bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein E DNA methylation and late-life disease
Authors: Karlsson Ida K , Ploner Alexander , Wang Yunzhang , Gatz Margaret , Pedersen Nancy L , Hägg Sara 
Published: February 2018

Abstract

Background
This study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimeŕs disease (AD) or cardiovascular disease (CVD).

Methods
DNA methylation across theAPOE gene has previously been categorized into three distinct regions: a hypermethylated region in the promoter, a hypomethylated region in the first two introns and exons and a hypermethylated region in the 3′exon that also harbours theAPOE ε2 and ε4 alleles. DNA methylation levels in leukocytes were measured using the Illumina 450K array in 447 Swedish twins (mean age 78.1 years). We used logistic regression to investigate whether methylation levels in those regions affect the odds of disease.

Results
We found that methylation levels in the promoter region were associated with dementia and AD after adjusting for sex, age at blood draw, education, smoking and relatedness among twins [odds ratio (OR) 1.32 per standard deviation increase in methylation levels, 95% confidence interval (CI) 1.08–1.62 for dementia; OR 1.38, 95% CI 1.07–1.78 for AD). We did not detect any difference in methylation levels between CVD cases and controls. Results were similar when comparing within discordant twin pairs, and did not differ as a function ofAPOE genotype.

Conclusions
We found that higher DNA methylation levels in the promoter region ofAPOE increase the odds of dementia and AD, but not CVD. The effect was independent ofAPOE genotype, indicating that allelic variation and methylation variation inAPOE may act independently to increase the risk of dementia.
Spinal Cord Stimulation for the Treatment of Chronic Pain Reduces Opioid Use and Results in Superior Clinical Outcomes When Used Without Opioids
Authors: Gee Lucy , Smith Heather C , Ghulam-Jelani Zohal , Khan Hirah , Prusik Julia , Feustel Paul J , McCallum Sarah E , Pilitsis Julie G 
Published: February 2018

Abstract

BACKGROUND
Chronic pain causes a significant burden to the US health care system, is difficult to treat, and remains a significant contributor to increased opioid use in the United States. Spinal cord stimulation (SCS) has been FDA approved for the treatment of chronic pain.

OBJECTIVE
To evaluate the hypothesis that SCS reduces opioid use, and alone maintains clinical outcome measures of pain and psychosocial determinants of health.

METHODS
In this prospective cohort study, we evaluated 86 patients undergoing SCS surgery for the treatment of chronic pain between September 2012 and August 2015. Preoperatively and postoperatively, patients completed the Numerical Rating Scale (NRS), McGill Pain Questionnaire (MPQ), Pain Catastrophizing Scale (PCS), Oswestry Disability Index (ODI), and Beck's Depression Inventory (BDI). VAS scores were retrospectively analyzed.

RESULTS
Fifty-three patients used opioids before SCS implantation. The 33 nonusers had lower mean VAS, NRS, and ODI scores than both opioid groups at 1 yr and improved significantly at 1 yr on the VAS (P < .001), NRS (P < .001), MPQ (P = .002), PCS (P < .001), BDI (P = .04), and ODI (P = .002). After surgery, 41.5% remained opioids and 58.5% reduced/eliminated use. Discontinued (n = 29) or reduced (n = 2) use resulted in VAS, NRS, total MPQ, and ODI score reduction (P < .001, P = .002, P = .002, and P = .009 respectively). At 1 yr, survey scores in opioid users were unchanged. There was no difference between groups in revision or failure rates.

CONCLUSION
Sixty-four percent of patients who were using opioids prior to SCS reduced (n = 2) or eliminated opioid use (n = 29) at 1 yr postoperatively. Patients who eliminated opioid use or never used opioids had superior clinical outcomes to those who continued use.
Autour des plus grands facteurs premiers d’entiers consÉcutifs voisins d’un entier criblé
Authors: Wang (Nancy) Zhiwei 
Published: February 2018

