Publications by authors named "Matthew Brown"

899 Publications

Polygenic risk scores and rheumatic diseases.

Chin Med J (Engl) 2021 Oct 20. Epub 2021 Oct 20.

Guy's & St Thomas' NHS Foundation Trust and King's College London NIHR Biomedical Research Centre, London, United Kingdom Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Translational Research Institute, Woolloongabba, Australia.

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http://dx.doi.org/10.1097/CM9.0000000000001845DOI Listing
October 2021

Upper Respiratory Tract Microbiome of Australian Aboriginal and Torres Strait Islander Children in Ear and Nose Health and Disease.

Microbiol Spectr 2021 Oct 20:e0036721. Epub 2021 Oct 20.

Australian Centre for Ecogenomics, The University of Queensland, St. Lucia, Australia.

The objective of this study was to examine the nasal microbiota in relation to otitis media (OM) status and nose health in Indigenous Australian children. Children 2 to 7 years of age were recruited from two northern Australian (Queensland) communities. Clinical histories were obtained through parent interviews and reviews of the medical records. Nasal cavity swab samples were obtained, and the children's ears, nose, and throat were examined. DNA was extracted and analyzed by 16S rRNA amplicon next-generation sequencing of the V3/V4 region, in combination with previously generated culture data. A total of 103 children were recruited (mean age, 4.7 years); 17 (16.8%) were healthy, i.e., normal examination results and no history of OM. The nasal microbiota differed significantly in relation to OM status and nose health. Children with historical OM had greater relative abundance of , compared to healthy children, despite both having healthy ears at the time of swabbing. Children with healthy noses had greater relative abundance of Staphylococcus aureus, compared to those with rhinorrhea. was correlated with in healthy children. Haemophilus and Streptococcus were correlated across phenotypes. was absent or was present with low relative abundance in healthy children and clustered around otopathogens. It correlated with and and form a synergism that promotes upper respiratory tract (URT)/ear health in Indigenous Australian children. likely represents " Ornithobacterium hominis" and in this population is correlated with a novel bacterium that appears to be related to poor URT/ear health. Recurring and chronic infections of the ear (OM) are disproportionately prevalent in disadvantaged communities across the globe and, in particular, within Indigenous communities. Despite numerous intervention strategies, OM persists as a major health issue and is the leading cause of preventable hearing loss. In disadvantaged communities, this hearing loss is associated with negative educational and social development outcomes, and consequently, poorer employment prospects and increased contact with the justice system in adulthood. Thus, a better understanding of the microbial ecology is needed in order to identify new targets to treat, as well as to prevent the infections. This study used a powerful combination of 16S rRNA gene sequencing and extended culturomics to show that Dolosigranulum pigrum, a bacterium previously identified as a candidate protective species, may require cocolonization with Corynebacterium pseudodiphtheriticum in order to prevent OM. Additionally, emerging and potentially novel pathogens and bacteria were identified.
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http://dx.doi.org/10.1128/Spectrum.00367-21DOI Listing
October 2021

Upper Respiratory Tract Microbiome of Australian Aboriginal and Torres Strait Islander Children in Ear and Nose Health and Disease.

Microbiol Spectr 2021 Oct 20:e0036721. Epub 2021 Oct 20.

Australian Centre for Ecogenomics, The University of Queensland, St. Lucia, Australia.

The objective of this study was to examine the nasal microbiota in relation to otitis media (OM) status and nose health in Indigenous Australian children. Children 2 to 7 years of age were recruited from two northern Australian (Queensland) communities. Clinical histories were obtained through parent interviews and reviews of the medical records. Nasal cavity swab samples were obtained, and the children's ears, nose, and throat were examined. DNA was extracted and analyzed by 16S rRNA amplicon next-generation sequencing of the V3/V4 region, in combination with previously generated culture data. A total of 103 children were recruited (mean age, 4.7 years); 17 (16.8%) were healthy, i.e., normal examination results and no history of OM. The nasal microbiota differed significantly in relation to OM status and nose health. Children with historical OM had greater relative abundance of , compared to healthy children, despite both having healthy ears at the time of swabbing. Children with healthy noses had greater relative abundance of Staphylococcus aureus, compared to those with rhinorrhea. was correlated with in healthy children. Haemophilus and Streptococcus were correlated across phenotypes. was absent or was present with low relative abundance in healthy children and clustered around otopathogens. It correlated with and and form a synergism that promotes upper respiratory tract (URT)/ear health in Indigenous Australian children. likely represents " Ornithobacterium hominis" and in this population is correlated with a novel bacterium that appears to be related to poor URT/ear health. Recurring and chronic infections of the ear (OM) are disproportionately prevalent in disadvantaged communities across the globe and, in particular, within Indigenous communities. Despite numerous intervention strategies, OM persists as a major health issue and is the leading cause of preventable hearing loss. In disadvantaged communities, this hearing loss is associated with negative educational and social development outcomes, and consequently, poorer employment prospects and increased contact with the justice system in adulthood. Thus, a better understanding of the microbial ecology is needed in order to identify new targets to treat, as well as to prevent the infections. This study used a powerful combination of 16S rRNA gene sequencing and extended culturomics to show that Dolosigranulum pigrum, a bacterium previously identified as a candidate protective species, may require cocolonization with Corynebacterium pseudodiphtheriticum in order to prevent OM. Additionally, emerging and potentially novel pathogens and bacteria were identified.
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http://dx.doi.org/10.1128/Spectrum.00367-21DOI Listing
October 2021

Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes.

