Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 535
Filtrar
1.
mSystems ; : e0057421, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34636670

RESUMO

The technological leap of DNA sequencing generated a tension between modern metagenomics and historical microbiology. We are forcibly harmonizing the output of a modern tool with centuries of experimental knowledge derived from culture-based microbiology. As a thought experiment, we borrow the notion of Cartesian doubt from philosopher Rene Descartes, who used doubt to build a philosophical framework from his incorrigible statement that "I think therefore I am." We aim to cast away preconceived notions and conceptualize microorganisms through the lens of metagenomic sequencing alone. Specifically, we propose funding and building analysis and engineering methods that neither search for nor rely on the assumption of independent genomes bound by lipid barriers containing discrete functional roles and taxonomies. We propose that a view of microbial communities based in sequencing will engender novel insights into metagenomic structure and may capture functional biology not reflected within the current paradigm.

2.
J Manag Care Spec Pharm ; 27(10): 1438-1446, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34595953

RESUMO

BACKGROUND: Oral oncolytics are becoming increasingly common in the treatment of solid and hematological malignancies. Medication adherence is especially important to ensure adequate drug levels to treat active malignancies, notably in curative-intent therapy. Further data are needed to quantify and confirm the effects of internal health-system specialty pharmacies (HSSPs) on medication adherence. OBJECTIVE: To confirm the effect of an internal HSSP compared with external specialty pharmacies on oncolytic adherence as measured by proportion of days covered (PDC), medication possession ratio (MPR), and time to treatment (TTT). METHODS: This single-center retrospective cohort study included patients receiving oral oncolytics through an internal HSSP or external specialty pharmacies between January 2019 and June 2020. Fill data were extracted from pharmacy claims databases and electronic medical records. The primary adherence outcome was patient-level PDC. Secondary adherence outcomes included patient-level MPR and TTT. For PDC and MPR analyses, patients with at least 3 fills per oncolytic were included. All patients were included for the TTT analysis. Chi-square or Fisher's exact tests were used to analyze categorical differences between pharmacy groups. Differences in continuous variables across pharmacy groups were evaluated using Wilcoxon rank-sum tests. RESULTS: 871 prescriptions met inclusion criteria: 549 patients were included in the PDC/MPR analysis, and 758 patients were included in the TTT analysis (patients might have multiple prescriptions). Patients who filled at an internal HSSP had a higher median PDC compared with those who filled at external specialty pharmacies (0.99 [IQR = 0.89-1.00] vs 0.91 [IQR = 0.76-0.98]; P < 0.01). The adherence rate as measured by MPR was higher for patients who used an internal HSSP compared with those who used external specialty pharmacies (MPR = 1.00 [IQR = 0.90-1.00] vs 0.93 [IQR = 0.76-1.00]; P < 0.01). Median TTT was lower for patients using the internal HSSP vs an external specialty pharmacy (5 days [IQR = 2-13] vs 27 days [IQR = 2-82], respectively; P < 0.01). CONCLUSIONS: Internal HSSP services improved adherence as measured by PDC and MPR. Significantly lower TTT was seen with the internal HSSP compared with external pharmacies. These data confirm and support use of internal HSSPs to dispense oral oncolytics for treatment of solid and hematological malignancies. DISCLOSURES: This study received no financial support. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

3.
J Am Soc Nephrol ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607911

RESUMO

Background: Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of GS, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a GS phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with GS-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced In NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF) and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV reduced maximal mitochondrial respiratory capacity in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a GS-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies.

