Publications by authors named "J H Hearn"

243 Publications

The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development?

Rheumatology (Oxford) 2021 Feb 25. Epub 2021 Feb 25.

Dept of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland New Zealand.

The circadian clock is a specialised cell signalling pathway present in all cells. Loss of clock function leads to tissue degeneration and premature aging in animal models demonstrating the fundamental importance of clocks for cell, tissue and organism health There is now considerable evidence that the chondrocyte circadian clock is altered in osteoarthritis (OA). The purpose of this review is to summarise current knowledge regarding the nature of the change in the chondrocyte clock in OA and the implications of this change for disease development. Expression of the core clock component, BMAL1, has consistently been shown to be lower in OA chondrocytes. This may contribute to changes in chondrocyte differentiation and extracellular matrix turnover in disease. Circadian clocks are highly responsive to environmental factors. Mechanical loading, diet, inflammation and oxidative insult can all influence clock function. These factors may contribute to causing the change in the chondrocyte clock in OA.
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http://dx.doi.org/10.1093/rheumatology/keab197DOI Listing
February 2021

The impact of neurological disability and sensory loss on mindfulness practice.

Disabil Rehabil 2021 Feb 23:1-9. Epub 2021 Feb 23.

School of Sport Science and Physical Activity, University of Bedfordshire, Luton, UK.

Objectives: Mindfulness-based approaches are increasingly recommended in the management of medical conditions associated with sensory loss and absence, such as Spinal Cord Injury (SCI), Multiple Sclerosis (MS) and Functional Neurological Disorder (FND). Yet the implications of undertaking practices such as body scanning when living with sensory loss have not been considered. This study aimed to explore the impact of sensory loss on the practice and experience of mindfulness in qualified mindfulness teachers with SCI/FND/MS.

Methods: Eight mindfulness teachers (5 females, 3 males) with SCI/FND/MS, sensory loss and wheelchair use were recruited from mindfulness teacher databases. In-depth, semi-structured interviews were undertaken, lasting between 50 and 93 min. Interviews were transcribed verbatim and analysed using Interpretative Phenomenological Analysis. Idiographic analyses for descriptive, linguistic and conceptual themes were completed before cross-case analyses.

Results: Analyses resulted in two superordinate themes: (1) Adopting your Body; and (2) Sensation without Loss. These themes reflected the challenge of overcoming initial resistance to areas of the body with sensory disruption, building a relationship with the whole body, such that sensory awareness could be visualised and experienced without proprioception.

Conclusions: Mindfulness offers a unique approach to accepting and working with the body after paralysis or sensory loss. Fundamental to the use of mindfulness with such populations, is the prioritisation of inclusive sensory language and exploring sensory absence as well as sensory presence. The cognitive and emotional outcomes of body scanning may be uniquely elevated in populations with neurophysiological disorders, highlighting the benefits of mindfulness for adaptive and protective self-management.IMPLICATIONS FOR REHABILITATIONMindfulness-based practices which focus on the body and sensation are accessible to people with neurological limitations.Mindfulness techniques can be extended through the use of visualisation strategies to encourage (non-proprioceptive) awareness of paralysed limbs or areas of the body with sensory loss.The language used in mindfulness-based interventions may need adapted by practitioners so that it remains inclusive for people with sensory loss as well as sensory presence.Additional care needs to be taken when using body scans during mindfulness as they have the potential to exacerbate psychological distress in people with reduced sensory awareness.
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http://dx.doi.org/10.1080/09638288.2021.1887946DOI Listing
February 2021

The Need for Ethnoracial Equity in Artificial Intelligence for Diabetes Management: Review and Recommendations.

J Med Internet Res 2021 Feb 10;23(2):e22320. Epub 2021 Feb 10.

Centre for Global eHealth Innovation, Techna Institute, University Health Network, Toronto, ON, Canada.

There is clear evidence to suggest that diabetes does not affect all populations equally. Among adults living with diabetes, those from ethnoracial minority communities-foreign-born, immigrant, refugee, and culturally marginalized-are at increased risk of poor health outcomes. Artificial intelligence (AI) is actively being researched as a means of improving diabetes management and care; however, several factors may predispose AI to ethnoracial bias. To better understand whether diabetes AI interventions are being designed in an ethnoracially equitable manner, we conducted a secondary analysis of 141 articles included in a 2018 review by Contreras and Vehi entitled "Artificial Intelligence for Diabetes Management and Decision Support: Literature Review." Two members of our research team independently reviewed each article and selected those reporting ethnoracial data for further analysis. Only 10 articles (7.1%) were ultimately selected for secondary analysis in our case study. Of the 131 excluded articles, 118 (90.1%) failed to mention participants' ethnic or racial backgrounds. The included articles reported ethnoracial data under various categories, including race (n=6), ethnicity (n=2), race/ethnicity (n=3), and percentage of Caucasian participants (n=1). Among articles specifically reporting race, the average distribution was 69.5% White, 17.1% Black, and 3.7% Asian. Only 2 articles reported inclusion of Native American participants. Given the clear ethnic and racial differences in diabetes biomarkers, prevalence, and outcomes, the inclusion of ethnoracial training data is likely to improve the accuracy of predictive models. Such considerations are imperative in AI-based tools, which are predisposed to negative biases due to their black-box nature and proneness to distributional shift. Based on our findings, we propose a short questionnaire to assess ethnoracial equity in research describing AI-based diabetes interventions. At this unprecedented time in history, AI can either mitigate or exacerbate disparities in health care. Future accounts of the infancy of diabetes AI must reflect our early and decisive action to confront ethnoracial inequities before they are coded into our systems and perpetuate the very biases we aim to eliminate. If we take deliberate and meaningful steps now toward training our algorithms to be ethnoracially inclusive, we can architect innovations in diabetes care that are bound by the diverse fabric of our society.
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http://dx.doi.org/10.2196/22320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904401PMC
February 2021

'We're all in the same boat': An Interpretative Phenomenological Analysis study of experiences of being an 'expert' during patient and public involvement within Child and Adolescent Mental Health Services (CAMHS).

