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2.
PLoS Med ; 21(4): e1004369, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38607977

RESUMO

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.


Assuntos
Diabetes Mellitus , Hipoglicemia , Humanos , Idoso , Registros Eletrônicos de Saúde , Estudos Retrospectivos , Hipoglicemia/diagnóstico , Hipoglicemia/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Hospitalização , Aprendizado de Máquina
3.
Acc Chem Res ; 56(14): 2015-2025, 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37384820

RESUMO

ConspectusElectrochemistry has a central role in addressing the societal issues of our time, including the United Nations' Sustainable Development Goals (SDGs) and beyond. At a more basic level, however, elucidating the nature of electrode-electrolyte interfaces is an ongoing challenge due to many reasons, but one obvious reason is the fact that the electrode-electrolyte interface is buried by a thick liquid electrolyte layer. This fact would seem to preclude, by default, the use of many traditional characterization techniques in ultrahigh vacuum surface science due to their incompatibility with liquids. However, combined UHV-EC (ultrahigh vacuum-electrochemistry) approaches are an active area of research and provide a means of bridging the liquid environment of electrochemistry to UHV-based techniques. In short, UHV-EC approaches are able to remove the bulk electrolyte layer by performing electrochemistry in the liquid environment of electrochemistry followed by sample removal (referred to as emersion), evacuation, and then transfer into vacuum for analysis.Through this Account, we highlight our group's activities using UHV-EC to bridge electrochemistry with UHV-based X-ray and ultraviolet photoelectron spectroscopy (XPS/UPS) and scanning tunneling microscopy (STM). We provide a background and overview of the UHV-EC setup, and through illustrative examples, we convey what sorts of insights and information can be obtained. One notable advance is the use of ferrocene-terminated self-assembled monolayers as a spectroscopic molecular probe, allowing the electrochemical response to be correlated with the potential-dependent electronic and chemical state of the electrode-monolayer-electrolyte interfacial region. With XPS/UPS, we have been able to probe changes in the oxidation state, valence structure, and also the so-called potential drop across the interfacial region. In related work, we have also spectroscopically probed changes in the surface composition and screening of the surface charge of oxygen-terminated boron-doped diamond electrodes emersed from high-pH solutions. Finally, we will give readers a glimpse into our recent progress regarding real-space visualizations of electrodes following electrochemistry and emersion using UHV-based STM. We begin by demonstrating the ability to visualize large-scale morphology changes, including electrochemically induced graphite exfoliation and the surface reconstruction of Au surfaces. Taking this further, we show that in certain instances atomically resolved specifically adsorbed anions on metal electrodes can be imaged. In all, we anticipate that this Account will stimulate readers to advance UHV-EC approaches further, as there is a need to improve our understanding concerning the guidelines that determine applicable electrochemical systems and how to exploit promising extensions to other UHV methods.

4.
Exp Eye Res ; : 110056, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39179169

RESUMO

Fuchs endothelial corneal dystrophy (FECD), a degenerative corneal condition, is characterized by the droplet-like accumulation of the extracellular matrix, known as guttae and progressive loss of corneal endothelial cells ultimately leading to visual distortion and glare. FECD can be influenced by environmental stressors and genetic conditions. However, the role of mitochondrial dysfunction for advancing FECD pathogenesis is not yet fully studied. Therefore, in the present study we sought to determine whether a combination of environmental stressors (ultraviolet-A (UVA) light and cigarette smoke condensate (CSC)) can induce mitochondrial dysfunction leading to FECD. We also investigated if MitoQ, a water-soluble antioxidant, can target mitochondrial dysfunction induced by UVA and CSC in human corneal endothelial cells mitigating FECD pathogenesis. We modeled the FECD by increasing exogenous oxidative stress with CSC (0.2%), UVA (25J/cm2) and a combination of UVA+CSC and performed a temporal analysis of their cellular and mitochondrial effects on HCEnC-21T immortalized cells in vitro before and after MitoQ (0.05 µM) treatment. Interestingly, we observed that a combination of UVA+CSC exposure increased mitochondrial ROS and fragmentation leading to a lower mitochondrial membrane potential and increased levels of cytochrome c release leading to apoptosis and cell death. MitoQ intervention successfully mitigated these effects and restored cell viability. The UVA+CSC model could be used to study stress induced mitochondrial dysfunction. Additionally, MitoQ can serve as a viable antioxidant in attenuating mitochondrial dysfunction, underscoring its potential as a molecular-focused treatment approach to combat FECD pathogenesis.

