A revised electronic version of RUCAM for the diagnosis of DILI.

BACKGROUND AND AIMS: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and iterative computer modeling. APPROACH AND RESULTS: RUCAM criteria were updated, clarified, and computerized. We removed criteria 3 (risk factors) for lack of added value and criteria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50-100 single-agent, nonherbal cases from both registries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories. CONCLUSIONS: RECAM is an evidence-based update that is at least as capable as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM's increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.

Dissipative Floquet Majorana Modes in Proximity-Induced Topological Superconductors.

We study a realistic Floquet topological superconductor, a periodically driven nanowire proximitized to an equilibrium s-wave superconductor. Because of the strong energy and density fluctuations caused by the superconducting proximity effect, the Floquet Majorana wire becomes dissipative. We show that the Floquet band structure is still preserved in this dissipative system. In particular, we find that the Floquet Majorana zero and π modes can no longer be simply described by the Floquet topological band theory. We also propose an effective model to simplify the calculation of the lifetime of these Floquet Majoranas and find that the lifetime can be engineered by the external driving field.

microRNA-216a protects against human retinal microvascular endothelial cell injury in diabetic retinopathy by suppressing the NOS2/JAK/STAT axis.

OBJECTIVE: Since microRNAs (miRNAs) represent as effective therapeutic targets for diabetic retinopathy (DR), we identified aberrantly expressed miRNAs related to cellular dysfunction in DR and further detected their potential targets. This study aimed to explore the synergistic effect of miR-216a, inducible nitric oxide synthase 2 (NOS2) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway on human retinal microvascular endothelial cell (HRMEC) injury in DR. METHODS: The differentially expressed genes in DR were obtained by GEO database, and the downstream signaling pathways and upstream targeted miRNAs were obtained through bioinformatics analysis. Subsequently, a DR model rat was established, and the target miR-216a was overexpressed to observe the pathological and morphological changes of the rat retina and the levels of inflammatory factors. Then, HRMECs were extracted and added with d-Glucose, and then transfected with miR-216a, NOS2 or adding JAK/STAT signaling pathway specific inhibitor to observe changes in cell activity and inflammatory damage. RESULTS: NOS2 was significantly upregulated, and the JAK/STAT signaling pathway was significantly activated in DR. miR-216a targeted NOS2, which played a protective role in the retina of DR rats. Moreover, in cell experiments, overexpression of miR-216a promoted the viability of HRMECs under d-glucose treatment, and inhibited NOS2 expression and the JAK/STAT signaling pathway activation. CONCLUSION: This study suggests that miR-216a protects against HRMECs injury in DR by suppressing the NOS2/JAK/STAT axis.

Trends in Enrollment, Clinical Characteristics, Treatment, and Outcomes According to Age in Non-ST-Segment-Elevation Acute Coronary Syndromes Clinical Trials.

BACKGROUND: Representation by age ensures appropriate translation of clinical trial results to practice, but, historically, older patients have been underrepresented in clinical trial populations. As the general population has aged, it is unknown whether clinical trial enrollment has changed in parallel. METHODS AND RESULTS: We studied time trends in enrollment, clinical characteristics, treatment, and outcomes by age among 76 141 patients with non-ST-segment-elevation acute coronary syndrome enrolled in 11 phase III clinical trials over 17 years (1994-2010). Overall, 19.7% of patients were ≥75 years; this proportion increased from 16% during 1994 to 1997 to 21% during 1998 to 2001 and 23.2% during 2002 to 2005, but declined to 20.2% in 2006 to 2010. The number of comorbidities increased with successive time periods irrespective of age. There were substantial increases in the use of evidence-based medication in-hospital and at discharge regardless of age. Although predicted 6-month mortality increased slightly over time, observed 6-month mortality declined significantly in all age strata (1994-1997 versus 2006-2010: <65 years: 3.0% versus 1.9%; 65-74 years: 7.5% versus 3.4%; 75-79 years: 13.0% versus 6.5%; 80-84 years: 17.6% versus 8.2%; and ≥85 years: 24.8% versus 12.6%). CONCLUSIONS: The distribution of enrollment by age in phase III non-ST-segment-elevation acute coronary syndrome trials was unchanged over time. Irrespective of age, post-myocardial infarction mortality decreased significantly over time, concurrent with increased evidence-based care and despite increasing comorbidities. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

Thermodynamically consistent master equation based on subsystem eigenstates.