Health Expect 2021 Feb 2. Epub 2021 Feb 2.

Manchester Metropolitan University, Manchester, UK.

Background: Patient and Public involvement (PPI) has rapidly evolved into a key component in shaping the delivery of health services. However, little is known about what it is like to participate in involvement procedures that include representatives of multiple groups and in the context of developing new interventions for Child and Adolescent Mental Health Services (CAMHS).

Objective: This study explored participants' experiences of PPI, following attending a 'consensus conference', during which their views were sought in relation to the development of a proposed staff-based intervention and key questions about its design and implementation.

Design: Qualitative, semi-structured interview study.

Setting And Participants: Six participants, including service users and various frontline clinical staff team members, who had experience of CAMHS were present at the consensus conference and then asked about their experiences of being involved via semi-structured interviews. The data were analysed using Interpretative Phenomenological Analysis (IPA). Young people, carers and frontline staff have been involved in the design and implementation throughout the broader programme of work of which this study forms part, although these groups were not directly involved in the design and implementation of this paper.

Results: Three key narratives were present: (a) Previous Experiences Driving Expectations, (b) 'We are all in the same boat' and (c) The Realization of Multiple Identities. The results suggest that PPI involvement is a complex process that may be driven by positive/negative expectations, but that individuals value learning about others and recognizing different perspectives while reaching shared goals in improving services.

Discussion And Conclusion: This study demonstrates the complexity of experience that service users and clinical staff face when engaging in involvement activities in CAMHS. The findings demonstrate the value in engaging multiple stakeholder groups while also highlighting the importance of proper consideration of the procedures involved and facilitators of engagement.
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http://dx.doi.org/10.1111/hex.13183DOI Listing
February 2021

DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna.

Epigenetics Chromatin 2021 Jan 6;14(1). Epub 2021 Jan 6.

Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Background: Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna.

Results: Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age.

Conclusions: Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.
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http://dx.doi.org/10.1186/s13072-020-00379-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789248PMC
January 2021

Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis.

Platelets 2020 Dec 7:1-11. Epub 2020 Dec 7.

Red Blood Cell Research Group, Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich , Zürich, Switzerland.

Ionotropic glutamate receptors include -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), kainate receptors (KAR), and -methyl-D-aspartate receptors (NMDAR). All function as cation channels; AMPAR and KAR are more permeable to sodium and NMDAR to calcium ions. Compared to the brain, receptor assemblies in platelets are unusual, suggesting distinctive functionalities. There is convincing evidence that AMPAR and KAR amplify platelet function and thrombus formation and . Transgenic mice lacking GluA1 and GluK2 (AMPAR and KAR subunits, respectively) have longer bleeding times and prolonged time to thrombosis in an arterial model. In humans, rs465566 KAR gene polymorphism associates with altered platelet responses suggesting enhanced aspirin effect. The NMDAR contribution to platelet function is less well defined. NMDA at low concentrations (≤10 μM) inhibits platelet aggregation and high concentrations (≥100 μM) have no effect. However, open NMDAR channel blockers interfere with platelet activation and aggregation induced by other agonists ; anti-GluN1 antibodies interfere with thrombus formation under high shear rates ; and rats vaccinated with GluN1 develop iron deficiency anemia suggestive of mild chronic bleeding. In this review, we summarize data on glutamate receptors in platelets and propose a unifying model that reconciles some of the opposing effects observed.
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http://dx.doi.org/10.1080/09537104.2020.1852542DOI Listing
December 2020

CYP6P9-Driven Signatures of Selective Sweep of Metabolic Resistance to Pyrethroids in the Malaria Vector Reveal Contemporary Barriers to Gene Flow.

Genes (Basel) 2020 Nov 5;11(11). Epub 2020 Nov 5.

LSTM Research Unit, Centre for Research in Infectious Diseases (CRID), P.O. Box 13591 Yaoundé, Cameroon.

Pyrethroid resistance in major malaria vectors such as threatens malaria control efforts in Africa. Cytochrome P450-mediated metabolic resistance is best understood for genes in southern Africa in . However, we do not know if this resistance mechanism is spreading across Africa and how it relates to broader patterns of gene flow across the continent. Nucleotide diversity of the gene and the diversity pattern of five gene fragments spanning a region of 120 kb around the gene were surveyed in mosquitoes from southern, eastern and central Africa. These analyses revealed that a resistance-associated allele has swept through southern and eastern Africa and is now fixed in these regions. A similar diversity profile was observed when analysing genomic regions located 34 kb upstream to 86 kb downstream of the locus, concordant with a selective sweep throughout the rp1 locus. We identify reduced gene flow between southern/eastern Africa and central Africa, which we hypothesise is due to the Great Rift Valley. These potential barriers to gene flow are likely to prevent or slow the spread of -based resistance mechanism to other parts of Africa and would to be considered in future vector control interventions such as gene drive.
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http://dx.doi.org/10.3390/genes11111314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694540PMC
November 2020

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

JAMA Oncol 2020 12;6(12):1912-1920

Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus.

Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer.

Design, Setting, And Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019.

Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy.

Main Outcomes And Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts.

Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782).

Conclusions And Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.
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http://dx.doi.org/10.1001/jamaoncol.2020.4922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582232PMC
December 2020

Development of a 3D-printed testicular cancer model for testicular examination education.

Can Urol Assoc J 2021 Apr;15(4):E221-E226

Department of Urology, Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.

Introduction: Testicular cancer is the most commonly diagnosed malignancy in young males. Testicular examination is a non-invasive and inexpensive means of detecting testicular cancer at an early stage. In this project, a set of 3D-printed models was developed to facilitate teaching testicular examination and improving understanding of testicular malignancies among patients and medical learners.

