Publications by authors named "Paul McCarthy"

61 Publications

Prolonged exposure to continuous renal replacement therapy in patients with acute kidney injury.

J Nephrol 2021 Jun 23. Epub 2021 Jun 23.

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Little is known about the process of deciding to discontinue continuous renal replacement therapy (CRRT) in patients with acute kidney injury (AKI) and the impact of CRRT duration on outcomes.

Methods: We report the clinical parameters of prolonged CRRT exposure and predictors of doubling of serum creatinine or need for dialysis at 90 days after CRRT with propensity score matching, including covariates that were likely to influence patients in the prolonged CRRT group.

Results: Among 104 survey responders, most use urine output (87%) to guide CRRT discontinuation, 24% use improvement in clinical or hemodynamic status. In the cohort study, of 854 included patients, 465 participated in the assessment of kidney recovery. Patients with prolonged CRRT had higher SOFA scores (11.9 vs. 11.2) and were more likely to be mechanically ventilated (99% vs. 84%) at CRRT initiation compared to patients without prolonged CRRT, p-value < 0.05. In multivariable logistic regression, daily urine output and cumulative fluid balance leading to CRRT discontinuation or day seven were independently associated with lower [OR 0.87 per 200 ml/day increase] and higher odds [OR 1.03 per 1-L increase] of requiring prolonged CRRT, respectively. After propensity score matching, prolonged exposure to CRRT was independently associated with increased risk of doubling serum creatinine or dialysis at 90 days, OR 3.1 (95% CI 1.23-8.3 p = 0.017).

Conclusions: Resolution of critical illness and signs of kidney recovery are important factors when considering CRRT discontinuation. Prolonged CRRT exposure may be associated with less chance of kidney recovery among survivors.
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http://dx.doi.org/10.1007/s40620-021-01097-9DOI Listing
June 2021

Successful treatment of intravenous drug abuser with refractory vasoplegic syndrome after mitral valve repair for infective endocarditis.

SAGE Open Med Case Rep 2021 3;9:2050313X211019788. Epub 2021 Jun 3.

Division of Cardiovascular and Thoracic Anesthesiology, West Virginia University, Morgantown, WV, USA.

Vasoplegic syndrome, a possible complication of cardiopulmonary bypass, is a critical state of unregulated systemic vasodilation with decreased vascular resistance and a pathological insensitivity to conventional inotropes and vasoconstrictors. This case demonstrates the use of methylene blue and hydroxocobalamin as medications in the treatment of refractory vasoplegic syndrome in the context of cardiac surgery due to their differences in mechanism of action. A 24-year-old female with history of intravenous drug abuse and hepatitis C infection underwent mitral valve repair for infective endocarditis. Preoperative transesophageal echocardiography showed normal right ventricular function, left ventricular ejection fraction of 65%-75%, and severe mitral regurgitation with vegetation. In order to maintain a mean arterial pressure over 60 mmHg during cardiopulmonary bypass, norepinephrine, epinephrine, and vasopressin infusions were required. Given the patient's minimal response to these medications, a 1.5 mg/kg bolus of intravenous methylene blue was also given intraoperatively; vasoplegic syndrome remained refractory in the post-cardiopulmonary bypass period. A 5 g dose of intravenous hydroxocobalamin was administered in the intensive care unit postoperatively. Postoperative liver function tests were abnormal, and post-cardiopulmonary bypass transesophageal echocardiography revealed mildly decreased right ventricular function. While in the intensive care unit, the patient was placed on venoarterial extracorporeal membrane oxygenation and underwent therapeutic plasma exchange. Vasopressors were weaned over the course of the next 24 h. The patient was able to be transferred out of the intensive care unit on postoperative day 5. Traditional vasoconstrictors activate signal transduction pathways that lead to myosin phosphorylation. Vasodilatory molecules such as nitric oxide (NO) activate the enzyme soluble guanylyl cyclase (sGC), ultimately leading to the dephosphorylation of myosin. Nitric Oxide Synthase (NOS) can potentially increase NO levels 1000-fold when activated by inflammatory cytokines. Methylene blue is a direct inhibitor of NOS. It also binds and inhibits sGC. Hydroxocobalamin is a direct inhibitor of NO, likely inhibits NOS and may also act through additional mechanisms.
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http://dx.doi.org/10.1177/2050313X211019788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182181PMC
June 2021

Integrating large-scale neuroimaging research datasets: Harmonisation of white matter hyperintensity measurements across Whitehall and UK Biobank datasets.

Neuroimage 2021 08 20;237:118189. Epub 2021 May 20.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Human Brain Activity, Department of Psychiatry, University of Oxford, Oxford, UK. Electronic address:

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise study sample differences contributing to differences in WMH variations across studies. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285593PMC
August 2021

Evolution of diversity and dominance of companies in online activity.

PLoS One 2021 28;16(4):e0249993. Epub 2021 Apr 28.

UTS Data Science Institute, University of Technology Sydney, Sydney, Australia.

