bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation
Authors: Simmons John K. , Michalowski Aleksandra M. , Gamache Benjamin J. , DuBois Wendy , Patel Jyoti , Zhang Ke , Gary Joy , Zhang Shuling , Gaikwad Snehal , Connors Daniel , Watson Nicholas , Leon Elena , Chen Jin-Qiu , Kuehl W. Michael , Lee Maxwell P. , Zingone Adriana , Landgren Ola , Ordentlich Peter , Huang Jing , Mock Beverly A. 
Published: May 2017

Abstract
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI&lt;1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient–derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared with single agents. A set of 37 genes cooperatively affected (34 downregulated; 3 upregulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes downregulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared with normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC-binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo. Mol Cancer Ther; 16(9); 2008–21. ©2017 AACR.
Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs
Authors: Kosiborod Mikhail , Cavender Matthew A. , Fu Alex Z. , Wilding John P. , Khunti Kamlesh , Holl Reinhard W. , Norhammar Anna , Birkeland Kåre I. , Jørgensen Marit Eika , Thuresson Marcus , Arya Niki , Bodegård Johan , Hammar Niklas , Fenici Peter 
Published: May 2017

Background:
Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class.

Methods:
Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany.

Results:

After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73;
P
<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57;
P
<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60;
P
<0.001) with no significant heterogeneity by country.

Conclusions:
In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02993614.
Risk of Ischemic Stroke Associated With Calcium Supplements With or Without Vitamin D: A Nested Case‐Control Study
Authors: de Abajo Francisco J. , Rodríguez‐Martín Sara , Rodríguez‐Miguel Antonio , Gil Miguel J. 
Published: May 2017

Background
There is controversy surrounding the risk of ischemic stroke associated with the use of calcium supplements either in monotherapy or in combination with vitamin D.

Methods and Results
A nested case‐control study was performed with patients aged 40 to 89 years old, among whom a total of 2690 patients had a first episode of nonfatal ischemic stroke and for which 19 538 controls were randomly selected from the source population and frequency‐matched with cases for age, sex, and calendar year. Logistic regression provided the odds ratios while adjusting for confounding factors. A sensitivity analysis was performed by restricting to patients who were new users of calcium supplements as either monotherapy or with vitamin D. Calcium supplementation with vitamin D was not associated with an increased risk of ischemic stroke (odds ratio 0.85; 95% confidence interval, 0.67–1.08) in the population as a whole or under any of the conditions examined (dose, duration, background cardiovascular risk, sex, or age). Calcium supplement monotherapy was not associated with an increased risk in the population as a whole (odds ratio 1.18; 95% confidence interval, 0.86–1.61), although a significant increased risk at high doses (≥1000 mg/day: odds ratio 2.09; 95% confidence interval, 1.25–3.49; <1000 mg: odds ratio 0.76; 95% confidence interval, 0.45–1.26) compared with nonuse was observed. The sensitivity analysis did not affect the inferences, with similar results observed among new users as to the overall study population.

Conclusions
This study suggests that calcium supplements given as monotherapy at high doses may increase the risk of ischemic stroke, whereas their combination with vitamin D seems to offset this hazard.
Systolic Blood Pressure Within 24 Hours After Thrombectomy for Acute Ischemic Stroke Correlates With Outcome
Authors: Mistry Eva A. , Mistry Akshitkumar M. , Nakawah Mohammad Obadah , Khattar Nicolas K. , Fortuny Enzo M. , Cruz Aurora S. , Froehler Michael T. , Chitale Rohan V. , James Robert F. , Fusco Matthew R. , Volpi John J. 
Published: May 2017

Background
Current guidelines suggest treating blood pressure above 180/105 mm Hg during the first 24 hours in patients with acute ischemic stroke undergoing any form of recanalization therapy. Currently, no studies exist to guide blood pressure management in patients with stroke treated specifically with mechanical thrombectomy. We aimed to determine the association between blood pressure parameters within the first 24 hours after mechanical thrombectomy and patient outcomes.

Methods and Results

We retrospectively studied a consecutive sample of adult patients who underwent mechanical thrombectomy for acute ischemic stroke of the anterior cerebral circulation at 3 institutions from March 2015 to October 2016. We collected the values of maximum, minimum, and average values of systolic blood pressure, diastolic blood pressure, and mean arterial pressures in the first 24 hours after mechanical thrombectomy. Primary and secondary outcomes were patients’ functional status at 90 days measured on the modified Rankin scale and the incidence and severity of intracranial hemorrhages within 48 hours. Associations were explored using an ordered multivariable logistic regression analyses. A total of 228 patients were included (mean age 65.8±14.3; 104 males, 45.6%). Maximum systolic blood pressure independently correlated with a worse 90‐day modified Rankin scale and hemorrhagic complications within 48 hours (adjusted odds ratio=1.02 [1.01–1.03],
P
=0.004; 1.02 [1.01–1.04],
P
=0.002; respectively) in multivariable analyses, after adjusting for several possible confounders.

