Publications by authors named "Shannon Kelly"

106 Publications

Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens.

Commun Biol 2021 Jul 16;4(1):883. Epub 2021 Jul 16.

Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates that underlie these persistent changes in neural function and behavior. However, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to stimulant drugs of abuse, such as cocaine. Here, we show that sex is a critical biological variable that defines drug-induced plasticity in the nucleus accumbens (NAc). Using quantitative mass spectrometry, we assessed the protein expression patterns induced by cocaine self-administration and demonstrated unique molecular profiles between males and females. We show that 1. Cocaine self-administration induces non-overlapping protein expression patterns in significantly regulated proteins in males and females and 2. Critically, cocaine-induced protein regulation differentially interacts with sex to eliminate basal sexual dimorphisms in the proteome. Finally, eliminating these baseline differences in the proteome is concomitant with the elimination of sex differences in behavior for non-drug rewards. Together, these data suggest that cocaine administration is capable of rewriting basal proteomic function and reward-associated behaviors.
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http://dx.doi.org/10.1038/s42003-021-02358-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285523PMC
July 2021

Remote Monitoring of Cardiovascular Implantable Electronic Devices in Canada: Survey of Patients and Device Health Care Professionals.

CJC Open 2021 Apr 20;3(4):391-399. Epub 2020 Nov 20.

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: Remote monitoring is used to supplement in-clinic follow-up for patients with cardiac implantable electronic devices (CIEDs) every 6-12 months. There is a need to optimize remote management for CIEDs because of the consistent increases in CIED implants over the past decade. The objective of this study was to investigate real and perceived barriers to the use of remote patient management strategies in Canada and to better understand how remote models of care can be optimized.

Methods: We surveyed 512 CIED patients and practitioners in 22 device clinics in Canada.

Results: Device clinic surveys highlighted significant variation and inconsistency in follow-up care for in-clinic and remote visits across and within clinics. This survey showed that funding policies and management of additional workflow are barriers to optimal use and uptake. Despite this, device clinics perceive remote follow-up as a valuable resource and an efficient way to manage patient follow-up. Patients were broadly satisfied with their CIED follow-up care but identified barriers related to coordination of care, visit logistics, and information needs. Views varied as a function of clinical or sociodemographic characteristics. Most patients (n = 228; 91%) expressed a desire to receive a phone call from their device clinic after a remote transmission has been received.

Conclusions: Lack of a unified, guideline-supported approach to follow-up after CIED implant, and discrepant funding policies across jurisdictions, are significant barriers to the use of remote patient management strategies in Canada. Efforts to increase or expand use of remote follow-up must recognize these barriers and the needs of specific subgroups of patients.
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http://dx.doi.org/10.1016/j.cjco.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129436PMC
April 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 2021

A randomized, placebo-controlled, double-blinded clinical trial of colchicine to improve vascular health in people living with HIV.

AIDS 2021 06;35(7):1041-1050

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine.

Objectives: People living with HIV (PWH) experience an increased burden of coronary artery disease (CAD) believed to be related, in part, to an interplay of chronically increased inflammation and traditional risk factors. Recent trials suggest cardiovascular benefits of the anti-inflammatory, colchicine, in HIV-seronegative CAD patients. However, the impact of colchicine on impaired vascular health, as measured by coronary endothelial function (CEF), an independent contributor to CAD, has not been studied in PWH. We tested the hypothesis that colchicine improves vascular health in PWH.

Design: This was a randomized, placebo-controlled, double-blinded trial in 81 PWH to test whether low-dose colchicine (0.6 mg daily) improves CEF over 8-24 weeks.

Methods: Coronary and systemic endothelial function and serum inflammatory markers were measured at baseline, and at 8 and 24 weeks. The primary endpoint was CEF, measured as the change in coronary blood flow from rest to that during an isometric handgrip exercise, an endothelial-dependent stressor, measured with non-invasive MRI at 8 weeks.

Results: Colchicine was well tolerated and not associated with increased adverse events. However, there were no significant improvements in coronary or systemic endothelial function or reductions in serum inflammatory markers at 8 or 24 weeks with colchicine as compared to placebo.

Conclusions: In PWH with no history of CAD, low-dose colchicine was well tolerated but did not improve impaired coronary endothelial function, a predictor of cardiovascular events. These findings suggest that this anti-inflammatory approach using colchicine in PWH does not improve vascular health, the central, early driver of coronary atherosclerosis.
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http://dx.doi.org/10.1097/QAD.0000000000002845DOI Listing
June 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature.

Physiol Genomics 2021 03 25;53(3):99-115. Epub 2021 Jan 25.

Department of Biomedical Sciences, University of Missouri, Columbia, Missouri.

Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly twofold increased risk of death compared with those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome data set in the RV of a preclinical model of cardiometabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, = 5) or Western diet and aortic-banding (WD-AB; = 4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared with CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using principal component analysis, weighted gene co-expression network analysis, module enrichment analysis, and ingenuity pathway analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardiometabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.
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http://dx.doi.org/10.1152/physiolgenomics.00093.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988741PMC
March 2021

Scoliosis Screening.

J Am Acad Orthop Surg 2021 May;29(9):370-379

From the Division of Orthopaedic Surgery and Sports Medicine, Children's National Hospital, Washington, DC (Oetgen, Kelly), and the Orthopaedic Surgery Department, George Washington University Hospital, Washington, DC (Heyer).

The national recommendations for school screening programs for scoliosis in the United States have undergone a shift in perspective over the past two decades. In 2004, the United States Preventive Services Task Force recommended against screening programs but changed its recommendation to be inconclusive in 2018. Early diagnosis of scoliosis can allow for close monitoring of the deformity and early initiation of bracing treatment when appropriate, with the goal of preventing costly and invasive surgical intervention. Several different diagnostic tools are available, including Adam's forward bending test alone, Adam's forward bending test with scoliometry, the humpometer, and Moiré topography, each with varying degrees of sensitivity and specificity. Controversy prevails over the cost efficacy of screening programs and possible unnecessary exposure of adolescents to radiation for confirmatory radiographs after a positive screening test. However, the recent definitive evidence of bracing treatment efficacy in slowing the progression of scoliotic curves and preventing the need for surgery indicates that school screening programs may still have a role in allowing early diagnosis.
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http://dx.doi.org/10.5435/JAAOS-D-20-00356DOI Listing
May 2021

Sex differences in dopamine release regulation in the striatum.

Neuropsychopharmacology 2021 02 14;46(3):491-499. Epub 2020 Dec 14.

Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.

The mesolimbic dopamine system-which originates in the ventral tegmental area and projects to the striatum-has been shown to be involved in the expression of sex-specific behavior and is thought to be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters-as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.
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http://dx.doi.org/10.1038/s41386-020-00915-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027008PMC
February 2021

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

Front Immunol 2020 6;11:584950. Epub 2020 Nov 6.

Laboratory of Evolutionary Genetics, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.
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http://dx.doi.org/10.3389/fimmu.2020.584950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677137PMC
June 2021

Diversity of variant alleles encoding Kidd, Duffy, and Kell antigens in individuals with sickle cell disease using whole genome sequencing data from the NHLBI TOPMed Program.

Transfusion 2021 02 24;61(2):603-616. Epub 2020 Nov 24.

Institute of Tropical Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Background: Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen-matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data.

Study Design And Methods: Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS-III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program.

Results: In SLC14A1, variants included four encoding a weak Jk phenotype and five null alleles (JK ). JKA*01N.09 was the most common JK . One possible JK mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fy (FY*X) and one corresponding to the c.-67T>C GATA mutation. The c.-67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting K phenotype, all in heterozygosity.

Conclusions: We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.
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http://dx.doi.org/10.1111/trf.16204DOI Listing
February 2021

Reduced Proactive Control Processes Associated With Behavioral Response Inhibition Deficits in Autism Spectrum Disorder.

Autism Res 2021 02 27;14(2):389-399. Epub 2020 Oct 27.

Clinical Child Psychology Program, University of Kansas, Lawrence, Kansas, USA.

Impairments in inhibitory control are common in individuals with autism spectrum disorder (ASD) and associated with multiple clinical issues. Proactive (i.e., delaying response onset) and reactive control mechanisms (i.e., stopping quickly) contribute to successful inhibitory control in typically developing individuals and may be compromised in ASD. We assessed inhibitory control in 58 individuals with ASD and 63 typically developing controls aged 5-29 years using an oculomotor stop-signal task during which participants made rapid eye movements (i.e., saccades) toward peripheral targets (i.e., GO trials) or inhibited saccades (i.e., STOP trials). Individuals with ASD exhibited reduced ability to inhibit saccades, reduced reaction time slowing (GO RT slowing), and faster stop-signal reaction times (SSRT) compared to controls. Across participants, stopping accuracy was positively related to GO RT slowing, and increased age was associated with higher stopping accuracy and GO RT slowing. Our results indicate that failures to proactively delay prepotent responses in ASD underpin deficits of inhibitory control and may contribute to difficulties modifying their behavior according to changes in contextual demands. These findings implicate frontostriatal brain networks in inhibitory control and core symptoms of ASD. LAY SUMMARY: Difficulties stopping actions are common in individuals with autism spectrum disorder (ASD) and are related to repetitive behaviors. This study compared the ability to stop eye movements in individuals with ASD and healthy peers. We found that individuals with ASD were less able to stop eye movements and that this difficulty was related to a reduced ability to delay their eye movements before seeing the cue to stop, not their ability to react quickly to this cue.
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http://dx.doi.org/10.1002/aur.2415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878417PMC
February 2021

Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis.