Ever since the web began, the number of websites has been growing exponentially. These websites cover an ever-increasing range of online services that fill a variety of social and economic functions across a growing range of industries. Yet the networked nature of the web, combined with the economics of preferential attachment, increasing returns and global trade, suggest that over the long run a small number of competitive giants are likely to dominate each functional market segment, such as search, retail and social media. Here we perform a large scale longitudinal study to quantify the distribution of attention given in the online environment to competing organisations. In two large online social media datasets, containing more than 10 billion posts and spanning more than a decade, we tally the volume of external links posted towards the organisations' main domain name as a proxy for the online attention they receive. We also use the Common Crawl dataset-which contains the linkage patterns between more than a billion different websites-to study the patterns of link concentration over the past three years across the entire web. Lastly, we showcase the linking between economic, financial and market data by exploring the relationships between online attention on social media and the growth in enterprise value in the electric carmaker Tesla. Our analysis shows that despite the fact that we observe consistent growth in all the macro indicators-the total amount of online attention, in the number of organisations with an online presence, and in the functions they perform-we also observe that a smaller number of organisations account for an ever-increasing proportion of total user attention, usually with one large player dominating each function. These results highlight how evolution of the online economy involves innovation, diversity, and then competitive dominance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249993PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081211PMC
April 2021

A prospective, real-world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE-02).

Br J Clin Pharmacol 2021 Apr 14. Epub 2021 Apr 14.

Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, Maryland, United States.

Aims: Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH).

Methods: Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post-administration. Patient-specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high-performance liquid chromatography with ultraviolet radiation detection (HPLC-UV) bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide.

Results: The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics.

Conclusions: CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.
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http://dx.doi.org/10.1111/bcp.14858DOI Listing
April 2021

Incremental effect of complications on mortality and hospital costs in adult ECMO patients.

Perfusion 2021 Mar 26:2676591211005697. Epub 2021 Mar 26.

Department of Cardiovascular and Thoracic Surgery, West Virginia University, Morgantown, WV, USA.

Introduction: Extracorporeal membrane oxygenation (ECMO) is a resource-intense modality whose usage is expanding rapidly. It is a costly endeavor and best conducted in a multidisciplinary setting. There is a growing impetus to mitigate the mortality and costs associated with ECMO. We sought to examine the impact of complications on mortality and hospital costs in patients on ECMO.

Methods: Using the NIS database, we performed multivariable logistic regression to assess the influence of complications on the primary outcome, in-hospital mortality. Similarly, we performed multivariable survey linear regression analysis to evaluate the effect of the complications on hospital costs.

Results: Of the 12,637 patients supported using ECMO between 2004 and 2013, 9836 (78%) developed at least one complication. The three most common complications were acute kidney injury (32.8%), bloodstream infection (31.8%), and bleeding (27.8%). An ECMO hospitalization with no complications was associated with median costs of $53,470, a single complication with costs of $97,560, two complications with costs of $139,035, and three complication with costs of $162,284. A single complication was associated with a 165% increase in odds of mortality. Two or three complications resulted in 375% or 627% higher odds of mortality, respectively. Having one, two, or three complications was associated with 24%, 38%, or 38% increase in median costs respectively (Figure 1). Complications associated with the highest median costs were central line-associated bloodstream infection $217,751; liver failure $176,201; bloodstream infection $169,529.

Conclusion: In-hospital mortality and costs increase with each incremental complication in patients on ECMO. Accurate prediction and mitigation of complications is likely to improve outcomes and cost.
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http://dx.doi.org/10.1177/02676591211005697DOI Listing
March 2021

Sporting Resilience During COVID-19: What Is the Nature of This Adversity and How Are Competitive Elite Athletes Adapting?

Front Psychol 2021 3;12:611261. Epub 2021 Mar 3.

Department School of Health & Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom.

The COVID-19 pandemic is a global health issue which has severely disrupted and deferred several landmark international sporting competitions. Like the general population, athletes have faced direct psychological consequences from COVID-19 in addition to cancelation of events, loss of support, lack of training, loss of earnings, hypervigilance, and anxiety among others. The aim of the present research was to identify the adversity experiences of athletes caused by COVID-19 (study 1) and explore the process of resilience used by competitive elite athletes for positive adaptation (study 2). Research has indicated psychological resilience to be a protective factor against similar adversities in the sporting context. The study uses an across-cases qualitative design comparing the real-time lived experiences of athletes during COVID-19 using narrative analysis. Data were collected from 10 competitive elite athletes from various countries, as part of a larger doctoral dissertation study during the lockdown period, using in-depth experiential interviews. Study 1 presents detailed narratives on the loss and incongruence, which were the two major adversities experienced. Study 2 outlines the process of resilience as narrated by the participants through the emergent and minimal-impact resilience trajectories. We discuss recommendations for interventions and the role of sports psychologists, coaches, and sporting organizations in ensuring athletes' mental health and their rehabilitation into post-COVID sports life.
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http://dx.doi.org/10.3389/fpsyg.2021.611261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966721PMC
March 2021

Neurological complications during veno-venous extracorporeal membrane oxygenation: Does the configuration matter? A retrospective analysis of the ELSO database.

Crit Care 2021 03 17;25(1):107. Epub 2021 Mar 17.

