bluuebunny/crossref_metadata_2025 huggingface dataset:
Quadriceps Tendon-Bone or Patellar Tendon-Bone Autografts When Reconstructing the Anterior Cruciate Ligament: A Meta-analysis
Authors: Riaz Osman , Aqil Adeel , Mannan Ashim , Hossain Fahad , Ali Mubusher , Chakrabarty Gautam , Radcliffe Graham
Published: June 2017

Objective:

We aimed to quantitatively assess the outcomes of studies, comparing the use of Bone-patellar tendon-bone (BPTB) and the quadriceps tendon-bone (QTB) autografts when reconstructing the anterior cruciate ligament (ACL).

Data Sources:

MEDLINE, Embase, and CINAHL databases were searched for relevant articles published between January 1980 and January 2015 for the purpose of identifying studies comparing BPTB and QTB autografts for ACL reconstruction. Included studies were assessed regarding their methodological quality before analysis. Outcomes analyzed were graft failure rates, objective and subjective stability assessments, as well as the presence and severity of donor site morbidity.

Main Results:

Five studies contributed to the quantitative analysis of 806 patients with 452 patients included in the BPTB group and 354 patients in the QTB group. Graft failure rates were similar between the 2 groups [odds ratio (OR) = 0.61; confidence interval (CI) = 0.17-2.15; Z = 0.78, P = 0.44]. There were no significant differences between the 2 groups when testing anteroposterior stability using an arthrometer (standardized mean difference = 0.07; CI = −0.12-0.25; Z = 0.70, P = 0.48). At 1 year postoperatively, there was no difference in the percentage of patients with a positive pivot shift test between the 2 groups (OR = 1.0; CI = 0.85-1.18; Z = 0.01, P = 0.99). However, significantly less patients had graft site pain 1 year after surgery in the QTB group (OR = 0.10; CI = 0.02-0.43; Z = 3.12, P = 0.002). Similarly, fewer patients reported moderate to severe pain while kneeling, in the QTB group (OR = 0.16; CI = 0.07-0.37; Z = 4.26, P < 0.001).

Conclusions:

This study demonstrates comparable survival rates and joint stability when BPTB and QTB grafts are used. However, fewer adverse donor site symptoms are evident with QTB grafts.

Level of Evidence:

III.
Genetic risk in chronic pancreatitis: the misfolding-dependent pathway
Authors: Sahin-Tóth Miklós
Published: June 2017

Purpose of review

Genetic risk in chronic pancreatitis is partly due to mutations that cause misfolding of digestive enzymes and elicit endoplasmic reticulum stress. This review examines recent developments in this concept.

Recent findings

The best characterized misfolding variants in the highly expressed digestive proteases cationic trypsinogen (PRSS1) and carboxypeptidase A1 (CPA1) are strong, causative risk factors for chronic pancreatitis and may be associated with autosomal dominant hereditary pancreatitis.

Properties of misfolding digestive enzyme mutants indicate that endoplasmic reticulum stress is a highly relevant pathological mechanism and a potential therapeutic target in chronic pancreatitis.
Update on classification and diagnosis of vascular malformations
Authors: McCuaig Catherine C.
Published: June 2017

Purpose of review

This review provides an update of the classification in the classification of vascular anomalies since April 2014 at the International Society for the Study of Vascular Anomalies meeting in Melbourne, Australia.

Recent findings

The reader will become familiar with how to diagnose the major vascular malformations, including capillary, venous, arteriovenous, and lymphatic and combinations thereof. In addition, vascular malformation syndromes, including those with overgrowth, will be clarified.