5.
Haemophilia ; 30(3): 609-616, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38523289

RESUMO

BACKGROUND: The healthcare systems in Asia vary greatly due to the socio-economic and cultural diversities which impact haemophilia management. METHODS: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region. FINDINGS: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under-diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability. CONCLUSION: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi-stakeholder involvement are needed.


Assuntos
Hemofilia A , Humanos , Hemofilia A/terapia , Hemofilia A/epidemiologia , Ásia/epidemiologia , Prevalência , Atenção à Saúde , Hemofilia B/terapia , Hemofilia B/epidemiologia
6.
Dement Geriatr Cogn Disord ; : 1-15, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39047685

RESUMO

INTRODUCTION: Despite the high prevalence of cognitive impairment or dementia post-coronary artery bypass grafting (CABG), the incidence of cognitive impairment or dementia post-CABG in contemporary practice is currently unclear. Therefore, this paper aims to investigate the incidence and associated risk factors of cognitive impairment or dementia in patients' post-CABG. METHODS: A systematic search across three databases (PubMed, SCOPUS, and Embase) was conducted for studies published in or after 2013 that reported cognitive impairment or dementia post-CABG. Subgroup analyses and meta-regression by risk factors were performed to determine their influence on the results. RESULTS: This analysis included 23 studies with a total of 2,620 patients. The incidence of cognitive impairment or dementia less than 1 month, 2 to 6 months, and more than 12 months post-CABG was 35.96% (95% confidence interval [CI]: 28.22-44.51, I2 = 87%), 21.33% (95% CI: 13.44-32.15, I2 = 88%), and 39.13% (95% CI: 21.72-58.84, I2 = 84%), respectively. Meta-regression revealed that studies with more than 80% of the cohort diagnosed with hypertension were significantly associated with incidence of cognitive impairment or dementia less than 1 month post-CABG. CONCLUSION: This meta-analysis demonstrates a high incidence of cognitive impairment or dementia in patients' post-CABG in contemporary practice, particularly less than 1 month post-CABG and more than 12 months post-CABG. We found that hypertension was a significant risk factor in the short-term (less than 1 month) follow-up period for cognitive impairment or dementia post-CABG. Future research should be done to assess strategies to reduce cognitive impairment post-CABG.

7.
Cereb Cortex ; 33(7): 3523-3537, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-35945687

RESUMO

Persistent delay-period activity in prefrontal cortex (PFC) has long been regarded as a neural signature of working memory (WM). Electrophysiological investigations in macaque PFC have provided much insight into WM mechanisms; however, a barrier to understanding is the fact that a portion of PFC lies buried within the principal sulcus in this species and is inaccessible for laminar electrophysiology or optical imaging. The relatively lissencephalic cortex of the New World common marmoset (Callithrix jacchus) circumvents such limitations. It remains unknown, however, whether marmoset PFC neurons exhibit persistent activity. Here, we addressed this gap by conducting wireless electrophysiological recordings in PFC of marmosets performing a delayed-match-to-location task on a home cage-based touchscreen system. As in macaques, marmoset PFC neurons exhibited sample-, delay-, and response-related activity that was directionally tuned and linked to correct task performance. Models constructed from population activity consistently and accurately predicted stimulus location throughout the delay period, supporting a framework of delay activity in which mnemonic representations are relatively stable in time. Taken together, our findings support the existence of common neural mechanisms underlying WM performance in PFC of macaques and marmosets and thus validate the marmoset as a suitable model animal for investigating the microcircuitry underlying WM.


Assuntos
Callithrix , Córtex Pré-Frontal , Animais , Callithrix/fisiologia , Córtex Pré-Frontal/fisiologia , Córtex Cerebral/fisiologia , Memória de Curto Prazo/fisiologia , Macaca
8.
Clin Exp Pharmacol Physiol ; 51(6): e13869, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38725222

RESUMO

Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness. To test our hypothesis, we evaluated the effect of EPO in healthy rats and rats with NAFLD induced by a high-fat, high-carbohydrate (HFHC) diet. After 12 weeks on the HFHC diet, NAFLD rats showed lower erythroid response to EPO treatment than healthy rats. We, then, determined that the primary cause of EPO hyporesponsiveness could be iron deficiency associated with inflammation, which reduces erythroid cell production. Specifically, the concentrations of hepcidin, ferritin, transferrin and white blood cells in NAFLD rats were 12.8-, 16.4-, 2.51- and 1.40-fold higher than those in healthy rats, respectively. However, erythroid cell types in the bone marrow of NAFLD rats were significantly reduced. In conclusion, our data suggest that NAFLD could be a risk factor for EPO responsiveness, which is attributed to functional iron deficiency associated with inflammation.


