Publications by authors named "Mark Murphy"

195 Publications

Comparison of Percutaneous Image-Guided Microwave and Cryoablation for Sarcoma Lung Metastases: 10-Year Experience.

AJR Am J Roentgenol 2021 Oct 6. Epub 2021 Oct 6.

Department of Radiology, Massachusetts General Hospital, Boston, USA.

Outcomes between percutaneous microwave (MWA) and cryoablation of sarcoma lung metastases have not been compared to our knowledge. To compare technical success, complications, local tumor control, and overall survival (OS) following MWA versus cryoablation of sarcoma lung metastases. This retrospective cohort study included 27 patients (16 women, 11 men; median age 64 years; Eastern Cooperative Oncology Group performance score 0-2) who underwent 39 percutaneous CT-guided ablation sessions (21 MWA, 18 cryoablation; 1-4 sessions per patient) to treat 65 sarcoma lung metastases (median 1 tumor per patient, range 1-12; median tumor diameter 11 mm, range 5-33 mm; 25% non-peripheral) from 2009 to 2021. We compared complications by ablation modality using generalized-estimating equations. We evaluated ablation modality, tumor size, and location (peripheral vs non-peripheral) in relation to local tumor progression using proportional Cox hazard models with death as competing risk. We estimated OS using the Kaplan-Meier method. Primary technical success was 97% for both modalities. Median follow-up was 23 months (range: 1-102 months; interquartile range: 12, 44 months). A total of 7/61 (12%) tumors progressed. Estimated 1-year and 2-year local control rates were, for tumors >1 cm, 97% and 95% following MWA versus 99% and 98% following cryoablation, and for tumors ≤1 cm, 74% and 62% following MWA versus 86% and 79% following cryoablation. Tumor size ≤1 cm was associated with decreased cumulative incidence of local progression (p =.048); ablation modality and tumor location were not associated with progression (p =.86; p =.54). Complications (CTCAE grade ≤3) occurred in 17/39 sessions (44%), prompting chest tube placement in nine (23%). No complications with grade ≥4 occurred. OS at 1-, 2-, and 3-years was 100%, 89%, and 82%, respectively. High primary technical success, local control, and OS support MWA and cryoablation for treating sarcoma lung metastases. Ablation modality and tumor location did not affect local progression. Treatment failure was low, especially for small tumors. No life-threatening complications occurred. Percutaneous MWA and cryoablation are both suited for treatment of sarcoma lung metastases, especially for tumors ≤1 cm, whether peripheral or non-peripheral. Complications, if they occur, are not life-threatening.
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http://dx.doi.org/10.2214/AJR.21.26551DOI Listing
October 2021

Building a bridge between patients and transplant healthcare professionals - a descriptive study.

Transpl Int 2021 Sep 15. Epub 2021 Sep 15.

Donation and Transplant Coordination Unit, Associate Professor Surgical Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.

This article describes a pathway for collaboration between transplant healthcare professionals and organ recipients. Under the umbrella of the European Society for Organ Transplantation (ESOT) a joint initiative started from three Sections and Committees of ESOT: EDTCO (European Donation and Transplant Coordination Organisation), ETHAP (European Transplant Allied Healthcare Professionals) and ELPAT (Ethical, Legal and Psycho-social Aspects of Transplantation). The formal 'kick-off' of the Advisory Board Meeting of the European Transplant Patient Organisation (ETPO) was during the ESOT congress in 2019. The aim was to produce a series of statements to serve as a path to dialogue between patients and transplant professionals and to define the next steps towards giving a voice to the patient network. To include the patients' perspectives, two surveys have been performed. The results identified the unmet needs and lead to a proposal for future plans. Educational activities have since started leading to a patient learning workstream. All initiatives taken have one purpose: to include patients, give them a voice and build a foundation for collaboration between patients and transplant professionals. ESOT has created a platform for mutual understanding, learning and a collaborative partnership between ETPO and European donation and transplant professionals.
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http://dx.doi.org/10.1111/tri.14111DOI Listing
September 2021

DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis.

Sex Dev 2021 Sep 1:1-14. Epub 2021 Sep 1.

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.

Transcriptional regulators related to the invertebrate sexual regulators doublesex and mab-3 occur throughout metazoans and control sex in most animal groups. Seven of these DMRT genes are found in mammals, and mouse genetics has shown that one, Dmrt1, plays a crucial role in testis differentiation, both in germ cells and somatic cells. Deletions and, more recently, point mutations affecting human DMRT1 have demonstrated that its heterozygosity is associated with 46,XY complete gonadal dysgenesis. Most of our detailed knowledge of DMRT1 function in the testis, the focus of this review, derives from mouse studies, which have revealed that DMRT1 is essential for male somatic and germ cell differentiation and maintenance of male somatic cell fate after differentiation. Moreover, ectopic DMRT1 can reprogram differentiated female granulosa cells into male Sertoli-like cells. The ability of DMRT1 to control sexual cell fate likely derives from at least 3 properties. First, DMRT1 functionally collaborates with another key male sex regulator, SOX9, and possibly other proteins to maintain and reprogram sexual cell fate. Second, and related, DMRT1 appears to function as a pioneer transcription factor, binding "closed" inaccessible chromatin and promoting its opening to allow binding by other regulators including SOX9. Third, DMRT1 binds DNA by a highly unusual form of interaction and can bind with different stoichiometries.
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http://dx.doi.org/10.1159/000518272DOI Listing
September 2021

Alpha-1 Antitrypsin Augmentation Inhibits Proteolysis of Neutrophil Membrane Voltage-Gated Proton Channel-1 in Alpha-1 Deficient Individuals.

