bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Sirolimus in Healthy Chinese Volunteers
Authors: Zhang Jing , Dai Ying , Liu Zhihong , Zhang Minxin , Li Chen , Chen Dingxiong , Song Hongtao 
Published: July 2017

Background:
Sirolimus is a promising immunosuppressive drug for preventing the rejection of organ transplants. However, inter-individual variability in sirolimus pharmacokinetics causes adverse drug reactions, compromising therapeutic efficacy. Sirolimus is primarily metabolized by cytochrome CYP3A4 and CYP3A5. This study aimed to clarify the effect of CYP3A genetic polymorphisms, including the CYP3A4*1G and CYP3A5*3 polymorphisms, on the pharmacokinetics of sirolimus.

Methods:
Thirty-one healthy Chinese volunteers were included in this study. Their genotypes were determined using the Sequenom MassARRAY iPLEX platform, and blood sirolimus concentrations at different time points were analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using WinNonlin version 5.2 software.

Results:
The allele frequencies of CYP3A4*1G and CYP3A5*3 were 25.8% and 71.0%, respectively. In CYP3A4*1G carriers (n = 13), the area under the curve AUC0–144, AUC0–∞, and Cmax were significantly lower (P < 0.05) than CYP3A4*1/*1 homozygous subjects (n = 18). Briefly, the AUC0–144, AUC0–∞, and Cmax of *1G/
*1G carrier were 315.2 ± 91.5, 372.0 ± 108.2, and 10.2 ± 1.6 ng/mL, respectively, and those of *1/*1 G*1/*1 G carrier were 440.8 ± 130.6, 537.4 ± 167.5, and 13.7 ± 4.3, respectively, whereas those of CYP3A4*1/*1 homozygous subjects were 540.2 ± 150.6, 626.6 ± 166.9, and 19.8 ± 7.5 ng/mL, respectively. In CYP3A5-nonexpressing subjects (*3/*3 homozygous carriers, n = 15), the AUC0–144 and Cmax were 549.6 ± 137.9 and 19.9 ± 7.9 ng/mL, respectively, and were significantly higher (P < 0.05) than the values in CYP3A5-expressing subjects (*1/*1homozygous carrier, n = 2; 314.2 ± 129.3 and 10.3 ± 2.2 ng/mL; *1/*3 heterozygous carrier, n = 15; 440.2 ± 146.3 and 14.6 ± 5.1 ng/mL, respectively).

Conclusions:

CYP3A4 and CYP3A5 genetic polymorphisms are important factors affecting pharmacokinetic parameters of sirolimus. Our data support the monitoring of blood sirolimus concentrations, especially in CYP3A5*1 and CYP3A4*1 G carriers, to ensure accurate dosing in the clinical setting.
Dried Blood Spot Sampling for Tacrolimus and Mycophenolic Acid in Children: Analytical and Clinical Validation
Authors: Martial Lisa C. , Hoogtanders Karin E. J. , Schreuder Michiel F. , Cornelissen Elisabeth A. , van der Heijden Jac , Joore Manuela A. , Van Maarseveen Erik M. , Burger David M. , Croes Sander , Brüggemann Roger J. M. , Aarnoutse Rob E. 
Published: July 2017

Background:
Tacrolimus and mycophenolic acid (MPA) are the backbone of immunosuppressive therapy after pediatric kidney transplantation. Dosing of these drugs is individualized by therapeutic drug monitoring. Dried blood spot (DBS) sampling may prove beneficial over conventional venous sampling. We aimed to develop and clinically validate a DBS method for tacrolimus and MPA in children.

Methods:
A joint DBS liquid chromatography-mass spectrometry assay for tacrolimus and MPA was developed. DBS-specific items included the hematocrit effect and influence of spot volume. Subsequently, a clinical validation study among children aged 2–18 years was performed to assess the agreement between observed and DBS-predicted venous concentrations. Agreement of the methods was assessed with Passing–Bablok regression, Bland–Altman plots, and quantification of the DBS predictive performance in terms of bias (median percentage prediction error) and precision (median absolute percentage prediction error), both should be <15%.

