bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion
Authors: Schwartz Lisa M. , Woloshin Steven , Lu Zhigang , Ross Kathryn M. , Tessema Frazer A. , Peter Doris , Kesselheim Aaron S. 
Published: November 2019

Background:
Recent court decisions have thrown into question the Food and Drug Administration’s rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians’ beliefs about drug efficacy.

Methods and Results:

In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%,
P
<0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, −6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, −24% to 7%]).

Conclusions:
Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers’ knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.
Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score
Authors: Marston Nicholas A. , Kamanu Frederick K. , Nordio Francesco , Gurmu Yared , Roselli Carolina , Sever Peter S. , Pedersen Terje R. , Keech Anthony C. , Wang Huei , Lira Pineda Armando , Giugliano Robert P. , Lubitz Steven A. , Ellinor Patrick T. , Sabatine Marc S. , Ruff Christian T. 
Published: November 2019

Background:
The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established.

Methods:
We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27–single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years.

Results:

After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (
P
trend
=0.007) and major coronary events (
P
trend
<0.0001). Individuals with intermediate and high genetic risk scores had 1.32- and 1.66-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 0.99; absolute risk reduction [ARR], 0.06%,
P
=0.89). In contrast, there was a 15% relative risk reduction (HR, 0.85 [0.74–0.98],
P
=0.024) and a 1.6% ARR in patients with multiple clinical risk factors but without high genetic risk and a 25% relative risk reduction (HR, 0.75 [0.60–0.94],
P
=0.013), and 3.0% ARR in patients with high genetic risk, irrespective of clinical risk (
P
trend
for HR=0.095, ARR
P
trend
=0.034). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk.

Conclusion:
Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest benefit from evolocumab, which mitigated this risk.
Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
Authors: Damask Amy , Steg P. Gabriel , Schwartz Gregory G. , Szarek Michael , Hagström Emil , Badimon Lina , Chapman M. John , Boileau Catherine , Tsimikas Sotirios , Ginsberg Henry N. , Banerjee Poulabi , Manvelian Garen , Pordy Robert , Hess Sibylle , Overton John D. , Lotta Luca A. , Yancopoulos George D. , Abecasis Goncalo R. , Baras Aris , Paulding Charles ,   On behalf of the Regeneron Genetics Center and the ODYSSEY OUTCOMES Investigators
Published: November 2019

Background:
Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment.

Methods:
ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients.

Results:

The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile;
P
<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46–0.86];
P
=0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78–0.98];
P
=0.022; interaction
P
=0.04).

Conclusions:
A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
<p><strong><em>Dichodontium opacifolium </em>Dix. in Christ. and <em>Dichodontium brasiliense </em>Broth. are both identical with <em>Chrysoblastella chilensis </em>(Mont.) Reim.</strong></p>
Authors: Sollman Philip 
Published: November 2019

The types of Dichodontium opacifolium Dix. in Christ. and Dichodontium brasiliense Broth. were compared. They are identical and the same as Chrysoblastella chilensis (Mont.) Reim.
<p><strong>Bdelloidea of China: a review of progress on systematics and biology, with a checklist of species</strong></p>
Authors: LIN JIAN-ZHEN , ZHANG ZHI-QIANG 
Published: November 2019

This paper reviews the research on the systematics and biology of the superfamily Bdelloidea in China, with an updated checklist of 48 species belonging to 16 genera in the family Cunaxidae and 26 species belonging to nine genera in the family Bdellidae. Important contributions to the Chinese fauna of the Bdellidae were made by Tseng Yi-Hsiung (Taiwan), Hong Mei (former with Fudan University in Shanghai) and Lin Jian-Zhen (and colleagues in Fujian Academy of Agricultural Sciences, Fuzhou), and those to the Cunaxidae by Tseng Yi-Hsiung, Li Long-Shu (and colleagues in Southwest University, Chongqing) and Lin Jian-Zhen (and colleagues). There have been relatively few studies on the biology and use in biological control of the Bdelloidea in China, and these are briefly reviewed.
Cinnarizine and sodium valproate as the preventive agents of pediatric migraine: A randomized double-blind placebo-controlled trial
Authors: Amanat Man , Togha Mansoureh , Agah Elmira , Ramezani Mahtab , Tavasoli Ali Reza , Azizi Malamiri Reza , Fashandaky Fariba , Heidari Morteza , Salehi Mona , Eshaghi Hamid , Ashrafi Mahmoud Reza 
Published: November 2019

