Publications by authors named "A Jay Freeman"

2,123 Publications

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Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.

PLoS One 2021 4;16(3):e0248011. Epub 2021 Mar 4.

Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America.

Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248011PLOS
March 2021

Global political responsibility for the conservation of albatrosses and large petrels.

Sci Adv 2021 Mar 3;7(10). Epub 2021 Mar 3.

MARE-Marine and Environmental Sciences Centre, ISPA-Instituto Universitário, Lisboa, Portugal.

Migratory marine species cross political borders and enter the high seas, where the lack of an effective global management framework for biodiversity leaves them vulnerable to threats. Here, we combine 10,108 tracks from 5775 individual birds at 87 sites with data on breeding population sizes to estimate the relative year-round importance of national jurisdictions and high seas areas for 39 species of albatrosses and large petrels. Populations from every country made extensive use of the high seas, indicating the stake each country has in the management of biodiversity in international waters. We quantified the links among national populations of these threatened seabirds and the regional fisheries management organizations (RFMOs) which regulate fishing in the high seas. This work makes explicit the relative responsibilities that each country and RFMO has for the management of shared biodiversity, providing invaluable information for the conservation and management of migratory species in the marine realm.
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http://dx.doi.org/10.1126/sciadv.abd7225DOI Listing
March 2021

Workers' compensation costs for healthcare caregivers: Home healthcare, long-term care, and hospital nurses and nursing aides.

Am J Ind Med 2021 Feb 22. Epub 2021 Feb 22.

Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.

Background: Healthcare workers (nurses and nursing aides) often have different exposures and injury risk factors depending on their occupational subsector and location (hospital, long-term care, or home health care).

Methods: A total of 5234 compensation claims for nurses and nursing aides who suffered injuries to their lower back, knee, and/or shoulder over a 5-year period were obtained from the Ohio Bureau of Workers' Compensation and analyzed. Injury causation data was also collected for each claim. The outcome variables included indemnity costs, medical costs, total costs, and the number of lost work days. The highest prescribed morphine equivalent dose for opioid medications was also calculated for each claim.

Results: Home healthcare nurses and nursing aides had the highest average total costs per claim. Hospital nurses and nursing aides had the highest total claim costs, of $5 million/year. Shoulder injuries for home healthcare nursing aides (HHNAs) had the highest average total claim costs ($20,600/injury) for all occupation, setting, and body area combinations. Opioids were most frequently prescribed for home healthcare nurses (HHNs) and nursing aides (18.9% and 17.7% having been prescribed opioids, respectively). Overexertion was the most common cause for HHN and nursing aide claims.

Conclusions: With the rapidly expanding workforce in the home healthcare sector, there is a potential health crisis from the continued expansion of home healthcare worker injuries and their associated costs. In addition, the potential for opioid drug usage places these workers at risk for future dependence, overdose, and prolonged disability. Future research is needed to investigate the specific and ideally reversible causes of injury in claims categorized as caused by overexertion.
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http://dx.doi.org/10.1002/ajim.23237DOI Listing
February 2021

MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha.

Respir Res 2021 Feb 17;22(1):57. Epub 2021 Feb 17.

Division of Neonatology, Department of Pediatrics, Women and Infants Center, University of Alabama At Birmingham, 176F Suite 9380619 South 19th Street, Birmingham, AL, 35249-7335, USA.

Background: MicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD).

Methods: Here we report a prospective cohort study of extremely preterm neonates wherein infants diagnosed with severe BPD expressed increased airway miR-219-5p and decreased platelet derived growth factor receptor alpha (PDGFR-α), a target of mir-219-5p and a key regulator of alveolarization, compared to post-conception age-matched term infants.

Results: miR-219-5p was highly expressed in the pulmonary epithelial lining in lungs of infants with BPD by in situ hybridization of human infant lungs. In both in vitro and in vivo (mouse) models of BPD, miR-219-5p was increased on exposure to hyperoxia compared with the normoxia control, with a complementary decrease of PDGFR-α. To further confirm the target relationship between miR-219 and PDGFR-α, pulmonary epithelial cells (MLE12) and lung primary fibroblasts were treated with a mimic of miR-219-5p and a locked nucleic acid (LNA) based inhibitor of miR-219-5p. In comparison with the control group, the level of miR-219 increased significantly after miR-219 mimic treatment, while the level of PDGFR-α declined markedly. LNA exposure increased PDGFR-α. Moreover, in BPD mouse model, over-expression of miR-219-5p inhibited alveolar development, indicated by larger alveolar spaces accompanied by reduced septation.

Conclusions: Taken together, our results demonstrate that increased miR-219-5p contributes to the pathogenesis of BPD by targeting and reducing PDGFR-α. The use of specific miRNA antagonists may be a therapeutic strategy for preventing the development of BPD.
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http://dx.doi.org/10.1186/s12931-021-01654-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891005PMC
February 2021

Evaluation of tools to assess operative competence in endovascular procedures: a systematic review.

ANZ J Surg 2021 Feb 15. Epub 2021 Feb 15.

