bluuebunny/crossref_metadata_2025 huggingface dataset:
LB19. Progress Toward a Vaccine for Maternal Immunization to Prevent Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Illness (LRTI) in Infants
Authors: Fries Louis , Thomas D Nigel , Smith Gale , Plested Joyce , Piedra Pedro , Patel Nita , Cho Iksung , Glenn Greg
Published: November 2018

Background

RSV is the leading cause of infant LRTI and hospitalization worldwide. The greatest burden of severe disease is in term infants <5 months old. Novavax is developing an aluminum-adjuvanted RSV F nanoparticle vaccine for use in the third trimester of pregnancy, with the goal of preventing medically significant infant RSV LRTI in the first 3–6 months of life via transplacental transfer of maternal antibodies.

Method

After dose-finding studies in 1,050 women, we studied vaccine safety and immunogenicity in a Phase 2 trial in 50 healthy third trimester pregnant women. Safety was assessed in mothers and infants, focusing on pregnancy and peri-partum outcomes. We measured binding and functional RSV antibodies in mothers at baseline, day 14, delivery, and days 35 and 180 post-partum, in cord blood, and in infant sera on days 14, 35, 60, and 180 of life. Anti-F antibody specificities were probed with biolayer interferometry and monoclonal antibodies (mabs) to known epitopes.

Result

In Phase 2, RSV F nanoparticle vaccine was immunogenic, safe, and well-tolerated in pregnant women. Anti-F IgG and neutralizing antibodies were elicited. Increases in antibodies competitive with mabs to neutralizing epitope sites Ø, VIII, II, and IV, and also the p27 domain displayed by the pre-fusogenic F protein, were present in maternal and infant sera of vaccinated subject pairs. Transplacental transfer of RSV antibodies was more efficient (110 to 120%) in women immunized >30 days before delivery compared with those vaccinated later; RSV antibody t1/2 ranged from 30 to 41 days in infants. We have subsequently enrolled 4,636 pregnant women and their infants in a global observer-blind, randomized, placebo-controlled Phase 3 trial assessing efficacy against medically significant RSV LRTI. In November 2017, an informational analysis performed by an independent statistician, the sponsor remaining blinded, yielded a posterior probability of ≥90% that efficacy was >0%.

Conclusion

RSV F nanoparticle vaccine is immunogenic in pregnancy, and neutralizing antibodies, including those competing for pre-and post-fusion F epitopes, are transferred efficiently transplacentally. An analysis of Phase 3 efficacy against medically signifcant infant RSV LRTI is projected for Q1, 2019.

Disclosures

L. Fries, Novavax: Employee and Shareholder, Salary. D. N. Thomas, Novavax: Employee, Salary. G. Smith, Novavax: Employee and Shareholder, Salary. J. Plested, Novavax: Employee, Salary. P. Piedra, Novavax: Collaborator, Consultant, Research Contractor and Scientific Advisor, Consulting fee, contract fees for immunologic assays and Research support. N. Patel, Novavax: Employee and Shareholder, Salary. I. Cho, Novavax: Employee and Shareholder, Salary. G. Glenn, Novavax: Employee and Shareholder, Salary.
Experimental Pain Is Alleviated by Manual Traction Itself Rather than Subjective Bias in the Knee: A Signal Detection Analysis
Authors: Shigetoh Hayato , Osumi Michihiro , Morioka Shu
Published: November 2018

Background

Manual traction is used for pain relief, but it is not clear whether the pain relief effect of manual traction is due to sensitivity or to subjective bias. The differences between manual traction and touch have also been unclear.

Objectives

We used signal detection theory to investigate whether manual traction and touch were effective for pain relief, and we compared the pain relief effect between manual traction and touch.

Design

Repeated measures and single blinding.

Methods

Twenty healthy adult volunteers performed an intensity judgment task immediately before and after each intervention. The intervention was either manual traction or touch for 10 minutes. We measured the intensity judgment task’s signal detection measures of hit rates, false alarm rates, sensitivity (d'), and response bias (C) in an Aδ fiber–mediated pain condition and C fiber–mediated pain condition.

Results

Manual traction did not provide a significant level of change, but its effect sizes differed. In our comparison of the effect sizes, manual traction tended to reduce the hit rate and altered the sensitivity value rather than the response bias in Aδ fiber–mediated pain. There was no significant difference in the amount of change in the hit rate between touch and manual traction regarding Aδ fiber–mediated pain and C fiber–mediated pain.

Conclusions

In terms of effect sizes, manual traction was effective for the pain relief of the first pain by producing a change in pain sensitivity rather than by subjective bias. Manual traction reduced the first pain, whereas touch reduced the first pain and second pain.
Feasibility and acceptability of a faith-based mind-body intervention among African American adults
Authors: Mama Scherezade K , Bhuiyan Nishat , Chaoul Alejandro , Cohen Lorenzo , Fagundes Christopher P , Hoover Diana S , Strong Larkin L , Li Yisheng , Nguyen Nga T , McNeill Lorna H
Published: November 2018

