bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Household Livestock Ownership and Childhood Stunting in Bangladesh – A Spatial Analysis
Authors: Hossain Md Belal , Khan Jahidur Rahman
Published: August 2019

Livestock is an integrated part of agriculture, yet the relationship between household livestock ownership and child nutrition is a significant knowledge gap. The present study aimed to assess the association between household livestock ownership and childhood stunting and to explore the geospatial variations at district level in Bangladesh. A complete data of 19 295 children aged below 5 years were extracted from the latest Bangladesh Multiple Indicator Cluster Survey 2012–13. The tropical livestock unit (TLU) score calculated as a weighted value for each livestock and categorized as low, medium, and high using tertile. A hierarchical Bayesian spatial logistic model was used to assess the association between TLU and childhood stunting. Children from the household with high TLU were 10% less likely to be stunted (adjusted posterior odds ratio: 0.90, 95% credible interval: 0.84–0.97) after controlling for demographic, socioeconomic, morbidity, place of residence and spatial effects. There was also a substantial spatial variation in childhood stunting across districts in Bangladesh with the highest burden in the Northern and North-Eastern regions. The positive effect of household livestock ownership on reducing child stunting suggests that, in addition to nutritional intervention in Bangladesh, efforts to strengthen livestock production would be beneficial for improving child nutrition status. However, a small effect size may be owing to the lack of dietary diversity, livestock health and productivity data as well as the complexity of the relationship, requiring further study. Furthermore, a significant regional disparity in stunting highlighted the importance of spatial targeting during the design of interventions and implementation.
The multifurcating skyline plot
Authors: Hoscheit Patrick , Pybus Oliver G
Published: August 2019

A variety of methods based on coalescent theory have been developed to infer demographic history from gene sequences sampled from natural populations. The ‘skyline plot’ and related approaches are commonly employed as flexible prior distributions for phylogenetic trees in the Bayesian analysis of pathogen gene sequences. In this work we extend the classic and generalized skyline plot methods to phylogenies that contain one or more multifurcations (i.e. hard polytomies). We use the theory of Λ-coalescents (specifically, Beta(2-α,α)-coalescents) to develop the ‘multifurcating skyline plot’, which estimates a piecewise constant function of effective population size through time, conditional on a time-scaled multifurcating phylogeny. We implement a smoothing procedure and extend the method to serially sampled (heterochronous) data, but we do not address here the problem of estimating trees with multifurcations from gene sequence alignments. We validate our estimator on simulated data using maximum likelihood and find that parameters of the Beta(2-α,α) -coalescent process can be estimated accurately. Furthermore, we apply the multifurcating skyline plot to simulated trees generated by tracking transmissions in an individual-based model of epidemic superspreading. We find that high levels of superspreading are consistent with the high-variance assumptions underlying Λ-coalescents and that the estimated parameters of the Λ-coalescent model contain information about the degree of superspreading.
DisCVR: Rapid viral diagnosis from high-throughput sequencing data
Authors: Maabar Maha , Davison Andrew J , Vučak Matej , Thorburn Fiona , Murcia Pablo R , Gunson Rory , Palmarini Massimo , Hughes Joseph
Published: August 2019

High-throughput sequencing (HTS) enables most pathogens in a clinical sample to be detected from a single analysis, thereby providing novel opportunities for diagnosis, surveillance, and epidemiology. However, this powerful technology is difficult to apply in diagnostic laboratories because of its computational and bioinformatic demands. We have developed DisCVR, which detects known human viruses in clinical samples by matching sample k-mers (twenty-two nucleotide sequences) to k-mers from taxonomically labeled viral genomes. DisCVR was validated using published HTS data for eighty-nine clinical samples from adults with upper respiratory tract infections. These samples had been tested for viruses metagenomically and also by real-time polymerase chain reaction assay, which is the standard diagnostic method. DisCVR detected human viruses with high sensitivity (79%) and specificity (100%), and was able to detect mixed infections. Moreover, it produced results comparable to those in a published metagenomic analysis of 177 blood samples from patients in Nigeria. DisCVR has been designed as a user-friendly tool for detecting human viruses from HTS data using computers with limited RAM and processing power, and includes a graphical user interface to help users interpret and validate the output. It is written in Java and is publicly available from http://bioinformatics.cvr.ac.uk/discvr.php.
Divergence dating using mixed effects clock modelling: An application to HIV-1
Authors: Bletsa Magda , Suchard Marc A , Ji Xiang , Gryseels Sophie , Vrancken Bram , Baele Guy , Worobey Michael , Lemey Philippe
Published: August 2019

