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Antibiotics may alter the gut microbiome, and this is one of the mechanisms by which antimicrobial resistance may be promoted. Suboptimal antimicrobial stewardship in Asia has been linked to antimicrobial resistance. We aim to examine the relationship between oral antibiotic use and composition and antimicrobial resistance in the gut microbiome in 1093 Bangladeshi infants. We leverage a trial of 8-month-old infants in rural Bangladesh: 61% of children were cumulatively exposed to antibiotics (most commonly cephalosporins and macrolides) over the 12-month study period, including 47% in the first 3 months of the study, usually for fever or respiratory infection. 16S rRNA amplicon sequencing in 11-month-old infants reveals that alpha diversity of the intestinal microbiome is reduced in children who received antibiotics within the previous 7 days; these samples also exhibit enrichment for Enterococcus and Escherichia/Shigella genera. No effect is seen in children who received antibiotics earlier. Using shotgun metagenomics, overall abundance of antimicrobial resistance genes declines over time. Enrichment for an Enterococcus-related antimicrobial resistance gene is observed in children receiving antibiotics within the previous 7 days, but not earlier. Presence of antimicrobial resistance genes is correlated to microbiome composition. In Bangladeshi children, community use of antibiotics transiently reprofiles the gut microbiome.
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Antibacterianos , Microbioma Gastrointestinal , RNA Ribossômico 16S , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Bangladesh/epidemiologia , Lactente , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , RNA Ribossômico 16S/genética , Masculino , Feminino , Administração Oral , Farmacorresistência Bacteriana/genética , Fezes/microbiologia , Metagenômica/métodos , Bactérias/genética , Bactérias/efeitos dos fármacos , Bactérias/classificação , Bactérias/isolamento & purificação , Cefalosporinas/administração & dosagem , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Enterococcus/efeitos dos fármacos , Enterococcus/genética , Enterococcus/isolamento & purificação , Gestão de AntimicrobianosRESUMO
OBJECTIVES: Common Variable Immunodeficiency Disorders (CVID) and Large Granular Lymphocytes leukemia (LGLL) exhibit diverse clinical manifestations including infections, dysimmunity, and lymphoproliferation. Recent decades have seen the discovery of new genes in the lymphopoiesis pathway, such as JAK-STAT. This case series supplemented by a literature review aims to describe clinical and biological characteristics of patients with both CIVD and LGLL. METHODOLOGY: Patients were included through a call for comments to French and Belgian centers and through a literature review via PubMed. Clinical characteristics were compared to two large French cohort involving CVID and LGLL patients. RESULTS: Twelve patients were included. In all cases, CVID precedes LLGL (median diagnosis delay for LLGL was 7 years). Most cases presented with splenomegaly and autoimmune cytopenia. Ten out of 12 patients underwent splenectomy during follow up. CONCLUSIONS: Patients with LGLL and CVID differ from patients without immune deficiency in term of clinical presentation and prognosis. We suggest CVID may act as a trigger of LGL lymphocytosis, due to endogenous and exogenous antigenic pressure leading to the selection of a dominant LGL clone and stimulation of the JAK-STAT pathway. The role of splenomegaly and splenectomy in LGLL onset warrant further investigation in future studies.
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Modern science is dependent on imaging on the nanoscale, often achieved through processes that detect secondary electrons created by a highly focused incident charged particle beam. Multiple types of measurement noise limit the ultimate trade-off between the image quality and the incident particle dose, which can preclude useful imaging of dose-sensitive samples. Existing methods to improve image quality do not fundamentally mitigate the noise sources. Furthermore, barriers to assigning a physically meaningful scale make the images qualitative. Here, we introduce ion count-aided microscopy (ICAM), which is a quantitative imaging technique that uses statistically principled estimation of the secondary electron yield. With a readily implemented change in data collection, ICAM substantially reduces source shot noise. In helium ion microscopy, we demonstrate 3[Formula: see text] dose reduction and a good match between these empirical results and theoretical performance predictions. ICAM facilitates imaging of fragile samples and may make imaging with heavier particles more attractive.
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Modern science is dependent on imaging on the nanoscale, often achieved through processes that detect secondary electrons created by a highly focused incident charged particle beam. Multiple types of measurement noise limit the ultimate trade-off between the image quality and the incident particle dose, which can preclude useful imaging of dose-sensitive samples. Existing methods to improve image quality do not fundamentally mitigate the noise sources. Furthermore, barriers to assigning a physically meaningful scale make the images qualitative. Here we introduce ion count-aided microscopy (ICAM), which is a quantitative imaging technique that uses statistically principled estimation of the secondary electron yield. With a readily implemented change in data collection, ICAM substantially reduces source shot noise. In helium ion microscopy, we demonstrate 3× dose reduction and a good match between these empirical results and theoretical performance predictions. ICAM facilitates imaging of fragile samples and may make imaging with heavier particles more attractive.
