Publications by authors named "Steven Jones"

919 Publications

The utility of color normalization for AI-based diagnosis of hematoxylin and eosin-stained pathology images.

J Pathol 2021 Sep 20. Epub 2021 Sep 20.

School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.

The color variation of hematoxylin and eosin (H&E)-stained tissues has presented a challenge for applications of artificial intelligence (AI) in digital pathology. Many color normalization algorithms have been developed in recent years in order to reduce the color variation between H&E images. However, previous efforts in benchmarking these algorithms have produced conflicting results and none have sufficiently assessed the efficacy of the various color normalization methods for improving diagnostic performance of AI systems. In this study, we systematically investigated eight color normalization algorithms for AI-based classification of H&E-stained histopathology slides, in the context of both using images from one center and from multiple centers. Our results show that color normalization does not consistently improve classification performance when both training and testing data are from a single center. However, using four multi-center datasets of two cancer types (ovarian and pleural) and objective functions, we show that color normalization can significantly improve the classification accuracy of images from external datasets (ovarian cancer: 0.25 AUC increase, p = 1.6 e-05, pleural cancer: 0.21 AUC increase, p = 1.4 e-10). Furthermore, we introduce a novel augmentation strategy by mixing color-normalized images using three easily accessible algorithms that consistently improves the diagnosis of test images from external centers, even when the individual normalization methods had varied results. We anticipate our study to be a starting point for reliable use of color normalization to improve AI-based, digital pathology-empowered diagnosis of cancers sourced from multiple centers. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5797DOI Listing
September 2021

Cardiac PANK1 Deletion Exacerbates Ventricular Dysfunction During Pressure Overload.

Am J Physiol Heart Circ Physiol 2021 Sep 17. Epub 2021 Sep 17.

Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KY, United States.

Coenzyme A (CoA) is an essential co-factor required for intermediary metabolism. Perturbations in homeostasis of CoA have been implicated in various pathologies; however, whether CoA homeostasis is changed and the extent to which CoA levels contribute to ventricular function and remodeling during pressure overload has not been explored. In this study, we sought to assess changes in CoA biosynthetic pathway during pressure overload and determine the impact of limiting CoA on cardiac function. We limited cardiac CoA levels by deleting the rate limiting enzyme in CoA biosynthesis, Pank1. We found that constitutive, cardiomyocyte-specific Pank1 deletion (cmPank1) significantly reduced PANK1 mRNA, PANK1 protein, and CoA levels compared to Pank1 sufficient littermates (cmPank1) but exerted no obvious deleterious impact on the mice at baseline. We then subjected both groups of mice to pressure overload-induced heart failure. Interestingly, there was more ventricular dilation in cmPank1 during pressure overload. To explore potential mechanisms contributing to this phenotype, we performed transcriptomic profiling, which suggested a role for Pank1 in regulating fibrotic and metabolic processes during pressure overload. Indeed, Pank1 deletion exacerbated cardiac fibrosis following pressure overload. Because we were interested in the possibility of early metabolic impacts in response to pressure overload, we performed untargeted metabolomics, which indicated significant changes to metabolites involved in fatty acid and ketone metabolism, among other pathways. Collectively, our study underscores the role of elevated CoA levels in supporting fatty acid and ketone body oxidation, which may be more important than CoA-driven, enzyme-independent acetylation in the failing heart.
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http://dx.doi.org/10.1152/ajpheart.00411.2021DOI Listing
September 2021

Field based lower limb strength tests provide insight into sprint and change of direction ability in academy footballers.

Scand J Med Sci Sports 2021 Aug 21. Epub 2021 Aug 21.

School of Health, Sport and Professional Practice, Faculty of Life Sciences and Education, University South Wales, Pontypridd, United Kingdom.

Conducting field-based strength assessments is embedded within football academy development processes. Yet, there is a limited understanding of how hip and groin strength assessments relate to vital game-based tasks such as sprinting and change of direction (COD) performance. Our aim was to explore field-based strength assessments and their relationships with both sprint and COD performance in male academy footballers. Participants (n = 146; age 14.2 ± 2.2 years; stature 166.3 ± 15.4 cm; body mass 55.6 ± 15.6 kg) performed maximal countermovement jump (CMJ), Nordic hamstring strength (NHS), isometric hip adductor (ADD)/abductor (ABD), 5 m, 10 m, 20 m sprints, and modified 505 agility test. All strength measures were allometrically scaled to account for body weight. Between-limb differences were reported as imbalance scores. Principal component analysis reduced sprint and COD variables to a single "running ability" component score. Scaled strength and imbalance, when controlled for age, were associated with "running ability" (adjusted R  = 0.78, p < 0.001). Significant effects on "running ability" included the following: age, CMJ impulse, NHS, and hip-ADD. When the sprint and COD variables were explored independently, age and CMJ-impulse were featured in all sprint and COD models. For 10 m and 20 m sprint distances, hip-ADD emerged as a significant effect. Mean 505 performance was explained by age, CMJ-impulse, hip-ADD, but also with the addition of NHS. Our findings suggest that insight into the underpinning strength qualities of "running ability" of academy footballers can be obtained from a suite of field-based tests.
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http://dx.doi.org/10.1111/sms.14039DOI Listing
August 2021

Angiotensinogen Takes Some of the Spotlight From Angiotensin II in the Cardiohepatic Axis.