The need to estimate divergence times in evolutionary histories in the presence of various sources of substitution rate variation has stimulated a rich development of relaxed molecular clock models. Viral evolutionary studies frequently adopt an uncorrelated clock model as a generic relaxed molecular clock process, but this may impose considerable estimation bias if discrete rate variation exists among clades or lineages. For HIV-1 group M, rate variation among subtypes has been shown to result in inconsistencies in time to the most recent common ancestor estimation. Although this calls into question the adequacy of available molecular dating methods, no solution to this problem has been offered so far. Here, we investigate the use of mixed effects molecular clock models, which combine both fixed and random effects in the evolutionary rate, to estimate divergence times. Using simulation, we demonstrate that this model outperforms existing molecular clock models in a Bayesian framework for estimating time-measured phylogenies in the presence of mixed sources of rate variation, while also maintaining good performance in simpler scenarios. By analysing a comprehensive HIV-1 group M complete genome data set we confirm considerable rate variation among subtypes that is not adequately modelled by uncorrelated relaxed clock models. The mixed effects clock model can accommodate this rate variation and results in a time to the most recent common ancestor of HIV-1 group M of 1920 (1915–25), which is only slightly earlier than the uncorrelated relaxed clock estimate for the same data set. The use of complete genome data appears to have a more profound impact than the molecular clock model because it reduces the credible intervals by 50 per cent relative to similar estimates based on short envelope gene sequences.
Subjective Age at Work: Feeling Younger or Older Than One’s Actual Age Predicts Perceived Control and Motivation at Work
Authors: Shane Jacob , Hamm Jeremy , Heckhausen Jutta
Published: August 2019

Using a life-span theoretical perspective, the present study examined how subjective age relates to perceived control and motivational investment in the work domain. Data from the Midlife in the United States National Study of Health and Well-Being (MIDUS I, II, and III; 1995–2013; n = 2,395) were analyzed using parallel process growth curve modeling. Our analyses used a mediation framework and focused on how changes in subjective age relate to changes in work-specific perceived control and motivational investment over time. Results suggested that feeling progressively younger than one’s actual age predicted increased levels of perceived control over and motivational investment in one’s work situation, as mediated by domain-general perceived control capacity and selective primary control striving, respectively. Results are discussed within the motivational theory of life-span development, specifically, how subjective age operates as a secondary control strategy that enhances or diminishes motivational investment and perceived control in work during midlife.
The Consequences of Structural Racism on MCAT Scores and Medical School Admissions: The Past Is Prologue
Authors: Lucey Catherine Reinis , Saguil Aaron
Published: August 2019

Those in medical education have a responsibility to prepare a physician workforce that can serve increasingly diverse communities, encourage healthy changes in patients, and advocate for the social changes needed to advance the health of all. The authors of this Perspective discuss many of the likely causes of the observed differences in mean Medical College Admission Test (MCAT) scores between students from groups well represented in medicine and those from groups underrepresented in medicine. The lower mean MCAT scores of underrepresented groups can present challenges to diversifying the physician workforce if medical schools only admit those applicants with the highest MCAT scores. The authors review the psychometric literature, which showed no evidence of bias in the exam, and note that the differences in mean MCAT scores between racial and ethnic groups are similar to those in other measures of academic achievement and performance on high-stakes tests.

The authors then describe the ways in which structural racism in the United States has contributed to differences in achievement for underrepresented students compared with well-represented students. These differences are not due to differences in aptitude but to differences in opportunities. The authors describe the widespread consequences of structural racism on economic success, educational opportunity, and bias in the educational environment. They close with 3 recommendations for medical schools that may mitigate the consequences of structural racism while maintaining academic standards and admitting students likely to succeed. Adopting these recommendations may help the medical profession build the diverse physician workforce needed to serve communities today.
Investigating Group Differences in Examinees’ Preparation for and Performance on the New MCAT Exam
Authors: Girotti Jorge A. , Chanatry Julie A. , Clinchot Daniel M. , McClure Stephanie C. , Swan Sein Aubrie , Walker Ian W. , Searcy Cynthia A.
Published: August 2019

In 2015, the Medical College Admission Test (MCAT) was redesigned to better assess the concepts and reasoning skills students need to be ready for the medical school curriculum. During the new exam’s design and rollout, careful attention was paid to the opportunities examinees had to learn the new content and their access to free and low-cost preparation resources. The design committee aimed to mitigate possible unintended effects of the redesign, specifically increasing historical mean group differences in MCAT scores for examinees from lower socioeconomic status (SES) backgrounds and races/ethnicities underrepresented in medicine compared with those from higher SES backgrounds and races/ethnicities not underrepresented in medicine.

In this article, the authors describe the characteristics and scores of examinees who took the new MCAT exam in 2017 and compare those trends with historical ones from 2013, presenting evidence that the diversity and performance of examinees has remained stable even with the exam’s redesign. They also describe the use of free and low-cost MCAT preparation resources and MCAT preparation courses for examinees from higher and lower SES backgrounds and who are enrolled in undergraduate institutions with more and fewer resources, showing that examinees from lower SES backgrounds and who attend institutions with fewer resources use many free and low-cost test preparation resources at lower rates than their peers. The authors conclude with a description of the next phase of this research: to gather qualitative and quantitative data about the preparation strategies, barriers, and needs of all examinees, but especially those from lower SES and underrepresented racial/ethnic backgrounds.
The Validity of Scores From the New MCAT Exam in Predicting Student Performance: Results From a Multisite Study
Authors: Busche Kevin , Elks Martha L. , Hanson Joshua T. , Jackson-Williams Loretta , Manuel R. Stephen , Parsons Wanda L. , Wofsy David , Yuan Kun
Published: August 2019

Purpose

The new Medical College Admission Test (MCAT) was introduced in April 2015. This report presents findings from the first study of the validity of scores from the new MCAT exam in predicting student performance in the first year of medical school (M1).

