bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of enriched 100Mo on Mo reaction yields
Authors: Jang Jaewoong , Uesaka Mitsuru
Published: April 2019

In accelerator-driven 99Mo/99mTc production, the 100Mo enrichment level should be chosen carefully as it greatly affects the yields of the involved Mo reactions. To facilitate selecting the 100Mo enrichment level, we defined a figure of merit called density change coefficient and developed its calculation program. Density change coefficients calculated for nine commercial enriched 100Mo products are presented and their use in selecting the 100Mo enrichment level is discussed.
Force of Infection and True Infection Rate of Dengue in Singapore: Implications for Dengue Control and Management
Authors: Tan Li Kiang , Low Swee Ling , Sun Haoyang , Shi Yuan , Liu Lilac , Lam Sally , Tan Hwee Huang , Ang Li Wei , Wong Wing Yan , Chua Rachel , Teo Diana , Ng Lee Ching , Cook Alex R
Published: April 2019

National data on dengue notifications do not capture all dengue infections and do not reflect the true intensity of disease transmission. To assess the true dengue infection rate and disease control efforts in Singapore, we conducted age-stratified serosurveys among residents after a 2013 outbreak that was the largest dengue outbreak on record. The age-weighted prevalence of dengue immunoglobulin G among residents was 49.8% (95% confidence interval: 48.4, 51.1) in 2013 and 48.6% (95% confidence interval: 47.0, 50.0) in 2017; prevalence increased with age. Combining these data with those from previous serosurveys, the year-on-year estimates of the dengue force of infection from 1930 to 2017 revealed a significant decrease from the late 1960s to the mid-1990s, after which the force of infection remained stable at approximately 10 per 1,000 persons per year. The reproduction number (R0) had also declined since the 1960s. The reduction in dengue transmission may be attributed to the sustained national vector program and partly to a change in the age structure of the population. The improved estimated ratio of notified cases to true infections, from 1:14 in 2005–2009 to 1:6 in 2014–2017, signifies that the national notification system, which relies on diagnosed cases, has improved over time. The data also suggest that the magnitudes of dengue epidemics cannot be fairly compared across calendar years and that the current disease control program remains applicable.
SPLATCHE3: simulation of serial genetic data under spatially explicit evolutionary scenarios including long-distance dispersal
Authors: Currat Mathias , Arenas Miguel , Quilodràn Claudio S , Excoffier Laurent , Ray Nicolas
Published: April 2019

SPLATCHE3 simulates genetic data under a variety of spatially explicit evolutionary scenarios, extending previous versions of the framework. The new capabilities include long-distance migration, spatially and temporally heterogeneous short-scale migrations, alternative hybridization models, simulation of serial samples of genetic data and a large variety of DNA mutation models. These implementations have been applied independently to various studies, but grouped together in the current version.

Availability and implementation

SPLATCHE3 is written in C++ and is freely available for non-commercial use from the website http://www.splatche.com/splatche3. It includes console versions for Linux, MacOs and Windows and a user-friendly GUI for Windows, as well as detailed documentation and ready-to-use examples.
Relating Δ17O Values of Animal Body Water to Exogenous Water Inputs and Metabolism
Authors: Whiteman John P , Sharp Zachary D , Gerson Alexander R , Newsome Seth D
Published: April 2019

The dynamics of animal body water and metabolism are integral aspects of biological function but are difficult to measure, particularly in free-ranging individuals. We demonstrate a new method to estimate inputs to body water via analysis of Δ17O, a measure of 17O/16O relative to 18O/16O. Animal body water is primarily a mixture of drinking or food water (meteoric water; Δ17O ≈ 0.030 per mille [‰]) and metabolic water synthesized from atmospheric oxygen (Δ17O ≈ –0.450‰). Greater drinking or food water intake should increase Δ17O toward 0.030‰, whereas greater metabolic rate should decrease Δ17O toward –0.450‰. We found that wild mammal Δ17O values generally increased with body mass, consistent with both a decline in mass-specific metabolic rate and an increase in water intake. Captive mouse (Peromyscus maniculatus) Δ17O values were higher than predicted but exhibited the expected relative change based on metabolic rate and water intake. Measurements of Δ17O may enable novel ecophysiological studies.
Subcutaneous implantable cardioverter defibrillators in patients with left ventricular assist devices: case report and comprehensive review
Authors: López-Gil María , Fontenla Adolfo , Delgado Juan F , Rodríguez-Muñoz Daniel
Published: April 2019

Background

Left ventricular assist devices (LVAD) are increasingly used in patients with advanced heart failure, many of whom have been or will be implanted with an implantable cardioverter defibrillator (ICD). Interaction between both devices is a matter of concern. Subcutaneous ICD (S-ICD) obtains its signals through subcutaneous vectors, which poses special challenges with regards to adequate performance following LVAD implantation.