Conclusions
Higher peak values of systolic blood pressure independently correlated with worse 90‐day modified Rankin scale and a higher rate of hemorrhagic complications. Further prospective studies are warranted to identify whether systolic blood pressure is a therapeutic target to improve outcomes.
General Anesthesia Versus Conscious Sedation for Endovascular Treatment of Acute Ischemic Stroke
Authors: Löwhagen Hendén Pia , Rentzos Alexandros , Karlsson Jan-Erik , Rosengren Lars , Leiram Birgitta , Sundeman Henrik , Dunker Dennis , Schnabel Kunigunde , Wikholm Gunnar , Hellström Mikael , Ricksten Sven-Erik 
Published: May 2017

Background and Purpose—
Retrospective studies have found that patients receiving general anesthesia for endovascular treatment in acute ischemic stroke have worse neurological outcome compared with patients receiving conscious sedation. In this prospective randomized single-center study, we investigated the impact of anesthesia technique on neurological outcome in acute ischemic stroke patients.

Methods—

Ninety patients receiving endovascular treatment for acute ischemic stroke in 2013 to 2016 were included and randomized to general anesthesia or conscious sedation. Difference in neurological outcome at 3 months, measured as modified Rankin Scale score, was analyzed (primary outcome) and early neurological improvement of National Institutes of Health Stroke Scale and cerebral infarction volume. Age, sex, comorbidities, admission National Institutes of Health Stroke Scale score, intraprocedural blood pressure, blood glucose, Paco
2
and Pco
2
modified Thrombolysis in Cerebral Ischemia score, and relevant time intervals were recorded.

Results—

In the general anesthesia group 19 of 45 patients (42.2%) and in the conscious sedation group 18 of 45 patients (40.0%) achieved a modified Rankin Scale score ≤2 (
P
=1.00) at 3 months, with no differences in intraoperative blood pressure decline from baseline (
P
=0.57); blood glucose (
P
=0.94); PaCO2 (
P
=0.68); time intervals (
P
=0.78); degree of successful recanalization, 91.1% versus 88.9% (
P
=1.00); National Institutes of Health Stroke Scale score at 24 hours 8 (3–5) versus 9 (2–15;
P
=0.60); infarction volume, 20 (10–100) versus 20(10–54) mL (
P
=0.53); and hospital mortality (13.3% in both groups;
P
=1.00).

Conclusions—
In endovascular treatment for acute ischemic stroke, no difference was found between general anesthesia and conscious sedation in neurological outcome 3 months after stroke.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01872884.
An Advent Witness
Authors: Beitler James Edward 
Published: May 2017

Scholars and critics have long recognized C. S. Lewis’s potent persuasiveness and acute audience awareness; however, only a few have written about Lewis’s self-designation as a “rhetor,” and scholarship exploring how Lewis’s writings work rhetorically remains in short supply. This article advances existing conversations about Lewis’s rhetoric through an investigation of appeals to ethos in his nonfiction. I contend that a primary way that Lewis establishes ethos is by demonstrating what Aristotle refers to as eunoia, goodwill towards one’s audience. Resonating with postures that Christians are often called to embrace during the Advent season, Lewis’s rhetoric of goodwill enables him to achieve one of his chief aims as a writer: preparing a way for the coming of the Lord into people’s lives. This mode of rhetorical engagement is also consistent with Lewis’s emphasis on the doctrine of the Incarnation, his interest in the concept of joy, and his conversion experience.
Prevalence of psychological distress: How do Australia and Canada compare?
Authors: Enticott Joanne C , Lin Elizabeth , Shawyer Frances , Russell Grant , Inder Brett , Patten Scott , Meadows Graham 
Published: May 2017