J Clin Invest 2021 Sep;131(17)

Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.

Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in β cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM β cells contributes to β cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in β cells of patients with T2DM and demonstrated that its expression was associated with loss of β cell transcriptional identity, intracellular alkalinization, and β cell dysfunction. In addition, we generated a β cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and β cell dysfunction. Importantly, improved glucose tolerance and enhanced β cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating β cell identity and function. These results suggest that increased β cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of β cell failure and should be considered as a potential therapeutic target.
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http://dx.doi.org/10.1172/JCI142365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409580PMC
September 2021

The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes.

Front Immunol 2021 16;12:739048. Epub 2021 Sep 16.

Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States.

Background: The pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic β-cells. Interactions between risk variants and environmental factors result in significant heterogeneity in clinical presentation among those who develop T1D. Although genetic risk is dominated by the human leukocyte antigen (HLA) class II and insulin () gene loci, nearly 150 additional risk variants are significantly associated with the disease, including polymorphisms in immune checkpoint molecules, such as .

Scope Of Review: In this review, we summarize the literature related to the T1D-associated risk variants in , which include a protein-coding variant (rs6043409, G>A; A263V) and an intronic polymorphism (rs2281808, C>T), and their potential impacts on the immunoregulatory signal regulatory protein (SIRP) family:CD47 signaling axis. We discuss how dysregulated expression or function of SIRPs and CD47 in antigen-presenting cells (APCs), T cells, natural killer (NK) cells, and pancreatic β-cells could potentially promote T1D development.

Major Conclusions: We propose a hypothesis, supported by emerging genetic and functional immune studies, which states a loss of proper SIRP:CD47 signaling may result in increased lymphocyte activation and cytotoxicity and enhanced β-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.
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http://dx.doi.org/10.3389/fimmu.2021.739048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481641PMC
September 2021

Osteology and relationships of Revueltosaurus callenderi (Archosauria: Suchia) from the Upper Triassic (Norian) Chinle Formation of Petrified Forest National Park, Arizona, United States.

Anat Rec (Hoboken) 2021 Sep 29. Epub 2021 Sep 29.

Department of Anatomy, Des Moines University, Des Moines, Iowa, USA.

Once known solely from dental material and thought to represent an early ornithischian dinosaur, the early-diverging pseudosuchian Revueltosaurus callenderi is described from a minimum of 12 skeletons from a monodominant bonebed in the upper part of the Chinle Formation of Arizona. This material includes nearly the entire skeleton and possesses a combination of plesiomorphic and derived character states that help clarify ingroup relationships within Pseudosuchia. A phylogenetic analysis recovers R. callenderi in a clade with Aetosauria and Acaenasuchus geoffreyi that is named Aetosauriformes. Key autapomorphies of R. callenderi include a skull that is longer than the femur, a complete carapace of dermal armor including paramedian and lateral rows, as well as ventral osteoderms, and a tail end sheathed in bone. Histology of the femur and associated osteoderms demonstrate that R. callenderi was slow growing and that the individuals from the bonebed were not young juveniles but had not ceased growing. A review of other material assigned to Revueltosaurus concludes that the genus cannot be adequately diagnosed based on the type materials of the three assigned species and that only R. callenderi can be confidently referred to Revueltosaurus.
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http://dx.doi.org/10.1002/ar.24757DOI Listing
September 2021

High Prevalence of Transjugular Intrahepatic Portosystemic Shunt Creation Without Prior Endoscopy During Acute Variceal Bleeding Hospitalization in the United States.

Hepatol Commun 2021 10 1;5(10):1784-1790. Epub 2021 Jul 1.

Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Current clinical guidelines by both American Association for the Study of Liver Disease and European Association for the Study of the Liver recommend endoscopy in all patients admitted with acute variceal bleeding within 12 hours of admission. Transjugular intrahepatic portosystemic shunt (TIPS) creation may be considered in patients at high risk if hemorrhage cannot be controlled endoscopically. We conducted a cross-sectional observational study to assess how frequently TIPS is created for acute variceal bleeding in the United States without preceding endoscopy. Adult patients undergoing TIPS creation for acute variceal bleeding in the United States (n = 6,297) were identified in the last 10 available years (2007-2016) of the National Inpatient Sample. Hierarchical logistic regression was used to examine the relationship between endoscopy nonutilization and hospital characteristics, controlling for patient demographics, income level, insurance type, and disease severity. Of 6,297 discharges following TIPS creation for acute variceal bleeding in the United States, 31% (n = 1,924) did not receive first-line endoscopy during the same encounter. Rates of "no endoscopy" decreased with increasing population density of the hospital county (nonmicropolitan counties 43%, n = 114; mid-size metropolitan county 35%, n = 513; and central county with >1 million population 23%, n = 527) but not by hospital teaching status (n = 1,465, 32% teaching vs. n = 430, 26% nonteaching; P = 0.10). Higher disease mortality risk (odds ratio, 0.42; 95% confidence interval, 0.22-0.80; P = 0.02) was associated with lower odds of noncompliance. Conclusion: One third of all patients undergoing TIPS creation for acute variceal bleeding in the United States do not receive first-line endoscopy during the same encounter. Patients admitted to urban hospitals are more likely to receive guideline-concordant care.
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http://dx.doi.org/10.1002/hep4.1756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485889PMC
October 2021

A Baker's Dozen of Top Antimicrobial Stewardship Intervention Publications in 2020.

Open Forum Infect Dis 2021 Sep 13;8(9):ofab422. Epub 2021 Aug 13.

Department of Pharmacy, University of South Carolina College of Pharmacy, Columbia, South Carolina, USA.

The number of articles related to antimicrobial stewardship published each year has increased significantly over the last decade. Keeping up with the literature, particularly the most innovative, well-designed, or applicable to one's own practice area, can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network reviewed antimicrobial stewardship-related, peer-reviewed literature from 2020 that detailed actionable interventions. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for teaching and training, and to identify novel or optimized stewardship opportunities within one's institution.
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http://dx.doi.org/10.1093/ofid/ofab422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454524PMC
September 2021

Isolation and engineering of a Listeria grayi bacteriophage.

Sci Rep 2021 Sep 23;11(1):18947. Epub 2021 Sep 23.

Laboratory Corporation of America Holdings, New Brighton, MN, 55112, USA.

The lack of bacteriophages capable of infecting the Listeria species, Listeria grayi, is academically intriguing and presents an obstacle to the development of bacteriophage-based technologies for Listeria. We describe the isolation and engineering of a novel L. grayi bacteriophage, LPJP1, isolated from farm silage. With a genome over 200,000 base pairs, LPJP1 is the first and only reported jumbo bacteriophage infecting the Listeria genus. Similar to other Gram-positive jumbo phages, LPJP1 appeared to contain modified base pairs, which complicated initial attempts to obtain genomic sequence using standard methods. Following successful sequencing with a modified approach, a recombinant of LPJP1 encoding the NanoLuc luciferase was engineered using homologous recombination. This luciferase reporter bacteriophage successfully detected 100 stationary phase colony forming units of both subspecies of L. grayi in four hours. A single log phase colony forming unit was also sufficient for positive detection in the same time period. The recombinant demonstrated complete specificity for this particular Listeria species and did not infect 150 non-L. grayi Listeria strains nor any other bacterial genus. LPJP1 is believed to be the first reported lytic bacteriophage of L. grayi as well as the only jumbo bacteriophage to be successfully engineered into a luciferase reporter.
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http://dx.doi.org/10.1038/s41598-021-98134-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460666PMC
September 2021

Pain in the Cancer Survivor.

Cancer Treat Res 2021 ;182:57-84

The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.

Recent decades have demonstrated significant strides in cancer screening, diagnostics and therapeutics. As such there have been dramatic changes in survival following a diagnosis of cancer.
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http://dx.doi.org/10.1007/978-3-030-81526-4_5DOI Listing
January 2021

Reply to Niv Ben-Shabat: Mortality in AS according to treatment.

Arthritis Care Res (Hoboken) 2021 Aug 26. Epub 2021 Aug 26.

Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.

We read with great interest the article by Niv Ben-Shabat et al. in Arthritis Care and Research titled "Mortality in ankylosing spondylitis according to treatment: a nationwide retrospective cohort study of 5900 patients from Israel" (1). The study concludes that ankylosing spondylitis (AS) is associated with reduced life expectancy, but not amongst the small subgroup of AS patients treated with TNF-inhibitors. We have concerns regarding the study design and analyses that underpin these findings.
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http://dx.doi.org/10.1002/acr.24773DOI Listing
August 2021

Pro-inflammatory β cell small extracellular vesicles induce β cell failure through activation of the CXCL10/CXCR3 axis in diabetes.

Cell Rep 2021 Aug;36(8):109613

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA; Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA.

Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress. We report that pro-inflammatory β cell small EVs (cytokine-exposed EVs [cytoEVs]) induce β cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8 T cells and macrophages. Proteomic analysis of cytoEVs shows enrichment of the chemokine CXCL10, with surface topological analysis depicting CXCL10 as membrane bound on cytoEVs to facilitate direct binding to CXCR3 receptors on the surface of β cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory β cell-derived small EVs in modulating β cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.
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http://dx.doi.org/10.1016/j.celrep.2021.109613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420815PMC
August 2021

Identifying Trajectories of Radiographic Spinal Disease in Ankylosing Spondylitis: A 15-year follow up study of the PSOAS Cohort.