4.
Sci Rep ; 11(1): 20295, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645849

RESUMO

Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

5.
Urol Oncol ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34580027

RESUMO

BACKGROUND: Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous ("high-low") cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC. METHODS: We used laboratory data for 3,385 patients diagnosed with mRCC from 2002 to 2017. We developed a LWAS framework, to examine the association with 53 common clinical laboratory tests results (641,712 measurements) and overall survival. We employed false-discovery rate to test the association of multiple laboratory tests with survival, and validated these results using 3 separate cohorts to generate a standardized hazard ratio (sHR), reported for a 1 standard deviation unit change in each laboratory test. RESULTS: The LWAS approach confirmed the association of laboratory values currently used in prognostic models with survival, including calcium (HR 1.35, 95%CI 1.24-1.48), leukocyte count (HR 1.40, 95%CI 1.30-1.51), platelet count (HR 1.36, 95%CI 1.27-1.51), and hemoglobin (HR 0.79, 95%CI 0.72-0.86). Use of these tests as continuous variables improved model performance. LWAS also identified acute phase reactants associated with survival not typically included in prognostic models, including serum albumin (HR 0.66, 95%CI 0.61-0.72), ferritin (HR 1.25, 95%CI 1.08-1.45), alkaline phosphatase (HR 1.31, 95%CI 1.23-1.40), and C-reactive protein (HR 1.70, 95%CI 1.14-2.53). CONCLUSIONS: Routinely measured laboratory tests can refine current prognostic models, facilitate comparisons across clinical trial cohorts, and match patients with specific systemic therapies.

6.
Dis Esophagus ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34553220

RESUMO

Telepathology, practicing pathology from a distance, allows experts to review cases without the need to transfer glass slides. Due to significant intra- and inter-observer variabilities in the histological evaluation of Barrett's esophagus (BE), current guidelines recommend expert consultation in cases of dysplasia. We aimed to determine whether telepathology using microscope videoconferencing can be reliably used for evaluation of BE. Biopsies from 62 patients with endoscopic findings of salmon colored mucosa extending ≥1 cm proximal to the gastroesophageal junction were randomly selected to represent benign esophagus, non-dysplastic BE, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Three gastrointestinal-trained pathologists reviewed the cases via videoconference microscopy followed by conventional microscopy. Intra-observer and pairwise inter-observer agreements between the conventional microscopy and videoconference methodologies were calculated for each of the three pathologists using Fleiss-Cohen weighted kappa (K) analysis. The intra-observer agreement for each pathologist's assessment of videoconference microscopy and glass slide readings showed very good reliability (K = 0.94, 95% confidence interval = 0.89-0.99; 0.88, 95% confidence interval = 0.79-0.98; 0.93, 95% confidence interval = 0.90-0.97). Mean pairwise inter-observer agreement was 0.90 for videoconference and 0.91 for conventional microscopy. Diagnosis and grading of BE using videoconference microscopy show similar reliability as conventional microscopy. Based on our findings, we propose that videoconferencing pathology is a valid instrument for evaluating BE.

7.
PLoS Biol ; 19(9): e3001398, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34555021

RESUMO

Hypothesis generation in observational, biomedical data science often starts with computing an association or identifying the statistical relationship between a dependent and an independent variable. However, the outcome of this process depends fundamentally on modeling strategy, with differing strategies generating what can be called "vibration of effects" (VoE). VoE is defined by variation in associations that often lead to contradictory results. Here, we present a computational tool capable of modeling VoE in biomedical data by fitting millions of different models and comparing their output. We execute a VoE analysis on a series of widely reported associations (e.g., carrot intake associated with eyesight) with an extended additional focus on lifestyle exposures (e.g., physical activity) and components of the Framingham Risk Score for cardiovascular health (e.g., blood pressure). We leveraged our tool for potential confounder identification, investigating what adjusting variables are responsible for conflicting models. We propose modeling VoE as a critical step in navigating discovery in observational data, discerning robust associations, and cataloging adjusting variables that impact model output.

