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Changing land use/land cover (LULC) and climate substantially affect the hydrological components of a watershed. This study explored the future impact of the hydrological responses due to the changing LULC and climate on the Big Creek Lake watershed in Alabama, USA, from 2021 to 2050 using the Soil and Water Assessment Tool (SWAT). Five climate model datasets were used under the moderate scenario (Representative Concentrative Pathways 4.5) and the extreme scenario (Representative Concentrative Pathways 8.5), and the datasets were downscaled and bias-corrected. In addition, changing the LULC of five categories was predicted by Cellular Automata Markov (CA- Markov). With these data combined with the elevation (Digital Elevation Model), soils, and weather data, the SWAT model was calibrated and validated for the studied watershed to quantify how climate change will affect streamflow, nitrogen, and phosphorus. Our results indicate streamflow will increase due to the 50-acre increase in urban LULC. As streamflow increases, the percolation, surface runoff, lateral flow, groundwater flow, and water yield will also increase because the streamflow impacts these hydrological components. Moreover, the increase rate in streamflow is the same for all the components for January, February, and March. Therefore, there is a strong correlation between these months. On the contrary, evaporation will be high in May, June, and July because of the increasing temperature and streamflow. However, the changes in the water hydrological parameters and total nitrogen and phosphorus will be more intense in RCP8.5 than in RCP4.5., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Phosphorus (P) and Ammonium Nitrogen (N) are essential nutrients for plants and environmental stability. However, their excess in water causes eutrophication, damaging aquatic ecosystems. While adsorption is a promising solution, finding affordable and efficient adsorbents remains a challenge. In this study, magnesium (Mg), iron (Fe), and Mg/Fe doped biochars (BC) adsorbents were synthesized, and evaluated for adsorption of individual P and N and a P + N mixture from a solution and wastewater from a wastewater treatment plant. Compared to other adsorbents, Mg/BC showed excellent performance in adsorbing phosphorus (P) and ammonium nitrogen (N) from aqueous solutions. It demonstrated a large adsorption capacity of 64.65 mg/g and 62.50 mg/g from individual P and N solutions, and 30.3 mg/g and 27.67 mg/g from the P and N mixture solution, respectively. In addition, Mg/BC efficiently removed P and N from real-life wastewater. In the real wastewater, P and N removal efficiencies reached 88.30% and 59.36%, respectively. Kinetics analysis revealed that the pseudo-second-order model accurately described the adsorption of phosphorus (P) and ammonium nitrogen (N) in all solutions. The adsorbent followed the monolayer-Langmuir isotherm for N ions and the multilayer-Freundlich isotherm for P, indicating efficient adsorption processes. Thermodynamic experiments indicated that the adsorption of P and N was not only feasible but also occurred spontaneously in a natural manner. This study revealed that the strategic modification of biochar plays a crucial role in advancing effective wastewater treatment technologies designed for nutrient removal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The aim of this study was to assess the prevalence and severity of apical periodontitis (AP) in subjects with different stages of chronic kidney disease (CKD) and its association with systemic markers., Methods: In this cross-sectional study, 105 patients with CKD (n = 35 each in the early, predialysis, and hemodialysis groups) and 105 healthy controls were included. The prevalence, number of teeth with AP (endodontic burden [EB]), and the severity of AP were recorded. High- sensitivity C-reactive protein, blood urea, and serum creatinine levels were also recorded. Logistic regression was applied to determine the possible association between CKD and AP in the study population, and linear regression was performed to predict the effect of AP on systemic markers in CKD patients., Results: AP in at least 1 tooth was found in 75.2% of CKD patients and 40.9% of the controls (P < .05). CKD patients were 4 times more likely to have AP than controls (P < .05; odds ratio = 3.954; 95% confidence interval, 2.09-7.45). EB and the severity of AP were also significantly higher in CKD patients than the healthy controls (P < .05). Although higher values of EB and severe AP were observed with the progression of disease, the difference was not significant. The severity of AP was significantly associated with an increase in serum creatinine, blood urea, and a decrease in estimated glomerular filtration rate (P < .05) in CKD patients., Conclusions: AP was significantly more prevalent in the CKD group. The association between the severity of AP and CKD markers suggests that AP could possibly alter the progression of CKD. However, these findings do not establish a cause-and-effect relationship., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Efficient treatment of nutrient-rich wastewater is of paramount importance for protecting the ecosystem. In this work, an efficient, abundant, and eco-friendly adsorbent was derived from biochar and employed for phosphorus (P) adsorption. The key factors influencing the P removal efficiency of the activated biochar, including P concentration, pH, dosage, temperature, adsorption time, and influence of co-existing ion type, were investigated. Maximum P adsorption percentage (100%) was obtained with 10 mg/L and zinc chloride activated biochar (BC-Zn) compared to the other activated biochars. Results show that by increasing the P concentration from 5 to 200 mg/L, the phosphorus adsorption capacity increases from 0.13 to 10.4 mg/g biochar. Isotherms and kinetic studies further show that the P adsorption follows the Langmuir and quasi-second-order kinetic models. The mechanistic investigation demonstrated that P adsorption occurred by precipitation reaction. Furthermore, P desorption has been studied at different time intervals to understand the P release rate after adsorption., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Hematopoietic stem cell transplant (HSCT) is the only curative treatment for several pediatric non-malignant disorders. A widely used conditioning backbone is busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG). Thiotepa has improved engraftment when added to this regimen, however the minimum effective dose (MED) of thiotepa to achieve engraftment while minimizing toxicities has not been well established., Objectives: The primary objective of this prospective feasibility study was to determine the MED of thiotepa (5mg/kg) in combination with reduced-dose busulfan, fludarabine or cyclophosphamide, and rATG required to achieve engraftment in >90% of HSCT recipients for non-malignant disorders with acceptable toxicity., Results: Six patients who received fully matched HSCT were enrolled. Patient diagnoses included Wiskott-Aldrich syndrome (n = 1), CD40L deficiency (n = 1), sickle cell disease (n = 2), autoinflammatory syndrome (n = 1), and paroxysmal nocturnal hemoglobinuria (n = 1). All six patients achieved engraftment prior to Day +42 and five patients had stable full donor engraftment. Two of the six patients (33%) developed acute GVHD and/or chronic GHVD, both of whom had sickle cell disease. At a median follow-up of 2.25 years post-transplant, all patients were alive without evidence of disease recurrence. None of the patients experienced grade 4 or 5 toxicities. Three out of six patients (50%) developed grade 3 adverse events. Neurocognitive functioning of children under 10 years of age was not adversely affected by this regimen., Conclusion: This approach shows acceptable toxicity and reliable engraftment in children with non-malignant disorders receiving related or unrelated HLA-matched transplants., (© 2023 Wiley Periodicals LLC.)