Medicina (Kaunas) 2021 Aug 10;57(8). Epub 2021 Aug 10.

Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, D02 YN77 Dublin, Ireland.

: Alpha-1 antitrypsin is a serine protease inhibitor that demonstrates an array of immunomodulatory functions. Individuals with the genetic condition of alpha-1 antitrypsin deficiency (AATD) are at increased risk of early onset emphysematous lung disease. This lung disease is partly driven by neutrophil mediated lung destruction in an environment of low AAT. As peripheral neutrophil hyper-responsiveness in AATD leads to excessive degranulation and increased migration to the airways, we examined the expression of the membrane voltage-gated proton channel-1 (HVCN1), which is integrally linked to neutrophil function. The objectives of this study were to evaluate altered HVCN1 in AATD neutrophils, serine protease-dependent degradation of HVCN1, and to investigate the ability of serum AAT to control HVCN1 expression. : Circulating neutrophils were purified from AATD patients ( = 20), AATD patients receiving AAT augmentation therapy ( = 3) and healthy controls ( = 20). HVCN1 neutrophil expression was assessed by flow cytometry and Western blot analysis. Neutrophil membrane bound elastase was measured by fluorescence resonance energy transfer. : In this study we demonstrated that HVCN1 protein is under-expressed in AATD neutrophils ( = 0.02), suggesting a link between reduced HVCN1 expression and AAT deficiency. We have demonstrated that HVCN1 undergoes significant proteolytic degradation in activated neutrophils ( < 0.0001), primarily due to neutrophil elastase activity ( = 0.0004). In addition, the treatment of AATD individuals with AAT augmentation therapy increased neutrophil plasma membrane HVCN1 expression ( = 0.01). : Our results demonstrate reduced levels of HVCN1 in peripheral blood neutrophils that may influence the neutrophil-dominated immune response in the AATD airways and highlights the role of antiprotease treatment and specifically AAT augmentation therapy in protecting neutrophil membrane expression of HVCN1.
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http://dx.doi.org/10.3390/medicina57080814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398194PMC
August 2021

Predicting Oral Beta-lactam susceptibilities against Streptococcus pneumoniae.

BMC Infect Dis 2021 Jul 13;21(1):679. Epub 2021 Jul 13.

Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background: Oral beta-lactam antimicrobials are not routinely tested against Streptococcus pneumoniae due to presumed susceptibility based upon penicillin minimum inhibitory concentration (MIC) testing. Currently, Clinical and Laboratory Standards Institute provides comments to use penicillin MIC ≤0.06 to predict oral cephalosporin susceptibility. However, no guidance is provided when cefotaxime MIC is known, leading to uncertainty with interpretation. The purpose of this study was to evaluate cefotaxime and penicillin MICs and their respective correlation to oral beta-lactam categorical susceptibility patterns.

Methods: 249 S. pneumoniae isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF) and then tested by broth microdilution method to penicillin, cefotaxime, amoxicillin, cefdinir, cefpodoxime, and cefuroxime.

Results: Using Clinical and Laboratory Standards Institute (CLSI) non-meningitis breakpoints for cefotaxime, 240/249 isolates were classified as susceptible. Of the cefotaxime susceptible isolates, 23% of the isolates are misrepresented as cefdinir susceptible. Amoxicillin correlated well with penicillin MIC breakpoints with only 1 discordant isolate out of 249.

Conclusion: The correlation between amoxicillin and penicillin creates a very reliable predictor to determine categorical susceptibility. However oral cephalosporins were not well predicted by either penicillin or cefotaxime leading to the possible risk of treatment failures. Caution should be used when transitioning to oral cephalosporins in cefotaxime susceptible isolates, especially with higher cefotaxime MICs.
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http://dx.doi.org/10.1186/s12879-021-06341-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278757PMC
July 2021

Receipt of medications for opioid use disorder among youth engaged in primary care: data from 6 health systems.

Addict Sci Clin Pract 2021 07 7;16(1):46. Epub 2021 Jul 7.

Kaiser Permanente Washington Health Research Institute, Seattle, USA.

Purpose: Little is known about prevalence and treatment of OUD among youth engaged in primary care (PC). Medications are the recommended treatment of opioid use disorder (OUD) for adolescents and young adults (youth). This study describes the prevalence of OUD, the prevalence of medication treatment for OUD, and patient characteristics associated with OUD treatment among youth engaged in PC.