Master equations under appropriate assumptions are efficient tools for the study of open quantum systems. For many-body systems, subsystems of which locally couple to thermal baths and weakly interact with each other, the local approach provides a more convenient description than the global approach. However, these local master equations are believed to generate inconsistencies with the laws of thermodynamics when intersubsystem interactions exist. Here we develop an alternative local master equation by virtue of similar approximations used in deriving the traditional Gorini-Kossakowski-Lindblad-Sudarshan master equation. In particular, we stick to using eigenstates of each subsystem to construct quantum jump operators, and the secular approximation is also employed to modify the intersubsystem interactions. Our results show that violations of thermodynamic laws will be avoided after correcting intersubsystem interactions. Finally, we study a two-qubit heat transfer model and this further shows the validity of our modified master equation.

Adsorption characteristics of sulfonamide antibiotic molecules on carbon nanotube and the effects of environment.

CONTEXT: In this paper, the adsorption characteristics of five sulfonamide antibiotic molecules on carbon nanotubes were investigated using density functional theory (DFT) calculations. The adsorption configurations of different adsorption sites were optimized, and the most stable adsorption configuration of each sulfonamide molecule was determined by adsorption energy comparison, and the relative adsorption stability of five sulfonamide molecules on carbon nanotubes was determined by comparing their adsorption energies, i.e., sulfamethazine > sulfadiazine > sulfamerazine > sulfamethoxazole > sulfanilamide. The electron densities of the adsorption configurations were then calculated to confirm that the adsorption of five sulfonamide drug molecules on carbon nanotubes should be physical adsorption. Moreover, the adsorption energy of five sulfonamide molecules on carbon nanotubes in the aqueous environment was larger than that in the vacuum even though the adsorption process remain to be physical adsorption. The adsorption characteristics of the five sulfonamide molecules in various acid-base environments were finally investigated. In contrast, the adsorption energies of the five drug molecules in acid-base environments were significantly reduced, indicating that carbon nanotubes may need to have a suitable pH range to achieve the optimal adsorption effect when they are used for the treatment of sulfonamide antibiotics. METHODS: In this paper, we use density functional theory (DFT) with PBE functional to study the adsorption properties of five sulfonamides on carbon nanotubes. The structural optimization and the calculation of electronic structural properties are carried out by CP2K package (version 7.1), adopting the DZVP-MOLOPT-SR-GTH basis set and Goedeck-Teter-Hutter (GTH) pseudo potential. Grimme's D3 correction is used to during all the calculations to correctly capture the influence of the van der Waals interactions.

Effect of ultrasound on the kinetics of anti-solvent crystallization of sucrose.

The effect of ultrasound on the kinetics of anti-solvent crystallization of sucrose was studied. The influence of temperature, stirring rate, supersaturation and ultrasonic power on the anti-solvent crystallization of sucrose was investigated. The relationship between infrared spectral characteristic band of sucrose and supersaturation was determined with an online reaction analyzer. The crystal size distribution of sucrose was detected by a laser particle-size analyzer. Ultrasound accelerated the crystallization process, and had no impact on the crystal shape. Abegg, Stevens and Larson model was fitted to the experimental data, and the results were the following: At 298.15 K, the average size of crystals was 133.8 µm and nucleation rate was 4.87 × 109 m-3·s-1 without ultrasound. In an ultrasonic field, the average size was 80.5 µm, and nucleation rate was 1.18 × 1011 m-3·s-1. Ultrasound significantly reduced the average size of crystals and improved the nucleation rate. It was observed that the crystal size decreased with the increase of stirring rate in silent environment. When the stirring rate increased from 250 to 400 rpm, the average size decreased from 173.0 to 132.9 µm. However, the stirring rate had no significant impact on the crystal size in the ultrasonic field. In addition, the activation energy of anti-solvent crystallization of sucrose was decreased, and the kinetic constant of nucleation rate was increased due to the effect of ultrasound. In the ultrasonic field, the activation energy was reduced from 20422.5 to 790.5 J·mol-1, and the kinetic constant was increased from 9.76 × 102 to 8.38 × 108.

