Publications by authors named "Yash Patel"

55 Publications

'It makes life so much easier'-experiences of users of the MicroGuide™ smartphone app for improving antibiotic prescribing behaviour in UK hospitals: an interview study.

JAC Antimicrob Resist 2021 Sep 12;3(3):dlab111. Epub 2021 Aug 12.

Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.

Objectives: To understand the impact on prescribing behaviour of an antimicrobial therapy guidelines smartphone app, in widespread use in hospitals in the UK.

Methods: Twenty-eight doctors and five nurse prescribers from four purposively selected hospitals in the UK participated in behavioural theory-informed semi-structured interviews about their experiences of using the MicroGuide™ smartphone app. Data were analysed using a thematic content analysis.

Results: Five themes emerged from the interview data: convenience and accessibility; validation of prescribing decisions; trust in app content; promotion of antimicrobial stewardship; and limitations and concerns. Participants appreciated the perceived convenience, accessibility and timesaving attributes of the app, potentially contributing to more prompt treatment of patients with time-critical illness. The interviewees also reported finding it reassuring to use the app to support decision-making and to validate existing knowledge. They trusted the app content authored by local experts and considered it to be evidence-based and up-to-date. This was believed to result in fewer telephone calls to the microbiology department for advice. Participants recognized the value of the app for supporting the goals of antimicrobial stewardship by promoting the responsible and proportionate use of antimicrobials. Finally, a number of limitations of the app were reported, including the risk of de-skilling trainees, cultural problems with using smartphones in clinical environments and software technical problems.

Conclusions: The MicroGuide app was valued as a means of addressing an unmet need for updated, concise, trustworthy specialist information in an accessible format at the bedside to support safe and effective antimicrobial prescribing.
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http://dx.doi.org/10.1093/jacamr/dlab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496772PMC
September 2021

Cardiovascular magnetic resonance findings in young adult patients with acute myocarditis following mRNA COVID-19 vaccination: a case series.

J Cardiovasc Magn Reson 2021 09 9;23(1):101. Epub 2021 Sep 9.

Division of Cardiology, Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Background: Messenger RNA (mRNA) coronavirus disease of 2019 (COVID-19) vaccine are known to cause minor side effects at the injection site and mild global systemic symptoms in first 24-48 h. Recently published case series have reported a possible association between acute myocarditis and COVID-19 vaccination, predominantly in young males.

Methods: We report a case series of 5 young male patients with cardiovascular magnetic resonance (CMR)-confirmed acute myocarditis within 72 h after receiving a dose of an mRNA-based COVID-19 vaccine.

Results: Our case series suggests that myocarditis in this setting is characterized by myocardial edema and late gadolinium enhancement in the lateral wall of the left ventricular (LV) myocardium, reduced global LV longitudinal strain, and preserved LV ejection fraction. All patients in our series remained clinically stable during a relatively short inpatient hospital stay.

Conclusions: In conjunction with other recently published case series and national vaccine safety surveillance data, this case series suggests a possible association between acute myocarditis and COVID-19 vaccination in young males and highlights a potential pattern in accompanying CMR abnormalities.
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http://dx.doi.org/10.1186/s12968-021-00795-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425992PMC
September 2021

Demographic Pattern and Mortality Risk Factors for Prescription Opioid Overdose Hospitalizations: Results From Nationwide Inpatient Sample Analysis.

Cureus 2021 Jun 15;13(6):e15674. Epub 2021 Jun 15.

Psychiatry, Drexel University College of Medicine, Philadelphia, USA.

Objectives To explore the demographic patterns of hospitalizations related to prescription opioid overdose (POD) and evaluate the mortality risk of association in POD inpatients. Methodology We conducted a cross-sectional study using the Nationwide Inpatient Sample of 184,711 POD inpatients. A binomial logistic regression model was used to evaluate the odds ratio (OR) of association for mortality risk due to comorbidities (substance use disorders (SUD) and medical complications) in POD inpatients. Results POD inpatients were majorly females (54.1%), older adults aged 51-75 years (48.5%), whites (81.5%), and from lower household income quartet (32.8%). The most prevalent comorbid SUD among POD inpatients was alcohol (15.7%), followed by cannabis (5.7%), cocaine (4.2%), and amphetamine (1.8%). Comorbid alcohol use disorders had a minimally increased association with mortality but were not statistically significant (OR = 1.036; P = 0.438). POD in patients with cardiac arrest had the highest risk of mortality (OR = 103.423; P < 0.001), followed by shock (OR = 15.367; P < 0.001), coma (OR = 13.427; P < 0.001), and respiratory failure (OR = 12.051; P < 0.001). Conclusions Our study indicates that the hospitalizations related to POD were more prevalent among females, elders between 51 and 75 years of age, whites, and those in the lower household income quartet. The prevalence of prescription opioid use and the hospitalization related to POD remains a significant public health issue. POD inpatients with medical complications were at a higher risk of mortality than with comorbid SUD.
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http://dx.doi.org/10.7759/cureus.15674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281797PMC
June 2021

Mediterranean, DASH, and Alternate Healthy Eating Index Dietary Patterns and Risk of Death in the Physicians' Health Study.

