bluuebunny/crossref_metadata_2025 huggingface dataset:
Tomographic weak lensing bispectrum: a thorough analysis towards the next generation of galaxy surveys
Authors: Rizzato Matteo , Benabed Karim , Bernardeau Francis , Lacasa Fabien
Published: October 2019

We address key points for an efficient implementation of likelihood codes for modern weak lensing large-scale structure surveys. Specifically, we focus on the joint weak lensing convergence power spectrum–bispectrum probe and we tackle the numerical challenges required by a realistic analysis. Under the assumption of (multivariate) Gaussian likelihoods, we have developed a high performance code that allows highly parallelized prediction of the binned tomographic observables and of their joint non-Gaussian covariance matrix accounting for terms up to the six-point correlation function and supersample effects. This performance allows us to qualitatively address several interesting scientific questions. We find that the bispectrum provides an improvement in terms of signal-to-noise ratio (S/N) of about 10 per cent on top of the power spectrum, making it a non-negligible source of information for future surveys. Furthermore, we are capable to test the impact of theoretical uncertainties in the halo model used to build our observables; with presently allowed variations we conclude that the impact is negligible on the S/N. Finally, we consider data compression possibilities to optimize future analyses of the weak lensing bispectrum. We find that, ignoring systematics, five equipopulated redshift bins are enough to recover the information content of a Euclid-like survey, with negligible improvement when increasing to 10 bins. We also explore principal component analysis and dependence on the triangle shapes as ways to reduce the numerical complexity of the problem.
Dark matter halo shapes in the Auriga simulations
Authors: Prada Jesus , Forero-Romero Jaime E , Grand Robert J J , Pakmor Rüdiger , Springel Volker
Published: October 2019

We present shape measurements of Milky Way–sized dark matter haloes at redshift z = 0 in a suite of 30 zoom simulations from the Auriga project. We compare the results in full magnetohydrodynamics against dark matter–only simulations and find a strong influence of baryons in making dark matter haloes rounder at all radii compared to their dark matter–only counterparts. At distances ≲30 kpc, rounder dark matter distributions correlate with extended massive stellar discs and low-core gas densities. We measure the alignment between the halo and the disc shapes at different radii and find a high degree of alignment at all radii for most of the galaxies. In some cases, the alignment significantly changes as a function of radius implying that the halo shape twists; this effect correlates with recently formed bulges and is almost absent in the dark matter–only simulations. In a comparison against observational constraints, we find that $20{{\ \rm per\ cent}}$ of haloes in our sample are consistent with observational results derived from the Pal 5 stream that favours an almost spherical shape. Including baryons is a required element to achieve this level of agreement. In contrast, none of the simulations (neither dark matter only nor with baryons) match the constraints derived from the Sagittarius stream that favour an oblate dark matter halo.
LIGO tells us LINERs are not optically thick RIAFs
Authors: Ford K E Saavik , McKernan B
Published: October 2019

Low ionization nuclear emission-line regions (LINERs) are a heterogeneous collection of up to one-third of galactic nuclei in the local Universe. It is unclear whether LINERs are simply the result of low accretion rates onto supermassive black holes (BHs) or whether they include a large number of optically thick radiatively inefficient but super-Eddington accretion flows (RIAFs). Optically thick RIAFs are typically discs of large-scale height or quasi-spherical gas flows. These should be dense enough to trap and merge a large number of the stellar mass BHs, which we expect to exist in galactic nuclei. Electromagnetic observations of photospheres of accretion flows do not allow us to break model degeneracies. However, gravitational wave observations probe the interior of accretion flows where the merger of stellar mass BHs can be greatly accelerated over the field rate. Here, we show that the upper limits on the rate of BH mergers observed with LIGO demonstrate that most LINERs cannot be optically thick RIAFs.
OHNOLOGS v2: a comprehensive resource for the genes retained from whole genome duplication in vertebrates
Authors: Singh Param Priya , Isambert Hervé
Published: October 2019

All vertebrates including human have evolved from an ancestor that underwent two rounds of whole genome duplication (2R-WGD). In addition, teleost fish underwent an additional third round of genome duplication (3R-WGD). The genes retained from these genome duplications, so-called ohnologs, have been instrumental in the evolution of vertebrate complexity, development and susceptibility to genetic diseases. However, the identification of vertebrate ohnologs has been challenging, due to lineage specific genome rearrangements since 2R- and 3R-WGD. We previously identified vertebrate ohnologs using a novel synteny comparison across multiple genomes. Here, we refine and apply this approach on 27 vertebrate genomes to identify ohnologs from both 2R- and 3R-WGD, while taking into account the phylogenetically biased sampling of available species. We assemble vertebrate ohnolog pairs and families in an expanded OHNOLOGS v2 database. We find that teleost fish have retained more 2R-WGD ohnologs than mammals and sauropsids, and that these 2R-ohnologs have retained significantly more ohnologs from the subsequent 3R-WGD than genes without 2R-ohnologs. Interestingly, species with fewer extant genes, such as sauropsids, have retained similar or higher proportions of ohnologs. OHNOLOGS v2 should allow deeper evolutionary genomic analysis of the impact of WGD on vertebrates and can be freely accessed at http://ohnologs.curie.fr.
IMG-ABC v.5.0: an update to the IMG/Atlas of Biosynthetic Gene Clusters Knowledgebase
Authors: Palaniappan Krishnaveni , Chen I-Min A , Chu Ken , Ratner Anna , Seshadri Rekha , Kyrpides Nikos C , Ivanova Natalia N , Mouncey Nigel J
Published: October 2019