Abstract
Denote by P+(n) (resp. P−(n)) the largest (resp. the smallest) prime factor of the integer n. In this paper, we prove that there exists a positive proportion of integers n having no small prime factor such that P+(n)&lt;P+(n+2). Especially, we prove that the pattern P+(P3)&lt;P+(P3+2) is realized by a positive proportion of P3 with P−(P3)&gt;x1/3−δ,0&lt;δ≤112, where P3 denote an integer having at most three prime factors taken with multiplicity. We also prove that the pattern P+(p−1)&lt;P+(p+1) holds for a positive proportion of primes under the Elliott-Halberstam conjecture.
Navigating the Complexities of Undergraduate Medical Curriculum Change: Change Leaders’ Perspectives
Authors: Velthuis Floor , Varpio Lara , Helmich Esther , Dekker Hanke , Jaarsma A. Debbie C. 
Published: February 2018

Purpose
Changing an undergraduate medical curriculum is a recurring, high-stakes undertaking at medical schools. This study aimed to explore how people leading major curriculum changes conceived of the process of enacting change and the strategies they relied on to succeed in their efforts.

Method
The first author individually interviewed nine leaders who were leading or had led the most recent undergraduate curriculum change in one of the eight medical schools in the Netherlands. Interviews were between December 2015 and April 2016, using a semistructured interview format. Data analysis occurred concurrently with data collection, with themes being constructed inductively from the data.

Results
Leaders conceived of curriculum change as a dynamic, complex process. They described three major challenges they had to deal with while navigating this process: the large number of stakeholders championing a multitude of perspectives, dealing with resistance, and steering the change process. Additionally, strategies for addressing these challenges were described. The authors identified an underlying principle informing the work of these leaders: being and remaining aware of emerging situations, and carefully constructing strategies for ensuring that the intended outcomes were reached and contributed to the progress of the change process.

Discussion
This empirical, descriptive study enriches the understanding of how institutional leaders navigate the complexities of major medical curriculum changes. The insights serve as a foundation for training and coaching future change leaders. To broaden the understanding of curriculum change processes, future studies could investigate the processes through alternative stakeholder perspectives.
Is Speed a Desirable Difficulty for Learning Procedures? An Initial Exploration of the Effects of Chronometric Pressure
Authors: Gas Becca L. , Buckarma EeeLN H. , Cook David A. , Farley David R. , Pusic Martin V. 
Published: February 2018

Purpose
To determine whether “chronometric pressure” (i.e., a verbal prompt to increase speed) could predictably alter medical learners’ speed–accuracy trade-off during a simulated surgical task, thus modifying the challenge.

Method
The authors performed a single-task, interrupted time-series study, enrolling surgery residents and medical students from two institutions in September and October 2015. Participants completed 10 repetitions of a simulated blood vessel ligation (placement of two ligatures 1 cm apart). Between repetitions 5 and 6, participants were verbally encouraged to complete the next repetition 20% faster than the previous one. Outcomes included time and accuracy (ligature tightness, placement distance). Data were analyzed using random-coefficients spline models.

Results
The authors analyzed data from 78 participants (25 medical students, 16 first-year residents, 37 senior [second-year or higher] residents). Overall, time decreased from the 1st (mean [standard deviation] 39.8 seconds [18.4]) to the 10th (29.6 [12.5]) repetition. The spline model showed a decrease in time between repetitions 5 and 6 of 8.6 seconds (95% confidence interval: −11.1, −6.1). The faster time corresponded with declines in ligature tightness (unadjusted difference −19%; decrease in odds 0.86 [0.76, 0.98]) and placement accuracy (unadjusted difference −5%; decrease in odds 0.86 [0.75, 0.99]). Significant differences in the speed–accuracy trade-off were seen by training level, with senior residents demonstrating the greatest decline in accuracy as speed increased.

Conclusions
Chronometric pressure influenced the speed–accuracy trade-off and modified the challenge level in a simulated surgical task. It may help unmask correctable deficiencies or false plateaus in learners’ skill development.
Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas
Authors: Simon James A. , Catherino William , Segars James H. , Blakesley Rick E. , Chan Anna , Sniukiene Vilma , Al-Hendy Ayman 
Published: February 2018

OBJECTIVE:
To assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas.

METHODS:
This phase 3, double-blind, placebo-controlled study enrolled premenopausal women (aged 18–50 years) with abnormal uterine bleeding, one or more discrete leiomyomas, and uterine size 20 weeks of gestation or less. Patients were randomized 1:1:1 to 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks followed by 12-week drug-free follow-up. Coprimary endpoints were rate of and time to amenorrhea, defined as no bleeding for the last 35 consecutive days of treatment. Secondary endpoints included rates of amenorrhea from day 11 and change from baseline to endpoint in the Revised Activities subscale of the Uterine Fibroid Symptom and Quality of Life questionnaire, which includes questions pertaining to physical and social activities. Safety assessments included adverse event monitoring and endometrial biopsies. A sample size of 150 was planned to compare separately each dose of ulipristal with placebo.