Case summary

We describe the case of a 24-year-old man implanted with an S-ICD because of idiopathic dilated cardiomyopathy, severe biventricular dysfunction, and self-limiting sustained ventricular tachycardias. After the implantation of a HeartMate 3™ (Left Ventricular Assist System, Abbott) several months later, the S-ICD became useless because of inappropriate sensing due to electromagnetic interference and attenuation of QRS voltage.

Discussion

We reviewed the reported cases in PubMed about the concomitant use of S-ICD and LVAD. Seven case reports about the performance of S-ICD in patients with an LVAD were identified, with discordant results. From these articles, we analyse the potential causes for these differing results. Pump location and operating rates in LVAD, as well as changes in the subcutaneous-electrocardiogram detected by the S-ICD after LVAD implantation are related to sensing disturbances when used in the same patient.
MRPS25 mutations impair mitochondrial translation and cause encephalomyopathy
Authors: Bugiardini Enrico , Mitchell Alice L , Rosa Ilaria Dalla , Horning-Do Hue-Tran , Pitmann Alan M , Poole Olivia V , Holton Janice L , Shah Sachit , Woodward Cathy , Hargreaves Iain , Quinlivan Rosaline , Amunts Alexey , Wiesner Rudolf J , Houlden Henry , Holt Ian J , Hanna Michael G , Pitceathly Robert D S , Spinazzola Antonella
Published: April 2019

Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25, which encodes for a structural component of the 28S small subunit of the mitochondrial ribosome (mS25). The variant segregated with the disease and substitutes a highly conserved proline residue with leucine (p.P72L) that, based on the high-resolution structure of the 28S ribosome, is predicted to compromise inter-protein contacts and destabilize the small subunit. Concordant with the in silico analysis, patient’s fibroblasts showed decreased levels of MRPS25 and other components of the 28S subunit. Moreover, assembled 28S subunits were scarce in the fibroblasts with mutant mS25 leading to impaired mitochondrial translation and decreased levels of multiple respiratory chain subunits. Crucially, these abnormalities were rescued by transgenic expression of wild-type MRPS25 in the mutant fibroblasts. Collectively, our data demonstrate the pathogenicity of the p.P72L variant and identify MRPS25 mutations as a new cause of mitochondrial translation defect.
On the average condition number of tensor rank decompositions
Authors: Breiding Paul , Vannieuwenhoven Nick
Published: April 2019

We compute the expected value of powers of the geometric condition number of random tensor rank decompositions. It is shown in particular that the expected value of the condition number of $n_1\times n_2 \times 2$ tensors with a random rank-$r$ decomposition, given by factor matrices with independent and identically distributed standard normal entries, is infinite. This entails that it is expected and probable that such a rank-$r$ decomposition is sensitive to perturbations of the tensor. Moreover, it provides concrete further evidence that tensor decomposition can be a challenging problem, also from the numerical point of view. On the other hand, we provide strong theoretical and empirical evidence that tensors of size $n_1~\times ~n_2~\times ~n_3$ with all $n_1,n_2,n_3 \geqslant 3$ have a finite average condition number. This suggests that there exists a gap in the expected sensitivity of tensors between those of format $n_1\times n_2 \times 2$ and other order-3 tensors. To establish these results we show that a natural weighted distance from a tensor rank decomposition to the locus of ill-posed decompositions with an infinite geometric condition number is bounded from below by the inverse of this condition number. That is, we prove one inequality towards a so-called condition number theorem for the tensor rank decomposition.
Emergence and spread of ciprofloxacin-resistant Neisseria gonorrhoeae in New South Wales, Australia: lessons from history
Authors: Hanrahan Jane K , Hogan Tiffany R , Buckley Cameron , Trembizki Ella , Mitchell Hazel , Lau Colleen L , Whiley David M , Lahra Monica M
Published: April 2019

Objectives

Our aim was to investigate the emergence and spread of ciprofloxacin resistance in clinical Neisseria gonorrhoeae isolates in New South Wales, Australia, from the first reported case in 1991 until ciprofloxacin resistance was sustained at or above the WHO threshold for treatment change of 5% (1999), to inform future strategies for controlling gonococcal antimicrobial resistance.

Methods

The index isolate and all subsequent clinical isolates of ciprofloxacin-resistant N. gonorrhoeae in New South Wales from 1991 to 1999 were genotyped using a previously described method on the Agena MassARRAY iPLEX platform. Region of acquisition data, where available, were used to determine whether cases were travel associated.

Results

In New South Wales, of the 325 ciprofloxacin-resistant N. gonorrhoeae isolates reported from 1991 to 1999, 98% (320/325) were able to be recovered and 100% (320/320) were genotyped. There were 66 different genotypes, comprising 1–99 isolates each. Notably no single clone was found to account for ciprofloxacin resistance being sustained in the population, with considerable variability in genotype prevalence observed throughout the study period. A total of 65% (209/320) of genotyped isolates had information regarding the likely place of acquisition; of these, 44% (93/209) were associated with overseas travel or sexual contact with an overseas visitor. The first ciprofloxacin-resistant N. gonorrhoeae in New South Wales was associated with travel to Thailand. Index cases of each resistant genotype were significantly more likely to have been acquired overseas (51.5%), predominantly in Asia (45%, 30/66).