Microbial secondary metabolism is a reservoir of bioactive compounds of immense biotechnological and biomedical potential. The biosynthetic machinery responsible for the production of these secondary metabolites (SMs) (also called natural products) is often encoded by collocated groups of genes called biosynthetic gene clusters (BGCs). High-throughput genome sequencing of both isolates and metagenomic samples combined with the development of specialized computational workflows is enabling systematic identification of BGCs and the discovery of novel SMs. In order to advance exploration of microbial secondary metabolism and its diversity, we developed the largest publicly available database of predicted BGCs combined with experimentally verified BGCs, the Integrated Microbial Genomes Atlas of Biosynthetic gene Clusters (IMG-ABC) (https://img.jgi.doe.gov/abc-public). Here we describe the first major content update of the IMG-ABC knowledgebase, since its initial release in 2015, refreshing the BGC prediction pipeline with the latest version of antiSMASH (v5) as well as presenting the data in the context of underlying environmental metadata sourced from GOLD (https://gold.jgi.doe.gov/). This update has greatly improved the quality and expanded the types of predicted BGCs compared to the previous version.
Unraveling allosteric landscapes of allosterome with ASD
Authors: Liu Xinyi , Lu Shaoyong , Song Kun , Shen Qiancheng , Ni Duan , Li Qian , He Xinheng , Zhang Hao , Wang Qi , Chen Yingyi , Li Xinyi , Wu Jing , Sheng Chunquan , Chen Guoqiang , Liu Yaqin , Lu Xuefeng , Zhang Jian
Published: October 2019

Allosteric regulation is one of the most direct and efficient ways to fine-tune protein function; it is induced by the binding of a ligand at an allosteric site that is topographically distinct from an orthosteric site. The Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) was developed ten years ago to provide comprehensive information related to allosteric regulation. In recent years, allosteric regulation has received great attention in biological research, bioengineering, and drug discovery, leading to the emergence of entire allosteric landscapes as allosteromes. To facilitate research from the perspective of the allosterome, in ASD 2019, novel features were curated as follows: (i) >10 000 potential allosteric sites of human proteins were deposited for allosteric drug discovery; (ii) 7 human allosterome maps, including protease and ion channel maps, were built to reveal allosteric evolution within families; (iii) 1312 somatic missense mutations at allosteric sites were collected from patient samples from 33 cancer types and (iv) 1493 pharmacophores extracted from allosteric sites were provided for modulator screening. Over the past ten years, the ASD has become a central resource for studying allosteric regulation and will play more important roles in both target identification and allosteric drug discovery in the future.
New insights into protein–DNA binding specificity from hydrogen bond based comparative study
Authors: Lin Maoxuan , Guo Jun-tao
Published: October 2019

Knowledge of protein–DNA binding specificity has important implications in understanding DNA metabolism, transcriptional regulation and developing therapeutic drugs. Previous studies demonstrated hydrogen bonds between amino acid side chains and DNA bases play major roles in specific protein–DNA interactions. In this paper, we investigated the roles of individual DNA strands and protein secondary structure types in specific protein–DNA recognition based on side chain-base hydrogen bonds. By comparing the contribution of each DNA strand to the overall binding specificity between DNA-binding proteins with different degrees of binding specificity, we found that highly specific DNA-binding proteins show balanced hydrogen bonding with each of the two DNA strands while multi-specific DNA binding proteins are generally biased towards one strand. Protein-base pair hydrogen bonds, in which both bases of a base pair are involved in forming hydrogen bonds with amino acid side chains, are more prevalent in the highly specific protein–DNA complexes than those in the multi-specific group. Amino acids involved in side chain-base hydrogen bonds favor strand and coil secondary structure types in highly specific DNA-binding proteins while multi-specific DNA-binding proteins prefer helices.
An independently validated survival nomogram for lower-grade glioma
Authors: Gittleman Haley , Sloan Andrew E , Barnholtz-Sloan Jill S
Published: October 2019

Background

Gliomas are the most common primary malignant brain tumor. Diffuse low-grade and intermediate-grade gliomas, which together compose the lower-grade gliomas (LGGs; World Health Organization [WHO] grades II and III), present a therapeutic challenge to physicians due to the heterogeneity of their clinical behavior. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a survival nomogram for patients with newly diagnosed LGG.

Methods

Data were obtained for newly diagnosed LGG patients from The Cancer Genome Atlas (TCGA) and the Ohio Brain Tumor Study (OBTS) with the following variables: tumor grade (II or III), age at diagnosis, sex, Karnofsky performance status (KPS), and molecular subtype (IDH mutant with 1p/19q codeletion [IDHmut-codel], IDH mutant without 1p/19q codeletion, and IDH wild-type). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using TCGA data and independently validated using the OBTS data. Models were internally validated using 10-fold cross-validation and externally validated with calibration curves.

