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Artificial Intelligence (AI) and Pharmacometrics: Time to Embrace, Capitalize and Advance?

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Artificial Intelligence (AI) and Pharmacometrics: Time to Embrace, Capitalize and Advance?

CPT Pharmacometrics Syst Pharmacol. 2019 Apr 21;:

Authors: Chaturvedula A, Calad-Thomson S, Liu C, Sale M, Gattu N, Goyal N

Abstract
Artificial intelligence (AI) has been described as the machine for the fourth industrial revolution. Without exception, AI is predicted to change the face of every industry. In the field of drug development, AI is employed to enhance efficiency. Pharmacometrics and systems pharmacology play a vital role in the drug development decision process. Thus, it is important to recognize and embrace the efficiencies that AI can bring to the pharmacometrics community. This article is protected by copyright. All rights reserved.

PMID: 31006175 [PubMed - as supplied by publisher]

Aggregated student confidence estimates support continuous quality improvements in a competencies-oriented curriculum.

Recent Research Articles from UNTHSC - Fri, 04/19/2019 - 05:52
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Aggregated student confidence estimates support continuous quality improvements in a competencies-oriented curriculum.

BMJ Open Qual. 2019;8(1):e000398

Authors: Papa FJ, Alexander JH

Abstract
Introduction: Competencies oriented medical curricula are intended to support the development of those specific tasks likely to improve patient care outcomes. In 2005, our institution developed curricular objectives and instructional activities intended to enable our students to competently perform four specific clinical tasks (diagnose, treat, manage and explain phenomena) for each of approximately 100 common and/or important patient presentations (eg, dyspnoea). However, competencies oriented curricula must also develop outcome metrics aligned with their objectives and instructional activities in order to launch a continuous quality improvement (CQI) programme. This investigation describes how a novel course evaluation methodology produced presentation and task-focused outcome metrics sufficient to support CQIs in our competencies-oriented curriculum.
Methods: Literature suggests that aggregated, group opinions are much more reliable than individual opinions in a variety of settings, including education. In 2010, we launched a course evaluation methodology using aggregated student self-assessments of their confidence in performing the four tasks trained to in each presentation-focused instructional activity. These aggregated estimates were transformed into a variety of graphic and tabular reports which faculty used to identify, and then remediate, those specific instructional activities associated with suboptimal presentation and task-focused confidence metrics.
Results: With academic year 2010-2011 serving as a baseline and academic year 2015-2016 as an endpoint, analysis of variance revealed a sustained and statistically significant gain in student confidence across this 6-year study period (p<0.001).
Discussion: This investigation demonstrated that aggregated, presentation and task-specific confidence estimates enabled faculty to pursue and attain CQIs in a competencies-oriented curriculum. Suggestions for new approaches to confidence-related research are offered.

PMID: 30997415 [PubMed]

Climatic adaptation in human inferior nasal turbinate morphology: Evidence from Arctic and equatorial populations.

Recent Research Articles from UNTHSC - Thu, 04/18/2019 - 05:40
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Climatic adaptation in human inferior nasal turbinate morphology: Evidence from Arctic and equatorial populations.

Am J Phys Anthropol. 2019 Apr 16;:

Authors: Marks TN, Maddux SD, Butaric LN, Franciscus RG

Abstract
OBJECTIVES: The nasal turbinates directly influence the overall size, shape, and surface area of the nasal passages, and thus contribute to intranasal heat and moisture exchange. However, unlike the encapsulating walls of the nasal cavity, ecogeographic variation in nasal turbinate morphology among humans has not yet been established. Here we investigate variation in inferior nasal turbinate morphology in two populations from climatically extreme environments.
MATERIALS AND METHODS: Twenty-three linear measurements of the inferior turbinate, nasal cavity walls, and airway passages were collected from CT scans of indigenous modern human crania from Equatorial Africa (n = 35) and the Arctic Circle (n = 35). MANOVA and ANCOVA were employed to test for predicted regional and sex differences in morphology between the samples.
RESULTS: Significant morphological differences were identified between the two regional samples, with no evidence of significant sexual dimorphism or region-sex interaction effect. Individuals from the Arctic Circle possessed superoinferiorly and mediolaterally larger inferior turbinates compared to Equatorial Africans. In conjunction with the surrounding nasal cavity walls, these differences in turbinate morphology produced airway dimensions that were both consistent with functional expectations and more regionally distinct than either skeletal component independently.
CONCLUSION: This study documents the existence of ecogeographic variation in human nasal turbinate morphology reflecting climate-mediated evolutionary demands on intranasal heat and moisture exchange. Humans adapted to cold-dry environments exhibit turbinate morphologies that enhance contact between respired air and nasal mucosa to facilitate respiratory air conditioning. Conversely, humans adapted to hot-humid environments exhibit turbinate morphologies that minimize air-to-mucosa contact, likely to minimize airflow resistance and/or facilitate expiratory heat-shedding.

