenção Primária à Saúde , Inquéritos e Questionários
10.
Hum Brain Mapp ; 42(8): 2434-2444, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33769661

RESUMO

Metabolic syndrome (MetS) is a major public health burden worldwide and associated with brain abnormalities. Although insulin resistance is considered a pivotal feature of MetS, its role in the pathogenesis of MetS-related brain alterations in the general population is unclear. Therefore, in 973 participants (mean age 52.5 years) of the population-based Rhineland Study, we assessed brain morphology in relation to MetS and insulin resistance, and evaluated to what extent the pattern of structural brain changes seen in MetS overlap with those associated with insulin resistance. Cortical reconstruction and volumetric segmentation were obtained from high-resolution brain images at 3 Tesla using FreeSurfer. The relations between metabolic measures and brain structure were assessed through (generalized) linear models. Both MetS and insulin resistance were associated with smaller cortical gray matter volume and thickness, but not with white matter or subcortical gray matter volume. Age- and sex-adjusted vertex-based brain morphometry demonstrated that MetS and insulin resistance were related to cortical thinning in a similar spatial pattern. Importantly, no independent effect of MetS on cortical gray matter was observed beyond the effect of insulin resistance. Our findings suggest that addressing insulin resistance is critical in the prevention of MetS-related brain changes in later life.


Assuntos
Córtex Cerebral/patologia , Substância Cinzenta/patologia , Resistência à Insulina , Síndrome Metabólica/patologia , Substância Branca/patologia , Adulto , Idoso , Córtex Cerebral/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Resistência à Insulina/fisiologia , Imageamento por Ressonância Magnética , Masculino , Síndrome Metabólica/diagnóstico por imagem , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem
11.
J Appl Microbiol ; 130(5): 1630-1644, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33073430

RESUMO

AIMS: This study was applied to evaluate the usefulness of a high-throughput sample preparation protocol prior to the application of quantitative real-time PCR (qPCR) for the early diagnosis of bloodstream and pyogenic infections in humans and animals compared to matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and classical culture. METHODS AND RESULTS: Saponin-mediated selective host cell lysis combined with DNase-1 was applied for processing of whole blood and pus clinical samples collected from suspected cases of septicaemia and pyogenic infections in humans and animals. The pre-PCR processing strategy enabled the recovery of microbial cells with no changes in their colony forming units immediately after the addition of saponin. DNase-1 was efficient for removing the DNAs from the host cells as well as dead cells with damaged cell membranes. The metagenomic qPCR and MALDI-TOF MS could identify the bacterial community of sepsis at species level with a concordance of 97·37% unlike the conventional culture. According to qPCR results, Staphylococcus aureus (24·24%) was predominated in animal pyogenic infections, whereas Klebsiella pneumonia (31·81%) was commonly detected in neonatal sepsis. CONCLUSIONS: Saponin combined with DNase-1 allowed the efficient recovery of microbial DNA from blood and pus samples in sepsis using qPCR assay. SIGNIFICANCE AND IMPACT OF THE STUDY: Metagenomic qPCR could identify a broad range of bacteria directly from blood and pus with more sensitivity, higher discriminatory power and shorter turnaround time than those using MALDI-TOF MS and conventional culture. This might allow a timely administration of a prompt treatment.


Assuntos
Bactérias/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sepse/diagnóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Bactérias/química , Bactérias/genética , Desoxirribonuclease I , Humanos , Saponinas , Sepse/microbiologia , Manejo de Espécimes , Supuração/diagnóstico , Supuração/microbiologia
12.
J Stroke Cerebrovasc Dis ; 29(8): 104875, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689648

RESUMO

INTRODUCTION: Facilitating stroke survivors and their caregivers to lead a fulfilling life after stroke requires service providers to think about their different needs. Poor post stroke care may lead to unmet needs in stroke survivors and stroke caregivers. This may compromise them in leading their lives optimally after stroke. OBJECTIVES & METHODOLOGY: This systematic narrative review examines articles published from 1990 to 2017, generated from Ovid, MEDLINE, CINAHL, and PubMed. The search was also supplemented by an examination of reference lists for related articles via Scopus. We included 105 articles. FINDINGS: We found that the type of unmet needs in stroke survivors and the contributing factors were substantially different from their caregivers. The unmet needs in stroke survivors ranged from health-related needs to re-integration into the community; while the unmet needs in stroke caregivers ranged from information needs to support in caring for the stroke survivors and caring for themselves. Additionally, the unmet needs in both groups were associated with different factors. CONCLUSION: More research is required to understand the unmet needs of stroke survivors and stroke caregivers to improve the overall post-stroke care services.