Authors:
Steven P Jones

Circ Res 2021 Aug 19;129(5):565-567. Epub 2021 Aug 19.

Diabetes and Obesity Center, University of Louisville, KY.

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http://dx.doi.org/10.1161/CIRCRESAHA.121.319784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384130PMC
August 2021

Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings.

Genes (Basel) 2021 Jul 8;12(7). Epub 2021 Jul 8.

Department of Medical Genetics, University of British Columbia (UBC), Vancouver, BC V6H 3N1, Canada.

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (, , , , and ). All are shared among the three children, except , which is only present in the most severely affected child. The compound heterozygous variants in and the maternally inherited variant in are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. is also involved in synapse functions, and and are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.
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http://dx.doi.org/10.3390/genes12071053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303619PMC
July 2021

Developing a recovery-focused therapy for older people with bipolar disorder: a qualitative focus group study.

BMJ Open 2021 08 4;11(8):e049829. Epub 2021 Aug 4.

Division of Health Research, Lancaster University, Lancaster, UK.

Objectives: As awareness of bipolar disorder (BD) increases and the world experiences a rapid ageing of the population, the number of people living with BD in later life is expected to rise substantially. There is no current evidence base for the effectiveness of psychological interventions for older adults with BD. This focus group study explored a number of topics to inform the development and delivery of a recovery-focused therapy (RfT) for older adults with BD.

Design: A qualitative focus group study.

Setting: Three focus groups were conducted at a university in the North West of England.

Participants: Eight people took part in the focus groups; six older adults with BD, one carer and one friend.

Results: Participant's responses clustered into six themes: (1) health-related and age-related changes in later life, (2) the experience of BD in later life, (3) managing and coping with BD in later life, (4) recovery in later life, (5) seeking helping in the future and (6) adapting RfT for older people.

Conclusions: Participants reported a range of health-related and age-related changes and strategies to manage their BD. Participants held mixed views about using the term 'recovery' in later life. Participants were in agreement that certain adaptations were needed for delivering RfT for older adults, based on their experience of living with BD in later life. The data collected as part of the focus groups have led to a number of recommendations for delivering RfT for older adults with BD in a randomised controlled trial (Clinical Trial Registration: ISRCTN13875321).
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http://dx.doi.org/10.1136/bmjopen-2021-049829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340279PMC
August 2021

Inflammation and cardiovascular disease: From mechanisms to therapeutics.

Am J Prev Cardiol 2020 Dec 21;4:100130. Epub 2020 Nov 21.

Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as "the fire within," is highly regulated, and is critical to host defense and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.
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http://dx.doi.org/10.1016/j.ajpc.2020.100130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315628PMC
December 2020

A comparative analysis of freeway crash incident clearance time using random parameter and latent class hazard-based duration model.

Accid Anal Prev 2021 Sep 22;160:106303. Epub 2021 Jul 22.

Dept. of Civil, Construction and Environmental Engineering, Univ. of Alabama, P.O. Box 870288, Tuscaloosa, AL 35487-0205, United States. Electronic address:

The effects of freeway incident clearance times on the flow of traffic have recently increased interests in understanding what factors influence incident durations. This has particularly become topical due to the financial and economic implications of traffic gridlocks caused by freeway incidents on industries and personal mobility. This paper presents two advanced econometric modeling methods, random parameters duration modeling and latent class duration modeling in understanding the factors that impact freeway incident clearance times in the State of Alabama. These two modeling approaches were further compared to identify which of them provides the best fit for the data with respect to accounting for unobserved heterogeneity. A total of 2206 freeway crash incident data from January 1 to December 31, 2018 were examined in developing the models. The study was based on a unique dataset that involved merging and matching Traffic Incident Management response data from the Alabama Department of Transportation (ALDOT) Traffic Management Center (TMC), freeway crash data from the Center for Advanced Public Safety (CAPS) at the University of Alabama, Alabama Service and Assistance Patrol (ASAP) data from ALDOT and traffic volume from ALDOT's Highway Performance Management System (HPMS). The model estimation results reveal that a total of nineteen variables were found statistically significant with five random variables (on-road, nighttime, rain, AADT, and ASAP existing coverage area) and fourteen fixed effects variables for the random parameters model. For latent class model, a total of eighteen variables were observed statistically significant within two distinct latent classes (Latent Class 1 with class membership probability of 0.23 and Latent Class 2 with class membership probability of 0.77) at a 0.05 significance level. A comparison of the two models reveals that the latent class model provides the better fit for the incident duration data. The findings of this study are expected to contribute to the body of knowledge on incident duration by employing two advanced econometric modeling methods and to inform statewide efforts in significantly reducing the duration of freeway incident clearance time. Moreover, this is to ensure that policy decisions that may arise from the findings of the study are sound and based on data-driven evidence.
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http://dx.doi.org/10.1016/j.aap.2021.106303DOI Listing
September 2021