Methods: This cross-sectional study includes youth aged 16-25 years engaged in PC. Eligible patients had ≥ 1 PC visit during fiscal years (FY) 2014-2016 in one of 6 health systems across 6 states. Data from electronic health records and insurance claims were used to identify OUD diagnoses, office-based OUD medication treatment, and patient demographic and clinical characteristics in the FY of the first PC visit during the study period. Descriptive analyses were conducted in all youth, and stratified by age (16-17, 18-21, 22-25 years).

Results: Among 303,262 eligible youth, 2131 (0.7%) had a documented OUD diagnosis. The prevalence of OUD increased by ascending age groups. About half of youth with OUD had documented depression or anxiety and one third had co-occurring substance use disorders. Receipt of medication for OUD was lowest among youth 16-17 years old (14%) and highest among those aged 22-25 (39%).

Conclusions: In this study of youth engaged in 6 health systems across 6 states, there was low receipt of medication treatment, and high prevalence of other substance use disorders and mental health disorders. These findings indicate an urgent need to increase medication treatment for OUD and to integrate treatment for other substance use and mental health disorders.
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http://dx.doi.org/10.1186/s13722-021-00249-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262000PMC
July 2021

Precision dosing of vancomycin: in defence of AUC-guided therapy in children.

J Antimicrob Chemother 2021 Sep;76(10):2494-2497

The Center for Clinical Pharmacology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

In 2020, new vancomycin guidelines were released, recommending the transition from trough-based to AUC24 monitoring for adult and paediatric patients. Given the resources required to achieve this transition, there has been debate about the costs and benefits of AUC24-based monitoring. A recent narrative review of vancomycin therapeutic drug monitoring in paediatrics claims to have uncovered the methodological weaknesses of the data that informed the guidelines and advises against premature adoption of AUC24-guided monitoring. In this article, we present supporting arguments for AUC24-guided monitoring in children, which include that: (i) troughs alone are inadequate surrogates for AUC24; (ii) vancomycin-associated nephrotoxicity has significant consequences that warrant optimization of dosing; (iii) a substantial portion of children receiving vancomycin are at high risk for poor outcomes and deserve targeted monitoring; and (iv) limited efficacy data in support of AUC24 is not a justification to revert to a less supported monitoring approach.
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http://dx.doi.org/10.1093/jac/dkab194DOI Listing
September 2021

The conserved sex regulator DMRT1 recruits SOX9 in sexual cell fate reprogramming.

Nucleic Acids Res 2021 06;49(11):6144-6164

Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455 USA.

Mammalian sexual development commences when fetal bipotential progenitor cells adopt male Sertoli (in XY) or female granulosa (in XX) gonadal cell fates. Differentiation of these cells involves extensive divergence in chromatin state and gene expression, reflecting distinct roles in sexual differentiation and gametogenesis. Surprisingly, differentiated gonadal cell fates require active maintenance through postnatal life to prevent sexual transdifferentiation and female cell fate can be reprogrammed by ectopic expression of the sex regulator DMRT1. Here we examine how DMRT1 reprograms granulosa cells to Sertoli-like cells in vivo and in culture. We define postnatal sex-biased gene expression programs and identify three-dimensional chromatin contacts and differentially accessible chromatin regions (DARs) associated with differentially expressed genes. Using a conditional transgene we find DMRT1 only partially reprograms the ovarian transcriptome in the absence of SOX9 and its paralog SOX8, indicating that these factors functionally cooperate with DMRT1. ATAC-seq and ChIP-seq show that DMRT1 induces formation of many DARs that it binds with SOX9, and DMRT1 is required for binding of SOX9 at most of these. We suggest that DMRT1 can act as a pioneer factor to open chromatin and allow binding of SOX9, which then cooperates with DMRT1 to reprogram sexual cell fate.
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http://dx.doi.org/10.1093/nar/gkab448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216462PMC
June 2021

The bowel and beyond: extracolonic findings from CT colonography.

Ir J Med Sci 2021 Mar 24. Epub 2021 Mar 24.

Radiology Department, St. James's Hospital, James's Street, Dublin 8, Ireland.

CT colonography has emerged as the investigation of choice for suspected colorectal cancer in patients when a colonoscopy in incomplete, is deemed high risk or is declined because of patient preference. Unlike a traditional colonoscopy, it frequently reveals extracolonic as well as colonic findings. Our study aimed to determine the prevalence, characteristics and potential significance of extracolonic findings on CT colonography within our own institution. A retrospective review was performed of 502 patients who underwent CT colonography in our institution between January 1, 2010 and January 4, 2015. Of 502 patients, 60.63% had at least one extracolonic finding. This was close to other similar-sized studies (Kumar et al. Radiology 236(2):519-526, 2005). However, our rate of E4 findings was significantly higher than that reported in larger studies at 5.3%(Pooler et al. AJR 206:313-318, 2016). The difference may be explained by our combination of symptomatic/screening patients or by the age and gender distribution of our population. Our study lends support to the hypothesis that CT colonography may be particularly useful in identifying clinically significant extracolonic findings in symptomatic patients. CT colonography may allow early identification of extracolonic malignancies and life-threatening conditions such as an abdominal aortic aneurysm at a preclinical stage when they are amenable to medical or surgical intervention. However, extracolonic findings may also result in unnecessary investigations for subsequently benign findings.
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http://dx.doi.org/10.1007/s11845-021-02595-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988374PMC
March 2021

Increased incidence of acute calculous cholecystitis observed during COVID-19 social restrictions.