Departments of Surgery, University of Maryland School of Medicine, Program in Trauma, R Adams Cowley Shock Trauma Center, Baltimore, USA.

Background: Single- (SL) and double-lumen (DL) catheters are used in clinical practice for veno-venous extracorporeal membrane oxygenation (V-V ECMO) therapy. However, information is lacking regarding the effects of the cannulation on neurological complications.

Methods: A retrospective observational study based on data from the Extracorporeal Life Support Organization (ELSO) registry. All adult patients included in the ELSO registry from 2011 to 2018 submitted to a single run of V-V ECMO were analyzed. Propensity score (PS) inverse probability of treatment weighting estimation for multiple treatments was used. The average treatment effect (ATE) was chosen as the causal effect estimate of outcome. The aim of the study was to evaluate differences in the occurrence and the type of neurological complications in adult patients undergoing V-V ECMO when treated with SL or DL cannulas.

Results: From a population of 6834 patients, the weighted propensity score matching included 6245 patients (i.e., 91% of the total cohort; 4175 with SL and 20,270 with DL cannulation). The proportion of patients with at least one neurological complication was similar in the SL (306, 7.2%) and DL (189, 7.7%; odds ratio 1.10 [95% confidence intervals 0.91-1.32]; p = 0.33). After weighted propensity score, the ATE for the occurrence of least one neurological complication was 0.005 (95% CI - 0.009 to 0.018; p = 0.50). Also, the occurrence of specific neurological complications, including intracerebral hemorrhage, acute ischemic stroke, seizures or brain death, was similar between groups. Overall mortality was similar between patients with neurological complications in the two groups.

Conclusions: In this large registry, the occurrence of neurological complications was not related to the type of cannulation in patients undergoing V-V ECMO.
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http://dx.doi.org/10.1186/s13054-021-03533-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968168PMC
March 2021

Utilization of Thromboelastogram and Inflammatory Markers in the Management of Hypercoagulable State in Patients with COVID-19 Requiring ECMO Support.

Case Rep Crit Care 2021 15;2021:8824531. Epub 2021 Jan 15.

Division of Cardiovascular Critical Care, Department of Cardiovascular and Thoracic Surgery, West Virginia University, Morgantown, WV, USA.

The role of extracorporeal membrane oxygenation (ECMO) in the management of critically ill patients with COVID-19 is evolving. Extracorporeal support independently confers an increased predilection for thrombosis, which can be exacerbated by COVID-19-associated coagulopathy. We present the successful management of a hypercoagulable state in two patients who required venovenous ECMO for the treatment of COVID-19. This included monitoring inflammatory markers (D-dimer and fibrinogen), performing a series of therapeutic plasma exchange procedures, and administering high-intensity anticoagulation therapy and thromboelastography- (TEG-) guided antiplatelet therapy. TPE was performed to achieve goal D-dimer less than 3000 ng/mL D-dimer units ( ≤ 232 ng/mL D-dimer units) and goal fibrinogen less than 600 mg/dL ( = 200-400 mg/dL). These therapies resulted in improved TEG parameters and normalized inflammatory markers. Patients were decannulated after 37 days and 21 days, respectively. Post-ECMO duplex ultrasound of the upper and lower extremities and cannulation sites revealed a nonsignificant deep venous thrombosis at the site of femoral cannulation in patient 2 and no deep venous thrombosis in patient 1. The results of this case report show successful management of a hypercoagulable state among COVID-19 patients requiring ECMO support by utilization of inflammatory markers and TEG.
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http://dx.doi.org/10.1155/2021/8824531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814409PMC
January 2021

Use of a chronic soft tissue expansion device to facilitate blepharoplasty in a horse with lower-lid cicatricial ectropion with a 14-year follow-up.

Vet Ophthalmol 2020 Sep 20;23(5):899-904. Epub 2020 Jul 20.

Eye Clinic for Animals, Artarmon, NSW, Australia.

A 3-year-old Thoroughbred filly presented to a referral equine hospital for surgical correction of a severe cicatricial lateral lower eyelid ectropion OD, with secondary exposure keratitis. The severity of the ectropion deemed that conventional ectropion repairs would be unsuccessful. Therefore, a soft tissue expansion device was used to create sufficient local tissue for a rotational graft with tension-relieving horizontal incisions to be performed to facilitate closure and acceptable eyelid apposition. The keratitis had resolved by two months postoperatively. There were no long-term complications and only mild recurrence of the keratitis observed 14-years postoperatively.
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http://dx.doi.org/10.1111/vop.12806DOI Listing
September 2020

The first juvenile dromaeosaurid (Dinosauria: Theropoda) from Arctic Alaska.

PLoS One 2020 8;15(7):e0235078. Epub 2020 Jul 8.

Perot Museum of Nature and Science, Dallas, TX, United States of America.

