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1.
Paediatr Anaesth ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34608715

RESUMO

BACKGROUND: Anatomically, the subglottic area and the cricoid ring are the narrowest portions of the larynx. To limit the potential for damage related to mucosal pressure injuries from the presence of an endotracheal tube, the cuff should be placed below the cricoid in children. Previously, no clinical or imaging method has been used in real time to determine the exact location of the endotracheal tube cuff after endotracheal intubation. Point-of-care ultrasound may provide an option as a safe and rapid means of visualizing the endotracheal tube cuff and its relationship to the cricoid ring thereby achieving ideal endotracheal tube cuff positioning-below the cricoid. METHODS: In this prospective, nonrandomized trial, point-of-care ultrasound was used following endotracheal intubation in children to evaluate the position of the endotracheal tube cuff in relationship to the cricoid and tracheal rings. After anesthesia was induced and the trachea was intubated, the endotracheal tube cuff and its position in relation to the cricoid and tracheal rings were identified in the longitudinal plane using point-of-care ultrasound. With the patient's neck in a neutral position, the level of the proximal (cephalad) margin of the saline-filled cuff of the endotracheal tube was identified and recorded in relationship to the cricoid and tracheal rings. The ideal position is defined as the cephalad margin of the endotracheal tube cuff below the level of the cricoid. RESULTS: The study cohort included 80 patients, ranging in age from 1 to 78 months. In all patients, the cuff of the ETT, cricoid, and tracheal rings were identified. The cephalad end of the endotracheal tube cuff was found at the level of the cricoid in 16.3% of patients, at the first tracheal ring in 27.5% of patients, at the second tracheal ring in 23.8% of patients, at the third tracheal ring in 17.5% of patients, and at below the fourth tracheal ring in 15% of patients. Initial endotracheal tube cuff position had no significant association with age, height, weight, endotracheal tube size, and endotracheal tube type. CONCLUSION: Point-of-care ultrasound provides a rapid and effective means of identifying the position of the endotracheal tube cuff in relationship to the cricoid ring. The technique may have applications in the perioperative arena, emergency departments, and intensive care units.

2.
J Food Prot ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34614187

RESUMO

Combined steam-ultrasound process was investigated for decontamination of freshly slaughtered broilers. Combined steam-ultrasound was delivered simultaneously through specially designed nozzles. The nozzles were installed inside of a constructed machine that allowed for continuous processing. The aim of this study was to evaluate the decontamination effect of the steam- ultrasound application with a capacity of 10,500 birds/hour on naturally contaminated broilers, using three different skin sampling areas for microbial analysis (back, breast and the neck skin). Microbial analysis of Campylobacter , Enterobacteriaceae and Total Viable Count (TVC), was performed pre- and -post steam-ultrasound treatment. A total of 648 skin samples were analyzed for Campylobacter and a total of 216 samples were analyzed for Enterobacteriaceae and TVC. R esults showed significant (p<0.001) Campylobacter reductions of 0.8 log, 1.1 log and 0.7 log, analyzed from skin samples taken from the back, breast and the neck, respectively. Significant reductions of Enterobacteriaceae (p<0.001) by 1.6 log, 1.9 log and 1.1 log and significant reductions of TVC (p<0.001) by 2.0 log, 2.4 log and 1.3 log were found on back, breasts and neck, respectively. Refrigeration effect on Campylobacter numbers pre- and post- steam-ultrasound treatment and incubation at 4°C for eight days was determined in a small trial with 12 samples. Results showed significant (p<0.01) reductions of 0.9 log analyzed on breast skin samples, and 0.7 log reduction (p<0.05) on neck skin samples. Results in this study showed that significant bacteria reduction was achieved on three different surface areas on broilers at a slaughter-speed of 10,500b/h with temperatures over 80°C. The rapid treatment of less than 1.5s exposure time per bird chamber, makes this technology potentially suitable for modern and fast poultry processing lines.