Faculty of Medicine and Health, Sydney Medical School - Education Office, The University of Sydney, Sydney, New South Wales, Australia.

Background: With an increase in the use of endovascular interventions as an alternative to open surgery and the unique technical skills required, current methods for assessing the competence of vascular surgery trainees may not be optimal, suggesting a need for a shift in assessment modalities. We conducted this systematic review to explore current assessment methods used in vascular surgery training to assess competence specific to endovascular procedures.

Methods: A comprehensive literature search was performed with a structured search strategy using terms focusing on endovascular procedures and assessment. Inclusion and exclusion criteria were used in order to screen for suitable articles.

Results: We identified 54 articles that satisfied the inclusion criteria. These included a single randomized controlled trial, a single systematic review, a single narrative review and a single literature review, with the vast majority having level 2 evidence. Global rating scales, proficiency assessments and written/oral examinations were described as standard current assessment tools. These modalities lack reproducibility and objectivity, neglecting the needs of assessment of endovascular procedures requiring specialized decision making and finger dexterity. Novel methods such as high fidelity simulation and virtual reality promote reproducible and objective assessment methods in the context of endovascular surgery, and have a promising future.

Conclusion: While current assessment methods in vascular surgery are widely supported the changing skills required of a vascular surgery trainee warrants a shift in assessment modalities to better align to these requirements. High fidelity simulations show promise, although they require more extensive research to understand their relative merits.
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http://dx.doi.org/10.1111/ans.16653DOI Listing
February 2021

Public-Private Partnerships: Compound and Data Sharing in Drug Discovery and Development.

SLAS Discov 2021 Feb 13:2472555220982268. Epub 2021 Feb 13.

Molecular AI, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Collaborative efforts between public and private entities such as academic institutions, governments, and pharmaceutical companies form an integral part of scientific research, and notable instances of such initiatives have been created within the life science community. Several examples of alliances exist with the broad goal of collaborating toward scientific advancement and improved public welfare. Such collaborations can be essential in catalyzing breaking areas of science within high-risk or global public health strategies that may have otherwise not progressed. A common term used to describe these alliances is (PPP). This review discusses different aspects of such partnerships in drug discovery/development and provides example applications as well as successful case studies. Specific areas that are covered include PPPs for sharing compounds at various phases of the drug discovery process-from compound collections for hit identification to sharing clinical candidates. Instances of PPPs to support better data integration and build better machine learning models are also discussed. The review also provides examples of PPPs that address the gap in knowledge or resources among involved parties and advance drug discovery, especially in disease areas with unfulfilled and/or social needs, like neurological disorders, cancer, and neglected and rare diseases.
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http://dx.doi.org/10.1177/2472555220982268DOI Listing
February 2021

Leveraging longitudinal clinical laboratory results to improve prenatal care.

Am J Manag Care 2021 02;27(2):60-65

TriCore Reference Laboratories, 1001 Woodward Pl NE, Albuquerque, NM 87102. Email:

Objectives: To assess the impact of providing laboratory-generated near-real-time clinical insights for pregnant Medicaid members to managed care organization (MCO) care coordinators.

Study Design: A prospective, nonrandomized feasibility study was conducted over 11 months to examine the benefits of laboratory-generated clinical insights on prenatal care quality metrics and clinical outcomes. Measures included early identification of pregnancy and births to facilitate care, care gaps with prenatal laboratory testing, emergency department (ED) visits, preterm births, and neonatal intensive care unit (NICU) admissions and length of stay.

Methods: Weekly MCO care coordinators were provided a laboratory-generated prenatal targeted intervention module (TIM) to supplement their existing systems in a longitudinal, patient-centric format. Care coordinators contacted patients for enrollment in prenatal or postpartum services based on the TIM, which identified concomitant health conditions, missing prenatal care, and risks.

Results: The prenatal TIM identified 1355 pregnant members, 77% (n = 1040) of whom were detected in the first trimester. A total of 488 births were identified within 24 hours of parturition. Sixty-four percent of women had at least 80% of prenatal care gaps associated with laboratory testing closed. Women with ongoing prenatal care had fewer ED visits (17% vs 23%) and NICU admissions (11% vs 18%) compared with those without prenatal care. After adjusting for confounders, ongoing prenatal care had a borderline effect at decreasing the probability of having an ED visit and a NICU admission.

Conclusions: An innovative collaboration between an MCO and a clinical laboratory improved quality measures for prenatal members enrolled in Medicaid.
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http://dx.doi.org/10.37765/ajmc.2021.88582DOI Listing
February 2021

The prevalence of human leucocyte antigen and human papillomavirus DNA in penile intraepithelial neoplasia in England 2011-2012.

Int J STD AIDS 2021 Feb 12:956462420970727. Epub 2021 Feb 12.

Dermatology Department, University College Hospital, Chelsea and Westminster Hospital, London, UK.

Background: The pathogenesis of penile intraepithelial neoplasia (PeIN) is unclear but human papillomavirus (HPV) infection and polymorphisms in human leucocyte antigen (HLA).

Objectives: To examine the prevalence of HPV DNA and HLA in PeIN.