RESULTS:
From March 2014 to March 2016, 157 patients were randomized. Demographics were similar across treatment groups. Amenorrhea was achieved by 25 of 53 (47.2% [97.5% CI 31.6–63.2]) and 28 of 48 (58.3% [97.5% CI 41.2–74.1]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 1 of 56 (1.8% [97.5% CI 0.0–10.9]) placebo-treated patients (both P<.001). Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001). Common adverse events (5% or greater in either ulipristal group during treatment) were hypertension, elevated blood creatinine phosphokinase, and hot flushes. Serious adverse events occurred in four patients, but none was considered related to treatment. Endometrial biopsies were benign.

CONCLUSION:
Ulipristal at 5 mg and 10 mg were well tolerated and superior to placebo in rate of and time to amenorrhea in women with symptomatic uterine leiomyomas.

CLINICAL TRIAL REGISTRATION:

Clinicaltrials.gov number, NCT02147197.
Exercise-Induced Abdominal Wall Muscle Injury Resulting in Rhabdomyolysis and Mimicking an Acute Abdomen
Authors: Echague Charlene G. , Csokmay John M. 
Published: February 2018

BACKGROUND:
Rhabdomyolysis is characterized by muscle necrosis and release of intracellular constituents, causing muscle pain, weakness, and myoglobinuria. This can be attributed to muscle injury after strenuous exercise. If the abdominal wall is involved, clinical presentation may resemble an acute abdomen.

CASE:
A 27-year-old woman, gravida 4 para 2, presented with swelling and pain of the mons pubis and abdominal pain after intense powerlifting 2 days prior. A computed tomography scan was performed, revealing abdominal wall inflammation. Although myoglobinuria was absent, there was high suspicion for rhabdomyolysis, which was confirmed by an elevated creatine kinase level. The patient improved after receiving intravenous fluids and abstaining from physical activity.

CONCLUSION:
Abdominal wall muscle injury resulting in rhabdomyolysis can imitate an acute abdomen in a healthy woman presenting with abdominal pain and swelling.
Factors Affecting the Severity of Neurological Disorders in Thoracic Idiopathic Spinal Cord Herniation
Authors: Nakashima Hiroaki , Kanemura Tokumi , Yagi Hideki , Kato Fumihiko , Sato Koji , Kamiya Mitsuhiro , Yoshihara Hisatake , Ito Kenyu , Matsuyama Yukihiro , Ishiguro Naoki , Imagama Shiro 
Published: February 2018

Study Design.
Retrospective multicenter case-controlled study.

Objective.
The objective of this study was to quantitatively examine imaging findings of idiopathic spinal cord herniation (ISCH) and determine the relationship between the image findings and the severity of pre- and postoperative neurological symptoms.

Summary of Background Data.
Many radiographic types of ISCH have been identified with regard to the location of the hernial opening or amount of herniated spinal cord. However, few previous studies have investigated the relationship between radiographic findings and the severity of neurological symptoms.

Methods.
Of 30,469 patients who underwent spinal surgery at 7 hospitals, 18 patients who underwent surgery for ISCH were identified. Their preoperative neurological severity, disease duration, magnetic resonance imaging findings, computed tomography myelography findings, surgical findings, and postoperative improvements were retrospectively examined. The spinal cord kink angle and minimum cord occupancy rate within the dural tube were measured. In addition, herniation was classified according to the location of the hiatus as either central (type C) or lateral (type L) type.

Results.
A negative correlation was found between the spinal cord kink angle and the minimum cord occupancy rate. Patient age was significantly higher in the severe paralysis group than in the mild paralysis group. In addition, the number of patients with type C herniation and the kink angle were significantly higher in the severe paralysis group. The number of patients with type L herniation was higher in the significant recovery group than in the mild recovery group; however, the difference was not significant.

Conclusion.
Patients with a large spinal cord kink angle had a smaller spinal cord occupancy rate within the dural tube, and this resulted in severe preoperative conditions. Type C ISCH cases had a severe preoperative neurological deficit and poor postoperative neurological recovery, and the spinal cord in such cases might be damaged irreversibly.