Nutrients 2021 May 31;13(6). Epub 2021 May 31.

Department of Medicine, Division of Aging, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA.

Objective: Our primary objective was to examine the associations of the Mediterranean (MED), the Dietary Approaches to Stop Hypertension (DASH), and the Alternate Healthy Eating Index (AHEI) diet with total mortality. Our secondary objective was to examine the association of these three dietary patterns with cardiovascular disease (CVD) and cancer mortality.

Research: Design and Methods: We prospectively studied 15,768 men from the Physicians' Health Study who completed a semi-quantitative food-frequency questionnaire. Scores from each dietary pattern were divided into quintiles. Multivariable Cox regression models were used to estimate hazard ratio's (95% confidence intervals) of mortality.

Results: At baseline, average age was 65.9 ± 8.9 years. There were 1763 deaths, including 488 CVD deaths and 589 cancer deaths. All diet scores were inversely associated with risk for all-cause mortality: Hazard ratios (95% CI) of all-cause mortality from lowest to highest quintile for MED diet were 1.0 (reference), 0.85 (0.73-0.98), 0.80 (0.69-0.93), 0.77 (0.66-0.90), and 0.68 (0.58-0.79); corresponding values were 1.0 (reference), 0.96 (0.82-1.12), 0.95 (0.82-1.11), 0.88 (0.75-1.04), and 0.83 (0.71-0.99) for DASH diet and 1.0 (reference), 0.88 (0.77-1.02), 0.82 (0.71-0.95), 0.69 (0.59, 0.81), and 0.56 (0.47-0.67) for AHEI diet, after adjusting for age, energy, smoking, exercise, BMI, hypertension, coronary heart disease, congestive heart failure, diabetes, and atrial fibrillation. For cause-specific mortality, MED and AHEI scores were inversely associated with lower risk for CVD mortality, whereas AHEI and MED scores were inversely associated with lower risk for cancer mortality.

Conclusion: Within this cohort of male physicians, AHEI, MED, and DASH scores were each inversely associated with mortality from all causes.
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http://dx.doi.org/10.3390/nu13061893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227858PMC
May 2021

Sugar-Sweetened Beverage Consumption and Calcified Atherosclerotic Plaques in the Coronary Arteries: The NHLBI Family Heart Study.

Nutrients 2021 May 22;13(6). Epub 2021 May 22.

Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA.

Background: Sugar-sweetened beverage (SSB) intake is associated with higher risk of weight gain, diabetes, hypertension, cardiovascular disease, and cardiovascular mortality. However, the association of SSB with subclinical atherosclerosis in the general population is unknown.

Objective: Our primary objective was to investigate the association between SSB intake and prevalence of atherosclerotic plaque in the coronary arteries in The National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study.

Methods: We studied 1991 participants of the NHLBI Family Heart Study without known coronary heart disease. Intake of SSB was assessed through a semi-quantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac Computed Tomography (CT) and prevalent CAC was defined as an Agatston score ≥100. We used generalized estimating equations to calculate adjusted prevalence ratios of CAC. A sensitivity analysis was also performed at different ranges of cut points for CAC.

Results: Mean age and body mass index (BMI) were 55.0 years and 29.5 kg/m, respectively, and 60% were female. In analysis adjusted for age, sex, BMI, smoking, alcohol use, physical activity, energy intake, and field center, higher SSB consumption was not associated with higher prevalence of CAC [prevalence ratio (95% confidence interval) of: 1.0 (reference), 1.36 (0.70-2.63), 1.69 (0.93-3.09), 1.21 (0.69-2.12), 1.05 (0.60-1.84), and 1.58 (0.85-2.94) for SSB consumption of almost never, 1-3/month, 1/week, 2-6/week, 1/day, and ≥2/day, respectively (p for linear trend 0.32)]. In a sensitivity analysis, there was no evidence of association between SSB and prevalent CAC when different CAC cut points of 0, 50, 150, 200, and 300 were used.

Conclusions: These data do not provide evidence for an association between SSB consumption and prevalent CAC in adult men and women.
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http://dx.doi.org/10.3390/nu13061775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224703PMC
May 2021

Control of Multigene Expression Stoichiometry in Mammalian Cells Using Synthetic Promoters.