Ir J Med Sci 2021 Mar 11. Epub 2021 Mar 11.

Department of Radiology, Mater Misericordiae University Hospital, Eccles St., Dublin 7, Ireland.

Purpose: In response to the outbreak of COVID-19 in Ireland, the government implemented a nationwide stay-at-home order, with the closure of all non-essential businesses. During this period, there was a significant increase in supermarket expenditure. It has been shown that stress, anxiety and boredom are triggers for unhealthy eating habits. Fat consumption is a risk factor for both the development of gallstones and, additionally, the development of acute calculous cholecystitis. The aim of this study was to assess the incidence of acute calculous cholecystitis during the nationwide lockdown and compare it to the same period one year prior.

Methods: A retrospective review of all emergency abdominal imaging performed during the first 5 weeks of the lockdown was completed using the hospital PACS (picture archiving and communication system). All cases of acute calculous cholecystitis were identified and compared with the same period 1 year prior.

Results: Eighteen cases of acute calculous cholecystitis were identified from 24 March to 27 April 2020. Eleven cases were identified during the same period in 2019. This represented an increase of 63%. Non-COVID-19-related emergency presentations decreased during this period, and imaging of emergency presentations decreased by 24%. The rate of scans positive for acute cholecystitis more than doubled (p < 0.037).

Conclusion: A statistically significant increase in cases of acute calculous cholecystitis was observed during a nationwide lockdown during the COVID-19 pandemic. It is hypothesised that this is due to increased consumption of fatty foods during this period due to stress, anxiety and boredom.
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http://dx.doi.org/10.1007/s11845-021-02587-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950421PMC
March 2021

Patient-reported factors influencing the choice of their kidney replacement treatment modality.

Nephrol Dial Transplant 2021 Mar 2. Epub 2021 Mar 2.

ERA-EDTA Registry, Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Access to various kidney replacement therapy (KRT) modalities for patients with end-stage kidney disease differs substantially within Europe.

Methods: European adults on KRT filled out an online or paper-based survey about factors influencing and experiences with modality choice (e.g. information provision, decision-making, reasons for choice) between November 2017 and January 2019. We compared countries with low-, middle- and high-Gross Domestic Product (GDP).

Results: 7,820 patients (mean age 59 years, 56% male, 63% on centre haemodialysis [CHD]) from 38 countries participated. Twenty-five percent had received no information on the different modalities and only 23% received information more than 12 months before KRT initiation. Patients were not informed about home haemodialysis [HHD] (42%) and comprehensive conservative management (33%). Besides nephrologists, nurses more frequently provided information in high-GDP countries whereas other physicians than nephrologists did so in low-GDP countries. Patients from low-GDP countries reported later information provision, less information about other modalities than CHD and lower satisfaction with information. The majority of modality decisions were made involving both patient and nephrologist. Patients reported subjective (e.g. quality of life, fears) and objective reasons (e.g. costs, availability of treatments) for modality choice. Patients had good experiences with all modalities, but experiences were better for HHD and kidney transplantation, and in middle- and high-GDP countries.

Conclusion: Our results suggest European differences in patient-reported factors influencing KRT modality choice, possibly caused by disparities in availability of KRT modalities, different healthcare systems and varying patients' preferences. Availability of home dialysis and kidney transplantation should be optimized.
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http://dx.doi.org/10.1093/ndt/gfab059DOI Listing
March 2021

How many medications do doctors in primary care use? An observational study of the DU90% indicator in primary care in England.

BMJ Open 2021 03 2;11(3):e043049. Epub 2021 Mar 2.

HRB Centre for Primary Care Research, Department of General Practice, RCSI University of Medicine and Health Sciences, Dublin, Ireland

Aim: To apply the drug utilisation 90% (DU90%) indicator (the number of unique drugs which makes up 90% of a doctor's prescribing) to general practitioner (GP) practices prescribing in England to examine time trends, practice-level variation, and relationships with practice characteristics, prescribing costs and low-value prescribing.

Study Design: Retrospective cohort study.

Setting: Primary care in England, using publicly available prescribing data available from the National Health Service (NHS) digital platform for 2013-2017.

Participants: All general practices in England (n=7620).

Primary And Secondary Outcome Measures: The DU90% was calculated on an annual basis for each practice based on medication British National Formulary codes. Low-value prescribing was defined using NHS 2017 guidance (including lidocaine plasters, liothyronine, omega-3 supplements). Descriptive statistics were generated per year on time trends and practice-level variation in the DU90%. Multilevel linear regression was used to examine the practice characteristics (relating to staff, patients and deprivation of the practice area).