PMID: 30993687 [PubMed - as supplied by publisher]

Does Mental Health Differ by Alcohol Use in Elderly Male Veterans?

Recent Research Articles from UNTHSC - Thu, 04/18/2019 - 05:40
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Does Mental Health Differ by Alcohol Use in Elderly Male Veterans?

Gerontol Geriatr Med. 2019 Jan-Dec;5:2333721419837803

Authors: Shaffer SE, Shaffer KJ, Perryman KD, Patterson JK, Hartos JL

Abstract
Introduction: With limited research for mental health and alcohol use among veterans in the general population and none for elderly male veterans only, the purpose is to assess whether mental health differs by alcohol use in elderly male veterans in the general population. Method: This cross-sectional analysis uses 2017 Behavioral Risk Factor Surveillance System data for male veterans aged 65 and older in general population samples from Florida (n = 1,700), Maryland (n = 1,060), New York (n = 552), and Washington (n = 1,031). Multiple logistic regression by state assessed the relationship between mental health and alcohol use, after controlling for health-related, demographic, and socioeconomic factors. Results: Across states, most participants reported good mental health (80%-84%) and more than half reported drinking (53%-63%). Adjusted results indicated that mental health did not differ by alcohol use in any state; however, it was related to physical health and activity limitations across states. Conclusion: Overall, alcohol use was not related to mental health in elderly male veterans in the general population; however, physical health status and activity limitations were. Practitioners should always screen for alcohol use and should automatically screen for mental health, physical health, and activity limitations when symptoms present for any and assess concurrent treatment and management strategies.

PMID: 30993150 [PubMed]

Combination of clotam and vincristine enhances anti-proliferative effect in medulloblastoma cells.

Recent Research Articles from UNTHSC - Wed, 04/17/2019 - 05:27

Combination of clotam and vincristine enhances anti-proliferative effect in medulloblastoma cells.

Gene. 2019 Apr 13;:

Authors: Patil S, Sankpal UT, Hurtado M, Bowman WP, Murray J, Borgmann K, Ghorpade A, Sutphin R, Eslin D, Basha R

Abstract
Medulloblastoma (MB) is characterized by highly invasive embryonal neuro-epithelial tumors that metastasize via cerebrospinal fluid. MB is difficult to treat and the chemotherapy is associated with significant toxicities and potential long-term disabilities. Previously, we showed that small molecule, clotam (tolfenamic acid: TA) inhibited MB cell proliferation and tumor growth in mice by targeting, survivin. Overexpression of survivin is associated with aggressiveness and poor prognosis in several cancers, including MB. The aim of this study was to test combination treatment involving Vincristine® (VCR), a standard chemotherapeutic drug for MB and TA against MB cells. DAOY and D283 MB cells were treated with 10 μg/mL TA or VCR (DAOY: 2 ng/mL; D283: 1 ng/mL) or combination (TA + VCR). These optimized doses were lower than individual IC50 values. The effect of single or combination treatment on cell viability (CellTiterGlo kit), Combination Index (Chou-Talalay method based on median-drug effect analysis), activation of apoptosis and cell cycle modulation (by flow cytometry using Annexin V and propidium iodide respectively) and the expression of associated markers including survivin (Western immunoblot) were determined. Combination Index showed moderate synergistic cytotoxic effect in both cells. When compared to individual agents, the combination of TA and VCR increased MB cell growth inhibition, induced apoptosis and caused cell cycle (G2/M phase) arrest. Survivin expression was also decreased by the combination treatment. TA is effective for inducing the anti-proliferative response of VCR in MB cells. MB has four distinct genetic/molecular subgroups. Experiments were conducted with MB cells representing two subgroups (DAOY: SHH group; D283: group 4/3). TA-induced inhibition of survivin expression potentially destabilizes mitotic microtubule assembly, sensitizing MB cells and enhancing the efficacy of VCR.

PMID: 30991098 [PubMed - as supplied by publisher]

The Effect of a Self-Efficacy-Enhancing Intervention on Perceived Self-Efficacy and Actual Adherence to Healthy Behaviours Among Women with Gestational Diabetes Mellitus.