Results

A final nomogram was validated for newly diagnosed LGG. Factors that increased the probability of survival included grade II tumor, younger age at diagnosis, having a high KPS, and the IDHmut-codel molecular subtype.

Conclusions

A nomogram that calculates individualized survival probabilities for patients with newly diagnosed LGG could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software for implementing this nomogram is provided: https://hgittleman.shinyapps.io/LGG_Nomogram_H_Gittleman/.

Key Points

1. A survival nomogram for lower-grade glioma patients has been developed and externally validated.

2. Free online software for implementing this nomogram is provided allowing for ease of use by practicing health care providers.
The Kinetics of Our Discontent
Authors: Döşemeci Mehmet
Published: October 2019

Why do we think of social struggles as movements? What is in motion and where is it going? Has struggle been thought and practised otherwise? Not as movement but as disruption, arrest, stasis? If so, what are struggles trying to stop? Asking these questions pushes us to think about struggle kinetically: to analyse social struggle through the register of motion and its interruption. This article questions why we have come to understand the history of social struggle through the category of movement and the consequences and costs of this understanding for historical analysis. Against this association, it underscores how movement, as a practice and idea, was central to the establishment and legitimation of the capitalist economy and, using two case studies of labour and the New Left, examines how significant strands of these struggles sought freedom in the arrest of its coerced motion. Drawing from these examples, the final section discusses the usefulness of kinetic analysis for historical inquiry.
The Normative Significance of Cognitive Science Reconsidered
Authors: Locke Dustin
Published: October 2019

Josh Greene famously argued that his cognitive-scientific results undermine deontological moral theorizing. Greene is wrong about this: at best, his research has revealed that at least some characteristically deontological moral judgments are sensitive to factors that we deem morally irrelevant. This alone is not enough to undermine those judgments. However, cognitive science could someday tell us more: it could tell us that in forming those judgments, we treat certain factors as reasons to believe as we do. If we independently deem such factors to be morally irrelevant, such a result would undermine those judgments and any moral theorizing built upon them. This paper attempts to bring charity, clarity, and epistemological sophistication to Greene's argument and those like it.
Historic Lynching and Corporal Punishment in Contemporary Southern Schools
Authors: Ward Geoff , Petersen Nick , Kupchik Aaron , Pratt James
Published: October 2019

This study examines how corporal punishment in contemporary public schools, a disciplinary practice concentrated in southeastern U.S. states, relates to histories of lynching in the region. Using school-level data from the U.S. Department of Education, we examine these relationships in a series of multi-level regression models. After controlling for numerous school- and county-level factors, we find an increased likelihood of corporal punishment for all students in counties where greater numbers of lynchings occurred, and that lynching is particularly predictive of corporal punishment for black students. Consistent with prior research associating historic lynching with contemporary violence, these results suggest general and race-specific legacies for violent school discipline. We consider potential mechanisms linking histories of lynching with school corporal punishment, and implications for research and policy.
Stemming the Tide of Elder Mistreatment: A Medical School–State Agency Collaborative
Authors: Dyer Carmel B. , Halphen John M. , Lee Jessica , Flores Renee J. , Booker James G. , Reilley Barbara , Burnett Jason
Published: October 2019

In 1995, the Texas Department of Family and Protective Services: Adult Protective Service Agency began a partnership with the Baylor College of Medicine geriatrics program to form the Texas Elder Abuse and Mistreatment (TEAM) Institute. The medical school–state agency partners overcame institutional and bureaucratic barriers to work collaboratively on mutually beneficial projects, including research and publications. Interprofessional students gained first-hand experience about abuse and neglect cases. As of 2019, there are 4 divisions: Clinical and Forensic Evaluation, Education and Outreach, Research and Program Evaluation, and Senior Justice. TEAM members have published numerous articles and chapters, educated members from multiple disciplines, and served thousands of mistreated older patients. In 2017, TEAM launched the first statewide telecommunication program for elder mistreatment to improve practice for the entire state. Perseverance, teamwork, and dedication to the mission of the intervention and prevention of elder mistreatment have sustained this program for over 30 years. This article describes the steps to forming TEAM, the institute’s early struggles, and the subsequent community and academic contributions of this medical school–state agency collaboration.
Association of Medicaid Expansion With Coverage and Access to Care for Pregnant Women
Authors: Clapp Mark A. , James Kaitlyn E. , Kaimal Anjali J. , Sommers Benjamin D. , Daw Jamie R.
Published: October 2019

OBJECTIVE:

To identify the association of the Affordable Care Act's Medicaid expansion with payment for delivery, early access to prenatal care, preterm birth, and birth weights considered small for gestational age (SGA).

METHODS:

A difference-in-difference design was used to assess changes in outcomes before and after Medicaid expansion in expansion states, using nonexpansion states as a control group. We used national birth certificate data from 2009 to 2017. Difference-in-difference linear probability models were used to assess the effects of the policy implementation, adjusting for demographics, month of birth, state, year, and county-level unemployment rates. Standard errors were clustered at the state level. Two prespecified subgroup analyses were performed of nulliparous women and women with no more than a high school diploma.