Recent observations and climate change projections indicate that changes in rainfall energy, intensity, duration, and frequency, which determine the erosive power of rainfall, will amplify erosion rates around the world. However, the magnitude and scope of these future changes in erosive power of rainfall remain largely unknown, particularly at finer-resolutions and local scales. Due to a lack of available projected future sub-hourly climate data, previous studies relied on aggregates (hourly, daily) rainfall data. The erosivity for the southeastern United States in this study was calculated using the RUSLE2 erosivity calculation method without data limitation and a recently published 15-min precipitation dataset. This precipitation data was derived from five NA-CORDEX climate models' precipitation products under the Representative Concentration Pathway (RCP) 8.5 scenario. In this dataset, hourly climate projections of precipitation were bias-corrected and temporally downscaled to 15-min resolution for 187 locations with collocated 15-min precipitation observations. Precipitation, erosivity (R-factor), and erosivity density (ED) estimations were provided for historical (1970-1999) and future (2030-2059) time periods. Ensemble results for projected values (as compared to historical values) showed increase in precipitation, erosivity, and erosivity density by 14 %, 47 %, and 29 %, respectively. The future ensemble model showed an average annual R-factor of 11,237±1299 MJ mm ha -1 h -1 yr -1 . These findings suggest that changes in rainfall intensity, rather than precipitation amount, may be driving the change in erosivity. However, the bias correction and downscaling limitations inherent in the original precipitation dataset and this study's analyses obscured this particular result. In general, coastal and mountainous regions are expected to experience the greatest absolute increase in erosivity, while other inland areas are expected to experience the greatest relative change. This study offers a novel examination of projected future precipitation characteristics in terms of erosivity and potential future erosion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

2,4,6-trinitrotoluene (TNT), a nitro-aromatic explosive commonly used for defense and several non-violent applications is contributing to serious environmental pollution problems including human health. The current study investigated the remediation potential of a native soil isolate, i.e., Indiicoccus explosivorum (strain S5-TSA-19) isolated from collected samples of an explosive manufacturing site, against TNT. The survivability of I. explosivorum against explosives is indirectly justified through its isolation; thus, it is being chosen for further study. At a TNT concentration of 120 mg/L within an optimized environment (i.e., at 30 °C and 120 rpm), the isolate was continually incubated for 30 days in a minimal salt medium (MSM). The proliferation of the isolate and the concentration of TNT, nitrate, nitrite, and ammonium ion were evaluated at a particular time during the experiment. Within 168 h (i.e., 7 days) of incubation, I. explosivorum co-metabolically degraded 100% TNT. The biodegradation procedure succeeded the first-order kinetics mechanism. Formations of additional metabolites like 2,4-dinitrotoluene (DNT), 2,4-diamino-6-nitrotoluene (2-DANT), and 2-amino-4,6-dinitrotoluene (2-ADNT), were also witnessed. TNT seems to be non-toxic for the isolate, as it reproduced admirably in TNT presence. To date, it is the first report of Indiicoccus explosivorum, efficiently bio-remediating TNT, i.e., a nitro-aromatic compound via different degradation pathways, leading to the production of simpler as well as less harmful end products. Further, at the field-scale application, Indiicoccus explosivorum may be explored for the bioremediation of TNT (i.e., a nitro-aromatic compound)-contaminated effluents., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Climate change impacts on precipitation characteristics will alter the hydrologic characteristics, such as peak flows, time to peak, and erosion potential of watersheds. However, many of the currently available climate change datasets are provided at temporal and spatial resolutions that are inadequate to quantify projected changes in hydrologic characteristics of a watershed. Therefore, it is critical to temporally disaggregate coarse-resolution precipitation data to finer resolutions for studies sensitive to precipitation characteristics. In this study, we generated novel 15-minute precipitation datasets from hourly precipitation datasets obtained from five NA-CORDEX downscaled climate models under RCP 8.5 scenario for the historical (1970-1999) and projected (2030-2059) years over the Southeast United States using a modified version of the stochastic method. The results showed conservation of mass of the precipitation inputs. Furthermore, the probability of zero precipitation, variance of precipitation, and maximum precipitation in the disaggregated data matched well with the observed precipitation characteristics. The generated 15-minute precipitation data can be used in all scientific studies that require precipitation data at that resolution., (© 2022. The Author(s).)