ACS Synth Biol 2021 05 3;10(5):1155-1165. Epub 2021 May 3.

Department of Chemical and Biological Engineering, The University of Sheffield, Mappin Street, Sheffield, S1 3JD, U.K.

To successfully engineer mammalian cells for a desired purpose, multiple recombinant genes are required to be coexpressed at a specific and optimal ratio. In this study, we hypothesized that synthetic promoters varying in transcriptional activity could be used to create single multigene expression vectors coexpressing recombinant genes at a predictable relative stoichiometry. A library of 27 multigene constructs was created comprising three discrete fluorescent reporter gene transcriptional units in fixed series, each under the control of either a relatively low, medium, or high transcriptional strength synthetic promoter in every possible combination. Expression of each reporter gene was determined by absolute quantitation qRT-PCR in CHO cells. The synthetic promoters did generally function as designed within a multigene vector context; however, significant divergences from predicted promoter-mediated transcriptional activity were observed. First, expression of all three genes within a multigene vector was repressed at varying levels relative to coexpression of identical reporter genes on separate single gene vectors at equivalent gene copies. Second, gene positional effects were evident across all constructs where expression of the reporter genes in positions 2 and 3 was generally reduced relative to position 1. Finally, after accounting for general repression, synthetic promoter transcriptional activity within a local multigene vector format deviated from that expected. Taken together, our data reveal that mammalian synthetic promoters can be employed in vectors to mediate expression of multiple genes at predictable relative stoichiometries. However, empirical validation of functional performance is a necessary prerequisite, as vector and promoter design features can significantly impact performance.
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http://dx.doi.org/10.1021/acssynbio.0c00643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296667PMC
May 2021

Pubertal Testosterone and the Structure of the Cerebral Cortex in Young Men.

Cereb Cortex 2021 05;31(6):2812-2821

Department of Psychology, University of Toronto, Toronto, ON M5S3G3, Canada.

Adolescence is a period of brain maturation that may involve a second wave of organizational effects of sex steroids on the brain. Rodent studies suggest that, overall, organizational effects of gonadal steroid hormones decrease from the prenatal/perinatal period to adulthood. Here we used multimodal magnetic resonance imaging to investigate whether 1) testosterone exposure during adolescence (9-17 years) correlates with the structure of cerebral cortex in young men (n = 216, 19 years of age); 2) this relationship is modulated by the timing of testosterone surge during puberty. Our results showed that pubertal testosterone correlates with structural properties of the cerebral cortex, as captured by principal component analysis of T1 and T2 relaxation times, myelin water fraction, magnetization transfer ratio, fractional anisotropy and mean diffusivity. Many of the correlations between pubertal testosterone and the cortical structure were stronger in individuals with earlier (vs. later) testosterone surge. We also demonstrated that the strength of the relationship between pubertal testosterone and cortical structure across the cerebral cortex varies as a function of inter-regional profiles of gene expression specific to dendrites, axonal cytoskeleton, and myelin. This finding suggests that the cellular substrate underlying the relationships between pubertal testosterone and cerebral cortex involves both dendritic arbor and axon.
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http://dx.doi.org/10.1093/cercor/bhaa389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107791PMC
May 2021

Sodium Intake and Heart Failure.

Int J Mol Sci 2020 Dec 13;21(24). Epub 2020 Dec 13.

Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, MA 02132, USA.

Sodium is an essential mineral and nutrient used in dietary practices across the world and is important to maintain proper blood volume and blood pressure. A high sodium diet is associated with increased expression of β-myosin heavy chain, decreased expression of α/β-myosin heavy chain, increased myocyte enhancer factor 2/nuclear factor of activated T cell transcriptional activity, and increased salt-inducible kinase 1 expression, which leads to alteration in myocardial mechanical performance. A high sodium diet is also associated with alterations in various proteins responsible for calcium homeostasis and myocardial contractility. Excessive sodium intake is associated with the development of a variety of comorbidities including hypertension, chronic kidney disease, stroke, and cardiovascular diseases. While the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend limiting sodium intake to both prevent and manage heart failure, the evidence behind such recommendations is unclear. Our review article highlights evidence and underlying mechanisms favoring and contradicting limiting sodium intake in heart failure.
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http://dx.doi.org/10.3390/ijms21249474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763082PMC
December 2020

Cellular correlates of cortical thinning throughout the lifespan.

Sci Rep 2020 12 11;10(1):21803. Epub 2020 Dec 11.

Centre for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Pb. 1094 Blindern, 0317, Oslo, Norway.