RESULTS:

The study sample included 8,701,889 women from 15 expansion states and 9,509,994 from 11 nonexpansion states. In the adjusted analysis, the percentage of Medicaid-covered deliveries increased by 2.3 absolute percentage points (95% CI 0.2–4.4, P=.04) in expansion states compared with nonexpansion states. There were no significant changes in the proportion of women who were uninsured, as there was a relative decrease in the percentage of deliveries covered by private insurance (−2.8 percentage points [95% CI −4.9 to −0.8, P=.01]). There were also no significant differences in the rate of women initiating prenatal care in the first trimester, preterm birth rates, or rates of low birth weight after the Medicaid expansion. Findings were similar in both subgroups.

CONCLUSION:

Medicaid expansion was associated with increased Medicaid coverage for childbirth in expansion states; similar gains in private coverage were seen in nonexpansion states. There were no associations with changes in early access to prenatal care, preterm birth, or SGA birth weights.
Development and Validation of a Machine Learning Algorithm for Predicting Response to Anticholinergic Medications for Overactive Bladder Syndrome
Authors: Sheyn David , Ju Mingxuan , Zhang Sixiao , Anyaeche Caleb , Hijaz Adonis , Mangel Jeffrey , Mahajan Sangeeta , Conroy Britt , El-Nashar Sherif , Ray Soumya
Published: October 2019

OBJECTIVE:

To develop and externally validate a prediction model for anticholinergic response in patients with overactive bladder (OAB).

METHODS:

A machine learning model to predict the likelihood of anticholinergic treatment failure was constructed using a retrospective data set (n=559) of female patients with OAB who were treated with anticholinergic medications between January 2010 and December 2017. Treatment failure was defined as less than 50% improvement in frequency, urgency, incontinence episodes, and nocturia, and the patient's subjective impression of symptomatic relief. Patients were stratified by age (younger than 40 years, 40–60 years, and older than 60 years), and number of previously failed medications. K-fold stratified cross-validation was performed on each stratum using machine learning algorithms. Of these, the random forest model was the most accurate. This model was refined using internal cross validation within each stratum. The area under the curve (AUC) was calculated for each stratum and used to identify the optimal operating points for prediction of treatment failure. The random forest model was then externally validated using a prospectively collected data set (n=82) of women treated with anticholinergic medications at a different clinical site between January 2018 and December 2018.

RESULTS:

The global accuracy of the final model was 80.3% (95% CI 79.1–81.3), and the AUC was 0.77 (95% CI 0.74–0.79). Using the external validation data set, the model's sensitivity and specificity was 80.4% (95% CI 66.5–89.7%) and 77.4% (95% CI 58.6–89.7%), respectively. The model performed best in women aged younger than 40 years (AUC 0.84, 95% CI 0.81–0.84) and worst in women aged older than 60 years who had previously failed medication (AUC 0.71, 95% CI 0.67–0.75).

CONCLUSION:

Our externally validated machine learning prediction model can predict anticholinergic treatment failure during the standard 3-month treatment trial period with greater than 80% accuracy. The model can be accessed at https://oabweb.herokuapp.com/app/pre/.
Association Between Stillbirth at 23 Weeks of Gestation or Greater and Severe Maternal Morbidity
Authors: Lewkowitz Adam K. , Rosenbloom Joshua I. , López Julia D. , Keller Matt , Macones George A. , Olsen Margaret A. , Cahill Alison G.
Published: October 2019

OBJECTIVE:

To estimate whether stillbirth at 23 weeks of gestation or more is associated with increased risk of severe maternal morbidity compared with live birth, when stratified by maternal comorbidities.

METHODS:

This retrospective cohort study used International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes within the Healthcare Cost and Utilization Project's Florida State Inpatient Database. The first delivery of female Florida residents aged 13–54 years old from 2005 to 2014 was included. The exposure was an ICD-9-CM code of stillbirth at 23 weeks of gestation or more; the control was an ICD-9-CM code of singleton live birth. Deliveries were stratified by the presence of 1 or more conditions within a well-validated maternal morbidity composite using ICD-9-CM codes during delivery hospitalization. The primary outcome was an ICD-9-CM diagnosis or procedure code during delivery hospitalization of any indices within the Centers for Disease Control and Prevention's severe maternal morbidity composite. Multivariable analyses adjusted for maternal sociodemographic factors and delivery mode to compare outcomes after stillbirth with live-birth delivery.

RESULTS:

Nine thousand five hundred twenty-three women who delivered stillborn fetuses and 1,353,044 with liveborn neonates were included. Among 6,590 stillbirths and 935,913 live births without maternal comorbidities, severe maternal morbidity was significantly more common during stillbirth delivery (n=345 [5.2%]), corresponding to a seven-fold increased risk compared with live birth (n=8,318 [0.9]; adjusted odds ratio [aOR] 7.05 [95% CI 6.27–7.93]). Among 2,933 stillbirths and 417,131 live births with maternal comorbidities, severe maternal morbidity was significantly more common during stillbirth delivery (n=390 [13.3%]): the risk was more than six-fold higher comparatively (n=11,122 [2.7%]; aOR 6.21 [95% CI 5.54–6.96]). Most maternal comorbidities were individually associated with higher risk of severe maternal morbidity during stillbirth compared with live-birth delivery.