Rheumatology (Oxford) 2021 Aug 24. Epub 2021 Aug 24.

Department of Medicine-Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA, USA.

Objectives: Little is known with certainty about the natural history of spinal disease progression in Ankylosing Spondylitis (AS). Our objective was to discover if there were distinct patterns of change in vertebral involvement over time and to study associated clinical factors.

Methods: Data were analyzed from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) observational cohort. All patients met modified New York Criteria for AS and had ≥2 sets of radiographs scored by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) by two independent readers between 2002-2017. Group-based trajectory modeling (GBTM) was used to classify patients into distinct groups of longitudinal mSASSS considering sociodemographic and clinical covariables. The optimal trajectory model and number of trajectories was selected using Nagin's Bayesian information criterion (BIC).

Results: A total of 561 patients with 1618 radiographs was analyzed. The optimum number of trajectory groups identified was four (BIC -4062). These groups were subsequently categorized as: non-progressors (204 patients), late-progressors (147 patients), early-progressors (107 patients) and rapid-progressors (103 patients). Baseline predictors associated with higher spinal disease burden groups included: baseline mSASSS, male gender, longer disease duration, elevated C-reactive protein and smoking history. In addition, time-varying anti-TNF use per year was associated with decreased mSASSS progression only in the rapid-progressor group.

Conclusions: GBTM identified 4 distinct patterns of spinal disease progression in the PSOAS cohort. Male gender, longer disease duration, elevated C-reactive protein and smoking were associated with higher spinal disease groups. Independent confirmation in other AS cohorts is needed to confirm these radiographic patterns.
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http://dx.doi.org/10.1093/rheumatology/keab661DOI Listing
August 2021

Flexor tendon injuries: Repair & Rehabilitation.

Injury 2021 Aug;52(8):2053-2067

Consultant Hand & Plastic Surgeon, Lothian Hand Unit, St John's Hospital, Livingston, West Lothian EH54 6PP, UK.

Flexor tendon injuries are common and occur mostly by penetrating trauma. Suspected flexor tendon injuries require a thorough clinical assessment and often are not isolated injuries. A detailed understanding of flexor tendon anatomy and spatial relationships is essential, especially when repairing multi-tendon injuries. Principles of flexor tendon repair include a strong suture construct, minimising gap formation between tendon ends, preserving tendon blood supply and providing a smooth repair interface. Moreover, adequate exposure of the zone of injury using full-thickness skin flaps and preservation of neurovascular and pulley structures is essential. In this article an overview of contemporary management strategies is presented. Today's hand surgeons and therapists can choose from a variety of treatment options when managing these important and potentially life-changing injuries.
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http://dx.doi.org/10.1016/j.injury.2021.07.036DOI Listing
August 2021

Here's the rub: A case of constrictive pericarditis in an adult with cystic fibrosis.

Respir Med Case Rep 2021 6;33:101434. Epub 2021 Jun 6.

J Willis Hurst Internal Medicine Residency Program, USA.

We present a rare coexistence of constrictive pericarditis in a patient with cystic fibrosis. Careful attention to cardiac friction rub auscultated on initial examination prompted echocardiography revealing constrictive pericarditis further confirmed by cardiac magnetic resonance imaging that allowed for dedicated treatment in addition to management of his concurrent respiratory infection.
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http://dx.doi.org/10.1016/j.rmcr.2021.101434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349017PMC
June 2021

Social-Ecological Factors Associated With Higher Levels of Resilience in Children and Youth After Disaster: The Importance of Caregiver and Peer Support.

Front Public Health 2021 29;9:682634. Epub 2021 Jul 29.

Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.

Children and youth are among the most vulnerable to the devastating effects of disaster due to the physical, cognitive, and social factors related to their developmental life stage. Yet children and youth also have the capacity to be resilient and act as powerful catalysts for change in their own lives and wider communities following disaster. Specific factors that contribute to resilience in children and youth, however, remain relatively unexplored. This article examines factors associated with high levels of resilience in 100 children and youth aged 5- to 18-years old who experienced the 2016 Fort McMurray, Alberta wildfire. A mixed-methods design was employed combining quantitative and qualitative data. Quantitative data was obtained from the Children and Youth Resilience Measure (CYRM-28) which measured individual, caregiver, and context factors influencing resilience processes among the participants. Qualitative data was collected through semi-structured interviews to gain further insight into the disaster experiences of children and youth. Quantitative findings reveal higher than average levels of resilience among the participants compared to normative scores. Qualitative findings suggest high levels of resilience were associated with both caregiver factors (specifically physical caregiving), and individual factors (primarily peer support). We discuss how physical caregiving and peer support during and after the wildfire helped mitigate the negative effects of disaster, thus bolstering children and youth's resilience. Implications for understanding the specific social-ecological factors that facilitate and support resiliency processes and overall recovery of children and youth following disaster are also discussed.
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http://dx.doi.org/10.3389/fpubh.2021.682634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358203PMC
August 2021

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models.