Vascular malformations are common. Capillary malformations are now better understood through an updated classification. Verrucous hemangioma is truly a venulocapillary malformation that extends into the subcutis.PIK3Ca-Related Overgrowth Syndromes encompass Klippel–Trenaunay, Congenital Lipomatous Asymmetric Overgrowth of the Trunk with Lymphatic, Capillary, Venous, and Combined-Type Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal Anomalies, Megalencephaly–Capillary Malformation–Polymicrogyria Syndrome (M-CAP), fibroadipose hyperplasia, and macrodactyly. Yet another syndrome should be highlighted: Capillary Malformation of the Lower Lip, Lymphatic Malformation of the Face and Neck, Asymmetry and Partial/Generalized Overgrowth. Knowledge of the genetic basis of vascular malformations will lead to future treatments.
Regenerative Rehabilitation: Combining Stem Cell Therapies and Activity-Dependent Stimulation
Authors: Moritz Chet T. , Ambrosio Fabrisia
Published: June 2017

The number of clinical trials in regenerative medicine is burgeoning, and stem cell/tissue engineering technologies hold the possibility of becoming the standard of care for a multitude of diseases and injuries. Advances in regenerative biology reveal novel molecular and cellular targets, with potential to optimize tissue healing and functional recovery, thereby refining rehabilitation clinical practice. The purpose of this review is to (1) highlight the potential for synergy between the fields of regenerative medicine and rehabilitation, a convergence of disciplines known as regenerative rehabilitation; (2) provide translational examples of regenerative rehabilitation within the context of neuromuscular injuries and diseases; and (3) offer recommendations for ways to leverage activity dependence via combined therapy and technology, with the goal of enhancing long-term recovery. The potential clinical benefits of regenerative rehabilitation will likely become a critical aspect in the standard of care for many neurological and musculoskeletal disorders.
Knowledge Translation in Rehabilitation: A Shared Vision
Authors: Moore Jennifer L. , Shikako-Thomas Keiko , Backus Deborah
Published: June 2017

Purpose:

Advances in rehabilitation provide the infrastructure for research and clinical data to improve care and patient outcomes. However, gaps between research and practice are prevalent. Knowledge translation (KT) aims to decrease the gap between research and its clinical use. This special communication summarizes KT-related proceedings from the 2016 IV STEP conference, describes current KT in rehabilitation science, and provides suggestions for its application in clinical care.

Summary of Key Points:

We propose a vision for rehabilitation clinical practice and research that includes the development, adaptation, and implementation of evidence-based practice recommendations, which will contribute to a learning health care system. A clinical research culture that supports this vision and methods to engage key stakeholders to innovate rehabilitation science and practice are described.

Conclusions:

Through implementation of this vision, we can lead an evolution in rehabilitation practice to ultimately prevent disabilities, predict better outcomes, exploit plasticity, and promote participation.
Goal Attainment Scaling to Evaluate Intervention on Individual Gains for Children Born Extremely Preterm
Authors: Brown Laura , Burns Yvonne R. , Watter Pauline , Gray Peter H.
Published: June 2017

Purpose:

To investigate the effect of group-based physical therapy on individual gains among preterm and/or extremely low-birth-weight children with minimal or mild impairment at 4 years using Goal Attainment Scaling (GAS). To explore the relationship between GAS with motor and postural outcomes and effect of gender on GAS scores.

Methods:

Twenty-four 4-year-old children (born <28 weeks' gestation and/or birth weight <1000 g) with minimal or mild motor impairment completed 6 group-based weekly intervention sessions and a goal-based home program. Assessments included GAS, Movement Assessment Battery for Children-Second Edition (MABC-2), postural stability, and limb strength after intervention.

Results:

GAS group T score improved, exceeding expected goal of “0” score after intervention (mean = 58.2, standard deviation = 0.82). GAS mean T-score and MABC-2 percentile were moderately correlated (r = 0.42, P = .04). Females improved more than males (P = .05).

Conclusions:

Goals were achieved above expected level after intervention and were related to motor coordination. Male gender is a risk factor for less favorable outcomes.
A Home-Based Body Weight-Supported Treadmill Program for Children With Cerebral Palsy: A Pilot Study
Authors: Visser Allie , Westman Marci , Otieno Sango , Kenyon Lisa
Published: June 2017

Purpose:

The purpose of this pilot study was to explore the effect and feasibility of a home-based body weight-supported treadmill training (BWSTT) program on walking capacity and functional mobility in children with cerebral palsy (CP).