Method

The authors analyzed data from the national population of 2016 matriculants with scores from the new MCAT exam (N = 7,970) and the sample of 2016 matriculants (N = 955) from 16 medical schools who volunteered to participate in the validity research. They examined correlations of students’ MCAT total scores and total undergraduate grade point averages (UGPAs), alone and together, with their summative performance in M1, and the success rate of students with different MCAT scores in their on-time progression to the second year of medical school (M2). They assessed whether MCAT scores provided comparable prediction of performance in M1 by students’ race/ethnicity, socioeconomic background, and gender.

Results

Correlations of MCAT scores with summative performance in M1 ranged from medium to large. Although MCAT scores and UGPAs provided similar prediction of performance in M1, using both metrics provided better prediction than either alone. Additionally, students with a wide range of MCAT scores progressed to M2 on time. Finally, MCAT scores provided comparable prediction of performance in M1 for students from different sociodemographic backgrounds.

Conclusions

This study provides early evidence that scores from the new MCAT exam predict student performance in M1. Future research will examine the validity of MCAT scores in predicting performance in later years.
Learning Challenges, Teaching Strategies, and Cognitive Load: Insights From the Experience of Seasoned Endoscopy Teachers
Authors: Sewell Justin L. , Bowen Judith L. , Cate Olle ten , O’Sullivan Patricia S. , Shah Brijen , Boscardin Christy K.
Published: August 2019

Purpose

Learners of medical procedures must develop, refine, and apply schemas for both cognitive and psychomotor constructs, which may strain working memory capacity. Procedures with limitations in visual and tactile information may add risk of cognitive overload. The authors sought to elucidate how experienced procedural teachers perceived learners’ challenges and their own teaching strategies in the exemplar setting of gastrointestinal endoscopy.

Method

The authors interviewed 22 experienced endoscopy teachers in the United States, Canada, and the Netherlands between May 2016 and March 2019 and performed thematic analysis using template analysis method. Interviews addressed learner challenges and teaching strategies from the teacher participants’ perspectives. Cognitive load theory informed data interpretation and analysis.

Results

Participants described taking steps to “diagnose” trainee ability and identify struggling trainees. They described learning challenges related to trainees (performance over mastery goal orientation, low self-efficacy, lack of awareness), tasks (psychomotor challenges, mental model development, tactile understanding), teachers (teacher–trainee relationship, inadequate teaching, teaching variability), and settings (internal/external distractions, systems issues). Participants described employing strategies that could match intrinsic load to learners’ levels (teaching along developmental continuum, motor instruction, technical assistance/takeover), minimize extraneous load (optimize environment, systems solutions, emotional support, define expectations), and optimize germane load (promote mastery, teach schemas, stop and focus).

Conclusions

Participants provided insight into possible challenges while learning complex medical procedures with limitations in sensory channels, as well as teaching strategies that may address these challenges at individual and systems levels. Using cognitive load theory, the authors provide recommendations for procedural teachers.
The Decline in Community Preceptor Teaching Activity: Exploring the Perspectives of Pediatricians Who No Longer Teach Medical Students
Authors: Paul Caroline R. , Vercio Chad , Tenney-Soeiro Rebecca , Peltier Chris , Ryan Michael S. , Van Opstal Elizabeth R. , Alerte Anton , Christy Cynthia , Kantor Julie L. , Mills William A. , Patterson Patricia B. , Petershack Jean , Wai Andrew , Beck Dallaghan Gary L.
Published: August 2019

Purpose

Difficulty in recruiting and retaining community preceptors for medical student education has been described in the literature. Yet little, if any, information is known about community outpatient preceptors who have stopped or decreased teaching time with students. This study aimed to examine these preceptors’ perspectives about this phenomenon.

Method

Using a phenomenology framework, this multi-institutional qualitative study used semistructured interviews with community pediatric preceptors who had stopped or reduced teaching time with medical students. Interviews were conducted between October 2017 and January 2018 and transcribed verbatim. Interviews explored factors for engaging in teaching, or decreasing or ceasing teaching, that would enable future teaching. An initial code book was developed and refined as data were analyzed to generate themes.

Results

Twenty-seven community pediatricians affiliated with 10 institutions participated. Thirty-seven codes resulted in 4 organizing themes: evolution of health care, personal barriers, educational system, and ideal situations to recruit and retain preceptors, each with subthemes.