Objective: To compare equivalent population-level mental health indicators in Canada and Australia, and articulate recommendations to support equitable mental health services. These are two somewhat similar resource-rich countries characterized by extensive non-metropolitan and rural regions as well as significant areas of socioeconomic deprivation. Methods: A cross-national epidemiology and equity study: primary outcome was Kessler Psychological Distress Scale (K10) in recent national surveys. A secondary outcome was mental disorders rate since these surveys were 5-years apart. Results: Elevated distress, defined by K10 scores (0–40 range) of 12 and over, affected 11.1% Australians and 12.0% Canadians. Elevated distress in both countries affected more people in the lowest income quintile (21–27%) compared to the richest (6%). In the lowest income quintile, 1-in-4 Australians and 1-in-5 Canadians reported elevated distress – twice the national average in both countries. Australians in the lowest income quintile (over 5 million people) have a significantly higher risk by over a 5% for elevated distress compared to their low-income Canadian counterparts. After adjusting for effects of age and gender, the relative odds in the lowest quintile compared to richest was 6.4 for Australians and 3.5 for Canadians, which remained significantly different thus confirming greater inequity in Australia. Mental disorders affected approximately 1-in-10 people in both countries. Conclusions: This adds to the mental health prevalence monitoring in these two countries by supporting an overall prevalence of elevated distress in approximately 1-in-10 people. It supports large-scale public health interventions that target elevated distress in people with low incomes to order to achieve the biggest impact, and, to reduce the greater inequity in mental health indicators in Australians, policy-makers should consider eliminating gap-fees as they are illegal in Canada. As encouraged by World Health Organization, we highlight the importance of such population-level studies so that cross-national results can be reliably compared.
Intravenous Fish Oil and Pediatric Intestinal Failure–Associated Liver Disease: Changes in Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Fatty Acids
Authors: Calkins Kara L. , DeBarber Andrea , Steiner Robert D. , Flores Martiniano J. , Grogan Tristan R. , Henning Susanne M. , Reyen Laurie , Venick Robert S. 
Published: May 2017

AbstractBackground: Soybean oil (SO) emulsions are associated with intestinal failure–associated liver disease (IFALD); fish oil (FO) emulsions are used to treat IFALD. SO and FO differ with respect to their fatty acid and phytosterol content. In children with IFALD whose SO was replaced with FO, we aimed to (1) quantify changes in erythrocyte fatty acids and plasma phytosterols, cytokines, and bile acids and (2) correlate these changes with direct bilirubin (DB). Design: This study enrolled IFALD children who received 6 months of FO. Blood samples were collected prior to FO, and after 2 weeks and 3 and 6 months of FO. The primary outcome was 3‐month vs baseline biomarker concentrations. Results: At study initiation, the median patient age was 3 months (interquartile range, 3–17 months), and mean ± standard deviation DB was 5.6 ± 0.7 mg/dL (n = 14). Cholestasis reversed in 79% of subjects. Eicosapentaenoic and docosahexaenoic acid was greater than baseline (P < .001, all time points). Linoleic and arachidonic acid and sitosterol and stigmasterol were less than baseline (P < .05, all time points). Three‐ and 6‐month interleukin‐8 (IL‐8) and total and conjugated bile acids were less than baseline (P < .05). Baseline IL‐8 was correlated with baseline DB (r = 0.71, P < .01). Early changes in stigmasterol and IL‐8 were correlated with later DB changes (r = 0.68 and 0.75, P < .05). Conclusion: Specific fat emulsion components may play a role in IFALD. Stigmasterol and IL‐8 may predict FO treatment response.
Oral Feeding Difficulties in Children With Short Bowel Syndrome: A Narrative Review
Authors: Hopkins Judy , Cermak Sharon A. , Merritt Russell J. 
Published: May 2017

AbstractChildren with short bowel syndrome (SBS) with associated intestinal failure may be unable to absorb sufficient nutrients to sustain life. Improvements in the medical management of SBS, including use of parenteral nutrition, has significantly increased life expectancy. Independence from parenteral nutrition further improves quality of life. However, children living with SBS often develop oral aversions and feeding difficulties. There is limited research and information on which to base interventions that will preserve and develop oral motor and feeding skills. The aims of this article are to explore what is known about children with SBS who exhibit oral aversion/feeding difficulties and to suggest research for possible future interventions that could help these children overcome oral aversion, eat orally, and increase participation and satisfaction in mealtimes. This review explores the complexity of feeding children with SBS. Three underlying themes emerged: physical, developmental, and social aspects of eating and mealtimes. Interdisciplinary teams are needed to effectively address these complex oral feeding problems. Accurate identification the underlying issues will allow healthcare providers to develop interventions to improve feeding outcomes for children with SBS. Future research should focus on evaluating the effectiveness of interventions that address each of the underlying issues.
Protein Carbonyl, But Not Malondialdehyde, Is Associated With ICU Mortality in Patients With Septic Shock
Authors: Costa Nara Aline , Gut Ana Lucia , Azevedo Paula Schmidt , Fernandes Ana Angelica Henrique , Polegato Bertha Furlan , Cunha Natália Baraldi , Bachiega Tatiana Fernanda , Lourenço Maria Angélica Martins , Júnior Edson Luiz Favero , Zornoff Leonardo Antonio Mamede , de Paiva Sergio Alberto Rupp , Minicucci Marcos Ferreira 
Published: May 2017