Compared to the osteological record of herbivorous dinosaurs from the Late Cretaceous Prince Creek Formation of northern Alaska, there are relatively fewer remains of theropods. The theropod record from this unit is mostly comprised of isolated teeth, and the only non-dental remains known can be attributed to the troodontid cf. Troodon and the tyrannosaurid Nanuqsaurus. Thus far, the presence of members of Dromaeosauridae has been limited to isolated teeth. Here we describe a symphyseal portion of a small dentary with two ziphodont teeth. Based on tooth shape, denticle morphology, and the position of the Meckelian groove, we attribute this partial dentary to a saurornitholestine dromaeosaurid. The fibrous bone surface, small size, and higher number of mesial denticles compared to distal ones point to a juvenile growth stage for this individual. Multivariate comparison of theropod teeth morphospace by means of principal component analysis reveals an overlap between this dentary and Saurornitholestinae dromaeosaurid morphospace, a result supported by phylogenetic analyses. This is the first confirmed non-dental fossil specimen from a member of Dromaeosauridae in the Arctic, expanding on the role of Beringia as a dispersal route for this clade between Asia and North America. Furthermore, the juvenile nature of this individual adds to a growing body of data that suggests Cretaceous Arctic dinosaurs of Alaska did not undergo long-distance migration, but rather they were year-round residents of these paleopolar latitudes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343144PMC
September 2020

Induced Hypothermia in Patients with Cardiac Arrest and a Non-shockable Rhythm: Meta-analysis and Trial Sequential Analysis.

Neurocrit Care 2021 02;34(1):279-286

Division of Cardiology, West Virginia University School of Medicine, Morgantown, WV, USA.

Background: Controversy surrounds utilization of induced hypothermia (IHT) in comatose cardiac arrest (CA) survivors with a non-shockable rhythm.

Methods: We conducted a meta-analysis and trial sequential analysis (TSA) comparing IHT with no IHT approaches in patients with CA and a non-shockable rhythm. The primary outcome of interest was favorable neurological outcomes (FNO) defined using the Cerebral Performance Category (CPC) score of 1 or 2. Secondary endpoints were survival at discharge and survival beyond 90 days.

Results: A total of 9 studies with 10,386 patients were included. There was no difference between both groups in terms of FNO (13% vs. 13%, RR 1.34, 95% CI 0.96-1.89, p = 0.09, I = 88%), survival at discharge (20% vs. 22%, RR 1.09, 95% CI 0.88-1.36, p = 0.42, I = 76%), or survival beyond 90 days (16% vs. 15%, RR 0.92, 95% CI 0.61-1.40, p = 0.69, I = 83%). The TSA showed firm evidence supporting the lack of benefit of IHT in terms of survival at discharge. However, the Z-curves failed to cross the conventional and TSA (futility) boundaries for FNO and survival beyond 90 days, indicating lack of sufficient evidence to draw firm conclusions regarding these outcomes.

Conclusion: In this meta-analysis of 9 studies, the utilization of IHT was not associated with a survival benefit at discharge. Although the meta-analysis showed lack of benefit of IHT in terms of FNO and survivals beyond 90 days, the corresponding TSA showed high probability of type-II statistical error, and therefore more randomized controlled trials powered for these outcomes are needed.
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http://dx.doi.org/10.1007/s12028-020-01034-xDOI Listing
February 2021

Confound modelling in UK Biobank brain imaging.

Neuroimage 2021 01 2;224:117002. Epub 2020 Jun 2.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, UK.

Dealing with confounds is an essential step in large cohort studies to address problems such as unexplained variance and spurious correlations. UK Biobank is a powerful resource for studying associations between imaging and non-imaging measures such as lifestyle factors and health outcomes, in part because of the large subject numbers. However, the resulting high statistical power also raises the sensitivity to confound effects, which therefore have to be carefully considered. In this work we describe a set of possible confounds (including non-linear effects and interactions that researchers may wish to consider for their studies using such data). We include descriptions of how we can estimate the confounds, and study the extent to which each of these confounds affects the data, and the spurious correlations that may arise if they are not controlled. Finally, we discuss several issues that future studies should consider when dealing with confounds.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610719PMC
January 2021

A Practice-Based, Clinical Pharmacokinetic Study to Inform Levetiracetam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration (PADRE-01).

Clin Transl Sci 2020 09 3;13(5):950-959. Epub 2020 Apr 3.

Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.

Limited data exist on the effect of continuous renal replacement therapy (CRRT) methods on anti-epileptic drug pharmacokinetics (PK). This prospective practice-based PK study aims to assess the impact of continuous venovenous hemofiltration (CVVH), a modality of CRRT, on levetiracetam PK in critically ill patients and to derive individualized dosing recommendations. Eleven patients receiving oral or intravenous levetiracetam and CVVH in various intensive care units at a large academic medical center were enrolled to investigate the need for dosing adjustments. Prefilter, postfilter, and ultrafiltrate samples were obtained before dosing, after the completion of the infusion or 1-hour postoral dose, and up to 6 additional time points postinfusion or postoral administration. Patient-specific blood and ultrafiltrate flow rates and laboratory values were also collected at the time of sampling. The average sieving coefficient (SC) for levetiracetam was 0.89 ± 0.1, indicating high filter efficiency. Six of the 11 patients experienced concentrations outside the reported therapeutic range (12-46 mg/L). The average volume of distribution was 0.73 L/kg. CVVH clearance contributes a major fraction of the total levetiracetam clearance (36-73%) in neurocritically ill patients. The average bias and precision of the estimated vs. observed total clearance value was ~ 10.6% and 21.5%. Major dose determinants were identified to be SC and effluent flow rate. Patients with higher ultrafiltrate rates will have increased drug clearance and, therefore, will require higher doses in order to match exposures seen in patients with normal renal function.
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http://dx.doi.org/10.1111/cts.12782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485952PMC
September 2020

Brain aging comprises many modes of structural and functional change with distinct genetic and biophysical associations.