Front Immunol 2021 29;12:723544. Epub 2021 Jul 29.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.

Graft--host disease (GVHD) is the most common cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation (HSCT) despite advances in conditioning regimens, HLA genotyping and immune suppression. While murine studies have yielded important insights into the cellular responses of GVHD, differences between murine and human biology has hindered the translation of novel therapies into the clinic. Recently, the field has expanded the ability to investigate primary human T cell responses through the transplantation of human T cells into immunodeficient mice. These xenogeneic HSCT models benefit from the human T cell receptors, CD4 and CD8 proteins having cross-reactivity to murine MHC in addition to several cytokines and co-stimulatory proteins. This has allowed for the direct assessment of key factors in GVHD pathogenesis to be investigated prior to entering clinical trials. In this review, we will summarize the current state of clinical GVHD research and discuss how xenogeneic HSCT models will aid in advancing the current pipeline of novel GVHD prophylaxis therapies into the clinic.
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http://dx.doi.org/10.3389/fimmu.2021.723544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358790PMC
July 2021

Using Machine Learning to Predict Remission in Patients With Major Depressive Disorder Treated With Desvenlafaxine : Utiliser l'apprentissage machine pour prédire la rémission chez les patients souffrant de trouble dépressif majeur traités par desvenlafaxine.

Can J Psychiatry 2021 Aug 11:7067437211037141. Epub 2021 Aug 11.

Department of Psychiatry, 3158University of Alberta, Edmonton, Alberta.

Background: Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients require several medication switches to achieve remission; selecting an effective antidepressant is typically a sequential trial-and-error process. Machine learning techniques may be able to learn models that can predict whether a specific patient will respond to a given treatment, before it is administered. This study uses baseline clinical data to create a machine-learned model that accurately predicts remission status for a patient after desvenlafaxine (DVS) treatment.

Methods: We applied machine learning algorithms to data from 3,399 MDD patients (90% of the 3,776 subjects in 11 phase-III/IV clinical trials, each described using 92 features), to produce a model that uses 26 of these features to predict symptom remission, defined as an 8-week Hamilton Depression Rating Scale score of 7 or below. We evaluated that learned model on the remaining held-out 10% of the data ( = 377).

Results: Our resulting classifier, a trained linear support vector machine, had a holdout set accuracy of 69.0%, significantly greater than the probability of classifying a patient correctly by chance. We demonstrate that this learning process is stable by repeatedly sampling part of the training dataset and running the learner on this sample, then evaluating the learned model on the held-out instances of the training set; these runs had an average accuracy of 67.0% ± 1.8%.

Conclusions: Our model, based on 26 clinical features, proved sufficient to predict DVS remission significantly better than chance. This may allow more accurate use of DVS without waiting 8 weeks to determine treatment outcome, and may serve as a first step toward changing psychiatric care by incorporating clinical assistive technologies using machine-learned models.
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http://dx.doi.org/10.1177/07067437211037141DOI Listing
August 2021

Nurturing Spiritual Resilience to Promote Post-disaster Community Recovery: The 2016 Alberta Wildfire in Canada.

Front Public Health 2021 23;9:682558. Epub 2021 Jul 23.

Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.

The 2016 Alberta wildfire, the largest insured natural disaster in Canada, led to a mass evacuation of residents of Fort McMurray, a small city in northern Alberta. The wildfire resulted in significant damages to housing and community infrastructure. The entire community was displaced for several weeks. Post-disaster, community members experienced individual and collective trauma, and other negative mental health impacts in response to the significant losses and grief they endured. Spirituality has been found to be a major protective factor in facilitating resiliency and recovery following the experience of disaster. Nonetheless, little focus has been directed toward how spirituality can strengthen and empower community capacity and growth during post-disaster recovery. Our study explored various meanings and concerns, along with tools and strategies that helped to nurture spiritual resilience and well-being among residents of Fort McMurray following the Alberta wildfire. Data were collected through interviews and focus group discussions with community influencers working to support long-term recovery efforts in the city. Participants identified a number of spiritual resources such as a strong sense of belonging, a shared positive outlook, faith and hope, compassion, and sense of gratitude, which contributed to increased resilience and positive health and well-being and helped them to support families and communities in the post disaster recovery period. Our findings indicate that spiritual values and beliefs can play a significant role in building resilience and promoting individual and communal healing and recovery post-disaster. These findings have important implications for post-disaster recovery strategies, as they highlight the need to ensure supports for interventions and initiatives that strengthen a collective sense of identity and social cohesion, informed by communal norms and beliefs, including programs and resources which support opportunities for reflexivity to foster shared healing and ongoing recovery processes.
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http://dx.doi.org/10.3389/fpubh.2021.682558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342851PMC
August 2021

PhyloFisher: A phylogenomic package for resolving eukaryotic relationships.

PLoS Biol 2021 Aug 6;19(8):e3001365. Epub 2021 Aug 6.