Level of Evidence: 4
Prediction Accuracy of Common Prognostic Scoring Systems for Metastatic Spine Disease
Authors: Choi David , Ricciardi Federico , Arts Mark , Buchowski Jacob M. , Bunger Cody , Chung Chun Kee , Coppes Maarten , Depreitere Bart , Fehlings Michael , Kawahara Norio , Leung Yee , Martin-Benlloch Antonio , Massicotte Eric , Mazel Christian , Meyer Bernhard , Oner Cumhur , Peul Wilco , Quraishi Nasir , Tokuhashi Yasuaki , Tomita Katsuro , Ulbricht Christian , Verlaan Jorrit-Jan , Wang Mike , Crockard Alan 
Published: February 2018

Study Design.
A prospective multicenter cohort study.

Objective.
To assess the clinical accuracy of six commonly cited prognostic scoring systems for patients with spinal metastases.

Summary of Background Data.
There are presently several available methods for the estimation of prognosis in metastatic spinal disease, but none are universally accepted by surgeons for clinical use. These scoring systems have not been rigorously tested and validated in large datasets to see if they are reliable enough to inform day-to-day patient management decisions. We tested these scoring systems in a large cohort of patients. A total of 1469 patients were recruited into a secure internet database, and prospectively collected data were analyzed to assess the accuracy of published prognostic scoring systems.

Methods.
We assessed six prognostic scoring systems, described by the first authors Tomita, Tokuhashi, Bauer, van der Linden, Rades, and Bollen. Kaplan–Meier survival estimates were created for different patient subgroups as described in the original publications. Harrell's C-statistic was calculated for the survival estimates, to assess the concordance between estimated and actual survival.

Results.
All the prognostic scoring systems tested were able to categorize patients into separate prognostic groups with different overall survivals. However none of the scores were able to achieve “good concordance” as assessed by Harrell's C-statistic. The score of Bollen and colleagues was found to be the most accurate, with a Harrell's C-statistic of 0.66.

Conclusion.
No prognostic scoring system was found to have a good predictive value. The scores of Bollen and Tomita were the most effective with Harrell's C-statistic of 0.66 and 0.65, respectively. Prognostic scoring systems are calculated using data from previous years, and are subject to inaccuracies as treatments advance in the interim. We suggest that other methods of assessing prognosis should be explored, such as prognostic risk calculation.

Level of Evidence: 3
Early Systemic Alterations in Severe Spinal Cord Injury
Authors: Rodríguez-Romero Violeta , Guízar-Sahagún Gabriel , Castañeda-Hernández Gilberto , Reyes José L. , Cruz-Antonio Leticia 
Published: February 2018

Study Design.
An experimental model of spinal cord injury (SCI) intended to characterize changes in renal function.

Objective.
The aim of this study was to evaluate the possible influence of SCI level on renal function during spinal shock.

Summary of Background Data.
SCI triggers multiple systemic and metabolic alterations. Among them, renal dysfunction stands out. Although several variables have been related to its extent, the impact of the cord injury level on renal function has not been clearly stated, particularly during the spinal shock.

Methods.
Anesthetized adult Sprague-Dawley rats were subjected to severe spinal cord contusion at low (T8) and high (T1) thoracic levels using the weight-drop method. Glomerular filtration rate (GFR) and tubular secretion (TS) were estimated 24 hours after injury, using a validated method based on the determination of plasma concentrations of iopamidol and p-aminohippuric acid by high-performance liquid chromatography.

Results.
GFR, fell to 33% (95% CI [24%, 43%]) and 10% (8%, 13%) of the sham-injured controls, whereas TS, decreased to 59% (95% CI [47%, 71%]), and 25% (18%, 32%) of the sham-injured controls, in T8 and T1 injury levels, respectively. Comparisons between cords injured and control rats, as well as between low and high-injured levels, were statistically significant (P < 0.01).

Conclusion.
Renal dysfunction occurs early after severe SCI. The damage is greater in high compared to low injuries. These findings could have important implications in the acute management of patients with high thoracic and cervical injuries, especially in pharmacotherapy using drugs eliminated by the kidney.