Assuntos
Cuidadores/psicologia , Necessidades e Demandas de Serviços de Saúde , Assistência de Longa Duração , Avaliação das Necessidades , Qualidade de Vida , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Sobreviventes/psicologia , Adaptação Psicológica , Idoso , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Alta do Paciente , Recuperação de Função Fisiológica , Autocuidado , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Resultado do Tratamento
13.
Med J Malaysia ; 75(4): 372-378, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32723997

RESUMO

INTRODUCTION: Biosimilar insulins have the potential to increase access to treatment among patients with diabetes mellitus (DM), reduce treatment costs, and expand market competition. There are no published studies evaluating the performance of biosimilar insulins in routine clinical practice in Asia. This study assessed the safety and effectiveness of biphasic isophane insulin injection in Malaysian DM patients. MATERIALS AND METHODS: In this open label, single-arm, observational, post marketing study, patients received biphasic isophane insulin injection as per the Prescribing Information; and were assessed for safety (adverse events including hypoglycaemia), effectiveness (glycosylated haemoglobin [HbA1c]; fasting blood sugar, [FBS]; and patient's condition by patient and physician) over a period of 24 weeks. RESULTS: Adult male and female diabetes patients (N=119; type 2 DM, n=117) with a mean (SD) diabetes duration of 13 years were included. No new safety signals have been identified. Significant reduction in HbA1c was observed at weeks 12 and 24 (mean [SD] - baseline: 9.6% [1.9]; Week 12: 9.0% [1.7] and at Week 24: 9.1% [1.7]; p < 0.001). There were 10 serious and 9 non-serious adverse events reported in the study. Expected mild events included hypoglycaemia and injection site pruritus. However, the majority of the adverse events were non-study drug related events. No deaths were reported during the study. DISCUSSION: Biphasic isophane insulin injection was well tolerated with no new safety concerns. It was found effective in post- marketing studies conducted in routine clinical settings when administered in DM patients in this study.


Assuntos
Medicamentos Biossimilares , Insulinas Bifásicas/efeitos adversos , Insulinas Bifásicas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Segurança do Paciente , Adulto , Povo Asiático , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Vigilância de Produtos Comercializados , Resultado do Tratamento
14.
Int J Obes (Lond) ; 43(3): 440-449, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30120431

RESUMO

BACKGROUND: The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this 'missing heritability' problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS. SUBJECTS AND METHODS: We determined the cytosine-adenine-guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models. RESULTS: We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation. CONCLUSIONS: Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.


Assuntos
Índice de Massa Corporal , Doenças do Sistema Nervoso Central/genética , Obesidade , Polimorfismo Genético/genética , Sequências Repetitivas de Ácido Nucleico/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Peptídeos
15.
Ann Neurol ; 82(3): 479-483, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28779551

RESUMO

Unintended weight loss is a hallmark of Huntington disease (HD), but it is unknown to what extent weight loss impacts the rate of disease progression. Therefore, using longitudinal data from the Enroll-HD study, we assessed the association between baseline body mass index (BMI) and the rate of clinical progression in 5,821 HD mutation carriers. We found that high baseline BMI was associated with a significantly slower rate of functional, motor, and cognitive deterioration (all p < 0.001), independent of mutant HTT CAG repeat size. Our findings provide strong rationale for exploration of systemic metabolism as a therapeutic target in HD. Ann Neurol 2017;82:479-483.


Assuntos
Índice de Massa Corporal , Peso Corporal/fisiologia , Doença de Huntington/fisiopatologia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Doença de Huntington/patologia , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Redução de Peso/fisiologia
17.
J Infect Dis ; 213(11): 1743-51, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26908756

RESUMO

BACKGROUND: Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. METHODS: Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. RESULTS: FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. CONCLUSIONS: FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. CLINICAL TRIALS REGISTRATION: NCT02044198.


Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Membrana/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adulto , ELISPOT , Eritrócitos/parasitologia , Feminino , Humanos , Imunogenicidade da Vacina , Estágios do Ciclo de Vida , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Plasmodium falciparum/fisiologia , Adulto Jovem
18.
J Infect Dis ; 214(5): 762-71, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27296848

RESUMO

BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION: NCT01857869.


Assuntos
Esquemas de Imunização , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Malária/prevenção & controle , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Adolescente , Adulto , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/imunologia , Afinidade de Anticorpos , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias Leves de Imunoglobulina/biossíntese , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
J Food Sci Technol ; 54(12): 4129-4134, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29085156

RESUMO

The influence of drying methods on selected mechanical properties and qualities of MR219 rice variety has been investigated. The results showed significant effects of drying methods on bending strength and head rice yields while the average bending strength of paddy were 28.6-31.8 MPa. The effect of drying methods on apparent modulus of elasticity of rice was not significant (204.5-222.4 MPa). The fracture energy of rice varied significantly under control drying but not with industrial drying methods. Higher temperature in drying by IBD contributed in making the grains tougher, where the effect of FBD temperature was positive toward the development of fracture energy inside rice kernel. IBD at temperature above 40 °C resulted in lower bending strength in rice kernels which affected head rice yield. Two stage paddy drying practices with FBD using temperature of 115-125 °C as first stage is still acceptable, and inclined bed dryer either as single stage or as second stage after FBD should be operated at temperature of <40 °C to maintain head rice yield. The whiteness and milling recovery of rice achieved from different drying methods were comparable.

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