Background: The objective of our study was to evaluate the association of serum malondialdehyde (MDA) and protein carbonyl concentration with intensive care unit (ICU) mortality in patients with septic shock. Methods: We prospectively evaluated 175 patients aged over 18 years with septic shock upon ICU admission. However, 16 patients were excluded. Thus, 159 patients were enrolled in the study. In addition, we evaluated 16 control patients. At the time of the patients’ enrollment, demographic information was recorded. Blood samples were taken within the first 24 hours of the patient’s admission to determine serum MDA and protein carbonyl concentrations. Results: The mean age was 67.3 ± 15.9 years, 44% were males, and the ICU mortality rate was 67.9%. Median MDA concentration was 1.53 (0.83-2.22) µmol/L, and median protein carbonyl concentration was 24.0 (12.7-32.8) nmol/mL. Patients who died during ICU stay had higher protein carbonyl concentration. However, there was no difference in MDA levels between these patients. Receiver operating characteristic curve analysis showed that higher levels of protein carbonyl were associated with ICU mortality (area under the curve: 0.955; 95% confidence interval [CI]: 0.918-0.992; P < .001) at the cutoff of >22.83 nmol/mL (sensibility: 80.4% and specificity: 98.1%). In the logistic regression models, protein carbonyl concentrations (odds ratio [OR]: 1.424; 95% CI: 1.268-1.600; P < .001), but not MDA concentrations (OR: 1.087; 95% CI: 0.805-1.467; P = .59), were associated with ICU mortality when adjusted for age, gender, and Acute Physiology and Chronic Health Evaluation (APACHE) II score; and when adjusted by APACHE II score, lactate, and urea; protein carbonyl concentrations (OR: 1.394; 95% CI: 1.242-1.564; P < .001); and MDA (OR: 1.054; 95% CI: 0.776-1.432; P = .73). Conclusion: In conclusion, protein carbonyl, but not MDA, concentration is associated with ICU mortality in patients with septic shock.
Assessment of Hypogonadism in Men With Type 2 Diabetes: A Cross-Sectional Study From Saudi Arabia
Authors: Al Hayek Ayman Abdullah , Robert Asirvatham Alwin , Alshammari Ghazi , Hakami Husain , Al Dawish Mohamed Abdulaziz 
Published: May 2017

Background/objectives:A high incidence of hypogonadism in men with type 2 diabetes (T2D) has been globally reported. This study aimed to determining the frequency of hypogonadism and related risk factors among men with T2D in a single-site hospital in Saudi Arabia.Design and methods:A cross-sectional study was performed on 157 men with T2D (between 30 and 70 years of age). Using a prestructured questionnaire, the demographic features of these patients were gathered and their medical records were referred to gather information regarding the duration of the diabetes, smoking habits, and the presence of retinopathy, neuropathy, and nephropathy. Besides these, the biochemical parameters, total testosterone (TT), free testosterone, sex hormone–binding globulin, follicle-stimulating hormone, luteinizing hormone, prolactin, serum lipids, and glycosylated hemoglobin were also recorded. All the patients submitted the fully completed Androgen Deficiency in Aging Male (ADAM) questionnaire. The combination of symptoms (positive ADAM score) plus a TT level ⩽8 nmol/L constituted the condition of hypogonadism.Results:The total frequency of hypogonadism was 22.9% (36/157). Of the 157 total patients, 123 (78.3%) were shown to be ADAM positive, and of these, 90 (73.2%) exhibited decreased libido, 116 (94.3%) had weak erections, and 99 (80.5%) reported more than 3 symptoms of ADAM. Of these hypogonadic patients, 22.2% (n = 8) revealed primary hypogonadism, whereas 77.8% (n = 28) showed secondary hypogonadism. From the univariate analysis conducted, significant relationship was observed between treatment type, body mass index (BMI), and hypogonadism. The regression analysis showed BMI acting an independent risk factor of hypogonadism.Conclusions:Saudi men with T2D revealed a high incidence of hypogonadism. Body mass index was identified as an independent risk factor for hypogonadism.