8.
BMC Med ; 19(1): 249, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34565368

RESUMO

BACKGROUND: For some SARS-CoV-2 survivors, recovery from the acute phase of the infection has been grueling with lingering effects. Many of the symptoms characterized as the post-acute sequelae of COVID-19 (PASC) could have multiple causes or are similarly seen in non-COVID patients. Accurate identification of PASC phenotypes will be important to guide future research and help the healthcare system focus its efforts and resources on adequately controlled age- and gender-specific sequelae of a COVID-19 infection. METHODS: In this retrospective electronic health record (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive reverse transcription-polymerase chain reaction (RT-PCR) test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3-6 and 6-9 months after the test and by age and gender. Data from longitudinal diagnosis records stored in EHRs from Mass General Brigham in the Boston Metropolitan Area was used for the analyses. Statistical analyses were performed on data from March 2020 to June 2021. Study participants included over 96 thousand patients who had tested positive or negative for COVID-19 and were not hospitalized. RESULTS: We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients' medical records 2 months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.60, 95% CI [1.94-3.46]), alopecia (OR 3.09, 95% CI [2.53-3.76]), chest pain (OR 1.27, 95% CI [1.09-1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22-2.10]), shortness of breath (OR 1.41, 95% CI [1.22-1.64]), pneumonia (OR 1.66, 95% CI [1.28-2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22-1.64]) is one of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65. CONCLUSIONS: The findings of this study confirm many of the post-COVID-19 symptoms and suggest that a variety of new diagnoses, including new diabetes mellitus and neurological disorder diagnoses, are more common among those with a history of COVID-19 than those without the infection. Additionally, more than 63% of PASC phenotypes were observed in patients under 65 years of age, pointing out the importance of vaccination to minimize the risk of debilitating post-acute sequelae of COVID-19 among younger adults.


Assuntos
COVID-19 , COVID-19/complicações , COVID-19/diagnóstico , Humanos , Fenótipo , Estudos Retrospectivos
9.
Clin Cancer Res ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475101

RESUMO

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. EXPERIMENTAL DESIGN: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/µmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. RESULTS: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. CONCLUSIONS: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

10.
Environ Health Perspect ; 129(8): 85001, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34435882

RESUMO

BACKGROUND: Recent developments in technologies have offered opportunities to measure the exposome with unprecedented accuracy and scale. However, because most investigations have targeted only a few exposures at a time, it is hypothesized that the majority of the environmental determinants of chronic diseases remain unknown. OBJECTIVES: We describe a functional exposome concept and explain how it can leverage existing bioassays and high-resolution mass spectrometry for exploratory study. We discuss how such an approach can address well-known barriers to interpret exposures and present a vision of next-generation exposomics. DISCUSSION: The exposome is vast. Instead of trying to capture all exposures, we can reduce the complexity by measuring the functional exposome-the totality of the biologically active exposures relevant to disease development-through coupling biochemical receptor-binding assays with affinity purification-mass spectrometry. We claim the idea of capturing exposures with functional biomolecules opens new opportunities to solve critical problems in exposomics, including low-dose detection, unknown annotations, and complex mixtures of exposures. Although novel, biology-based measurement can make use of the existing data processing and bioinformatics pipelines. The functional exposome concept also complements conventional targeted and untargeted approaches for understanding exposure-disease relationships. CONCLUSIONS: Although measurement technology has advanced, critical technological, analytical, and inferential barriers impede the detection of many environmental exposures relevant to chronic-disease etiology. Through biology-driven exposomics, it is possible to simultaneously scale up discovery of these causal environmental factors. https://doi.org/10.1289/EHP8327.

11.
Pac Symp Biocomput ; 26: 309-315, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34409132

RESUMO

The environment plays an important role in mediating human health. In this session we consider research addressing ways to overcome the challenges associated with studying the multifaceted and ever-changing environment. Environmental health research has a need for technological and methodological advances which will further our knowledge of how exposures precipitate complex phenotypes and exacerbate disease.