Methods: Five scrotum models were designed: a control model with healthy testes, and four models containing a healthy testicle and a testicle with an endophytic mass of varying size. The anatomy, texture, and composition of the 3D-printed models were refined using an iterative process between the design team and urologists. The completed models were assessed by six urologists, two urology nurse practitioners, and 32 medical learners. Participants were asked to inspect and palpate each model, and to provide feedback using a five-point Likert scale.

Results: Clinicians reported that the models enabled accurate simulation of a testicular examination involving both healthy and pathologic testes (χ̄=4.3±1.0). They agreed that the models would be useful teaching tools for both medical learners (χ̄=4.8±0.5) and patients (χ̄=4.8±0.7). Following an educational session with the models, medical learners reported improvements in confidence and skill in performing a testicular examination.

Conclusions: 3D-printed models can effectively simulate palpation of both healthy and pathologic testes. The developed models have the potential to be a useful adjunct in teaching testicular examination and in demonstrating abnormal findings that require further investigation.
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http://dx.doi.org/10.5489/cuaj.6675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021429PMC
April 2021

From Inquilines to Gall Inducers: Genomic Signature of a Life-Style Transition in Synergus Gall Wasps.

Genome Biol Evol 2020 11;12(11):2060-2073

Department of Bioinformatics and Genetics, Swedish Museum of Natural History.

Gall wasps (Hymenoptera: Cynipidae) induce complex galls on oaks, roses, and other plants, but the mechanism of gall induction is still unknown. Here, we take a comparative genomic approach to revealing the genetic basis of gall induction. We focus on Synergus itoensis, a species that induces galls inside oak acorns. Previous studies suggested that this species evolved the ability to initiate gall formation recently, as it is deeply nested within the genus Synergus, whose members are mostly inquilines that develop inside the galls of other species. We compared the genome of S. itoensis with that of three related Synergus inquilines to identify genomic changes associated with the origin of gall induction. We used a novel Bayesian selection analysis, which accounts for branch-specific and gene-specific selection effects, to search for signatures of selection in 7,600 single-copy orthologous genes shared by the four Synergus species. We found that the terminal branch leading to S. itoensis had more genes with a significantly elevated dN/dS ratio (positive signature genes) than the other terminal branches in the tree; the S. itoensis branch also had more genes with a significantly decreased dN/dS ratio. Gene set enrichment analysis showed that the positive signature gene set of S. itoensis, unlike those of the inquiline species, is enriched in several biological process Gene Ontology terms, the most prominent of which is "Ovarian Follicle Cell Development." Our results indicate that the origin of gall induction is associated with distinct genomic changes, and provide a good starting point for further characterization of the genes involved.
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http://dx.doi.org/10.1093/gbe/evaa204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674688PMC
November 2020

A 6.5-kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy.

Mol Ecol 2020 11 11;29(22):4395-4411. Epub 2020 Oct 11.

Vector Biology Department, Liverpool School of Tropical Medicine, Liverpool, UK.

Elucidating the complex evolutionary armory that mosquitoes deploy against insecticides is crucial to maintain the effectiveness of insecticide-based interventions. Here, we deciphered the role of a 6.5-kb structural variation (SV) in driving cytochrome P450-mediated pyrethroid resistance in the malaria vector, Anopheles funestus. Whole-genome pooled sequencing detected an intergenic 6.5-kb SV between duplicated CYP6P9a/b P450s in pyrethroid-resistant mosquitoes through a translocation event. Promoter analysis revealed a 17.5-fold higher activity (p < .0001) for the SV- carrying fragment than the SV- free one. Quantitative real-time PCR expression profiling of CYP6P9a/b for each SV genotype supported its role as an enhancer because SV+/SV+ homozygote mosquitoes had a significantly greater expression for both genes than heterozygotes SV+/SV- (1.7- to 2-fold) and homozygotes SV-/SV- (4-to 5-fold). Designing a PCR assay revealed a strong association between this SV and pyrethroid resistance (SV+/SV+ vs. SV-/SV-; odds ratio [OR] = 2,079.4, p < .001). The 6.5-kb SV is present at high frequency in southern Africa (80%-100%) but absent in East/Central/West Africa. Experimental hut trials revealed that homozygote SV mosquitoes had a significantly greater chance to survive exposure to pyrethroid-treated nets (OR 27.7; p < .0001) and to blood feed than susceptible mosquitoes. Furthermore, mosquitoes homozygote-resistant at the three loci (SV+/CYP6P9a_R/CYP6P9b_R) exhibited a higher resistance level, leading to a far superior ability to survive exposure to nets than those homozygotes susceptible at the three loci, revealing a strong additive effect. This study highlights the important role of structural variations in the development of insecticide resistance in malaria vectors and their detrimental impact on the effectiveness of pyrethroid-based nets.
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http://dx.doi.org/10.1111/mec.15645DOI Listing
November 2020

Virtual care models for cancer survivorship.

NPJ Digit Med 2020 2;3:113. Epub 2020 Sep 2.

Division of Urology, Department of Surgery, University of Toronto, Toronto, ON Canada.

Virtual care models for cancer survivorship are needed to support patients living with the chronic effects of cancer treatment, while increasing health system capacity. Characteristics that may be critical to their success have not been adequately studied. This scoping review summarizes previous efforts to virtualize survivorship care to inform future innovations in the field. Four databases were searched for articles published before January 2020, and 24 articles that met selection criteria were included in this analysis. Rationale for pursuing virtual models of care shared two common objectives: (1) the need for sustainable survivorship care, and (2) the opportunity to improve survivorship outcomes. Breast cancer ( = 10) and prostate cancer ( = 4) were the most targeted cancers for virtual survivorship care. The implemented technologies included web platforms ( = 15), telephone calls ( = 12), and smartphone or tablet applications ( = 5). A variety of healthcare professionals were effectively involved in the provision of virtual care. Future virtual care models may benefit from integrating with existing health systems and services, repurposing common technologies, involving allied health professionals, and engaging patients and caregivers from diverse communities in the design of virtual services.
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http://dx.doi.org/10.1038/s41746-020-00321-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468136PMC
September 2020

Parallel worlds and personified pain: A mixed-methods analysis of pain metaphor use by women with endometriosis.