Nonmyeloablative (NMA) haploidentical hematopoietic stem cell transplantation for sickle cell disease has significantly increased donor availability for transplant and is increasingly used as curative treatment. The authors describe 3 pediatric patients who rejected grafts after an NMA regimen, previously reported to result in good engraftment rates in the mainly adult population. In this manuscript, potential factors contributing to rejection are described and discussed. The authors emphasize the need to further optimize the NMA regimens in pediatric patients and perform haploidentical transplants for sickle cell disease on clinical trials., Competing Interests: V.B. is currently receiving support from the NHLBI, HRSA, Micelle BioPharma, and Pfizer. He is on the Sanofi-advisory board. J.L. is receiving support from NIH-R01CA132946 and Live Like Bella FLD OH (9LA04). The remaining authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

2,4,6-trinitrotoluene or TNT, a commonly used explosive, can pollute soil and groundwater. Conventional remediation practices for the TNT-contaminated sites are neither eco-friendly nor cost-effective. However, exploring bacteria to biodegrade TNT into environment-friendly compound(s) is an interesting area to explore. In this study, an indigenous bacterium, Pseudarthrobacter chlorophenolicus, strain S5-TSA-26, isolated from explosive contaminated soil, was investigated for potential aerobic degradation of TNT for the first time. The isolated strain of P. chlorophenolicus was incubated in a minimal salt medium (MSM) containing 120 mg/L TNT for 25 days at specified conditions. TNT degradation pattern by the bacterium was monitored at regular interval using UV-Vis spectrophotometry, high-performance liquid chromatography, and liquid chromatography mass spectrophotometric, by estimating nitrate, nitrite, and ammonium ion concentration and other metabolites such as 2,4-dinitrotoluene (DNT), 2-amino-4,6-dinitrotoluene (2-ADNT), and 2,4-diamino-6-nitrotoluene (2-DANT). It was observed that, in the presence of TNT, there was no reduction in growth of the bacterium although it multiplied well in the presence of TNT along with no considerable morphological changes. Furthermore, it was found that TNT degraded completely within 15 days of incubation. Thus, from this study, it may be concluded that the bacterium has the potential for degrading TNT completely with the production of non-toxic by-products and might be an important bacterium for treating TNT (i.e., a nitro-aromatic compound)-contaminated sites.

Agricultural water quality projects in two distinct topographic regions in Wisconsin collected 5 to 10 yr of continuous stream discharge, suspended sediment (SS), total P (TP), and total dissolved P (TDP) in four watersheds (2100-5000 ha) from 2006 to 2016. Previous agricultural nonpoint SS and TP reduction efforts in two of these watersheds documented cold versus warm season differences in water quality response. The goal of this study was to identify seasonal partitioning of SS, TP, and TDP in storm event loads to inform stream water quality protection efforts. We used National Weather Service Coop Observer frost depth reports to identify dates when watershed soils were frozen. By comparing daily mean event discharge for dates relative to frost, we identified a 32-d post-frost high-discharge "thaw" period. Combined, the frozen and thaw periods contributed about half of the annual SS and TP runoff event loads, ranging from 47 to 63% for SS and from 45 to 51% for TP. The proportion of runoff event TDP during this time was even higher, 62 to 79%, with the majority during thaw. Watershed average volumetric runoff coefficients (event flow/precipitation and snowmelt) were two to four times higher during the freeze and the thaw compared with the rest of the year. To reduce total stream loads in regions with similar climates to Wisconsin, this study indicates that using management practices that curb sediment and P delivery to streams in the winter and early spring may be as important as those designed for nonfrozen conditions., (© 2019 The Author(s). Re-use requires permission from the publisher.)

Acute myeloid leukemia (AML) is a heterogeneous disease with dismal response warranting the need for enhancing our understanding of AML biology. One prognostic feature associated with inferior response is the presence of activating mutations in FMS-like tyrosine kinase 3 (FLT3) especially occurrence of internal tandem duplication (FLT3-ITD). Although poorly understood, differential metabolic and signaling pathways associated with FLT3-ITD might contribute towards the observed poor prognosis. We performed a non-targeted global metabolic profiling of matched cell and plasma samples obtained at diagnosis to establish metabolic differences within FLT3-ITD and FLT3-WT pediatric AML. Metabolomic profiling by Ultra-High Performance-Liquid-Chromatography-Mass Spectrometry identified differential abundance of 21 known metabolites in plasma and 33 known metabolites in leukemic cells by FLT3 status. These metabolic features mapped to pathways of significant biological importance. Of interest were metabolites with roles in cancer, cell progression and involvement in purine metabolism and biosynthesis, cysteine/methionine metabolism, tryptophan metabolism, carnitine mediated fatty acid oxidation, and lysophospholipid metabolism. Although validation in a larger cohort is required, our results for the first time investigated global metabolic profile in FLT3-ITD AML.