Recent Research Articles from UNTHSC - Wed, 04/17/2019 - 05:27
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The Effect of a Self-Efficacy-Enhancing Intervention on Perceived Self-Efficacy and Actual Adherence to Healthy Behaviours Among Women with Gestational Diabetes Mellitus.

Sultan Qaboos Univ Med J. 2018 Nov;18(4):e513-e519

Authors: Al-Hashmi I, Hodge F, Nandy K, Thomas E, Brecht ML

Abstract
Objectives: This study aimed to evaluate the effectiveness of a self-efficacy-enhancing intervention (SEEI) on perceived self-efficacy and actual adherence to healthy behaviours among women with gestational diabetes mellitus (GDM).
Methods: This comparative pre-post study was conducted at the Antenatal Clinic of the Sultan Qaboos University Hospital, Muscat, Oman, between October 2016 and January 2017. A total of 90 adult Omani women with GDM were randomised to either a control group receiving standard prenatal care or a SEEI group. The SEEI group received an additional health education session and biweekly text messages to encourage adherence to healthy behaviours. All participants completed self-reported standardised questionnaires to determine perceived self-efficacy and actual adherence at baseline and after four weeks.
Results: At baseline, there were no significant differences between the control and SEEI groups in mean scores for perceived self-efficacy (122.9 ± 19.9 versus 118.2 ± 19.5; P = 0.26) or actual adherence to healthy behaviours (3.1 ± 1.2 versus 3.2 ± 1.0; P = 0.23). However, after four weeks, there was a significant positive difference between the SEEI and control groups in terms of pre-post change in scores for both perceived self-efficacy (9.9 ± 19.6 versus -1.8 ± 17.6; P <0.05) and actual adherence to healthy behaviours (1.5 ± 1.1 versus 0.4 ± 0.8; P <0.01).
Conclusion: The SEEI was found to significantly improve perceived self-efficacy and actual adherence to healthy behaviours among a group of Omani women with GDM.

PMID: 30988972 [PubMed - in process]

CRHR2 (Corticotropin-Releasing Hormone Receptor 2) in the Nucleus of the Solitary Tract Contributes to Intermittent Hypoxia-Induced Hypertension.

Recent Research Articles from UNTHSC - Wed, 04/17/2019 - 05:27
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CRHR2 (Corticotropin-Releasing Hormone Receptor 2) in the Nucleus of the Solitary Tract Contributes to Intermittent Hypoxia-Induced Hypertension.

Hypertension. 2018 10;72(4):994-1001

Authors: Wang LA, Nguyen DH, Mifflin SW

Abstract
This study tested the hypothesis that CRHRs (corticotropin-releasing hormone receptors) in the nucleus of the solitary tract (NTS) contribute to the hypertension induced by intermittent hypoxia (IH) exposure in rats. Initial studies using in situ hybridization revealed low mRNA level of CRHR1 (CRH type 1 receptor) but high mRNA level of CRHR2 (CRH type 2 receptor) in the NTS. Calcium imaging studies on NTS slice preparations using Fura-2-acetoxymethyl ester demonstrated that CRH induced a transient increase of intracellular calcium level. The CRH-induced calcium response was reproduced in the presence of TTX (tetrodotoxin) but was abolished by depletion of extracellular calcium or by the L-type calcium channel blocker Nifedipine. The CRH-induced calcium influx was attenuated by the CRHR2 antagonist K41498 but not by the CRHR1 antagonist NBI-35 965. Calcium influx can be induced by the CRHR2 agonist Urocortin II but not by the CRHR1 agonist Stressin 1. IH exposure did not affect CRHR1 mRNA level but significantly decreased CRHR2 mRNA level and the CRH-induced calcium influx in the NTS. Further in vivo studies showed that intra-fourth ventricle infusion of K41498 did not affect the basal blood pressure but significantly attenuated the IH-induced hypertension; intra-fourth ventricle infusion of Urocortin II significantly increased basal blood pressure and exacerbated the IH-induced hypertension. Collectively, these results suggest that CRHR2 in the NTS contributes to the IH-induced hypertension; downregulation of CRHR2 and CRHR2-mediated calcium influx in the NTS may serve as an adaptive response to protect against the IH-induced hypertension.

PMID: 30354709 [PubMed - indexed for MEDLINE]

Folic acid supplementation does not attenuate thermoregulatory or cardiovascular strain of older adults exposed to extreme heat and humidity.