Elife 2020 03 5;9. Epub 2020 Mar 5.

Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), University of Oxford, Oxford, United Kingdom.

Brain imaging can be used to study how individuals' brains are aging, compared against population norms. This can inform on aspects of brain health; for example, smoking and blood pressure can be seen to accelerate brain aging. Typically, a single 'brain age' is estimated per subject, whereas here we identified 62 modes of subject variability, from 21,407 subjects' multimodal brain imaging data in UK Biobank. The modes represent different aspects of brain aging, showing distinct patterns of functional and structural brain change, and distinct patterns of association with genetics, lifestyle, cognition, physical measures and disease. While conventional brain-age modelling found no genetic associations, 34 modes had genetic associations. We suggest that it is important not to treat brain aging as a single homogeneous process, and that modelling of distinct patterns of structural and functional change will reveal more biologically meaningful markers of brain aging in health and disease.
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http://dx.doi.org/10.7554/eLife.52677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162660PMC
March 2020

A Theory of Challenge and Threat States in Athletes: A Revised Conceptualization.

Front Psychol 2020 6;11:126. Epub 2020 Feb 6.

Department of Psychology, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom.

The Theory of Challenge and Threat States in Athletes (TCTSA) provides a psychophysiological framework for how athletes anticipate motivated performance situations. The purpose of this review is to discuss how research has addressed the 15 predictions made by the TCTSA, to evaluate the mechanisms underpinning the TCTSA in light of the research that has emerged in the last 10 years, and to inform a revised TCTSA (TCTSA-R). There was support for many of the 15 predictions in the TCTSA, with two main areas for reflection identified: to understand the physiology of challenge and to re-evaluate the concept of resource appraisals. This re-evaluation informs the TCTSA-R, which elucidates the physiological changes, predispositions, and cognitive appraisals that mark challenge and threat states. First, the relative strength of the sympathetic nervous system response is outlined as a determinant of challenge and threat patterns of reactivity and we suggest that oxytocin and neuropeptide Y are also key indicators of an adaptive approach to motivated performance situations and can facilitate a challenge state. Second, although predispositions were acknowledged within the TCTSA, how these may influence challenge and threat states was not specified. In the TCTSA-R, it is proposed that one's propensity to appraise stressors is a challenge that most strongly dictates acute cognitive appraisals. Third, in the TCTSA-R, a more parsimonious integration of Lazarusian ideas of cognitive appraisal and challenge and threat is proposed. Given that an athlete can make both challenge and threat primary appraisals and can have both high or low resources compared to perceived demands, a 2 × 2 bifurcation theory of challenge and threat is proposed. This reflects polychotomy of four states: high challenge, low challenge, low threat, and high threat. For example, in low threat, an athlete can evince a threat state but still perform well so long as they perceive high resources. Consequently, we propose suggestions for research concerning measurement tools and a reconsideration of resources to include social support. Finally, applied recommendations are made based on adjusting demands and enhancing resources.
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http://dx.doi.org/10.3389/fpsyg.2020.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016194PMC
February 2020

Data supporting Maastrichtian paleoclimate variables applying a multi proxy approach to a paleosol profile, Arctic Alaska.

Data Brief 2020 Apr 25;29:105191. Epub 2020 Jan 25.

The University of Western Ontario, Department of Earth Sciences, London, Ontario, N6A 5B7, Canada.

We provide the dataset of climate variables related to the research article "Paleoclimate reconstruction of the Prince Creek Formation, Arctic Alaska, during Maastrichtian global warming" [1]. The dataset includes mean annual precipitation (MAP) values determined using two independent proxies, estimates of the oxygen isotope composition of meteoric water (δO) obtained from smectites and a comparison with previously published siderite data. We also provide the data used to calculate the total flux of CO required for the weathering of silicates. This dataset is an example of a multi proxy approach that could add further insight for researchers in the selection of suitable proxies for paleoclimatic interpretations.
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http://dx.doi.org/10.1016/j.dib.2020.105191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013348PMC
April 2020

Social media-predicted personality traits and values can help match people to their ideal jobs.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

Faculty of Engineering and Information Technology, The University of Technology Sydney, Ultimo NSW 2007, Australia.

Work is thought to be more enjoyable and beneficial to individuals and society when there is congruence between one's personality and one's occupation. We provide large-scale evidence that occupations have distinctive psychological profiles, which can successfully be predicted from linguistic information unobtrusively collected through social media. Based on 128,279 Twitter users representing 3,513 occupations, we automatically assess user personalities and visually map the personality profiles of different professions. Similar occupations cluster together, pointing to specific sets of jobs that one might be well suited for. Observations that contradict existing classifications may point to emerging occupations relevant to the 21st century workplace. Findings illustrate how social media can be used to match people to their ideal occupation.
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http://dx.doi.org/10.1073/pnas.1917942116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936692PMC
December 2019

Dinosaur ichnology and sedimentology of the Chignik Formation (Upper Cretaceous), Aniakchak National Monument, southwestern Alaska; Further insights on habitat preferences of high-latitude hadrosaurs.