Br J Health Psychol 2021 May 13;26(2):271-288. Epub 2020 Sep 13.

Manchester Metropolitan University, UK.

Objectives: Endometriosis is a long-term condition in which endometrial-like tissue grows outside of the womb, causing intense chronic pain. Previous work has demonstrated the physical and emotional impact on women who live with endometriosis, and metaphors can play an influential role in communicating the experience of pain, but there exists little understanding of the role and impact of such language for women with endometriosis.

Design: A qualitative, semi-structured interview design.

Methods: Conceptual Metaphor Theory (CMT) and Interpretative Phenomenological Analysis (IPA) were utilized in a mixed-methods study to examine the prevalence, types, and meaning of metaphors and metaphor use as a health communication strategy. Twenty-one women aged between 23 and 53 years (mean age 36.1 years) with endometriosis took part in audio-recorded interviews.

Results: The women reported experiencing symptoms for an average of 11 years before receiving a formal diagnosis of endometriosis, and the mean age of diagnosis was 27.6 years. Seven distinct conceptual metaphors were identified in 221 metaphorical expressions used across all participants, with most common ones referring to pain as physical properties of elements such as temperature and pressure, physical damage, and an external attacker. IPA revealed three themes pertaining to the feeling of vulnerability and helplessness, pain being incomprehensible, and a drive to manage and conceal pain simultaneously.

Conclusions: This study demonstrates the power of language in facilitating understanding and empathy in the listener, alongside the challenge of communicating endometriosis pain to others. Imagery-based techniques may assist in adaptation to, interpretation, and acceptance of pain to reduce pain-related distress.
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http://dx.doi.org/10.1111/bjhp.12472DOI Listing
May 2021

A prospective study evaluating the integration of a multifaceted evidence-based medicine curriculum into early years in an undergraduate medical school.

BMC Med Educ 2020 Aug 24;20(1):278. Epub 2020 Aug 24.

University of Buckingham Medical School, Hunter Street, Buckingham, MK18 1EG, UK.

Background: The importance of ensuring medical students are equipped with the skills to be able to practice evidence-based medicine (EBM) has been increasingly recognized in recent years. However, there is limited information on an effective EBM curriculum for undergraduate medical schools. This study aims to test the feasibility of integrating a multifaceted EBM curriculum in the early years of an undergraduate medical school. This was subsequently evaluated using the validated Fresno test and students' self-reported knowledge and attitudes as they progressed through the curriculum.

Methods: EBM was integrated horizontally and vertically into the curriculum into the first 2 years of undergraduate medical school. First year medical students were recruited to participate in the study. The 212-point Fresno test was administered along with a locally developed questionnaire at baseline before EBM teaching in year one and at the end of EBM teaching in year two.

Results: Thirty-one students participated at baseline and 55 students participated at the end of second year EBM teaching. For the 18 students who completed the Fresno at both time points, the average score increased by 38.7 marks (p < 0.001) after EBM teaching. Students felt confident in formulating clinical questions and in critically appraising journal articles after EBM teaching. EBM was perceived to be important to their future practice as a doctor and for improving patient outcomes at both time points.

Conclusions: It has been feasible to integrate a multifaceted, EBM curriculum from the first year of an undergraduate medical program. Early evaluation of the curriculum using the Fresno test has shown a significant increase in students' EBM knowledge. The curriculum also demonstrated an increase in students' perceptions of the clinical relevance of EBM in their developing practice.
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http://dx.doi.org/10.1186/s12909-020-02140-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445898PMC
August 2020

Lived Experiences and Technological Literacy of Heart Failure Patients and Clinicians at a Cardiac Care Centre in Uganda.

Ann Glob Health 2020 07 28;86(1):85. Epub 2020 Jul 28.

Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, CA.

Background: Digital health could serve as a low-cost means of enabling better self-care in patients living with heart failure (HF) in resource-limited settings such as Uganda. However, digital health interventions previously deployed in such settings have been unsuccessful due to a lack of local patient and clinician engagement in the design process.

Objective: To engage Ugandan HF patients and clinicians regarding their experiences with HF management and technology, so as to inform the future design of a digital health intervention for HF patients in Uganda.

Methods: The study employed a convergent parallel mixed-methods design. Data collection was completed at the Uganda Heart Institute in Kampala, Uganda. Data were ascertained through a patient survey and semi-structured interviews completed with HF patients, caregivers, physicians, and nurses. A conventional content analysis approach was used to qualitatively examine interview transcripts.

Findings: Survey data were collected from 101 HF patients (62 female/39 male, aged 54.2 ± 17.5 years). Nearly half (48%) disagreed that they knew what to do in response to changes in their HF symptoms. Almost all patients (98%) had access to a mobile device. Many patients (63%) identified as comfortable in using mobile money - a local set of services that use Unstructured Supplementary Service Data (USSD). Interviews were completed with 19 HF patients, three caregivers, seven physicians, and three nurses. Qualitative analysis revealed four clusters of themes: overdependence of patients on the clinic, inconvenience associated with attending the clinic, inconsistent patient self-care behaviours at home, and technological abilities that favoured USSD-based services.