3.
Ophthalmol Ther ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633635

RESUMO

The combined effects of fossil fuel combustion, mass agricultural production and deforestation, industrialisation and the evolution of modern transport systems have resulted in high levels of carbon emissions and accumulation of greenhouse gases, causing profound climate change and ozone layer depletion. The consequential depletion of Earth's natural ecosystems and biodiversity is not only a devastating loss but a threat to human health. Sustainability-the ability to continue activities indefinitely-underpins the principal solutions to these problems. Globally, the healthcare sector is a major contributor to carbon emissions, with waste production and transport systems being amongst the highest contributing factors. The aim of this review is to explore modalities by which the healthcare sector, particularly ophthalmology, can reduce carbon emissions, related costs and overall environmental impact, whilst maintaining a high standard of patient care.

4.
Sci Rep ; 11(1): 17758, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493784

RESUMO

DNA viruses can exploit host cellular epigenetic processes to their advantage; however, the epigenome status of most DNA viruses remains undetermined. Third generation sequencing technologies allow for the identification of modified nucleotides from sequencing experiments without specialized sample preparation, permitting the detection of non-canonical epigenetic modifications that may distinguish viral nucleic acid from that of their host, thus identifying attractive targets for advanced therapeutics and diagnostics. We present a novel nanopore de novo assembly pipeline used to assemble a misidentified Camelpox vaccine. Two confirmed deletions of this vaccine strain in comparison to the closely related Vaccinia virus strain modified vaccinia Ankara make it one of the smallest non-vector derived orthopoxvirus genomes to be reported. Annotation of the assembly revealed a previously unreported signal peptide at the start of protein A38 and several predicted signal peptides that were found to differ from those previously described. Putative epigenetic modifications around various motifs have been identified and the assembly confirmed previous work showing the vaccine genome to most closely resemble that of Vaccinia virus strain Modified Vaccinia Ankara. The pipeline may be used for other DNA viruses, increasing the understanding of DNA virus evolution, virulence, host preference, and epigenomics.

5.
Braz J Biol ; 83: e246727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468521

RESUMO

Unavailability of probiotics in fish digestive system fingerlings is unable to digest and absorb their food properly. The current research was conducted to investigate the influence of probiotics added Linseed meal based (LMB) diet on hematology and carcass composition of Labeo rohita juveniles. Hematological parameters are essential diagnostics used to estimate the health status of fish. The usage of probiotics for fish health improvement is becoming common due to the higher demand for environment-friendly culture system in water. Linseed meal was used as a test ingredient to prepare six experimental test diets by adding probiotics (0, 1, 2, 3, 4 and 5 g/kg) and 1% indigestible chromic oxide for seventy days. According to their live wet weight, five percent feed was given to fingerlings twice a day. Fish blood and carcass samples (Whole body) were taken for hematological and carcass analysis at the end of the experiment. The highest carcass composition (crude protein; 18.72%, crude fat; 8.80% and gross energy; 2.31 kcal/g) was observed in fish fed with test diet II supplemented with probiotics (2 g/kg). Moreover, maximum RBCs number (2.62× 106mm-3), WBCs (7.84×103mm-3), PCV (24.61), platelets (63.85) and hemoglobin (7.87) had also been reported in the fish fingerlings fed on 2 g/kg of probiotics supplemented diet. Results indicated that probiotics supplementation has a critical role in improvement of fingerlings' body composition and hematological indices. Present findings showed that probiotics supplementation at 2 g/kg level in linseed by-product-based diet was very useful for enhancing the overall performance of L. rohita fingerlings.


Assuntos
Cyprinidae , Linho , Probióticos , Ração Animal/análise , Animais , Dieta/veterinária
6.
BMC Public Health ; 21(1): 1735, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34560858