Recent Research Articles from UNTHSC - Wed, 04/17/2019 - 05:27
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Folic acid supplementation does not attenuate thermoregulatory or cardiovascular strain of older adults exposed to extreme heat and humidity.

Exp Physiol. 2018 08;103(8):1123-1131

Authors: Gagnon D, Romero SA, Cramer MN, Kouda K, Poh PYS, Ngo H, Jay O, Crandall CG

Abstract
NEW FINDINGS: What is the central question of this study? Does folic acid supplementation alleviate thermoregulatory and cardiovascular strain of older adults during exposure to extreme heat and humidity? What is the main finding and its importance? Folic acid supplementation for 6 weeks did not affect whole-limb blood flow/vasodilatation, core and skin temperatures, heart rate, blood pressure and cardiac output. Thus, 6 weeks of folic acid supplementation does not alleviate thermoregulatory or cardiovascular strain of healthy older adults exposed to extreme heat and humidity.
ABSTRACT: Folic acid supplementation reverses age-related reductions in cutaneous vasodilatation during passive heating. However, it is unknown if folic acid supplementation alleviates thermoregulatory and cardiovascular strain experienced by older adults during heat exposure. We evaluated the effect of folic acid supplementation on thermoregulatory and cardiovascular responses of nine healthy older adults (61-72 years, 3 males/6 females) exposed to extreme heat and humidity. Participants rested at 42°C while relative humidity was increased from 30% to 70% in 2% increments every 5 min. The protocol was performed before (CON) and after (FOLIC) 6 weeks of folic acid supplementation (5 mg day-1 ). Local cutaneous vascular conductance (CVC, laser-Doppler flowmetry), forearm vascular conductance (FVC, Doppler ultrasound), mean skin and oesophageal temperatures, heart rate, blood pressure and cardiac output were measured. Folic acid supplementation increased fasting serum folate concentrations (P < 0.01). Absolute CVC was greater throughout the protocol following supplementation (CON: 1.29 ± 0.16 units mmHg-1 vs. FOLIC: 1.65 ± 0.24 units mmHg-1 , P < 0.01). However, normalized CVC (CON: 54 ± 8% vs. FOLIC: 59 ± 7%, P = 0.22), FVC (CON: 3.47 ± 0.76 ml mmHg-1 vs. FOLIC: 3.40 ± 0.56 ml mmHg-1 , P = 0.93), mean skin (P = 0.81) and oesophageal (CON: 36.87 ± 0.28°C vs. folic: 36.90 ± 0.25°C, P = 0.98) temperatures, heart rate (CON: 83 ± 10 beats min-1 vs. FOLIC: 84 ± 8 beats min-1 , P = 0.64), blood pressure (P = 0.71) and cardiac output (P = 0.20) were unaffected by folic acid supplementation. These results demonstrate that 6 weeks of folic acid supplementation does not alleviate thermoregulatory or cardiovascular strain of healthy older adults exposed to extreme heat and humidity.

PMID: 29873123 [PubMed - indexed for MEDLINE]

Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in a Murine Model of Pyelonephritis.

Recent Research Articles from UNTHSC - Wed, 04/17/2019 - 05:27
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Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in a Murine Model of Pyelonephritis.

Antimicrob Agents Chemother. 2018 01;62(1):

Authors: Weiss WJ, Pulse ME, Nguyen P, Peterson K, Silva J, Simecka JW, Valtierra D, Sabet M, Griffith DC

Abstract
The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

PMID: 29038270 [PubMed - indexed for MEDLINE]

Locomotor activity and discriminative stimulus effects of five novel synthetic cathinone analogs in mice and rats.

Recent Research Articles from UNTHSC - Tue, 04/16/2019 - 05:15

Locomotor activity and discriminative stimulus effects of five novel synthetic cathinone analogs in mice and rats.