Physical activity reduces cancer risk, yet African American adults remain insufficiently active, contributing to cancer health disparities. Harmony & Health (HH) was developed as a culturally adapted mind-body intervention to promote physical activity, psychosocial well-being, and quality of life among a church-based sample of overweight/obese, insufficiently active African American adults. Men and women were recruited to the study through an existing church partnership. Eligible participants (N = 50) were randomized to a movement-based mind-body intervention (n = 26) or waitlist control (n = 24). Participants in the intervention attended 16 mind-body sessions over 8 weeks and completed a physical assessment, questionnaires on moderate-to-vigorous physical activity (MVPA) and psychosocial factors, and accelerometry at baseline (T1), post-intervention (T2), and 6 week follow-up (T3). Eighty percent of participants (94% women, M age = 49.7 ± 9.4 years, M body mass index = 32.8 ± 5.2 kg/m2) completed the study, and 61.5% of intervention participants attended ≥10 mind-body sessions. Participants self-reported doing 78.8 ± 102.9 (median = 40.7, range: 0–470.7) min/day of MVPA and did 27.1 ± 20.7 (median = 22.0, range: 0–100.5) min/day of accelerometer-measured MVPA at baseline. Trends suggest that mind-body participants self-reported greater improvements in physical activity and psychosocial well-being from baseline to post-intervention than waitlist control participants. HH is feasible and acceptable among African American adults. Trends suggest that the mind-body intervention led to improvements in physical activity and psychosocial outcomes. This study extends the literature on the use of mind-body practices to promote physical and psychological health and reduce cancer disparities in African American adults.
Significant Reduction of Pulmonary Embolism in Orthopaedic Trauma Patients
Authors: Starr Adam J. , Shirley Zachary , Sutphin Patrick D. , Sanders Drew , Eastman Alexander , Au Brigham , Sathy Ashoke , Hu Gene , Gebrelul Aaron , Minei Joseph , Cripps Michael W.
Published: November 2018

Objectives:

To report results of a protocol to lessen incidence of pulmonary embolism (PE) among orthopaedic trauma patients.

Design:

Retrospective review.

Setting:

Level 1 trauma center.

Patient/Participants:

Orthopaedic trauma inpatients were included in the study.

Intervention:

On arrival, an orthopaedic trauma patient's PE risk is calculated using a previously developed tool. If possible, patients at high risk are given their first dose of enoxaparin before leaving the emergency room. If other injuries preclude enoxaparin, then chemoprophylaxis is held for 24 hours. Twenty-four hours after arrival, the patient's ability to receive enoxaparin is reassessed. If possible, enoxaparin is started, with dosing twice a day. If enoxaparin is still contraindicated, a removable inferior vena cava filter is placed. Adequacy of enoxaparin dosing is tested using anti-factor Xa assay, drawn 4 hours after the third dose of enoxaparin. If the anti-factor Xa result is less than 0.2 IU/mL, a removable inferior vena cava filter is placed. If the result is 0.2–0.5 IU/mL, enoxaparin dosing is continued. If greater than 0.5 IU/mL, the dose of enoxaparin is reduced.

Outcome Measure:

The main outcome measure was rate of PE.

Results:

From September 1, 2015 to December 31, 2015, our hospital admitted 420 orthopaedic trauma patients. Fifty-one patients were classed as high risk for PE. In September through December 2015, 9 sustained PE, 1 of which was fatal. From September 1, 2016 to December 31, 2016, our hospital admitted 368 orthopaedic trauma patients with comparable age and Injury Severity Score to 2015. Forty patients were at high risk for PE, 1 sustained a nonfatal PE. PE incidence from September to December 2016 was significantly lower than in 2015 (P = 0.02). Overall, 26 patients managed under the new protocol had IVCFs placed, 21 had their filters removed, and 3 died with filters in place. There were no complications during filter placement or removal. One patient had hemorrhage felt to be attributable to enoxaparin.

Conclusions:

Our protocol emphasizes more robust enoxaparin dosing, and more frequent use of IVCF, but only among those at high risk. We lessened the incidence of PE, with a low complication rate.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Noncontact sports participation in adolescent idiopathic scoliosis: effects on parent-reported and patient-reported outcomes
Authors: Segreto Frank A. , Messina James C. , Doran James P. , Walker Sarah E. , Aylyarov Alexandr , Shah Neil V. , Mixa Patrick J. , Ahmed Natasha , Paltoo Karen , Opare-Sem Kwaku , Kaur Harleen , Day Louis M. , Naziri Qais , Paulino Carl B. , Scott Claude B. , Hesham Khalid , Urban William P. , Diebo Bassel G.
Published: November 2018