Methods: Adult Caucasian men with a clinical and histological diagnosis of PeIN, that is, Bowenoid papulosis (BP), Bowen's disease of penis (BDP) and erythroplasia of Queyrat (EQ) were selected and phenotyped from the clinical records. DNA was extracted from blood and paraffin-embedded sections for HLA and HPV typing, respectively. Human leucocyte antigen allele frequencies were compared with those derived from the UK-based Caucasian population.

Results: Seventy-two cases of PeIN (20 BP, 34 BDP and 18 EQ) were studied. Human papillomavirus DNA was identified in 65/72 (90.2%) PeIN; types were detected in 62/72 (85%) followed by types in 9/72 (12.5%) and cutaneous types in 7/72 (9.7%); HPV16 was the most prevalent genotype at 35/72 (48.6%) followed by HPV33 at 7/72 (9.7%); multiple infections were seen in 18/72 (25%) PeIN. HLA-C*15 (Bonferroni corrected = 0.049) confers susceptibility to PeIN, whereas HLA-DQA1*01 (corrected = 0.02) protects against PeIN. HPV16-associated PeIN cases showed no statistically significant association with HLA genotype after multiple corrections.

Conclusion: Human papillomavirus is involved in the pathogenesis of PeIN. Immunogenotype may play a role in the pathogenesis of PeIN.
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http://dx.doi.org/10.1177/0956462420970727DOI Listing
February 2021

Epithelial Regeneration After Doxorubicin Arises Primarily From Early Progeny of Active Intestinal Stem Cells.

Cell Mol Gastroenterol Hepatol 2021 Feb 8. Epub 2021 Feb 8.

Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina. Electronic address:

Background & Aims: aISCs (aISCs) are sensitive to acute insults including chemotherapy and irradiation. Regeneration after aISC depletion has primarily been explored in irradiation (IR). However, the cellular origin of epithelial regeneration after doxorubicin (DXR), a common chemotherapeutic, is poorly understood.

Methods: We monitored DXR's effect on aISCs by enumerating Lgr5-eGFP and Olfm4 crypts, cleaved caspase-3 (CASP3) immunofluorescence, and time-lapse organoid imaging. Lineage tracing from previously identified regenerative cell populations (Bmi1, Hopx, Dll1, and Defa6) was performed with DXR damage. Lineage tracing from aISCs was compared with lineage tracing from early progeny cells (transit-amplifying cells arising from aISCs 1 day predamage) in the context of DXR and IR. We compared stem cell and DNA damage response (DDR) transcripts in isolated aISCs and early progeny cells 6 and 24 hours after DXR.

Results: Epithelial regeneration after DXR primarily arose from early progeny cells generated by aISCs. Early progeny cells upregulated stem cell gene expression and lacked apoptosis induction (6 hours DXR: 2.5% of CASP3 cells, p<0.0001). aISCs downregulated stem cell gene expression and underwent rapid apoptosis (6 hours DXR: 63.4% of CASP3 cells). There was minimal regenerative contribution from Bmi1, Hopx, Dll1, and Defa6-expressing populations. In homeostasis, 48.4% of early progeny cells were BrdU, and expressed low levels of DDR transcripts.

Conclusions: We show that DXR effectively depleted aISCs in the small intestine and subsequent epithelial regeneration depended on nonquiescent early progeny cells of aISCs. The chemoresistant phenotype of the early progeny cells may rely on a dampened DDR in contrast to aISCs' robust DDR, which facilitates expeditious apoptosis.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.015DOI Listing
February 2021

Prognostic significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for advanced non-small cell lung cancer patients with high PD-L1 tumor expression receiving pembrolizumab.

Transl Lung Cancer Res 2021 Jan;10(1):355-367

Department of Mathematics and Statistics, University of Victoria, Victoria, BC, Canada.

Background: We investigated the association of peripheral blood inflammatory markers with overall survival (OS) in pembrolizumab treated advanced non-small cell lung cancer (aNSCLC) patients with programmed death ligand 1 (PD-L1) expression ≥50%. Clinical risk factors for development of immune-related adverse events (irAE) were also explored.

Methods: aNSCLC patients with high PD-L1 expression receiving pembrolizumab monotherapy outside of clinical trials were identified retrospectively. All patients were treated at one of six British Columbia Cancer clinics between August 2017 and June 2019. Patients were dichotomized using baseline neutrophil-to-lymphocyte ratio (NLR,
Results: Among 220 patients, median age was 70.0 years, 55.0% were female, 40.5% had baseline Eastern Cooperative Oncology Group performance status (ECOG PS) 2/3, and 95.5% received frontline pembrolizumab. Median OS for the cohort was 11.8 months (95% CI: 8.7-15.4). On multivariable analysis, baseline NLR ≥6.4 [hazard ratio (HR): 2.31, 95% confidence interval (CI): 1.46-3.64, P<0.001], baseline PLR ≥441.8 (HR: 2.03, 95% CI 1.22-3.37, P=0.006), and pre-treatment ECOG PS 2/3 (HR: 2.19, 95% CI: 1.48-3.26, P<0.001) were associated with worse OS. The incidence of any grade irAE and irAE grade ≥3 were 40.5% and 12.3%, respectively. ECOG PS 2/3 (. 0/1) patients were at 3.76-fold higher risk of developing an irAE by the 8-month landmark (P=0.002).