Conclusions

From the viewpoints of physicians who had decreased or stopped teaching students, this study more deeply explores previously described reasons contributing to the decline of community preceptors, adds newly described barriers, and offers strategies to help counter this phenomenon based on preceptors’ perceptions. These findings appear to be manifestations of deeper issues including the professional identify of clinical educators. Understanding the barriers and strategies and how they relate to preceptors themselves should better inform education leaders to more effectively halt the decline of community precepting and enhance the clinical precepting environment for medical students.
It Is Time to Prioritize Education and Well-Being Over Workforce Needs in Residency Training
Authors: Wolpaw Jed T.
Published: August 2019

Residents inhabit an ambiguous world. They are no longer medical students but are still learners. They are not yet attendings but are still paid employees. This ambiguity leads to a misalignment of departmental incentives and trainee expectations. Trainees expect their learning and well-being to be prioritized, while departments are under pressure to meet staffing needs and cut costs. This sets up a fundamental disconnect between the “formal” Accreditation Council for Graduate Medical Education (ACGME) message of well-being and the dominant “hidden” workplace forces that pull in the opposite direction, possibly contributing to the epidemic of burnout in trainees. It is critical that all parties—health systems, graduate medical education (GME) programs, the ACGME, and residents—recognize this disconnect and collaborate to meaningfully implement current ACGME requirements to decompress work intensity and address well-being. Real change will require more than general directives. The ACGME will likely need to take the lead and consider taking a design-thinking approach to structuring regulations governing how and when residents work and how they are supported. It would also be worthwhile to revisit the Institute of Medicine recommendations on GME from 2014 related to funds flow and transformation initiatives. Taking a more comprehensive approach to residents as people, workers, and vital health care professionals is the right thing to do and may well improve retention, reduce burnout, decrease medical errors, and improve care.
Surgery for Unilateral Sacral Fractures: Are the Indications Clear?
Authors: Vallier Heather A. , Lowe Jason A. , Agel Julie , Mullis Brian H. , Jones Clifford B. , Teague David , Kempton Laurence , Miller Anna N. , Spitler Clay A. , Kubiak Erik , Routt Milton L. Chip. , Leighton Ross , Morshed Saam , Tornetta Paul
Published: August 2019

Objectives:

To evaluate unilateral sacral fractures and compare those treated operatively versus nonoperatively to determine indications for surgery.

Design:

Prospective, multicenter, observational study.

Setting:

Sixteen trauma centers.

Patients/Participants:

Skeletally mature patients with pelvic ring injury and unilateral zone 1 or 2 sacral fractures and without anteroposterior compression injuries.

Main Outcome Measurements:

Injury plain anteroposterior, inlet, and outlet radiographs and computed tomography scans of the pelvis were evaluated for fracture displacement.

Results:

Three hundred thirty-three patients with unilateral sacral fractures and a mean age of 41 years with a mean Injury Severity Score of 15 were included. Ninety-two percent sustained lateral compression injuries, and 63% of all fractures were in zone 1. Thirty-three percent of patients were treated operatively, including all without lateral compression patterns. Operative patients were more likely to have zone 2 fractures (54%) and to have posterior cortical displacement (29% vs. 6.2%), both with P < 0.001. Over 60% of all patients had no posterior displacement. Mean rotational displacements comparing the injured side versus the intact side were no different for patients treated operatively compared with those treated nonoperatively.

Conclusions:

Most unilateral sacral fractures are minimally or nondisplaced. Many patients with radiographically similar fractures were treated operatively and nonoperatively by different surgeons. This suggests an opportunity to develop consistent indications for treatment.

Level of Evidence:

Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Treating the Orthopaedic Trauma Knowledge Gap: Quantification of Orthopaedic Resident Knowledge Gaps and Validation of a Multimodal Course to Address the Deficiencies
Authors: Graves Matt L. , Paryavi Ebrahim , Hung Leroy , Reilly Mark C. , Guy Pierre , O'Toole Robert V.
Published: August 2019

Objectives:

To determine whether knowledge-based deficiencies are adequately addressed at the AO North America Basic Principles of Fracture Management course.

Design:

Pretest, posttest.

Setting:

Eighteen national trauma courses.

Participants:

Two thousand one hundred forty-nine learners.

Intervention:

Pre- and postcourse 20-item tests of basic fracture knowledge, including 14 trauma topics.

Main Outcome Measures:

Deficiencies were defined as <60% correct answers on the precourse test. Postcourse knowledge gaps were defined as <75% correct responses.

Results:

Deficiencies were noted in 7 of the 14 topics on the precourse test. All topics with deficiencies on the precourse test were shown to have statistically significant improvement in postcourse test scores. All topics without deficiencies were shown to have statistically significant improvement in postcourse test scores. The average overall precourse test score was 63% (95% confidence interval, 61%–65%), and the average overall postcourse test score was 81% (95% confidence interval, 79%–83%). The pretest to posttest difference was statistically significant (P < 0.05). The control questions, covering material that was not discussed in the course, did not have statistically significant improvement in scores.