Purpose: Cardiac imaging expenditures have come under scrutiny, and a focus on appropriate use criteria (AUC) has arisen to ensure cost-effective resource utilization. Although AUC has been developed by clinical experts, it has not undergone rigorous quality assurance testing to ensure that inappropriate indications for testing yield little clinical benefit. The objective of the study was to evaluate the potential incremental prognostic value of coronary computed tomographic angiography (CCTA) in the different AUC categories., Materials and Methods: Consecutive patients enrolled into a cardiac CT Registry were collated. Patient indications were reviewed and based on the 2010 AUC (appropriate, uncertain, and inappropriate). Patients were followed-up for death, myocardial infarction (MI), and late revascularization, with the primary composite endpoint being cardiac death, nonfatal MI, and late revascularization. The prognostic value of CCTA over clinical variables in each of the AUC categories was assessed., Results: Indications for CCTA were appropriate, uncertain, and inappropriate in 1284 (66.5%), 312 (16.2%), and 334 (17.3%) patients, respectively. Rates of all-cause of death, cardiac death, nonfatal MI, and late revascularization were similar across patients with appropriate, uncertain, and inappropriate indications for CCTA. Moreover, in each AUC category, CCTA had incremental prognostic value over a routine clinical risk score (National Cholesterol Education Program) with hazard ratios of 9.98, 7.39, and 5.61., Conclusions: CCTA has incremental prognostic value in all AUC categories, even when the reason for the study was deemed "inappropriate." This suggests that CCTA may still have clinical value in "inappropriate" indications and that further quality assurance AUC studies are needed.

Background: Appropriate Use Criteria (AUC) guidelines for cardiac computed tomography (CCT) were developed to limit testing to reasonable clinical settings. However, significant testing is still done for inappropriate indications. This study investigates the impact of AUC on evaluability of CCT to determine if inappropriate tests result in a greater proportion of nondiagnostic results., Methods: Investigators reviewed the medical records of 2417 consecutive patients who underwent CCT at the University of Ottawa Heart Institute. We applied the 2010 AUC and classified them as appropriate, inappropriate, or uncertain. Unclassifiable tests, as well as those with uncertain appropriateness, were excluded from the final analysis. Cardiac computed tomography results were classified as diagnostic if (1) all coronary segments were visualized, evaluable, and without obstructive stenosis; or (2) obstructive coronary artery disease with greater than 50% diameter stenosis in at least 1 coronary artery. All other test results were considered nondiagnostic., Results: Of the 1984 patients included in the final analysis, 1522 patients (76.7%) had indications that were appropriate, whereas the remaining 462 (23.3%) were inappropriate. Inappropriate tests resulted in a higher rate of nondiagnostic results compared with appropriate CCT (9.0% vs 6.2%, P = 0.034). Inappropriate tests also had significantly more studies with nonevaluable segments than appropriate tests (24.5% vs 16.4%, P < 0.001) and were more likely to reveal obstructive coronary disease than appropriate CCT (50.5% vs 32.7%, P < 0.001)., Conclusions: Cardiac computed tomography done for inappropriate indications may be associated with lower diagnostic yield and could impact future downstream resource utilization and health care costs.

Background: As new technologies allow investigators to collect multiple forms of molecular data (genomic, epigenomic, transcriptomic, etc) and multiple endpoints on a clinical trial cohort, it will become necessary to effectively integrate all these data in a way that reliably identifies biologically important genes., Methods: We introduce CC-PROMISE as an integrated data analysis method that combines components of canonical correlation (CC) and projection onto the most interesting evidence (PROMISE). For each gene, CC-PROMISE first uses CC to compute scores that represent the association of two forms of molecular data with each other. Next, these scores are substituted into PROMISE to evaluate the statistical evidence that the molecular data show a biologically meaningful relationship with the endpoints., Results: CC-PROMISE shows outstanding performance in simulation studies and an example application involving pediatric leukemia. In simulation studies, CC-PROMISE controls the type I error (misleading significance) rate very near the nominal level across 100 distinct null settings in which no molecular-endpoint association exists. Also, CC-PROMISE has better statistical power than three other methods that control type I error in 396 of 400 (99 %) alternative settings for which a molecular-endpoint association is present; the power advantage of CC-PROMISE exceeds 30 % in 127 of the 400 (32 %) alternative settings. These advantages of CC-PROMISE are also observed in an example application., Conclusion: CC-PROMISE very effectively identifies genes for which some form of molecular data shows a biologically meaningful association with multiple related endpoints., Availability: The R package CCPROMISE is currently available from www.stjuderesearch.org/site/depts/biostats/software .