PLoS One 2020 21;15(10):e0240584. Epub 2020 Oct 21.

Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Background: Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.

Methods: We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.

Results: Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.

Conclusions: Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.

Registration: PROSPERO no. CRD 42015026049.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577505PMC
December 2020

The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma.

Cancer Med 2020 11 9;9(21):8144-8158. Epub 2020 Oct 9.

Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra-Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma.

Methods: Two p53 wild-type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host.

Results: The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death.

Conclusion: This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.
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http://dx.doi.org/10.1002/cam4.3407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643634PMC
November 2020

Implementation and expansion of a preoperative COVID-19 testing process for pediatric surgical patients.

Paediatr Anaesth 2020 08;30(8):952-953

Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Hospital, The George Washington University, Washington, DC, USA.

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http://dx.doi.org/10.1111/pan.13963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537163PMC
August 2020

Association of HIV infection with clinical and laboratory characteristics of sickle cell disease.

BMC Infect Dis 2020 Aug 27;20(1):638. Epub 2020 Aug 27.

University of California, San Francisco (UCSF), San Francisco, CA, USA.

Background: Sickle cell disease (SCD) is a multisystem disorder characterized by a wide spectrum of clinical manifestations and severity. Studies investigating potential effects of co-morbid human immunodeficiency virus (HIV) and SCD have produced conflicting results, and additional investigations are needed to elucidate whether the interaction between the two disease states might impact both HIV and SCD clinical outcomes. The association of HIV infection with clinical and laboratory characteristics of patients with SCD was assessed.

Methods: This nested case-control study included individuals with SCD with HIV treated at six Brazilian SCD centers. Clinical and laboratory data were abstracted from medical records. HIV positive participants were compared to age, gender, center, and SCD genotype matched HIV negative participants (ratio 1:4). Individual clinical outcomes as well as a composite outcome of any SCD complication and a composite outcome of any HIV-related complication were compared between the two groups.

Results: Fifteen HIV positive participants were included, 12 (80%) alive and 3 (20%) deceased. Most of the HIV positive patients had HbSS (60%; n = 9), 53% (n = 8) were female, and mean age was 30 ± 13 years. The frequency of individual SCD complications of acute chest syndrome/pneumonia, sepsis/bacteremia, pyelonephritis, ischemic stroke, hemorrhagic stroke, abnormal transcranial Doppler (TCD), and pulmonary hypertension was higher in HIV positive participants when compared to HIV negative, although analyzed individually none were statistically significant. HIV positive participants had significantly higher risk of any SCD complication and of a composite HIV-related complication compared to the HIV negative group (HR = 4.6; 95%CI 1.1-19.6; P = 0.04 and HR = 7.7; 95%CI 1.5-40.2; P = 0.02, respectively). There was a non-significant trend towards higher risk of any infections in participants with HIV positive (HR = 3.5; 95%CI 0.92-13.4; P = 0.07). Laboratory parameters levels were not significantly different in individuals with and without HIV.

Conclusions: In summary, our study in SCD patients shows that those with HIV have an increased risk of any SCD complication and HIV-related complications, as well as a suggestive but not significantly increased risk of infections.
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http://dx.doi.org/10.1186/s12879-020-05366-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457248PMC
August 2020

Automated exchange compared to manual and simple blood transfusion attenuates rise in ferritin level after 1 year of regular blood transfusion therapy in chronically transfused children with sickle cell disease.

Transfusion 2020 11 19;60(11):2508-2516. Epub 2020 Aug 19.

Department of Pediatrics, Division of Hematology/Oncology, Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Background: Optimal strategies for regular blood transfusion therapy are not well defined in sickle cell disease (SCD). This analysis tested the hypothesis that in the first of year of regular transfusions, when chelation therapy use is minimal, automated exchange transfusion would be the superior method for attenuating the rise in ferritin levels compared to simple and manual exchange transfusions.

Study Design And Methods: The Silent Cerebral Infarct Multi-Center Clinical Trial randomly allocated children with SCD and silent cerebral infarcts to receive standard care or regular transfusions with a target pre-transfusion HbS concentration ≤ 30% and minimum hemoglobin level > 9.0 g/dL. Participants with at least nine transfusions and sufficient ferritin testing in the first year of the trial were included in a planned secondary analysis. Ferritin levels by the end of the first study year were compared between participants receiving automatic exchange transfusion, manual exchange transfusion, and simple transfusion.

Results: A total of 83 participants were analyzed. During the first year of the study, 75.9% of the participants had >80% of transfusions via one transfusion method. At baseline no significant differences in ferritin levels were observed in the three transfusion groups (p = 0.1). After 1 year of transfusions the median (interquartile range) ferritin levels in the simple transfusion (n = 40), manual exchange transfusion (n = 34) and automatic exchange transfusion (n = 9) groups were 1800 ng/mL (1426-2204 ng/mL), 1530 ng/mL (1205-1805 ng/mL), and 355 ng/mL (179-579 ng/mL), respectively (p < 0.001).