Results: Among 7620 practices, mean DU90% ranged from 130.0 to 131.0 across study years, and regarding variation between practices, there was a 1.4-fold difference between the lowest and highest 5% of practices. A range of medications were included in the DU90% of virtually all practices, including atorvastatin, levothyroxine, omeprazole, ramipril, amlodipine, simvastatin and aspirin. A higher volume of prescribing was associated with a lower DU90%, while having more patients, higher proportions of patients who are women or aged ≥45 years, higher number of GPs working in the practice and being in a more deprived area were associated with a higher DU90%. Practices in higher quintiles of DU90% had higher levels of low-priority prescribing and prescribing costs.

Conclusion: GP practices typically use 130 different medications in the bulk of their prescribing. Higher DU90% was associated with higher levels of low-priority prescribing and prescribing costs. Increasing use of personal formularies may enhance prescribing quality and reduce costs.
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http://dx.doi.org/10.1136/bmjopen-2020-043049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929869PMC
March 2021

The Rolling Stones: A case report of two surgical abdomens linked by migrating gallstones.

Int J Surg Case Rep 2021 Mar 18;80:105658. Epub 2021 Feb 18.

Radiology Department, St. James's Hospital, James's Street, Dublin 8, Ireland.

Introduction: Acute abdominal pain accounts for 5% of all presentations to the emergency department (Stoker et al., 2009). Two of the most common causes are acute appendicitis and acute cholecystitis (Ferris et al., 2017).

Presentation: A 70-year-old man presented with acute calculous cholecystitis. He subsequently deteriorated clinically and re-imaging revealed interval migration of stones from the biliary system to the appendix with resultant acute appendicitis.

Discussion: Although both acute appendicitis and acute cholecystitis are common, dual pathology is rare. There are a small number of case reports of gallstones causing appendicitis (Vicari, 1964; Siegal et al., 1990; Meade, 1960).

Conclusion: Our case report nicely illustrates. a) The importance of considering dual pathology, especially when there is an unexpected change in the patient's clinical status. b) The CT features of two common acute surgical pathologies. c) The value of cholecystostomy- performed in the Interventional Radiology suite- as a temporizing measure to allow the patient to recover from a critical illness.
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http://dx.doi.org/10.1016/j.ijscr.2021.105658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921502PMC
March 2021

(Lour.) Decne. Extract Alleviates Oxidative Stress and Inflammatory Mediators Produced by RAW264.7 Macrophages.

Oxid Med Cell Longev 2021 4;2021:8658314. Epub 2021 Feb 4.

School of Preclinical Sciences, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.

(Lour.) Decne. () is widely used in Northern Thai cuisine as local vegetables and commercial herb tea products. In the present study, extract (GIE) was evaluated for its antioxidant and anti-inflammatory effects in LPS plus IFN--induced RAW264.7 cells. Major compounds in GIE were evaluated using GC-MS and found 16 volatile compounds presenting in the extract. GIE exhibited antioxidant activity by scavenging the intracellular reactive oxygen species (ROS) production and increasing superoxide dismutase 2 (SOD2) mRNA expression in LPS plus IFN--induced RAW264.7 cells. GIE showed anti-inflammatory activity through suppressing nitric oxide (NO), proinflammatory cytokine production interleukin 6 (IL-6) and also downregulation of the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and IL-6 mRNA levels in LPS plus IFN--induced RAW264.7 cells. Mechanism studies showed that GIE suppressed the NF-B p65 nuclear translocation and slightly decreased the phosphorylation of NF-B p65 (p-NF-B p65) protein. Our studies applied the synchrotron radiation-based FTIR microspectroscopy (SR-FTIR), supported by multivariate analysis, to identify the FTIR spectral changes based on macromolecule alterations occurring in RAW264.7 cells. SR-FTIR results demonstrated that the presence of LPS plus IFN- in RAW264.7 cells associated with the increase of amide I/amide II ratio (contributing to the alteration of secondary protein structure) and lipid content, whereas glycogen and other carbohydrate content were decreased. These findings lead us to believe that GIE may prevent oxidative damage by scavenging intracellular ROS production and activating the antioxidant gene, SOD2, expression. Therefore, it is possible that the antioxidant properties of GIE could modulate the inflammation process by regulating the ROS levels, which lead to the suppression of proinflammatory cytokines and genes. Therefore, GIE could be developed into a novel antioxidant and anti-inflammatory agent to treat and prevent diseases related to oxidative stress and inflammation.
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http://dx.doi.org/10.1155/2021/8658314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878084PMC
May 2021

Mechanical loading of bioengineered skeletal muscle in vitro recapitulates gene expression signatures of resistance exercise in vivo.

J Cell Physiol 2021 Sep 15;236(9):6534-6547. Epub 2021 Feb 15.

Institute for Physical Performance, Norwegian School of Sport Sciences (NiH), Oslo, Norway.