Results:
A total of 40 tacrolimus and 32 MPA samples were available from 28 children. Conversion factors were used to predict venous concentrations from DBS. For tacrolimus, 95% of the individual ratios of predicted and observed concentrations were within a range of 0.74–1.28, with 85% of these ratios between 0.80 and 1.20 (Bland–Altman plots). For MPA, the 95% limits of agreement represented a broader range of 0.49–1.49%, and 72% of individual ratios were between the 0.80 and 1.20 limits. Median percentage prediction error and median absolute percentage prediction error were less than 15% for both drugs.

Conclusions:
A DBS assay was developed for tacrolimus and MPA. Tacrolimus venous concentrations could be adequately predicted from DBS. DBS analysis of MPA seemed to be a semiquantitative measurement at the most when compared with conventional plasma analysis, considering the high variability between observed and predicted concentrations. Next, home-based DBS sampling of tacrolimus for the purpose of therapeutic drug monitoring will be implemented into routine clinical care.
Recurrence Rates Over 20 Years in the Treatment of Malignant Melanoma: Immediate Versus Delayed Reconstruction
Authors: Koolen Pieter G.L. , Matos Tiago R. , Ibrahim Ahmed M.S. , Sun Jie , Lee Bernard T. , Frankenthaler Robert A. , Lin Samuel J. 
Published: July 2017

Background:
Wide local excision (WLE) with a safety margin is the standard of treatment for primary head and neck cutaneous malignant melanoma (HNCMM). Studies have demonstrated inconsistency in recurrence rates following immediate versus delayed reconstruction. The objectives of this study were to assess and compare recurrence rates after WLE of HNCMM followed by immediate or delayed reconstruction in determining recurrence-free survival estimates.

Methods:
A consecutive, retrospective analysis of 451 patients undergoing WLE of primary HNCMM followed by reconstruction over a period of 20 years was performed. Patients were divided into 2 groups based on timing of reconstruction (immediate versus delayed). Univariate analyses were performed to assess distributions. Kaplan–Meier survival analysis and multivariate Cox proportional hazard analyses were performed to estimate recurrence-free survival.

Results:
Tumor specimen positive margins were comparable between immediate and delayed reconstruction groups (P = 0.129). Univariate analysis demonstrated comparable local melanoma recurrence after immediate or delayed reconstruction (41.4% versus 53.3%; P = 0.399). After adjusting for prognostic factors, multivariate analysis also failed to demonstrate an association between reconstruction timing and local recurrence-free survival (P = 0.167).

Conclusions:
In this long-term study, we were not able to demonstrate an association between reconstruction timing and local recurrence-free survival after excision WLE of HNCMM, rendering immediate reconstruction a reliable approach. In addition, the presence of ulceration and a positive sentinel lymph node were positively associated with the risk of recurrence.
COMPARISON OF 2D AND 3D VIDEO DISPLAYS FOR TEACHING VITREORETINAL SURGERY
Authors: Chhaya Nisarg , Helmy Omar , Piri Niloofar , Palacio Agustina , Schaal Shlomit 
Published: July 2017

Purpose:
To compare medical students' learning uptake and understanding of vitreoretinal surgeries by watching either 2D or 3D video recordings.

Methods:
Three vitreoretinal procedures (tractional retinal detachment, exposed scleral buckle removal, and four-point scleral fixation of an intraocular lens [TSS]) were recorded simultaneously with a conventional recorder for two-dimensional viewing and a VERION 3D HD system using Sony HVO-1000MD for three-dimensional viewing. Two videos of each surgery, one 2D and the other 3D, were edited to have the same content side by side. One hundred UMass medical students randomly assigned to a 2D group or 3D, then watched corresponding videos on a MacBook. All groups wore BiAL Red-blue 3D glasses and were appropriately randomized. Students filled out questionnaires about surgical steps or anatomical relationships of the pathologies or tissues, and their answers were compared.

Results:
There was no significant difference in comprehension between the two groups for the extraocular scleral buckle procedure. However, for the intraocular TSS and tractional retinal detachment videos, the 3D group performed better than 2D (P < 0.05) on anatomy comprehension questions.