Comparing risks against benefits of adolescent idiopathic scoliosis (AIS) patients participating in sports represents a controversial topic in the literature. Previous studies have reported sports participation as a possible risk factor for AIS development, while others describe its functional benefits for AIS athletes. The objective of this study was to determine if sports participation had an impact on pain, function, mental status, and self-perception of deformity in patients and their parents. Patients had full spine radiographs and completed baseline surveys of demographics, socioeconomics, and patient-reported outcomes (PRO): Scoliosis Research Society (SRS)-30, Body Image Disturbance Questionnaire, and Spinal Appearance Questionnaire (SAQ: Children and Parent). Patients were grouped by their participation (sports) or nonparticipation (no-sports) in noncontact sports. Demographics, radiographic parameters, and PRO were compared using parametric/nonparametric tests with means/medians reported. Linear regression models identified significant predictors of PRO. Forty-nine patients were included (sports: n=29, no-sports: n=20). Both groups had comparable age, sex, BMI, bracing status, and history of physical therapy (all P>0.05). Sports and no-sports also had similar coronal deformity (major Cobb: 31.1° vs. 31.5°). Sagittal alignment profiles (pelvic incidence, pelvic incidence minus lumbar lordosis, thoracic kyphosis, and sagittal vertical axis) were similar between groups (all P>0.05). Sports had better SRS-30 (Function, Self-image, and Total) scores, SAQ-Child Expectations, and SAQ-Parent Total Scores (P<0.05). Regression models revealed major Cobb angle (β coefficient: −0.312) and sports participation (β coefficient: 0.422) as significant predictors of SRS-30 Function score (R=0.434, P<0.05). Our data show that for AIS patients with statistically similar bracing status and coronal and sagittal deformities, patients who participated in sports were more likely to have improved functionality, self-image, expectations, and parental perception of deformity. Further investigation is warranted to acquire a comprehensive understanding of the relationship between AIS and patient participation in sports. Maintaining moderate levels of physical activity and participating in safe sports may benefit treatment outcomes. Level of Evidence III – Retrospective Comparative Study.
Tönnis triple pelvic osteotomy for the management of late residual acetabular dysplasia: mid-term to long-term follow-up study of 54 patients
Authors: Farsetti Pasquale , Caterini Roberto , De Maio Fernando , Potenza Vito , Efremov Kristian , Ippolito Ernesto
Published: November 2018

The authors reviewed 54 (58 hips) patients with acetabular dysplasia following developmental dislocation of the hip (DDH), treated by triple pelvic osteotomy according to the Tönnis technique. The aim of our study was to report the long-term clinical and radiographic results of the operation at a mean follow-up of 12 years (from 7 to 20). At diagnosis, all the hips were painful, the Wiberg angle measured less than 20°, and no radiographic signs of osteoarthritis were present. At follow-up, 82.7% of the operated hips showed either excellent or good results, according to Harris, and the Wiberg angle measured an average of 34° (from 26° to 45°). We encountered five complications: one acetabular malrotation and four asymptomatic ischial nonunions. In conclusion, we believe that, although Bernese periacetabular osteotomy is nowadays considered the gold standard for the surgical treatment of the dysplastic hip following DDH, Tönnis osteotomy represents a good treatment option: it is technically easy, enables direct visualization of the three osteotomies, leads to few complications, and its learning curve is short. The absence of radiographic signs of osteoarthritis and hip congruency before surgery are the basic requirements to achieve a successful result.
Role of immunotherapy in stage III nonsmall cell lung cancer
Authors: Wrona Anna
Published: November 2018

Purpose of review

Despite aggressive treatment based on definitive chemoradiotherapy, 5-year overall survival in unresectable stage III nonsmall cell lung cancer remains poor (15–20%). The novel immunotherapy based on immune checkpoint inhibitors (ICIs) presents as the therapeutic ‘Holly Grail’ in lung cancer treatment.

Recent findings

Preclinical models provide evidence of immunotherapy–radiotherapy (IM-RT) synergy. The exposure to ionizing radiation turns tumor in an in-situ vaccine, primes the innate immune system, increases immunotherapy efficacy by overcoming the immunosuppressive microenvironment of immune-resistant tumors and promotes a systemic, out-of-field antitumor T-cell-mediated response called abscopal effect. The immunomodulatory and abscopal effects of radiotherapy can be further enhanced by combining with systemic immunotherapies. The phase III START trial proved that liposomal vaccine – tecemotide (L-BLP25) administered as maintenance therapy after concurrent chemoradiotherapy (CRT) in LA-NSCLC prolongs survival. In the phase III PACIFIC trial consolidation with durvalumab, an anti-PDL-1 antibody, was associated with survival benefit in patients diagnosed with LA-NSCLC who responded to concurrent chemoradiotherapy.

PACIFIC trial results are expected to definitely establish durvalumab as standard consolidation strategy in LA-NSCLC. Many clinical trials are ongoing in the field of immunoradiotherapy in LA-NSCLC to define the optimal conditions for this therapeutic combination.
Red meat intake, CYP2E1 and PPARγ polymorphisms, and colorectal cancer risk
Authors: Kim Na-Hui , Seol Ju Eun , Kim Jeongseon , Lee Bong-Hwa , Hwang Dae-Yong , Jeong Jinyoung , Lee Hun-Jae , Ahn Yoon-Ok , Kim Dong-Hyun , Lee Jung Eun
Published: November 2018