Drug Alcohol Depend. 2019 Apr 06;199:50-58

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
BACKGROUND: The development of novel synthetic psychoactive substances continues to accelerate. There are little or no data on the pharmacological mechanisms, behavioral effects, or abuse liability of many of the newer compounds, despite increasing reports of severe adverse effects in recreational users.
METHODS: The current study investigated the discriminative stimulus and locomotor stimulant effects of a group of synthetic cathinone analogs: N-ethylpentylone, dimethylone, dibutylone, clephedrone, 3',4'-tetramethylene-α-pyrrolidinovalerophenone (TH-PVP). Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine or MDMA from vehicle.
RESULTS: N-Ethylpentylone, dimethylone, dibutylone and clephedrone increased locomotor activity. Maximal effects were similar among the test compounds. Relative potencies were: methamphetamine > N-ethylpentylone > clephedrone > dimethylone > MDMA > cocaine > dibutylone. TH-PVP dose-dependently depressed locomotor activity. N-Ethylpentylone, dimethylone, dibutylone and clephedrone substituted fully for the discriminative stimulus effects of methamphetamine. N-Ethylpentylone, dibutylone and clephedrone fully substituted for cocaine, whereas dimethylone produced a maximum of 67% drug-appropriate responding. Dimethylone, dibutylone and clephedrone fully substituted for MDMA, whereas N-ethylpentylone produced only 50% drug-appropriate responding. TH-PVP produced a maximum of 38% methamphetamine-appropriate responding, 50% cocaine-appropriate responding, and less than 1% MDMA-appropriate responding.
CONCLUSIONS: These data provide initial evidence that the novel psychoactive substances N-ethylpentylone, dimethylone, dibutylone, and clephedrone demonstrate potential for abuse as psychostimulants and/or club drugs, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine, cocaine and/or MDMA. TH-PVP has minimal activity in the assays tested and may have little or no abuse liability.

PMID: 30986635 [PubMed - as supplied by publisher]

Distinguishing Comorbidity, Disability, and Frailty.

Recent Research Articles from UNTHSC - Tue, 04/16/2019 - 05:15

Distinguishing Comorbidity, Disability, and Frailty.

Curr Geriatr Rep. 2018 Dec;7(4):201-209

Authors: Espinoza SE, Quiben M, Hazuda HP

Abstract
Purpose of review: Over half of the older adults in U.S. have multimorbidity, defined broadly as the presence of 2 or more chronic diseases in an individual. Multimorbidity has significant overlap with disability and frailty. In this review, we broadly review the concepts of multimorbidity, disability, and frailty, as well as their interrelationships, and ability to predict future adverse health outcomes in older adults.
Recent findings: Depending on the study, the prevalence of individuals with all three of multimorbidity, disability, and frailty ranges from 2-20%. Multimorbidity and patterns of multimorbidity are predictive of functional limitations, disability, health care usage, and mortality. The degree to which multimorbidity predicts these outcomes depends on many factors but partly upon the population examined and the presence of frailty and disability.
Summary: Multimorbidity is an emerging public health concern that is observed with and predictive of disability and frailty.

PMID: 30984516 [PubMed]

Disparities in Hospice Utilization for Older Cancer Patients Living in the Deep South.

Recent Research Articles from UNTHSC - Mon, 04/15/2019 - 05:08

Disparities in Hospice Utilization for Older Cancer Patients Living in the Deep South.

J Pain Symptom Manage. 2019 Apr 11;:

Authors: Turkman YE, Williams CP, Jackson BE, Dionne-Odom JN, Taylor R, Ejem D, Kvale E, Pisu M, Bakitas M, Rocque GB

Abstract
CONTEXT: Hospice utilization is an end-of-life quality indicator. The Deep South has known disparities in palliative care that may affect hospice utilization.
OBJECTIVES: To evaluate the association among Deep South patient and hospital characteristics and hospice utilization.
METHODS: This retrospective cohort study evaluated patient and hospital characteristics associated with hospice among Medicare cancer decedents aged ≥65 in 12 southeastern cancer centers between 2012-2015. We examined patient-level characteristics (age, race, gender, cancer type, and received patient navigation) and hospital-level characteristics (board-certified palliative physician, inpatient palliative care beds, and hospice ownership). Outcomes included hospice (within 90 vs 3 days of death). Relative risks (RR) and 95% confidence intervals evaluated the association between patient- and hospital-level characteristics and hospice outcomes using generalized log-linear models with Poisson distribution and robust variance estimates.
RESULTS: Of 12,725 cancer decedents, 4,142 (33%) did not utilize hospice. "No hospice" was associated with non-white (RR 1.24, 95% CI 1.17, 1.32) and non-navigated patients (RR 1.17, 95% CI 1.10, 1.25), and those at a hospital with inpatient palliative care beds (RR 1.15, 95% CI 1.10, 1.21). "Late hospice" (20%; n=1,458) was associated with being male (RR 1.31, 95% CI 1.19, 1.44) and seen at a hospital without inpatient palliative care beds (RR 0.82, 95% CI 0.75, 0.90).
CONCLUSION: Hospice utilization differed by patient and hospital characteristics. Patients who were non-white, and non-navigated; and, hospitals with inpatient palliative care beds were associated with no hospice. Research should focus on ways to improve hospice utilization in Deep South older cancer patients.