Conclusion:
Three-dimensional videos may have value in teaching intraocular ophthalmic surgeries. Surgical procedure steps and basic ocular anatomy may have to be reviewed to ensure maximal teaching efficacy.
Comparison of Collagen Cross-Linking and Amniotic Membrane Transplantation in an Experimental Alkali Burn Rabbit Model
Authors: Subasi Sevgi , Altintas Ozgul , Yardimoglu Melda , Yazir Yusufhan , Karaman Suleyman , Rencber Selenay Furat , Kavram Kubra 
Published: July 2017

Purpose:
To compare the effects of collagen cross-linking (CXL) and amniotic membrane transplantation (AMT) on acute corneal alkali burns.

Methods:
After establishment of an alkali burn model, 32 rabbits were divided into 4 groups: control group, AMT group, CXL group, and AMT + CXL (combined) group. Clinical parameters, including epithelial wound, opacity, ulceration, and neovascularization, were evaluated on postinjury days 1, 7, 14, and 18. Histological parameters were examined in hematoxylin/eosin (H&E) and Masson trichrome–stained corneal sections. Immunohistochemical analyses, including a terminal deoxynucleotidyl transferase–mediated biotin–deoxyuridine triphosphate nick-end labeling assay and cluster of differentiation 68 (CD68) labeling, were performed to determine the apoptotic index and macrophage activation.

Results:
On postinjury day 18, the epithelial wound of AMT {4.08% [interquartile range (IQR), 0.68%–5.22%]}, CXL [1.84% (IQR, 0.01%–3.89%)], and combined [3.44% (IQR, 0.01%–4.36%)] groups were significantly lower than the control [15.23% (IQR, 9.86%–23.06%)] group (P = 0.003). No significant difference was detected between the groups in terms of opacity (P = 0.303). Neovascularization was the least severe in the CXL group [16.18% (IQR, 8.39%–21.28%)] and the most severe in the AMT [34.47% (IQR, 17.71%–62.77%)] and combined [35.12% (IQR, 31.96%–59.98%)] groups on day 18 (P = 0.033). Significant increases in the apoptotic index and CD68 labeling were detected in the CXL and combined groups compared with those in the control group (P = 0.047 and P = 0.001, respectively).

Conclusions:
CXL treatment is an effective adjuvant treatment for promoting reepithelialization, reducing inflammation and neovascularization, and preventing ulceration in acute alkali burns. Providing AMT after suppressing inflammation may be a more effective treatment.
Crisaborole Topical Ointment, 2%
Authors: Parker James K. , Jacob Sharon E. 
Published: July 2017

ABSTRACT
A drug is defined as a substance that exerts a physiologic effect upon introduction to a biological system. These drugs may come in various forms including ingested pills, topical creams or ointments, and inhaled or injected substances. The purpose of this column is to bring attention to common drugs used in dermatology, their usage and purpose, their mechanisms, and available alternatives. This edition focuses on crisaborole and its use in the treatment of atopic dermatitis.
Impact of Ramadan on emergency department visits and on medical emergencies
Authors: Al Assaad Reem G. , Bachir Rana , El Sayed Mazen J. 
Published: July 2017

Background
Fasting during Ramadan is important to Muslims. This study describes changes in emergency department (ED) visits and in frequencies of emergency conditions and impact on clinical outcomes during Ramadan in a tertiary care center in Beirut, Lebanon.

Patients and methods
Patients presenting to ED during Ramadan 1 month before and 1 month after Ramadan over a 3-year period with specific conditions (acute coronary syndrome, stroke, seizure, diabetes, renal colic, headache or hypertension) were included. Clinical and sociodemographic characteristics, ED volume, diagnoses, and outcomes were examined during two periods (Ramadan vs. non-Ramadan). Multiple logistic regressions were performed to identify the impact of Ramadan on ED bounce-back and mortality at ED discharge.

Results
A total of 3536 patients were included. The daily average ED volume was higher during non-Ramadan months (145.65±22.14) compared with Ramadan (128.85±14.52). The average ED length of stay was higher during Ramadan (5.42±14.86 vs. 3.96±4.29 h; P=0.006). Frequencies and admission rates for the selected diseases were comparable during the two periods, except for patients with acute coronary syndrome or stroke who had lower admission rates during Ramadan.
ED bounce-back rates and mortality at ED discharge were higher during Ramadan (odds=1.34, 95% confidence interval: 1.03–1.74 and odds ratio=2.88, 95% confidence interval: 1.01–8.27, respectively).