RESUMO

BACKGROUND: Flood disaster preparedness among the community seldom received attention. Necessary intervention must be taken to prevent the problem. Health Education Based Intervention (HEBI) was developed following the Health Belief Model, particularly in improving flood disaster preparedness among the community. The main objective of this study is to assess the effect of HEBI on improving flood disaster preparedness among the community in Selangor. This study aims to develop, implement, and evaluate the impact of health education-based intervention (HEBI) based on knowledge, skills, and preparedness to improve flood disaster preparedness among the community in Selangor. METHOD: A single-blind cluster randomized controlled trial will conduct at six districts in Selangor. Randomly selected respondents who fulfilled the inclusion criteria will be invited to participate in the study. Health education module based on Health Believed Theory will be delivered via health talks and videos coordinated by liaison officers. Data at three-time points at baseline, immediate, and 3 months post-intervention will be collected. A validated questionnaire will assess participants' background characteristics, knowledge, skill, and preparedness on disaster preparedness and perception towards disaster. Descriptive and inferential statistics will be applied for data analysis using IBM Statistical Package for Social Sciences version 25. Longitudinal correlated data on knowledge, skills, preparedness, and perception score at baseline, immediate post-intervention, and 6 months post-intervention will be analyzed using Generalized Estimating Equations (GEE). DISCUSSION: It is expected that knowledge, skills, preparedness, and flood disaster perception score are more significant in the intervention group than the control group, indicating the Health Education Based Intervention (HEBI). TRIAL REGISTRATION: Thai Clinical Trial TCTR20200202002 .

7.
J Med Chem ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570513

RESUMO

The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.

8.
Nat Commun ; 12(1): 5543, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545078

RESUMO

N6,2'-O-dimethyladenosine (m6Am) is an abundant RNA modification located adjacent to the 5'-end of the mRNA 7-methylguanosine (m7G) cap structure. m6A methylation on 2'-O-methylated A at the 5'-ends of mRNAs is catalyzed by the methyltransferase Phosphorylated CTD Interacting Factor 1 (PCIF1). The role of m6Am and the function of PCIF1 in regulating host-pathogens interactions are unknown. Here, we investigate the dynamics and reprogramming of the host m6Am RNA methylome during HIV infection. We show that HIV infection induces a dramatic decrease in m6Am of cellular mRNAs. By using PCIF1 depleted T cells, we identify 2237 m6Am genes and 854 are affected by HIV infection. Strikingly, we find that PCIF1 methyltransferase function restricts HIV replication. Further mechanism studies show that HIV viral protein R (Vpr) interacts with PCIF1 and induces PCIF1 ubiquitination and degradation. Among the m6Am genes, we find that PCIF1 inhibits HIV infection by enhancing a transcription factor ETS1 (ETS Proto-Oncogene 1, transcription factor) stability that binds HIV promoter to regulate viral transcription. Altogether, our study discovers the role of PCIF1 in HIV-host interactions, identifies m6Am modified genes in T cells which are affected by viral infection, and reveals how HIV regulates host RNA epitranscriptomics through PCIF1 degradation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina/análogos & derivados , HIV-1/metabolismo , Proteínas Nucleares/metabolismo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo , Regiões 5' não Traduzidas/genética , Adenosina/metabolismo , Genoma Viral , Infecções por HIV/virologia , HIV-1/genética , Humanos , Metilação , Estabilidade Proteica , Proteólise , Proteína Proto-Oncogênica c-ets-1/metabolismo , RNA/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , Transcrição Genética , Replicação Viral
9.
Retina ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34267118

RESUMO

PURPOSE: To explore the characteristics of choroidal tissue in patients with and without central serous chorioretinopathy (CSC) using an automated system of image analysis to determine known and novel metrics. METHODS: This was a retrospective case-control analysis of optical coherence tomography (OCT) scans of patients seen at Manchester Royal Eye Hospital, UK, comparing patients with active CSC to an age and gender-matched group with no CSC using a purpose-built automated system of image analysis. The expert system segments and measures established and novel features of choroid using a combination of thresholding, noise removal and morphological techniques. RESULTS: A total of 72 patients were included in this study, with 40 included in the group with CSC and 32 patient controls with no CSC. There were significant increases from normal to CSC of median choroidal vascular index, 54.7(Median absolute deviation=9.8) to 61.2(4.3) and all choroidal thickness indices including maximum depth, from 249.0(90.1) µm to 372.3(80.3) µm. For novel measures there was a significant increase in tissue entropy from 6.68(0.28) to 6.95(0.17) and area of the largest five vessels from 6.28(3.04) mm2 to 9.10(3.49) mm2. The ratio of vessel lumen to stromal tissue intensity was conversely significantly reduced from 0.674(0.11) in normal patients to 0.59(0.06) in CSC. CONCLUSIONS: The automated system of choroidal analysis expands on the utility of known measures and introduces novel metrics. These findings contribute pathophysiological insights and metrics for further assessment and research on conditions affecting choroidal tissue.