Microscopic metavehicles powered and steered by embedded optical metasurfaces.

Nat Nanotechnol 2021 09 22;16(9):970-974. Epub 2021 Jul 22.

Department of Physics, Chalmers University of Technology, Gothenburg, Sweden.

Nanostructured dielectric metasurfaces offer unprecedented opportunities to manipulate light by imprinting an arbitrary phase gradient on an impinging wavefront. This has resulted in the realization of a range of flat analogues to classical optical components, such as lenses, waveplates and axicons. However, the change in linear and angular optical momentum associated with phase manipulation also results in previously unexploited forces and torques that act on the metasurface itself. Here we show that these optomechanical effects can be utilized to construct optical metavehicles-microscopic particles that can travel long distances under low-intensity plane-wave illumination while being steered by the polarization of the incident light. We demonstrate movement in complex patterns, self-correcting motion and an application as transport vehicles for microscopic cargoes, which include unicellular organisms. The abundance of possible optical metasurfaces attests to the prospect of developing a wide variety of metavehicles with specialized functional behaviours.
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http://dx.doi.org/10.1038/s41565-021-00941-0DOI Listing
September 2021

Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study.

Eur Heart J 2021 Jul 19. Epub 2021 Jul 19.

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA.

Aims: Emerging evidence suggests that remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease (ASCVD). We aimed to estimate RC-related risk beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in patients without known ASCVD.

Methods And Results: We pooled data from 17 532 ASCVD-free individuals from the Atherosclerosis Risk in Communities study (n = 9748), the Multi-Ethnic Study of Atherosclerosis (n = 3049), and the Coronary Artery Risk Development in Young Adults (n = 4735). RC was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in RC vs. LDL-C discordant/concordant groups using difference in percentile units (>10 units) and clinically relevant LDL-C targets. The mean age of participants was 52.3 ± 17.9 years, 56.7% were women and 34% black. There were 2143 ASCVD events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log RC was associated with higher ASCVD risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.45-1.89]. Moreover, the discordant high RC/low LDL-C group, but not the low RC/high LDL-C group, was associated with increased ASCVD risk compared to the concordant group (HR 1.21, 95% CI 1.08-1.35). Similar results were shown when examining discordance across clinical cutpoints.

Conclusions: In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of RC association with ASCVD, surprisingly beyond apoB, and the potential value of targeted RC-lowering in primary prevention need to be further investigated.
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http://dx.doi.org/10.1093/eurheartj/ehab432DOI Listing
July 2021

Interactions and implications of Fuzzy-Trace theory for risk taking behaviors in bipolar disorder.

J Affect Disord 2021 10 27;293:305-313. Epub 2021 Jun 27.

Division of Health Research, Faculty of Health and Medicine, Lancaster University, Lancaster, UK. Electronic address:

Background: According to Fuzzy-Trace Theory (FTT), qualitative, bottom-line, "gist" reasoning leads to less risk taking and more mature decision-making, less easily swayed by emotions than quantitative, detail-oriented, "verbatim" reasoning. In Bipolar disorder deleterious risky behaviors are common. Prior research confirmed the relationships posited between FTT and risk taking. We aim to understand whether FTT acts upon risk taking in the manner proposed in the FTT framework, namely, that (a) gist "values" mediate the role of "categorical gist". Furthermore, the roles of mania and impulsivity, cited as factors for risk-taking, remain to be clarified. In this study, we investigate if (b) manic symptoms and impulsivity moderate these relationships.

Methods: Participants (N = 105) completed an online survey including demographics, clinical variables, symptomatology, FTT, risk taking and risk perception.

Results: Mediational models indicated that (a) Gist Values mediated Categorical Gist's effect on risk taking, as expected by the FTT framework. (b) Impulsivity moderates risk taking, but manic-type symptomatology does not.

Limitations: Voluntary, self-report surveys may have low participant motivation and limit the diagnostic validity and the inpatient generalizability of the results.