Methods:

A within-subjects, repeated-measures design was used. Ten children with CP ages 6 to 16 years participated in pre- and postintervention testing sessions, an initial home training session, and a 12-week home-based BWSTT program conducted 3 to 4 times per week by a parent or caregiver for up to 20 minutes each session. Multiple outcome measures for walking capacity and functional mobility were used.

Results:

As a group, participants demonstrated significant improvements in walking capacity and functional mobility at the completion the 12-week intervention program.

Conclusions:

Additional research regarding home-based BWSTT programs in children with CP is warranted and should focus on identifying specific parameters that promote achievement of optimal functional outcomes.
Stepping Up to Rethink the Future of Rehabilitation: IV STEP Considerations and Inspirations
Authors: Kimberley Teresa Jacobson , Novak Iona , Boyd Lara , Fowler Eileen , Larsen Deborah
Published: June 2017

Background and Purpose:

The IV STEP conference challenged presenters and participants to consider the state of science in rehabilitation, highlighting key area of progress since the previous STEP conference related to prediction, prevention, plasticity, and participation in rehabilitation.

Key Points:

Emerging from the thought-provoking discussions was recognition of the progress we have made as a profession and a call for future growth. In this summary article, we present a recap of the key points and call for action. We review the information presented and the field at large as it relates to the 4 Ps: prediction, prevention, plasticity, and participation.

Recommendations for Practice:

Given that personalized medicine is an increasingly important approach that was clearly woven throughout the IV STEP presentations, we took the liberty of adding a fifth “P,” Personalized, in our discussion of the future direction of the profession.
Physical Exercise and Physical Activity for Children and Adolescents With Juvenile Idiopathic Arthritis: A Literature Review
Authors: Catania Hilenia , Fortini Viola , Cimaz Rolando
Published: June 2017

Purpose:

This is a review of studies that investigate the efficacy of exercise therapy and physical activity for children with juvenile idiopathic arthritis since the 2008 Cochrane Review.

Method:

Studies were identified that investigated the use of physical activity and exercise therapy in the treatment of children and adolescents with juvenile idiopathic arthritis, excluding the Cochrane Review. Two reviewers individually analyzed the results of the search to determine the eligibility of studies. The randomized controlled trial study designs were evaluated using PEDro scales.

Conclusions and Recommendations for Clinical Practice:

Recent literature supports the importance of the combination of strengthening, stretching, proprioceptive, and balance exercises and activities in water. Many of the reviewed studies proposed an intensive program of physical activity and exercise therapy, conducted 3 times a week for 12 weeks.
Whole Blood Redox Potential Correlates With Progressive Accumulation of Oxygen Debt and Acts as A Marker of Resuscitation in A Swine Hemorrhagic Shock Model
Authors: Daniels Rodney C. , Jun Hyesun , Tiba Hakam , McCracken Brendan , Herrera-Fierro Pilar , Collinson Maryanne , Ward Kevin R.
Published: June 2017

Introduction:

Oxidation-reduction reactions involve electron exchanges that require optimal balance for proper cell function. This balance is measured via redox potential and reflects oxidative stress. Despite the critical role of oxidative stress in critical illness and injury, little is known regarding redox potential. We hypothesize redox potential measurements will correlate with accumulation of O2 debt produced by hemorrhage over time.

Methods:

Ten swine were studied using a polytrauma hemorrhagic shock model. Whole blood and plasma redox potential measures were obtained at defined stages of O2 debt (20 mL/kg, 40 mL/kg, 60 mL/kg, 80 mL/kg), and through resuscitation. Redox potential was determined by measuring open circuit potential using novel gold nanoporous electrodes with Ag/AgCl reference.