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INTRODUCTION: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS: The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS: This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment. TRIAL REGISTRATION NUMBER: ACTRN12613000794707.
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Autoimunidade , Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/etiologia , Feminino , Gravidez , Austrália/epidemiologia , Estudos Prospectivos , Masculino , Criança , Lactente , Recém-Nascido , Fatores de Risco , Adulto , Ilhotas Pancreáticas/imunologia , Estudos Longitudinais , Seguimentos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Pré-Escolar , Pais , Genótipo , Antígenos HLA/genéticaRESUMO
Ion mobility (IM) is often combined with LC-MS experiments to provide an additional dimension of separation for complex sample analysis. While highly complex samples are better characterized by the full dimensionality of LC-IM-MS experiments to uncover new information, downstream data analysis workflows are often not equipped to properly mine the additional IM dimension. For many samples the data acquisition benefits of including IM separations are all that is necessary to uncover sample information and the full dimensionality of the data is not required for data analysis. Postacquisition reduction and adaptation of the dimensions of LC-IM-MS and IM-MS experiments into an LC-MS format opens the possibility to use a plethora of existing software tools. In this work, we developed data file conversion tools to reduce the complexity of IM data analysis. Three data file transformations are introduced in the PNNL PreProcessor software: (1) mapping the IM axis to the LC axis for IM-MS data, (2) converting the drift time vs m/z space to CCS/z vs m/z space, and (3) transforming All Ions IM/MS mobility aligned fragmentation data to a standard LC-MS DDA data file format. These new data file conversions are demonstrated with corresponding lipidomics and proteomics workflows that leverage existing LC-MS data analysis software to highlight the benefits of the data transformations.
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BACKGROUND: A range of strategies are available that can improve the outcomes of older persons particularly in relation to basic activities of daily living during and after an acute care (AC) episode. This paper outlines the original development of outcome-oriented quality indicators (QIs) in relation to common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. METHODS: Design QIs were developed using evidence from literature, expert opinion, field study data and a formal voting process. A systematic literature review of literature identified existing QIs (there were no outcome QIs) and evidence of interventions that improve older persons' outcomes in AC. Preliminary indicators were developed by two expert panels following consideration of the evidence. After analysis of the data from field testing (indicator prevalence, variability across sites), panel meetings refined the QIs prior to a formal voting process. SETTING: Data was collected in nine Australian general medical wards. PARTICIPANTS: Patients aged 70 years and over, consented within 24 h of admission to the AC ward. MEASUREMENTS: The interRAI Acute Care - Comprehensive Geriatric Assessment (interRAI AC-CGA) was administered at admission and discharge; a daily risk assessment in hospital; 28-day phone follow-up and chart audit. RESULTS: Ten outcome QIs were established which focused on common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. CONCLUSION: Ten outcome QIs were developed. These QIs can be used to identify areas where specific action will lead to improvements in the quality of care delivered to older persons in hospital.
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Avaliação Geriátrica , Indicadores de Qualidade em Assistência à Saúde , Humanos , Idoso , Indicadores de Qualidade em Assistência à Saúde/normas , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos , Feminino , Masculino , Atividades Cotidianas , Hospitalização , Idoso Fragilizado , Avaliação de Resultados da Assistência ao PacienteRESUMO
BACKGROUND: Knowledge of local antibiotic resistance data provided by antibiograms (cumulative-antimicrobial-susceptibility-tests) can assist prescribers to make appropriate empirical antibiotic choices. OBJECTIVE: This study explored the perceptions and knowledge of key stakeholders about the role of antibiograms in residential aged care facilities (RACF), and to understand barriers and enablers of antibiogram development and implementation in this setting. METHOD: Semi-structured interviews were conducted with aged-care health professionals ('end-users') and antibiogram content experts. This study was conducted in Queensland, Australia in 2023. Using qualitative techniques, framework thematic analysis was used to identify themes, which were mapped to the 'Integrated Promoting Action on Research Implementation in Health Services' framework constructs. RESULTS: Twenty interviews were conducted comprising of five 'content-experts' and fifteen 'end-users'. Five themes were identified which indicated lack of knowledge about how to use antibiograms, and its availability. Potential insufficient data was the primary issue identified by content experts with regards to feasibility of annual antibiograms. Pragmatic solutions were offered, such as pooling pathology data from facilities in the same geographical location, extending antibiogram data to two-or three-yearly, or utilising local hospital antibiograms. Presenting antibiogram data in a mode and format suiting preferences of individual users would encourage uptake and improve usability. Antimicrobial stewardship (AMS) champions and pharmacists were highlighted as drivers of educating and promoting antibiogram use. CONCLUSION: Clinicians recognised the potential role of antibiograms in improving empirical antibiotic prescribing choices. Establishing their baseline knowledge provides an essential starting point for the education needs of this group. This study provides practical recommendations regarding the presentation of antibiograms to ensure appropriate use and uptake as an AMS tool in RACFs. Pragmatic solutions suggested to overcome challenges of antibiogram development for RACFs should be applied and evaluated to determine feasibility of RACF-specific antibiograms.