10.
Ann Saudi Med ; 41(3): 147-156, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34085548

RESUMO

BACKGROUND: Multiple studies have investigated medication errors in hospitals in Saudi Arabia; however, prevalence data on prescribing errors and associated factors remains uncertain. OBJECTIVE: Assess the prevalence, type, severity, and factors associated with prescribing errors. DESIGN: Retrospective database review. SETTING: Large tertiary care setting in Riyadh. PATIENTS AND METHODS: We described and analyzed data related to prescribing errors in adults (>14 years of age) from the Medication Error Electronic Report Forms database for the two-year period from January 2017 to December 2018. MAIN OUTCOME MEASURE: The prevalence of prescribing errors and associated factors among adult patients. SAMPLE SIZE: 315 166 prescriptions screened. RESULTS: Of the total number of inpatient and outpatient prescriptions screened, 4934 prescribing errors were identified for a prevalence of 1.56%. The most prevalent types of prescribing errors were improper dose (n=1516; 30.7%) and frequency (n=987; 20.0%). Two-thirds of prescribing errors did not cause any harm to patients. Most prescribing errors were made by medical residents (n=2577; 52%) followed by specialists (n=1629; 33%). Prescribing errors were associated with a lack of documenting clinical information (adjusted odds ratio: 14.1; 95% CI 7.7-16.8, P<.001) and prescribing anti-infective medications (adjusted odds ratio 2.9; 95% CI 1.3-5.7, P<.01). CONCLUSION: Inadequate documentation in electronic health records and prescribing of anti-infective medications were the most common factors for predicting prescribing errors. Future studies should focus on testing innovative measures to control these factors and their impact on minimizing prescribing errors. LIMITATIONS: Polypharmacy was not considered; the data are from a single healthcare system. CONFLICT OF INTEREST: None.


Assuntos
Prescrições de Medicamentos , Erros de Medicação , Adulto , Humanos , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Atenção Terciária à Saúde
11.
Food Chem Toxicol ; 154: 112354, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34146620

RESUMO

Preparations of the fungus Cordyceps sinensis and bovine colostrum are considered nutraceuticals due to their anti-inflammatory, repair and gut alimentation properties in mammalian models. To reduce the reliance on rodents in routine experimentation, we gauged the capacity of nutraceuticals to alleviate gastric damage in an insect surrogate, Galleria mellonella. Larvae were reared on standard or supplemented diets - 10% (w/w) colostrum, 10% (w/w) C. sinensis, or 5% + 5% each - prior to receiving an oral dose of the NSAID indomethacin (30 mg/kg) or challenged with the bacterial pathogen Campylobacter jejuni (1-3 x106) via two inoculation routes. Insects reared on a cordyceps-supplemented diet proved most resistant to indomethacin-induced gut leakiness, and displayed stable health indices after C. jejuni challenge (~77% survival). Insects reared on a colostrum-supplemented diet also showed recalcitrance in the gut, but were more sensitive to C. jejuni when injected directly into the body cavity (50% survival). The nutraceutical blend yielded improved health outcomes when compared to the standard diet, but was not as effective as either nutraceutical alone. Our findings represent clear evidence that insects were more resistant to known chemical and microbial agitators when reared on nutraceutical-supplemented diets - toxicological endpoints that are shared with vertebrate studies.