Atrial fibrillation (AF) is a common cardiac arrhythmia and is associated with an increased risk of ischemic stroke. The aim of this study was to identify practice patterns of Canadian resident physicians pertaining to stroke prevention in nonvalvular AF according to the Canadian Cardiovascular Society guidelines. A Web-based survey consisting of 16 multiple-choice questions was distributed to 11 academic centres. Questions involved identification of risks of stroke, bleeding, and selection of appropriate therapy in clinical scenarios that involve a patient with AF with a Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) score of 3 and no absolute contraindications to anticoagulation. There were 1014 total respondents, of whom 570 were internal, 247 family, 137 emergency medicine, and 60 adult cardiology residents. For a patient with a new diagnosis of AF, warfarin was chosen by 80.3%, novel oral anticoagulants (NOACs) by 60.3%, and acetylsalicylic acid (ASA) by 7.2% of residents. To a patient with a history of gastrointestinal bleed during ASA treatment, warfarin was recommended by 75.1%, NOACs by 36.1%, ASA by 12.1%, and 4% were unsure. For a patient with a history of an intracranial bleed, warfarin was recommended by 38.8%, NOACs by 23%, ASA by 24.8%, and 18.2% were unsure. For a patient taking warfarin who had a labile international normalized ratio, 89% would switch to a NOAC and 29.5% would continue warfarin. This study revealed that, across a wide sampling of disciplines and centres, resident physician choices of anticoagulation in nonvalvular AF differ significantly from contemporary Canadian Cardiovascular Society guidelines., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aim: We evaluated the pharmacogenetic influence of genetic polymorphisms in folate pathway genes in Indian rheumatoid arthritis patients receiving methotrexate (MTX)., Patients & Methods: Twelve polymorphisms within nine folate pathway genes were analyzed for association with MTX response in 322 Indian rheumatoid arthritis (RA) patients and MTX pharmacokinetics in 94 RA patients., Results: Polymorphisms in GGH, SHMT1 and TS were associated with MTX-related adverse events while SNPs in MTHFR and RFC1/SLC19A1 were associated with MTX efficacy. TS5'UTR and SHMT1 polymorphisms were associated with higher plasma levels of MTX., Conclusion: Polymorphisms in folate-MTX pathway genes contribute to MTX response and affect MTX concentrations in Indian RA patients. A toxicogenetic index could identify patients who develop adverse events to MTX., Competing Interests: Financial & competing interests disclosure Y Ghodke-Puranik is thankful to Council for Scientific and Industrial Research, New Delhi, India, for senior research fellowship and AS Puranik is thankful Lady Tata Memorial Trust, Mumbai, India for senior research fellowship. J Lamba is supported by NIH grants: R01CA132946 and R21CA155524. TB Niewold is supported by grants from: the NIH (AR060861, AR057781, AR065964, AI071651), Rheumatology Research Foundation, Cure JM Foundation, the Mayo Clinic Foundation, and the Foundation of Minnesota. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Background: Frequent idiopathic premature ventricular contractions (PVCs) have been associated with left ventricular cardiomyopathy. Idiopathic PVCs often originate from the right ventricular outflow tract (RVOT), and radiofrequency catheter ablation (RFCA) is being used as a treatment to alleviate symptoms. A meta-analysis was performed to evaluate RFCA for the treatment of frequent idiopathic PVCs on heart function., Methods and Results: A literature search was conducted using Medline and Embase to identify studies evaluating the effects of RFCA as treatment for PVCs originating from the RVOT. Articles were chosen if they reported the effect of RFCA on the quantity of PVCs or ventricular function. Only studies in English were included. Articles were excluded if they did not separate results for PVCs originating from areas other than the RVOT. A total of 450 articles were retrieved from electronic searches, and 14 articles were included in this systematic review. Six of these were meta-analyzed (N = 70) and showed a reduction in the total number of PVCs in 24 hours after RFCA by a mean of -30089.44 confidence interval [CI]: -31658.47, -28520.40, P < 0.00001). Left ventricular ejection fraction (LVEF) was reported in five of the 14 studies, which included 108 patients. RFCA significantly improved LVEF by a mean of 10.36 (CI: 8.75, 11.97, P < 0.00001) in patients with frequent PVCs from the RVOT. The remaining studies reported their results differently and were not included in the meta-analyses but were described separately., Conclusions: RFCA reduces the number of PVCs and improves the cardiac function in patients with idiopathic frequent PVCs originating from the RVOT., (©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.)