Cortical thinning occurs throughout the entire life and extends to late-life neurodegeneration, yet the neurobiological substrates are poorly understood. Here, we used a virtual-histology technique and gene expression data from the Allen Human Brain Atlas to compare the regional profiles of longitudinal cortical thinning through life (4004 magnetic resonance images [MRIs]) with those of gene expression for several neuronal and non-neuronal cell types. The results were replicated in three independent datasets. We found that inter-regional profiles of cortical thinning related to expression profiles for marker genes of CA1 pyramidal cells, astrocytes and, microglia during development and in aging. During the two stages of life, the relationships went in opposite directions: greater gene expression related to less thinning in development and vice versa in aging. The association between cortical thinning and cell-specific gene expression was also present in mild cognitive impairment and Alzheimer's Disease. These findings suggest a role of astrocytes and microglia in promoting and supporting neuronal growth and dendritic structures through life that affects cortical thickness during development, aging, and neurodegeneration. Overall, the findings contribute to our understanding of the neurobiology underlying variations in MRI-derived estimates of cortical thinning through life and late-life disease.
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http://dx.doi.org/10.1038/s41598-020-78471-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732849PMC
December 2020

The linearized disposition index augments understanding of treatment effects in diabetes.

Am J Physiol Endocrinol Metab 2021 01 30;320(1):E169-E177. Epub 2020 Nov 30.

Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.

The disposition index, calculated by multiplying measures of insulin secretion and insulin sensitivity, is widely applied as a sensitivity-adjusted measure of insulin secretion. We have recently shown that linearizing the underlying relationship uniquely permits identification of terms relating to maximal insulin secretion capacity and the secretion-coupling relationship, with both terms separately contributing to differences in the secretion-sensitivity relationship across gradations of glycemia. Here, we demonstrate the application of this linearized equation to the evaluation of treatment-induced changes in the insulin secretion-sensitivity relationship. We applied a combination of repeated-measures multivariate linear regression (evaluating treatment-induced changes in the joint relationship of insulin sensitivity and secretion) plus mixed-model repeated measures (evaluating treatment effects on maximal secretion capacity and on the secretion-sensitivity coupling slope) and compared against a usual application of the disposition index calculated from the same measurements. This novel approach allows a more informative description of treatment-induced changes compared with the usual disposition index, including isolating the source of change within the mutually adjusted relationship and identifying treatment-induced changes in the secretion-sensitivity coupling slope and in maximal insulin secretion. Application of this linearized approach provides an expanded understanding of treatment-induced changes in the insulin sensitivity-secretion relationship. The linearized insulin secretion-sensitivity relationship allows separate evaluation of the secretion-sensitivity slope and of maximal insulin secretion. Here, we demonstrate the application of this methodology to the evaluation of clinical trial data, showing that it provides an expanded understanding of treatment-induced changes compared with the disposition index.
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http://dx.doi.org/10.1152/ajpendo.00397.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194409PMC
January 2021

Variation in nutrition education practices in SWEET pediatric diabetes centers-an international comparison.

Pediatr Diabetes 2021 03 3;22(2):215-220. Epub 2020 Dec 3.

Department of Endocrinology, John Hunter Children's Hospital, Newcastle, New South Wales, Australia.

Background: Nutrition education is central to pediatric type 1 diabetes management. Dietary management guidelines for type 1 diabetes are evidence based, but implementation may be challenging and inconsistent. We describe variation in the practice of nutrition education across pediatric diabetes centers globally and explore associations with A1c and BMI.

Methods: In 2018, 77 pediatric diabetes clinics in the SWEET network received a survey about nutrition education. Using data submitted to the registry, regression analysis corrected for age, diabetes duration, BMI, and sex was used to compare survey parameters with A1c and BMI.

Results: Fifty-three centers who collectively cared for 22,085 patients aged 0 to 18 with type 1 diabetes responded. Median A1c was 7.68% [IQR 7.37-8.03], age 13.13 y [12.60-13.54], insulin pump use 39.1%, and continuous glucose monitor use 37.3%. 34% reported screening for disordered eating, but only 15.1% used validated screening tools. Recommending insulin boluses for snacks in patients taking insulin via injection varied, with 23% of the clinics giving this recommendation to half or fewer patients. In regression analysis, instructing patients to take insulin for snacks was the only survey parameter associated with the percent of clinic percent of patients attaining A1c <7.5% (<58 mmol/mol, P = 0.018) and < 7.0% (<53 mmol/mol, P = 0.026).

Conclusions: There is considerable variation in nutrition education for pediatric patients with type 1 diabetes across this international registry. Consistently recommending independent of treatment modality (insulin pump or injections) that patients take insulin for snacks and more uniformity in screening for disordered eating are improvement opportunities.
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http://dx.doi.org/10.1111/pedi.13161DOI Listing
March 2021

Regadenoson administration and QT interval prolongation during pharmacological radionuclide myocardial perfusion imaging.