Theoretical investigation complexation characteristics and UV-Vis absorption spectral properties of CdTe QDs with four capping agents.

In this paper, density functional theory (DFT) and time-dependent density functional theory (TDDFT) are used to study the complexation characteristics CdTe QDs with four different capping agents, i.e. 3-mercaptopropionic acid (MPA), reduced glutathione (GSH), 1-thioglycerol (TG) and 2-mercaptoethanesulfonate (MES). The properties of these complexes are analyzed by the complexation free energies, bond lengths, LOL, ADCH charges, frontier molecular orbitals and the UV-Vis absorption spectra. The results indicate that the four capping agents could form stable complexes with CdTe QDs. Whether the four capping agents interact with (CdTe)6 or (CdTe)9, MES has the strongest complexation ability with CdTe QDs and the MES-complexes are the most stable. For (CdTe)6, A2-MES is the most stable configuration. The complexation free energy and bond length of A2-MES are - 74.50 kcal/mol and 2.461 Å, respectively. When (CdTe)9 as substrate, A4-MES is the most stable configuration and corresponding complexation free energy is - 100.97 kcal/mol, which is followed by A4-MPA (- 57.75 kcal/mol) and A3-TG (- 60.20 kcal/mol), while A4-GSH (- 44.47 kcal/mol) is the weakest. Moreover, the electron amount transferred from MES to CdTe QDs is the most, and the ADCH charge value is 1.47 e. The absorption intensity of UV-visible light after complexation is also the largest. This is consistent with the result of the complexation free energy. Thus, it can be seen that the complexation abilities of four capping agents are in order of MES > MPA≈TG > GSH.

Relative peripheral refraction and its role in myopia onset in teenage students.

AIM: To characterize peripheral refraction and its relationship with myopia development in a selected group of male teenage Chinese students. METHODS: This 2-year prospective cohort study randomly enrolled 85 non-myopic boys (age, 14-16y) from the Experimental Class of Air Force in China. Cycloplegic peripheral refraction was examined at 0°, ±10°, and ±20° along the horizontal visual field in the right eye at the baseline and 2-year follow-up. RESULTS: The incidence of myopia at the 2-year follow-up was 15.29% (13/85). The baseline central refraction (CR) and peripheral refraction at ±10° were significantly lower in students who developed myopia than in those who did not (P<0.05). Relative peripheral refraction (RPR) did not differ between students with and without myopia (P>0.05). At the 2-year follow-up, the RPR at ±10° and 20° nasal was significantly more hyperopic in the myopic group than in the non-myopic group. Multiple linear regression analysis indicated that the change in CR was significantly correlated with the changes in RPR at 20° nasal, 10° nasal, and 20° temporal. Multivariate Logistic regression analysis indicated that the baseline CR [odds ratio (OR): 0.092, 95% confidence interval (CI): 0.012-0.688, P=0.020] and the baseline RPR at 10° nasal (OR: 0.182, 95%CI: 0.042-0.799, P=0.024) were significantly correlated with incident myopia (Omnibus test, χ 2=10.20, P=0.006). CONCLUSION: CR change is significantly correlated with changes in RPR, and students who develop myopia have more relative peripheral hyperopia. More baseline CR and relative peripheral hyperopia at 10° nasal are protective of myopia onset.

Expression of the embryonic stem cell transcription factor SOX2 in human skin: relevance to melanocyte and merkel cell biology.