Conclusion: Automated exchange transfusion, when compared to other transfusion methods, is the optimal transfusion strategy for attenuating increase in ferritin levels in children with SCD.
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http://dx.doi.org/10.1111/trf.15982DOI Listing
November 2020

Rapid review methods more challenging during COVID-19: commentary with a focus on 8 knowledge synthesis steps.

J Clin Epidemiol 2020 10 29;126:177-183. Epub 2020 Jun 29.

Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, 209 Victoria Street, East Building, Toronto, Ontario M5B 1T8, Canada; Department of Geriatric Medicine, University of Toronto, 27 King's College Circle, Toronto, Ontario M5S 1A1, Canada.

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http://dx.doi.org/10.1016/j.jclinepi.2020.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836683PMC
October 2020

Virtual follow-up and care for patients with cardiac electronic implantable devices: protocol for a systematic review.

Syst Rev 2020 06 27;9(1):153. Epub 2020 Jun 27.

School of Epidemiology and Public Health, University of Ottawa, 101 - 600 Peter Morand Crescent, Ottawa, Ontario, K1G 5Z3, Canada.

Background: Capacity to deliver outpatient care for patients with cardiac implantable electronic devices (CIEDs) may soon be outweighed by need. This systematic review aims to investigate the comparative effectiveness, safety, and cost for virtual or remote clinic interventions for patients with CIEDs and explores how outcomes may be influenced by patient or system factors in-depth.

Methods: We will perform a systematic literature search in MEDLINE, Embase, PsycINFO, CINAHL, Proquest Dissertations & Theses, other EBM Reviews, and trial registry databases. Two authors will independently screen titles and abstracts for eligibility. We will include randomized and non-randomized controlled trials, quasi-randomized and experimental studies, cohort, and case-control studies. Study populations of interest are individuals with a CIED (pacemaker, ICD, CRT). Eligibility will be restricted to virtual or remote follow-up or care interventions compared to any other approach. The co-primary outcomes of interest are mortality and patient satisfaction. Secondary outcomes include clinical effectiveness (e.g., ICD shock, time-to-detection of medical event, hospitalizations), safety (e.g., serious or device-related adverse events), device efficacy (e.g., transmissions, malfunctions), costs, workflow (e.g., resources, process outcomes, time-saved), and patient reported (e.g., burden, quality of life). Data will be extracted by one author and checked by a second using a standardized template. We will use published frameworks to capture data relevant to intervention effects that may be influenced by intervention definition or complexity, context and setting, or in socially disadvantaged populations. Detailed descriptive results will be presented for all included studies and outcomes, and where feasible, synthesized using meta-analysis. Risk of bias will be assessed by two review authors independently using Cochrane Risk of Bias tools. Certainty of evidence will be assessed using the GRADE approach.

Discussion: Increases in number of CIEDs implanted, combined with an aging population and finite health resource allocations at the system-level may lead to increased reliance on virtual follow-up or care models in the future. These models must prioritize consistent, equitable, and timely care as a priority. Results from this systematic review will provide important insight into the potential contextual factors which moderate or mediate the effectiveness, safety, and cost of virtual follow-up or care models for patients.

Systematic Review Registration: PROSPERO registration number CRD42020145210.
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http://dx.doi.org/10.1186/s13643-020-01406-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321546PMC
June 2020

Patient and healthcare provider reported barriers and enablers to virtual or remote-only follow-up models for cardiovascular implantable electronic devices: protocol for a qualitative framework synthesis.

Syst Rev 2020 06 24;9(1):151. Epub 2020 Jun 24.

School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Background: Virtual care models are used to follow-up patients with cardiovascular implantable electronic devices (CIED), including pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapy. There is increasing interest in the expansion of virtual, or even remote-only, CIED care models to alleviate resource and economic burden to both patients and specialty device clinics and to maintain or improve equity and access to high-quality cardiovascular care. This qualitative framework synthesis aims to identify barriers and enablers to virtual care models from both the perspective of the patient and device clinics. How setting, context, equity factors or other aspects influence these factors, or satisfaction with care, will also be investigated.

Methods: We will perform a systematic literature search in MEDLINE, Embase, PsycINFO, CINAHL, Proquest Dissertations & Theses, other EBM Reviews, and trial registry databases. Screening will be completed by two independent review authors. Original research articles having a qualitative component (i.e., qualitative, mixed-, or multi-method) are eligible. Study populations of interest are (a) individuals with a CIED or (b) healthcare providers involved in any aspect of virtual or remote follow-up of patients with CIEDs. Eligibility will be restricted to studies published after January 1, 2000 in English or French. Data will be captured using standardized templates based on the domains and constructs of the Theoretical Domains Framework and the Warwick Patient Experiences Framework. The Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research will be applied to all included studies. The GRADE-CERQual approach will be applied to assess and summarize confidence in key findings. Reporting will follow the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) statement. Detailed descriptive results will be presented, and summary of qualitative findings tables will be produced.