Assuntos
Biologia Computacional , Saúde Ambiental , Humanos , Fenótipo
12.
J Comput Chem ; 42(26): 1861-1872, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34287986

RESUMO

Since December 2019, coronavirus disease (COVID-19) has claimed the lives of millions of people across the globe. To date, no medicine is available for the responsible virus SARS-CoV-2. 3CLpro, that is, 3-chymotrypsin-like protease, the main protease (Mpro ), has an important role in cleaving pp1a and pp1ab polyproteins. This Mpro serves as an important target in drug designing against COVID-19. Herein, the study includes the investigation, screening, and identification of potent leads from (Withania sps.), against SARS-CoV-2, using virtual screening, molecular docking, and molecular dynamics (MD) simulations. Seventy-three natural compounds from this important medicinal plant were screened. The Binding affinity was used to identify the most probable target to inhibit the Mpro , compounds 27-hydroxywithanolide F (W32, -11.5 kcal/mol), withanolide A (W56, -11.4 kcal/mol), and withacoagulin H (W30, -11.1 kcal/mol) showed highest binding energy. Lipinski's rule, followed by drug-likability and likeness screening, resulted in 36 molecules. Further, MD simulation of 50 ns predicted withacoagulin H possessing strong binding affinity and hydrogen-bonding interactions with the active site. The binding free energy calculation showed the most negative energy of withacoagulin H (-63.463 KJ/mol) compared to other selected compounds. The study also compared the bonding energy of already reported repurposed and newly synthesized drugs. Further, absorption, distribution, metabolism, and excretion predictions were made to found a good balance of potency. Hence the following screened compounds from Withania sps. could serve as the potential leads for drug development against COVID-19.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/enzimologia , Withania/química , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , SARS-CoV-2/efeitos dos fármacos
13.
J Biomol Struct Dyn ; : 1-20, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238127

RESUMO

Wild thyme (Thymus serpyllum L.) of family Laminaceae is an unexplored perennial medicinal shrub. Aerial part of this plant is traditionally used for the treatment of respiratory and gastrointestinal problems. The current study was designed to evaluate the GC-MS, antimicrobial and synergistic potential of T. serpyllum essential oil (TEO). Chemical characterization of TEO showed the presence of thymol (15.79%), Phenol, 2-(1,1-dimethylethyl) (11.55%), o-Cymene (10.96%) as major phytocompounds. Antimicrobial activity of TEO in terms zone of inhibition (ZOI) varied from 13.66 ± 0.58 mm to 33.66 ± 1.52 mm, while, thymol (10%, v/v) showed ZOI ranged from 15.5 ± 0.5 mm to 26.33 ± 2.08 mm against tested bacterial and fungal species. MIC of TEO was 0.039% to 0.078% against tested bacterial and fungal species, whereas, thymol showed 1.25% to 2.5% MIC against tested bacterial and fungal species. Different combinations of TEO (2MIC to ½MIC) and thymol (2MIC to ½MIC) with antibacterial and antifungal antibiotics (2MIC to ½MIC) were found to increase the efficacy of antibiotics by 4-130 folds against bacterial and fungal pathogens. Molecular docking showed the good binding of thymol with both bacterial and fungal targets. Whereas MD simulation showed the stability of thymol complexed with target proteins over 100 ns time scale. Thymol also fulfills the Lipinski rule and showed characteristics similar to that of drugs. Therefore, it can be concluded from the present study that TEO and its major phytocompound, thymol can act as a bioactivity enhancer of antibacterial and antifungal antibiotics and could be used as a potential candidate to fight against antimicrobial drug resistance.Communicated by Ramaswamy H. Sarma.

14.
Inform Med Unlocked ; : 100670, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34307830

RESUMO

Novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has claimed more than 3.3 million lives worldwide and still counting. As per the GISAID database, the genomics of SARS-CoV-2 has been extensively studied, with more than 500 genome submissions per day. Out of several hotspot mutations within the SARS-CoV-2 genome, recent research has focused mainly on the missense variants. Moreover, significantly less attention has been accorded to delineate the role of the untranslated regions (UTRs) of the SARS-CoV-2 genome in the disease progression and etiology. One of the most frequent 5' UTR variants in the SARS-CoV-2 genome is the C241T, with a global frequency of more than 95 %. In the present study, the effect of the C241T mutation has been studied with respect to the changes in RNA structure and its interaction with the host replication factors MADP1 Zinc finger CCHC-type and RNA-binding motif 1 (hnRNP1). The results obtained from molecular docking and molecular dynamics simulation indicated weaker interaction of C241T mutant stem-loops with the host transcription factor MADP1, indicating a reduced replication efficiency. The results are also correlated with increased recovery rates and decreased death rates of global SARS-CoV-2 cases.