Assuntos
Eritropoetina , Hepatopatia Gordurosa não Alcoólica , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Masculino , Ratos Sprague-Dawley , Dieta Hiperlipídica/efeitos adversos , Hepcidinas/metabolismo
9.
BMC Nephrol ; 25(1): 164, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745129

RESUMO

BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. CASE PRESENTATION: A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). CONCLUSION: Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Fator H do Complemento , Doença de Still de Início Tardio , Humanos , Doença de Still de Início Tardio/complicações , Doença de Still de Início Tardio/diagnóstico , Doença de Still de Início Tardio/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/imunologia , Fator H do Complemento/imunologia , Adulto , Masculino , Autoanticorpos/sangue , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/complicações , Síndrome de Ativação Macrofágica/imunologia
10.
Lifetime Data Anal ; 30(1): 34-58, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36821062

RESUMO

Survival causal effect estimation based on right-censored data is of key interest in both survival analysis and causal inference. Propensity score weighting is one of the most popular methods in the literature. However, since it involves the inverse of propensity score estimates, its practical performance may be very unstable, especially when the covariate overlap is limited between treatment and control groups. To address this problem, a covariate balancing method is developed in this paper to estimate the counterfactual survival function. The proposed method is nonparametric and balances covariates in a reproducing kernel Hilbert space (RKHS) via weights that are counterparts of inverse propensity scores. The uniform rate of convergence for the proposed estimator is shown to be the same as that for the classical Kaplan-Meier estimator. The appealing practical performance of the proposed method is demonstrated by a simulation study as well as two real data applications to study the causal effect of smoking on survival time of stroke patients and that of endotoxin on survival time for female patients with lung cancer respectively.


Assuntos
Modelos Estatísticos , Fumar , Humanos , Feminino , Interpretação Estatística de Dados , Simulação por Computador , Pontuação de Propensão
11.
Am J Physiol Cell Physiol ; 325(6): C1401-C1414, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37842750

RESUMO

Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We addressed here whether cardioplegia essential for cardiopulmonary bypass surgery activates Nrf2, a transcription factor regulating the expression of antioxidant and detoxification genes. With commonly used cardioplegic solutions, high K+, low K+, Del Nido (DN), histidine-tryptophan-ketoglutarate (HTK), and Celsior (CS), we found that DN caused a significant increase of Nrf2 protein in AC16 human cardiomyocytes. Tracing the ingredients in DN led to the discovery of KCl at the concentration of 20-60 mM capable of significant Nrf2 protein induction. The antioxidant response element (ARE) luciferase reporter assays confirmed Nrf2 activation by DN or KCl. Transcriptomic profiling using RNA-seq revealed that oxidation-reduction as a main gene ontology group affected by KCl. KCl indeed elevated the expression of classical Nrf2 downstream targets, including TXNRD1, AKR1C, AKR1B1, SRXN1, and G6PD. DN or KCl-induced Nrf2 elevation is Ca2+ concentration dependent. We found that KCl decreased Nrf2 protein ubiquitination and extended the half-life of Nrf2 from 17.8 to 25.1 mins. Knocking out Keap1 blocked Nrf2 induction by K+. Nrf2 induction by DN or KCl correlates with the protection against reactive oxygen species generation or loss of viability by H2O2 treatment. Our data support that high K+ concentration in DN cardioplegic solution can induce Nrf2 protein and protect cardiomyocytes against oxidative damage.NEW & NOTEWORTHY Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We report here that Del Nido cardioplegic solution or potassium is an effective inducer of Nrf2 transcription factor, which controls the antioxidant and detoxification response. This indicates that Del Nido solution is not only essential for open heart surgery but also exhibits cardiac protective activity.


Assuntos
Doença da Artéria Coronariana , Traumatismo por Reperfusão , Humanos , Soluções Cardioplégicas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2/genética , Miócitos Cardíacos , Potássio , Antioxidantes/farmacologia , Peróxido de Hidrogênio/farmacologia , Parada Cardíaca Induzida/métodos , Estresse Oxidativo , Aldeído Redutase
12.
EMBO J ; 38(18): e100811, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31436334

RESUMO

The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single-cell RNA sequencing on 20,009 cells from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct cell populations representing all known neural retinal cells: rod photoreceptors, cone photoreceptors, Müller glia, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, astrocytes, and microglia. Our data captured molecular profiles for healthy and putative early degenerating rod photoreceptors, and revealed the loss of MALAT1 expression with longer post-mortem time, which potentially suggested a novel role of MALAT1 in rod photoreceptor degeneration. We have demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to understanding retinal biology and disease.