12.
BMC Health Serv Res ; 21(1): 432, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957900

RESUMO

BACKGROUND: Prescribing errors (PEs) are a common cause of morbidity and mortality, both in community practice and in hospitals. Pharmacists have an essential role in minimizing and preventing PEs, thus, there is a need to document the nature of pharmacists' interventions to prevent PEs. The purpose of this study was to describe reported interventions conducted by pharmacists to prevent or minimize PEs in a tertiary care hospital. METHODS: A retrospective analysis of the electronic medical records data was conducted to identify pharmacists' interventions related to reported PEs. The PE-related data was extracted for a period of six-month (April to September 2017) and comprised of patient demographics, medication-related information, and the different interventions conducted by the pharmacists. The study was carried in a tertiary care hospital in Riyadh region. The study was ethically reviewed and approved by the hospital IRB committee. Descriptive analyses were appropriately conducted using the IBM SPSS Statistics. RESULTS: A total of 2,564 pharmacists' interventions related to PEs were recorded. These interventions were reported in 1,565 patients. Wrong dose (54.3 %) and unauthorized prescription (21.9 %) were the most commonly encountered PEs. Anti-infectives for systemic use (49.2 %) and alimentary tract and metabolism medications (18.2 %) were the most common classes involved with PEs. The most commonly reported pharmacists' interventions were dose adjustments (44.0 %), restricted medication approvals (21.9 %), and therapeutic duplications (11 %). CONCLUSIONS: In this study, PEs occurred commonly and pharmacists' interventions were critical in preventing possible medication related harm to patients. Care coordination and prioritizing patient safety through quality improvement initiatives at all levels of the health care system can play a key role in this quality improvement drive. Future studies should evaluate the impact of pharmacists' interventions on patient outcomes.


Assuntos
Farmacêuticos , Serviço de Farmácia Hospitalar , Estudos Transversais , Hospitais , Humanos , Pacientes Internados , Erros de Medicação/prevenção & controle , Papel Profissional , Estudos Retrospectivos
13.
Dev Comp Immunol ; 122: 104126, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33965446

RESUMO

The co-evolutionary arms race between disease-causing agents and their insect victims is ancient and complex - leading to the development of specialised attack and defence strategies. Among such strategies is the capacity of fungal and oomycete pathogens to deploy degradative enzymes, notably proteases, to facilitate infection directly across the integument. To counter these proteases, insects such as the greater wax moth Galleria mellonella release metalloprotease inhibitors and other immune factors to thwart the invading fungus. To date, molecular-based confirmation of insect metalloprotease inhibitor's incontrovertible role in antifungal defence has been lacking. We targeted the IMPI gene for suppression using RNAi and exposed those insects to the entomopathogenic fungus Metarhizium brunneum ARSEF4556. Levels of IMPI were reduced significantly in the integument (10-fold) and fat body (5-fold) of RNAi-treated insects when compared to control larvae, and displayed a significantly higher mortality rate. We also surveyed candidate immune/detoxification gene expression levels (e.g., DOPA decarboxylase, galiomycin) in three tissues (integument, midgut, fat body) in order to gauge any potential non-target effects of RNAi. The loss of IMPI via RNAi compromises antifungal defences and leaves G. mellonella vulnerable to infection.

14.
Cell Rep ; 35(6): 109091, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33961823

RESUMO

It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.


Assuntos
COVID-19/genética , Metiltransferases/metabolismo , SARS-CoV-2/genética , Adenosina/metabolismo , COVID-19/metabolismo , Linhagem Celular , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Humanos , Imunidade Inata/genética , Metilação , Metiltransferases/genética , RNA Viral/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , SARS-CoV-2/patogenicidade , Transdução de Sinais
15.
Stem Cell Reports ; 16(3): 437-445, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33631122

RESUMO

COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.