Conclusions:

Residents are entering residency programs with limited knowledge of fracture care, and significant gaps remain at the junior level at the time of course participation, suggesting that supplemental fracture courses play an important role in resident education. Validation of short-term learning is possible through a pretest and posttest technique, and it can guide design changes, as opposed to relying on satisfaction surveys alone.
Practice Patterns for Management of Pediatric Femur Fractures in Low- and Middle-Income Countries
Authors: Curran Patrick F. , Albright Patrick , Ibrahim John M. , Ali Syed H. , Shearer David W. , Sabatini Coleen S.
Published: August 2019

Background:

Femoral shaft fractures in children are common in low and middle income countries. In high-income countries, patient age, fracture pattern, associated injuries, child/family socioeconomic status, and surgeon preference dictate fracture management. There is limited literature on treatment patterns for pediatric femur fractures in resource-limited settings. This study surveys surgeons from low (LIC), lower-middle (LMIC), and upper-middle income (UMIC) countries regarding treatment patterns for pediatric femur fractures.

Methods:

Surgeons completed an electronic survey reporting surgeon demographics and treatment preference for pediatric femur fractures. Treatment preferences and indications for treatment were separated into 4 groups: infant (0 to 6 mo); toddler (7 mo to 4 y); child (5 to 12 y); adolescent (12 to 17 y). The survey was available in English, Spanish, and French. Analysis was completed with t test and χ2 test for continuous and categorical variables, respectively, and weighted Pearson correlation (P<0.05).

Results:

Survey respondents consisted of 413 surgeons from 83 countries (20 LIC, 33 LMIC, 30 UMIC). The majority of respondents were fellowship trained (83%) most commonly in pediatrics (26%) and trauma (43%). Most treated >10 pediatric femur fractures per year (68%). Respondents reported treating infant femur fractures nonoperatively using Pavlik harness (19%), spica cast (60%), or traction with delayed spica cast (14%). Decreasing socioeconomic status was associated with higher nonoperative treatment rate in toddlers, children, and adolescents. Respondents commonly utilize bed rest and traction for child femur fractures in LICs (63%) and LMICs (65%) compared with UMICs (35%) (UMIC vs. LMIC P<0.001; UMIC vs. LIC P<0.001). Surgeries in children more commonly involve open reduction with internal fixation (UMIC 19%, LMIC 33%, LIC 40%; P<0.05 between UMIC-LMIC and UMIC-LIC).

Conclusion:

This is one of the largest surveys describing treatment patterns for pediatric femur fractures in low and middle income countries. Differences are evident including lower operative treatment rate in younger children and lower intramedullary fixation rates in older children. Future studies should investigate the value of treatment options in resource-limited settings.

Level of Evidence:

Level II—prospective comparative study.
Operating Room Intervention Rates After Orthopaedic Resident-reduced Pediatric Both-Bone Forearm Fractures Relative to the Academic Calendar
Authors: Wu John C. , Daley Erika , Koueiter Denise M. , Lilly Ryan , Vara Alexander D. , Settecerri Jeffrey J.
Published: August 2019

Background:

The purpose of this study was to evaluate the operating room (OR) intervention rates and quality of fracture reductions for pediatric diaphyseal both-bone forearm fractures performed by orthopaedic residents relative to the academic year. OR intervention was defined as any procedure performed in the OR, including closed reduction and casting, and was used to identify fractures that required secondary intervention after initial closed reduction performed by an orthopaedic resident in the emergency department.

Methods:

A retrospective analysis identified pediatric patients presenting at our institution with both-bone forearm fractures from July 2010 to June 2016. Emergency-room sedation time, highest experience of orthopaedic resident documented to be present at the time of sedation (in postgraduate months), and frequencies of OR intervention were obtained by chart review. Fracture characteristics were determined by radiographic review. Immediate postreduction radiographs were used to measure cast indices, and adequacy of reduction was determined by postreduction angulation and translation.

Results:

During the time period studied, 470 both-bone forearm reductions under sedation were performed by an orthopaedic resident at our institution. Of these, 41 fractures (41 patients) required 42 OR interventions (40 involved surgical fixation and 2 were repeat closed reductions). The academic year was divided into quartiles. The April to June quartile had the highest overall percentage of OR intervention (10.6%), followed by July to September (8.6%); however, there was no significant difference between quartiles in the percentages of reductions that needed OR intervention (P=0.553). There was also no correlation between the experience level of the resident performing the reduction (based on postgraduate months) and the frequency of OR intervention (P=0.244). The anteroposterior (AP) and lateral reduction grades did not vary based on quarters (P=0.584; 0.353). The ability to obtain adequate reduction and the rate of unacceptable cast index were also not significantly different between quarters (P=0.347 and 0.465).

Conclusions:

We found no significant difference in rates of OR intervention or the quality of reduction for pediatric both-bone diaphyseal forearm fractures treated by orthopaedic residents relative to the academic year.