SOX2 is a gene located on chromosome 3q26.33 that encodes a transcription factor important to maintenance of embryonic neural crest stem cell pluripotency. We have identified rare SOX2-immunoreactive cells in normal human skin at or near the established stem cell niches. Three subsets of SOX2-positive cells were defined in these regions: those expressing only SOX2 and those that co-expressed SOX2 and either CK20 or microphthalmia-associated transcription factor, which are consistent with dichotomous differentiation of SOX2-expressing precursors along neuroendocrine (Merkel cell) or melanocytic lines, respectively. Examination of Merkel cell carcinomas confirmed nuclear SOX2 expression in this tumor type. In human patient melanoma, strong nuclear expression of SOX2 was noted in a subset of tumors, and the ability to detect SOX2 in lesional cells significantly correlated with primary tumor thickness in a survey cohort. To assess the potential role of SOX2 in melanoma growth, an in vivo tumorigenesis assay was used. Whereas SOX2 knockdown failed to influence proliferation of cultured melanoma cells in vitro, tumor xenografts generated with the SOX2-knockdown cell line showed significant decrease in mean tumor volume as compared with controls. In aggregate, these findings suggest that SOX2 is a novel biomarker for subpopulations of normal skin cells that reside in established stem cell niches and that might relate to Merkel cell and melanocyte ontogeny and tumorigenesis.

Methodological evaluation and comparison of five urinary albumin measurements.

BACKGROUND: Microalbuminuria is an indicator of kidney damage and a risk factor for the progression kidney disease, cardiovascular disease, and so on. Therefore, accurate and precise measurement of urinary albumin is critical. However, there are no reference measurement procedures and reference materials for urinary albumin. METHODS: Nephelometry, turbidimetry, colloidal gold method, radioimmunoassay, and chemiluminescence immunoassay were performed for methodological evaluation, based on imprecision test, recovery rate, linearity, haemoglobin interference rate, and verified reference interval. Then we tested 40 urine samples from diabetic patients by each method, and compared the result between assays. RESULTS: The results indicate that nephelometry is the method with best analytical performance among the five methods, with an average intraassay coefficient of variation (CV) of 2.6%, an average interassay CV of 1.7%, a mean recovery of 99.6%, a linearity of R=1.00 from 2 to 250 mg/l, and an interference rate of <10% at haemoglobin concentrations of <1.82 g/l. The correlation (r) between assays was from 0.701 to 0.982, and the Bland-Altman plots indicated each assay provided significantly different results from each other. CONCLUSION: Nephelometry is the clinical urinary albumin method with best analytical performance in our study.

Rational design of monolayer transition metal dichalcogenide@fullerene van der Waals photovoltaic heterojunctions with time-domain density functional theory simulations.

van der Waals heterojunctions formed by transition metal dichalcogenides (TMDs) and fullerenes are promising candidates for novel photovoltaic devices due to the excellent optoelectronic properties of both TMDs and fullerenes. However, relevant experimental and theoretical investigations remain scarce to the best of our knowledge. Herein, we have first employed static density functional theory (DFT) calculations in combination with time-domain density functional theory (TDDFT) based nonadiabatic dynamics simulations to rationally evaluate the photovoltaic performances of four TMD@fullerene heterostructures, i.e. WSe2@C60, WSe2@C70, MoTe2@C60 and MoTe2@C70, respectively. Our simulation results indicate that the C70-based heterostructures overall have better photoinduced electron transfer efficiencies than their C60-based counterparts, among which the performance of the WSe2@C70 heterostructure is the best and the electron transfer from WSe2 to C70 almost accomplishes within 1 ps. In addition, the large build-in potential of about 0.75 eV of WSe2@C70 is beneficial for the charge separation processes. Our present work not only selects the van der Waals TMD@fullerene heterojunctions that might have excellent photovoltaic properties, but also paves the way for the rational design of novel heterojunctions with better optoelectronic performances with DFT and TDDFT simulations in the future.

Refractive Change and Incidence of Myopia Among A Group of Highly Selected Senior High School Students in China: A Prospective Study in An Aviation Cadet Prerecruitment Class.