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Antibacterianos , Testes de Sensibilidade Microbiana , Humanos , Antibacterianos/uso terapêutico , Instituição de Longa Permanência para Idosos , Feminino , Masculino , Queensland , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Idoso , Participação dos Interessados , Gestão de Antimicrobianos , Pessoa de Meia-IdadeRESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.
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Incretinas , Hepatopatia Gordurosa não Alcoólica , Humanos , Incretinas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
We report the results of fabricating fiber array unit (FAU) connectors using a near IR laser welding process, locking fibers in proper position on planar glass substrates and forming strong glass-to-glass bonds, followed by final assembly using lower coefficient of thermal expansion (CTE) epoxies. A thin metal film deposited on the glass substrate provides the absorption required to attain interfacial temperatures suitable for glass-to-glass bonding. This method allows the elimination of dedicated expensive V-groove plates while still maintaining very good fiber placement accuracy. The use of epoxy is minimized to simply securing macro packaging components and protecting fibers from environmental pressure, temperature, and humidity variation. The thermal expansion properties of the epoxy used were essential for the long-term FAU reliability.
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Background: Interval throwing programs (ITP) have been used for decades to enable baseball pitchers to return to competition after injury or surgery by gradually applying load to the throwing arm. Past programs have been based on personal experience; however, advances in our understanding of the biomechanics and workloads of throwing allow for a more modern data-based program to be developed. Hypothesis/Purpose: To 1) develop a updated ITP for rehabilitation of modern baseball pitchers based upon biomechanical and throwing workload data, and 2) compare the updated program with a past program to determine differences in chronic workload and acute:chronic workload ratios (ACWR). Study Design: Cross-sectional study. Methods: Workloads (i.e. daily, acute, chronic, and ACWR) for the original ITP were built from the prescribed throwing schedule. Elbow varus torque per throw was calculated based upon a relationship between elbow varus torque and throwing distance. Throw counts, daily/chronic/acute workloads, and ACWR were calculated and plotted over time. A new ITP was built to model current pitcher's throwing schedules and gradually increased ACWR over time. Results: The original ITP had a throwing schedule of 136 days, final chronic workload 15.0, and the ACWR above or below the "safe" range (i.e. 0.7 - 1.3) for 18% of the program with a peak of 1.61. The updated ITP was built to consist of a 217-day schedule, final chronic workload of 10.8, and deviated from the safe range for 9% of the program, with a peak of 1.33. Conclusion: The newly created ITP is more familiar to modern baseball pitchers while exhibiting a more gradual buildup of chronic workload than traditional ITP programs. This ITP may be used to return baseball pitchers back to competition as safely and efficiently as possible, and potentially with less risk of setbacks or reinjury. The ITP may be used following common injuries or surgeries to the throwing shoulder and elbow, such as Tommy John surgery, while also serving as a basis for future development of shorter duration ITPs. Level of Evidence: 2c.
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The Covid pandemic necessitated changes in traditional mentorship and educational roles. We offer our experience in structuring a virtual dermatopathology mentorship in the midst of the pandemic. Virtual mentorships have many benefits including ease of access, lack of geographic restrictions, and financial savings, though there still remains an important and irreplaceable role for in-person relationships.