Subsurface band application of poultry litter has been shown to reduce the transport of nutrients from fields in surface runoff compared with conventional surface broadcast application. Little research has been conducted to determine the effects of surface broadcast application and subsurface banding of litter on nutrients in leachate. Therefore, a field experiment was conducted to determine the effects of subsurface band application and surface broadcast application of poultry litter on nutrient losses in leachate. Zero-tension pan and passive capillary fiberglass wick lysimeters were installed in situ 50 cm beneath the soil surface of an established tall fescue ( Schreb.) pasture on a sandy loam soil. The treatments were surface broadcast and subsurface-banded poultry litter at 5 Mg ha and an unfertilized control. Results of the rainfall simulations showed that the concentrations of PO-P and total phosphorus (TP) in leachate were reduced by 96 and 37%, respectively, in subsurface-banded litter treatment compared with the surface-applied litter treatment. There was no significant difference in PO-P concentration between control and subsurface-banded litter treatment in leachate. The trend in the loading of nutrients in leachate was similar to the trend in concentration. Concentration and loading of the nutrients (TP, PO-P, NH-N, and NO-N) in runoff from the subsurface-banded treatment were significantly less than for the surface-applied treatment and were similar to those from control plots. These results show that, compared with conventional surface broadcast application of litter, subsurface band application of litter can greatly reduce loss of P in surface runoff and leachate., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Aim: The aim was to determine if the University of Minnesota (MN, USA) healthcare students' perceived value of pharmacogenomics matches their self-observed comfort and education in pharmacogenomics., Materials & Methods: A 24-question, anonymous, online survey was distributed to all pharmacy, nursing and medical students enrolled at the University of Minnesota., Results: Among healthcare students, 70.6% agreed or strongly agreed that pharmacogenomics should be an important part of their curriculum; however, only 11.1% agreed or strongly agreed that it actually is. Only 29.7% of students reported taking a genetics course that specifically addressed the applications of genetics in pharmacy, and those students were more likely to feel comfortable interpreting information from a pharmacogenetics test, answering questions on pharmacogenomics, educating patients on risks and benefits of testing, and were comfortable that they knew which medications required pharmacogenomics testing., Conclusion: Healthcare students consider pharmacogenomics to be an important area of clinical practice; yet generally express it has not been an important part of their curriculum. Education emphasizing medical applications of pharmacogenomics can increase student comfort level in pharmacogenomics practice.

The main objective of this study was to investigate the feasibility of using PharmGKB, a pharmacogenomic database, as a source of training data in combination with text of MEDLINE abstracts for a text mining approach to identification of potential gene targets for pathway-driven pharmacogenomics research. We used the manually curated relations between drugs and genes in PharmGKB database to train a support vector machine predictive model and applied this model prospectively to MEDLINE abstracts. The gene targets suggested by this approach were subsequently manually reviewed. Our quantitative analysis showed that a support vector machine classifiers trained on MEDLINE abstracts with single words (unigrams) used as features and PharmGKB relations used for supervision, achieve an overall sensitivity of 85% and specificity of 69%. The subsequent qualitative analysis showed that gene targets "suggested" by the automatic classifier were not anticipated by expert reviewers but were subsequently found to be relevant to the three drugs that were investigated: carbamazepine, lamivudine and zidovudine. Our results show that this approach is not only feasible but may also find new gene targets not identifiable by other methods thus making it a valuable tool for pathway-driven pharmacogenomics research., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A(1), A(2A), or A(3) receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A(2B) receptors. Clofarabine and cladribine both bound to the A(2A) receptor with a K (i) of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A(3) receptor with a K (i) of 10 μM, and none of these compounds bound to the A(2B) receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A(1) receptor. In addition, clofarabine, cladribine, and fludarabine were A(1) agonists (IC(50) 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K (i) > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.

Objective: To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response., Patients and Methods: In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing., Results: At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less., Conclusion: Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Aims: Sleep apnoea (SA) is a common problem among congestive heart failure (CHF) patients. Evidence has shown that cardiac resynchronization therapy (CRT) reduces morbidity and mortality associated with CHF. The aim of this paper was to review studies evaluating the reduction of the Apnoea-Hypopnoea Index (AHI) in patients with SA after treatment with CRT and to perform a meta-analysis to estimate the true effect of CRT on SA., Methods and Results: A systematic electronic literature search was conducted in Medline and Embase to identify studies reporting on the effects of CRT on SA. A hand search of five major cardiology societies was performed to identify any unpublished studies through structured abstracts submitted to conference proceedings. To be eligible for inclusion, studies had to include a comparison of CRT vs. no pacing and use AHI as an outcome. Non-English studies were excluded. Nine manuscripts and five abstracts were identified for review. Six manuscripts and three abstracts were included in meta-analysis, which included 170 patients. After treatment with CRT, a significant reduction in AHI was found in patients with central sleep apnoea (CSA) with a mean reduction of -13.05 (CI -16.74 to -9.36; P < 0.00001) but not in patients with obstructive sleep apnoea (13.32; CI -9.04 to 2.39; P = 0.25)., Conclusion: Cardiac resynchronization therapy reduces the severity of SA. Major effects are seen in patients with CSA. The presence of SA may be an additional consideration when deciding on which heart failure patients will receive CRT.