Background Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents. Methods We carried out a randomized double-blind placebo-controlled trial in the Children’s Medical Center and Sina hospital, Tehran, Iran. Eligible participants were randomly assigned in 1:1:1 ratio via interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The primary endpoints were the mean change in frequency and intensity of migraine attacks from baseline to the last 4 weeks of trial. The secondary endpoint was the efficacy of each drug in the prevention of migraine. The drug was considered effective if it decreased migraine frequency by more than 50% in the double-blind phase compared with the baseline. Safety endpoint was adverse effects that were reported by children or their parents. Results A total of 158 children participated. The frequency of migraine attacks significantly reduced compared to baseline in cinnarizine (difference: −8.0; 95% confidence interval (CI): −9.3 to −6.6), sodium valproate (difference: −8.3; 95% confidence interval: −9.3 to −7.2), and placebo (difference: −4.4; 95% confidence interval: −5.4 to −3.4) arms. The decrease was statistically greater in cinnarizine (difference: −3.6; 95% confidence interval: −5.5 to −1.6) and sodium valproate (difference: −3.9; 95% confidence interval: −5.8 to −1.9) arms, compared to placebo group. Children in all groups had significant reduction in intensity of episodes compared to baseline (cinnarizine: −4.6; 95% confidence interval: −5.2 to −4.0; sodium valproate: −4.0; 95% confidence interval: −4.8 to −3.3; placebo: −2.6; 95% confidence interval: −3.4 to −1.8). The decrease was statistically greater in cinnarizine (difference: −2.0; 95% confidence interval: −3.2 to −0.8) and sodium valproate (difference: −1.5; 95% confidence interval: −2.7 to −0.3) arms, compared to the placebo group. Seventy-one percent of individuals in the cinnarizine group, 66% of cases in the sodium valproate group, and 42% of people in the placebo arm reported more than 50% reduction in episodes at the end of the trial. The odds ratio for >50% responder rate was 3.5 (98.3% confidence interval: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% confidence interval: 1.0 to 6.9) for sodium valproate versus placebo. Nine individuals reported adverse effects (three in cinnarizine, five in sodium valproate, and one in the placebo group) and one case in the sodium valproate group discontinued the therapy due to severe sedation. Conclusion Cinnarizine and sodium valproate could be useful in migraine prophylaxis in children and adolescents. Trial registration: IRCT201206306907N4.
Hypocholesterolemia in cats: a multicenter retrospective study of 106 cats
Authors: Bowman Claudia , Viall Austin , Rudinsky Adam , Gilor Chen , Palerme Jean-Sébastien 
Published: November 2019

Objectives The aim of this study was to describe the clinicopathologic findings and associated diseases found in a population of hypocholesterolemic cats referred to two tertiary care facilities. Methods An electronic medical record search was performed at two veterinary university referral centers to identify cats with serum cholesterol values below the reference interval between January 2004 and 2016. Clinicopathologic data were reviewed for each case and cats were classified into specific disease categories based on clinical diagnosis. Median cholesterol values were compared between disease categories, as well as between survivors and non-survivors. Results In total, 106 hypocholesterolemic cats were included. The median age of the cats was 6 years (range 0.24–18 years). The most common disease categories were gastrointestinal (25.9%), hepatobiliary (19.8%), hematologic (14.8%) and urogenital (14.8%). Though median serum cholesterol values did not differ significantly between survivors and non-survivors, cats with concurrent hypoalbuminemia were at higher risk (odds ratio 15.6, 95% confidence interval 5.2–46.6; P <0.0001) of not surviving to discharge than cats with normal serum albumin concentrations. Conclusions and relevance Taken together, our data suggest that while the degree of hypocholesterolemia did not appear to influence survival rates, the concurrent presence of hypocholesterolemia and hypoalbuminemia was associated with a worse prognosis.
Sensory mapping of lumbar facet joint pain: a feasibility study
Authors: Kanakarajan Saravanakumar , Fernando Kasun , Dharmavaram Sudhindra , Galley Helen F 
Published: November 2019