Conclusions

The continued importation of multiple genotypes, rather than the expansion of a single genotype, led to ciprofloxacin-resistant N. gonorrhoeae being established in New South Wales.
Deescalating Adjuvant Trastuzumab in HER2-Positive Early-Stage Breast Cancer: A Systemic Review and Meta-Analysis
Authors: Goldvaser Hadar , Korzets Yasmin , Shepshelovich Daniel , Yerushalmi Rinat , Sarfaty Michal , Ribnikar Domen , Thavendiranathan Paaladinesh , Amir Eitan
Published: April 2019

Background

One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results.

Methods

A search of PubMed and abstracts from key conferences identified randomized trials that compared abbreviated trastuzumab therapy to 1 year of treatment in early-stage HER2-positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted for disease-free survival (DFS) and overall survival (OS). Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor expression, and the duration of abbreviated trastuzumab (9–12 weeks vs 6 months). Odds ratios (ORs) and 95% confidence intervals were computed for prespecified cardiotoxicity events including cardiac dysfunction and congestive heart failure. P values were two-sided.

Results

Analysis included six trials comprising 11 603 patients. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI = 1.05 to 1.25, P  = .002) and OS (HR = 1.15, 95% CI = 1.02 to 1.29. P = .02). The effect on DFS was not influenced by estrogen receptor status (P for the subgroup difference = .23), nodal involvement (P = .44), or the different duration of trastuzumab in the experimental arm (P = .09). Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI = 0.55 to 0.81, P < .001) and congestive heart failure (OR = 0.66, 95% CI = 0.50 to 0.86, P = .003).

Conclusions

Compared with 1 year, shorter duration of adjuvant trastuzumab is associated with statistically significantly worse DFS and OS despite favorable cardiotoxicity profile. One year of targeted HER2 treatment should remain the standard adjuvant treatment in early-stage HER2-positive disease with appropriate cardiac monitoring.
Genome-Wide Analysis of Glioblastoma Patients with Unexpectedly Long Survival
Authors: Richardson Timothy E , Patel Seema , Serrano Jonathan , Sathe Adwait Amod , Daoud Elena V , Oliver Dwight , Maher Elizabeth A , Madrigales Alejandra , Mickey Bruce E , Taxter Timothy , Jour George , White Charles L , Raisanen Jack M , Xing Chao , Snuderl Matija , Hatanpaa Kimmo J
Published: April 2019

Glioblastoma (GBM), representing WHO grade IV astrocytoma, is a relatively common primary brain tumor in adults with an exceptionally dismal prognosis. With an incidence rate of over 10 000 cases in the United States annually, the median survival rate ranges from 10–15 months in IDH1/2-wildtype tumors and 24–31 months in IDH1/2-mutant tumors, with further variation depending on factors such as age, MGMT methylation status, and treatment regimen. We present a cohort of 4 patients, aged 37–60 at initial diagnosis, with IDH1-mutant GBMs that were associated with unusually long survival intervals after the initial diagnosis, currently ranging from 90 to 154 months (all still alive). We applied genome-wide profiling with a methylation array (Illumina EPIC Array 850k) and a next-generation sequencing panel to screen for genetic and epigenetic alterations in these tumors. All 4 tumors demonstrated methylation patterns and genomic alterations consistent with GBM. Three out of four cases showed focal amplification of the CCND2 gene or gain of the region on 12p that included CCND2, suggesting that this may be a favorable prognostic factor in GBM. As this study has a limited sample size, further evaluation of patients with similar favorable outcome is warranted to validate these findings.
The new Hungarian asset management foundation
Authors: Menyhei Ákos
Published: April 2019

The most important global issues of wealth planning are privacy, asset protection, and tax compliance. The ultimate question is how these needs match with the current and future legal environment. Obviously, privacy is under attack and the implementation of the fifth Anti-Money Laundering Directive is sweeping away the remaining ruins of it. The separation of private and business assets is one of the bases of the legal work and, during the last 10 years, tax compliance was forced out by The Organisation for Economic Co-operation and Development (OECD) Member States, achieving the result that assets are declared and taxed. There is very little room for manoeuvre, if someone wants to achieve all three aims at once. The new Hungarian asset management foundation—a hybrid of a trust and a private foundation—provides an excellent solution to link privacy, asset protection, and tax compliance together.
“You Want Me to Assess What?”: Faculty Perceptions of Assessing Residents From Outside Their Specialty
Authors: Burm Sarah , Sebok-Syer Stefanie S. , Lingard Lorelei , VanHooren Tamara , Chahine Saad , Goldszmidt Mark , Watling Christopher J.
Published: April 2019

Problem

Competency-based medical education (CBME) demands that residents be directly observed performing clinical tasks; however, many faculty lack assessment expertise, and some programs lack resources and faculty numbers to fulfill CBME’s mandate. To maximize limited faculty resources, the authors explored training and deploying faculty to assess residents in specialties outside their own.