Understanding the role of mechanical loading and exercise in skeletal muscle (SkM) is paramount for delineating the molecular mechanisms that govern changes in muscle mass. However, it is unknown whether loading of bioengineered SkM in vitro adequately recapitulates the molecular responses observed after resistance exercise (RE) in vivo. To address this, the transcriptional and epigenetic (DNA methylation) responses were compared after mechanical loading in bioengineered SkM in vitro and after RE in vivo. Specifically, genes known to be upregulated/hypomethylated after RE in humans were analyzed. Ninety-three percent of these genes demonstrated similar changes in gene expression post-loading in the bioengineered muscle when compared to acute RE in humans. Furthermore, similar differences in gene expression were observed between loaded bioengineered SkM and after programmed RT in rat SkM tissue. Hypomethylation occurred for only one of the genes analysed (GRIK2) post-loading in bioengineered SkM. To further validate these findings, DNA methylation and mRNA expression of known hypomethylated and upregulated genes post-acute RE in humans were also analyzed at 0.5, 3, and 24 h post-loading in bioengineered muscle. The largest changes in gene expression occurred at 3 h, whereby 82% and 91% of genes responded similarly when compared to human and rodent SkM respectively. DNA methylation of only a small proportion of genes analyzed (TRAF1, MSN, and CTTN) significantly increased post-loading in bioengineered SkM alone. Overall, mechanical loading of bioengineered SkM in vitro recapitulates the gene expression profile of human and rodent SkM after RE in vivo. Although some genes demonstrated differential DNA methylation post-loading in bioengineered SkM, such changes across the majority of genes analyzed did not closely mimic the epigenetic response to acute-RE in humans.
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http://dx.doi.org/10.1002/jcp.30328DOI Listing
September 2021

Prevalence and Medication Treatment of Opioid Use Disorder Among Primary Care Patients with Hepatitis C and HIV.

J Gen Intern Med 2021 04 10;36(4):930-937. Epub 2021 Feb 10.

Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, STE 1600, Seattle, WA, 98101 (206) 948-1933, USA.

Background: Hepatitis C and HIV are associated with opioid use disorders (OUD) and injection drug use. Medications for OUD can prevent the spread of HCV and HIV.

Objective: To describe the prevalence of documented OUD, as well as receipt of office-based medication treatment, among primary care patients with HCV or HIV.

Design: Retrospective observational cohort study using electronic health record and insurance data.

Participants: Adults ≥ 18 years with ≥ 2 visits to primary care during the study (2014-2016) at 6 healthcare systems across five states (CO, CA, OR, WA, and MN).

Main Measures: The primary outcome was the diagnosis of OUD; the secondary outcome was OUD treatment with buprenorphine or oral/injectable naltrexone. Prevalence of OUD and OUD treatment was calculated across four groups: HCV only; HIV only; HCV and HIV; and neither HCV nor HIV. In addition, adjusted odds ratios (AOR) of OUD treatment associated with HCV and HIV (separately) were estimated, adjusting for age, gender, race/ethnicity, and site.

Key Results: The sample included 1,368,604 persons, of whom 10,042 had HCV, 5821 HIV, and 422 both. The prevalence of diagnosed OUD varied across groups: 11.9% (95% CI: 11.3%, 12.5%) for those with HCV; 1.6% (1.3%, 2.0%) for those with HIV; 8.8% (6.2%, 11.9%) for those with both; and 0.92% (0.91%, 0.94%) among those with neither. Among those with diagnosed OUD, the prevalence of OUD medication treatment was 20.9%, 16.0%, 10.8%, and 22.3%, for those with HCV, HIV, both, and neither, respectively. HCV was not associated with OUD treatment (AOR = 1.03; 0.88, 1.21), whereas patients with HIV had a lower probability of OUD treatment (AOR = 0.43; 0.26, 0.72).

Conclusions: Among patients receiving primary care, those diagnosed with HCV and HIV were more likely to have documented OUD than those without. Patients with HIV were less likely to have documented medication treatment for OUD.
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http://dx.doi.org/10.1007/s11606-020-06389-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041979PMC
April 2021

Results of the European EDITH nephrologist survey on factors influencing treatment modality choice for end-stage kidney disease

Nephrol Dial Transplant 2021 01 22. Epub 2021 Jan 22.

ERA-EDTA Registry, Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Access to forms of dialysis, kidney transplantation (Tx) and comprehensive conservative management (CCM) for patients with end-stage kidney disease (ESKD) varies across European countries. Attitudes of nephrologists, information provision and decision-making may influence this access and nephrologists may experience several barriers when providing treatments for ESKD.

Methods: We surveyed European nephrologists and kidney transplant surgeons treating adults with ESKD about factors influencing modality choice. Descriptive statistics were used to compare the opinions of professionals from European countries with low-, middle- and high-gross domestic product purchasing power parity (GDP PPP).