PLoS One 2019 30;14(10):e0223471. Epub 2019 Oct 30.

Department of Natural History and Planetary Sciences, Hokkaido University, Hokkaido, Japan.

While there are now numerous records of dinosaurs from Cretaceous rocks around the state of Alaska, very few fossil records of terrestrial vertebrates are known from the Mesozoic rocks of the southwestern part of the state. Here we report the new discovery of extensive occurrences of dinosaur tracks from Aniakchak National Monument of the Alaska Peninsula. These tracks are in the Late Cretaceous (Maastrichtian) Chignik Formation, a cyclic sequence of rocks, approximately 500-600 m thick, representing shallow marine to nearshore marine environments in the lower part and continental alluvial coastal plain environments in the upper part of the section. These rocks are part of the Peninsular Terrane and paleomagnetic reconstructions based on the volcanic rocks of this terrane suggest that the Chignik Formation was deposited at approximately its current latitude which is almost 57° N. Recent field work in Aniakchak National Monument has revealed over 75 new track sites, dramatically increasing the dinosaur record from the Alaska Peninsula. Most of the combined record of tracks can be attributed to hadrosaurs, the plant-eating duck-billed dinosaurs. Tracks range in size from those made by full-grown adults to juveniles. Other tracks can be attributed to armored dinosaurs, meat-eating dinosaurs, and two kinds of fossil birds. The track size of the predatory dinosaur suggests a body approximately 6-7 m long, about the estimated size of the North Slope tyrannosaurid Nanuqsaurus. The larger bird tracks resemble Magnoavipes denaliensis previously described from Denali National Park, while the smaller bird tracks were made by a bird about the size of a modern Willet. Previous interdisciplinary sedimentologic and paleontologic work in the correlative and well-known dinosaur bonebeds of the Prince Creek Formation 1400km-1500km further north in Alaska suggested that high-latitude hadrosaurs preferred distal coastal plain or lower delta plain habitats. The ichnological record being uncovered in the Chignik Formation of southwestern Alaska is showing that the hadrosaur tracks here were also made in distal coastal and delta plain conditions. This similarity may corroborate the habitat preference model for Cretaceous high-latitude dinosaurs proposed for the data gathered from the Prince Creek Formation, and may indicate that at least Beringian hadrosaurids had similar habitat preferences regardless of latitude.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223471PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821036PMC
March 2020

Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics.

Brain 2019 10;142(10):2938-2947

Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Oxford, UK.

Ninety per cent of the human population has been right-handed since the Paleolithic, yet the brain signature and genetic basis of handedness remain poorly characterized. Here, we correlated brain imaging phenotypes from ∼9000 UK Biobank participants with handedness, and with loci found significantly associated with handedness after we performed genome-wide association studies (GWAS) in ∼400 000 of these participants. Our imaging-handedness analysis revealed an increase in functional connectivity between left and right language networks in left-handers. GWAS of handedness uncovered four significant loci (rs199512, rs45608532, rs13017199, and rs3094128), three of which are in-or expression quantitative trait loci of-genes encoding proteins involved in brain development and patterning. These included microtubule-related MAP2 and MAPT, as well as WNT3 and MICB, all implicated in the pathogenesis of diseases such as Parkinson's, Alzheimer's and schizophrenia. In particular, with rs199512, we identified a common genetic influence on handedness, psychiatric phenotypes, Parkinson's disease, and the integrity of white matter tracts connecting the same language-related regions identified in the handedness-imaging analysis. This study has identified in the general population genome-wide significant loci for human handedness in, and expression quantitative trait loci of, genes associated with brain development, microtubules and patterning. We suggest that these genetic variants contribute to neurodevelopmental lateralization of brain organization, which in turn influences both the handedness phenotype and the predisposition to develop certain neurological and psychiatric diseases.
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http://dx.doi.org/10.1093/brain/awz257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763735PMC
October 2019

Coagulation Factor Levels and Underlying Thrombin Generation Patterns in Adult Extracorporeal Membrane Oxygenation Patients.

Anesth Analg 2019 09;129(3):659-666

From the Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.

Background: There is a paucity of data on the underlying procoagulant-anticoagulant balance during extracorporeal membrane oxygenation (ECMO). We hypothesized that adult ECMO patients would have an imbalance between procoagulant and anticoagulant factors, leading to an abnormal underlying thrombin generation (TG) pattern.

Methods: Twenty adult venoarterial (VA) ECMO patients had procoagulant and anticoagulant factor levels measured temporally on ECMO day 1 or 2, day 3, and day 5. In heparin-neutralized plasma, underlying TG patterns, and sensitivity to activated protein C were assessed using calibrated automated thrombogram. TG parameters including lag time, peak TG, and endogenous thrombin potential (ETP) were compared against 5 normal plasma controls (3 males and 2 females) obtained from a commercial supplier. Thrombomodulin (TM) was added to some samples to evaluate for activated protein C resistance.