Department of Biological Sciences, Mississippi State University, Mississippi State, Mississippi, United States of America.

Phylogenomic analyses of hundreds of protein-coding genes aimed at resolving phylogenetic relationships is now a common practice. However, no software currently exists that includes tools for dataset construction and subsequent analysis with diverse validation strategies to assess robustness. Furthermore, there are no publicly available high-quality curated databases designed to assess deep (>100 million years) relationships in the tree of eukaryotes. To address these issues, we developed an easy-to-use software package, PhyloFisher (https://github.com/TheBrownLab/PhyloFisher), written in Python 3. PhyloFisher includes a manually curated database of 240 protein-coding genes from 304 eukaryotic taxa covering known eukaryotic diversity, a novel tool for ortholog selection, and utilities that will perform diverse analyses required by state-of-the-art phylogenomic investigations. Through phylogenetic reconstructions of the tree of eukaryotes and of the Saccharomycetaceae clade of budding yeasts, we demonstrate the utility of the PhyloFisher workflow and the provided starting database to address phylogenetic questions across a large range of evolutionary time points for diverse groups of organisms. We also demonstrate that undetected paralogy can remain in phylogenomic "single-copy orthogroup" datasets constructed using widely accepted methods such as all vs. all BLAST searches followed by Markov Cluster Algorithm (MCL) clustering and application of automated tree pruning algorithms. Finally, we show how the PhyloFisher workflow helps detect inadvertent paralog inclusions, allowing the user to make more informed decisions regarding orthology assignments, leading to a more accurate final dataset.
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http://dx.doi.org/10.1371/journal.pbio.3001365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345874PMC
August 2021

Novel doublesex duplication associated with sexually dimorphic development of dogface butterfly wings.

Mol Biol Evol 2021 Jul 29. Epub 2021 Jul 29.

Department of Biological Sciences, Auburn University, USA.

Sexually dimorphic development is responsible for some of the most remarkable phenotypic variation found in nature. Alternative splicing of the transcription factor gene doublesex is a highly conserved developmental switch controlling the expression of sex specific pathways. Here, we leverage sex-specific differences in butterfly wing color pattern to characterize the genetic basis of sexually dimorphic development. We use RNA-seq, immunolocalization, and motif binding site analysis to test specific predictions about the role of Doublesex in the development of structurally-based ultraviolet (UV) wing patterns in Zerene cesonia (Southern Dogface). Unexpectedly, we discover a novel duplication of Doublesex that shows a sex-specific burst of expression associated with the sexually dimorphic UV coloration. The derived copy consists of a single exon that encodes a DNA binding but no protein binding domain, and has experienced rapid amino-acid divergence. We propose the novel dsx paralog may suppress UV scale differentiation in females, which is supported by an excess of Dsx binding sites at cytoskeletal and chitin-related genes with sex-biased expression. These findings illustrate the molecular flexibility of the dsx gene in mediating the differentiation of secondary sexual characteristics.
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http://dx.doi.org/10.1093/molbev/msab228DOI Listing
July 2021

Nurse-led telephone notification of a prostate cancer diagnosis: Prospective analysis of men's preferences for and experiences of a same-day assessment and diagnostic clinic.

Eur J Cancer Care (Engl) 2021 Jul 26. Epub 2021 Jul 26.

Medical School, Surgery, University of Western Australia, Perth, Western Australia, Australia.

Objective: The 'One Stop Prostate Clinic' (OSPC) was a same-day prostate cancer assessment and/or diagnostic clinic. Preferences and experiences of men who received initial telephone notification of their prostate biopsy results (cancer or benign) by the OSPC Clinical Nurse (CN) are reported.

Methods: Prospective mixed methods study using survey instrument and thematic analysis of OSPC preferences and experiences.

Results: One thousand men attended the OSPC between August 2011 and November 2017, 876 underwent prostate biopsies; 790/876 (90%) men consented to telephone notification of biopsy results, 5/876 (1%) declined and 79/876 (9%) were ineligible/not contacted. 220/403 men (55%) returned the OSPC questionnaire; 135/220 (61%) men received a cancer diagnosis, 119/132 (90%) would choose this method again and 7/132 (5.5%) would not and 6/132 (4.5%) were unsure; 94/135 (70%) reported no disadvantages with this notification method. Overall satisfaction rate with the OSPC was 96% (209/218) men.

Conclusion: Initial telephone notification of prostate biopsy results by the OSPC CN was preferred by the vast majority of eligible men. Many men with a cancer diagnosis did not experience any disadvantages. This method of results delivery can be incorporated by other tumour groups.
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http://dx.doi.org/10.1111/ecc.13493DOI Listing
July 2021

Intra-Aortic Balloon Pump as a Bridge to Durable Left Ventricular Assist Device.

J Am Heart Assoc 2021 08 26;10(15):e019376. Epub 2021 Jul 26.

Georgetown University School of Medicine Washington DC.