Indian Heart J 2020 Jul - Aug;72(4):296-298. Epub 2020 Jul 3.

BronxCare Health System, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address:

The objective of our study is to assess change in QTc interval with Regadenoson administration during myocardial perfusion imaging (MPI). We conducted a retrospective, observational analysis of 1497 consecutive patients who underwent pharmacological radionuclide MPI. On multivariate logistic regression analyses, there was no statistical significance of QTc prolongation when adjusted for ischemia/fixed perfusion defect on MPI and QT prolonging medications being taken prior to stress testing. However, a positive stress ECG after Regadenoson injection had a statistical significance (p value 0.0004). Regadenoson is a safe drug for use in MPI with little, if any, side effects of major clinical significance.
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http://dx.doi.org/10.1016/j.ihj.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474107PMC
March 2021

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

Hum Brain Mapp 2020 Jul 29. Epub 2020 Jul 29.

Division of Mental Health and Addicition, Oslo University Hospital, Oslo, Norway.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.
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http://dx.doi.org/10.1002/hbm.25098DOI Listing
July 2020

Unique corneal tomography features of allergic eye disease identified by OCT imaging and artificial intelligence.

J Biophotonics 2020 10 12;13(10):e202000156. Epub 2020 Aug 12.

Imaging, Biomechanics and Mathematical Modeling solution, Narayana Nethralaya Foundation, Bangalore, India.

The purpose of this study was to assess unique corneal tomographic parameters of allergic eye disease (AED) using optical coherence tomography (OCT) and artificial intelligence (AI). A total of 57 eyes diagnosed with AED were included. The curvature and aberrations of the air-epithelium (A-E) and epithelium-Bowman's layer (E-B) interfaces were calculated. Random forest AI models were built combing this data with the parameters of healthy, forme fruste keratoconus (FFKC) and KC eyes. The AI models were cross-validated with 3-fold random sampling. Each model was limited to 10 trees. The AI model incorporating both A-E and E-B parameters provided the best classification of AED eyes (area under the curve = 0.958, sensitivity = 80.7%, specificity = 98.5%, precision = 88.2%). Further, the E-B interface parameters provided the highest information gain in the AI model. A few AED eyes (n = 9) had tomography parameters similar to FFKC and KC eyes and may be at risk of progression to KC.
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http://dx.doi.org/10.1002/jbio.202000156DOI Listing
October 2020

Evolution Reveals a Single Mutation as Sole Source of Src-Family Kinase C-Helix-out Inhibitor Resistance.

ACS Chem Biol 2020 08 15;15(8):2175-2184. Epub 2020 Jul 15.

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, United States.

Understanding cancer cell drug resistance to protein-tyrosine kinase inhibitors, which often arises from acquired mutations in the target kinase, is central to the development of more durable therapies. Experimental systems that reveal potential paths to resistance for a given inhibitor and kinase target have an important role in preclinical development of kinase inhibitor drugs. Here, we employed a codon mutagenesis strategy to define the mutational landscape of acquired resistance in HCK, a member of the SRC tyrosine kinase family and therapeutic target in acute myeloid leukemia (AML). Using PCR-based saturation mutagenesis, we created a cDNA library designed to replace each codon in the HCK open reading frame with all possible codons. This HCK mutant library was used to transform Rat-2 fibroblasts, followed by selection for resistant colonies with A-419259, a pyrrolopyrimidine HCK inhibitor and drug lead for AML. X-ray crystallography has shown that A-419259 binding induces outward rotation of the kinase domain αC-helix, a conformation incompatible with phosphotransfer. Remarkably, only a single resistance mutation evolved during A-419259 selection: histidine substitution for threonine at the gatekeeper position in the kinase domain. Deep sequencing confirmed representation of nearly all other missense mutations across the entire HCK open reading frame. This observation suggests that A-419259 and other C-helix-out Src-family kinase inhibitors may have a narrow path to acquired resistance in the context of AML cases where Hck is an oncogenic driver.
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http://dx.doi.org/10.1021/acschembio.0c00373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136437PMC
August 2020

Assessment of Neurobiological Mechanisms of Cortical Thinning During Childhood and Adolescence and Their Implications for Psychiatric Disorders.

JAMA Psychiatry 2020 Nov;77(11):1127-1136

Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.

Importance: Many psychiatric disorders can be conceptualized as disorders of brain maturation during childhood and adolescence. Discovering the neurobiological underpinnings of brain maturation may elucidate molecular pathways of vulnerability and resilience to such disorders.

Objective: To investigate the underlying neurobiological mechanisms of age-associated cortical thinning during maturation and their implications for psychiatric disorders.