Conclusions: Ugandan HF patients possess unmet information needs that leave them ill-equipped to care for themselves. Future digital health interventions for this population should empower patients with HF-specific information and reassurance in their self-care abilities. Based on patient preferences, such systems should harness USSD technology with which most patients are already comfortable.
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http://dx.doi.org/10.5334/aogh.2905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413178PMC
July 2020

'Trying to bring attention to your body when you're not sure where it is': An interpretative phenomenological analysis of drivers and barriers to mindfulness for people with spinal cord injury.

Br J Health Psychol 2021 Feb 4;26(1):161-178. Epub 2020 Aug 4.

The University of Derby, UK.

Objectives: Work is beginning to explore the impact of mindfulness in managing the physical and psychological health of people with spinal cord injury (SCI). However, no previous work has sought to understand what drives people with such conditions to try mindfulness, and what barriers are experienced in accessing mindfulness.

Design: An exploratory, qualitative, interview design, utilizing interpretative phenomenological analysis.

Methods: Semi-structured interviews were conducted with 11 people with SCI who had experience of mindfulness since sustaining their injury. Verbatim transcripts were analysed using IPA to understand the lived experience of mindfulness post-SCI.

Results: Analysis suggested that managing physical and mental health, and viewing mindfulness as proactive and protective were key drivers for exploring mindfulness. However, multiple barriers to accessing opportunities and developing capability impeded engagement. These included the focus on areas of the body that participants had reduced sensation in, physical environments that could not be navigated in a wheelchair, social stigma surrounding the use of mindfulness, and a sense of obligation and risk of failure implied by perceived requirements for engagement.

Conclusions: The results demonstrate the need for specific interventions to accommodate the reduced sensory and physical function experienced by people with neurological conditions and to enhance sense of control and autonomy. In addition, recommendations include minimizing the stigma surrounding mindfulness, and the potentially demotivating impact of the perception of 'failing' to engage.
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http://dx.doi.org/10.1111/bjhp.12462DOI Listing
February 2021

Daphnia magna modifies its gene expression extensively in response to caloric restriction revealing a novel effect on haemoglobin isoform preference.

Mol Ecol 2020 09 30;29(17):3261-3276. Epub 2020 Jul 30.

Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

Caloric restriction (CR) produces clear phenotypic effects within and between generations of the model crustacean Daphnia magna. We have previously established that micro-RNAs and cytosine methylation change in response to CR in this organism, and we demonstrate here that CR has a dramatic effect on gene expression. Over 6,000 genes were differentially expressed between CR and well-fed D. magna, with a bias towards up-regulation of genes under caloric restriction. We identified a highly expressed haemoglobin gene that responds to CR by changing isoform proportions. Specifically, a transcript containing three haem-binding erythrocruorin domains was strongly down-regulated under CR in favour of transcripts containing fewer or no such domains. This change in the haemoglobin mix is similar to the response to hypoxia in Daphnia, which is mediated through the transcription factor hypoxia-inducible factor 1, and ultimately the mTOR signalling pathway. This is the first report of a role for haemoglobin in the response to CR. We also observed high absolute expression of superoxide dismutase (SOD) in normally fed individuals, which contrasts with observations of high SOD levels under CR in other taxa. However, key differentially expressed genes, like SOD, were not targeted by differentially expressed micro-RNAs. Whether the link between haemoglobin and CR occurs in other organisms, or is related to the aquatic lifestyle, remains to be tested. It suggests that one response to CR may be to simply transport less oxygen and lower respiration.
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http://dx.doi.org/10.1111/mec.15557DOI Listing
September 2020

Nephroureterectomy of Right-to-Left Crossed Fused Renal Ectopia with Urothelial Carcinoma.

Cureus 2020 Jun 10;12(6):e8544. Epub 2020 Jun 10.

Urology, Memorial University of Newfoundland, St. John's, CAN.

Urothelial carcinoma in a crossed fused renal ectopia (CFRE) is an exceedingly rare clinical finding. We describe the surgical management used to treat upper tract urothelial carcinoma in a 64-year-old man with a right-to-left CFRE. Nephroureterectomy with bladder cuff excision was the treatment of choice. The fused kidney was carefully dissected until an area of demarcation emerged between the vasculature supplying the left and right moieties. Pressure was applied to the isthmus separating the two moieties, and a sharp incision was made to release the left moiety. The operation was completed with limited blood loss. Pathology revealed a high-grade T3 papillary urothelial carcinoma with negative margins. To our knowledge, the case is the first to report urothelial carcinoma in a right-to-left CFRE.
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http://dx.doi.org/10.7759/cureus.8544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357307PMC
June 2020

-Methyl-D-Aspartate Receptors in Hematopoietic Cells: What Have We Learned?

Front Physiol 2020 17;11:577. Epub 2020 Jun 17.

Red Blood Cell Research Group, Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zürich, Switzerland.