15.
BMJ Open ; 11(7): e052287, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321310

RESUMO

OBJECTIVE: To better understand diverse experts' views about the ethical implications of ongoing research funded by the National Institutes of Health that uses machine learning to predict HIV/AIDS risk in sub-Saharan Africa (SSA) based on publicly available Demographic and Health Surveys data. DESIGN: Three rounds of semi-structured surveys in an online expert panel using a modified Delphi approach. PARTICIPANTS: Experts in informatics, African public health and HIV/AIDS and bioethics were invited to participate. MEASURES: Perceived importance of or agreement about relevance of ethical issues on 5-point unipolar Likert scales. Qualitative data analysis identified emergent themes related to ethical issues and development of an ethical framework and recommendations for open-ended questions. RESULTS: Of the 35 invited experts, 22 participated in the online expert panel (63%). Emergent themes were the inclusion of African researchers in all aspects of study design, analysis and dissemination to identify and address local contextual issues, as well as engagement of communities. Experts focused on engagement with health and science professionals to address risks, benefits and communication of findings. Respondents prioritised the mitigation of stigma to research participants but recognised trade-offs between privacy and the need to disseminate findings to realise public health benefits. Strategies for responsible communication of results were suggested, including careful word choice in presentation of results and limited dissemination to need-to-know stakeholders such as public health planners. CONCLUSION: Experts identified ethical issues specific to the African context and to research on sensitive, publicly available data and strategies for addressing these issues. These findings can be used to inform an ethical implementation framework with research stage-specific recommendations on how to use publicly available data for machine learning-based predictive analytics to predict HIV/AIDS risk in SSA.


Assuntos
Síndrome de Imunodeficiência Adquirida , África ao Sul do Saara , Técnica Delfos , Ética em Pesquisa , Humanos , Aprendizado de Máquina
16.
Am J Hum Genet ; 108(9): 1551-1557, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34329581

RESUMO

Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.


Assuntos
Consenso , Curadoria de Dados/normas , Doenças Genéticas Inatas/genética , Genômica/normas , Anotação de Sequência Molecular/normas , Austrália , Biomarcadores/metabolismo , Curadoria de Dados/métodos , Atenção à Saúde , Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Genômica/métodos , Humanos , Aplicativos Móveis/provisão & distribuição , Terminologia como Assunto , Reino Unido
17.
MMWR Morb Mortal Wkly Rep ; 70(24): 879-887, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34138835

RESUMO

Early during the COVID-19 pandemic, nearly two thirds of unpaid caregivers of adults reported adverse mental or behavioral health symptoms, compared with approximately one third of noncaregivers† (1). In addition, 27% of parents of children aged <18 years reported that their mental health had worsened during the pandemic (2). To examine mental health during the COVID-19 pandemic among U.S. adults on the basis of their classification as having a parenting role (i.e., unpaid persons caring for children and adolescents aged <18 years, referred to as children in this report) or being an unpaid caregiver of adults (i.e., persons caring for adults aged ≥18 years),§ CDC analyzed data from cross-sectional surveys that were administered during December 2020 and February-March 2021 for The COVID-19 Outbreak Public Evaluation (COPE) Initiative.¶ Respondents were categorized as parents only, caregivers of adults only, parents-caregivers (persons in both roles), or nonparents/noncaregivers (persons in neither role). Adjusted odds ratios (aORs) for any adverse mental health symptoms, particularly suicidal ideation, were higher among all respondents who were parents, caregivers of adults, or both compared with respondents who were nonparents/noncaregivers and were highest among persons in both roles (parents-caregivers) (any adverse mental health symptoms: aOR = 5.1, 95% confidence interval [CI] = 4.1-6.2; serious suicidal ideation: aOR = 8.2, 95% CI = 6.5-10.4). These findings highlight that parents and caregivers, especially those balancing roles both as parents and caregivers, experienced higher levels of adverse mental health symptoms during the COVID-19 pandemic than adults without these responsibilities. Caregivers who had someone to rely on for support had lower odds of experiencing any adverse mental health symptoms. Additional measures are needed to improve mental health among parents, caregivers, and parents-caregivers.