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COVID-19 , Dermatologia , Mentores , Humanos , Dermatologia/educação , Telemedicina , Patologia/educação , SARS-CoV-2RESUMO
OBJECTIVES: Falls pose a significant challenge in residential aged care facilities (RACFs). Existing falls prediction tools perform poorly and fail to capture evolving risk factors. We aimed to develop and internally validate dynamic fall risk prediction models and create point-based scoring systems for residents with and without dementia. MATERIALS AND METHODS: A longitudinal cohort study using electronic data from 27 RACFs in Sydney, Australia. The study included 5492 permanent residents, with a 70%-30% split for training and validation. The outcome measure was the incidence of falls. We tracked residents for 60 months, using monthly landmarks with 1-month prediction windows. We employed landmarking dynamic prediction for model development, a time-dependent area under receiver operating characteristics curve (AUROCC) for model evaluations, and a regression coefficient approach to create point-based scoring systems. RESULTS: The model identified 15 independent predictors of falls in dementia and 12 in nondementia cohorts. Falls history was the key predictor of subsequent falls in both dementia (HR 4.75, 95% CI, 4.45-5.06) and nondementia cohorts (HR 4.20, 95% CI, 3.87-4.57). The AUROCC across landmarks ranged from 0.67 to 0.87 for dementia and from 0.66 to 0.86 for nondementia cohorts but generally remained between 0.75 and 0.85 in both cohorts. The total point risk score ranged from -2 to 57 for dementia and 0 to 52 for nondementia cohorts. DISCUSSION: Our novel risk prediction models and scoring systems provide timely person-centered information for continuous monitoring of fall risk in RACFs. CONCLUSION: Embedding these tools within electronic health records could facilitate the implementation of targeted proactive interventions to prevent falls.
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Demência , Instituição de Longa Permanência para Idosos , Idoso , Humanos , Estudos Longitudinais , Fatores de Risco , EletrônicaRESUMO
The possibility that acquired traits can be transmitted across generations has been the subject of intense research in the past decades. This biological process is of major interest to many scientists and has profound implications for biology and society but has complex mechanisms and is therefore challenging to study. Because it involves factors independent from the DNA sequence, this form of heredity is classically referred to as epigenetic inheritance. Many studies have examined how life experiences and various environmental factors can cause phenotypes that are heritable and be manifested in subsequent generations. Recognizing the major importance and complexity of this research, the fourth edition of the Epigenetic Inheritance Symposium Zürich brought together experts from diverse disciplines to address current questions in the field of epigenetic inheritance and present recent findings. The symposium had sessions dedicated to epidemiological evidence and animal models, transmission mechanisms, methodologies and the far-reaching impact on society and evolution. This report summarizes the talks of speakers and describes additional activities offered during the symposium including poster sessions and an art competition on the topic of epigenetic inheritance.
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Aims: The aim of this study is to determine the predictors of overall survival (OS) and predictive factors of poor prognosis of conventional high-grade osteosarcoma of the limbs in a single-centre in South Africa. Methods: We performed a retrospective cross-sectional analysis to identify the prognostic factors that predict the OS of patients with histologically confirmed high-grade conventional osteosarcoma of the limbs over ten years. We employed the Cox proportional regression model and the Kaplan-Meier method for statistical analysis. Results: This study comprised 77 patients at a three-year minimum follow-up. The predictors of poor OS were: the median age of ≤ 19 years (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.92 to 0.99; p = 0.021); median duration of symptoms ≥ five months (HR 0.91; 95% CI 0.83 to 0.99; p < 0.037); metastasis at diagnosis (i.e. Enneking stage III) (HR 3.33; 95% CI 1.81 to 6.00; p < 0.001); increased alkaline phosphatase (HR 3.28; 95% CI 1.33 to 8.11; p < 0.010); palliative treatment (HR 7.27; 95% CI 2.69 to 19.70); p < 0.001); and amputation (HR 3.71; 95% CI 1.12 to 12.25; p < 0.032). In contrast, definitive surgery (HR 0.11; 95% CI 0.03 to 0.38; p < 0.001) and curative treatment (HR 0.18; 95% CI 0.10 to 0.33; p < 0.001) were a protective factor. The Kaplan-Meier median survival time was 24 months, with OS of 57.1% at the three years. The projected five-year event-free survival was 10.3% and OS of 29.8% (HR 0.76; 95% CI 0.52 to 1.12; p = 0.128). Conclusion: In this series of high-grade conventional osteosarcoma of the appendicular skeleton from South Africa, 58.4% (n = 45) had detectable metastases at presentation; hence, an impoverished OS of five years was 29.8%. Large-scale future research is needed to validate our results.