CONCLUSION:

Though severe maternal morbidity is overall uncommon, delivering a stillborn fetus 23 weeks of gestation or greater is associated with increased likelihood of severe maternal morbidity, particularly among women with comorbidities, suggesting health care providers must be vigilant about severe maternal morbidity during stillbirth delivery.
Cognitive Profiles and Autism Symptoms in Comorbid Down Syndrome and Autism Spectrum Disorder
Authors: Hamner Taralee , Hepburn Susan , Zhang Fengqing , Fidler Deborah , Robinson Rosenberg Cordelia , Robins Diana L. , Lee Nancy R.
Published: October 2019

Objective:

The prevalence of comorbid autism spectrum disorder (ASD) in children with Down syndrome (DS) is estimated to be around 16%. This study aims to fill gaps in the literature by describing developmental and behavioral phenotypes in this group relative to those with DS or ASD in isolation.

Methods:

Participants included 173 children (Mage= 73 months) with ASD, DS, or DS + ASD. Two 3 × 2 repeated-measures analyses of variance were completed with between-subject factors of the diagnostic group (DS, ASD, and DS + ASD) and within-subject factors of cognitive performance (verbal and nonverbal developmental quotient [DQ]) or ASD symptoms (social affect [SA] and restricted and repetitive behaviors [RRBs]).

Results:

Significant group-by-scale interactions were found, and pairwise comparisons revealed that for verbal DQ, DS + ASD < DS, ASD, whereas for nonverbal DQ, DS + ASD < DS < ASD. For SA, DS < DS + ASD < ASD, whereas for RRB, DS, DS + ASD < ASD.

Conclusion:

Findings suggest greater cognitive impairment in DS + ASD on both verbal and nonverbal measures. Despite these significant cognitive challenges, ASD symptoms appeared less severe in DS + ASD relative to peers with ASD in isolation, although SA symptoms were elevated over DS-only. This unique DS + ASD presentation has important implications for early identification and intervention. Given previous research suggesting relative social strengths in DS and less severe ASD symptoms documented in this study, future research may benefit from investigating different aspects of SA (i.e., components related to reciprocal social interaction vs. social communication) in those with DS + ASD to more clearly delineate the social phenotype in this group and potentially inform intervention efforts.
Translucent and Ultrasonographic Studies of the Inferior Labial Artery for Improvement of Filler Injection Techniques
Authors: Tansatit Tanvaa , Phumyoo Thirawass , MCCabe Hannah , Jitaree Benrita
Published: October 2019

Background:

Lower lip augmentation by filler injection is an aesthetic procedure essential for achieving a feminine look and to enhance attractiveness. Complications as a result of injury to the inferior labial artery can result in undesirable outcomes.

Methods:

The translucent technique was used to study the origin of the inferior labial artery in 11 cadavers. Ultrasonography of the inferior labial artery was also performed in 20 volunteers, which provided supplemental data to this study, in relation to establishing recommendations for filler injection.

Results:

Five different types of inferior labial artery were described. These types were found in various combination patterns. Types 2, 4, and 5 are more vulnerable to arterial injury during filler injection. Ultrasonography revealed a depth of 6 mm and an arterial position at the vermillion border as the dangerous injection plane.

Conclusion:

The origins and courses of the inferior labial artery are classified into 5 types. These types are often found in combination with each other in different faces, resulting in large anatomical variation between people. Types of combination influence severity of lower lip necrosis when arterial injury occurs. The physician should be aware of these anatomical variations during aesthetic treatments and reconstructive procedures to avoid the dangers of accidental arterial injury.
SUBRETINAL DRUSENOID DEPOSIT IN AGE-RELATED MACULAR DEGENERATION
Authors: Chen Ling , Messinger Jeffrey D. , Zhang Yuhua , Spaide Richard F. , Freund K. Bailey , Curcio Christine A.
Published: October 2019

Purpose:

To clarify the role of subretinal drusenoid deposits (SDD; pseudodrusen) in the progression of age-related macular degeneration through high-resolution histology.

Methods:

In 33 eyes of 32 donors (early age-related macular degeneration, n = 15; geographic atrophy, n = 9; neovascular age-related macular degeneration, n = 7; unremarkable, n = 2), and 2 eyes of 2 donors with in vivo multimodal imaging including optical coherence tomography, examples of SDD contacting photoreceptors were assessed.

Results:

Subretinal drusenoid deposits were granular extracellular deposits at the apical retinal pigment epithelium (RPE); the smallest were 4-µm wide. Outer segment (OS) fragments and RPE organelles appeared in some larger deposits. A continuum of photoreceptor degeneration included OS disruption, intrusion into inner segments, and disturbance of neurosensory retina. In a transition to outer retinal atrophy, SDD appeared to shrink, OS disappeared, inner segment shortened, and the outer nuclear layer thinned and became gliotic. Stage 1 SDD on optical coherence tomography correlated with displaced OS. Confluent and disintegrating Stage 2 to 3 SDD on optical coherence tomography and dot pseudodrusen by color fundus photography correlated with confluent deposits and ectopic RPE.