Level of Evidence:

Level III—comparative cohort study.
Image-guidance, Robotics, and the Future of Spine Surgery
Authors: Ahern Daniel P. , Gibbons Denys , Schroeder Gregory D. , Vaccaro Alexander R. , Butler Joseph S.
Published: August 2019

Spine surgery has seen considerable advancements over the last 2 decades, particularly in the fields of image-guidance and robotics. These technologies offer the potential to overcome the various technical challenges in spinal surgery, such as physical and mental fatigue, hand tremor, difficulties with manual dexterity, and surgical precision. This review provides an overview of the image-guidance and robotics systems currently available. It will also provide an insight into the emerging technologies in development in the field of spine surgery. Image-guided and robotic-assisted surgical systems have been demonstrated to be safe, accurate, and time-efficient. Future advancements in the field include “augmented reality” systems, which build on these navigation platforms, but are yet to come to market. These developing technologies have considerable potential to improve the field of spine surgery. Further research is required in this area to determine superiority of these developing technologies over conventional techniques before widespread use should be adapted.
Human papillomavirus vaccination in immigrants and descendants of immigrants in Denmark
Authors: Hertzum-Larsen Rasmus , Thomsen Louise T. , Frederiksen Kirsten , Kjær Susanne K.
Published: August 2019

Objective

In Denmark, human papillomavirus (HPV) vaccination has been offered at age of 12 to girls born in 1996 and later. In this cohort study, we examined routine HPV vaccination uptake in immigrants and descendants from different countries and regions compared with native Danes, including the influence of socioeconomic characteristics and potential changes in uptake by birth cohort.

Methods

In nationwide registers, we identified all girls born in 1996–2003 (n = 260 251) and obtained information on country of origin, HPV vaccinations and parents’ income and employment. Vaccination was defined as receiving ≥1 dose within 2 years after eligibility for routine vaccination. Odds ratios (ORs) were estimated by logistic regression separately for birth cohorts 1996–2000 and 2001–2003.

Results

Uptake in immigrants and descendants varied by country and region of origin. Overall, immigrants had lower uptake than native Danes, in birth cohorts 1996–2000 [79% vs. 93%, OR = 0.31; 95% confidence interval (CI), 0.29–0.34] and 2001–2003 (63% vs. 73%, OR = 0.60; 95% CI, 0.54–0.66). Descendants had lower uptake than native Danes in cohorts 1996–2000 (89% vs. 93%, OR = 0.65; 95% CI, 0.60–0.68), but higher uptake in cohorts 2001–2003 (76% vs. 73%, OR = 1.15; 95% CI, 1.08–1.21). Most associations were attenuated, but not entirely explained, when adjusting for socioeconomic characteristics.

Conclusion

HPV vaccination uptake varied by country and region. Most immigrants had lower uptake than native Danes, and in most groups, this was not fully explained by socioeconomic differences. Patterns in descendants were mixed. Interventions to increase uptake should be tailored to specific groups of immigrants/descendants.
Sevoflurane Preconditioning Prevents Septic Myocardial Dysfunction in Lipopolysaccharide-Challenged Mice
Authors: Li Jianling , Liu Panhong , Li Hongmei , Wang Yanping , Chen Yifei , Qi Renbin , Li Yalan
Published: August 2019

Myocardial dysfunction accompanied by severe sepsis could significantly increase the mortality rate of septic patients. This study investigated the effects and the potential mechanisms of sevoflurane preconditioning on septic myocardial dysfunction, which was induced by lipopolysaccharide (LPS; from Escherichia coli O55:B5; 18 mg/kg) in mice. Results indicated that 1 hour after the administration, LPS induced a significant increase in cell-surface Toll-like receptor 4 (TLR4), cytoplasmic IKKα protein expression, and nuclear translocation of nuclear factor kappa-B (NF-κB) protein (P < 0.05), which was attenuated by preconditioning with sevoflurane. Two hours after the administration, inhalation of sevoflurane significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-10 (P < 0.05). Twelve hours after administration, LPS caused pathological damage to the heart and elevated the serum levels of lactate dehydrogenase (LDH) and creatine kinase-MB (P < 0.05). Echocardiography indicated that sevoflurane preconditioning significantly improved systolic and diastolic function. The inhalation of sevoflurane inhibited increases in myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), TNF-α, and IL-1β levels (P < 0.05) induced by endotoxemia, whereas IL-6 release was facilitated. Sevoflurane attenuated the myocardial levels of nitric oxide (P < 0.05) without an apparent influence on malondialdehyde (MDA) or superoxide dismutase (P > 0.05). In conclusion, our study indicates that exposure to 2% sevoflurane before LPS challenge is protective against myocardial dysfunction. Sevoflurane preconditioning may attenuate neutrophil infiltration and the release of inflammatory mediators during endotoxemia.
Exploration of Physiological and Pathophysiological Implications of miRNA-143 and miRNA-145 in Cerebral Arteries
Authors: Christensen Simon Topp , Johansson Sara Ellinor , Warfvinge Karin , Braun Thomas , Boettger Thomas , Edvinsson Lars , Haanes Kristian Agmund
Published: August 2019