Conclusions: The results move beyond a focus on mood-related aspects of Bipolar disorder and confirm the importance of understanding reasoning processes like FTT in combination with impulsivity, as potential behavioral factors of risk taking in Bipolar disorder. The clarifications on FTT's functioning as a mechanism prescribe possible openings for more efficacious reduction of risky behaviors through behavioral interventions focusing on value creation.
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http://dx.doi.org/10.1016/j.jad.2021.06.035DOI Listing
October 2021

Psychological therapy for mood instability within bipolar spectrum disorder: a randomised, controlled feasibility trial of a dialectical behaviour therapy-informed approach (the ThrIVe-B programme).

Int J Bipolar Disord 2021 Jul 1;9(1):20. Epub 2021 Jul 1.

Washington Singer Labs., University of Exeter Department of Psychology, Perry Road, Exeter, EX4 4QG, UK.

Background: A subgroup of those with bipolar spectrum disorders experience ongoing mood fluctuations outside of full episodes. We conducted a randomised, controlled feasibility study of a Dialectical Behavioural Therapy-informed approach for bipolar mood fluctuations (Therapy for Inter-episode mood Variability in Bipolar [ThrIVe-B]). Our study aimed to examine the feasibility and acceptability of a future definitive trial evaluating the clinical and cost effectiveness of the ThrIVe-B programme. Participants were required to meet diagnostic criteria for a bipolar spectrum disorder and report frequent mood swings outside of acute episodes. They were randomised to treatment as usual (control arm) or the ThrIVe-B intervention plus treatment as usual (intervention arm). Follow-up points were at 3, 6, 9 and 15 months after baseline, with 9 months as the primary end point. To evaluate feasibility and acceptability we examined recruitment and retention rates, completion rates for study measures, adverse events and feedback from participants on their experience of study participation and therapy.

Results: Of the target 48 participants, 43 were recruited (22 in the intervention arm; 21 in the control arm), with a recruitment rate of 3.9 participants per month. At 9 months 74% of participants engaged in research follow-up assessment, exceeding the pre-specified criterion of 60%. There were no serious concerns about the safety of the research procedures or the intervention. On one of the four candidate primary outcome measures, the 95% CI for the between-group mean difference score excluded the null effect and included the minimal clinically important difference, favouring the intervention arm, whilst on no measure was there evidence of deterioration in the intervention arm relative to the control arm. Attendance of the intervention (50% attending at least half of the mandatory sessions) was below the pre-specified continuation criterion of 60%, and qualitative feedback from participants indicated areas that may have hampered or facilitated engagement.

Conclusions: It is broadly feasible to conduct a trial of this design within the population of people with frequent bipolar mood swings. Changes should be made to the therapy to increase uptake, such as simplifying content and considering individual rather than group delivery. Trial registration ISRCTN: ISRCTN54234300. Registered 14th July 2017, http://www.isrctn.com/ISRCTN54234300.
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http://dx.doi.org/10.1186/s40345-021-00226-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245616PMC
July 2021

Clinical and cost outcomes following genomics-informed treatment for advanced cancers.

Cancer Med 2021 Aug 21;10(15):5131-5140. Epub 2021 Jun 21.

Cancer Control Research, BC Cancer, Vancouver, Canada.

Background: Single-arm trials are common in precision oncology. Owing to the lack of randomized counterfactual, resultant data are not amenable to comparative outcomes analyses. Difference-in-difference (DID) methods present an opportunity to generate causal estimates of time-varying treatment outcomes. Using DID, our study estimates within-cohort effects of genomics-informed treatment versus standard care on clinical and cost outcomes.

Methods: We focus on adults with advanced cancers enrolled in the single-arm BC Cancer Personalized OncoGenomics program between 2012 and 2017. All individuals had a minimum of 1-year follow up. Logistic regression explored baseline differences across patients who received a genomics-informed treatment versus a standard care treatment after genomic sequencing. DID estimated the incremental effects of genomics-informed treatment on time to treatment discontinuation (TTD), time to next treatment (TTNT), and costs. TTD and TTNT correlate with improved response and survival.

Results: Our study cohort included 346 patients, of whom 140 (40%) received genomics-informed treatment after sequencing and 206 (60%) received standard care treatment. No significant differences in baseline characteristics were detected across treatment groups. DID estimated that the incremental effect of genomics-informed versus standard care treatment was 102 days (95% CI: 35, 167) on TTD, 91 days (95% CI: -9, 175) on TTNT, and CAD$91,098 (95% CI: $46,848, $176,598) on costs. Effects were most pronounced in gastrointestinal cancer patients.

Conclusions: Genomics-informed treatment had a statistically significant effect on TTD compared to standard care treatment, but at increased treatment costs. Within-cohort evidence generated through this single-arm study informs the early-stage comparative effectiveness of precision oncology.
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http://dx.doi.org/10.1002/cam4.4076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335838PMC
August 2021

A Scalable Strand-Specific Protocol Enabling Full-Length Total RNA Sequencing From Single Cells.