Design, Setting, And Participants: This multicohort analysis used data from 3 community-based studies. The Saguenay Youth Study provided data from 1024 adolescents who were recruited at a single site in Quebec, Canada. The IMAGEN cohort provided data from 1823 participants who were recruited in 8 European cities. The Brazil High Risk Cohort Study for the Development of Childhood Psychiatric Disorders provided data from 815 participants who were recruited in 2 Brazilian cities. Cortical thickness was estimated from the results of magnetic resonance imaging (MRI) scans, and age-associated cortical thinning was estimated in 34 cortical regions. Gene expression from the Allen Human Brain Atlas was aligned with the same regions. Similarities in the interregional profiles of gene expression and the profiles of age-associated cortical thinning were measured. The involvement of dendrites, dendritic spines, and myelin was tested using 3 gene panels. Enrichment for genes associated with psychiatric disorders was tested among the genes associated with thinning and their coexpression networks. Data analysis was conducted between March and October 2019.

Main Outcomes And Measures: MRI-derived estimates of age-associated cortical thinning and gene expression in 34 cortical regions.

Results: A total of 3596 individuals aged 9 to 21 years were included in this study. Of those, 1803 participants (50.1%) were female, and the mean (SD) age was 15.2 (2.6) years. Interregional profiles of age-associated cortical thinning were associated with interregional gradients in the expression of genes associated with dendrites, dendritic spines, and myelin; the variance in thinning explained by the gene panels across different points ranged from 0.45% to 10.55% for the dendrite panel, 0.00% to 9.98% for the spine panel, and 0.19% to 26.39% for the myelin panel. These genes and their coexpression networks were enriched for genes associated with several psychiatric disorders.

Conclusions And Relevance: In this study, genetic similarity between interregional variation in cortical thinning during maturation and multiple psychiatric disorders suggests overlapping molecular underpinnings. This finding adds to the understanding of the neurodevelopmental mechanisms of psychiatric disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.1495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301307PMC
November 2020

Virtual histology of multi-modal magnetic resonance imaging of cerebral cortex in young men.

Neuroimage 2020 09 22;218:116968. Epub 2020 May 22.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada; Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address:

Neurobiology underlying inter-regional variations - across the human cerebral cortex - in measures derived with multi-modal magnetic resonance imaging (MRI) is poorly understood. Here, we characterize inter-regional variations in a large number of such measures, including T1 and T2 relaxation times, myelin water fraction (MWF), T1w/T2w ratio, mean diffusivity (MD), fractional anisotropy (FA), magnetization transfer ratio (MTR) and cortical thickness. We then employ a virtual-histology approach and relate these inter-regional profiles to those in cell-specific gene expression. Virtual histology revealed that most MRI-derived measures, including T1, T2 relaxation time, MWF, T1w/T2w ratio, MTR, FA and cortical thickness, are associated with expression profiles of genes specific to CA1 pyramidal cells; these genes are enriched in biological processes related to dendritic arborisation. In addition, T2 relaxation time, MWF and T1w/T2w ratio are associated with oligodendrocyte-specific gene-expression profiles, supporting their use as measures sensitive to intra-cortical myelin. MWF contributes more variance than T1w/T2w ratio to the mean oligodendrocyte expression profile, suggesting greater sensitivity to myelin. These cell-specific MRI associations may help provide a framework for determining which MRI sequences to acquire in studies with specific neurobiological hypotheses.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116968DOI Listing
September 2020

Age-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study.

Front Psychiatry 2020 4;11:342. Epub 2020 May 4.

Institute of Neurodegenerative Diseases (IMN), CNRS, CEA, Bordeaux, France.

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process.
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http://dx.doi.org/10.3389/fpsyt.2020.00342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212692PMC
May 2020

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Hum Brain Mapp 2020 May 18. Epub 2020 May 18.

Division of Psychological & Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technischen Universität Dresden, Dresden, Germany.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
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http://dx.doi.org/10.1002/hbm.25029DOI Listing
May 2020

Restriction of memory B cell differentiation at the germinal center B cell positive selection stage.

J Exp Med 2020 07;217(7)

Immunity and Cancer, Francis Crick Institute, London, UK.

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.
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http://dx.doi.org/10.1084/jem.20191933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336312PMC
July 2020

Sweat monitoring beneath garments using passive, wireless resonant sensors interfaced with laser-ablated microfluidics.

NPJ Digit Med 2020 30;3:62. Epub 2020 Apr 30.

1Department of Chemical and Biological Engineering, Iowa State University, Ames, IA USA.