Purpose: To assess the incidence rate of myopia, refractive change, and the effects of influencing factors on a group of highly selected senior high school students in an Aviation Cadet prerecruitment class in China. Methods: A total of 800 nonmyopic, male, Grade 9 students aged 14- to 16-years old with cycloplegic refraction of -0.25 or greater diopters (D) to 1.75 D or less in both eyes were enrolled in May 2016. During their senior high school studies, students had one 20-minute physical training period a day, and they were encouraged to participate in outdoor activities during class recess without any time limits. The first follow-up was 8 months after enrollment when they were in Grade 10, and the second follow-up was 1 year after the first follow-up when they were in Grade 11. Comprehensive ocular examinations and a detailed questionnaire, which included questions about outdoor activity time, parental myopia, and near work, were completed at each follow-up. Results: The average spherical equivalent refraction (SER) of the right eyes was 0.39 ± 0.44 D at baseline, 0.16 ± 0.41 D at the first follow-up, and -0.10 ± 0.38 D at the second follow-up. The cumulative refractive change was -0.50 D (95% confidence interval [CI], -0.53 to -0.47). The cumulative incidence rate of myopia was 15.5% (124/800). Incident myopia was significantly associated with outdoor activity for more than 1 versus less than 0.5 hr/d (odds ratio [OR] = 0.272, 95% CI, 0.132-0.560), baseline refraction (OR = 0.079, 95% CI, 0.041-0.153), maternal myopia (OR = 2.251, 95% CI, 1.160-4.368), longer class time (OR =3.215, 95% CI, 1.088-9.499), frequent, continuous, and long time reading/writing (OR = 1.620, 95% CI, 1.022-2.570), and shorter reading/writing distance (OR = 1.828, 95% CI, 1.065-3.140). In multiple linear regression model, having outdoor activity for more than 1 hr/d was protective from cumulative SER decrease. A higher baseline refraction together with longer reading/writing time, frequent, continuous, and longtime reading/writing, and shorter reading/writing distance were risk factors for SER decrease. Conclusions: In this cohort of highly selected, nonmyopic students, longer outdoor activity time was a protective factor for both incident myopia and refractive change of myopic shift. The risk factors for incident myopia included lower hyperopic baseline refraction, more near work, and maternal myopia. The risk factors for refractive change of myopic shift included more hyperopic baseline refraction and more near work.

Prediction of one-year survival in high-risk patients with acute coronary syndromes: results from the SYNERGY trial.

BACKGROUND: Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality. OBJECTIVE: The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS. DESIGN AND PARTICIPANTS: A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial. MEASUREMENTS: Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper. RESULTS: Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82). CONCLUSIONS: Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS.

Impact of initial heart rate and systolic blood pressure on relation of age and mortality among fibrinolytic-treated patients with acute ST-elevation myocardial infarction presenting with cardiogenic shock.

Older age is associated with worse outcomes in patients with cardiogenic shock complicating ST-elevation myocardial infarction (STEMI). However, significant heterogeneity exists in different age groups with respect to outcomes. Identification of factors that modulate age-related risk of death in patients with cardiogenic shock may help clinical decision making and facilitate patient counseling. Accordingly, we evaluated 761 patients with STEMI who presented with cardiogenic shock and received fibrinolysis. We categorized patients into 3 age groups (<60 years, n = 224; 60 to 75 years, n = 360; and > or = 75 years, n = 177). Death at 30 days occurred in 118 patients <60 years of age (53%), 214 patients 60 to 75 years of age (59%), and 127 patients > or = 75 years of age (72%) with cardiogenic shock. Factors associated with death (per 10-U change) on multivariable analysis were older age (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.23 to 1.66), higher heart rate (OR 1.27, 95% CI 1.19 to 1.35), and lower systolic blood pressure (OR 1.32, 95% CI 1.23 to 1.41, c index 0.79). Important interactions were found with age, heart rate, and systolic blood pressure, suggesting that, although age was a strong independent predictor of death in patients with a heart rate < or = 100 beats/min, it was less strongly related to death in patients with a heart rate >100 beats/min in whom prognosis was uniformly poor. Further, elderly patients with a systolic blood pressure >80 mm Hg had substantial chance of recovery. In contrast, those with a systolic blood pressure < or = 80 mm Hg and heart rate >100 beats/min had 30-day death rates >90% even if they were young. In conclusion, our data suggest that, although elderly patients with cardiogenic shock have poor prognosis, presenting heart rate and systolic blood pressure provide important information to differentiate who may have greater chance of recovery. This information may help physicians in deciding treatment options for patients with cardiogenic shock and counseling them about their risks.

Tubular proteinuria is the dominant type of proteinuria in an elderly community population in China.