Results:

Whole blood redox potential showed negative change as O2 debt accumulated, exhibiting positive response during resuscitation, and correlated with O2 debt across all animals (P < 0.001). Redox potential changes throughout O2 debt accrual were significant compared with baseline (P≤0.05), and at end resuscitation compared with O2 debt 60 mL/kg (P = 0.05) and 80 mL/kg (P = 0.02). Whole blood redox potential measures also correlated with oxygen extraction ratio, ScvO2, and lactic acid, appearing very sensitive to acute changes. Plasma redox potential showed no correlation with O2 debt.

Conclusions:

Whole blood redox potential demonstrates significant correlation to O2 debt at all stages in this model. These results set the stage for further study of redox potential as a direct measure of oxidative stress and potential clinical tool. Given redox potential plasma performance, these measures should be made in whole blood versus plasma.
Caring for Older Surgical Patients
Authors: Chesney Tyler R. , Pang George , Ahmed Najma
Published: June 2017

Objective:

To gain contemporary insights from residents and surgeons regarding the care of older surgical patients.

Background Data:

With worldwide aging, efforts over the past decade have attempted to increase surgeons’ abilities to care for older adults, but a current understanding of attitudes, knowledge, practices, and needs is missing.

Methods:

Between July 2016 and September 2016 we conducted a national Web-based survey sampling all general surgery residents and academic general surgeons using a questionnaire designed and tested for this purpose. Summative scales within each domain (attitudes, knowledge, practices, and needs) were created and compared between groups. Open-ended responses were analyzed with thematic analysis.

Results:

Ninety-four of 172 invited residents (55%) and 80 of 243 invited surgeons (33%) across 14 general surgery programs responded with no missing data. Both groups had favorable attitudes (83% vs 68%, P = 0.02). However, 80% of residents and 76% of surgeons had medium-level knowledge test scores, and few had prior training. Most respondents reported only sometimes performing guideline-recommended practices (71% vs 73%, P = 0.55). Gaps in training and care delivery were identified. Residents wanted focused, high-yield materials and case-oriented practical skills training. Respondents reported further improvements may come from building surgeons’ capacity, enhancing collaboration including perioperative geriatric services, better preoperative assessment, increased adherence to perioperative guidelines, and greater community-based supports to recovery.

Conclusions:

Residents and surgeons have favorable attitudes, but only moderate geriatric-specific knowledge and only some guideline-adherent practices. We identified gaps in training and care delivery with targets for future knowledge translation and quality improvement initiatives.
Effect of Sleeve Gastrectomy on Thyroid Function in Chinese Euthyroid Obese Patients
Authors: Yang Jingge , Gao Zhiguang , Yang Wah , Zhou Xiangmao , Lee Shing , Wang Cunchuan
Published: June 2017

Background:

Changes in thyroid function following bariatric surgery in euthyroid obese patients have yielded inconsistent results. Nevertheless, no data exist on changes in thyroid function after bariatric surgery in Chinese obese subjects.

Objectives:

The objective of this study is to evaluate the influence of weight reduction on thyroid function following laparoscopic sleeve gastrectomy (LSG) in patients with normal thyroid function.

Patients and Methods:

Serum free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) levels were retrospectively analyzed before and 12 months after LSG in euthyroid patients with morbid obesity. Correlation between weight loss after LSG and changes in thyroid function were investigated.

Results:

In total, 16 patients who underwent LSG were included in the study. Mean BMI change from 35.78 to 23.66 kg/m2 (P<0.000) after LSG was associated with a mean reduction in the TSH from 2.31 to 1.54 mU/L (P=0.022), whereas FT4 (15.19±0.33 pmol/L at baseline and 14.85±0.58 pmol/L at 12 mo after LSG; P=0.583) and FT3 (4.98±0.15 pmol/L at baseline and 4.77±0.60 pmol/L at 12 mo after surgery; P=0.406) levels remained steady. Decrease in TSH was significantly correlated with decrease in BMI at 12 months after surgery but did not correlate with excess weight loss and total weight loss.