CYP3A4 expression in breast cancer correlates with decreased overall survival, but the mechanisms are unknown. Cytochrome P450 gene profiling by RNAi silencing demonstrates that CYP3A or 2C8 gene expression is specifically required for growth of the breast cancer lines MCF7, T47D, and MDA-MB-231. CYP3A4 silencing blocks the cell cycle at the G(2)/M checkpoint and induces apoptosis in the MCF7 line, thereby inhibiting anchorage-dependent growth and survival. CYP3A4 was profiled for NADPH-dependent arachidonic acid (AA) metabolism and synthesized AA epoxygenase products (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acid (EET) (total turnover of ∼2 pmol/pmol CYP3A4/min) but not hydroxylase products (±)-15-, (±)-19-, or 20-hydroxyeicosatetraenoic acid. Furthermore, eicosanoid profiling revealed that MCF7 cells synthesize EETs in a CYP3A4-dependent manner. The (±)-14,15-EET regioisomer selectively rescues breast cancer cells from CYP3A4 silencing in a concentration-dependent fashion and promotes mitogenesis and anchorage-dependent cloning. Stat3 (Tyr-705) phosphorylation was inhibited by CYP3A4 silencing, providing a potential mechanism for CYP3A4 involvement in breast cancer cell growth. Silencing Stat3 blocks breast cancer cell growth and abrogates (±)-14,15-EET-induced proliferation, indicating a Stat3 requirement for (±)-14,15-EET-mediated cell growth. Although silencing of CYP3A4 reduces nuclear Tyr(P)-705-Stat3, (±)-14,15-EET restores this signaling process and promotes Tyr(P)-705-Stat3 translocation to the nucleus, suggesting that (±)-14,15-EET may be involved in an autocrine/paracrine pathway driving cell growth. These studies indicate that CYP3A4 is a highly active AA epoxygenase that promotes Stat3-mediated breast cancer cell growth in part through (±)-14,15-EET biosynthesis. Furthermore, these studies indicate an essential role for Stat3 as a mediator of epoxygenase activity in breast cancer., (© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.)

Health-care information technology and genotyping technology are both advancing rapidly, creating new opportunities for medical and scientific discovery. The convergence of these two technologies is now facilitating genetic association studies of unprecedented size within the context of routine clinical care. As a result, the medical community will soon be presented with a number of novel opportunities to bring functional genomics to the bedside in the area of pharmacotherapy. By linking biological material to comprehensive medical records, large multi-institutional biobanks are now poised to advance the field of pharmacogenomics through three distinct mechanisms: (i) retrospective assessment of previously known findings in a clinical practice-based setting, (ii) discovery of new associations in huge observational cohorts, and (iii) prospective application in a setting capable of providing real-time decision support. This review explores each of these translational mechanisms within a historical framework.

Motivation: In some applications, prior biological knowledge can be used to define a specific pattern of association of multiple endpoint variables with a genomic variable that is biologically most interesting. However, to our knowledge, there is no statistical procedure designed to detect specific patterns of association with multiple endpoint variables., Results: Projection onto the most interesting statistical evidence (PROMISE) is proposed as a general procedure to identify genomic variables that exhibit a specific biologically interesting pattern of association with multiple endpoint variables. Biological knowledge of the endpoint variables is used to define a vector that represents the biologically most interesting values for statistics that characterize the associations of the endpoint variables with a genomic variable. A test statistic is defined as the dot-product of the vector of the observed association statistics and the vector of the most interesting values of the association statistics. By definition, this test statistic is proportional to the length of the projection of the observed vector of correlations onto the vector of most interesting associations. Statistical significance is determined via permutation. In simulation studies and an example application, PROMISE shows greater statistical power to identify genes with the interesting pattern of associations than classical multivariate procedures, individual endpoint analyses or listing genes that have the pattern of interest and are significant in more than one individual endpoint analysis., Availability: Documented R routines are freely available from www.stjuderesearch.org/depts/biostats and will soon be available as a Bioconductor package from www.bioconductor.org.

In the present study we have investigated the characteristics of folding and unfolding pathways of two model proteins, ovalbumin and alpha-lactalbumin, monitored through the changes in surface hydrophobicity using fluorescence and circular dichroism spectroscopy. In the unfolding process, it was observed that ovalbumin and alpha-lactalbumin followed a three state transition pathway involving an intermediate state having high surface hydrophobicity. The intermediate state has also been characterized by circular dichroism spectroscopy, and it was found that the intermediate retained almost the same secondary structure as the native proteins, and therefore it can be referred to as molten globule state. The refolding process was monitored using fluorescence and circular dichroism spectroscopy, and it was observed that the refolding of alpha-lactalbumin was reversible and proceeded through the accumulation of similar type of intermediates as observed during its unfolding pathway. However, on refolding from the guanidine hydrochloride-denatured state, ovalbumin reached a different folded state.

Background: Hospitalized infants undergo multiple, repeated painful procedures. Despite continued efforts to prevent procedural pain and improve pain management, clinical guidelines and standards frequently do not reflect the highest quality evidence from systematic reviews., Objective: To critically appraise all systematic reviews on the effectiveness of procedural pain interventions in hospitalized infants., Methods: A structured review was conducted on published systematic reviews and meta-analyses of pharmacological and nonpharmacological interventions of acute procedural pain in hospitalized infants. Searches were completed in the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL and PsycINFO. Two reviewers independently selected articles for review and rated the methodological quality of the included reviews using a validated seven-point quality assessment measure. Any discrepancies were resolved by a third reviewer., Results: Of 1469 potential systematic reviews on interventions for painful procedures in hospitalized infants, 11 high-quality reviews were included in the analysis. Pharmacological interventions supported by research evidence included premedication for intubation, dorsal penile nerve block and EMLA (AstraZeneca Canada, Inc) for circumcision, and sucrose for single painful procedures. Non-nutritive sucking, swaddling, holding, touching, positioning, facilitative tucking, breast feeding and supplemental breast milk were nonpharmacological interventions supported for procedural pain., Conclusion: There is a growing number of high-quality reviews supporting procedural pain management in infants. Ongoing research of single, repeated and combined pharmacological and nonpharmacological interventions is required to provide the highest quality evidence to clinicians for decision-making on optimal pain management.