Front Genet 2021 3;12:665888. Epub 2021 Jun 3.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

RNA sequencing (RNAseq) has been widely used to generate bulk gene expression measurements collected from pools of cells. Only relatively recently have single-cell RNAseq (scRNAseq) methods provided opportunities for gene expression analyses at the single-cell level, allowing researchers to study heterogeneous mixtures of cells at unprecedented resolution. Tumors tend to be composed of heterogeneous cellular mixtures and are frequently the subjects of such analyses. Extensive method developments have led to several protocols for scRNAseq but, owing to the small amounts of RNA in single cells, technical constraints have required compromises. For example, the majority of scRNAseq methods are limited to sequencing only the 3' or 5' termini of transcripts. Other protocols that facilitate full-length transcript profiling tend to capture only polyadenylated mRNAs and are generally limited to processing only 96 cells at a time. Here, we address these limitations and present a novel protocol that allows for the high-throughput sequencing of full-length, total RNA at single-cell resolution. We demonstrate that our method produced strand-specific sequencing data for both polyadenylated and non-polyadenylated transcripts, enabled the profiling of transcript regions beyond only transcript termini, and yielded data rich enough to allow identification of cell types from heterogeneous biological samples.
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http://dx.doi.org/10.3389/fgene.2021.665888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209500PMC
June 2021

Personal recovery in bipolar disorder: Systematic review and "best fit" framework synthesis of qualitative evidence - a POETIC adaptation of CHIME.

J Affect Disord 2021 09 28;292:375-385. Epub 2021 May 28.

Spectrum Centre for Mental Health Research, Division of Health Research, Lancaster University, Health Innovation One, Sir John Fisher Drive, LA1 4AT Lancaster, UK.

Background: Personal recovery, living a satisfying, hopeful life alongside symptoms, has become an increasingly valued aim across mental health care agendas internationally. However, there is little understanding of how people experience personal recovery alongside the mood challenges characteristic of a bipolar disorder diagnosis. Personal recovery frameworks have been developed for populations with mixed psychiatric diagnoses, predominantly psychotic disorders.

Methods: This systematic review of qualitative data used the widely adopted personal recovery processes Connectedness, Hope and optimism, Identity, Meaning and purpose, Empowerment (CHIME) in a "best fit" framework synthesis to understand personal recovery experiences in bipolar disorder. Included studies were coded with deductive framework analysis based on the CHIME processes and inductive thematic analysis for aspects beyond the a priori framework.

Results: A comprehensive search of six literature databases led to inclusion of twelve articles published 2010-2020. Deductive coding supported the fit with the CHIME framework but revealed difficulties, losses, and tensions within and across recovery processes. The proposed framework for personal recovery in bipolar disorder, Purpose and meaning, Optimism and hope, Empowerment, Tensions, Identity, Connectedness (POETIC), organises all CHIME processes around these tensions.

Limitations: Diversity among study participants was limited with majority middle-aged, female, Western participants.

Conclusions: The compact POETIC personal recovery framework tailored for bipolar disorder is directly applicable to clinical practice with personal recovery objectives. It highlights the need for professionals to introduce personal recovery in a realistic and balanced way to address recent criticism by service user organisations of personal recovery as overly optimistic.
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http://dx.doi.org/10.1016/j.jad.2021.05.051DOI Listing
September 2021

Deep-learning based classification distinguishes sarcomatoid malignant mesotheliomas from benign spindle cell mesothelial proliferations.

Mod Pathol 2021 Jun 10. Epub 2021 Jun 10.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.

Sarcomatoid mesothelioma is an aggressive malignancy that can be challenging to distinguish from benign spindle cell mesothelial proliferations based on biopsy, and this distinction is crucial to patient treatment and prognosis. A novel deep learning based classifier may be able to aid pathologists in making this critical diagnostic distinction. SpindleMesoNET was trained on cases of malignant sarcomatoid mesothelioma and benign spindle cell mesothelial proliferations. Performance was assessed through cross-validation on the training set, on an independent set of challenging cases referred for expert opinion ('referral' test set), and on an externally stained set from outside institutions ('externally stained' test set). SpindleMesoNET predicted the benign or malignant status of cases with AUC's of 0.932, 0.925, and 0.989 on the cross-validation, referral and external test sets, respectively. The accuracy of SpindleMesoNET on the referral set cases (92.5%) was comparable to the average accuracy of 3 experienced pathologists on the same slide set (91.7%). We conclude that SpindleMesoNET can accurately distinguish sarcomatoid mesothelioma from benign spindle cell mesothelial proliferations. A deep learning system of this type holds potential for future use as an ancillary test in diagnostic pathology.
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http://dx.doi.org/10.1038/s41379-021-00850-6DOI Listing
June 2021

Behavioral pathways in bicycle-motor vehicle crashes: From contributing factors, pre-crash actions, to injury severities.