Conclusions:

Weight loss after LSG is accompanied by significant decrease in serum TSH level but no change in serum FT4 and FT3 levels. However, further work is required to elucidate the mechanism.
Ready or Not? Obstetrics and Gynecology Resident Preparedness for Female Pelvic Medicine and Reconstructive Surgery Training
Authors: Dune Tanaka J. , Blackwell Robert H. , Griffin Arianna , Taege Susanne , Sung Juliana , Mueller Elizabeth R. , Brubaker Linda
Published: June 2017

Objective

The aim of this study was to assess the perception of female pelvic medicine and reconstructive surgery (FPMRS) program directors (PDs) and obstetrics and gynecology (OG) FMPRS fellows regarding the adequacy of OG residency as preparation for FPMRS fellowship.

Methods

Electronic invitations to complete a modified version of a validated survey were extended to FPMRS PDs and their second- and third-year OG FPMRS fellows who had just completed their first or second year of FPMRS fellowship, respectively. The survey consisted of 5 domains; qualitative questions and recommendations for improvement were elicited.

Results

Program directors (33%, 16/48) and second-year (64%, 29/45) and third-year (53%, 26/49) fellows completed the surveys. While incoming fellows were deemed professional, serious surgical skill competency issues were identified: (1) PDs felt they could not leave their incoming fellow to operate independently on a major case for 30 minutes while in the next room compared with fellow responses (PDs: 33.3% vs second-year fellows: 67.9%; P = 0.03); (2) no PDs felt their fellows could suture laparoscopically; and (3) there was group consensus that incoming fellows were not proficient at cystoscopy (PDs: 40.0%, second-year fellows: 39.3%, third-year fellows: 32.0%; P = 0.82). Mostly, fellows could clinically evaluate and manage patients. Program directors thought their fellows had better understanding of statistics than fellows believed of themselves (P = 0.05). Increasing FPMRS exposure during residency was favored as the method to better prepare OG residents for fellowship.

Conclusions

Quantitative and emerging qualitative outcomes highlight that fellows are professional and are largely able to evaluate and care for patients but that achieving independence, surgical skills, and scholarship requires further training.
Pudendal Neuromodulation as a Treatment for Persistent Genital Arousal Disorder—A Case Series
Authors: Gaines Natalie , Odom Brian D. , Killinger Kim A. , Peters Kenneth M.
Published: June 2017

Background

Persistent genital arousal disorder (PGAD) is a rare life-altering condition characterized by unwanted, uncomfortable genital sensations or spontaneous orgasms without physical or emotional stimulation. Its etiology remains unclear, and a variety of treatments have been attempted with incomplete resolution. We propose that chronic pudendal neuromodulation (CPN) may be a useful treatment for PGAD symptoms.

Methods

A retrospective chart review was performed for women older than 18 years with a diagnosis of PGAD that had staged neuromodulation with placement of a tined lead at the pudendal nerve. Demographic, operative, and postoperative data were collected. A survey was then sent to these women to assess additional demographic data, preoperative and postoperative symptoms, and patient satisfaction. Descriptive statistics were performed.

Results

Six women underwent CPN for PGAD. Mean age was 52 (SD, 9) years. Five (83%) of 6 were still implanted at time of survey, at a mean of 38 months after implantation; 1 device was removed for nonuse. Four of 6 completed surveys and were still using their device. Three of 4 had met their treatment goals and were satisfied with CPN; 3 of 4 felt CPN was the most useful treatment modality they had used overall. Chronic pudendal neuromodulation also improved chronic pelvic pain (4/4), bowel function (3/4), and bladder function (3/4).

Conclusions

Chronic pudendal neuromodulation can be an effective treatment for decreasing frequency of PGAD symptoms and providing symptom relief.
Women's Perception of Their Vulvar Appearance in a Predominantly Low-Income, Minority Population
Authors: Truong Christina , Amaya Stephanie , Yazdany Tajnoos
Published: June 2017

Objectives

The aim of this study was to investigate the effect of certain predictors, such as age and media exposure, on a woman's perception of her vulva anatomy.