Conclusion
EDs might experience a decrease in volumes, higher length of stay, and potentially worse outcomes during Ramadan. Changes in the frequencies of ED visits related to common conditions are not expected. Prospective studies documenting fasting status would clarify further the impact of Ramadan.
The impact of medical specialist staffing on emergency department patient flow and satisfaction
Authors: van der Linden M. Christien , de Beaufort Roeline A.Y. , Meylaerts Sven A.G. , van den Brand Crispijn L. , van der Linden Naomi 
Published: July 2017

Objective
The aim of this study was to describe the impact of additional medical specialists, non-emergency physicians (non-EPs), performing direct supervision or a combination of direct and indirect supervision at an EP-led emergency department (ED), on patient flow and satisfaction.

Patients and methods
An observational, cross-sectional, three-part study was carried out including staff surveys (n=379), a before and after 16-week data collection using data of visits during the peak hours (n=5270), and patient questionnaires during 1 week before the pilot and during week 5 of the pilot. Content analysis and descriptive statistics were used for analyses.

Results
The value of being present at the ED was acknowledged by medical specialists in 49% of their surveys and 35% of the EPs’ and ED nurses’ surveys, especially during busy shifts. Radiologists were most often (67.3%) convinced of their value of being on-site, which was agreed upon by the ED professionals. Perceived improved quality of care, shortening of length of stay, and enhanced peer consultation were mentioned most often.
During the pilot period, length of stay of boarded patients decreased from 197 min (interquartile range: 121 min) to 181 min (interquartile range: 113 min, P=0.006), and patient recommendation scores increased from −15 to +20.

Conclusion
Although limited by the mix of direct and indirect supervision, our results suggest a positive impact of additional medical specialists during busy shifts. Throughput of admitted patients and patient satisfaction improved during the pilot period. Whether these findings differ between direct supervision and combination of direct and indirect supervision by the medical specialists requires further investigation.
Endoscopic mucosal resection and endoscopic submucosal dissection: technique and new directions
Authors: Nishizawa Toshihiro , Yahagi Naohisa 
Published: July 2017

Purpose of review
Most of small tumours in gastrointestinal tract are easily removed by endoscopic mucosal resection (EMR). However, EMR are sometimes not reliable to ensure the complete resection for large tumours. Although endoscopic submucosal dissection (ESD) was developed, it had a higher risk for complications such as perforation and bleeding. The techniques and clinical outcomes of EMR and ESD are reviewed.

Recent findings
ESD is more effective for early gastric and oesophageal cancer with higher en-bloc resection rate and lower local recurrence in comparison to EMR. Several studies report favourable long-term outcomes of ESD. ESD has become a standard technique in Japan and other East Asian countries. Piecemeal resection using EMR technique is widely accepted for colorectal large adenomas and results in good clinical outcomes in most patients. However, apparent cancerous lesions need endoscopic en-bloc resection by ESD.

Summary
Further development of the technique, devices and training systems will promote worldwide standardization of ESD.
Antibiotic resistance in Helicobacter pylori
Authors: Alba Claudio , Blanco Ana , Alarcón Teresa 
Published: July 2017

Purpose of review
Treatment of Helicobacter pylori is difficult nowadays because of its high resistance. The prevalence and mechanism of resistance, the different methods to detect it and the clinical implication of resistance were addressed in several research papers last year.

Recent findings
Clarithromycin-resistant H. pylori has been recognized by the WHO as ‘high priority’, for which new antibiotics are needed. Moreover, the Maastricht consensus recommended, in areas with high resistance, that susceptibility tests should be performed, at least after a treatment failure.