PMID: 30981781 [PubMed - as supplied by publisher]

Population Pharmacokinetics of Pemetrexed in Adult Non-Small Cell Lung Cancer in Indian Patients.

Recent Research Articles from UNTHSC - Fri, 04/12/2019 - 07:40
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Population Pharmacokinetics of Pemetrexed in Adult Non-Small Cell Lung Cancer in Indian Patients.

J Clin Pharmacol. 2019 Apr 11;:

Authors: Srinivasan M, Chaturvedula A, Fossler MJ, Patil A, Gota V, Prabhash K

Abstract
The objective of the study was to develop a population pharmacokinetic model of pemetrexed and identify factors contributing to variability in exposure in Indian patients. Plasma samples were obtained from a cohort of 85 patients following 500 mg/m2 intravenous infusion and population pharmacokinetic analysis was performed using NONMEM (version 7.3.0). The stochastic approximation expectation maximization method was used to estimate parameters. The full covariate model approach was used by specifying clinically meaningful covariates a priori. Credible intervals obtained using Markov chain Monte Carlo Bayesian analysis were used to reduce the full covariate model by eliminating the covariates whose CI included the null. Model qualification was performed using visual predictive check and bootstrap. The final population parameter estimates and relative standard error for clearance (CL) was 3.3 L/h (10.8), central volume of distribution (V1) was 5.2 L (7.8), peripheral volume of distribution (V2) was 5.9 L (14.5) and intercompartmental clearance (Q) was 6.8 L/h (14.3). A large between-subject variability (50%-108% coefficient of variation) was observed in pharmacokinetic parameters. The percent coefficient of variation for the area under the plasma concentration-time curve from time zero to infinity was 72% and for maximum concentration was 68.25%. Diagnostic plots showed no major bias in the model. The final model included V1, V2, and Q scaled to body surface area raised to a fixed exponent of 1. Creatinine clearance and sex on clearance and albumin on V1 were statistically significant covariates based on Bayesian credible interval. However, traditional bootstrap resulted in a 95% confidence interval of the sex effect parameter including null. Given the size and nonsignificant sex effect in traditional bootstrap, it is considered clinically not significant.

PMID: 30973978 [PubMed - as supplied by publisher]

A genome-wide association study of tramadol metabolism from post-mortem samples.

Recent Research Articles from UNTHSC - Fri, 04/12/2019 - 07:40
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A genome-wide association study of tramadol metabolism from post-mortem samples.

Pharmacogenomics J. 2019 Apr 11;:

Authors: Wendt FR, Rahikainen AL, King JL, Sajantila A, Budowle B

Abstract
Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.

PMID: 30971809 [PubMed - as supplied by publisher]

Ledipasvir/Sofosbuvir Effectively Treats Hepatitis C Virus Infections in an Underserved Population.

Recent Research Articles from UNTHSC - Fri, 04/12/2019 - 07:40
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Ledipasvir/Sofosbuvir Effectively Treats Hepatitis C Virus Infections in an Underserved Population.

Dig Dis Sci. 2018 12;63(12):3233-3240

Authors: Stewart RA, MacDonald BR, Chu TC, Moore JD, Fasanmi EO, Ojha RP

Abstract
BACKGROUND: Underserved populations have an unequal burden of HCV infections and poor outcomes with interferon-based treatments. Direct-acting antivirals have the potential to reduce these inequalities.
AIMS: We aimed to estimate sustained virologic response (SVR) following treatment with sofosbuvir-based regimens for HCV infections among underserved individuals and summarize the frequency of SVR across published studies of underserved populations.
METHODS: We used data from a clinical cohort of patients aged ≥ 18 years who initiated sofosbuvir-based regimens for HCV infection between February 2014 and June 2016 at an urban public hospital network that serves as the healthcare safety-net for Tarrant County, Texas. We estimated SVR with corresponding 95% confidence limits (CL). In addition, we systematically reviewed the evidence to identify other studies of direct-acting antivirals among underserved populations.
RESULTS: Our study population comprised 435 patients. The majority of patients were aged ≥ 50 years (76%), male (52%), non-Hispanic White (54%), HCV genotype 1 (79%) and treated with ledipasvir/sofosbuvir (69%). Overall SVR was 89% (95% CL 86, 92%) and highest for ledipasvir/sofosbuvir (SVR = 95%, 95% CL 92, 97%). The reported SVR following direct-acting antivirals among 837 underserved patients from three other studies ranged between 90 and 99%.
CONCLUSIONS: Our results suggest that direct-acting antivirals, particularly ledipasvir/sofosbuvir, are generally effective for achieving SVR among underserved patients with HCV infections and may help reduce inequalities in HCV prevalence and outcomes for this vulnerable population.