Left ventricular assist devices (LVAD) are increasingly being used as destination therapy in patients with Stage D heart failure. It has been reported that a majority of patients who receive a durable LVAD (dLVAD) present in cardiogenic shock due to decompensated heart failure (ADHF-CS). As it stands, there is no consensus on the optimal management strategy for patients presenting with ADHF. Bridging with intra-aortic balloon pumps (IABPs) continues to be a therapeutic option in patients with hemodynamic instability due to cardiogenic shock. The majority of data regarding the use of IABP in cardiogenic shock come from studies in patients presenting with acute myocardial infarction with cardiogenic shock and demonstrates that there is no benefit of routine IABP use in this patient population. However, the role of IABPs as a bridge to dLVAD in ADHF-CS has yet to be determined. The hemodynamic changes seen in acute myocardial infarction with cardiogenic shock are known to be different and more acutely impaired than those presenting with ADHF-CS as evidenced by differences in pressure/volume loops. Thus, data should not be extrapolated across these 2 very different disease processes. The aim of this review is to describe results from contemporary studies examining the use of IABPs as a bridge to dLVAD in patients with ADHF-CS. Retrospective evidence from large registries suggests that the use of IABP as a bridge to dLVAD is feasible and safe when compared with other platforms of temporary mechanical circulatory support. However, there is currently a paucity of high-quality evidence examining this increasingly important clinical question.
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http://dx.doi.org/10.1161/JAHA.120.019376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475697PMC
August 2021

Informing the classification and assessment of positive emotional experiences: A multisample examination of hierarchical positive emotionality models.

Psychol Assess 2021 Nov 22;33(11):1038-1049. Epub 2021 Jul 22.

Department of Psychology.

Despite being multifaceted in nature, positive emotional (PE) experiences often are studied using only global PE ratings, and measures assessing more specific PE facets do not converge in their assessment approaches. To address these issues, we examined hierarchical factor structures of ratings of positive emotionality, which reflect propensities toward experiencing PE, in both online community adult ( = 375) and undergraduate ( = 447) samples. Preregistered analyses indicated (a) a broad distinction between tendencies to experience social affection and other PE types, and that (b) PE ratings can be differentiated by as many as four replicable factors of Joviality, . These PE dimensions were associated with distinct personality and psychopathology profiles. Examples of these distinctive associations included Joviality displaying robust positive associations with grandiosity and exhibitionism; conversely, although Social Affection and Joviality were strongly correlated, Social Affection showed associations in the opposite direction with grandiosity and exhibitionism. Other notable results include Serenity (e.g., feeling relaxed) showing negative associations with negative emotionality at a magnitude indicating that Serenity may reflect low levels of negative emotionality to a considerable degree. Collectively, these results highlight the need to consider distinct PE facets in addition to global PE ratings when assessing PE, as important nuance may be lost otherwise. Furthermore, our results indicate the need for additional research clarifying PE structure at different levels of abstraction to inform future measure development efforts and assessment approaches. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0001052DOI Listing
November 2021

Germline ERBB3 mutation in familial non-small cell lung carcinoma: Expanding ErbB's role in oncogenesis.

Hum Mol Genet 2021 Jul 19. Epub 2021 Jul 19.

Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102.

Introduction: Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2.

Materials And Methods: Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and sub-cellular localisation were assessed, and cellular proliferation, pAkt/Akt, and pERK levels determined.

Results: A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80kD form (which enhances proliferation) compared to the full-length (180kD) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localisation pre- and post-EGF stimulation; however, EGFR levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared to wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 minutes post-stimulation compared to wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic.

Conclusions: This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.
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http://dx.doi.org/10.1093/hmg/ddab172DOI Listing
July 2021

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study.

Lancet Rheumatol 2021 Sep 8;3(9):e627-e637. Epub 2021 Jul 8.

St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, King's College London, London, UK.

Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose.

Methods: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination.

Findings: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31-52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67-87] of 77) than in controls (17 [100%; 80-100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21-73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40-236]) than in controls (317 [213-487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141-418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls.

Interpretation: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S2665-9913(21)00212-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266273PMC
September 2021

Collective Trauma and Mental Health in Adolescents: A Retrospective Cohort Study of the Effects of Retraumatization.

Front Psychiatry 2021 25;12:682041. Epub 2021 Jun 25.

Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.

In the wake of the massive Canadian wildfire of May 2016 in the area of Fort McMurray Alberta, we observed increased rates of mental health problems, particularly post-traumatic stress disorder (PTSD), in school-aged adolescents (ages 11-19). Surprisingly, we did not see these rates decline over the 3.5-year follow-up period. Additionally, our research suggested that the impact of this mass incident resulted in other unanticipated effects, including the finding that children who were not present for and relatively unaffected by the wildfire showed a similar PTSD symptom profile to children more directly involved, suggesting some degree of spillover or stress contagion. A potential explanation for these high rates in individuals who were not present could be undiagnosed retraumatization in some of the students. To investigate this possibility, we compared two groups of students: those who reported the wildfire as their most significant trauma ( = 740) and those who had their most significant trauma prior to the wildfire ( = 295). Those with significant pre-existing trauma had significantly higher rates of both depression and PTSD symptoms, although, unexpectedly the groups exhibited no differences in anxiety level. Taken together, this evidence suggests retraumatization is both longer-lasting and more widespread than might be predicted on a case-by-case basis, suggesting the need to reconceptualize the role of past trauma history in present symptomatology. These findings point to the need to recognize that crises instigated by natural disasters are mass phenomena which expose those involved to numerous unanticipated risks. New trauma-informed treatment approaches are required that incorporate sensitivity to the collective impact of mass crises, and recognize the risk of poorer long-term mental health outcomes for those who experienced trauma in the past.
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http://dx.doi.org/10.3389/fpsyt.2021.682041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267583PMC
June 2021