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with a high short-term mortality rate which leads to cognitive impairments that reduce the quality of life of the majority of patients. The miRNA-143/145 cluster is highly expressed in vascular smooth muscle cells (VSMC) and has been shown to be necessary for differentiation and function, as well as an important determinant for phenotypic modulation/switching of VSMCs in response to vascular injury. We aimed to determine whether miRNA-143 and miRNA-145 are important regulators of phenotypical changes of VSMCs in relation to SAH, as well as establishing their physiological role in the cerebral vasculature. We applied quantitative PCR to study ischemia-induced alterations in the expression of miRNA-143 and miRNA-145, for rat cerebral vasculature, in an ex vivo organ culture model and an in vivo SAH model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 knockout mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our SAH model, despite the upregulation of miR-145 in the organ culture model. Regarding physiological function, miRNA-143 and miRNA-145 are very important for general contractility in cerebral vessels in response to depolarization, angiotensin II, and endothelin-1. Applying an anti-miRNA targeting approach in SAH does not seem to be a feasible approach because miRNA-143 and miRNA-145 are not upregulated following SAH. The knockout mouse data suggest that targeting miRNA-143 and miRNA-145 would lead to a general reduced contractility of the cerebral vasculature and unwanted dedifferentiation of VSMCs.
Generation and Validation of a Limited Sampling Strategy to Monitor Mycophenolic Acid Exposure in Children With Nephrotic Syndrome
Authors: Benz Marcus R. , Ehren Rasmus , Kleinert Daniela , Müller Carsten , Gellermann Jutta , Fehrenbach Henry , Schmidt Heinrich , Weber Lutz T.
Published: August 2019

Background:

Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome.

Methods:

We performed 27 complete PK profiles in 23 children in remission [mean age (±SD):12.3 ± 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors.

Results:

Mean daily dose of MMF was 927 ± 209 mg/m2 of body surface area resulting in a mean MPA-AUC0-12 value of 59.2 ± 29.3 mg × h/L and a predose level of 3.03 ± 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC0-12 was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC0-12 was moderate (r
2 = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC0-12 = 8.7 + 4.63 × C0 + 1.90 × C1 + 1.52 × C2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r
2 = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r
2 = 0.95) and low percentage prediction error (5.57%).

Conclusions:

An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy.
Pharmacodynamic Monitoring of Mycophenolic Acid Therapy: Improved Liquid Chromatography–Tandem Mass Spectrometry Method for Measuring Inosin-5′-Monophosphate Dehydrogenase Activity
Authors: Weißbarth Gero , Wiesen Martin H. J. , Fietz Cornelia , Streichert Thomas , Ehren Rasmus , Weber Lutz T. , Müller Carsten
Published: August 2019

Background:

Mycophenolic acid (MPA), a powerful inhibitor of lymphocyte proliferation, is widely used in transplantation medicine and as a glucocorticoid-sparing agent in rheumatic and inflammatory diseases. As inosine-5′-monophosphate dehydrogenase (IMPDH), the target enzyme of MPA, shows high interindividual variability in its basal activity, the assessment of IMPDH activity in addition to pharmacokinetic monitoring has emerged as a strategy to individualize MPA pharmacotherapy.

Methods:

A liquid chromatography–tandem mass spectrometry method was developed to measure IMPDH activity in peripheral blood mononuclear cells from lithium-heparinized blood. Stable isotope-labeled analogs of analytes were used as internal standards for the quantitative analyses of xanthosine-5′-monophosphate (XMP) and adenosine-5′-monophosphate (AMP). IMPDH activity was expressed as enzymatic production of XMP per time normalized to the AMP concentration. Validation and evaluation of the new method were performed by using blood samples from healthy volunteers (n = 10).

Results:

Linearity was demonstrated over the concentration ranges of 0.25–80 μM for XMP and 4–80 µM for AMP (R2 > 0.99). Between-day and within-day assay precisions and accuracies were within the acceptance criterion of ±15%. Matrix effects were fully compensated by the coelution of internal standards. Specific and linear XMP production (R2 > 0.99) and the inhibition of IMPDH activity by MPA at clinically relevant doses were demonstrated.

Conclusions:

In this study, a liquid chromatography–tandem mass spectrometry method to measure IMPDH activity was established and fully evaluated for matrix and ion suppression effects. The method enabled precise quantification of IMPDH activity for the improvement of pharmacokinetic/pharmacodynamic therapeutic drug monitoring approaches to optimize immunosuppressive treatment with MPA.
Population Pharmacokinetics of Ganciclovir in Critically Ill Patients
Authors: Krens Stefanie D. , Hodiamont Caspar J. , Juffermans Nicole P. , Mathôt Ron A.A. , van Hest Reinier M.
Published: August 2019

Background:

The pharmacokinetic (PK) data of ganciclovir (GCV), a first-line antiviral treatment for cytomegalovirus infections, in critically ill patients are limited. This study aimed at characterizing GCV population PK and interindividual variability (IIV) in intensive care unit (ICU) patients. Secondary objectives were to identify patient characteristics responsible for IIV and simulate GCV exposure for different dosing regimens.

Method:

In this retrospective observational study, clinical data and serum GCV levels were collected from ICU patients on intravenous GCV. PK modeling, covariate analyses, and explorative Monte Carlo dosing simulations (MCS) were performed using nonlinear mixed-effects modeling. Bootstrap and visual predictive checks were used to determine model adequacy.