PMID: 30014226 [PubMed - indexed for MEDLINE]

A Case-Based Method for New Resident Orientation.

Recent Research Articles from UNTHSC - Wed, 04/10/2019 - 07:19
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A Case-Based Method for New Resident Orientation.

J Grad Med Educ. 2018 Jun;10(3):351-353

Authors: Nash LR

PMID: 29946403 [PubMed - indexed for MEDLINE]

Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine.

Recent Research Articles from UNTHSC - Tue, 04/09/2019 - 07:11
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Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine.

Neurotoxicology. 2018 07;67:121-128

Authors: Salvatore MF, Nejtek VA, Khoshbouei H

Abstract
Methamphetamine (MA) exposure may increase the risk of motor or cognitive impairments similar to Parkinson's disease (PD) by middle age. Although damage to nigrostriatal or mesoaccumbens dopamine (DA) neurons may occur during or early after MA exposure, overt PD-like symptoms at a younger age may not manifest due to compensatory mechanisms to maintain DA neurotransmission. One possible compensatory mechanism is increased tyrosine hydroxylase (TH) phosphorylation. In the rodent PD 6-OHDA model, nigrostriatal lesion decreases TH protein in both striatum and substantia nigra (SN). However, DA loss in the SN is significantly less than that in the striatum. An increase in ser31 TH phosphorylation in the SN may increase TH activity in response to TH loss. To determine if similar compensatory mechanisms may be engaged in young mice after MA exposure, TH expression, phosphorylation, and DA tissue content were evaluated, along with dopamine transporter expression, 21 days after cessation of MA (24 mg/kg, daily, 14 days). DA tissue content was unaffected by the MA regimen in striatum, nucleus accumbens, SN, or ventral tegmental area (VTA), despite decreased TH protein in SN and VTA. In the SN, but not striatum, ser31 phosphorylation increased over 2-fold. This suggests that increased ser31 TH phosphorylation may be an inherent compensatory mechanism to attenuate DA loss against TH loss, similar to that in an established PD model. These results also indicate the somatodendritic compartments of DA neurons are more vulnerable to TH protein loss than terminal fields following MA exposure.

PMID: 29782882 [PubMed - indexed for MEDLINE]

Adherence and viral suppression among participants of the Patient-centered HIV Care Model project-a collaboration between community-based pharmacists and HIV clinical providers.

Recent Research Articles from UNTHSC - Sun, 04/07/2019 - 06:50
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Adherence and viral suppression among participants of the Patient-centered HIV Care Model project-a collaboration between community-based pharmacists and HIV clinical providers.

Clin Infect Dis. 2019 Apr 06;:

Authors: Byrd KK, Hou JG, Bush T, Hazen R, Kirkham H, Delpino A, Weidle PJ, Shankle MD, Camp NM, Suzuki S, Clay PG, Patient-centered HIV Care Model Team

Abstract
BACKGROUND: HIV viral suppression (VS) decreases morbidity, mortality, and transmission risk.
METHODS: The Patient-centered HIV Care Model (PCHCM) integrated community-based pharmacists with HIV medical providers and required them to share patient clinical information, identify therapy-related problems, and develop therapy-related action plans.Proportions of persons adherent to antiretroviral therapy (Proportion of Days Covered [PDC] ≥90%) and virally suppressed (HIV RNA <200 copies/mL), pre- and post-PCHCM implementation, were compared. Factors associated with post-implementation VS were determined using multivariable logistic regression. Participant demographics, baseline viral load (VL), and PDC were explanatory variables in the models. PDC was modified to account for time to last VL in the year post-implementation, and stratified as: ≥90%, <90-80%, <80-50%, <50%.
RESULTS: The 765 enrolled participants were 43% non-Hispanic black, 73% male, with a median age of 48 years (interquartile range: 38-55); 421 and 649 were included in the adherence and VS analyses, respectively. Overall, proportions adherent to therapy remained unchanged. However, VS improved a relative 15% (75% to 86%, p<0.001). Persons with higher modified PDC (adjusted odds ratio [AOR] 1.74 per one-level increase in PDC category; 95% CI: 1.30-2.34) and those virally suppressed at baseline (AOR 7.69; CI: 3.96-15.7) had greater odds of post-implementation suppression. Although non-Hispanic black persons (AOR 0.29; CI: 0.12-0.62) had lower odds of suppression, VS improved a relative 23% (63% to 78%, p<0.001), pre- to post-implementation.
CONCLUSION: Integrated care models between community-based pharmacists and primary medical providers may identify and address HIV therapy-related problems and improve overall VS among persons with HIV.