PURPOSE: To explore the types of proteinuria in the elderly population in China. METHODS: Seven hundred and fourteen elderly people (≥ 60 years old) from Tianjin, China, were selected for the study. The albumin-to-creatinine ratio and α1-microglobulin-to-creatinine ratio from morning urine samples were used as indicators of proteinuria. The prevalence of proteinuria was evaluated and the proportion of three different types of proteinuria (mixed, glomerular, and tubular) was assessed in the subjects by analyzing these indicators. RESULTS: Of the 714 subjects, 29.13 % had elevated ACR and 46.36 % had elevated MCR. The proportion of subjects with either elevated ACR or MCR was 53.78 %. The correlation between MCR and ACR was moderate (r = 0.58, R (2) = 0.34, P < 0.001). Overall, tubular proteinuria was dominant (45.83 %), followed by mixed glomerular and tubular proteinuria (35.68 %), and significantly higher than glomerular proteinuria. A diet high in salt was the independent risk factor for tubular proteinuria; physical activity was the independent risk factor for glomerular proteinuria. The risk of glomerular proteinuria was lower in males than in females, but the risk of tubular proteinuria was higher in males. CONCLUSIONS: The prevalence of tubular proteinuria was higher than that of glomerular proteinuria, and the risk factors are different, in the elderly in China; therefore, tubular damage markers should get more attention in the overall population.

Safety of octreotide in hospitalized infants.

BACKGROUND: Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile of octreotide in hospitalized infants has not been described; we sought to fill this information gap. METHODS: We identified all infants exposed to at least 1 dose of octreotide from a cohort of 887,855 infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. We collected laboratory and clinical information while infants were exposed to octreotide and described the frequency of baseline diagnoses, laboratory abnormalities, and clinical adverse events (AEs). RESULTS: A total of 428 infants received 490 courses of octreotide. The diagnoses most commonly associated with octreotide use were chylothorax (50%), pleural effusion (32%), and hypoglycemia (22%). The most common laboratory AEs that occurred during exposure to octreotide were thrombocytopenia (47/1000 infant-days), hyperkalemia (21/1000 infant-days), and leukocytosis (20/1000 infant-days). Hyperglycemia occurred in 1/1000 infant-days and hypoglycemia in 3/1000 infant-days. Hypotension requiring pressors (12%) was the most common clinical AE that occurred during exposure to octreotide. Necrotizing enterocolitis was observed in 9/490 (2%) courses, and death occurred in 11 (3%) infants during octreotide administration. CONCLUSION: Relatively few AEs occurred during off-label use of octreotide in this cohort of infants. Additional studies are needed to further evaluate the safety, dosing, and efficacy of this medication in infants.

Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients: Insights From Clinical Trials Over 17 Years.

BACKGROUND: Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched. METHODS AND RESULTS: Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non-ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61-75] versus 64 [interquartile range 56-72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, ß-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan-Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%-7.6%] to 4.5% [95% confidence interval 4.0%-5.0%] among women and 6.3% [95% confidence interval 6.0%-6.7%] to 3.1% [95% confidence interval 2.9%-3.4%] among men during the 17-year period. CONCLUSIONS: The relative proportion of women in non-ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

Merkel cell carcinoma: lack of KIT positivity and implications for the use of imatinib mesylate.

The large variability (7% to 100%) in previously reported rates of receptor tyrosine kinase KIT expression in Merkel cell carcinoma (MCC) may be owing to the use of heat-induced epitope retrieval. High frequency of reported KIT reactivity by immunohistochemistry (IHC) in part prompted the initiation of a phase 2 clinical trial of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, East Hanover, NJ) for the treatment of advanced MCC. Our experience has been that a small number of MCCs (12.5%) are positive for KIT by IHC. We also found a higher rate of apparently KIT-positive MCCs (75%) using heat-induced epitope retrieval. Our anecdotal experience with the use of imatinib mesylate has been disappointing. As IHC detection of KIT expression does not correlate with the presence of KIT-activating mutations, protein expression as tested by IHC should not be used to determine if patients would respond to imatinib mesylate. Indeed, our review of the literature and the apparent lack of efficacy of imatinib mesylate for MCC in a recent phase 2 trial suggest a minor role for KIT signaling in MCC tumorigenesis.