Assuntos
Encéfalo/virologia , COVID-19/virologia , Células-Tronco Pluripotentes Induzidas/virologia , Pulmão/virologia , Células-Tronco Neurais/virologia , Organoides/virologia , SARS-CoV-2/patogenicidade , Apoptose/fisiologia , Encéfalo/metabolismo , COVID-19/metabolismo , Células Cultivadas , Proteínas do Sistema Complemento/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Inflamação/metabolismo , Inflamação/virologia , Pulmão/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Neurônios/virologia , Organoides/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Células-Tronco/virologia
16.
Ophthalmol Ther ; 10(1): 1-3, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33528760

RESUMO

2020 will forever be marked as a year that brought with it an unprecedented number of challenges for the healthcare community. COVID-19 had monumental effects on all fields, including ophthalmology. Considering this we are truly thankful for all of the support we have received, despite the pressures brought about by the pandemic. We are very grateful to our Editorial and Advisory boards who have continued to offer their advice, to our authors for working with us to help publish their work, and to our readers for engaging with our content. The Editorial below has been authored by Ophthalmology and Therapy's EU Editor-in-Chief Professor Tariq Aslam. Professor Aslam writes about his aspirations for the healthcare and ophthalmology community in 2021, and how the journal hopes to play its part in facing these challenges.

17.
Small ; 17(15): e2006050, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502104

RESUMO

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor characterized by high cellular and molecular heterogeneity, hypervascularization, and innate drug resistance. Cellular components and extracellular matrix (ECM) are the two primary sources of heterogeneity in GBM. Here, biomimetic tri-regional GBM models with tumor regions, acellular ECM regions, and an endothelial region with regional stiffnesses patterned corresponding to the GBM stroma, pathological or normal brain parenchyma, and brain capillaries, are developed. Patient-derived GBM cells, human endothelial cells, and hyaluronic acid derivatives are used to generate a species-matched and biochemically relevant microenvironment. This in vitro study demonstrates that biophysical cues are involved in various tumor cell behaviors and angiogenic potentials and promote different molecular subtypes of GBM. The stiff models are enriched in the mesenchymal subtype, exhibit diffuse invasion of tumor cells, and induce protruding angiogenesis and higher drug resistance to temozolomide. Meanwhile, the soft models demonstrate enrichment in the classical subtype and support expansive cell growth. The three-dimensional bioprinting technology utilized in this study enables rapid, flexible, and reproducible patient-specific GBM modeling with biophysical heterogeneity that can be employed by future studies as a tunable system to interrogate GBM disease mechanisms and screen drug compounds.


Assuntos
Bioimpressão , Neoplasias Encefálicas , Glioblastoma , Linhagem Celular Tumoral , Células Endoteliais , Humanos , Microambiente Tumoral
18.
ACS Chem Biol ; 16(2): 324-333, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33412003

RESUMO

N6-methyladenosine (m6A) has emerged as the most abundant mRNA modification that regulates gene expression in many physiological processes. m6A modification in RNA controls cellular proliferation and pluripotency and has been implicated in the progression of multiple disease states, including cancer. RNA m6A methylation is controlled by a multiprotein "writer" complex including the enzymatic factor methyltransferase-like protein 3 (METTL3) that regulates methylation and two "eraser" proteins, RNA demethylase ALKBH5 (ALKBH5) and fat mass- and obesity-associated protein (FTO), that demethylate m6A in transcripts. FTO can also demethylate N6,2'-O-dimethyladenosine (m6Am), which is found adjacent to the m7G cap structure in mRNA. FTO has recently gained interest as a potential cancer target, and small molecule FTO inhibitors such as meclofenamic acid have been shown to prevent tumor progression in both acute myeloid leukemia and glioblastoma in vivo models. However, current FTO inhibitors are unsuitable for clinical applications due to either poor target selectivity or poor pharmacokinetics. In this work, we describe the structure-based design, synthesis, and biochemical evaluation of a new class of FTO inhibitors. Rational design of 20 small molecules with low micromolar IC50's and specificity toward FTO over ALKBH5 identified two competitive inhibitors FTO-02 and FTO-04. Importantly, FTO-04 prevented neurosphere formation in patient-derived glioblastoma stem cells (GSCs) without inhibiting the growth of healthy neural stem cell-derived neurospheres. Finally, FTO-04 increased m6A and m6Am levels in GSCs consistent with FTO inhibition. These results support FTO-04 as a potential new lead for treatment of glioblastoma.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Adenosina/análogos & derivados , Adenosina/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Desmetilação/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Simulação de Acoplamento Molecular , Células-Tronco Neoplásicas , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , RNA/química , RNA/metabolismo
19.
BMC Genomics ; 22(1): 87, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509090