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Background: Traumatic brachial plexus injuries (TBPIs) are debilitating and complex to treat. The last five decades have seen advances in surgical management, and consequently improved functional outcomes in patients with these injuries. There is limited data available describing the outcomes of surgically managed TBPIs within the South African context. This study aimed to identify the common causes of injury, injury characteristics, and functional outcomes of surgically managed patients with TBPIs. Methods: We conducted a retrospective chart review of all adult patients that underwent surgery for TBPIs over a period of ten years at a specialised hand unit in South Africa. The minimum follow-up period was one year. Patient demographic details, injury characteristics and functional outcomes were collected. Statistical analysis was performed to determine factors associated with functional outcomes. A good functional outcome for recovery was defined as a Medical Research Council (MRC) grade of three or more for the affected elements of the plexus at the most recent follow-up. Results: Forty-seven patients of median age 32 years were included in the final analysis. Most patients were male (87.2 %). The majority of patients were injured in motor vehicle accidents (MVAs) or from penetrating stab wounds (48.9 % and 38.3 % respectively). The median pre-operative MRC grade of the affected elements of the brachial plexus was 0.0, and post-operatively was 2.0. Fourteen patients (14 of 47, 29.8 %) had a good outcome and 33 had a poor outcome (33 of 47, 70.2 %). There was no difference in outcome comparing penetrating injury mechanisms to closed traction or blunt injuries, (p = 0.386, OR 1.75, 95 % CI 0.49-6.20). All patients with pan-plexal injuries had a poor outcome (15 of 33, 46 %). All patients who received intercostal (6 of 33, 18 %) or phrenic nerve transfers (3 of 33, 9 %) had a poor outcome. Conclusion: Adult traumatic BPIs in this South African sample typically presented more than two months after injury and were comprised of a high proportion of penetrating injuries. Just under a third of surgically managed patients had a good outcome. Pan plexal injuries have uniformly poor outcomes. We recommend early referral for all TBPIs to a unit that manages BPI to improve outcomes.
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Objectives: Recognition of the cognitive status of patients is important so that care can be tailored accordingly. The objective of this integrative review was to report on the current practices that acute care hospitals use to identify people with cognitive impairment and how information about cognition is managed within the healthcare record as well as the approaches required and recommended by policies. Methods: Following Whittemore & Knafl's five-step method, we systematically searched Medline, CINAHL, and Scopus databases and various grey literature sources. Articles relevant to the programs that have been implemented in acute care hospitals regarding the identification of cognitive impairment and management of cognition information were included. The Mixed Methods Appraisal Tool and AACODS (Authority, Accuracy, Coverage, Objectivity, Date, Significance) Checklist were used to evaluate the quality of the studies. Thematic analysis was used to present and synthesise results. This review was pre-registered on PROSPERO ( CRD42022343577). Results: Twenty-two primary studies and ten government/industry publications were included in the analysis. Findings included gaps between practice and policy. Although identification of cognitive impairment, transparency of cognition information, and interaction with patients, families, and carers (if appropriate) about this condition were highly valued at a policy level, sometimes in practice, cognitive assessments were informal, patient cognition information was not recorded, and interactions with patients, families, and carers were lacking. Discussion: By incorporating cognitive assessment, developing an integrated information management system using information technology, establishing relevant laws and regulations, providing education and training, and adopting a national approach, significant improvements can be made in the care provided to individuals with cognitive impairment.
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BACKGROUND: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. RESULTS: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer's disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. CONCLUSIONS: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.
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Metilação de DNA , Epigênese Genética , Feminino , Gravidez , Recém-Nascido , Humanos , Neuroglia , Córtex Cerebral , Neurônios/metabolismoRESUMO
Breast cancer is a significant global health burden, causing a substantial number of deaths. Systemic metastatic tumour cell dissemination is a major cause of poor outcomes. Understanding the mechanisms underlying metastasis is crucial for effective interventions. Changes in the extracellular matrix play a pivotal role in breast cancer metastasis. In this work, we present an advanced multimodal X-ray computed tomography, by combining Small-angle X-ray Scattering Tensor Tomography (SAXS-TT) and X-ray Fluorescence Computed Tomography (XRF-CT). This approach likely brings out valuable information about the breast cancer metastasis cascade. Initial results from its application on a breast cancer specimen reveal the collective influence of key molecules in the metastatic mechanism, identifying a strong correlation between zinc accumulation (associated with matrix metalloproteinases MMPs) and highly oriented collagen. MMPs trigger collagen alignment, facilitating breast cancer cell intravasation, while iron accumulation, linked to angiogenesis and vascular endothelial growth factor VEGF, supports cell proliferation and metastasis. Therefore, these findings highlight the potential of the advanced multimodal X-ray computed tomography approach and pave the way for in-depth investigation of breast cancer metastasis, which may guide the development of novel therapeutic approaches and enable personalised treatment strategies, ultimately improving patient outcomes in breast cancer management.