Conclusion:

Subretinal drusenoid deposits may start at the RPE as granular, extracellular deposits. Photoreceptor OS, RPE organelles, and cell bodies may appear in some advanced deposits. A progression to atrophy associated with deposit diminution was confirmed. Findings support a biogenesis hypothesis of outer retinal lipid cycling.
VITAMIN A DEFICIENCY MONITORED BY QUANTITATIVE SHORT WAVELENGTH FUNDUS AUTOFLUORESCENCE IN A CASE OF BARIATRIC SURGERY
Authors: Lima de Carvalho Jose Ronaldo , Tsang Stephen H. , Sparrow Janet R.
Published: October 2019

Background/Purpose:

Bariatric surgery is recognized as a treatment option for obesity. However, the cost-efficiency of screening for serum vitamin A and the effectiveness of its oral supplementation in these patients remain unclear. Here, we report a case in which vitamin A and carotenoid deficiency after bariatric surgery were monitored by noninvasive quantitative fundus autofluorescence imaging.

Methods:

Case report.

Results:

A 62-year-old man presented with a history of progressive night blindness. He had duodenal switch surgery 13 years earlier. One year before the initial visit, he had begun oral supplements of vitamins A. Short wavelength fundus autofluorescence images acquired for quantitative fundus autofluorescence revealed an intensity that was lower than the healthy-eye range. Scotopic rod-specific full-field electroretinograms were extinguished. These findings were consistent with vitamin A deficiency. The patient was given intramuscular vitamin A injections. At follow-up, quantitative fundus autofluorescence improved, ERG increased to normal, but macular pigment was unchanged.

Conclusion:

Oral vitamin A supplementation may not be sufficient after mal-absorptive surgery and a quantitative and noninvasive short wavelength fundus autofluorescence imaging technique may be useful to monitor the status of vitamin A and the carotenoids comprising macular pigment in the retina.
Genitourinary vascularized composite allotransplantation: a review of penile transplantation
Authors: Jonczyk Michael M. , Tratnig-Frankl Philipp , Cetrulo Curtis L.
Published: October 2019

Purpose of review

Vascularized composite allotransplantation (VCA) has developed over the past 20 years, resulting in promising new reconstructive prospects for extensive soft tissue defects. More than 200 VCAs have been performed worldwide, including five genitourinary (GU)VCAs and here we review the most recent literature in this field.

Recent findings

Developments in GUVCA are continuously evolving to improve patient outcomes and suggest ethical equivalency to solid organ transplant. Recent treatment options have focused on preventing GUVCA complications by acknowledging the immunogenic tissue composition of the penis to treat rejection episodes and implementing stem cell transplant to recognized the GUVCA as self. Utilizing modern, postoperative, treatments can minimize complications and although the ethical dilemma remains, the morality of performing a GUVCA has diminished. The ethical focus relic's on standardization of patient safety.

GUVCA has become an established reconstructive surgical option. The prospect of VCA's future insinuates systemization between multidisciplinary VCA programs and the United Network for Organ Sharing in efforts to endorse ethical standardization. Over the last five years, the unprecedented outcomes have shown purpose to GUVCA that initiates an obligation to help those with severe genitourinary tissue defects. Progress in immunobiology continues to evolve optimal immunosuppression drug regimens and tolerance induction protocols, highlighting potential new immunologic pathways for graft acceptance.
Neoadjuvant Radiotherapy Versus Surgery Alone for Stage II/III Mid-low Rectal Cancer With or Without High-risk Factors
Authors: Deng Xiangbing , Liu Ping , Jiang Dan , Wei Mingtian , Wang Xin , Yang Xuyang , Zhang Yuanchuan , Wu Bing , Liu Yanjun , Qiu Meng , Zhuang Hua , Zhou Zongguang , Li Yunfeng , Xu Feng , Wang Ziqiang
Published: October 2019

Objective:

The aim of this study was to compare stage II/III rectal cancers with or without high-risk factors, and evaluate the effect of neoadjuvant radiotherapy (NRT) in these 2 cohorts.

Background:

NRT is often used in stage II/III rectal cancers to improve local control, while not affecting overall survival. However, good-quality surgery without NRT may also achieve good local control in selected patients.

Methods:

According to risk-stratification criteria and clinical staging, consecutive eligible participants of stage II/III rectal cancer were preoperatively classified into patients with (high-risk) or without (low-risk) high-risk factors. Both groups were respectively randomized to receive either short-course radiotherapy (SCRT) + total mesorectal excision (TME) or TME alone, forming the following 4 groups: high-risk patients with (HiR) or without (HiS) radiation, and low-risk patients with (LoR) or without (LoS) radiation. The primary endpoint was local recurrence. The secondary endpoints included overall survival, disease-free survival, distant recurrence, quality of surgery, and safety (NCT01437514).

Results:

In total, 401 patients were analyzed. With a median 54 months’ follow-up, low-risk patients obtained better 3-year cumulative incidence of local recurrence (2.2% vs 11.0%, P = 0.006), overall survival rate (86.9%vs 76.5%, P = 0.002), disease-free survival rate (87.0% vs 67.9%, P < 0.001), and cumulative incidence of distant recurrence (12.5% vs 29.4%, P < 0.001) than high-risk patients. With regard to 3-year cumulative incidence of local recurrence, no differences were observed between the LoR and LoS groups (1.2% vs 3.0%, P = 0.983) or the HiR and HiS groups (12.9% vs 8.9%, P = 0.483).