Level of Evidence. N/A
Determining the Upper and Lower Limits of Cerebral Autoregulation With Cerebral Oximetry Autoregulation Curves: A Case Series
Authors: Rivera-Lara Lucia , Zorrilla-Vaca Andres , Healy Ryan J. , Ziai Wendy , Hogue Charles , Geocadin Romergryko , Radzik Batya , Palmisano Caitlin , Mirski Marek A. 
Published: February 2018

Objective:
Critical care guidelines recommend a single target value for mean arterial blood pressure in critically ill patients. However, growing evidence regarding cerebral autoregulation challenges this concept and supports individualizing mean arterial blood pressure targets to prevent brain and kidney hypo- or hyperperfusion. Regional cerebral oxygen saturation derived from near-infrared spectroscopy is an acceptable surrogate for cerebral blood flow and has been validated to measure cerebral autoregulation. This study suggests a novel mechanism to construct autoregulation curves based on near-infrared spectroscopy–measured cerebral oximetry.

Design:
Case-series study.

Setting:
Neurocritical care unit in a tertiary medical center.

Patients:
Patients with acute neurologic injury and Glasgow coma scale score less than or equal to 8.

Measurements and Main Results:
Autoregulation curves were plotted using the fractional-polynomial model in Stata after multimodal continuous monitoring of regional cerebral oxygen saturation and mean arterial blood pressure. Individualized autoregulation curves of seven patients exhibited varying upper and lower limits of autoregulation and provided useful clinical information on the autoregulation trend (curves moving to the right or left during the acute coma period). The median lower and upper limits of autoregulation were 86.5 mm Hg (interquartile range, 74–93.5) and 93.5 mm Hg (interquartile range, 83–99), respectively.

Conclusions:
This case-series study showed feasibility of delineating real trends of the cerebral autoregulation plateau and direct visualization of the cerebral autoregulation curve after at least 24 hours of recording without manipulation of mean arterial blood pressure by external stimuli. The integration of multimodal monitoring at the bedside with cerebral oximetry provides a noninvasive method to delineate daily individual cerebral autoregulation curves.
Characteristics of Infants With Congenital Diaphragmatic Hernia Who Need Follow-Up of Pulmonary Hypertension
Authors: Kraemer Ulrike S. , Leeuwen Lisette , Krasemann Thomas B. , Wijnen René M. H. , Tibboel Dick , IJsselstijn Hanneke 
Published: February 2018

Objectives:
Pulmonary hypertension is one of the main causes of mortality and morbidity in patients with congenital diaphragmatic hernia. Currently, it is unknown whether pulmonary hypertension persists or recurs during the first year of life.

Design:
Prospective longitudinal follow-up study.

Setting:
Tertiary university hospital.

Patients:
Fifty-two congenital diaphragmatic hernia patients admitted between 2010 and 2014.

Interventions:
None.

Measurements and Main Results:
Pulmonary hypertension was measured using echocardiography and electrocardiography at 6 and 12 months old. Characteristics of patients with persistent pulmonary hypertension were compared with those of patients without persistent pulmonary hypertension. At follow-up, pulmonary hypertension persisted in four patients: at 6 months old, in three patients (patients A–C), and at 12 months old, in two patients (patients C and D). Patients with persistent pulmonary hypertension had a longer duration of mechanical ventilation (median 77 d [interquartile range, 49–181 d] vs median 8 d [interquartile range, 5–15 d]; p = 0.002) and hospital stay (median 331 d [interquartile range, 198–407 d) vs median 33 d (interquartile range, 16–59 d]; p = 0.003) than patients without persistent pulmonary hypertension. The proportion of patients with persistent pulmonary hypertension (n = 4) treated with inhaled nitric oxide (100% vs 31%; p = 0.01), sildenafil (100% vs 15%; p = 0.001), and bosentan (100% vs 6%; p < 0.001) during initial hospital stay was higher than that of patients without persistent pulmonary hypertension (n = 48). At 6 months, all patients with persistent pulmonary hypertension were tube-fed and treated with supplemental oxygen and sildenafil.

Conclusions:
Less than 10% of congenital diaphragmatic hernia patients had persistent pulmonary hypertension at ages 6 and/or 12 months. Follow-up for pulmonary hypertension should be reserved for congenital diaphragmatic hernia patients with echocardiographic signs of persistent pulmonary hypertension at hospital discharge and/or those treated with medication for pulmonary hypertension at hospital discharge.