The -methyl-D-aspartate receptor (NMDAR) provides a pathway for glutamate-mediated inter-cellular communication, best known for its role in the brain but with multiple examples of functionality in non-neuronal cells. Data previously published by others and us provided evidence that NMDARs regulate platelet and red blood cell (RBC) production. Here, we summarize what is known about these hematopoietic roles of the NMDAR. Types of NMDAR subunits expressed in megakaryocytes (platelet precursors) and erythroid cells are more commonly found in the developing rather than adult brain, suggesting trophic functions. Nevertheless, similar to their neuronal counterparts, hematopoietic NMDARs function as ion channels, and are permeable to calcium ions (Ca). Inhibitors that block open NMDAR (memantine and MK-801) interfere with megakaryocytic maturation and proplatelet formation in primary culture. The effect on proplatelet formation appears to involve Ca influx-dependent regulation of the cytoskeletal remodeling. In contrast to normal megakaryocytes, NMDAR effects in leukemic Meg-01 cells are diverted away from differentiation to increase proliferation. NMDAR hypofunction triggers differentiation of Meg-01 cells with the bias toward erythropoiesis. The underlying mechanism involves changes in the intracellular Ca homeostasis, cell stress pathways, and hematopoietic transcription factors that upon NMDAR inhibition shift from the predominance of megakaryocytic toward erythroid regulators. This ability of NMDAR to balance both megakaryocytic and erythroid cell fates suggests receptor involvement at the level of a bipotential megakaryocyte-erythroid progenitor. In human erythroid precursors and circulating RBCs, NMDAR regulates intracellular Ca homeostasis. NMDAR activity supports survival of early proerythroblasts, and in mature RBCs NMDARs impact cellular hydration state, hemoglobin oxygen affinity, and nitric oxide synthase activity. Overexcitation of NMDAR in mature RBCs leads to Ca overload, K loss, RBC dehydration, and oxidative stress, which may contribute to the pathogenesis of sickle cell disease. In summary, there is growing evidence that glutamate-NMDAR signaling regulates megakaryocytic and erythroid cells at different stages of maturation, with some intriguing differences emerging in NMDAR expression and function between normal and diseased cells. NMDAR signaling may provide new therapeutic opportunities in hematological disease, but applicability needs to be confirmed.
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http://dx.doi.org/10.3389/fphys.2020.00577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311790PMC
June 2020

Low-coverage genomic data resolve the population divergence and gene flow history of an Australian rain forest fig wasp.

Mol Ecol 2020 10 13;29(19):3649-3666. Epub 2020 Jul 13.

Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.

Population divergence and gene flow are key processes in evolution and ecology. Model-based analysis of genome-wide data sets allows discrimination between alternative scenarios for these processes even in nonmodel taxa. We used two complementary approaches (one based on the blockwise site frequency spectrum [bSFS], the second on the pairwise sequentially Markovian coalescent [PSMC]) to infer the divergence history of a fig wasp, Pleistodontes nigriventris. Pleistodontes nigriventris and its fig tree mutualist Ficus watkinsiana are restricted to rain forest patches along the eastern coast of Australia and are separated into The Northern population is to the north of the Southern populations by two dry forest corridors (the Burdekin and St. Lawrence Gaps). We generated whole genome sequence data for two haploid males per population and used the bSFS approach to infer the timing of divergence between northern and southern populations of P. nigriventris, and to discriminate between alternative isolation with migration (IM) and instantaneous admixture (ADM) models of postdivergence gene flow. Pleistodontes nigriventris has low genetic diversity (π = 0.0008), to our knowledge one of the lowest estimates reported for a sexually reproducing arthropod. We find strongest support for an ADM model in which the two populations diverged ca. 196 kya in the late Pleistocene, with almost 25% of northern lineages introduced from the south during an admixture event ca. 57 kya. This divergence history is highly concordant with individual population demographies inferred from each pair of haploid males using PSMC. Our analysis illustrates the inferences possible with genome-level data for small population samples of tiny, nonmodel organisms and adds to a growing body of knowledge on the population structure of Australian rain forest taxa.
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http://dx.doi.org/10.1111/mec.15523DOI Listing
October 2020

An Africa-wide genomic evolution of insecticide resistance in the malaria vector Anopheles funestus involves selective sweeps, copy number variations, gene conversion and transposons.

PLoS Genet 2020 06 4;16(6):e1008822. Epub 2020 Jun 4.

Vector Biology Department, Liverpool School of Tropical Medicine (LSTM), Pembroke Place, Liverpool, United Kingdom.

Insecticide resistance in malaria vectors threatens to reverse recent gains in malaria control. Deciphering patterns of gene flow and resistance evolution in malaria vectors is crucial to improving control strategies and preventing malaria resurgence. A genome-wide survey of Anopheles funestus genetic diversity Africa-wide revealed evidences of a major division between southern Africa and elsewhere, associated with different population histories. Three genomic regions exhibited strong signatures of selective sweeps, each spanning major resistance loci (CYP6P9a/b, GSTe2 and CYP9K1). However, a sharp regional contrast was observed between populations correlating with gene flow barriers. Signatures of complex molecular evolution of resistance were detected with evidence of copy number variation, transposon insertion and a gene conversion between CYP6P9a/b paralog genes. Temporal analyses of samples before and after bed net scale up suggest that these genomic changes are driven by this control intervention. Multiple independent selective sweeps at the same locus in different parts of Africa suggests that local evolution of resistance in malaria vectors may be a greater threat than trans-regional spread of resistance haplotypes.
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http://dx.doi.org/10.1371/journal.pgen.1008822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297382PMC
June 2020

Caffeine-Induced Psychosis and a Review of Statutory Approaches to Involuntary Intoxication.

J Am Acad Psychiatry Law 2020 Sep 13;48(3):376-383. Epub 2020 May 13.

Dr. Hearn is Assistant Professor of Psychiatry, Department of Psychiatry and Behavioral Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri. Ms. Reiff is Office Head and Attorney, Dillon Trial Office of the Colorado Public Defender, Dillon, Colorado. Dr. McBride is Program Director, Child and Adolescent Psychiatry Residency, and Assistant Clinical Professor, Department of Psychiatry and Behavioral Sciences, University of California, Davis. Dr. Kelly is Senior Psychiatrist, Coalinga State Hospital, Coalinga, California, and Program Director, Forensic Psychiatry Fellowship, San Mateo County Behavioral Health and Recovery Services, San Mateo, California.