Conclusions: High NLR and PLR were associated with shorter OS in a cohort of patients receiving largely frontline pembrolizumab for aNSCLC in routine practice. ECOG PS 2/3 was associated with higher risk of developing an irAE. Given that NLR and PLR values are easily obtainable, prospective studies are warranted to confirm their prognostic significance in this patient population and explore a predictive utility.
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http://dx.doi.org/10.21037/tlcr-20-541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867765PMC
January 2021

The adverse effects of bisphosphonates in breast cancer: A systematic review and network meta-analysis.

PLoS One 2021 5;16(2):e0246441. Epub 2021 Feb 5.

Department of Pure Mathematics & Mathematical Statistics, Winton Centre for Risk & Evidence Communication, University of Cambridge, Cambridge, United Kingdom.

Background: Bisphosphonate drugs can be used to improve the outcomes of women with breast cancer. Whilst many meta-analyses have quantified their potential benefits for patients, attempts at comprehensive quantification of potential adverse effects have been limited. We undertook a meta-analysis with novel methodology to identify and quantify these adverse effects.

Methods: We systematically reviewed randomised controlled trials in breast cancer where at least one of the treatments was a bisphosphonate (zoledronic acid, ibandronate, pamidronate, alendronate or clodronate). Neoadjuvant, adjuvant and metastatic settings were examined. Primary outcomes were adverse events of any type or severity (excluding death). We carried out pairwise and network meta-analyses to estimate the size of any adverse effects potentially related to bisphosphonates. In order to ascertain whether adverse effects differed by individual factors such as age, or interacted with other common adjuvant breast cancer treatments, we examined individual-level patient data for one large trial, AZURE.

Findings: We identified 56 trials that reported adverse data, which included a total of 29,248 patients (18,301 receiving bisphosphonate drugs versus 10,947 not). 24 out of the 103 different adverse outcomes analysed showed a statistically and practically significant increase in patients receiving a bisphosphonate drug compared with those not (2 additional outcomes that appeared statistically significant came only from small studies with low event counts and no clinical suspicion so are likely artifacts). Most of these 24 are already clinically recognised: 'flu-like symptoms, fever, headache and chills; increased bone pain, arthralgia, myalgia, back pain; cardiac events, thromboembolic events; hypocalcaemia and osteonecrosis of the jaw; as well as possibly stiffness and nausea. Oral clodronate appeared to increase the risk of vomiting and diarrhoea (which may also be increased by other bisphosphonates), and there may be some hepatotoxicity. Four additional potential adverse effects emerged for bisphosphonate drugs in this analysis which have not classically be recognised: fatigue, neurosensory problems, hypertonia/muscle spasms and possibly dysgeusia. Several symptoms previously reported as potential side effects in the literature were not significantly increased in this analysis: constipation, insomnia, respiratory problems, oedema or thirst/dry mouth. Individual patient-level data and subgroup analysis revealed little variation in side effects between women of different ages or menopausal status, those with metastatic versus non-metastatic cancer, or between women receiving different concurrent breast cancer therapies.

Conclusions: This meta-analysis has produced estimates for the absolute frequencies of a range of side effects significantly associated with bisphosphonate drugs when used by breast cancer patients. These results show good agreement with previous literature on the subject but are the first systematic quantification of side effects and their severities. However, the analysis is limited by the availability and quality of data on adverse events, and the potential for bias introduced by a lack of standards for reporting of such events. We therefore present a table of adverse effects for bisphosphonates, identified and quantified to the best of our ability from a large number of trials, which we hope can be used to improve the communication of the potential harms of these drugs to patients and their healthcare providers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864400PMC
February 2021

Clinical evaluation of type 2 disease status in a real-world population of difficult to manage asthma using historic electronic healthcare records of blood eosinophil counts.

Clin Exp Allergy 2021 Feb 2. Epub 2021 Feb 2.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Blood eosinophil measurement is essential for the phenotypic characterization of patients with difficult asthma and in determining eligibility for anti-IL-5/IL-5Rα biological therapies. However, assessing such measures over limited time spans may not reveal the true underlying eosinophilic phenotype, as treatment, including daily oral corticosteroid therapy, suppresses eosinophilic inflammation and asthma is intrinsically variable.

Methods: We interrogated the electronic healthcare records of patients in the Wessex AsThma CoHort of difficult asthma (WATCH) study (UK). In 501 patients being evaluated in this tertiary care centre for difficult to control asthma, all requested full blood count test results in a 10-year retrospective period from the index WATCH assessment were investigated (n = 11,176).