The association between red meat intake and colorectal cancer (CRC) may be modulated by genetic polymorphisms of cytochrome P450 2E1 (CYP2E1), a key enzyme in the metabolism of nitrosamines, and peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involved in adipogenesis and lipid and glucose metabolism. We conducted a case–control study of 971 patients with CRC and 658 controls who were admitted to two university hospitals between 1995 and 2004 in Seoul, Korea. Participants were asked about red meat intake by using a validated food frequency questionnaire. Polymorphisms of CYP2E1 (rs3813867) and PPARγ (rs1801282 or rs3856806) were identified using the TaqMan assay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models. We found that the association between red meat and CRC varied by CYP2E1 polymorphisms; ORs (95% CIs) for at least five or more vs. less than one time/week of red meat intake were 2.77 (1.23–6.25) among individuals with C alleles of CYP2E1 and 0.89 (0.51–1.54) among individuals with the GG allele (P
interaction=0.05). Compared with those individuals with the CC allele, increasing risk of CRC with increasing red meat intake was more pronounced among individuals with T alleles of PPARγC161T (rs3856806), but the association was not significant. Our data provide evidence that East Asians with the variant type of CYP2E1 may have high susceptibility to development of CRC risk.
Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper
Authors: Herpain Antoine , Bouchez Stefaan , Girardis Massimo , Guarracino Fabio , Knotzer Johann , Levy Bruno , Liebregts Tobias , Pollesello Piero , Ricksten Sven-Erik , Riha Hynek , Rudiger Alain , Sangalli Fabio
Published: November 2018

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate–sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.
Effect of a 30-Month Health-Promoting Program on the Prevalence of Cardiovascular Risk Factors in Patients With First Episode Schizophrenia
Authors: Søgaard Hans J. , Højlund Mikkel , Elliott Anja , Viuff Anne G. , Vandborg Kirsten , Viuff Jakob , Munk-Jørgensen Povl , Hjorth Peter
Published: November 2018

Background:

Lifestyle interventions aimed at reducing cardiovascular risk factors in patients with first-episode schizophrenia (FES) have shown modest efficacy, probably owing to a short observation period and the presumption of linear trajectories of cardiovascular risk factors.

Study Question:

How prevalent are abnormal cardiovascular values in patients with FES and how do cardiovascular risk factors develop during a 30-month program?

Study Design:

A 30-month naturalistic longitudinal study of 136 consecutively referred patients with FES from 2 outpatient clinics. The health-promoting program consisted of individual guidance, group sessions, and normal treatment and care.

Measures and Outcomes:

The prevalence of abnormal cardiovascular risk factors (body mass index, waist circumference (WC), body fat percentage, systolic and diastolic blood pressure, pulse, total cholesterol, high- and low-density lipoproteins, triglycerides, mean glucose, and visceral adiposity index) was estimated at index. The cardiovascular risk factor trajectories were analyzed with longitudinal mixed-effect models.

Results:

The patient with FES showed elevated cardiovascular risk factors at index. Thus, 56.8% of the patients were overweight in different grades and 50.4% had increased WC. A total of 81.8% had high level of body fat and hypertension prevalence with only 20% with normal blood pressure. Important changes during the intervention period were that the risk factors weight and WC were increasing the first 581 and 646 days, after which they decreased. Almost all cardiovascular risk factors worsened initially, improving after 1–2 years.

Conclusions:

Patients with FES show increases in cardiovascular risk factors at index. Short observation periods and the presumption of linear trajectories may indicate that the effect of health-promoting programs is ineffective, as the effects are curvilinear and improvements appear only after 1 year. The implication clinically is the importance of a long intervention period regarding lifestyle modifications to ascertain improvement among patients with FES.
Models of Care—There Is More Than One Way to Deliver
Authors: Sironi Giovanna , Barr Ronald D. , Ferrari Andrea
Published: November 2018

Adolescents and young adults (AYAs) with cancer constitute a particular group of patients with unique features, whose needs during and after treatment are poorly met. A standardized model of care for them has yet to be established, as neither the pediatric nor the adult oncology systems seamlessly fit their needs. Regardless of the setting in which they are treated, their health care providers should be aware of the impact that the disease and its treatments have on these especially vulnerable patients. Simple ways of improving the AYA experience should be considered: reducing isolation through connections with peers, adapting the staff's approach to the emotional and developmental needs of this age group, and modifying the hospital environment making it more age appropriate. Commitment of national governments is valuable; building and sharing international experience will accelerate advances in clinical care, education, and research. Further progress in the care of AYA cancer patients is still needed to improve their outcomes.
Intraoral Endoscopic Ligation of Maxillary Artery in the Infratemporal Fossa
Authors: Polev Georgiy A. , Carrau Ricardo L. , Golbin Denis A. , Avdeeva Klementina S. , Grachev Nickolai S. , Vorozhtsov Igor N. , Lasunin Nikolay V. , Cherekaev Vasily A. , Salas Galicia Juan Eugenio
Published: November 2018

Ligation of the sphenopalatine and posterior nasal arteries is indicated for posterior epistaxis as initial treatment or when conservative measures fail. In some patients, a transnasal approach or its alternative transantral approach are not possible due to tumor filling the nasal corridor, pterygopalatine fossa, or maxillary sinus. Aim of this study was to evaluate feasibility of endoscopically assisted transoral approach for the ligation of the maxillary artery (MA). Six fresh cadaver specimens (12 sides), previously prepared with intravascular injections of colored latex, were dissected. A combined transnasal and transoral approach exposed the MA from the deep belly of the temporalis muscle laterally to its terminal branches medially. Anatomical relationships of the MA with the deep belly of the temporalis muscle and the lower head of the lateral pterygoid muscle, and feasibility of access to the MA via a transoral approach were assessed. In all specimens, the MA was found at the point where horizontal fibers of the lower head of the lateral pterygoid muscle cross the vertical fibers of the deep belly of the temporalis muscle. In 5 specimens, the artery ran anteriorly and laterally to lower head of the lateral pterygoid muscle, and in 1 specimen, it ran posteriorly and medially to this muscle, diving between its fibers. The modified endoscopically assisted transoral approach is feasible to ligate the MA. It can be used for proximal vascular control in cases when transnasal and transantral approaches are not viable.
MR-TRYX: A Mendelian randomization framework that exploits horizontal pleiotropy to infer novel causal pathways
Authors: Cho Yoonsu , Haycock Philip C , Sanderson Eleanor , Gaunt Tom R , Zheng Jie , Morris Andrew P , Smith George Davey , Hemani Gibran
Published: November 2018