Results: Procoagulant factors (factor [F] II, FV, and FX) were mostly in normal reference ranges and gradually increased during the first 5 ECMO days (P = .022, <.001, <.001). FVIII levels were elevated at all time points and did not change (P = .766). In contrast, FXI was in the low-normal range but did not increase during ECMO (P = .093). Antithrombin (AT) and protein C levels were below normal but increased during the first 5 ECMO days (P = .002 and P = .014). Heparinase-treated samples showed prolonged lag time, increased peak TG, and increased ETP compared to controls; mean difference in lag time on ECMO day 1 or 2 = 6.0 minutes (99% confidence interval [CI], 2.8-9.2), peak TG = 193.4 (99% CI, 122.5-264.3), and ETP = 1170.4 (99% CI, 723.2-1617.6). After in vitro TM treatment, differences in TG parameters were accentuated and ECMO samples appeared insensitive to TM treatment; mean difference in lag time on ECMO day 1 or 2 = 9.3 minutes (99% CI, 6.2-12.4), peak TG = 233.0 (99% CI, 140.9-325.1), and ETP = 1322.5 (99% CI, 764.8-1880.2). Similar differences in TG parameters were observed on ECMO days 3 and 5.

Conclusions: Contact activation occurs during ECMO, but procoagulant factor levels are generally preserved. Although heparin-neutralized TG is delayed, peak TG and ETP are supranormal in the setting of high FVIII and low AT and protein C levels. Resistance to TM is also apparent. These changes demonstrate a possible mechanism for hypercoagulability during adult VA ECMO.
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http://dx.doi.org/10.1213/ANE.0000000000004275DOI Listing
September 2019

Inpatient management strategies in a severe case of heparin-induced thrombocytopenia.

Transfus Apher Sci 2019 Aug 9;58(4):525-528. Epub 2019 Jul 9.

WVU Heart and Vascular Institute, One Medical Center Drive, PO Box 8003, Morgantown, WV, 26506, United States. Electronic address:

We present important laboratory testing and clinical management strategies used to safely discharge home a 69-year old woman with heparin-induced thrombocytopenia (HIT) from the hospital. She was admitted for a coronary artery bypass graft procedure for which she was anticoagulated with heparin. Shortly after the procedure she developed thrombocytopenia and was diagnosed with HIT using the 4Ts scoring system, a latex-enhanced immunoassay (LEI) screen and confirmatory serotonin release assay. Her anticoagulation was switched from heparin to argatroban, and response to treatment was monitored in the laboratory using LEI. Unfortunately, she also received platelet transfusions and subsequently developed multifocal deep vein thrombosis with worsening platelet counts with nadir less than 10 x 10^3/μL. After five therapeutic plasma exchange procedures we noted an improvement in platelet counts, which plateaued into the 50s x 10^3/μL. Furthermore, the LEI remained positive. At this juncture we decided to transition from argatroban to fondaparinux so that she could leave the hospital in stable condition. Upon follow-up with hematology she exhibited no worsening clinical signs or symptoms of disease, and platelet counts markedly improved to within normal limits of detection. In this report we examine the utility of LEI in monitoring patients with HIT, therapeutic plasma exchange in the management of severe HIT (with thrombosis), and the use of subcutaneous fondaparinux in managing HIT in the outpatient setting.
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http://dx.doi.org/10.1016/j.transci.2019.06.030DOI Listing
August 2019

The First Definite Lambeosaurine Bone From the Liscomb Bonebed of the Upper Cretaceous Prince Creek Formation, Alaska, United States.

Sci Rep 2019 03 29;9(1):5384. Epub 2019 Mar 29.

University of Alaska, Department of Geosciences, Fairbanks, Alaska, 99775, United States.

The Prince Creek Formation of Alaska, a rock unit that represents lower coastal plain and delta deposits, is one of the most important formations in the world for understanding vertebrate ecology in the Arctic during the Cretaceous. Here we report on an isolated cranial material, supraoccipital, of a lambeosaurine hadrosaurid from the Liscomb Bonebed of the Prince Creek Formation. The lambeosaurine supraoccipital has well-developed squamosal bosses and a short sutural surface with the exoccipital-opisthotic complex, and is similar to lambeosaurine supraoccipitals from the Dinosaur Park Formation in having anteriorly positioned squamosal bosses. Affinities with Canadian lambeosaurines elucidate more extensive faunal exchange between the Arctic and lower paleolatitudes which was previously suggested by the presence of Edmontosaurus, Pachyrhinosaurus, tyrannosaurids, and troodontids in both regions. The presence of one lambeosaurine and nine hadrosaurine supraoccipitals in the Liscomb Bonebed suggests hadrosaurine dominated faunal structure as in the Careless Creek Quarry of the USA that was also deposited under a near-shore environment. It differs from the lambeosaurine dominant structures of localities in Russia and China interpreted as inland environments. This may suggest that lambeosaurines had less preference for near-shore environments than hadrosaurines in both Arctic and lower paleolatitudes.
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http://dx.doi.org/10.1038/s41598-019-41325-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440964PMC
March 2019

An unusual association of hadrosaur and therizinosaur tracks within Late Cretaceous rocks of Denali National Park, Alaska.