Results: In 235 biological therapy-naïve participants who had 10 or more measures in this time period, 40.3% were eosinophilic (blood eosinophils ≥300 cells/µl) at WATCH enrolment whilst an additional 43.1%, though not eosinophilic at enrolment, demonstrated eosinophilia at least once in the preceding decade. Persistent eosinophilia was associated with worse post-bronchodilator airway obstruction and higher Fractional exhaled Nitric Oxide (FeNO). In contrast, the 16.6% of patients who never demonstrated eosinophilia at this blood eosinophil threshold showed preserved lung function and lower markers of Type 2 inflammation.

Conclusions: This highlights the central role that type 2 inflammation, as indicated by blood eosinophilia, has in difficult asthma and suggests that longitudinal electronic healthcare record analysis can be an important tool in clinical asthma phenotyping, providing insight that may help understand disease progression and better guide more specific treatment approaches.
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http://dx.doi.org/10.1111/cea.13841DOI Listing
February 2021

Daratumumab for delayed RBC engraftment following major ABO mismatched haploidentical bone marrow transplantation.

Transfusion 2021 Feb 2. Epub 2021 Feb 2.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature.

Study Design And Materials: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia.

Results: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin.

Conclusion: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.
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http://dx.doi.org/10.1111/trf.16281DOI Listing
February 2021

More stories to tell: NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1, a salicylic acid receptor.

Plant Cell Environ 2021 Jan 25. Epub 2021 Jan 25.

Institute of Plant Protection, Jiangsu Academy of Agricultural Sciences, Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Nanjing, China.

Salicylic acid (SA) plays pivotal role in plant defense against biotrophic and hemibiotrophic pathogens. Tremendous progress has been made in the field of SA biosynthesis and SA signaling pathways over the past three decades. Among the key immune players in SA signaling pathway, NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1) functions as a master regulator of SA-mediated plant defense. The function of NPR1 as an SA receptor has been controversial; however, after years of arguments among several laboratories, NPR1 has finally been proven as one of the SA receptors. The function of NPR1 is strictly regulated via post-translational modifications and transcriptional regulation that were recently found. More recent advances in NPR1 biology, including novel functions of NPR1 and the structure of SA receptor proteins, have brought this field forward immensely. Therefore, based on these recent discoveries, this review acts to provide a full picture of how NPR1 functions in plant immunity and how NPR1 gene and NPR1 protein are regulated at multiple levels. Finally, we also discuss potential challenges in future studies of SA signaling pathway.
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http://dx.doi.org/10.1111/pce.14003DOI Listing
January 2021

Research Evaluation Alongside Clinical Treatment in COVID-19 (REACT COVID-19): an observational and biobanking study.

BMJ Open 2021 01 22;11(1):e043012. Epub 2021 Jan 22.

Faculty of Medicine, University of Southampton, Southampton, UK.

Introduction: The COVID-19 pandemic caused by SARS-CoV-2 places immense worldwide demand on healthcare services. Earlier identification of patients at risk of severe disease may allow intervention with experimental targeted treatments, mitigating the course of their disease and reducing critical care service demand.

Methods And Analysis: This prospective observational study of patients tested or treated for SARS-CoV-2, who are under the care of the tertiary University Hospital Southampton NHS Foundation Trust (UHSFT), captured data from admission to discharge; data collection commenced on 7 March 2020. Core demographic and clinical information, as well as results of disease-defining characteristics, was captured and recorded electronically from hospital clinical record systems at the point of testing. Manual data were collected and recorded by the clinical research team for assessments which are not part of the structured electronic healthcare record, for example, symptom onset date. Thereafter, participant records were continuously updated during hospital stay and their follow-up period. Participants aged >16 years were given the opportunity to provide consent for excess clinical sample storage with optional further biological sampling. These anonymised samples were linked to the clinical data in the Real-time Analytics for Clinical Trials platform and were stored within a biorepository at UHSFT.

Ethics And Dissemination: Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent for the database-only cohort; the procedures conform with the Declaration of Helsinki. The study design, protocol and patient-facing documentation for the biobanking arm of the study have been approved by North West Research Ethics Committee (REC 17/NW/0632) as an amendment to the National Institute for Health Research Southampton Clinical Research Facility-managed Southampton Research Biorepository. This study will be published as peer-reviewed articles and presented at conferences, presentations and workshops.
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http://dx.doi.org/10.1136/bmjopen-2020-043012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830323PMC
January 2021

Closing Gaps in Lifestyle Adherence for Secondary Prevention of Coronary Heart Disease.

Am J Cardiol 2021 Jan 14. Epub 2021 Jan 14.