Approach

In spring 2017, 10 MD and 2 PhD assessors at a medium-sized medical school in Ontario, Canada, participated in a 4-hour training session, which focused on providing formative assessments of patient handover, a core competency of medical practice. Assessors were deployed to 2 clinical settings outside their own specialty—critical care and pediatrics—each completing 11 to 26 assessments of residents delivering patient handover. Assessors were subsequently interviewed regarding their experiences.

Outcomes

While assessors felt able to judge handover performance outside their specialty, their sense of comfort varied with their own prior experiences in the given settings. Lack of familiarity with the process of handover in a specific setting directly influenced assessors’ perceptions of their own credibility. Although assessors identified the potential benefits of cross-specialty assessment, they also cited challenges to sustaining this approach.

Next Steps

Findings indicate a possible “contextual threshold” for cross-specialty assessment: tasks with high context specificity might not be suitable for cross-specialty assessment. Introducing higher-fidelity simulation into the training protocol and ensuring faculty members are remunerated for their time are necessary to establish future opportunities for shared assessment resources across training programs.
Reducing Risk in Total Joint Arthroplasty: Assessing Mental Health, Mood, and Movement Disorders
Authors: Keswani Aakash , Chen Darwin
Published: April 2019

Preoperative and postoperative mental health status (MHS) of total joint arthroplasty patients can affect immediate and long-term outcomes following surgery. Alterations in MHS can be acute or chronic. The most common etiologies include acute changes due to (1) delirium or stroke, (2) movement disorders (Alzheimer dementia, Parkinson disease, multiple sclerosis, epilepsy), and (3) mood/behavior disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia). Across etiologies, alterations in MHS are associated with worse clinical/patient-reported outcomes and greater total cost of care. Prevention via pharmacologic and nonpharmacologic approaches is the cornerstone of management for changes in MHS due to postoperative delirium/stroke. Parkinson disease, multiple sclerosis, and epilepsy must be addressed presurgery and postsurgery via tailored care pathways to minimize complications, limit disease progression, and ensure maximal functional recovery. Major depressive disorder, anxiety, bipolar, and schizophrenia require screening and proactive, longitudinal treatment where from all members of the care team. Beyond reviewing outcomes impact and management of MHS-altering conditions in arthroplasty patients, we provide a framework for evidence-based interventions organized by disease-type to enable effective perioperative optimization and postoperative care for these patients.
Prevalence of positive screening test results and agreement between cytology and human papillomavirus testing in primary cervical cancer screening in North-Western Romania
Authors: Şuteu Ofelia , Blaga Mihaiela L. , Nygård Mari , Leinonen Maarit K. , Nicula Florian , Păiş Rodica , Coza Daniela , Cadariu Patriciu A. , Melnic Adriana , Andreassen Trude , Hashim Dana , Weiderpass Elisabete
Published: April 2019

Using data from a pilot study conducted in North-Western Romania, we aimed to estimate the prevalence of abnormal cytology and positive high-risk human papillomavirus (hr-HPV) test results in an ethnically diverse screening population and to assess the agreement between cytology and hr-HPV testing to evaluate the feasibility of integrating the latter as a primary test in the national cervical cancer screening program. The cross-sectional pilot study included Roma women, other ethnic minorities, and women in rural remote areas. Samples were taken for liquid-based cytology and hr-HPV testing (Hybrid Capture 2 DNA test) by a mobile health unit. The prevalence of positive screening results and the agreement between cytology and hr-HPV testing were estimated by κ coefficient. A total of 1019 women were included in the study. The population prevalence of positive screening results was similar for both tests (12%). The prevalence of abnormal cytology increased with increasing age, whereas the prevalence of positive hr-HPV test showed a bimodal age pattern. Substantial differences in the prevalence of abnormal cytology were found by ethnicity, with highest prevalence in Romanian women (14%), followed by Roma women (6%) and women of other ethnicities (5%) (P = 0.002). Similar ethnic differences in the prevalence of positive hr-HPV test were not observed. The overall agreement of positive screening results between the two methods was fair (κ = 0.25; 95% confidence interval = 0.18–0.30, P < 0.001) and ranged from poor to substantial depending on the age group. The prevalence of abnormal cytology result was high and similar to the prevalence of positive hr-HPV test result, which could allow for the implementation of hr-HPV testing as a primary test in the cervical cancer screening program in Romania.
Intranasal Opioid-Induced Destruction of the Nose and Throat
Authors: Sutherland Laura , Sutherland Anne , Khalil Diana , Safneck Janice , Meen Eric
Published: April 2019

Les opioïdes jouent un rôle important dans le traitement de la douleur de nombreux patients, mais sont de plus en plus associés au trouble de l’utilisation de substances et à des effets indésirables en Amérique du Nord. Dans cette étude de cas, nous décrivons le premier cas canadien de séquelles significatives intranasales et pharyngiques suite à l’utilisation d’opioïdes intranasaux. Les approches de diagnostic et de traitement sont ensuite décrites. Chez les patients présentant des représentations atypiques, les lésions tissulaires induites par les opioïdes intranasaux devraient être envisagées dans le diagnostic différentiel des lésions tumorales otolaryngologiques. Ce cas souligne l’importance de pouvoir reconnaître les complications otolaryngologiques de la mauvaise utilisation des opioïdes intranasaux et traiter ainsi de manière appropriée en utilisant une approche multidisciplinaire.