The hypothesis was tested that sequence diversity in breast cancer resistance protein (BCRP)'s cis-regulatory region is a significant determinant of BCRP expression. The BCRP promoter and intron 1 were resequenced in lymphoblast DNA from the polymorphism discovery resource (PDR) 44 subset. BCRP single nucleotide polymorphisms (SNPs) were genotyped in donor human livers, intestines, and lymphoblasts quantitatively phenotyped for BCRP mRNA expression. Carriers of the -15622C>T SNP had lower BCRP expression in multiple tissues. The intron 1 SNP 16702C>T was associated with high expression in livers; 1143G>A was associated with low expression in intestine; 12283T>C was associated with higher expression in the PDR44 and White livers. The -15994C>T promoter SNP was significantly associated with higher BCRP expression in multiple tissues. Patients with the -15994C>T genotype had substantially higher clearance of p.o. imatinib. We next determined whether BCRP expression was related to polymorphic alternative splicing or alternative promoter use. Liver polymorphically expressed an alternatively spliced mRNA [splice variant (SV) 1] skipping exon 2. Although SV1+ livers did not uniformly carry the exon 2 G34A allele, 90% of G34A livers expressed SV1 (versus 4% of 34GG livers). BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype and may be due, in part, to polymorphic exon 2 splicing. Analysis of allele expression imbalance (AEI) showed that PDR44 samples with AEI had lower BCRP mRNA expression; however, no linked cis-polymorphisms were identified. BCRP used multiple promoters, and livers differentially using alternative exon 1b had lower BCRP. In conclusion, BCRP expression in lymphoblasts, liver, and intestine is associated with novel promoter and intron 1 SNPs.

Background: Acute pain is a common experience for hospitalized children. Despite mounting research on treatments for acute procedure-related pain, it remains inadequately treated., Objective: To critically appraise all systematic reviews on the effectiveness of acute procedure-related pain management in hospitalized children., Methods: Published systematic reviews and meta-analyses on pharmacological and nonpharmacological management of acute procedure-related pain in hospitalized children aged one to 18 years were evaluated. Electronic searches were conducted in the Cochrane Database of Systematic Reviews, Medline, EMBASE, the Cumulative Index to Nursing and Allied Health Literature and PsycINFO. Two reviewers independently selected articles for review and assessed their quality using a validated seven-point quality assessment measure. Any disagreements were resolved by a third reviewer., Results: Of 1469 published articles on interventions for acute pain in hospitalized children, eight systematic reviews met the inclusion criteria and were included in the analysis. However, only five of these reviews were of high quality. Critical appraisal of pharmacological pain interventions indicated that amethocaine was superior to EMLA (AstraZeneca Canada Inc) for reducing needle pain. Distraction and hypnosis were nonpharmacological interventions effective for management of acute procedure-related pain in hospitalized children., Conclusions: There is growing evidence of rigorous evaluations of both pharmacological and nonpharmacological strategies for acute procedure-related pain in children; however, the evidence underlying some commonly used strategies is limited. The present review will enable the creation of a future research plan to facilitate clinical decision making and to develop clinical policy for managing acute procedure-related pain in children.

The hypothesis was tested that sequence diversity in pregnane X receptor (PXR) cis-regulatory regions is a significant determinant of variation in inducible and constitutive CYP3A4 expression. A combination of comparative genomics and computational algorithms was used to select regions of the human PXR promoter and intron 1 that were resequenced in the polymorphism discovery resource 24 DNA subset. PXR single nucleotide polymorphisms (SNP) were then genotyped in donor human livers phenotyped for CYP3A4 and multidrug resistance protein 1 mRNA and primary human hepatocytes phenotyped for basal and rifampin-inducible CYP3A4 activity. The human PXR promoter [16.9 kilobase (kb)] was significantly larger than in rodents (2.9 kb). Eighty-nine SNPs were identified in the promoter and intron 1 of PXR. The SNPs most consistently associated with CYP3A4 phenotypic measures were a 44477T>C(-1359) promoter SNP (in linkage disequilibrium with SNP 463970, a 6-base pair deletion in intron 1a, and SNP 46551, a C nucleotide insertion in intron 1b); SNP 63396C>T in intron 1 (in linkage disequilibrium with SNP 63704A>G, a 63813(CAAA)(CA) variable repeat, and SNP 65104T>C); and SNP 56348C>A, SNP 69789A>G, and SNP 66034T>C. Donor livers with the variant PXR alleles had altered hepatic expression of PXR targets compared with livers with PXR wild-type alleles. These results identified PXR promoter and intron 1 SNPs associated with PXR target gene expression (CYP3A4) in donor livers and cultured hepatocytes and that a striking number of the linked intron 1 SNPs will affect putative binding sites for hepatic nuclear factor 3beta (FOXA2), a transcription factor linked with PXR expression.