Summary
Metronidazole and clarithromycin resistance rates are alarming although they vary among populations. Tetracycline and amoxicillin-resistance are very low in most countries. H. pylori resistance can be detected by phenotypic or by molecular methods. Different break points may be used when performing an antimicrobial susceptibility test, so comparing resistance among different populations is challenging. Genomic techniques open new possibilities in the diagnosis of H. pylori, and the detection of H. pylori and its antimicrobial resistance in faeces is an interesting approach. Eradication rates are dependent on the susceptibility of the strain to metronidazole and clarithromycin, being lower in patients infected with a resistant strain.
The Influence of Income and Formal Education on Damage in Brazilian Patients With Systemic Lupus Erythematosus
Authors: Teixeira Roberto Cordeiro de Andrade , Borba Neto Eduardo Ferreira , Christopoulos Georges Basile , Sato Emilia Inoue 
Published: July 2017

Objective
The aim of this study was to evaluate the association of socioeconomic status and American College of Rheumatology/Systemic Lupus International Collaborating Clinics Damage Index (SDI) score in Brazilian patients with systemic lupus erythematosus (SLE).

Methods
Five hundred twenty-three patients (SLE ACR criteria) 18 years or older who were at 12 months or greater since diagnosis were included. Socioeconomic status was assessed by per-capita income and years of education. Race was categorized as white and nonwhite. The SDI and Mexican SLE Disease Activity Index were used.

Statistical Analysis
Mean ± SD and median were used for descriptive analysis. Student t test, Mann-Whitney U test, χ2 test, and Spearman rank correlation coefficient and univariate and multivariate regression analyses were performed. The level of significance was set at 5% for all statistical tests.

Results
Ninety-six percent were female, 51.2% were nonwhite, and the mean age was 37.8 ± 1.4 years. Disease duration was 8.2 ± 10.3 years and formal education was 10.2 ± 3.5 years. Unemployment among patients was 63.7%, with median monthly per-capita income of US $276. Mean SDI score was 1.4 ± 1.52, and 65.6% had some type of damage (SDI ≥1). Patients with SDI of 1 or greater had lower income (P = 0.039). Nonwhite patients had higher SDI than did white patients (P = 0.005). The SDI presented a positive correlation with disease duration (P < 0.001) and age (P < 0.001) and a negative correlation with years of education (P = 0.001). Working patients had lower SDI than did inactive ones (P ≤ 0.001). In a multivariate analysis, older age, higher disease duration, nonwhite race, low income, and out-of-work profile were associated with damage.

Conclusions
Besides nonmodifiable characteristics such as longer disease duration and older age, low income was also associated with damage. Therefore, interventions to give adequate socioeconomic support are necessary to improve outcome, mainly in poorer and nonwhite SLE patients.
Rheumatologists Modestly More Likely to Counsel Smokers in Visits Without Rheumatoid Arthritis Control
Authors: Vreede Andrew P. , Johnson Heather M. , Piper Megan , Panyard Daniel J. , Wong Joanna C. , Bartels Christie M. 
Published: July 2017

Background
Among patients with rheumatoid arthritis (RA), smoking increases risk of severe RA and pulmonary and cardiovascular disease. Despite this, little is known about smoking cessation counseling by rheumatologists.

Objectives
We examined predictors of tobacco counseling in RA patients who smoke including the effect of perceived RA control. We hypothesized that patients with controlled RA would receive more counseling according to the competing demands model, which explains that preventive care gaps occur as a result of competing provider, patient, and clinic factors.

Methods
This secondary data analysis involved RA patients with an additional cardiovascular disease risk factor identified in an academic medical center 2004–2011. Trained abstractors assessed documented smoking counseling and rheumatologists’ impression of RA control in clinic notes. We used multivariable logistic regression to predict having received smoking cessation counseling, including sociodemographics and comorbidity in models.

Results
We abstracted 3396 RA visits, including 360 visits (10%) with active smokers. Perceived controlled RA was present in 31% of visits involving smokers (39% in nonsmokers). Beyond nurse documentation, providers documented smoking status in 39% of visit notes with smokers and smoking cessation counseling in 10%. Visits with controlled versus active RA were less likely to include counseling (odds ratio, 0.3; confidence interval, 0.1–0.97). Counseling was more likely in visits with prevalent cardiovascular, pulmonary, and psychiatric disease, but decreased with obesity.

Conclusions
Smoking cessation counseling was documented in 10% of visits and was less likely when RA was controlled. Given smoking’s impact on RA and long-term outcomes, systematic cessation counseling efforts are needed.