Assuntos
COVID-19/psicologia , Cuidadores/psicologia , Transtornos Mentais/epidemiologia , Pais/psicologia , Adolescente , Adulto , Idoso , COVID-19/epidemiologia , Cuidadores/economia , Cuidadores/estatística & dados numéricos , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto Jovem
18.
Aust J Gen Pract ; 50(6): 369-376, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34059843

RESUMO

BACKGROUND: Dry eye disease (DED) is a common condition frequently encountered yet underdiagnosed in primary care. It can lead to significant morbidity, affecting quality of life. The causes are numerous, while treatment is continually changing. OBJECTIVE: This article provides essential information on DED for the general practitioner. While the concept of DED can appear to be simple, several issues need to be considered before arriving at the diagnosis and initiating treatment. This article discusses the approach to DED based on pathophysiology, symptoms and examination, leading to appropriate and effective treatment. DISCUSSION: While DED appears to be underdiagnosed, there has been an increased effort to provide validated symptom questionnaires, such as the ocular surface disease index and five-item dry-eye questionnaire, to aid in diagnosing and grading the severity of DED. This has helped with deciding on best management and appropriate treatment options for the patient.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34140231

RESUMO

BACKGROUND: Radial access is now considered the preferred approach for coronary angiography and percutaneous coronary intervention because of the low risk of vascular complications. However, radial access failure is not uncommon, leading to crossover to a different access site. The CHA2DS2-VASc score is used to estimate stroke risk in patients with atrial fibrillation. Our study aimed to assess the CHA2DS2-VASc score in predicting failure of the transradial approach, resulting in crossover to transfemoral access (TFA) for coronary angiography. METHODS: We performed a single-center, non-randomized, retrospective study. The study included 1775 patients who underwent coronary angiography with or without subsequent percutaneous intervention between July 2018 and October 2019. The study population was divided into three groups based on the CHA2DS2-VASc score: low (≤2), intermediate (3-4), and high score (≥5) groups. The association between the CHA2DS2-VASc score and radial access failure was evaluated and compared between the groups. RESULTS: A total of 197 patients (11.1%) had crossover to the femoral artery. A large percentage of patients (19.2%) had radial access failure in the high CHA2DS2-VASc score group (≥5) compared with 12.5% in the intermediate score group (3-4) and only 6.3% in the low score group (≤2). The highest crossover rate (42.9%) was observed in patients with a CHA2DS2-VASc score of 8. Higher CHA2DS2-VASc scores were also associated with increased fluoroscopy time, contrast administration, and radiation exposure. CONCLUSION: The CHA2DS2-VASc score can predict failure of the transradial approach, with a score of ≥5 having the highest correlation of failure requiring crossover to TFA.

20.
Theranostics ; 11(15): 7130-7143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158840

RESUMO

Rationale: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods: Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo, to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results: No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions: Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.


Assuntos
Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos , Glioma , Indóis/administração & dosagem , Proteínas de Neoplasias/metabolismo , Imagem Óptica , Panitumumabe/administração & dosagem , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Feminino , Glioma/diagnóstico por imagem , Glioma/metabolismo , Glioma/cirurgia , Humanos , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...