Opioids play an important part in the pain management of many patients, but are increasingly associated with substance use disorder and adverse events in North America. In this case report, we describe the first noted Canadian case of significant intranasal and pharyngeal sequelae of intranasal opioid use. Diagnostic and treatment approaches are then described. In patients with atypical presentations, intranasal opioid-induced tissue damage should be considered in the differential diagnosis of otolaryngologic tissue damage. This case highlights the importance of being able to recognize the otolaryngologic complications of intranasal opioid misuse and thereby appropriately treat using a multidisciplinary approach.
Leaving Hospital Against Medical Advice After Methadone Discontinuation in the Intensive Care Unit: A Case Report
Authors: Young Samantha , Ahamad Keith , Fairbairn Nadia
Published: April 2019

Methadone is an effective and widely used opioid agonist treatment for reduction and cessation of illicit opioid use. Once a stable dose is achieved, interruptions in treatment are not recommended given the increased risk of relapse and the potential for overdose. Despite comprehensive clinical care guidance on the initiation and administration of methadone in the outpatient setting, there is limited guidance for the continuation of methadone in the hospital or critical care setting. Additionally, little is known about potential morbidity associated with methadone treatment interruption in hospital. This case describes the clinical course of a 58-year-old female who had been on a stable dose of methadone at 120 mg daily. She was admitted to the intensive care unit following the onset of decreased level of consciousness and hypoxia with subsequent respiratory failure. Although intubated in the intensive care unit, her methadone was discontinued. Given the length of time methadone was withheld, she required re-initiation at a dose of 30 mg daily. This led to severe withdrawal symptoms, use of illicit opioids while in hospital, and eventually leaving hospital prematurely against medical advice despite potentially life-threatening active medical issues. This case highlights the potential morbidity of methadone treatment interruption in the hospital setting. Additional research is needed to understand how to manage methadone and potential treatment interruptions during acute medical illness.
Dipyridamole Augments Three-Dimensionally Printed Bioactive Ceramic Scaffolds to Regenerate Craniofacial Bone
Authors: Lopez Christopher D. , Diaz-Siso J. Rodrigo , Witek Lukasz , Bekisz Jonathan M. , Gil Luiz F. , Cronstein Bruce N. , Flores Roberto L. , Torroni Andrea , Rodriguez Eduardo D. , Coelho Paulo G.
Published: April 2019

Background:

Autologous bone grafts remain a standard of care for the reconstruction of large bony defects, but limitations persist. The authors explored the bone regenerative capacity of customized, three-dimensionally printed bioactive ceramic scaffolds with dipyridamole, an adenosine A2A receptor indirect agonist known to enhance bone formation.

Methods:

Critical-size bony defects (10-mm height, 10-mm length, full-thickness) were created at the mandibular rami of rabbits (n = 15). Defects were replaced by a custom-to-defect, three-dimensionally printed bioactive ceramic scaffold composed of β-tricalcium phosphate. Scaffolds were uncoated (control), collagen-coated, or immersed in 100 μM dipyridamole. At 8 weeks, animals were euthanized and the rami retrieved. Bone growth was assessed exclusively within scaffold pores, and evaluated by micro–computed tomography/advanced reconstruction software. Micro–computed tomographic quantification was calculated. Nondecalcified histology was performed. A general linear mixed model was performed to compare group means and 95 percent confidence intervals.

Results:

Qualitative analysis did not show an inflammatory response. The control and collagen groups (12.3 ± 8.3 percent and 6.9 ± 8.3 percent bone occupancy of free space, respectively) had less bone growth, whereas the most bone growth was in the dipyridamole group (26.9 ± 10.7 percent); the difference was statistically significant (dipyridamole versus control, p < 0.03; dipyridamole versus collagen, p < 0.01 ). There was significantly more residual scaffold material for the collagen group relative to the dipyridamole group (p < 0.015), whereas the control group presented intermediate values (nonsignificant relative to both collagen and dipyridamole). Highly cellular and vascularized intramembranous-like bone healing was observed in all groups.

Conclusion:

Dipyridamole significantly increased the three-dimensionally printed bioactive ceramic scaffold’s ability to regenerate bone in a thin bone defect environment.
Current Concepts in Feminizing Gender Surgery
Authors: Safa Bauback , Lin Walter C. , Salim Ali M. , Deschamps-Braly Jordan C. , Poh Melissa M.
Published: April 2019

Learning Objectives:

After reading this article and viewing the video, the participant should be able to: 1. Discuss appropriate treatment guidelines, including preoperative mental health and hormonal treatment before gender-affirmation surgery. 2. Name various surgical options for facial, chest, and genital feminization. 3. Recognize key steps and anatomy during facial feminization, feminizing mammaplasty, and vaginoplasty. 4. Discuss major risks and complications of vaginoplasty.