Lifespan Cardiovascular Institute, and Department of Medicine, Division of Cardiology, Brown University, Alpert Medical School, Providence, Rhode Island. Electronic address:

The secondary prevention (SP) of coronary heart disease (CHD) has become a major public health and economic burden worldwide. In the United States, the prevalence of CHD has risen to 18 million, the incidence of recurrent myocardial infarctions (MI) remains high, and related healthcare costs are projected to double by 2035. In the last decade, practice guidelines and performance measures for the SP of CHD have increasingly emphasized evidence-based lifestyle (LS) interventions, including healthy dietary patterns, regular exercise, smoking cessation, weight management, depression screening, and enrollment in cardiac rehabilitation. However, data show large gaps in adherence to healthy LS behaviors and low rates of enrollment in cardiac rehabilitation in patients with established CHD. These gaps may be related, since behavior change interventions have not been well integrated into traditional ambulatory care models in the United States. The chronic care model, an evidence-based practice framework that incorporates clinical decision support, self-management support, team-care delivery and other strategies for delivering chronic care is well suited for both chronic CHD management and prevention interventions, including those related to behavior change. This article reviews the evidence base for LS interventions for the SP of CHD, discusses current gaps in adherence, and presents strategies for closing these gaps via evidence-based and emerging interventions that are conceptually aligned with the elements of the chronic care model.
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http://dx.doi.org/10.1016/j.amjcard.2021.01.005DOI Listing
January 2021

Designing the GALAXY study: Partnering with the cystic fibrosis community to optimize assessment of gastrointestinal symptoms.

J Cyst Fibros 2021 Jan 12. Epub 2021 Jan 12.

University of North Carolina, Atrium Health, Charlotte, NC, USA.

Background: Gastrointestinal (GI) involvement among persons with cystic fibrosis (CF) is highly prevalent, representing a significant source of morbidity. Persons with CF have identified GI concerns as a top research priority, yet universal clinical outcome measures capturing many of the GI symptoms experienced in CF are lacking. The GALAXY study was envisioned to address this unmet need.

Methods: The GALAXY study team partnered with Community Voice, a community of patients with CF and their caregivers, to identify the patient reported outcome measures that most accurately reflected their experience with GI symptoms in CF. We also surveyed CF care teams to identify the comfort level of various team members (providers, nurses and dieticians) in managing a variety of GI conditions.

Results: Members of Community Voice identified the combination of PAC-SYM, PAGI-SYM, PAC-QOL and the Bristol Stool scale with three additional symptom-specific questions as patient-reported outcome measures that comprehensively captured the CF experience with GI disease. CF care team providers reported a high level of comfort in treating GI conditions including constipation (92%), GERD (93%), and gassiness (77%), however comfort level was limited to only first-line interventions.

Conclusion: By partnering with persons with CF as well as their caregivers and medical providers, the GALAXY study is designed to uniquely capture the prevalence and severity of GI involvement among persons with CF in a manner that reflects the CF patient experience. The results of GALAXY will inform the development of future interventional trials and serve as a reproducible and objective study endpoint.
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http://dx.doi.org/10.1016/j.jcf.2020.12.021DOI Listing
January 2021

Does variation in trait schizotypy and frequency of cannabis use influence the acute subjective, cognitive and psychotomimetic effects of delta-9-tetrahydrocannabinol? A mega-analysis.

J Psychopharmacol 2021 Jan 9:269881120959601. Epub 2021 Jan 9.

Clinical Psychopharmacology Unit, University College London, Gower Street, London, UK.

Background: While the acute effects of cannabis are relatively benign for most users, some individuals experience significant adverse effects. This study aimed to identify whether variation in schizotypal personality traits and frequency of cannabis use influence the acute effects of delta-9-tetrahydrocannabinol (THC).

Methods: Individual participant data from four double-blind, randomised, placebo-controlled, acute crossover studies involving 128 cannabis users were combined for a mega-analysis. Using multilevel linear models and moderation analyses, frequency of cannabis use and schizotypal personality traits were investigated as potential moderators of the subjective, cognitive and psychotomimetic effects of acute THC.

Results: There was evidence of a moderating effect where increased frequency of cannabis use was associated with reduced intensity of subjective (changes in alertness and feeling stoned) and psychosis-like effects following THC when compared with placebo. Moderating effects of cannabis use frequency on acute memory impairment were weak. Trait schizotypy did not moderate the acute psychosis-like effects of THC compared with placebo.

Conclusions: Our results suggest that a pattern of domain-specific tolerance develops to the acute effects of THC. Tolerance to the alertness-reducing effects occurred more readily than tolerance to psychotomimetic effects. Only partial tolerance to feeling stoned was found, and there was weak evidence for tolerance to memory impairment. Trait schizotypy did not moderate THC's effects on psychotomimetic symptoms.
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http://dx.doi.org/10.1177/0269881120959601DOI Listing
January 2021

Landscape of Mentorship and its Effects on Success in Cardiology.

JACC Basic Transl Sci 2020 Dec 23;5(12):1181-1186. Epub 2020 Dec 23.

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, USA.

The effects of mentorship on measurable outcomes of success and the aspects of mentorship that are most valuable in promoting the careers of cardiologists are unclear. To address this, we conducted a large-scale survey of cardiologists in a real-world setting. We identified factors that enhance the mentorship experience, and found that mentee needs change with career stage. Importantly, satisfaction with the mentoring relationship is significantly associated with perceived satisfaction in achieving professional goals. Furthermore, we found that gender and race concordance in mentoring relationships is an important variable with the potential to increase diversity in the field of cardiology.
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http://dx.doi.org/10.1016/j.jacbts.2020.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775959PMC
December 2020

Characterization of autoantibodies, immunophenotype and autoimmune disease in a prospective cohort of patients with idiopathic CD4 lymphocytopenia.