Conclusions and Relevance:

Stratification of stage II/III rectal cancers according to risk factors to more precise subclassifications may result in noteworthy differences in survivals and local pelvic control. An extremely low cumulative incidence of local recurrence and survivals in low-risk patients can be achieved with upfront good quality of surgery alone. This trial, owing to the insufficient power, could not prove the noninferiority of surgery alone, but suggest a discriminative use of NRT according to clinical risk stratification in stage II/III rectal cancer.
Withdrawing noninvasive ventilation at end-of-life care: is there a right time?
Authors: Tripodoro Vilma A. , Rabec Claudio A. , De Vito Eduardo L.
Published: October 2019

Purpose of review

The purpose of this review is the ‘when’ and ‘how’ of the matter of withdrawing noninvasive ventilation (NIV) at end-of-life (EoL) setting, having in mind the implications for patients, families and healthcare team.

Recent findings

Several recent publications raised the place and potential applications of NIV at EoL setting. However, there are no clear guidelines about when and how to withdraw NIV in these patients. Continuing NIV in a failing clinical condition may unnecessarily prolong the dying process. This is particularly relevant as frequently, EoL discussions are started only when patients are in severe distress, and they have little time to discuss their preferences and decisions.

Better advanced chronic disease and EoL condition definitions, as well as identification of possible scenarios, should help to decision-making and find the appropriate time to initiate, withhold and withdraw NIV. This review emphasized the relevance of an integrated approach across illness’ trajectories and key transitions of patients who will need EoL care and such sustaining support measure.
Meaningful measures in cancer cachexia: implications for practice and research
Authors: McDonald James J. , Fallon Marie T. , Laird Barry J.A.
Published: October 2019

Purpose of review

Cancer cachexia is a complex inflammatory syndrome, which presents with a variety of discrete symptoms and signs. This creates a challenge for both clinicians and researchers in recognizing and assessing the syndrome. This review explores the evidence for various measures used in the assessment of cachexia.

Recent findings

Objectively, cachexia may be assessed using CT-derived measures of skeletal muscle [skeletal muscle index (SMI) and skeletal muscle density (SMD)]. Evidence suggests that SMD may be of equal or greater value than SMI in assessing cachexia. Inflammatory markers are also used, and include interleukin(IL)-1α; IL-1β; IL-6 and Interferon Gamma (IFNγ). Other robust measures include performance status and the modified Glasgow prognostic score (mGPS). These measures, however, are more commonly used in academia. By comparison, clinical assessment is limited to individual measures of patient function, such as hand grip strength (HGS), calf circumference, gait speed, and the ‘timed up and go test’ (TUG). These have each been linked with components of cachexia but are less well evidenced. Evidence also exists for patient-reported quality-of-life measures, based upon the EORTC- QLQ-C30 questionnaire, in assessing cachexia.

Further assessment is required to compare clinical measures of cachexia and determine their utility.
Development and Validation of a Socioeconomic Kidney Transplant Derailers Index
Authors: Peipert John D. , Beaumont Jennifer L. , Robbins Mark L. , Paiva Andrea L. , Anderson Crystal , Cui Yujie , Waterman Amy D.
Published: October 2019

Background.

Socioeconomic barriers can prevent successful kidney transplant (KT) but are difficult to measure efficiently in clinical settings. We created and validated an individual-level, single score Kidney Transplant Derailers Index (KTDI) and assessed its association with waitlisting and living donor KT (LDKT) rates.

Methods.

The dataset included 733 patients presenting for KT evaluation in a transplant center in California. Exploratory factor analysis was used to identify socioeconomic barriers to KT (derailers) to include in the index. Potential KT derailers included health insurance, employment, financial insecurity, educational attainment, perception of neighborhood safety, access to a vehicle, having a washer/dryer, and quality of social support. Validity was tested with associations between KTDI scores and the following: (1) the Area Deprivation Index (ADI) and (2) time to KT waitlisting and LDKT.

Results.

Nine derailers were retained, omitting only social support level from the original set. The KTDI was scored by summing the number of derailers endorsed (mean: 3.0; range: 0–9). Black patients had higher estimated KTDI scores than other patient groups (versus White patients, 3.8 versus 2.1; P < 0.001, effect size = 0.81). In addition, the KTDI was associated with the ADI (γ = 0.70, SE = 0.07; P < 0.001). Finally, in comparison to the lower tertile, patients in the upper and middle KTDI tertiles had lower hazard of waitlisting (upper tertile hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.25-0.45; middle tertile HR: 0.54, 95% CI: 0.40-0.72) and receiving an LDKT (upper tertile HR: 0.15, 95% CI: 0.08-0.30; middle tertile HR: 0.35, 95% CI: 0.20-0.62). These associations remained significant when adjusting for the ADI and other patient characteristics.

Conclusions.

The KTDI is a valid indicator of socioeconomic barriers to KT for individual patients that can be used to identify patients at risk for not receiving a KT.
Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys
Authors: Hameed Ahmer M. , Lu David B. , Patrick Ellis , Xu Bo , Hu Min , Chew Yi Vee , Keung Karen , P’ng Chow H. , Gaspi Renan , Zhang Chris , Robertson Paul , Alexander Stephen , Thomas Gordon , Laurence Jerome , De Roo Ronald , Wong Germaine , Miraziz Ray , O’Grady Greg , Yuen Lawrence , Hawthorne Wayne J. , Rogers Natasha M. , Pleass Henry C.
Published: October 2019

Background.