Assuntos
Degeneração Neural/genética , RNA Longo não Codificante/genética , Retina/química , Análise de Célula Única/métodos , Transcriptoma , Autopsia , Análise por Conglomerados , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Especificidade de Órgãos , Células Fotorreceptoras Retinianas Bastonetes/química , Análise de Sequência de RNA , Aprendizado de Máquina não Supervisionado
13.
J Exp Bot ; 74(17): 5307-5326, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37279568

RESUMO

High-throughput phenotyping (HTP) has expanded the dimensionality of data in plant research; however, HTP has resulted in few novel biological discoveries to date. Field-based HTP (FHTP), using small unoccupied aerial vehicles (UAVs) equipped with imaging sensors, can be deployed routinely to monitor segregating plant population interactions with the environment under biologically meaningful conditions. Here, flowering dates and plant height, important phenological fitness traits, were collected on 520 segregating maize recombinant inbred lines (RILs) in both irrigated and drought stress trials in 2018. Using UAV phenomic, single nucleotide polymorphism (SNP) genomic, as well as combined data, flowering times were predicted using several scenarios. Untested genotypes were predicted with 0.58, 0.59, and 0.41 prediction ability for anthesis, silking, and terminal plant height, respectively, using genomic data, but prediction ability increased to 0.77, 0.76, and 0.58 when phenomic and genomic data were used together. Using the phenomic data in a genome-wide association study, a heat-related candidate gene (GRMZM2G083810; hsp18f) was discovered using temporal reflectance phenotypes belonging to flowering times (both irrigated and drought) trials where heat stress also peaked. Thus, a relationship between plants and abiotic stresses belonging to a specific time of growth was revealed only through use of temporal phenomic data. Overall, this study showed that (i) it is possible to predict complex traits using high dimensional phenomic data between different environments, and (ii) temporal phenomic data can reveal a time-dependent association between genotypes and abiotic stresses, which can help understand mechanisms to develop resilient plants.


Assuntos
Fenômica , Zea mays , Zea mays/genética , Estudo de Associação Genômica Ampla , Fenótipo , Genômica/métodos
14.
Exp Eye Res ; 231: 109499, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37169279

RESUMO

Fuchs Endothelial Corneal Dystrophy (FECD), a late-onset oxidative stress disorder, is the most common cause of corneal endothelial degeneration and is genetically associated with CTG repeat expansion in Transcription Factor 4 (TCF4). We previously reported accumulation of nuclear (nDNA) and mitochondrial (mtDNA) damage in FECD. Specifically, mtDNA damage was a prominent finding in development of disease in the ultraviolet-A (UVA) induced FECD mouse model. We hypothesize that an aberrant DNA repair may contribute to the increased DNA damage seen in FECD. We analyzed differential expression profiles of 84 DNA repair genes by real-time PCR arrays using Human DNA Repair RT-Profiler plates using cDNA extracted from Descemet's membrane-corneal endothelium (DM-CE) obtained from FECD patients with expanded (>40) or non-expanded (<40) intronic CTG repeats in TCF4 gene and from age-matched normal donors. Change in mRNA expression of <0.5- or >2.0-fold in FECD relative to normal was set as cutoff for down- or upregulation. Downregulated mitochondrial genes were further validated using the UVA-based mouse model of FECD. FECD specimens exhibited downregulation of 9 genes and upregulation of 8 genes belonging to the four major DNA repair pathways, namely, base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double strand break (DSB) repair, compared to normal donors. MMR gene MSH2 and BER gene POLB were preferentially upregulated in expanded FECD. BER genes LIG3 and NEIL2, DSB repair genes PARP3 and TOP3A, NER gene XPC, and unclassified pathway gene TREX1, were downregulated in both expanded and non-expanded FECD. MtDNA repair genes, Lig3, Neil2, and Top3a, were also downregulated in the UVA-based mouse model of FECD. Our findings identify impaired DNA repair pathways that may play an important role in DNA damage due to oxidative stress as well as genetic predisposition noted in FECD.