Discussion: While a number of trials have captured the clinical effectiveness and safety of virtual follow-up for CIEDs, there has been less attention given to factors affecting use and implementation of remote care by patients and healthcare providers or satisfaction with care. Results from this qualitative framework synthesis will provide important lived experience data from both patients and healthcare providers which will be essential to incorporate in clinical guidelines.

Systematic Review Registration: PROSPERO CRD42020160533.
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http://dx.doi.org/10.1186/s13643-020-01410-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315548PMC
June 2020

Blood utilization and characteristics of patients treated with chronic transfusion therapy in a large cohort of Brazilian patients with sickle cell disease.

Transfusion 2020 08 24;60(8):1713-1722. Epub 2020 Jun 24.

Fundação Hemominas/Minas Gerais Hemocenter, Minas Gerais, Brazil.

Background: Red blood cell (RBC) transfusions are used in sickle cell disease (SCD) to treat acute complications or as chronic transfusion therapy (CTT) to prevent severe manifestations. The objectives of this study were to describe blood utilization and adverse events (AEs) associated with RBCs in the Brazilian SCD population and compare characteristics of patients treated or not with CTT.

Study Design And Methods: A SCD cohort was established at six Brazilian centers. Medical and blood bank records were abstracted for clinical and transfusion history. Two controls not treated with CTT matched on center, SCD genotype, sex, and age were selected for each CTT case within the cohort to compare characteristics between the two groups.

Results: Most of the 2794-member cohort had received a transfusion (75.0% of children and 89.2% of adults) with 29.2% of patients receiving transfusion in the prior year. There were 170 (10.6%) children and 115 (9.2%) adults treated with CTT. Children not treated with CTT were more likely to have pain and acute chest hospitalizations in the prior year (25.3% vs. 11.9%, p = 0.0003; and 22.0% vs. 10.7%, p = 0.002, respectively). Both iron overload and alloimmunization were more common in CTT cases compared to controls (65.6% vs. 17.0% and 36.2% vs. 15.9%, respectively). A higher proportion of adults treated with CTT demonstrated oxygen saturation of greater than 95% compared to controls not treated (51.1% vs. 39.2%), while there was no difference in oxygenation between children treated or not. Of 4501 transfusion episodes, 28 (0.62%) AEs were reported. There was no difference in AEs associated with transfusions for acute indications versus CTT.

Conclusion: Red blood cell transfusion was common in Brazilian SCD patients, with utilization driven by CTT. Transfusion reactions were not common; however, alloimmunization and iron overload were frequent among those on CTT, highlighting the need for novel clinical strategies to mitigate these risks.
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http://dx.doi.org/10.1111/trf.15818DOI Listing
August 2020

A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies.

Neuropsychopharmacology 2020 08 6;45(9):1463-1472. Epub 2020 May 6.

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.

A large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus. Thus, delineating neural control of behavior requires a dissociation between stimulus valence and stimulus-driven behavior. We developed the Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence in mice. First, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. Next, discriminative stimuli are presented concurrently allowing for parsing innate behavioral strategies based on reward seeking and avoidance. Lastly, responding in the face of punishment is assessed, thus examining  how positive and negative outcomes are relatively valued. First, we identified sex-specific behavioral strategies, showing that females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. Next, we show that chemogenetically inhibiting D1 medium spiny neurons (MSNs) in the nucleus accumbens-a population that has been linked to reward-driven behavior-reduces positive and increases negative reinforcement learning rates. Thus, D1 MSNs modulate stimulus processing, rather than motivated responses or the reinforcement process itself. Together, the MCOAT has broad utility for understanding complex behaviors as well as the definition of the discrete information encoded within cellular populations.
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http://dx.doi.org/10.1038/s41386-020-0692-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360782PMC
August 2020

Influence of sickle cell disease on susceptibility to HIV infection.

PLoS One 2020 8;15(4):e0218880. Epub 2020 Apr 8.

Vitalant Research Institute, San Francisco, CA, United States of America.

People with sickle cell disease (SCD) are reported to have low rates of HIV infection, slower progression to AIDS and lower HIV-associated mortality compared to the general population. Mechanisms of potential resistance to HIV in SCD are incompletely understood. We retrospectively reviewed the Transfusion Safety Study to compare HIV status between people with SCD and other congenital anemias who were routinely exposed to blood products during the high-risk period before HIV screening implementation. Non-SCD congenital anemia diagnosis was associated with a higher risk of HIV acquisition compared to SCD (OR 13.1 95%CI 1.6-108.9). In addition, we prospectively enrolled 30 SCD cases and 30 non-SCD controls to investigate potential mechanisms of resistance to HIV in SCD. CCR5 and CCR7 expression was lower and CD4 expression was higher on CD4+ T cells from SCD cases compared to controls. Surface expression of CD4+ T cell CXCR4, CD38 and HLA-DR did not differ between the groups. SCD CD4+ T cells were not less susceptible to HIV infection than controls. Levels of multiple cytokines were elevated in the SCD plasma, but SCD plasma compared to control plasma did not inhibit HIV infection of target cells. In conclusion, our epidemiological data support people with SCD being resistant to HIV infection. Potential mechanisms include lower CD4+ T cell expression of CCR5 and CCR7, balanced by increased CD4 expression and cytokine levels, which did not result in in vitro resistance to HIV infection. Further study is needed to define the risk and pathophysiology of HIV in persons with SCD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218880PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141606PMC
July 2020