PMID: 30953062 [PubMed - as supplied by publisher]

Social Determinants of Human Papillomavirus Vaccine Uptake: An Assessment of Publicly Available Data.

Recent Research Articles from UNTHSC - Sat, 04/06/2019 - 06:38
Related Articles

Social Determinants of Human Papillomavirus Vaccine Uptake: An Assessment of Publicly Available Data.

Public Health Rep. 2019 Apr 05;:33354919838219

Authors: Maness SB, Thompson EL

Abstract
OBJECTIVES:: Despite cancer prevention benefits associated with the human papillomavirus (HPV) vaccine, uptake in the United States is relatively low among males and females. Our objective was to use the Healthy People 2020 social determinants of health framework to determine the availability and characteristics of data on economic, educational, social, health care, and community factors affecting HPV vaccine uptake in the United States.
METHODS:: We included the most recent data sets from 6 publicly available, US-based, federally funded surveys that contained at least 1 measure of HPV vaccination among adolescents and young adults. We searched each data set for any social determinants of health measures within the 5 domains of the framework: economic stability, education, social and community context, health and health care, and neighborhood and built environment.
RESULTS:: The social determinants of health domains of education, economic stability, and health and health care appeared in all data sets. The domains of social and community context and neighborhood and built environment appeared in only 3 data sets. Even when domains were represented, we discovered gaps in the data sets, in which only limited measures of the social determinants were available.
CONCLUSION:: The addition of questions about the social determinants of health to the surveys that generate these data sets, particularly in the domains of social and community context and neighborhood and built environment, would strengthen the ability of public health researchers, policy makers, and professionals to identify associations between the social determinants of health and HPV vaccine uptake.

PMID: 30951641 [PubMed - as supplied by publisher]

Variations of the lung microbiome and immune response in mechanically ventilated surgical patients.

Recent Research Articles from UNTHSC - Sat, 04/06/2019 - 06:38
Related Articles

Variations of the lung microbiome and immune response in mechanically ventilated surgical patients.

PLoS One. 2018;13(10):e0205788

Authors: Huebinger RM, Smith AD, Zhang Y, Monson NL, Ireland SJ, Barber RC, Kubasiak JC, Minshall CT, Minei JP, Wolf SE, Allen MS

Abstract
Mechanically ventilated surgical patients have a variety of bacterial flora that are often undetectable by traditional culture methods. The source of infection in many of these patients remains unclear. To address this clinical problem, the microbiome profile and host inflammatory response in bronchoalveolar lavage samples from the surgical intensive care unit were examined relative to clinical pathology diagnoses. The hypothesis was tested that clinical diagnosis of respiratory tract flora were similar to culture positive lavage samples in both microbiome and inflammatory profile. Bronchoalveolar lavage samples were collected in the surgical intensive care unit as standard of care for intubated individuals with a clinical pulmonary infection score of >6 or who were expected to be intubated for >48 hours. Cytokine analysis was conducted with the Bioplex Pro Human Th17 cytokine panel. The microbiome of the samples was sequenced for the 16S rRNA region using the Ion Torrent. Microbiome diversity analysis showed the culture-positive samples had the lowest levels of diversity and culture negative with the highest based upon the Shannon-Wiener index (culture positive: 0.77 ± 0.36, respiratory tract flora: 2.06 ± 0.73, culture negative: 3.97 ± 0.65). Culture-negative samples were not dominated by a single bacterial genera. Lavages classified as respiratory tract flora were more similar to the culture-positive in the microbiome profile. A comparison of cytokine expression between groups showed increased levels of cytokines (IFN-g, IL-17F, IL-1B, IL-31, TNF-a) in culture-positive and respiratory tract flora groups. Culture-positive samples exhibited a more robust immune response and reduced diversity of bacterial genera. Lower cytokine levels in culture-negative samples, despite a greater number of bacterial species, suggest a resident nonpathogenic bacterial community may be indicative of a normal pulmonary environment. Respiratory tract flora samples were most similar to the culture-positive samples and may warrant classification as culture-positive when considering clinical treatment.

PMID: 30356313 [PubMed - indexed for MEDLINE]

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