Sweat loss can help determine hydration status of individuals working in harsh conditions, which is especially relevant to those who wear thick personal protective equipment (PPE) such as firefighters. A wireless, passive, conformable sweat sensor sticker is described here that can be worn under and interrogated through thick clothing to simultaneously measure sweat loss volume and conductivity. The sticker consists of a laser-ablated, microfluidic channel and a resonant sensor transducer. The resonant sensor is wirelessly read with a handheld vector network analyzer coupled to two, co-planar, interrogation antennas that measure the transmission loss. A sweat proxy is used to fill the channels and it is determined that the sensor can orthogonally determine the sweat conductivity and volume filled in the channel via peak transmission loss magnitude and frequency respectively. A four-person study is then used to determine level of sensor variance caused by local tissue dielectric heterogeneity and sensor-reader orientation.
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http://dx.doi.org/10.1038/s41746-020-0270-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193562PMC
April 2020

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

Cereb Cortex 2020 06;30(7):4121-4139

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04109 Leipzig, Germany.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.
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http://dx.doi.org/10.1093/cercor/bhaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947185PMC
June 2020

Unsupervised clustering for phenotypic stratification of clinical, demographic, and stress attributes of cardiac risk in patients with nonischemic exercise stress echocardiography.

Echocardiography 2020 04 17;37(4):505-519. Epub 2020 Mar 17.

Division of Cardiology, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai St. Luke's, New York, NY, USA.

Introduction And Aim: Patients undergoing exercise echocardiography with no evidence of myocardial ischemia are considered a low-risk group; however, this group is likely heterogeneous in terms of short-term adverse events and subsequent cardiac testing. We hypothesized that unsupervised cluster modeling using clinical and stress characteristics can detect heterogeneity in cardiovascular risk and need for subsequent cardiac testing among these patients.

Methods: We retrospectively studied 445 patients who had exercise echocardiography results negative for myocardial ischemia. All patients were followed for adverse cardiovascular events, subsequent cardiac testing, and nonacute coronary syndrome (ACS) revascularization. The heterogeneity of the study subjects was tested using computational clustering, an exploratory statistical method designed to uncover invisible natural groups within data. Clinical and stress predictors of adverse events were extracted and used to construct 3 unsupervised cluster models: clinical, stress, and combined. The study population was split into training (357 patients) and testing sets (88 patients).

Results: In the training set, the clinical, stress, and combined cluster models yielded 5, 4, and 3 clusters, respectively. Each model had 1 high-risk and 1 low-risk cluster while other clusters were intermediate. The combined model showed a better predictive ability compared to the clinical or stress models alone. The need for future testing mirrored the pattern of adverse cardiovascular events. A risk score derived from the combined cluster model predicted end points with acceptable accuracy. The patterns of risk and the calculated risk scores were preserved in the testing set.

Conclusions: Patients with no evidence of ischemia on exercise stress echocardiography represent a heterogeneous group. Cluster-based modeling using combined clinical and stress characteristics can expose this heterogeneity. The findings can help better risk-stratify this group of patients and aid cost-effective healthcare utilization toward better diagnostics and therapeutics.
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http://dx.doi.org/10.1111/echo.14638DOI Listing
April 2020

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.

Hum Brain Mapp 2020 Mar 10. Epub 2020 Mar 10.

McLean Hospital, Harvard Medical School, Belmont, Massachusetts.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.
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http://dx.doi.org/10.1002/hbm.24972DOI Listing
March 2020

A platform for context-specific genetic engineering of recombinant protein production by CHO cells.

J Biotechnol 2020 Mar 27;312:11-22. Epub 2020 Feb 27.

Advanced Biomanufacturing Centre, Department of Chemical and Biological Engineering, University of Sheffield, Mappin St., Sheffield S1 3JD, UK. Electronic address:

An increasing number of engineered therapeutic recombinant proteins with unpredictable manufacturability are currently filling industrial cell line development pipelines. These proteins can be "difficult-to-express" (DTE) in that production of a sufficient quantity of correctly processed recombinant product by engineered mammalian cells is difficult to achieve. In these circumstances, identification of appropriate cell engineering strategies to increase yield is difficult as constraints are cell line and product-specific. Here we describe and validate the development of a high-throughput microscale platform for multiparallel testing of multiple functional genetic components at varying stoichiometry followed by assessment of their effect on cell functional performance. The platform was used to compare and identify optimal cell engineering solutions for both transient and stable production of a model DTE IgG1 monoclonal antibody. We simultaneously tested the functional effect of 32 genes encoding discrete ER or secretory pathway components, each at varying levels of expression and utilized in different combinations. We show that optimization of functional gene load and relative stoichiometry is critical and optimal cell engineering solutions for stable and transient production contexts are significantly different. Our analysis indicates that cell engineering workflows should be cell line, protein product and production-process specific; and that next-generation cell engineering technology that enables precise control of the relative expression of multiple functional genetic components is necessary to achieve this.
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http://dx.doi.org/10.1016/j.jbiotec.2020.02.012DOI Listing
March 2020

Burden of disease from shingles and post-herpetic neuralgia in the over 80 year olds in the UK.