Results: In total, 681 professionals from 33 European countries participated. Respondents from all GDP categories indicated that ∼10% of patients received no information before the start of renal replacement therapy (RRT) (P = 0.106). Early information provision and more involvement of patients in decision-making were more frequently reported in middle- and high-GDP countries (P < 0.05). Professionals' attitudes towards several treatments became more positive with increasing GDP (P < 0.05). Uptake of in-centre haemodialysis was sufficient to 73% of respondents, but many wanted increased uptake of home dialysis, Tx and CCM. Respondents experienced different barriers according to availability of specific treatments in their centre. The occurrence of barriers (financial, staff shortage, lack of space/supplies and patient related) decreased with increasing GDP (P < 0.05).

Conclusions: Differences in factors influencing modality choice when providing RRT or CCM to adults with ESKD were found among low-, middle- and high-GDP countries in Europe. Therefore a unique pan-European policy to improve access to treatments may be inefficient. Different policies for clusters of countries could be more useful.
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http://dx.doi.org/10.1093/ndt/gfaa342DOI Listing
January 2021

The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration.

Platelets 2021 Jan 11:1-10. Epub 2021 Jan 11.

Drug Discovery Biology, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.

Here, we report the characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration.
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http://dx.doi.org/10.1080/09537104.2020.1869711DOI Listing
January 2021

Acute severe respiratory syndrome coronavirus-2 treatment overview for pediatrics.

Curr Opin Pediatr 2021 02;33(1):129-135

Division of Infectious Diseases.

Purpose Of Review: The novel severe respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has caused a world-wide pandemic with devastating effects. Fortunately, most children display only mild-to-moderate symptoms, but there are a subset that will have severe symptoms warranting treatment. This review evaluates the current evidence for antiviral and anti-inflammatory treatment of acute SARS-COV-2 infections, including coronavirus disease 2019 in pediatrics.

Recent Findings: Treatment recommendations continue to evolve with emerging results from clinical trials. Initial therapies were tailored to repurposed medications, and have now transitioned toward more specific antiviral therapy. In addition to specific antiviral therapy, there is also support to modulate the immune system and reduce inflammatory damage seen in coronavirus disease 2019. Much of the data result from adult studies with subsequent extrapolation to pediatrics.

Summary: Recommended therapy will continue to adapt as results return from clinical trials. A continued commitment from the National Institutes of Health and research community to assist in determining optimal therapies for pediatric patients is essential. Until then, most recommendations will likely be informed from the results seen in adult populations.
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http://dx.doi.org/10.1097/MOP.0000000000000983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861135PMC
February 2021

Altered Degranulation and pH of Neutrophil Phagosomes Impacts Antimicrobial Efficiency in Cystic Fibrosis.

Front Immunol 2020 18;11:600033. Epub 2020 Dec 18.

Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.

Studies have endeavored to understand the cause for impaired antimicrobial killing by neutrophils of people with cystic fibrosis (PWCF). The aim of this study was to focus on the bacterial phagosome. Possible alterations in degranulation of cytoplasmic granules and changes in pH were assessed. Circulating neutrophils were purified from PWCF (n = 28), PWCF receiving ivacaftor therapy (n = 10), and healthy controls (n = 28). Degranulation was assessed by Western blot analysis and flow cytometry. The pH of phagosomes was determined by use of BCECF-AM-labelled or SNARF labelled . The antibacterial effect of all treatments tested was determined by colony forming units enumeration. Bacterial killing by CF and healthy control neutrophils were found to differ (p = 0.0006). By use of flow cytometry and subcellular fractionation the kinetics of intraphagosomal degranulation were found to be significantly altered in CF phagosomes, as demonstrated by increased primary granule CD63 (p = 0.0001) and myeloperoxidase (MPO) content (p = 0.03). In contrast, decreased secondary and tertiary granule CD66b (p = 0.002) and decreased hCAP-18 and MMP-9 (p = 0.02), were observed. After 8 min phagocytosis the pH in phagosomes of neutrophils of PWCF was significantly elevated (p = 0.0001), and the percentage of viable bacteria was significantly increased compared to HC (p = 0.002). Results demonstrate that the recorded alterations in phagosomal pH generate suboptimal conditions for MPO related peroxidase, and α-defensin and azurocidine enzymatic killing of and . The pattern of dysregulated MPO degranulation (p = 0.02) and prolonged phagosomal alkalinization in CF neutrophils were normalized following treatment with the ion channel potentiator ivacaftor (p = 0.04). Our results confirm that alterations of circulating neutrophils from PWCF are corrected by CFTR modulator therapy, and raise a question related to possible delayed proton channel activity in CF.
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http://dx.doi.org/10.3389/fimmu.2020.600033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775508PMC
June 2021

Environmental risk factors associated with pulmonary isolation of nontuberculous mycobacteria, a population-based study in the southeastern United States.

Sci Total Environ 2021 Apr 18;763:144552. Epub 2020 Dec 18.

United States Environmental Protection Agency, Office of Research and Development, Research Triangle Park, NC, USA.