Sci Rep 2018 08 3;8(1):11706. Epub 2018 Aug 3.

Department of Biological Sciences, University of Wisconsin-Parkside, Kenosha, Wisconsin, 53141, United States.

We report details of a unique association of hadrosaur and therizinosaur tracks found in the Late Cretaceous lower Cantwell Formation, Denali National Park, central Alaska Range, Alaska. This rock unit is now well-documented as a source of thousands of fossil footprints of vertebrates such as fishes, pterosaurs, and avialan and non-avialan dinosaurs. The lower Cantwell Formation in this area consists of numerous fining-upward successions of conglomerates and pebbly sandstones, cross-stratified and massive sandstones, interbedded sandstones and siltstones, organic-rich siltstones and shales, and rare, thin, bentonites, typically bounded by thin coal seams, and it contains a diverse fossil flora. We report the first North American co-occurrence of tracks attributable to hadrosaurs and therizinosaurs in the lower Cantwell Formation. Although previously un-reported in North America, this association of hadrosaur and therizinosaur tracks is more characteristic of the correlative Nemegt Formation in central Asia, perhaps suggesting that parameters defining the continental ecosystem of central Asia were also present in this part of Alaska during the Latest Cretaceous.
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http://dx.doi.org/10.1038/s41598-018-30110-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076232PMC
August 2018

Development and validation of a HPLC-UV assay for quantification of levetiracetam concentrations in critically ill patients undergoing continuous renal replacement therapy.

Biomed Chromatogr 2018 Aug 30;32(8):e4257. Epub 2018 Apr 30.

Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.

Limited clinical data exists on the effects of continuous renal replacement therapy (CRRT) on drug pharmacokinetics. A high-performance liquid chromatography with ultraviolet detection method was developed and validated to determine levetiracetam concentrations in human plasma and CRRT effluent samples. Five hundred microliters of human plasma and 250 μL effluent samples were used to quantify levetiracetam. Plasma samples were purified by protein precipitation, evaporated under nitrogen gas at room temperature and reconstituted in 50 mm potassium dihydrogen phosphate buffer (pH of 4.5). Reverse-phase chromatographic separation was achieved within 20 min using a mobile phase eluting gradient of 50 mm potassium dihydrogen phosphate and acetonitrile. UV detection was set at 195 nm. The calibration curve was found to be linear over the range of 2-80μg/mL. Inter- and intra-day precisions were < 8% for both plasma and effluent samples. The accuracy was determined to be within -12-10% of nominal concentrations. The method was selective and sensitive with a lower limit of quantification of 2 μg/mL. Overall recovery of levetiracetam from plasma was ~100%. The validated assay was successfully applied in a pharmacokinetic study to determine potential dose adjustments in patients undergoing CRRT and receiving levetiracetam.
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http://dx.doi.org/10.1002/bmc.4257DOI Listing
August 2018

Lacosamide Pharmacokinetics in a Critically Ill Patient Receiving Continuous Venovenous Hemofiltration.

Pharmacotherapy 2018 02 18;38(2):e17-e21. Epub 2017 Dec 18.

Section of Neurocritical Care, Program in Trauma, University of Maryland School of Medicine, Baltimore, Maryland.

Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high-performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5-12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half-life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH.
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http://dx.doi.org/10.1002/phar.2063DOI Listing
February 2018

Editorial: Mental Health Challenges in Elite Sport: Balancing Risk with Reward.

Front Psychol 2017 25;8:1892. Epub 2017 Oct 25.

School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom.

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http://dx.doi.org/10.3389/fpsyg.2017.01892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661081PMC
October 2017

Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.

Neuroimage 2018 02 24;166:400-424. Epub 2017 Oct 24.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, UK.

UK Biobank is a large-scale prospective epidemiological study with all data accessible to researchers worldwide. It is currently in the process of bringing back 100,000 of the original participants for brain, heart and body MRI, carotid ultrasound and low-dose bone/fat x-ray. The brain imaging component covers 6 modalities (T1, T2 FLAIR, susceptibility weighted MRI, Resting fMRI, Task fMRI and Diffusion MRI). Raw and processed data from the first 10,000 imaged subjects has recently been released for general research access. To help convert this data into useful summary information we have developed an automated processing and QC (Quality Control) pipeline that is available for use by other researchers. In this paper we describe the pipeline in detail, following a brief overview of UK Biobank brain imaging and the acquisition protocol. We also describe several quantitative investigations carried out as part of the development of both the imaging protocol and the processing pipeline.
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http://dx.doi.org/10.1016/j.neuroimage.2017.10.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770339PMC
February 2018

Observational Assessment in the Febrile Infant.

Authors:
Paul L McCarthy

Pediatrics 2017 07 6;140(1). Epub 2017 Jun 6.

Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut

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http://dx.doi.org/10.1542/peds.2017-1100DOI Listing
July 2017