Transgender and gender-nonconforming individuals may experience conflict between their gender identity and their gender assigned at birth. With recent advances in health care and societal support, appropriate treatment has become newly accessible and has generated increased demand for gender-affirming care, which is globally guided by the World Professional Association for Transgender Health. This CME article reviews key terminology and standards of care, and provides an overview of various feminizing gender-affirming surgical procedures.
Accelerator-based X-ray sources: synchrotron radiation, X-ray free electron lasers and beyond
Authors: Ishikawa Tetsuya
Published: April 2019

The evolution of synchrotron radiation (SR) sources and related sciences is discussed to explain the ‘generation’ of the SR sources. Most of the contemporary SR sources belong to the third generation, where the storage rings are optimized for the use of undulator radiation. The undulator development allowed to reduction of the electron energy of the storage ring necessary for delivering 10 keV X-rays from the initial 6–8 GeV to the current 3 Gev. Now is the transitional period from the double-bend-achromat lattice-based storage ring to the multi-bend-achromat lattice to achieve much smaller electron beam emittance. Free electron lasers are the other important accelerator-based light sources which recently reached hard X-ray regime by using self-amplified spontaneous emission scheme. Future accelerator-based X-ray sources should be continuous wave X-ray free electron lasers and pulsed X-ray free electron lasers. Some pathways to reach the future case are discussed.

This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
XMaS @ the ESRF
Authors: Bikondoa Oier , Bouchenoire Laurence , Brown Simon D. , Thompson Paul B. J. , Wermeille Didier , Lucas Chris A. , Cooper Malcolm J. , Hase Thomas P. A.
Published: April 2019

This paper describes the motivation for the design and construction of a beamline at the European Synchrotron Radiation Facility (ESRF) for the use of UK material scientists. Although originally focused on the study of magnetic materials, the beamline has been running for 20 years and currently supports a very broad range of science as evidenced by the research topics highlighted in this article. We describe how the beamline will adapt to align with the ESRF's upgrade to a diffraction limited storage ring.

This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
The development and exploitation of synchrotron single-crystal diffraction for chemistry and materials
Authors: Clegg William
Published: April 2019

A historical account is given of the 25-year development of dedicated synchrotron beamlines for single-crystal diffraction as applied to the so-called small-molecule fields of chemistry and materials science. Designs have drawn on previous successful models in macromolecular crystallography, with appropriate modifications in view of the different properties and behaviour of the respective sample types. Key factors in making these facilities attractive and productive for users include familiarity of operational procedures and the availability of experimental techniques and features normally found in local chemical crystallography laboratories, especially for the handling of samples and processing of diffraction data. Beamlines dedicated to single-crystal diffraction rather than shared with other techniques can be optimized for effective and efficient use. The experience gained from the original design, development and exploitation of stations 9.8 and 16.2SMX at the Daresbury Laboratory Synchrotron Radiation Source and beamline 11.3.1 at the Advanced Light Source have led to highly productive current facilities at ALS beamline 12.2.1 and Diamond Light Source beamline I19, including the recent introduction of remote-access operation. Such facilities have generated and continue to provide major impact in academic and commercial research that could otherwise not be achieved, including patents and applications in pharmaceuticals, energy and gas storage systems, and government policy.

This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
Synchrotron radiation biomedical imaging and radiotherapy: from the UK to the Antipodes
Authors: Hall Christopher , Lewis Robert
Published: April 2019

Although the general public might think of ‘X-rays’ as they are applied to imaging (radiography) and for the treatment of disease (radiotherapy), the use of synchrotron radiation (SR) X-ray beams in these areas of science was a minor activity 50 years ago. The largest gains in science from SR were seen to be in those areas where signals were weakest in laboratory instruments, such as X-ray diffraction and spectroscopy. As the qualities of SR X-rays were explored and more areas of science adopted SR-based methods, this situation changed. About 30 years ago, the clinical advantages of using SR X-ray beams for radiography, radiotherapy and clinical diagnostics started to be investigated. In the UK, a multi-disciplinary group, consisting of clinicians, medical physicists and other scientists working mainly with the Synchrotron Radiation Source (SRS) in Cheshire, started to investigate techniques for diagnosis and potentially a cure for certain cancers. This preliminary work influenced the design of new facilities being constructed around the world, in particular the Imaging and Medical Beam Line on the Australian Synchrotron in Melbourne. Two authors moved from the UK to Australia to participate in this exciting venture. The following is a personal view of some of the highlights of the early-year SRS work, following through to the current activities on the new facility in Australia.