Objective: To evaluate the feasibility of sensory mapping of lumbar facet joint pain in patients scheduled to undergo radiofrequency (RF) denervation. Design: Prospective cohort study. Setting: University teaching hospital. Subjects: A total of 15 participants listed for RF denervation of lumbar facet joint. Method: After written informed consent, participants were recruited to the study. Participants completed a pain diagram prior to their procedure. After successful image-guided placement of RF cannulas, the sensory detection threshold using 50 Hz stimulation was obtained, followed by application of suprathreshold stimulation. Participants mapped their stimulated area in comparison to their pre-procedure pain diagram. Results: All 15 participants had previously undergone diagnostic blocks. All participants were able to report either pain or paraesthesia during suprathreshold stimulation. In total, 14 out of 15 participants reported complete coverage of their usual painful area with suprathreshold stimulation of nerves scheduled for RF denervation. In one of the participants, an area of upper lumbar pain was not covered during suprathreshold stimulation. Nearly two-thirds of the participants (n = 9), reported either pain or paraesthesia, outside their normal painful area during suprathreshold stimulation. A total of 71 nerves were scheduled for RF denervation. Sensory electrical stimulation was successfully achieved in 68 out of 71 nerves (96%). The average sensory detection threshold was found to be 0.3 V while the suprathreshold stimulation was 0.6 V. Conclusion: Lumbar facet joint pain can be mapped using suprathreshold sensory stimulation, which has the potential to introduce objectivity during RF denervation.
Frail Patients Benefit From Less Invasive Procedures
Authors: Stenvers Elke , Mars Riemke C. , Zuurmond Rutger G. 
Published: November 2019

Purpose: A traumatic periprosthetic fracture (PPF) is a long-term complication of total hip arthroplasty. Treatment options include revision, open reposition and internal fixation (ORIF), and minimally invasive techniques (MITs). To select the optimal surgical procedure, the level of frailty has to be considered, especially in patients with geriatric trauma. The aim of this study is to determine whether a frail patient has a better outcome postoperatively after less invasive treatment. Methods and materials: Sixty-three patients with an PPF were analyzed in this retrospective study. The level of frailty was obtained by the complex fracture frailty index (CFFI). The CFFI combines comorbidities, laboratory tests, physical abilities, social factors, and cognitive functions. Primary outcomes in this study include mortality, minor complications, and 3 major complications (deceased, reoperation or immobility after 1 year). Results: Thirty frail patients had lower survival rates ( P = .014) and significantly more major complications with a relative risk of 3.7 ( P = .02). In the entire group of 63 patients, there were no significant differences detected in the outcome measures; however, when specified in a subgroup of 30 frail patients according to our CFFI, significant differences were found. Patients treated with MIT had significantly less major and minor complications compared to ORIF and revision. Furthermore, patients treated with ORIF experienced significantly less minor complications than with revision surgery ( P = .015). Discussion and conclusion: This study shows that frail patients can be adequately detected using our frailty score CFFI and have a lower survival rate, regardless the type of surgery. Another finding is that for frail patients, more invasive surgery has a negative influence on the outcome of the treatment. Therefore, it is of great importance to assess and use the patient’s level of frailty to determine the surgical procedure for a PPF.
Developing Children’s Oral Health Assessment Toolkits Using Machine Learning Algorithm
Authors: Wang Y. , Hays R.D. , Marcus M. , Maida C.A. , Shen J. , Xiong D. , Coulter I.D. , Lee S.Y. , Spolsky V.W. , Crall J.J. , Liu H. 
Published: November 2019