How fluoroquinolone preauthorization affects third- and fourth-generation cephalosporin use and resistance in a large academic hospital.

Infect Control Hosp Epidemiol 2021 Jul 8:1-12. Epub 2021 Jul 8.

Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama.

Objective: We observed an overall increase in the use of third- and fourth-generation cephalosporins after fluoroquinolone preauthorization was implemented. We examined the change in specific third- and fourth-generation cephalosporin use, and we sought to determine whether there was a consequent change in non-susceptibility of select Gram-negative bacterial isolates to these antibiotics.

Design: Retrospective quasi-experimental study.

Setting: Academic hospital.

Intervention: Fluoroquinolone preauthorization was implemented in the hospital in October 2005. We used interrupted time series (ITS) Poisson regression models to examine trends in monthly rates of ceftriaxone, ceftazidime, and cefepime use and trends in yearly rates of nonsusceptible isolates (NSIs) of select Gram-negative bacteria before (1998-2004) and after (2006-2016) fluoroquinolone preauthorization was implemented.

Results: Rates of use of ceftriaxone and cefepime increased after fluoroquinolone preauthorization was implemented (ceftriaxone RR, 1.002; 95% CI, 1.002-1.003; P < .0001; cefepime RR, 1.003; 95% CI, 1.001-1.004; P = .0006), but ceftazidime use continued to decline (RR, 0.991, 95% CI, 0.990-0.992; P < .0001). Rates of ceftazidime and cefepime NSIs of Pseudomonas aeruginosa (ceftazidime RR, 0.937; 95% CI, 0.910-0.965, P < .0001; cefepime RR, 0.937; 95% CI, 0.912-0.963; P < .0001) declined after fluoroquinolone preauthorization was implemented. Rates of ceftazidime and cefepime NSIs of Enterobacter cloacae (ceftazidime RR, 1.116; 95% CI, 1.078-1.154; P < .0001; cefepime RR, 1.198; 95% CI, 1.112-1.291; P < .0001) and cefepime NSI of Acinetobacter baumannii (RR, 1.169; 95% CI, 1.081-1.263; P < .0001) were increasing before fluoroquinolone preauthorization was implemented but became stable thereafter: E. cloacae (ceftazidime RR, 0.987; 95% CI, 0.948-1.028; P = .531; cefepime RR, 0.990; 95% CI, 0.962-1.018; P = .461) and A. baumannii (cefepime RR, 0.972; 95% CI, 0.939-1.006; P = .100).

Conclusions: Fluoroquinolone preauthorization may increase use of unrestricted third- and fourth-generation cephalosporins; however, we did not observe increased antimicrobial resistance to these agents, especially among clinically important Gram-negative bacteria known for hospital-acquired infections.
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http://dx.doi.org/10.1017/ice.2021.229DOI Listing
July 2021

Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process.

J Cannabis Res 2021 Jul 2;3(1):22. Epub 2021 Jul 2.

Departments of Clinical Neurological Sciences and Oncology, Earl Russell Chair of Pain Medicine, Western University, 800 Commissioners Road East, London, ON, N6A 5W9, Canada.

Background: Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed.

Methods: Using a multistage modified Delphi process, twenty global experts across nine countries developed consensus-based recommendations on how to dose and administer medical cannabis in patients with chronic pain.

Results: There was consensus that medical cannabis may be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed. A routine protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg CBD twice daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. A conservative protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg once daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC. A rapid protocol where the clinician initiates the patient on a balanced THC:CBD variety at 2.5-5 mg of each cannabinoid once or twice daily and titrates by 2.5-5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day.

Conclusions: In summary, using a modified Delphi process, expert consensus-based recommendations were developed on how to dose and administer medical cannabis for the treatment of patients with chronic pain.
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http://dx.doi.org/10.1186/s42238-021-00073-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252988PMC
July 2021

Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

Ann Rheum Dis 2021 09 20;80(9):1168-1174. Epub 2021 Apr 20.

Rheumatology Department, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Objective: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.

Methods: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), and sacroiliac MRI.

Results: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for these values were 51.9% and 97.9%, respectively.

Conclusions: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.
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http://dx.doi.org/10.1136/annrheumdis-2020-219446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364478PMC
September 2021
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