In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying novel pathways to the traits under investigation. Here, we developed the MR-TRYX framework, following the advice of William Bateson to “TReasure Your eXceptions”. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across thousands of complete GWAS summary datasets in the MR-Base database to systematically identify other (“candidate”) traits that associate with the outliers. We developed a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways were uncovered with already established causal effects, validating the approach, but also novel putative causal pathways. Adjustment for pleiotropic pathways reduced the heterogeneity across the analyses.
Object visibility, not energy expenditure, accounts for spatial biases in human grasp selection
Authors: Maiello Guido , Paulun Vivian C. , Klein Lina K. , Fleming Roland W.
Published: November 2018

Humans exhibit spatial biases when grasping objects. These biases may be due to actors attempting to shorten their reaching movements and therefore minimize energy expenditures. An alternative explanation could be that they arise from actors attempting to minimize the portion of a grasped object occluded from view by the hand. We re-analyze data from a recent study, in which a key condition decouples these two competing hypotheses. The analysis reveals that object visibility, not energy expenditure, most likely accounts for spatial biases observed in human grasping.
Diffusion MRI Indices and their Relation to Cognitive Impairment in Brain Aging: The updated multi-protocol approach in ADNI3
Authors: Zavaliangos-Petropulu Artemis , Nir Talia M. , Thomopoulos Sophia I. , Reid Robert I. , Bernstein Matt A. , Borowski Bret , Jack Clifford R. , Weiner Michael W. , Jahanshad Neda , Thompson Paul M. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: November 2018

Brain imaging with diffusion-weighted MRI (dMRI) is sensitive to microstructural white matter changes associated with brain aging and neurodegeneration. In its third phase, the Alzheimer’s Disease Neuroimaging Initiative (ADNI3) is collecting data across multiple sites and scanners using different dMRI acquisition protocols, to better understand disease effects. It is vital to understand when data can be pooled across scanners, and how the choice of dMRI protocol affects the sensitivity of extracted measures to differences in clinical impairment. Here, we analyzed ADNI3 data from 317 participants (mean age: 75.4±7.9 years; 143 men/174 women), who were each scanned at one of 47 sites with one of six dMRI protocols using scanners from three different manufacturers. We computed four standard diffusion tensor imaging (DTI) indices including fractional anisotropy (FADTI) and mean, radial, and axial diffusivity, and one FA index based on the tensor distribution function (FATDF), in 24 bilaterally averaged white matter regions of interest. We found that protocol differences significantly affected dMRI indices, in particular FADTI. We ranked the diffusion indices for their strength of association with four clinical assessments. In addition to diagnosis, we evaluated cognitive impairment as indexed by three commonly used screening tools for detecting dementia and Alzheimer’s disease: the Alzheimer’s Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating scale sum-of-boxes (CDR-sob). Using a nested random-effects model to account for protocol and site, we found that across all dMRI indices and clinical measures, the hippocampal-cingulum and fornix (crus) / stria terminalis regions most consistently showed strong associations with clinical impairment. Overall, the greatest effect sizes were detected in the hippocampal-cingulum and uncinate fasciculus for associations between axial or mean diffusivity and CDR-sob. FATDF detected robust widespread associations with clinical measures, while FADTI was the weakest of the five indices for detecting associations. Ultimately, we were able to successfully pool dMRI data from multiple acquisition protocols from ADNI3 and detect consistent and robust associations with clinical impairment and age.
The Fate of Glutamine in Human Metabolism. The interplay with glucose in proliferating cells
Authors: Mazat Jean-Pierre , Ransac Stéphane
Published: November 2018

Genome-scale models of metabolism (GEM) are used to study how metabolism varies in different physiological conditions. However, the great number of reactions involved in GEM makes it difficult to understand these variations. In order to have a more understandable tool, we developed a reduced metabolic model of central carbon and nitrogen metabolism, C2M2N with 77 reactions, 54 internal metabolites and 3 compartments, taking into account the actual stoichiometry of the reactions, including the stoichiometric role of the cofactors and the irreversibility of some reactions. In order to model OXPHOS functioning, the proton gradient through the inner mitochondrial membrane is represented by two pseudo-metabolites DPH (ΔpH) and DPSI (Δψ).