Objectives: Evaluating children’s oral health status and treatment needs is challenging. We aim to build oral health assessment toolkits to predict Children’s Oral Health Status Index (COHSI) score and referral for treatment needs (RFTN) of oral health. Parent and Child toolkits consist of short-form survey items (12 for children and 8 for parents) with and without children’s demographic information (7 questions) to predict the child’s oral health status and need for treatment. Methods: Data were collected from 12 dental practices in Los Angeles County from 2015 to 2016. We predicted COHSI score and RFTN using random Bootstrap samples with manually introduced Gaussian noise together with machine learning algorithms, such as Extreme Gradient Boosting and Naive Bayesian algorithms (using R). The toolkits predicted the probability of treatment needs and the COHSI score with percentile (ranking). The performance of the toolkits was evaluated internally and externally by residual mean square error (RMSE), correlation, sensitivity and specificity. Results: The toolkits were developed based on survey responses from 545 families with children aged 2 to 17 y. The sensitivity and specificity for predicting RFTN were 93% and 49% respectively with the external data. The correlation(s) between predicted and clinically determined COHSI was 0.88 (and 0.91 for its percentile). The RMSEs of the COHSI toolkit were 4.2 for COHSI (and 1.3 for its percentile). Conclusions: Survey responses from children and their parents/guardians are predictive for clinical outcomes. The toolkits can be used by oral health programs at baseline among school populations. The toolkits can also be used to quantify differences between pre- and post-dental care program implementation. The toolkits’ predicted oral health scores can be used to stratify samples in oral health research. Knowledge Transfer Statement: This study creates the oral health toolkits that combine self- and proxy- reported short forms with children’s demographic characteristics to predict children’s oral health and treatment needs using Machine Learning algorithms. The toolkits can be used by oral health programs at baseline among school populations to quantify differences between pre and post dental care program implementation. The toolkits can also be used to stratify samples according to the treatment needs and oral health status.
Tourmaline from the Solnechnoe tin deposit, Khabarovsk Krai, Russia
Authors: Baksheev Ivan A. , Vigasina Marina F. , Yapaskurt Vasily O. , Bryzgalov Igor A. , Gorelikova Nina V. 
Published: November 2019

AbstractTourmaline from the Solnechnoe hydrothermal granitoid-related tin deposit in the Khabarovsk Krai, Russian Far East has been studied with electron microprobe, infrared and Mössbauer spectroscopy. Tourmaline formed in three distinct stages with different types of chemical substitution. Tourmaline from the first unmineralised stage is classified as dravite or schorl, which could be enriched locally in Ca, the X-site vacancy and F. This tourmaline is characterised by the Fe ↔ Mg and X vacancy + Al ↔ Na + Fe substitutions. The second, molybdenum-stage tourmaline, is schorl–dravite and fluor-schorl–fluor-dravite enriched in Ca, and a few compositions belong to the calcic group. The predominant substitution is Ca + Mg ↔ Na + Al. The third, tin-stage tourmaline, is classified as schorl–dravite with some tourmalines being fluor-schorl, oxy-schorl, foitite and magnesio-foitite. The tin-stage tourmaline is characterised by the substitutions Fe2+ ↔ Mg, Altot + O2– ↔ Fe2+ + OH–, and Fe3+ ↔ Altot. An increase of the Fe3+/Fetot value from 3–9% in the molybdenum stage to 12–16% in the tin-stage tourmalines indicates an increase in oxidation potential, which possibly contributed to cassiterite deposition. Comparison of tourmalines from greisen, porphyry and intrusion-related tin deposits worldwide shows they differ in primary chemical substitutions so can be characterised by this mechanism. The Fe3+/Fetot value in tourmaline also appears to be one of the indications for the tin deposit type. The Fe3+/Fetot value increases from <10% in greisen tourmaline through 15% in tourmaline from intrusion-related deposits to 20% in tourmaline from porphyry deposits.