The prevalence of pulmonary nontuberculous mycobacteria (NTM) disease is increasing in the United States. Associations were evaluated among residents of central North Carolina between pulmonary isolation of NTM and environmental risk factors including: surface water, drinking water source, urbanicity, and exposures to soils favorable to NTM growth. Reports of pulmonary NTM isolation from patients residing in three counties in central North Carolina during 2006-2010 were collected from clinical laboratories and from the State Laboratory of Public Health. This analysis was restricted to patients residing in single family homes with a valid residential street address and conducted at the census block level (n = 13,495 blocks). Negative binomial regression models with thin-plate spline smoothing function of geographic coordinates were applied to assess effects of census block-level environmental characteristics on pulmonary NTM isolation count. Patients (n = 507) resided in 473 (3.4%) blocks within the study area. Blocks with >20% hydric soils had 26.8% (95% confidence interval (CI): 1.8%, 58.0%), p = 0.03, higher adjusted mean patient counts compared to blocks with ≤20% hydric soil, while blocks with >50% acidic soil had 24.8% (-2.4%, 59.6%), p = 0.08 greater mean patient count compared to blocks with ≤50% acidic soil. Isolation rates varied by county after adjusting for covariates. The effects of using disinfected public water supplies vs. private wells, and of various measures of urbanicity were not significantly associated with NTM. Our results suggest that proximity to certain soil types (hydric and acidic) could be a risk factor for pulmonary NTM isolation in central North Carolina.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317204PMC
April 2021

Clinical Guideline Highlights for the Hospitalist: Therapeutic Monitoring of Vancomycin.

J Hosp Med 2020 12;15(12):740-742

Pharmacometrics Center of Excellence, Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois.

Guideline Title: Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists RELEASE DATE: Online: March 19, 2020 PRIOR VERSION: 2009 DEVELOPERS: American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP) FUNDING SOURCE: ASHP, IDSA, PIDS, SIDP TARGET POPULATION: Adults, children, and neonates treated for documented or presumed methicillin-resistant Staphylococcus aureus infection.
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http://dx.doi.org/10.12788/jhm.3507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034673PMC
December 2020

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of β-Lactam Antibiotics in Critically Ill Children.

J Clin Pharmacol 2021 04 27;61(4):565-573. Epub 2020 Oct 27.

Division of Clinical Pharmacology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

There has been increasing interest in incorporating β-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.
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http://dx.doi.org/10.1002/jcph.1773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061424PMC
April 2021

Periprosthetic Hip Joint Infection and Its Diagnosis.

Radiology 2020 10 18;297(1):E240. Epub 2020 Aug 18.

Department of Radiology, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland.

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http://dx.doi.org/10.1148/radiol.2020202755DOI Listing
October 2020

Targeting IgG Autoantibodies for Improved Cytotoxicity of Bactericidal Permeability Increasing Protein in Cystic Fibrosis.

Front Pharmacol 2020 17;11:1098. Epub 2020 Jul 17.

Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.

In people with cystic fibrosis (PWCF), inflammation with concurrent infection occurs from a young age and significantly influences lung disease progression. Studies indicate that neutrophils are important effector cells in the pathogenesis of CF and in the development of anti-neutrophil cytoplasmic autoantibodies (ANCA). ANCA specific for bactericidal permeability increasing protein (BPI-ANCA) are detected in people with CF, and correlate with infection with . The aim of this study was to determine the signaling mechanism leading to increased BPI release by CF neutrophils, while identifying IgG class BPI-ANCA in CF airways samples as the cause for impaired antimicrobial activity of BPI against Plasma and/or bronchoalveolar lavage fluid (BAL) was collected from PWCF (n = 40), CF receiving ivacaftor therapy (n = 10), non-CF patient cohorts (n = 7) and healthy controls (n = 38). Plasma and BAL BPI and BPI-ANCA were measured by ELISA and GTP-bound Rac2 detected using an assay. The antibacterial effect of all treatments tested was determined by colony forming units enumeration. Levels of BPI are significantly increased in plasma (p = 0.007) and BALF (p < 0.0001) of PWCF. The signaling mechanism leading to increased degranulation and exocytosis of BPI by CF neutrophils (p = 0.02) involved enhancement of Rac2 GTP-loading (p = 0.03). The full-length BPI protein was detectable in all CF BAL samples and patients displayed ANCA with BPI specificity. IgG class autoantibodies were purified from CF BAL complexed to BPI (n=5), with IgG autoantibody cross-linking of antigen preventing BPI induced killing (p < 0.0001). Results indicate that the immune-mediated diminished antimicrobial defense, attributed to anti-BPI-IgG, necessitates the formation of a drug/immune complex intermediate that can maintain cytotoxic effects of BPI towards Gram-negative pathogens, with the potential to transform the current treatment of CF airways disease.
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http://dx.doi.org/10.3389/fphar.2020.01098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379883PMC
July 2020

Correction to: Development of an intervention to facilitate implementation and uptake of diabetic retinopathy screening.

Implement Sci 2020 Jul 30;15(1):61. Epub 2020 Jul 30.

School of Public Health, University College Cork, Western Gateway Building, Western Rd, Cork, Ireland.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13012-020-01026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393863PMC
July 2020
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