Clin Immunol 2021 Mar 7;224:108664. Epub 2021 Jan 7.

Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address:

Objective: Characterize autoantibodies and autoimmune diseases in a prospective cohort of patients with Idiopathic CD4 Lymphocytopenia (ICL) a rare immunodeficiency characterized by an absolute CD4 T count of <300 cells/μl in the absence of HIV or HTLV infection.

Methods: Single-Center prospective study of 67 patients conducted over an 11-year period. Rheumatologic evaluation and measurement of autoantibodies were systematically conducted, and flow cytometry of immune cell subsets was performed in a subset of patients.

Results: 54% of referred patients had clinical evidence of autoimmunity, with 34% having at least one autoimmune disease, most commonly autoimmune thyroid disease. 19%, had autoantibodies or incomplete features of autoimmune disease. Patients with autoimmune disease had more elevated serum immunoglobulins, and more effector memory T cells than those without autoimmunity.

Conclusions: Evidence of autoimmunity, including autoimmune diseases, is more prevalent in ICL than the general population, and should be considered part of this syndrome.
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http://dx.doi.org/10.1016/j.clim.2021.108664DOI Listing
March 2021

An Unusual Pattern of Premature Cervical Spine Degeneration in STAT3-LOF.

J Clin Immunol 2021 Apr 6;41(3):576-584. Epub 2021 Jan 6.

Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Loss of function mutations in STAT3 (STAT3-LOF; autosomal dominant hyper-IgE (Job's) syndrome) are associated with a variety of musculoskeletal manifestations, including scoliosis, osteoporosis, and minimal trauma fractures. This retrospective magnetic resonance (MR) imaging study sought to characterize an unusual pattern of cervical spine degeneration among a cohort of STAT3-LOF patients. Cervical spine MR images of the STAT3-LOF cohort (n = 38) were assessed for a variety of degenerative changes and compared to age-matched groups of controls (n = 42) without known immune or musculoskeletal abnormalities. A unique pattern of premature cervical spine degeneration was identified among the STAT3-LOF cohort which included straightening and eventual reversal of the normal cervical lordosis, mainly due to multi-level spondylolisthesis, as well as early development of spinal canal narrowing, cord compression, and myelomalacia. Cervical spine degeneration in the STAT3-LOF cohort was significantly worse than controls in both the 30-45 and 45 + age groups. Moderate to severe degenerative changes were present after age 30, and markedly worsened over time in several cases. Bone mineral density (BMD) had a moderate negative correlation with cervical degeneration severity and a strong negative correlation with age among STAT3-LOF participants. Cervical degeneration in STAT3-LOF appears to be progressive and could result in cord compromise if left unaddressed. Focused history and physical examination for signs of neurologic compromise as well as periodic MR imaging are thus recommended for the evaluation of premature cervical spine degeneration in STAT3-LOF patients after age 30 so that timely surgical interventions may be considered to prevent spinal cord damage and permanent neurological deficits.
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http://dx.doi.org/10.1007/s10875-020-00926-zDOI Listing
April 2021

Mixed acinar and macrocystic ductal prostatic adenocarcinoma.

Lancet Oncol 2021 01;22(1):e37

Department of Urology, University College London Hospital NHS Foundation Trust, London, UK; Division of Surgery & Interventional Science, University College London, London, UK.

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http://dx.doi.org/10.1016/S1470-2045(20)30435-6DOI Listing
January 2021

A Modified Newcastle-Ottawa Scale for Assessment of Study Quality in Genetic Urological Research.

Eur Urol 2021 Mar 26;79(3):325-326. Epub 2020 Dec 26.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

Our modification of the traditional Newcastle-Ottawa scale enables urological researchers to effectively appraise and communicate the quality of genetic-based research in urology.
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http://dx.doi.org/10.1016/j.eururo.2020.12.017DOI Listing
March 2021

Tissue specific diversification, virulence and immune response to BCG in a patient with an IFN-γ R1 deficiency.

Virulence 2020 Dec;11(1):1656-1673

Department of Laboratory Medicine, Clinical Center, NIH , Bethesda, USA.

: We characterized BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. : We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine). Distinct BCG-vaccine derived clinical strains were recovered from the patient's lungs and brain. : BCG strains were phenotypically (growth, antibiotic susceptibility, lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell infection models were used to assess apoptosis, necrosis, cytokine release, autophagy, and JAK-STAT signaling. : Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 mutations conferring high- and low-level rifampin resistance; the latter displayed clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in operon genes, respectively. Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and Mycolic acid components in BCG-lung, compared to parent BCG-vaccine. infected cells showed that the BCG-lung induced a higher cytokine release, necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. : During a chronic-disseminated BCG infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.
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http://dx.doi.org/10.1080/21505594.2020.1848108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781554PMC
December 2020

The uncertainty trope: the duty to treat during a pandemic.

Australas Psychiatry 2020 Dec 23:1039856220975286. Epub 2020 Dec 23.

Training Network B Psychiatry Training Centre, Australia.