Assuntos
DNA Glicosilases , Distrofia Endotelial de Fuchs , Animais , Camundongos , Humanos , Distrofia Endotelial de Fuchs/genética , Distrofia Endotelial de Fuchs/metabolismo , Endotélio Corneano/metabolismo , Predisposição Genética para Doença , Reparo do DNA/genética , DNA Mitocondrial/genética , DNA Glicosilases/genética , DNA Glicosilases/metabolismo
15.
Haemophilia ; 29(4): 1074-1086, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37335575

RESUMO

BACKGROUND: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia. OBJECTIVES: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors. METHODS: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment. RESULTS: Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037). CONCLUSION: A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.


Assuntos
Disfunção Cognitiva , Hemofilia A , Adulto , Humanos , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/patologia , População do Leste Asiático , Hemofilia A/complicações , Neuroimagem , Fatores de Risco , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Hemofilia B/complicações
16.
Biometrics ; 79(4): 2933-2946, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37345491

RESUMO

The prevalence of data collected on the same set of samples from multiple sources (i.e., multi-view data) has prompted significant development of data integration methods based on low-rank matrix factorizations. These methods decompose signal matrices from each view into the sum of shared and individual structures, which are further used for dimension reduction, exploratory analyses, and quantifying associations across views. However, existing methods have limitations in modeling partially-shared structures due to either too restrictive models, or restrictive identifiability conditions. To address these challenges, we propose a new formulation for signal structures that include partially-shared signals based on grouping the views into so-called hierarchical levels with identifiable guarantees under suitable conditions. The proposed hierarchy leads us to introduce a new penalty, hierarchical nuclear norm (HNN), for signal estimation. In contrast to existing methods, HNN penalization avoids scores and loadings factorization of the signals and leads to a convex optimization problem, which we solve using a dual forward-backward algorithm. We propose a simple refitting procedure to adjust the penalization bias and develop an adapted version of bi-cross-validation for selecting tuning parameters. Extensive simulation studies and analysis of the genotype-tissue expression data demonstrate the advantages of our method over existing alternatives.


Assuntos
Algoritmos , Simulação por Computador
17.
J Thromb Thrombolysis ; 55(1): 83-91, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36192663

RESUMO

Hypertrophic cardiomyopathy predisposes to acute cerebrovascular events including ischaemic stroke, transient ischaemic attack and systemic thromboembolism. Atrial fibrillation confers even higher risk. We aim to report the incidence of these complications and to investigate the impact of atrial fibrillation on the ischaemic risk in patients with hypertrophic cardiomyopathy. A literature search was performed on PubMed, Scopus, Embase/Ovid and Cochrane library from inception to 20th March 2021. We compared the incidence of ischaemic strokes, transient ischaemic attack, non-specified thromboembolism events and systemic thromboembolism in hypertrophic cardiomyopathy patients with or without atrial fibrillation. Non-specified thromboembolism events in our paper referred to thromboembolic events whereby types were not specified in the studies. Meta-analysis was performed using StataSE 16 software, and heterogeneity was assessed using I2 test. A total of 713 studies were identified. Thirty-five articles with 42,570 patients were included. The pooled incidence of stroke/ transient ischaemic attack was 7.45% (95% confidence interval [CI] 5.80-9.52, p < 0.001) across 24 studies with a total of 37,643 hypertrophic cardiomyopathy patients. Atrial fibrillation significantly increased the risk of total stroke/ transient ischaemic attack (Risk Ratio 3.26, 95% CI 1.75-6.08, p < 0.001, I2 = 76.0). The incidence of stroke/ transient ischaemic attack was 9.30% (95% CI 6.64-12.87, p = 0.316) in the apical hypertrophic cardiomyopathy subgroup. Concomitant atrial fibrillation in hypertrophic cardiomyopathy increases the risk of thromboembolic events including ischaemic stroke and transient ischaemic attack. The apical subgroup shows a similar risk of acute cerebrovascular events as the overall hypertrophic cardiomyopathy population.