Methods

We recruited 346 female visitors from a county teaching hospital to complete questionnaires that determine the following: demographics, satisfaction with their vulvar appearance, whether they consider their vulvar anatomy to be normal, exposure to media (namely having had Internet access or learned about genitalia from the Internet or any type of pornography), and consideration of cosmetic vulvar surgery for themselves. The participants were divided into 2 age groups; group I (45 years or older) and group II (18–44 years). Personal satisfaction, self-perceived normality, and one's consideration of cosmetic vulvar surgery were then compared between the 2 groups.

Results

A large percentage of women considered their vulva to be “normal,” 93.1% of group I versus 96.0% of group II (P = 0.24). For group I, 87.5% were satisfied with their vulva versus 91.5% of group II (P = 0.24). The participants with media exposure report self-perceived normal-appearing vulvas at higher rates than those not exposed to media (96.7% vs 90.8%, respectively; P = 0.03). Of those who were satisfied with their vulvar appearance, 92.3% were exposed to media, whereas 84.5% were not exposed (P = 0.03). However, of the participants who reported consideration of vulvar surgery, 74.4% of them had exposure to media, whereas 25.6% had no media exposure (P = 0.034).

Conclusions

Age does not play a significant role in determining a woman's acceptance of the appearance of her vulvar anatomy. However, media exposure was a significant determinant for self-perception, satisfaction, and desire for cosmetic vulvar surgery.
Long-Term Outcomes After Ventral Rectopexy With Sacrocolpo- or Hysteropexy for the Treatment of Concurrent Rectal and Pelvic Organ Prolapse
Authors: Jallad Karl , Ridgeway Beri , Paraiso Marie Fidela R. , Gurland Brooke , Unger Cecile A.
Published: June 2017

Objective

The primary objective is to describe the long-term anatomic and subjective outcomes in women undergoing ventral rectopexy with sacrocolpo- or hysteropexy. The secondary objective is to describe the perioperative adverse events.

Methods

This is a retrospective cohort of women who underwent ventral rectopexy with either concurrent sacrocolpo- or hysteropexy at a tertiary care center between 2009 and 2015. A composite outcome for recurrent pelvic organ prolapse and rectal prolapse was defined as subjective failure (vaginal or rectal prolapse symptoms), objective failure (prolapse to or beyond the hymen or full thickness rectal prolapse), or any retreatment for prolapse. Patient's Global Impression of Change was recorded at baseline and at all follow-up visits. Perioperative adverse events were defined a priori and collected up to 6 weeks after surgery.

Result

A total of 59 patients underwent a ventral rectopexy, either a sacrocolpopexy (48/59, 81.3%) or sacrohysteropexy (11/59, 18.6%). The median follow-up after surgery for all patients was 17 months (range, 1–76) with a composite success rate for both pelvic organ prolapse and rectal prolapse (estimated by Kaplan-Meier method) of 57.4%. Forty (91%) of 44 patients reported a Patient's Global Impression of Change score of 6 or 7, indicating significant improvement after surgery. Of the patients, 15 (25.4%) experienced a perioperative adverse event. Use of biologic graft was associated with a higher rate of adverse event (40.0% [95% confidence interval, 24.6–57.5] vs 10.3% [95% confidence interval, 3.6–26.3]; P < 0.01).

Conclusions

Ventral rectopexy with sacrocolpo- or hysteropexy is associated with significant improvement in anatomic and subjective outcomes. One in 4 women experienced a perioperative adverse event.
Trends and Clinical Practice Patterns of Sacral Neuromodulation for Overactive Bladder
Authors: Elterman Dean S. , Chughtai Bilal , Vertosick Emily , Thomas Dominique , Eastham James , Sandhu Jaspreet
Published: June 2017

Objectives

The aim of this study was to investigate surgical practice patterns of American urologists treating refractory overactive bladder (OAB) over the past decade. Refractory OAB remains a management challenge to urologists. When multiple medical therapies have failed, treatment options may include sacral neuromodulation (SNM) or surgery such as augmentation cystoplasty (AC).