Caffeine is the most commonly ingested psychoactive substance in the world. Although caffeine-use disorder is not recognized as a formal diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, five disorders related to caffeine use are enumerated therein. An evolving literature suggests that caffeine is one of many licit substances that may cause psychotic symptoms in higher doses. Here, we present a case in which a defendant ingested large quantities of caffeine, which result in transient psychosis and a successful affirmative defense of involuntary intoxication. The purpose of this article is to summarize states' statutory approaches to involuntary intoxication, given that the term is defined variably, if defined at all. Evaluators must be careful to apply jurisdictionally appropriate standards in involuntary intoxication defenses because the bar for this total defense differs across localities.
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http://dx.doi.org/10.29158/JAAPL.003923-20DOI Listing
September 2020

Addition of Androgen-Deprivation Therapy or Brachytherapy Boost to External Beam Radiotherapy for Localized Prostate Cancer: A Network Meta-Analysis of Randomized Trials.

J Clin Oncol 2020 09 12;38(26):3024-3031. Epub 2020 May 12.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.

Purpose: In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT.

Materials And Methods: A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve.

Results: Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio [HR], 0.71 [95% CI, 0.62 to 0.81]), whereas the addition of BT did not significantly improve OS (HR, 1.03 [95% CI, 0.78 to 1.36]). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 [95% CI, 0.52 to 0.89]). Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.

Conclusion: Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.
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http://dx.doi.org/10.1200/JCO.19.03217DOI Listing
September 2020

A systematic review and taxonomy of tools for evaluating evidence-based medicine teaching in medical education.

Syst Rev 2020 04 24;9(1):91. Epub 2020 Apr 24.

Centre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences, Oxford, OX2 6GG, UK.

Background: The importance of teaching the skills and practice of evidence-based medicine (EBM) for medical professionals has steadily grown in recent years. Alongside this growth is a need to evaluate the effectiveness of EBM curriculum as assessed by competency in the five 'A's': asking, acquiring, appraising, applying and assessing (impact and performance). EBM educators in medical education will benefit from a compendium of existing assessment tools for assessing EBM competencies in their settings. The purpose of this review is to provide a systematic review and taxonomy of validated tools that evaluate EBM teaching in medical education.

Methods: We searched MEDLINE, EMBASE, Cochrane library, Educational Resources Information Centre (ERIC), Best Evidence Medical Education (BEME) databases and references of retrieved articles published between January 2005 and March 2019. We have presented the identified tools along with their psychometric properties including validity, reliability and relevance to the five domains of EBM practice and dimensions of EBM learning. We also assessed the quality of the tools to identify high quality tools as those supported by established interrater reliability (if applicable), objective (non-self-reported) outcome measures and achieved ≥ 3 types of established validity evidence. We have reported our study in accordance with the PRISMA guidelines.

Results: We identified 1719 potentially relevant articles of which 63 full text articles were assessed for eligibility against inclusion and exclusion criteria. Twelve articles each with a unique and newly identified tool were included in the final analysis. Of the twelve tools, all of them assessed the third step of EBM practice (appraise) and four assessed just that one step. None of the twelve tools assessed the last step of EBM practice (assess). Of the seven domains of EBM learning, ten tools assessed knowledge gain, nine assessed skills and-one assessed attitude. None addressed reaction to EBM teaching, self-efficacy, behaviours or patient benefit. Of the twelve tools identified, six were high quality. We have also provided a taxonomy of tools using the CREATE framework, for EBM teachers in medical education.

Conclusions: Six tools of reasonable validity are available for evaluating most steps of EBM and some domains of EBM learning. Further development and validation of tools that evaluate all the steps in EBM and all educational outcome domains are needed.

Systematic Review Registration: PROSPERO CRD42018116203.
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http://dx.doi.org/10.1186/s13643-020-01311-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183115PMC
April 2020

Exploring the Mechanisms of Multiple Insecticide Resistance in a Highly -Infected Malaria Vector Sensu Stricto from Sahel of Northern Nigeria.

Genes (Basel) 2020 04 22;11(4). Epub 2020 Apr 22.

Vector Biology Department, Liverpool School of Tropical Medicine (LSTM), Liverpool L3 5QA, UK.

The Nigerian Government is scaling up the distribution of insecticide-treated bed nets for malaria control, but the lack of surveillance data, especially in the Sudan/Sahel region of the country, may hinder targeting priority populations. Here, the vectorial role and insecticide resistance profile of a population of a major malaria vector sensu stricto from Sahel of Nigeria was characterised. s.s. was the only vector found, with a high human blood index (100%) and a biting rate of 5.3/person/night. High infection was discovered (sporozoite rate = 54.55%). The population is resistant to permethrin (mortality = 48.30%, LT = 65.76 min), deltamethrin, DDT (dichlorodiphenyltrichloroethane) and bendiocarb, with mortalities of 29.44%, 56.34% and 54.05%, respectively. Cone-bioassays established loss of efficacy of the pyrethroid-only long-lasting insecticidal nets (LLINs); but 100% recovery of susceptibility was obtained for piperonylbutoxide (PBO)-containing PermaNet3.0. Synergist bioassays with PBO and diethyl maleate recovered susceptibility, implicating CYP450s (permethrin mortality = 78.73%, χ = 22.33, < 0.0001) and GSTs (DDT mortality = 81.44%, χ = 19.12, < 0.0001). A high frequency of 119F mutation (0.84) was observed (OR = 16, χ = 3.40, = 0.05), suggesting the preeminent role of metabolic resistance. These findings highlight challenges associated with deployment of LLINs and indoor residual spraying (IRS) in Nigeria.
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http://dx.doi.org/10.3390/genes11040454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230678PMC
April 2020

N-Methyl-D-Aspartate Receptor Hypofunction in Meg-01 Cells Reveals a Role for Intracellular Calcium Homeostasis in Balancing Megakaryocytic-Erythroid Differentiation.

Thromb Haemost 2020 Apr 14;120(4):671-686. Epub 2020 Apr 14.

Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.