J Safety Res 2021 06 18;77:229-240. Epub 2021 Mar 18.

Alabama Transportation Institute, The University of Alabama, Tuscaloosa, AL 35487, United States. Electronic address:

Introduction: This study performed a path analysis to uncover the behavioral pathways (from contributing factors, pre-crash actions to injury severities) in bicycle-motor vehicle crashes.

Method: The analysis investigated more than 7,000 bicycle-motor vehicle crashes in North Carolina between 2007 and 2014. Pre-crash actions discussed in this study are actions of cyclists and motorists prior to the event of a crash, including "bicyclist failed to yield," "motorist failed to yield," "bicyclist overtaking motorist," and "motorist overtaking bicyclist."

Results: Model results show significant correlates of pre-crash actions and bicyclist injury severity. For example, young bicyclists (18 years old or younger) are 23.5% more likely to fail to yield to motor traffic prior to the event of a crash than elder bicyclists. The "bicyclist failed to yield" action is associated with increased bicyclist injury severity than other actions, as this behavior is associated with an increase of 5.88 percentage points in probability of a bicyclist being at least evidently injured. The path analysis can highlight contributing factors related to risky pre-crash actions that lead to severe injuries. For example, bicyclists traveling on regular vehicle travel lanes are found to be more likely to involve the "bicyclist failed to yield" action, which resulted in a total 44.38% (7.04% direct effect + 37.34% indirect effect) higher likelihood of evident or severe injuries. The path analysis can also identify factors (e.g., intersection) that are not directly but indirectly correlated with injury severity through pre-crash actions. Practical Applications: This study offers a methodological framework to quantify the behavioral pathways in bicycle-motor vehicle crashes. The findings are useful for cycling safety improvements from the perspective of bicyclist behavior, such as the educational program for cyclists.
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http://dx.doi.org/10.1016/j.jsr.2021.02.015DOI Listing
June 2021

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.

J Clin Invest 2021 07;131(14)

College of Applied Medical Sciences, Taibah University, Madina, Saudi Arabia.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.
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http://dx.doi.org/10.1172/JCI147834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279578PMC
July 2021

Experiences of Using Positive Airway Pressure for Treatment of Obstructive Sleep Apnoea: A Systematic Review and Thematic Synthesis.

Sleep 2021 May 27. Epub 2021 May 27.

Lancaster University, England (UK).

Study Objectives: Sub-optimal use of positive airway pressure (PAP) to treat obstructive sleep apnoea (OSA) continues to be a major challenge to effective treatment. Meanwhile, the individual and societal impacts of untreated OSA make effective treatment a priority. Although extensive research has been conducted into factors that impact PAP use, it is estimated that at least half of users do not use it as prescribed. However, the voice of users is notably minimal in the literature. A systematic review and qualitative metasynthesis of PAP user experience was conducted to contribute to understandings of how PAP is experienced and to inform how usage could be improved.

Methods: PsycINFO, MEDLINE, CINAHL and EMBASE databases were systematically searched. Primary research findings of adult experiences using PAP that had been inductively analysed were included. Papers were critically appraised using the CASP qualitative checklist to generate a "hierarchy of evidence". Thematic synthesis was then conducted to generate analytical themes. Results were presented in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).

Results: 25 papers reporting on over 398 people's experiences were analysed to generate 4 themes: Journey to PAP, Discomfort from and around PAP, Adapting to and using PAP, and Benefits from PAP. Author reflexivity and vulnerability to bias is acknowledged.

Conclusions: The findings highlight the applicability of a biopsychosocial understanding to PAP use. This metasynthesis gave voice to user experiences, revealing barriers to PAP use at a healthcare service level across the world, and suggests ways services can address these barriers.
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http://dx.doi.org/10.1093/sleep/zsab135DOI Listing
May 2021

An approach to rapid characterization of DMD copy number variants for prenatal risk assessment.

Am J Med Genet A 2021 08 21;185(8):2541-2545. Epub 2021 May 21.

Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada.

Prenatal detection of structural variants of uncertain significance, including copy number variants (CNV), challenges genetic counseling, and creates ambiguity for expectant parents. In Duchenne muscular dystrophy, variant classification and phenotypic severity of CNVs are currently assessed by familial segregation, prediction of the effect on the reading frame, and precedent data. Delineation of pathogenicity by familial segregation is limited by time and suitable family members, whereas analytical tools can rapidly delineate potential consequences of variants. We identified a duplication of uncertain significance encompassing a portion of the dystrophin gene (DMD) in an unaffected mother and her male fetus. Using long-read whole genome sequencing and alignment of short reads, we rapidly defined the precise breakpoints of this variant in DMD and could provide timely counseling. The benign nature of the variant was substantiated, more slowly, by familial segregation to a healthy maternal uncle. We find long-read whole genome sequencing of clinical utility in a prenatal setting for accurate and rapid characterization of structural variants, specifically a duplication involving DMD.
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http://dx.doi.org/10.1002/ajmg.a.62349DOI Listing
August 2021

The Sweet Smell of Progress With Hyaluronan and Heart Failure.