To illustrate the interest of such a reduced and quantitative model of metabolism in mammalian cells, we used Flux Balance Analysis (FBA), to study all the possible fates of glutamine in metabolism. Our analysis shows that glutamine can supply carbon sources for cell energy production and can be used as carbon and nitrogen sources to synthesize essential metabolites. Finally, we studied the interplay between glucose and glutamine for the formation of cell biomass according to ammonia microenvironment. We then propose a quantitative analysis of the Warburg effect.
Systematic Allelic Analysis Defines the Interplay of Key Pathways in X Chromosome Inactivation
Authors: Nesterova Tatyana B , Wei Guifeng , Coker Heather , Pintacuda Greta , Bowness Joseph S , Zhang Tianyi , Almeida Mafalda , Bloechl Bianca , Moindrot Benoit , Carter Emma J , Rodrigo Ines Alvarez , Pan Qi , Bi Ying , Song Chun-Xiao , Brockdorff Neil
Published: November 2018

Xist RNA, the master regulator of X chromosome inactivation, acts in cis to induce chromosome silencing through the stepwise recruitment of factors that modify underlying chromatin structure. Whilst considerable progress has been made towards defining key silencing factors and the elements to which they bind, their relative contribution to silencing different genes, and their relationship with one another is poorly understood. Here we describe a systematic analysis of Xist-mediated allelic silencing in ES cell-based models. We show that Spen, recruited through the Xist A-repeat, plays a central role, being critical for silencing of all except a subset of weakly expressed genes. Polycomb, recruited through the Xist B/C-repeat, also plays a key role, favouring silencing of genes with pre-existing H3K27me3 chromatin. LBR and the Rbm15/ m6A-methyltransferase complex, previously proposed to have a central role, make at most a minor contribution to gene silencing. We integrate our findings in a comprehensive model for Xist-mediated chromosome silencing.
Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
Authors: Jeffries Aaron R , Maroofian Reza , Salter Claire G. , Chioza Barry A. , Cross Harold E. , Patton Michael A. , Temple I. Karen , Mackay Deborah , Rezwan Faisal I. , Aksglæde Lise , Baralle Diana , Dabir Tabib , Hunter Matthew Frank , Kamath Arveen , Kumar Ajith , Newbury-Ecob Ruth , Selicorni Angelo , Springer Amanda , Maldergem Lionel van , Varghese Vinod , Yachelevich Naomi , Tatton-Brown Katrina , Mill Jonathan , Crosby Andrew H. , Baple Emma
Published: November 2018

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns inDNMT3Ac.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novoDNMT3Avariants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.
Worldwide phylogeography and history of wheat genetic diversity
Authors: Balfourier François , Bouchet Sophie , Robert Sandra , Oliveira Romain De , Rimbert Hélène , Kitt Jonathan , Choulet Frédéric ,   International Wheat Genome Sequencing Consortium,   BreedWheat Consortium, Paux Etienne
Published: November 2018

Since its domestication in the Fertile Crescent ~8,000 to 10,000 years ago, wheat has undergone a complex history of spread, adaptation and selection. To get better insights into the wheat phylogeography and genetic diversity, we describe allele distribution through time using a set of 4,506 landraces and cultivars originating from 105 different countries genotyped with a high-density SNP array. Although the genetic structure of landraces is collinear to ancient human migration roads, we observe a reshuffling through time, related to breeding programs, with the apparition of new alleles enriched with structural variations that may be the signature of introgressions from wild relatives after 1960.

One Sentence Summary

A phylogeographical study reveals the complex history of wheat genetic diversity through time and space.
Identification of slow-cycling germline stem cells and their regulation by PLZF
Authors: Sharma Manju , Srivastava Anuj , Fairfield Heather E. , Bergstrom David , Flynn William F. , Braun Robert E
Published: November 2018

Long-term maintenance of spermatogenesis in mammals is supported by GDNF, an essential growth factor required for spermatogonial stem cell (SSC) self-renewal. Exploiting a transgenic GDNF overexpression model, which expands and normalizes the pool of undifferentiated spermatogonia between Plzf+/+ and Plzflu/lu mice, we used RNAseq to identify a rare subpopulation of cells that express EOMES, a T-box transcription factor. Lineage tracing and busulfan challenge show that these are long-term SSCs that contribute to steady state spermatogenesis as well as regeneration following chemical injury. EOMES+ SSCs have a lower proliferation index than EOMES− GFRA1+ spermatogonia in wild-type but not in Plzflu/lu mice. This comparison demonstrates that PLZF regulates their proliferative activity and suggests that EOMES+ SSCs are lost through proliferative exhaustion in Plzflu/lu mice. Single cell RNA sequencing of EOMES+ cells from Plzf+/+ and Plzflu/lu mice support a hierarchical model of both slow- and rapid-cycling SSCs.
Bayesian meta-analysis across genome-wide association studies of diverse phenotypes
Authors: Trochet Holly , Pirinen Matti , Band Gavin , Jostins Luke ,   Wellcome Trust Case-Control Consortium 2, McVean Gilean , Spencer Chris C. A.
Published: November 2018

Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic basis of diseases and traits, but most studies have been conducted in isolation, with a focus on either a single or a set of closely related phenotypes. We describe MetABF, a simple Bayesian framework for performing integrative meta-analysis across multiple GWAS using summary statistics. The approach is applicable across a wide range of study designs and can increase the power by 50% compared to standard frequentist tests when only a subset of studies have a true effect. We demonstrate its utility in a meta-analysis of 20 diverse GWAS which were part of the Wellcome Trust Case-Control Consortium 2. The novelty of the approach is its ability to explore, and assess the evidence for, a range of possible true patterns of association across studies in a computationally efficient framework.
DEAH-box helicase 37 (DHX37) defects are a novel molecular etiology of 46,XY gonadal dysgenesis spectrum
Authors: Silva Thatiana E. da , Gomes Nathalia L. , Lerario Antonio M. , Keegan Catherine E. , Nishi Mirian Y. , Carvalho Filomena M. , Vilain Eric , Barseghyan Hayk , Martinez-Aguayo Alejandro , Forclaz María V. , Papazian Regina , Carvalho Luciani R. , Costa Elaine M. F. , Mendonca Berenice B. , Domenice Sorahia
Published: November 2018

46,XY gonadal dysgenesis is a heterogeneous disorder of sex development (DSD) that features abnormal gonadal development and varying degrees of undervirilization of the external genitalia, ranging from micropenis to female-like genitalia. Embryonic testicular regression syndrome (ETRS; MIM: 273250) is considered part of the clinical spectrum of 46,XY gonadal dysgenesis. Most ETRS patients present micropenis or atypical genitalia associated with a complete absence of gonadal tissue in one or both sides. In most patients with gonadal dysgenesis, the genetic diagnosis is unclear. We performed whole exome sequencing in ETRS patients and identified a rare variant, the p.Arg308Gln, in DEAH (Asp-Glu-Ala-His) box polypeptide 37 (DHX37) in 5 affected individuals from three unrelated families. We expanded the analysis of DHX37 coding region to additional 71 patients with 46,XY gonadal dysgenesis and identified the p.Arg308Gln and three other DHX37 missense variants (p.Arg151Trp, p.Thr304Met and p.Arg674Trp) in 11 affected members from eight distinct families (8 patients with ETRS, two with partial gonadal dysgenesis and one 46,XY DSD female patient previously gonadectomized). The p.Arg308Gln and p.Arg674Trp recurrent variants were identified in six and three families, respectively. Segregation analysis revealed sex-limited autosomal dominant inheritance in 4 families, autosomal dominant with incomplete penetrance in one family and autosomal recessive in another family. Immunohistochemical analysis of normal testes revealed that DHX37 is expressed in germ cells at different stages of maturation.

This study demonstrates an expressive frequency of rare predicted to be deleterious DHX37 variants in 46,XY gonadal dysgenesis group, particularly those individuals exhibiting the ETRS phenotype (25% and 50%, respectively).

Our findings indicate that DHX37 is a new player in the complex cascade of male gonadal differentiation and maintenance, thus establishing a novel and frequent molecular etiology for 46,XY gonadal dysgenesis spectrum, mainly for embryonic testicular regression syndrome.
Lack of detectable neoantigen depletion in the untreated cancer genome
Authors: Eynden Jimmy Van den , Jiménez-Sánchez Alejandro , Miller Martin L. , Larsson Erik
Published: November 2018

Somatic mutations in cancer can result in the presentation of mutated peptides on the cell surface, eliciting an immune response. Mutant peptides are presented via HLA molecules and are known as neoantigens. It has been suggested that selection acts against the underlying mutations, leading to neoantigen depletion. Knowing the extent of this specific form of immunoediting may provide fundamental insights into tumour-immune interactions during tumour evolution. Here, we quantified the extent of neoantigen depletion in a wide range of human cancers by studying somatic mutations in the HLA-binding annotated exome, i.e. genomic regions that can be translated into presented peptides. We initially observed reduced non-synonymous mutation rates in presented regions, suggestive of neoantigen depletion. However, when compared to the expected mutation rates from a trinucleotide-based mutational signature model, depletion signals were negligible. This is explained by correlative relationships between the likelihood of mutagenesis in different nucleotide sequences and predicted HLA affinities for corresponding peptides. Our results suggest that signals of immunogenic negative selection are weak or absent in cancer genomics data and that other mechanisms to escape immune responses early during tumour evolution might be more efficient.
TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells
Authors: Wu Bin , Blot Francois G.C. , Wong Aaron B. , Osório Catarina , Adolfs Youri , Pasterkamp R. Jeroen , Hartmann Jana , Becker Esther B. E. , Boele Henk-Jan , Zeeuw Chris I. De , Schonewille Martijn
Published: November 2018

Despite the canonical homogenous character of its organization, the cerebellum plays differential computational roles in distinct types of sensorimotor behaviors. However, the molecular and cell physiological underpinnings are unclear. Here we determined the contribution of transient receptor potential cation channel type C3 (TRPC3) to signal processing in different cerebellar modules. Using gain-of-function and loss-of-function mouse models, we found that TRPC3 controls the simple spike activity of zebrin-negative (Z–), but not of zebrin-positive (Z+), Purkinje cells. Moreover,in vivoTRPC3 also regulated complex spike firing and its interaction with simple spikes exclusively in Z– Purkinje cells. Finally, we found that eyeblink conditioning, related to Z– modules, but not compensatory eye movement adaptation, linked to Z+ modules, was affected in TRPC3 loss-of-function mice. Together, our results indicate that TRPC3 is essential for the cellular heterogeneity that introduces distinct physiological properties in an otherwise homogeneous population of Purkinje cells, conjuring functional heterogeneity in cerebellar sensorimotor integration.
Transcriptional heterogeneity in cancer-associated regulatory T cells is predictive of survival
Authors: Borcherding Nicholas , Ahmed Kawther K. , Voigt Andrew P. , Vishwakarma Ajaykumar , Kolb Ryan , Kluz Paige , Pandey Gaurav , Gibson-Corley Katherine N. , Klesney-Tait Julia , Zhu Yuwen , Lu Jinglu , Lu Jinsong , Huang Xian , Cheng Jinke , Zheng Song Guo , Wu Xuefeng , Zakharia Yousef , Zhang Weizhou
Published: November 2018