The release of calcium ions (Ca) from the endoplasmic reticulum (ER) and related store-operated calcium entry (SOCE) regulate maturation of normal megakaryocytes. The -methyl-D-aspartate (NMDA) receptor (NMDAR) provides an additional mechanism for Ca influx in megakaryocytic cells, but its role remains unclear. We created a model of NMDAR hypofunction in Meg-01 cells using CRISPR-Cas9 mediated knockout of the gene, which encodes an obligate, GluN1 subunit of the NMDAR. We found that compared with unmodified Meg-01 cells, Meg-01- cells underwent atypical differentiation biased toward erythropoiesis, associated with increased basal ER stress and cell death. Resting cytoplasmic Ca levels were higher in Meg-01- cells, but ER Ca release and SOCE were lower after activation. Lysosome-related organelles accumulated including immature dense granules that may have contributed an alternative source of intracellular Ca. Microarray analysis revealed that Meg-01- cells had deregulated expression of transcripts involved in Ca metabolism, together with a shift in the pattern of hematopoietic transcription factors toward erythropoiesis. In keeping with the observed pro-cell death phenotype induced by deletion, memantine (NMDAR inhibitor) increased cytotoxic effects of cytarabine in unmodified Meg-01 cells. In conclusion, NMDARs comprise an integral component of the Ca regulatory network in Meg-01 cells that help balance ER stress and megakaryocytic-erythroid differentiation. We also provide the first evidence that megakaryocytic NMDARs regulate biogenesis of lysosome-related organelles, including dense granules. Our results argue that intracellular Ca homeostasis may be more important for normal megakaryocytic and erythroid differentiation than currently recognized; thus, modulation may offer therapeutic opportunities.
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http://dx.doi.org/10.1055/s-0040-1708483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286128PMC
April 2020

HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer.

JAMA Oncol 2020 04 9;6(4):e196496. Epub 2020 Apr 9.

GU Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Importance: The adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).

Objective: To examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data.

Design, Setting, And Participants: The E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.

Interventions: Men were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone.

Main Outcomes And Measures: Two-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype.

Results: Of 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.

Conclusions And Relevance: Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.
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http://dx.doi.org/10.1001/jamaoncol.2019.6496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042830PMC
April 2020

Mindfulness for pain, depression, anxiety, and quality of life in people with spinal cord injury: a systematic review.

BMC Neurol 2020 Jan 21;20(1):32. Epub 2020 Jan 21.

Department of Psychology, University of Derby, Kedleston Road, Derby, DE22 1GB, UK.

Background: Populations with reduced sensory and motor function, such as spinal cord injury (SCI) are at increased risk of depression, anxiety, pain, and poorer quality of life (QoL). Mindfulness-Based Interventions (MBIs) have been developed with the aim of improving outcomes for people with SCI. To understand the value of MBIs, a systematic review was conducted pertaining to the use of MBIs, and interventions including elements of mindfulness, with people with SCI.

Methods: Databases were reviewed from 1996 to October 2018 (updated January 2020). Eligibility criteria included the assessment of at least one of the common secondary consequences of SCI (i.e. risk of depression, anxiety, pain, and QoL), describe the use of mindfulness training as a component part of an intervention, or as the whole intervention. The Cochrane Collaboration Risk of Bias and The Effective Public Health Practice Project Quality Assessment Tools were utilised for quality appraisals. Two assessors appraised the studies and demonstrated good agreement (Cohen's k = .848, p < .001).

Results: Five papers met the inclusion criteria, and demonstrated a range of results of interventions delivered individually, in a group format, in person, and online. Only one study reported significant reductions in pain-related outcomes (with moderate effect sizes), with the remaining studies (n = 4) demonstrating no change. Four studies described reductions in depressive symptoms and three reported reductions in anxiety. Despite the importance of good QoL as a goal for people with SCI, few studies (n = 2) assessed this as an outcome with no improvements reported. Study quality ranged from high to low/weak.

Conclusions: The findings in this review provide mixed support for the use of mindfulness to improve outcomes after SCI. In particular, findings indicate that mindfulness may be particularly effective for improving symptoms of depression and anxiety. This review highlights the requirement for more rigorous, high-quality research, particularly larger randomised-controlled trials with long-term follow-up, in this area. The small number of studies included in the present review mean that conclusions drawn are preliminary and thus reflects the paucity of the research in the area to date.
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http://dx.doi.org/10.1186/s12883-020-1619-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971852PMC
January 2020

Forensic Fellowship: Will a Clearer Process Produce More Forensic Fellows?

Acad Psychiatry 2020 04 23;44(2):147-148. Epub 2019 Dec 23.

Saint Louis University School of Medicine, Saint Louis, MI, USA.

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http://dx.doi.org/10.1007/s40596-019-01176-xDOI Listing
April 2020

Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline.

J Clin Oncol 2020 03 12;38(7):753-766. Epub 2019 Dec 12.

Weill Cornell Medicine/Cornell University, New York, NY.

Purpose: To provide evidence-based recommendations to practicing clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non-small-cell lung cancer (NSCLC) and SCLC.

Methods: ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, radiology, primary care, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2019. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.

Results: The literature search identified 14 relevant studies to inform the evidence base for this guideline.

Recommendations: Patients should undergo surveillance imaging for recurrence every 6 months for 2 years and then annually for detection of new primary lung cancers. Chest computed tomography imaging is the optimal imaging modality for surveillance. Fluorodeoxyglucose positron emission tomography/computed tomography imaging should not be used as a surveillance tool. Surveillance imaging may not be offered to patients who are clinically unsuitable for or unwilling to accept further treatment. Age should not preclude surveillance imaging. Circulating biomarkers should not be used as a surveillance strategy for detection of recurrence. Brain magnetic resonance imaging should not be used for routine surveillance in stage I-III NSCLC but may be used every 3 months for the first year and every 6 months for the second year in patients with stage I-III small-cell lung cancer who have undergone curative-intent treatment.
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http://dx.doi.org/10.1200/JCO.19.02748DOI Listing
March 2020