This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
Transforming X-ray detection with hybrid photon counting detectors
Authors: Förster Andreas , Brandstetter Stefan , Schulze-Briese Clemens
Published: April 2019

Hybrid photon counting (HPC) detectors have radically transformed basic research at synchrotron light sources since 2006. They excel at X-ray diffraction applications in the energy range from 2 to 100 keV. The main reasons for their superiority are the direct detection of individual photons and the accurate determination of scattering and diffraction intensities over an extremely high dynamic range. The detectors were first adopted in macromolecular crystallography where they revolutionized data collection. They were soon also used for small-angle scattering, coherent scattering, powder X-ray diffraction, spectroscopy and increasingly high-energy applications. Here, we will briefly survey the history of HPC detectors, explain their technology and then show in detail how improved detection has transformed a wide range of experimental techniques. We will end with an outlook to the future, which will probably see HPC technology find even broader use, for example, in electron microscopy and medical applications.

This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
Myosin XI Interacting with a RabE GTPase Is Required for Polarized Growth
Authors: Orr Robert G. , Furt Fabienne , Warner Erin L. , Agar Erin M. , Garbarino Jennifer M. , Cabral Sarah E. , Dubuke Michelle L. , Butt Allison M. , Munson Mary , Vidali Luis
Published: April 2019

The fundamental eukaryotic process of intracellular trafficking requires the interconnected activity of molecular motors trafficking vesicular cargo within a dynamic cytoskeletal network. However, in plants, few mechanistic details are known about how molecular motors associate with their secretory cargo to support the ubiquitous processes of polarized growth and cell division. A yeast two-hybrid screen of aPhyscomitrella patenslibrary identified a RabE GTPase as an interactor of myosin XI and subsequently demonstrated all five RabE members interact with myosin XI. Consistent with a role in polarized transport, we observed RabE at the growing cell apex and at the expanding cell plate during cell division. An in vivo cross-correlation analysis of fluorescently tagged RabE and myosin XI revealed that both species are spatiotemporally coupled, demonstrating their simultaneous involvement in polarized growth. To determine if myosin XI and RabE are directly coupled, we first computationally predicted myosin XI:RabE interface through a homology modeling-directed approach. We identified a structurally conserved residue on myosin XI, V1422, that when mutated abolished RabE binding in the yeast two-hybrid system and resulted in unpolarized plants instead of the characteristic network of filamentous cells when regenerated from single cells. Together, this work demonstrates the requirement of a direct myosin XI:RabE interaction for polarized growth in plants.
Long read sequencing reveals a novel class of structural aberrations in cancers: identification and characterization of cancerous local amplifications
Authors: Sakamoto Yoshitaka , Xu Liu , Seki Masahide , Yokoyama Toshiyuki T. , Kasahara Masahiro , Kashima Yukie , Ohashi Akihiro , Shimada Yoko , Motoi Noriko , Tsuchihara Katsuya , Kobayashi Susumu , Kohno Takashi , Shiraishi Yuichi , Suzuki Ayako , Suzuki Yutaka
Published: April 2019

Here we report identification of a new class of local structural aberrations in lung cancers. The whole-genome sequencing of cell lines using a long read sequencer, PromethION, demonstrated that typical cancerous mutations, such as point mutations, large deletions and gene fusions can be detected also on this platform. Unexpectedly, we revealed unique structural aberrations consisting of complex combinations of local duplications, inversions and micro deletions. We further analyzed and found that these mutations also occurin vivo, even in key cancer-related genes. These mutations may elucidate the molecular etiology of patients for whom causative cancerous events and therapeutic strategies remain elusive.
The desmosomal cadherin Desmogon is necessary for the structural integrity of the Medaka notochord
Authors: Seleit Ali , Gross Karen , Woelk Michaela , Autorino Camilla , Onistschenko Jasmin , Centanin Lazaro
Published: April 2019

The notochord is an embryonic tissue that acts as a precursor to the spine. It is composed of outer sheath cells and inner vacuolated cells. Together they ensure the ability of the notochord to act as a hydrostatic skeleton until ossification begins. To date, there is still a paucity in our understanding of how the notochord cell types are specified and the molecular players controlling both their formation and maintenance remain poorly understood. Here we report thatdesmogon, a desmosomal cadherin, is essential for proper vacuolated cell shape and therefore correct notochord morphology. We tracedesmogon+precursors and uncover an early developmental heterogeneity that dictates the balance of vacuolated and sheath cell formation. We demonstrate that the growth of vacuolated cells occurs asynchronously and reveal the presence of distinct injury sensing mechanisms in the notochord. Additionally, using a small-scale F0 CRISPR screen we implicate uncharacterized genes in notochordal integrity.
Dual delivery of nucleic acids and PEGylated-bisphosphonates via calcium phosphate nanoparticles
Authors: Bisso Sofia , Mura Simona , Castagner Bastien , Couvreur Patrick , Leroux Jean-Christophe
Published: April 2019