RESUMO

BACKGROUND: More accurate and complete reference genomes have improved understanding of gene function, biology, and evolutionary mechanisms. Hybrid genome assembly approaches leverage benefits of both long, relatively error-prone reads from third-generation sequencing technologies and short, accurate reads from second-generation sequencing technologies, to produce more accurate and contiguous de novo genome assemblies in comparison to using either technology independently. In this study, we present a novel hybrid assembly pipeline that allowed for both mitogenome de novo assembly and telomere length de novo assembly of all 7 chromosomes of the model entomopathogenic fungus, Metarhizium brunneum. RESULTS: The improved assembly allowed for better ab initio gene prediction and a more BUSCO complete proteome set has been generated in comparison to the eight current NCBI reference Metarhizium spp. genomes. Remarkably, we note that including the mitogenome in ab initio gene prediction training improved overall gene prediction. The assembly was further validated by comparing contig assembly agreement across various assemblers, assessing the assembly performance of each tool. Genomic synteny and orthologous protein clusters were compared between Metarhizium brunneum and three other Hypocreales species with complete genomes, identifying core proteins, and listing orthologous protein clusters shared uniquely between the two entomopathogenic fungal species, so as to further facilitate the understanding of molecular mechanisms underpinning fungal-insect pathogenesis. CONCLUSIONS: The novel assembly pipeline may be used for other haploid fungal species, facilitating the need to produce high-quality reference fungal genomes, leading to better understanding of fungal genomic evolution, chromosome structuring and gene regulation.


Assuntos
Genoma Mitocondrial , Metarhizium , Sequenciamento de Nucleotídeos em Larga Escala , Metarhizium/genética , Análise de Sequência de DNA , Telômero/genética
20.
PLoS One ; 16(1): e0245321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33434202

RESUMO

OBJECTIVES: Evidence regarding the prevalence of medication prescribing errors (PEs) and potential factors that increase PEs among patients treated in the emergency department (ED) are limited. This study aimed to explore the prevalence and nature of PEs in discharge prescriptions in the ED and identify potential risk factors associated with PEs. METHODS: This was a prospective observational cross-sectional study in an ambulatory ED in a tertiary teaching hospital. Data were collected for six months using a customized reporting tool. All patients discharged from ED with a discharged prescription within the study period were enrolled in this study. RESULTS: About 13.5% (n = 68) of the 504 prescriptions reviewed (for 504 patients) had at least one error. Main PEs encountered were wrong dose (23.2%), wrong frequency (20.7%), and wrong strength errors (14.6%). About 36.8% of identified PEs were related to pediatric prescriptions, followed by the acute care emergency unit (26.5%) and the triage emergency unit (20.6%). The main leading human-related causes associated with PEs were lack of knowledge (40.9%) followed by an improper selection from a computer operator list (31.8%). The leading contributing systems related factors were pre-printed medication orders (50%), lack of training (31.5%), noise level (13.0%), and frequent interruption of prescriber and distraction (11.1%). Prescribers' involved with the identified errors were resident physicians (39.4%), specialists (30.3%), and (24.4%) were made by general practitioners. Physicians rejected around 12% of the pharmacist-raised recommendations related to the identified PEs as per their clinical judgment. CONCLUSION: PEs in ED setting are common, and multiple human and systems-related factors may contribute to the development of PEs. Further training to residents and proper communication between the healthcare professionals may reduce the risk of PEs in ED.


Assuntos
Erros de Medicação/estatística & dados numéricos , Estudos Transversais , Prescrições de Medicamentos , Serviço Hospitalar de Emergência , Feminino , Hospitais de Ensino , Humanos , Prescrição Inadequada , Conhecimento , Masculino , Alta do Paciente , Médicos/psicologia , Médicos/estatística & dados numéricos , Estudos Prospectivos , Centros de Atenção Terciária
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