Hb S/-Thalassemia in the REDS-III Brazil Sickle Cell Disease Cohort: Clinical, Laboratory and Molecular Characteristics.

Hemoglobin 2020 Jan 16;44(1):1-9. Epub 2020 Mar 16.

Vitalant Research Institute, San Francisco, CA, USA.

We described the clinical, laboratory and molecular characteristics of individuals with Hb S (: c.20A>T)/β-thalassemia (Hb S/β-thal) participating in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) Brazil Sickle Cell Disease cohort. gene sequencing was performed to genotype each β-thal mutation. Patients were classified as Hb S/β-thal, Hb S/β-thal-severe or Hb S/β-thal based on prior literature and databases of hemoglobin (Hb) variants. Characteristics of patients with each β-thal mutation were described and the clinical profile of patients grouped into Hb S/β-thal, Hb S/β-thal and Hb S/β-thal-severe were compared. Of the 2793 patients enrolled, 84 (3.0%) had Hb S/β-thal and 83 (3.0%) had Hb S/β-thal; 40/83 (48.2%) patients with Hb S/β-thal had mutations defined as severe. We identified 19 different β-thal mutations, eight Hb S/β-thal, three Hb S/β-thal-severe and eight Hb S/β-thal. The most frequent β and β mutations were codon 39 (: c.118C>T) and IVS-I-6 (T>C) (: c.92+6T>C), respectively. Individuals with Hb S/β-thal had a similar clinical and laboratory phenotype when compared to those with Hb S/β-thal-severe. Individuals with Hb S/β-thal-severe had significantly lower total Hb and Hb A levels and higher Hb S, white blood cell (WBC) count, platelets and hemolysis markers when compared to those with Hb S/β-thal. Likewise, individuals with Hb S/β-thal-severe showed a significantly higher occurrence of hospitalizations, vaso-occlusive events (VOE), acute chest syndrome (ACS), splenic sequestration, blood utilization, and hydroxyurea (HU) therapy.
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http://dx.doi.org/10.1080/03630269.2020.1731530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225056PMC
January 2020

ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

PLoS One 2020 19;15(2):e0229179. Epub 2020 Feb 19.

Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Canada.

Background: We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC).

Methods: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046.

Results: Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39-0.54]; ceritinib 0.52 [0.42-0.64]; alectinib 300 BID 0.16 [0.08-0.33]; alectinib 600 BID 0.23 [0.17-0.30]; brigatinib 0.23 [0.15-0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17-0.70]; alectinib v. ceritinib 0.30 [0.14-0.64]; brigatinib v. crizotinib 0.49 [0.33-0.73]; brigatinib v. ceritinib 0.43 [0.27-0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39-0.83]) and crizotinib (0.68 [0.48-0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56-2.79]) and alectinib (1.60 [1.00-2.58]) but not ceritinib (1.25 [0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants.

Conclusion(s): Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229179PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029857PMC
May 2020

Use of an automated pyrosequencing technique for confirmation of sickle cell disease.

PLoS One 2019 12;14(12):e0216020. Epub 2019 Dec 12.

Instituto de Medicina Tropical de São Paulo, Laboratório de Parasitologia, LIM 46, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil.

Background: The diagnosis of sickle cell disease (SCD) is made by hemoglobin assays such as high-performance liquid chromatography (HPLC), isoelectric focusing and cellulose acetate or citrate agar electrophoresis. These assays are easy to perform and used in large-scale newborn screening in many countries. These tests however may not easily differentiate Sβ0 thalassemia from SS or identify other hemoglobin variants, and in this case, hemoglobin (HBB) gene sequencing may be necessary.

Objectives: To develop a high throughput DNA based confirmatory assay for SCD and to detect mutations in the HBB gene.

Methods: We developed an automated pyrosequencing technique (PyS) based on QIAGEN technology (Hilden, Germany) to detect homozygous or heterozygous hemoglobin S mutations as well as hemoglobin C mutations. The technique was tested on 2,748 samples from patients enrolled in a multi-center SCD cohort in Brazil. Patients were previously tested using HPLC to diagnose SCD as part of routine clinical care. Any subjects with discrepant results between HPLC and PyS or with heterozygous hemoglobin S detected had Sanger sequencing of the HBB gene.