Assuntos
Fibrilação Atrial , Isquemia Encefálica , Cardiomiopatia Hipertrófica , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Tromboembolia , Humanos , Acidente Vascular Cerebral/etiologia , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/complicações , Tromboembolia/etiologia , Tromboembolia/complicações , AVC Isquêmico/complicações , Cardiomiopatia Hipertrófica/complicações , Fatores de Risco
18.
Nutr Res Rev ; 36(2): 216-231, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34670637

RESUMO

Poor nutritional intake is common among older adults. Given that nutrition knowledge is an important determinant of eating behaviour and nutritional status, understanding areas of inadequate knowledge can guide educational interventions to reduce risk of nutritional deficiencies and promote healthy ageing. This review investigated tools assessing general nutritional knowledge of older adults and their carers. Following the Joanna Briggs for Scoping Reviews guidelines, 4 databases (MEDLINE, CINAHL, Global Health and Embase) and grey literature were searched. Studies of any type containing general nutrition knowledge assessment tools for older adults or their carers were included. In total, 6934 articles were identified, of which 24 met the eligibility criteria, and 23 unique nutrition knowledge assessment tools were included. Of these tools, 14 were original, 6 were modified from other tools and 3 used dietary-related responses from national dietary survey questions. 6 tools were developed for carers (mostly nurses) and 17 tools for older adults. Tools had between 4 and 110 items. The most common topics for general nutrition knowledge questions were related to nutrients and roles, food sources of nutrients, and diet-disease relationships. 8 tools were developed prior to 2000. Most studies did not specify or assess psychometric properties of the tool, with only 9 (38 %) and 6 (26 %) studies testing for reliability and validity, respectively, and only 1 tool was considered reliable. Additional research for the development of reliable and validated tools or the validation of existing tools to assess nutrition knowledge of older adults and their carers is needed across different healthcare settings.


Assuntos
Cuidadores , Desnutrição , Humanos , Idoso , Reprodutibilidade dos Testes , Avaliação Nutricional , Desnutrição/prevenção & controle , Estado Nutricional
19.
J Oral Maxillofac Surg ; 81(10): 1227-1243, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37478897

RESUMO

PURPOSE: Le Fort I maxillary impaction is an orthognathic surgical procedure to reposition the maxillary complex superiorly. The objective of this study is to investigate if maxillary impaction negatively affects the nasal airway. METHODS: A systematic review with meta-analysis was performed to investigate the effects of maxillary impaction on the nasal cavity. PubMed, Embase, and Cochrane Library databases were accessed. Observational studies, nonrandomized, and randomized controlled trials were included if Le Fort 1 maxillary impaction and nasal airway outcomes assessments were performed. Studies were excluded if maxillary impaction or nasal airway outcome assessment was not performed or if the study included patients with cleft or craniofacial syndromes, previous nasal surgeries, or active respiratory tract. The demographic data, study methodology, magnitude of maxillary impaction, and outcomes related to the nasal airway were collected. These outcomes includes anatomical changes (evaluated by rhinoscopy, acoustic rhinometry, and computed tomography), changes to nasal airflow and resistance (evaluated by rhinomanometry) and changes to quality of life. RESULTS: The search yielded 7517 studies. Ten studies were included after the application of the selection criteria. A total of 126 patients underwent pure maxillary impaction, 97 underwent maxillary impaction and advancement, and 12 had impaction with setback. Despite that maxillary impactions decreased the nasal cavity volume by +21.7%, the cross-sectional area of the narrowest parts of the cavity was only reduced by -8.4%. Maxillary impactions generally increases the nasal airflow (+12.6%) while reducing nasal resistance (-20.2%). Rhinoscopies also showed a reduction in nasal obstruction. CONCLUSION: Maxillary impaction did not negatively affect the nasal airway. The surgeries did not lead to the reduction of the cross-sectional area at the strictures of the nasal cavities. The nasal airflow and resistance was not decreased and increased, respectively. The quality of life of the patients was also not shown to have worsened.

20.
Int J Mol Sci ; 24(4)2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36834828

RESUMO

Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified >60 genetic risk factors for AMD; however, the expression profile and functional role of many of these genes remain elusive in human RPE. To facilitate functional studies of AMD-associated genes, we developed a human RPE model with integrated CRISPR interference (CRISPRi) for gene repression by generating a stable ARPE19 cell line expressing dCas9-KRAB. We performed transcriptomic analysis of the human retina to prioritise AMD-associated genes and selected TMEM97 as a candidate gene for knockdown study. Using specific sgRNAs, we showed that knockdown of TMEM97 in ARPE19 reduced reactive oxygen species (ROS) levels and exerted a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports a potential role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi RPE platform generated here provided a useful in vitro tool for functional studies of AMD-associated genes.


Assuntos
Estudo de Associação Genômica Ampla , Degeneração Macular , Humanos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Epitélio Pigmentado da Retina/metabolismo , Degeneração Macular/metabolismo , Estresse Oxidativo , Epitélio/metabolismo
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