Normothermic machine perfusion (NMP) may allow resuscitation and improved assessment of kidneys before transplantation. Using discarded human kidneys, we investigated the mechanistic basis and translational potential of NMP compared with cold static storage (CS).

Methods.

Discarded deceased donor kidneys (n = 15) underwent 1-hour NMP following CS. Renal perfusion, biochemical, and histologic parameters were recorded. NMP was directly compared with CS in paired donor kidneys using simulated transplantation with allogeneic whole blood, followed by assessment of the aforementioned parameters, in addition to RNA sequencing.

Results.

Kidneys were successfully perfused, with improved renal blood flows and resistance over the course of perfusion, and evidence of urine output (median 21 mL), in all but one kidney. NMP completely resolved nonperfused regions in discarded donation after circulatory death kidneys. In paired kidneys (n = 4 pairs), transcriptomic analyses showed induction of stress and inflammatory pathways in NMP kidneys, with upregulation of pathways promoting cell survival and proliferation. Furthermore, the NMP pairs had significantly better renal perfusion (1.5–2 fold improvement) and functional parameters, and amelioration of cell death, oxidative stress, and complement activation.

Conclusions.

In this pilot preclinical study using simulated transplantation of paired kidneys, NMP of discarded marginal kidneys demonstrated some significant mechanistic benefits in comparison to CS alone. NMP may have potential to reduce organ discards and enhance early graft function in such kidneys.
Conscious perception of flickering stimuli in binocular rivalry and continuous flash suppression is not affected by tACS-induced SSR modulation
Authors: Schauer Georg , Ogawa Carolina Yuri , Tsuchiya Naotsugu , Bartels Andreas
Published: October 2019

The content of conscious perception is known to correlate with steady-state responses (SSRs), yet their causal relationship remains unclear. Can we manipulate conscious perception by directly interfering with SSRs through transcranial alternating current stimulation (tACS)? Here, we directly addressed this question in three experiments involving binocular rivalry and continuous flash suppression (CFS). Specifically, while participants (N=24) viewed either binocular rivalry or tried to detect stimuli masked by CFS, we applied sham or real tACS across parieto-occipital cortex at either the same or a different frequency and phase as an SSR eliciting flicker stimulus. We found that tACS did not differentially affect conscious perception in the forms of predominance, CFS detection accuracy, reaction time, or metacognitive sensitivity, confirmed by Bayesian statistics. We conclude that tACS application at frequencies of stimulus-induced SSRs does not have perceptual effects and that SSRs may be epiphenomenal to conscious perception.
RRP7A links primary microcephaly to radial glial cells and dysfunction of ribosomal biogenesis, neurogenesis and ciliary resorption
Authors: Farooq Muhammad , Lindbæk Louise , Krogh Nicolai , Doganli Canan , Keller Cecilie , Mönnich Maren , Sakthivel Srinivasan , Mang Yuan , Fatima Ambrin , Andersen Vivi Søgaard , Hussain Muhammad. S. , Eiberg Hans , Hansen Lars , Kjaer Klaus Wilbrandt , Gopalakrishnan Jay , Pedersen Lotte Bang , Møllgård Kjeld , Nielsen Henrik , Baig Shahid. M. , Tommerup Niels , Christensen Søren Tvorup , Larsen Lars Allan
Published: October 2019

Introductory paragraph

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability1. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role1. Using homozygosity mapping and whole exome sequencing, we identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, which segregated with MCPH in a consanguineous family with 10 affected individuals. RRP7A is expressed in neural stem cells/radial glial cells of the developing human forebrain, and targeted mutation of Rrp7a leads to defects in both neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in processing of ribosomal RNA, resorption of primary cilia and cell cycle progression. Finally, analysis of zebrafish embryos with loss-of-function mutation in rrp7a confirmed that RRP7A depletion causes reduced brain size, impaired neurogenesis and cell proliferation as well as defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH.
Measuring anesthetic resistance in Drosophila by VAAPR
Authors: Petersen E. Nicholas , Clowes Katherine R. , Hansen Scott B.
Published: October 2019

Volatile anesthetics are compounds which are commonly used to induce a reversable loss of consciousness (LOC) in animals. The molecular mechanism of how anesthetics induce LOC is largely unknown. However, observations have been made which show that there are genetically-encoded traits which influence the effective concentration of anesthetics in the inducement of LOC. Despite this long-term observation, little progress has been made in identifying genes involved in anesthetic sensitivity. One reason for this is that many techniques to test anesthetic sensitivity are technically challenging and are inhibitory for high-throughput studies. Here we introduce a technique for testing volatiles and aerosols with positional recording (VAAPR), a method which allows for high-throughput testing of the effect of anesthetics and other aerosolized drugs using Drosophila. Using VAAPR we show that the enzyme phospholipase D (PLD) significantly shifts the concentration of diethyl ether, chloroform, and isoflurane needed to induce LOC in Drosophila. We also show that PLD is required for a paradoxical hyperactivity phenotype. We expect that this technique will allow for additional genes to be found which control anesthetic sensitivity as well as other behavioral phenotypes.