Regulatory T cells (Tregs) are a population of T cells that exert a suppressive effect on a variety of immune cells and non-immune cells. The suppressive effects of Tregs are detrimental to anti-tumor immunity. Recent investigations into cancer-associated Tregs have identified common expression patterns for tumor-infiltration, however the functional heterogeneity in tumor-infiltrating (TI) Treg is largely unknown. We performed single-cell sequencing on immune cells derived from renal clear cell carcinoma (ccRCC) patients, isolating 160 peripheral-blood (PB) Tregs and 574 TI Tregs. We identified distinct transcriptional TI Treg cell fates, with a suppressive subset expressing CD177. We demonstrate CD177+ TI-Tregs have preferential suppressive effects in vivo and ex vivo. Gene signatures derived the CD177+ Treg subset had superior ability to predict survival in ccRCC and seven other cancer types. Further investigation into the development and regulation of TI-Treg heterogeneity will be vital to the application of tumor immunotherapies that possess minimal side effects.
Development of the Brief Personal Values Inventory for sense of values in the Japanese general population
Authors: Ozawa Sachiyo , Iijima Yudai , Ando Shuntaro , Okada Naohiro , Kawashima Tomoko , Ohta Kazusa , Yamasaki Syudo , Kasai Kiyoto , Nishida Atsushi , Nakatani Hironori , Koike Shinsuke
Published: November 2018

The Portrait Values Questionnaire (PVQ) is a widely used questionnaire for assessing sense of values; however, it has limitations, especially for children. Therefore, the present study aims to develop a questionnaire for sense of values, called the Brief Personal Values Inventory (BPVI), consisting of simple questions and a smaller number of items compared to the PVQ. We first created 12 items for the BPVI and then tested their validity and reliability in 167 Japanese general population (81 males, mean age (SD) [range]: 23.4 (8.2) [15-57] years). Each of these items was correlated with one or more values in the PVQ-57. The BPVI items covered all higher-order values in Schwartz’s theory (Openness to Change, Self-Enhancement, Conservation, and Self-Transcendence). In sum, the BPVI has an acceptable criterion-related validity and corresponds to higher-order values in Schwartz’s value theory. The BPVI is suitable for a reliable and direct comparison of sense of values between children and adults, which may be useful for elucidating the developmental pathway of personal sense of values.
Homeostatic versus pathological functions of Dual Leucine Zipper Kinase in the adult mouse brain
Authors: Goodwani Sunil , Hamby Mary E , Buggia-Prevot Virginie , Acton Paul , Fernandez Celia , Al-Ouran Rami , Jiang Yongying , Soth Michael , Jones Philip , Ray William J.
Published: November 2018

Dual Leucine Zipper Kinase (DLK, Map3k12), is an injury-induced axonal protein that governs the balance between degeneration and regeneration through its downstream effectors c-jun N-terminal kinase (JNK) and phosphorylated c-jun (p-c-Jun). DLK is generally considered to be inactive in healthy neurons until induced by injury. However we report that DLK in the cerebellum appears constitutively active and drives nuclear p-c-Jun in cerebellar granule neurons in the absence of injury. In contrast the adult hippocampus expresses similar levels of apparently constitutively active DLK, but p-c-Jun is lower and does not accumulate in the nucleus. Injury is required there for p-c-jun nuclear expression, because in the rTg4510 model of tauopathy, where there is extensive hippocampal pathology, nuclear p-c-Jun is induced in a DLK-dependent manner. This context-specific regulation of DLK signaling could relate to availability of JNK scaffolding proteins, as the cerebellum preferentially expresses JNK-interacting protein-1 (JIP-1) whereas the hippocampus contains more JIP-3 and Plenty of SH3 (POSH). To understand how DLK signaling differs between the hippocampus and cerebellum, we selectively blocked DLK and measured changes in protein and mRNA expression. In the cerebellum, p-c-Jun levels correlated with synaptophysin, suggesting a link between DLK activity and synaptic maintenance. In rTg4510 mice, hippocampal p-c-Jun instead correlated with markers of neuronal injury and gliosis (Iba1 and GFAP). RNA sequencing revealed that in both brain regions DLK inhibition reduced expression of JNK/c-Jun pathway components and a novel set of co-regulated genes. In the cerebellum, Jun mRNA levels were co-regulated with genes mapping to metabolic pathways, while in the rTg4510 hippocampus, Jun-correlated mRNAs correspond primarily to neuroinflammation. These data suggest that in the uninjured cerebellum, DLK/p-c-Jun signaling is linked to synaptic regulation, but in the hippocampus, pathologically activated DLK/p-c-Jun signaling regulates genes associated with the injury response.