Despite many years of research and a few success stories with gene therapeutics, efficient and safe DNA delivery remains a major bottleneck for the clinical translation of gene-based therapies. Gene transfection with calcium phosphate (CaP) nanoparticles brings the advantages of low toxicity, high DNA entrapment efficiency and good endosomal escape properties. The macroscale aggregation of CaP nanoparticles can be easily prevented through surface coating with bisphosphonate conjugates. Bisphosphonates, such as alendronate, recently showed promising anticancer effects. However, their poor cellular permeability and preferential bone accumulation hamper their full application in chemotherapy. Here, we investigated the dual delivery of plasmid DNA and alendronate using CaP nanoparticles, with the goal to facilitate cellular internalization of both compounds and potentially achieve a combined pharmacological effect on the same or different cell lines. A pH-sensitive poly(ethylene glycol)-alendronate conjugate was synthetized and used to formulate stable plasmid DNA-loaded CaP nanoparticles. These particles displayed good transfection efficiency in cancer cells and a strong cytotoxic effect on macrophages. The in vivo transfection efficiency, however, remained low, calling for an improvement of the system, possibly with respect to the extent of particle uptake and their physical stability.

Graphical abstract
Adaptive substitutions underlying cardiac glycoside insensitivity in insects exhibit epistasis in vivo
Authors: Taverner Andrew M. , Yang Lu , Barile Zackery J. , Lin Becky , Peng Julie , Pinharanda Ana , Rao Arya , Roland Bartholomew P. , Talsma Aaron D. , Wei Daniel , Petschenka Georg , Palladino Michael J. , Andolfatto Peter
Published: April 2019

Predicting how species will respond to selection pressures requires understanding the factors that constrain their evolution. We use genome engineering of Drosophila to investigate constraints on the repeated evolution of unrelated herbivorous insects to toxic cardiac glycosides, which primarily occurs via a small subset of possible functionally-relevant substitutions to Na+,K+-ATPase. Surprisingly, we find that frequently observed adaptive substitutions at two sites, 111 and 122, are lethal when homozygous and adult heterozygotes exhibit dominant neural dysfunction. We identify a phylogenetically correlated substitution, A119S, that partially ameliorates the deleterious effects of substitutions at 111 and 122. Despite contributing little to cardiac glycoside-insensitivity in vitro, A119S, like substitutions at 111 and 122, substantially increases adult survivorship upon cardiac glycoside exposure. Our results demonstrate the importance of epistasis in constraining adaptive paths. Moreover, by revealing distinct effects of substitutions in vitro and in vivo, our results underscore the importance of evaluating the fitness of adaptive substitutions and their interactions in whole organisms.
Memory for Individual Items is Related to Non-Reinforced Preference Change
Authors: Botvinik-Nezer Rotem , Bakkour Akram , Salomon Tom , Shohamy Daphna , Schonberg Tom
Published: April 2019

It is commonly assumed that memories contribute to value-based decisions. Nevertheless, most theories of value-based decision-making do not account for memory influences on choice. Recently, new interest has emerged in the interactions between these two fundamental processes, mainly using reinforcement-based paradigms. Here, we aimed to study the role memory processes play in preference change following the non-reinforced cue-approach training (CAT) paradigm. In CAT, the mere association of cued items with a speeded motor response influences choices. Previous studies with this paradigm showed that a single training session induces a long-lasting effect of enhanced preferences for high-value trained stimuli, that is maintained for several months. We hypothesized that CAT influences memory accessibility for trained items, leading to enhanced accessibility of their positive associative memories and in turn to preference changes. In two pre-registered experiments, we tested whether memory for trained items was enhanced following CAT, in the short and in the long-term, and whether memory modifications were related to choices. We found that memory was enhanced for trained items and that better memory was correlated with enhanced preferences at the individual item level, both immediately and one month following CAT. Our findings show that memory plays a central role in value-based decision-making following CAT, even in the absence of external reinforcements. These findings contribute to new theories relating memory and value-based decision-making and set the groundwork for the implementation of novel behavioral interventions that lead to long-lasting behavioral change.
Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling
Authors: Segura-Bayona Sandra , Villamor-Payà Marina , Attolini Camille Stephan-Otto , Stracker Travis H.
Published: April 2019

The Tousled like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperones and are regulated by the DNA damage response. Depletion of TLK activity caused replication stress, increased chromosomal instability and cell arrest or death. Here, we show that stalled forks in TLK depleted cells are processed by BLM, SAMHD1 and the MRE11 nuclease to generate ssDNA and activate checkpoint signaling. TLK depletion also impaired heterochromatin maintenance, inducing features of alternative lengthening of telomeres and increasing spurious expression of other repetitive elements, associated with impaired deposition of the histone variant H3.3. TLK depletion culminated in a BLM-dependent, STING-mediated innate immune response. In many human cancers, TLK1/2 expression correlated with signatures of chromosomal instability and anti-correlated with STING and innate and adaptive immune response signatures. Together, our results show that TLK activity protects replication forks from active processing, contributes to chromatin silencing and suppresses innate immune responses, suggesting that TLK amplification may protect chromosomally unstable cancers from immune detection.