Results:

In total, 128 GCV measurements were obtained from 34 patients. GCV PK conformed to a 1-compartment model with first-order elimination. After multivariate analyses, only the estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (P < 0.001) was included as a covariate. In the final model, the estimated clearance (CL) and volume of distribution (V1) were 2.3 L/h and 42 L, respectively, for a patient with the median CKD-EPI of the population (65 mL/min per 1.73 m2). The association between CKD-EPI and CL decreased the residual variability from 0.56 to 0.43 and V1-IIV from 114% to 80%, whereas CL-IIV changed from 43% to 47%. MCS revealed that a substantial number of patients may not achieve the GCV PK/pharmacodynamic target trough level (>1.5 mg/L) when administering the label-recommended dose reductions for patients with CKD-EPI <50 mL/min.

Conclusions:

A large IIV was observed in GCV PK among ICU patients. CKD-EPI could partially explain the IIV, although a large part of the variability remains unclear. MCS suggested that recommended dose reductions for CKD-EPI <50 mL/min may lead to subtherapeutic plasma GCV levels in these patients.
Excretion of Antipsychotics Into the Amniotic Fluid, Umbilical Cord Blood, and Breast Milk: A Systematic Critical Review and Combined Analysis
Authors: Schoretsanitis Georgios , Westin Andreas A. , Deligiannidis Kristina M. , Spigset Olav , Paulzen Michael
Published: August 2019

Background:

Antipsychotics are being increasingly prescribed during pregnancy and in the postpartum period. However, knowledge regarding the ability of antipsychotics to enter the fetal, newborn, and infant circulation presents inconsistencies. Evidence for penetration ratios in an array of matrices will contribute to further studies examining the mechanistic pathway from antipsychotic use to adverse events.

Methods:

A systematic literature search of PubMed and EMBASE was performed to identify studies assessing the concentrations of antipsychotics in maternal blood (serum or plasma), amniotic fluid, umbilical cord blood, and/or breast milk. The penetration ratios were estimated by dividing the antipsychotic concentrations in the target matrix (ie, amniotic fluid, umbilical cord blood or breast milk) by the maternal concentration. Data are provided in means with ranges or SD depending on data availability.

Results:

Forty-nine eligible studies were identified. For amniotic fluid, the penetration ratios were estimated for quetiapine, clozapine, and flupentixol, with quetiapine displaying the highest ratio (mean 0.59, range 0.09–1.70 versus 0.56, range 0.31–0.82 for clozapine and 0.24, range 0.23–0.24 for flupentixol). For umbilical cord blood, olanzapine had the highest ratio (mean 0.71 ± 0.42) followed by haloperidol (mean 0.66 ± 0.40) and paliperidone (mean 0.53, range 0.50–0.58). In case of breast milk, the highest ratio was observed for amisulpride (mean 14.42, range 11.86–19.50) followed by clozapine (mean 3.19, range 2.79–4.32) and haloperidol (mean 3.11, range 0.59–6.67).

Conclusions:

The ability of antipsychotics to enter the fetal, newborn, and infant circulation varies considerably among antipsychotics. Given sampling constraints of other matrices, measuring antipsychotic concentrations in maternal blood may represent the least expensive, most readily available, and reliable estimate of fetal/infant exposure.
Monitoring Prenatal Exposure to Buprenorphine and Methadone
Authors: Di Trana Annagiulia , La Maida Nunzia , Tittarelli Roberta , Huestis Marilyn A. , Pichini Simona , Busardò Francesco P. , Carlier Jeremy
Published: August 2019

Purpose:

Buprenorphine and methadone are international gold standards for managing opioid use disorders. Although they are efficacious in treating opioid dependence, buprenorphine and methadone present risks, especially during pregnancy, causing neonatal abstinence syndrome and adverse obstetrical outcomes. Buprenorphine and methadone are also abused during pregnancy, and identifying their use is important to limit unprescribed prenatal exposure. Previous studies have suggested that concentrations of buprenorphine, but not methadone markers in unconventional matrices may predict child outcomes, although currently only limited data exist. We reviewed the literature on concentrations of buprenorphine, methadone, and their metabolites in unconventional matrices to improve data interpretation.

Methods:

A literature search was conducted using scientific databases (PubMed, Scopus, Web of Science, and reports from international institutions) to review published articles on buprenorphine and methadone monitoring during pregnancy.

Results:

Buprenorphine and methadone and their metabolites were quantified in the meconium, umbilical cord, placenta, and maternal and neonatal hair. Methadone concentrations in the meconium and hair were typically higher than those in other matrices, although the concentrations in the placenta and umbilical cord were more suitable for predicting neonatal outcomes. Buprenorphine concentrations were lower and required sensitive instrumentation, as measuring buprenorphine glucuronidated metabolites is critical to predict neonatal outcomes.

Conclusions:

Unconventional matrices are good alternatives to conventional ones for monitoring drug exposure during pregnancy. However, data are currently scarce on buprenorphine and methadone during pregnancy to accurately interpret their concentrations. Clinical studies should be conducted with larger cohorts, considering confounding factors such as illicit drug co-exposure.