Results: We identified 168 samples with discrepant results between HPLC and PyS and 100 with concordant PyS = heterozygous S and HPLC, which would suggest SB-thalassemia or other heterozygous S variants. The PyS assay correctly identified 1906 (98.7%) of the 1930 HbSS and 628 (98.7%) of the 636 HbSC samples. Of the 179 remaining samples, PyS correctly indicated S heterozygosis in 165 (92.2%). Of the 165 heterozygous S samples confirmed by Sanger as consistent with Sβ thalassemia genotype, 84 samples were classified as Sβ0 thalassemia and 81 as Sβ+ thalassemia. The most frequent beta thalassemia mutations of Sβ0 and Sβ+ were HBB: c.118C>T (Gln40Stop) and HBB c.92 + 6T> C, respectively.

Discussion: The PyS proved to be satisfactory for large-scale confirmatory testing of hemoglobin mutation. Moreover, with this study we were able to describe the most common β+ and β0 mutations in SCD patients with Sβ-thalassemia in a large multi-institutional SCD cohort in Brazil.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216020PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907837PMC
March 2020

Prevalence of serologic markers of transfusion and sexually transmitted infections and their correlation with clinical features in a large cohort of Brazilian patients with sickle cell disease.

Transfusion 2020 02 5;60(2):343-350. Epub 2019 Dec 5.

Vitalant Research Institute, San Francisco, California.

Background: Patients with sickle cell disease (SCD) often require red blood cell (RBC) transfusion for clinical complications, so may be exposed to transfusion-transmitted infections (TTIs). The prevalence of markers for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and B (HBV), human T-cell lymphotropic virus (HTLV-1/2), Chagas disease, and syphilis in an SCD cohort in Brazil were studied.

Study Design And Methods: Clinical history, interview data, blood samples, and medical chart review data were collected during cohort enrollment from November 2013 to May 2015. Serologic markers of infection were assessed. Standard measures of statistical association were calculated, and multivariable models were developed for the most prevalent infections to identify associated factors.

Results: Infection markers were evident in 5.2% (144/2779) of the enrolled cohort. Anti-HCV was detected in 69 (2.5%), syphilis antibodies in 34 (1.2%), anti-HTLV-1/2 in 17 (0.6%), HBV surface antigen in 13 (0.5%), Chagas disease antibodies in 13 (0.5%), and anti-HIV in 8 (0.3%) of participants. Factors associated with increased odds of being anti-HCV reactive were older age, illegal drug use, increasing number of RBCs, more than three pain crises in the previous year, and geographic location. Syphilis was associated with older age, females, and smoking history.

Conclusion: HCV infection was more common in older patients who may have received RBCs before testing was performed on donations, suggesting possible historic transfusion transmission. The cohort showed decreasing rates of infections and a reduction in transfusion transmission markers in younger patients compared to historical literature except for syphilis, indicating contemporary reduced risk of TTI.
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http://dx.doi.org/10.1111/trf.15619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010912PMC
February 2020

Nanoscale delivery systems in treatment of posterior ocular neovascularization: strategies and potential applications.

Ther Deliv 2019 11 13;10(11):737-747. Epub 2019 Nov 13.

Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, 12901 Bruce B Downs Blvd, MDC 30, Tampa, FL 33612-4749, USA.

Pathologic posterior neovascularization of eye is a major cause of irreversible vision loss and limitations of therapeutics to be successfully delivered to back of the eye has been a main obstacle for its effective treatment. Current pharmacological treatment using anti-VEGF agents being delivered intravitreally are effective but complicated due to anatomical and physiological barriers, as well as administration of high and frequent doses. With expanding horizons of nanotechnology, it can be possible to formulate promising nanoscale delivery system to improve penetration and sustained the release of therapeutic in posterior segment of the eye. Taking into consideration advances in the field of nanoscale delivery systems, this special report focuses on emerging strategies and their applications for treatment of posterior ocular neovascularization.
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http://dx.doi.org/10.4155/tde-2019-0025DOI Listing
November 2019

Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study.

J Sex Med 2019 12 24;16(12):1988-1999. Epub 2019 Oct 24.

University of São Paulo, São Paulo, Brazil.

Introduction: Priapism is the persistent and painful erection of the penis and is a common sickle cell disease (SCD) complication.

Aim: The goal of this study was to characterize clinical and genetic factors associated with priapism within a large multi-center SCD cohort in Brazil.

Methods: Cases with priapism were compared to SCD type-matched controls within defined age strata to identify clinical outcomes associated with priapism. Whole blood single nucleotide polymorphism genotyping was performed using a customized array, and a genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms associated with priapism.

Main Outcome Measure: Of the 1,314 male patients in the cohort, 188 experienced priapism (14.3%).