Background: Past guidance in the codes of practice urged doctors to provide treatment even in the context of extreme adversities. Despite the significant societal changes of recent times, contemporary guidance regarding the duty to treat during a pandemic has been limited.

Objective: The authors herewith examine deontological aspects pertaining to the duty to treat during a pandemic and the potential disruptions to health care services.

Conclusion: The ethical, legal and professional guidance for duty of care during a pandemic is uncertain and demands further debate.
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http://dx.doi.org/10.1177/1039856220975286DOI Listing
December 2020

Prostate Radiofrequency Focal Ablation (ProRAFT) Trial: A Prospective Development Study Evaluating a Bipolar Radio frequency Device to Treat Prostate Cancer.

J Urol 2020 Dec 14:101097JU0000000000001567. Epub 2020 Dec 14.

Division of Surgery and Interventional Sciences, University College London, London, United Kingdom.

Purpose: We determined the early efficacy of bipolar radiofrequency ablation with a coil design for focal ablation of clinically significant localized prostate cancer visible at multiparametric magnetic resonance imaging.

Material And Methods: A prospective IDEAL phase 2 development study (Focal Prostate Radiofrequency Ablation, NCT02294903) recruited treatment-naïve patients with a single focus of significant localized prostate cancer (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multiparametric magnetic resonance imaging. Intervention was a focal ablation with a bipolar radiofrequency system (Encage™) encompassing the lesion and a predefined margin using nonrigid magnetic resonance imaging-ultrasound fusion. Primary outcome was the proportion of men with absence of significant localized disease on biopsy at 6 months. Trial followup consisted of serum prostate specific antigen, multiparametric magnetic resonance imaging at 1 week, and 6 and 12 months post-ablation. Validated patient reported outcome measures for urinary, erectile and bowel functions, and adverse events monitoring system were used. Analyses were done on a per-protocol basis.

Results: Of 21 patients recruited 20 received the intervention. Baseline characteristics were median age 66 years (IQR 63-69) and preoperative median prostate specific antigen 7.9 ng/ml (5.3-9.6). A total of 18 patients (90r%) had Gleason 7 disease with median maximum cancer 7 mm (IQR 5-10), for a median of 2.8 cc multiparametric magnetic resonance imaging lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores 6, IQR 5-8) showed absence of significant localized prostate cancer in 16/20 men (80%), concordant with multiparametric magnetic resonance imaging. There was a low profile of side effects at patient reported outcome measures analysis and there were no serious adverse events.

Conclusions: Focal therapy of significant localized prostate cancer associated with a magnetic resonance imaging lesion using bipolar radiofrequency showed early efficacy to ablate cancer with low rates of genitourinary and rectal side effects.
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http://dx.doi.org/10.1097/JU.0000000000001567DOI Listing
December 2020

Blood Type Is Not Associated with Changes in Cardiometabolic Outcomes in Response to a Plant-Based Dietary Intervention.

J Acad Nutr Diet 2020 Nov 10. Epub 2020 Nov 10.

Background: Risk of cardiovascular disease is lower in individuals with blood type O and increased in individuals with blood type A, compared with those in other blood groups. However, little evidence is available regarding whether individuals with different blood types benefit from different diet recommendations.

Objective: As part of a larger intervention trial using a low-fat vegan diet, this study ascertained whether changes in cardiometabolic outcomes were associated with ABO blood type.

Design: A secondary analysis among intervention-group participants in a 16-week randomized clinical trial.

Participants/setting: In a larger study of overweight individuals randomly assigned to follow a low-fat vegan diet or to make no diet changes for 16 weeks, ABO blood typing was conducted on 68 intervention-group participants.

Intervention: Intervention-group participants were asked to follow a low-fat vegan diet and attend weekly educational classes to aid in diet adherence.

Main Outcome Measures: Body weight, fat mass, visceral fat volume, blood lipid levels, fasting plasma glucose levels, and glycated hemoglobin concentrations.

Statistical Analyses Performed: Student t tests compared participants with blood type A to all other participants, and individuals with blood type O to all other participants.

Results: There were no significant differences in any outcome between individuals of blood type A and all other participants, or between individuals of blood type O and all other participants. Mean body weight change was -5.7 kg for blood type A participants and -7.0 kg for all other participants (P = 0.09), and was -7.1 kg for type O participants and -6.2 kg for all other participants (P = 0.33). Mean total cholesterol decreased 17.2 mg/dL in the type A group and 18.3 mg/dL for all other participants (P = 0.90), and decreased 17.4 mg/dL among type O participants and 18.4 mg/dL for all other participants (P = 0.89).

Conclusions: Blood type was not associated with the effects of a plant-based diet on body weight, body fat, plasma lipid concentrations, or glycemic control.
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http://dx.doi.org/10.1016/j.jand.2020.08.079DOI Listing
November 2020

Comparisons of early and late presentation to hospital in COVID-19 patients.

Respirology 2021 02 6;26(2):204-205. Epub 2020 Dec 6.

University Hospital Southampton NHS Foundation Trust, Southampton, UK.

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http://dx.doi.org/10.1111/resp.13985DOI Listing
February 2021