Hypertension 2021 Jun 12;77(6):1928-1930. Epub 2021 May 12.

Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY (S.P.J.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415039PMC
June 2021

A clinical transcriptome approach to patient stratification and therapy selection in acute myeloid leukemia.

Nat Commun 2021 04 30;12(1):2474. Epub 2021 Apr 30.

Experimental Medicine Program, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.
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http://dx.doi.org/10.1038/s41467-021-22625-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087683PMC
April 2021

Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease.

Dev Cell 2021 05 22;56(9):1238-1252.e5. Epub 2021 Apr 22.

Ely and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94115, USA; Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94115, USA; Division of Maternal-Fetal Medicine, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94122, USA. Electronic address:

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.
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http://dx.doi.org/10.1016/j.devcel.2021.04.001DOI Listing
May 2021

Coronary heart disease risk: Low-density lipoprotein and beyond.

Trends Cardiovasc Med 2021 Apr 17. Epub 2021 Apr 17.

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA; Community Hospital General Medical Center, Sterling, IL, USA. Electronic address:

Coronary heart disease (CHD) is the leading cause of morbidity and mortality world-wide and has been characterized as a chronic immunoinflammatory, fibroproliferative disease fueled by lipids. Great advances have been made in elucidating the complex mechanistic interactions among risk factors associated with CHD, yielding abundant success towards preventive measures and the development of pharmaceuticals to prevent and treat CHD via attenuation of lipoprotein-mediated risk. However, significant residual risk remains. Several potentially modifiable CHD risk factors ostensibly contributing to this residual risk have since come to the fore, including systemic inflammation, diabetes mellitus, high-density lipoprotein, plasma triglycerides (TG) and remnant lipoproteins (RLP), lipoprotein(a) (Lp[a]), and vascular endothelial dysfunction (ED). Herein, we summarize the body of evidence implicating each of these risk factors in residual CHD risk.
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http://dx.doi.org/10.1016/j.tcm.2021.04.002DOI Listing
April 2021

Patient-Derived Xenografts as an Innovative Surrogate Tumor Model for the Investigation of Health Disparities in Triple Negative Breast Cancer.

Womens Health Rep (New Rochelle) 2020 24;1(1):383-392. Epub 2020 Sep 24.

Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Despite a decline in overall incidence rates for cancer in the past decade, due in part to impressive advancements in both diagnosis and treatment, breast cancer (BC) remains the leading cause of cancer-related deaths in women. BC alone accounts for ∼30% of all new cancer diagnoses in women worldwide. Triple-negative BC (TNBC), defined as having no expression of the estrogen or progesterone receptors and no amplification of the HER2 receptor, is a subtype of BC that does not benefit from the use of estrogen receptor-targeting or HER2-targeting therapies. Differences in socioeconomic factors and cell intrinsic and extrinsic characteristics have been demonstrated in Black and White TNBC patient tumors. The emergence of patient-derived xenograft (PDX) models as a surrogate, translational, and functional representation of the patient with TNBC has led to the advances in drug discovery and testing of novel targeted approaches and combination therapies. However, current established TNBC PDX models fail to represent the diverse patient population and, most importantly, the specific ethnic patient populations that have higher rates of incidence and mortality. The primary aim of this review is to emphasize the importance of using clinically relevant translatable tumor models that reflect TNBC human tumor biology and heterogeneity in high-risk patient populations. The focus is to highlight the complexity of BC as it specifically relates to the management of TNBC in Black women. We discuss the importance of utilizing PDX models to study the extracellular matrix (ECM), and the distinct differences in ECM composition and biophysical properties in Black and White women. Finally, we demonstrate the crucial importance of PDX models toward novel drug discovery in this patient population.
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http://dx.doi.org/10.1089/whr.2020.0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784803PMC
September 2020

NTRK2 Fusion driven pediatric glioblastoma: Identification of oncogenic Drivers via integrative Genome and transcriptome profiling.

Clin Case Rep 2021 Mar 10;9(3):1472-1477. Epub 2021 Feb 10.

Division of Anatomic Pathology Children's and Women's Health Centre of British Columbia Vancouver BC Canada.

This is the first report of a NACC2-NTRK2 fusion in a histological glioblastoma. Oncogenomic analysis revealed this actionable fusion oncogene in a pediatric cerebellar glioblastoma, which would not have been identified through routine diagnostics, demonstrating the value of clinical genome profiling in cancer care.
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http://dx.doi.org/10.1002/ccr3.3804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981675PMC
March 2021

The transcriptional landscape of Shh medulloblastoma.