PLoS One 2020 25;15(2):e0229224. Epub 2020 Feb 25.

Merck Sharp & Dohme Limited, Hoddesdon, Hertfordshire, United Kingdom.

Background: The current UK vaccination programme for herpes zoster (HZ) excludes people aged ≥80 years. This study aimed to quantify the number of individuals ≥80 years who missed HZ vaccination and the consequent epidemiological and economic burden of HZ and post-herpetic neuralgia (PHN).

Methods: Immunocompetent individuals aged ≥80 years between 1st September 2013 and 31st December 2017 in the Clinical Practice Research Datalink were selected and linked to Hospital Episodes Statistics, where available. Rates of HZ and PHN and healthcare resource utilisation were investigated for the overall study population and by age group (80-84, 85-89, ≥90 years old) and the burden of HZ and PHN was projected to the UK population.

Results: 4,858 HZ episodes and 464 PHN cases were identified in 255,165 individuals over 576,421 person-years (PY). Rates of HZ and PHN were 8.43 (95% confidence interval [CI] 8.19-8.66) and 0.80 (0.73-0.87) per 1,000 PY respectively and lowest in those aged ≥90 (HZ rate 7.37/1,000 PY; PHN rate 0.56/1,000 PY). Within HZ episodes, 10.27% of GP visits, 5.82% of prescribed medications and 21.65% of hospitalisations were related to HZ/PHN. Median length of hospitalisation increased from 7.0 days for all-cause to 10.5 days for HZ/PHN related hospitalisations. Individuals ≥90 stayed in hospital a median of 3-4 days longer than younger groups. Approximately 2.23 million individuals in the UK missed HZ vaccination since 2013 (1.86 million had never been eligible and 365,000 lost eligibility for HZ vaccination), resulting in an estimated 43,149 HZ episodes.

Conclusion: This study highlights the impact of the 80-year upper age limit policy on the health system. Our study estimates that 2.23 million individuals in the UK may have lost the opportunity to be vaccinated and that their burden of HZ and PHN remains high, especially among the very elderly.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041808PMC
May 2020

Epithelium Zernike Indices and Artificial Intelligence Can Differentiate Epithelial Remodeling Between Flap and Flapless Refractive Procedures.

J Refract Surg 2020 Feb;36(2):97-103

Purpose: To evaluate epithelial Zernike indices as a differentiator of epithelial remodeling after different refractive procedures.

Methods: Optical coherence tomography (OCT) images of 22 laser in situ keratomileusis, 22 small incision lenticule extraction, 15 photorefractive keratectomy (PRK), and 17 transepithelial PRK eyes were evaluated retrospectively before and after surgery. A custom algorithm was used to calculate the epithelial Zernike indices from the three-dimensional distribution of epithelial thickness distribution. The epithelial Zernike indices were also compared with the local measurements of epithelial thickness, used conventionally from the current clinical OCT. A decision tree classifier was built, one in which flap/cap and surface procedures were classified (2G) and another in which all surgical groups were classified separately (4G).

Results: Local measurements of thicknesses changed significantly after all surgeries (P < .05), but these changes were similar in magnitude between the surgical platforms (P > .05). The surgeries not only changed the epithelial Zernike indices (P < .05), but also resulted in differential changes in epithelial thickness distribution based on the type of surgery (P < .05). In the 2G analyses with local measurements of epithelial thickness, the area under the curve, sensitivity, and specificity were 0.57 ± 0.07, 42.11%, and 57.89%, respectively. Further, the accuracy was limited to less than 60%. In the 2G analyses with epithelial Zernike indices, the area under the curve, sensitivity, and specificity were 0.79 ± 0.05, 86.4%, and 71.9%, respectively. Here, the accuracy was limited between 70% and 80%. Similar trends were observed with 4G analyses.

Conclusions: The epithelial Zernike indices were significantly better in identifying surgery-specific three-dimensional remodeling of the thickness compared to local measurements of epithelial thickness. Further, the changes in Zernike indices were independent of the magnitude of refractive error but not the type of surgery. [J Refract Surg. 2020;36(2):97-103.].
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http://dx.doi.org/10.3928/1081597X-20200103-01DOI Listing
February 2020

A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents.

Mol Psychiatry 2021 Aug 3;26(8):3795-3805. Epub 2020 Jan 3.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.
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http://dx.doi.org/10.1038/s41380-019-0640-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332371PMC
August 2021
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