Results: Priapism was more common among older patients (P = .006) and more severe SCD genotypes such as homozygous SS (P < .0001). In the genotype- and age-matched analyses, associations with priapism were found for pulmonary hypertension (P = .05) and avascular necrosis (P = .01). The GWAS suggested replication of a previously reported candidate gene association of priapism for the gene transforming growth factor beta receptor 3 (TGFBR3) (P = 2 × 10).

Clinical Implications: Older patients with more severe genotypes are at higher risk of priapism, and there is a lack of consensus on standard treatment strategies for priapism in SCD.

Strengths & Limitations: This study characterizes SCD patients with any history of priapism from a large multi-center cohort. Replication of the GWAS in an independent cohort is required to validate the results.

Conclusion: These findings extend the understanding of risk factors associated with priapism in SCD and identify genetic markers to be investigated in future studies to further elucidate priapism pathophysiology. Ozahata M, Page GP, Guo Y, et al. Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study. J Sex Med 2019;16:1988-1999.
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http://dx.doi.org/10.1016/j.jsxm.2019.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904926PMC
December 2019

Precision Sensorimotor Control in Aging FMR1 Gene Premutation Carriers.

Front Integr Neurosci 2019 2;13:56. Epub 2019 Oct 2.

Clinical Child Psychology Program, Life Span Institute and Kansas Center for Autism Research and Training (K-CART), University of Kansas, Lawrence, KS, United States.

Background: Individuals with premutation alleles of the gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition affecting sensorimotor function. Information on quantitative symptom traits associated with aging in premutation carriers is needed to clarify neurodegenerative processes contributing to FXTAS.

Materials And Methods: 26 premutation carriers ages 44-77 years and 31 age-matched healthy controls completed rapid (2 s) and sustained (8 s) visually guided precision gripping tasks. Individuals pressed at multiple force levels to determine the impact of increasing the difficulty of sensorimotor actions on precision behavior. During initial pressing, reaction time, the rate at which individuals increased their force, the duration of pressing, and force accuracy were measured. During sustained gripping, the complexity of the force time series, force variability, and mean force were examined. During relaxation, the rate at which individuals decreased their force was measured. We also examined the relationships between visuomotor behavior and cytosine-guanine-guanine (CGG) repeat length and clinically rated FXTAS symptoms.

Results: Relative to controls, premutation carriers showed reduced rates of initial force generation during rapid motor actions and longer durations of their initial pressing with their dominant hand. During sustained force, premutation carriers demonstrated reduced force complexity, though this effect was specific to younger premutation carries during dominant hand pressing and was more severe for younger relative to older premutation carriers at low and medium force levels. Increased reaction time and lower sustained force complexity each were associated with greater CGG repeat length for premutation carriers. Increased reaction time and increased sustained force variability were associated with more severe clinically rated FXTAS symptoms.

Conclusion: Overall our findings suggest multiple sensorimotor processes are disrupted in aging premutation carriers, including initial force control guided by feedforward mechanisms and sustained sensorimotor behaviors guided by sensory feedback control processes. Results indicating that sensorimotor issues in aging premutation carriers relate to both greater CGG repeat length and clinically rated FXTAS symptoms suggest that quantitative tests of precision sensorimotor ability may serve as key targets for monitoring FXTAS risk and progression.
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http://dx.doi.org/10.3389/fnint.2019.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783559PMC
October 2019

Quality of life in pre-adolescent children with sickle cell disease in Brazil.

Pediatr Hematol Oncol 2019 Nov 6;36(8):457-467. Epub 2019 Sep 6.

Vitalant Research Institute, San Francisco, CA, USA.

Sickle cell disease (SCD) affects more than 13 million people and can have a significant impact on the quality of life (QoL) of those persons. We performed a cross-sectional study to evaluate the QoL in SCD children 8-12 years old enrolled from November 2014 to March 2016 in a large multicenter cohort study in Brazil. The PedsQL™ SCD Module was used to evaluate QoL in 412 children from six Brazilian health centers. The mean age of participants was 10.5 years and 193(46.7%) were women. The mean global score was 60.7, with a Cronbach´s alpha of 0.92. There were significant differences in socioeconomic demographics and treatments among participants at the six centers, but age, income, SCD genotype, and use of hydroxyurea did not significantly affect the QoL scores. After adjustment for all of these variables in a linear regression model, a significant difference was observed by site in global QoL score and the dimensions 'worry II'(β0 = 20.7,  < .00), 'treatment´(β0 = 66.8,  < .00) and communication II'(β0 = 45.8,  < .00). These dimensions are affected by the capacity of health professionals to provide clinical and psychological support to patients. Our results suggest that QoL of this patient population varied according the health center even adjusted by sociodemographics characteristics. Additional training of health professionals in psychological and clinical support could directly reduce patient apprehension about the disease its clinical complications.
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http://dx.doi.org/10.1080/08880018.2019.1660743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872937PMC
November 2019