Nat Commun 2021 03 19;12(1):1749. Epub 2021 Mar 19.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-21883-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819PMC
March 2021

Branched-chain amino acids predict incident diabetes in the Brazilian Longitudinal Study of Adult Health - ELSA-Brasil.

Diabetes Res Clin Pract 2021 Apr 10;174:108747. Epub 2021 Mar 10.

Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, Av. Lineu Prestes 2565 - 4° floor, CEP: 05508-000 São Paulo, SP, Brazil; Centro de Pesquisa do Hospital Universitário, Universidade de São Paulo, Av. Lineu Prestes 2565, 3rd floor, CEP 05508-000 São Paulo, SP, Brazil. Electronic address:

Aims: To evaluate the role of branch chain amino acid (BCAA) concentrations as a predictor for incident type 2 diabetes (DM).

Methods: Participants from ELSA-Brasil without diabetes at baseline and followed for 3.9 ± 0.6 years were included in the analysis. The determinations of BCAA (valine, leucine, isoleucine) were performed by proton nuclear magnetic resonance spectroscopy. Cardiometabolic profile and incidence of DM were evaluated according to quartiles of BCAA at baseline, stratified by sex.

Results: From 3,828 participants (56% female, 50.5 ± 8.7 years) 299 (8.5%) were diagnosed with DM. For both sexes, a worsening of cardiometabolic profile was observed across increasing BCAA quartiles. In survival analysis, incidence rates of DM for the entire period were highest in participants in the third and fourth quartile of BCAA (log Rank analysis < 0.001 for both sexes). In Cox regression analysis, for men, the HR (95%CI) for risk of DM was 2.24 (1.24-4.03) for those from the fourth quartile of BCAA, while in women it was 1.94 (1.07-3.50), comparing to first quartile of BCAA after adjustments for age, BMI, physical activity, family history of DM, pre-diabetes, blood pressure, total cholesterol and HOMA-IR.

Conclusions: Higher levels of BCAA were independently predictors of DM.
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http://dx.doi.org/10.1016/j.diabres.2021.108747DOI Listing
April 2021

Injury-severity analysis of lane change crashes involving commercial motor vehicles on interstate highways.

J Safety Res 2021 02 1;76:30-35. Epub 2020 Dec 1.

Department of Civil, Construction and Environmental Engineering, The University of Alabama Tuscaloosa, AL, United States. Electronic address:

Introduction: One of the challenging tasks for drivers is the ability to change lanes around large commercial motor vehicles. Lane changing is often characterized by speed, and crashes that occur due to unsafe lane changes can have serious consequences. Considering the economic importance of commercial trucks, ensuring the safety, security, and resilience of freight transportation is of paramount concern to the United States Department of Transportation and other stakeholders.

Method: In this study, a mixed (random parameters) logit model was developed to better understand the relationship between crash factors and associated injury severities of commercial vehicle crashes involving lane change on interstate highways. The study was based on 2009-2016 crash data from Alabama.

Results: Preliminary data analysis showed that about 4% of the observed crashes were major injury crashes and drivers of commercial motor vehicles were at-fault in more than half of the crashes. Acknowledging potential crash data limitations, the model estimation results reveal that there is increased probability of major injury when lane change crashes occurred on dark unlit portions of interstates and involve older drivers, at-fault commercial vehicle drivers, and female drivers. The results further show that lane change crashes that occurred on interstates with higher number of travel lanes were less likely to have major injury outcomes. Practical Applications: These findings can help policy makers and state transportation agencies increase awareness on the hazards of changing lanes in the immediate vicinity and driving in the blind spots of large commercial motor vehicles. Additionally, law enforcement efforts may be intensified during times and locations of increased unsafe lane changing activities. These findings may also be useful in commercial vehicle driver training and driver licensing programs.
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http://dx.doi.org/10.1016/j.jsr.2020.11.001DOI Listing
February 2021

Megabase-scale methylation phasing using nanopore long reads and NanoMethPhase.

Genome Biol 2021 02 22;22(1):68. Epub 2021 Feb 22.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.

The ability of nanopore sequencing to simultaneously detect modified nucleotides while producing long reads makes it ideal for detecting and phasing allele-specific methylation. However, there is currently no complete software for detecting SNPs, phasing haplotypes, and mapping methylation to these from nanopore sequence data. Here, we present NanoMethPhase, a software tool to phase 5-methylcytosine from nanopore sequencing. We also present SNVoter, which can post-process nanopore SNV calls to improve accuracy in low coverage regions. Together, these tools can accurately detect allele-specific methylation genome-wide using nanopore sequence data with low coverage of about ten-fold redundancy.
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http://dx.doi.org/10.1186/s13059-021-02283-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898412PMC
February 2021
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