Methods

Data on SNM and AC performed between 2003 and 2012 by certifying and recertifying urologists were obtained in the form of annualized case logs from the American Board of Urology (ABU). Associations between surgeon characteristics (type of certification, annual volume, practice type, and location) and these procedures were evaluated.

Results

Over the past decade, 756 of 6355 urologists certified with the ABU performed SNM or AC for the treatment of refractory OAB. Forty-five (6%) of these surgeons completed fellowships in female urology and 71 surgeons (9%) completed another type of fellowship program. Surgeons recertifying with ABU performed 76% of all SNM procedures. Although SNM and AC have increased from 64 to 2086 between 2003 and 2012, however, this is mainly driven by the increase of SNM from 48 to 2068 cases. Rates of AC have remained stable with 14 to 38 cases reported annually. However, they have declined relative to the total, from 25% in 2003 to less than 1% in 2012.

Conclusions

Sacral neuromodulation has increased dramatically over the past decade in surgeons certified with the ABU. This is in contrast to AC, which while remaining stable in number of procedures.
Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases
Authors: Muller Mandy , Glaunsinger Britt A.
Published: June 2017

During lytic Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, the viral endonu-clease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3’ UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.

AUTHOR SUMMARY

The ability of viruses to control the host gene expression environment is crucial to promote viral infection. Many viruses express factors that reduce host gene expression through widespread mRNA decay. However, some mRNAs escape this fate, like the transcript encoding the immunoregulatory cytokine IL-6 during KSHV infection. IL-6 escape relies on an RNA regulatory element located in its 3’UTR and involves the recruitment of a protective protein complex. Here, we show that this escape extends beyond KSHV to a variety of related and unrelated viral endonucleases. However, the IL-6 element does not protect against cellular endonucleases, revealing for the first time a virus-specific nuclease escape element. We identified a related escape element in the GADD45B mRNA, which displays several similarities with the IL-6 element. However, these elements assemble a largely distinct complex of proteins, leading to differences in the breadth of their protective capacity. Collectively, these findings reveal how a putative new class of RNA elements function to control RNA fate in the background of widespread mRNA degradation by viral endonucleases.
Chromatin accessibility dynamics of myogenesis at single cell resolution
Authors: Pliner Hannah A. , Packer Jonathan , McFaline-Figueroa José L. , Cusanovich Darren A. , Daza Riza , Srivatsan Sanjay , Qiu Xiaojie , Jackson Dana , Minkina Anna , Adey Andrew , Steemers Frank J. , Shendure Jay , Trapnell Cole
Published: June 2017

Over a million DNA regulatory elements have been cataloged in the human genome, but linking these elements to the genes that they regulate remains challenging. We introduce Cicero, a statistical method that connects regulatory elements to target genes using single cell chromatin accessibility data. We apply Cicero to investigate how thousands of dynamically accessible elements orchestrate gene regulation in differentiating myoblasts. Groups of co-accessible regulatory elements linked by Cicero meet criteria of “chromatin hubs”, in that they are physically proximal, interact with a common set of transcription factors, and undergo coordinated changes in histone marks that are predictive of gene expression. Pseudotemporal analysis revealed a subset of elements bound by MYOD in myoblasts that exhibit early opening, potentially serving as the initial sites of recruitment of chromatin remodeling and histone-modifying enzymes. The methodological framework described here constitutes a powerful new approach for elucidating the architecture, grammar and mechanisms ofcis-regulation on a genome-wide basis.
Wakefulness fluctuations elicit behavioural and neural reconfiguration of awareness
Authors: Noreika Valdas , Canales-Johnson Andrés , Johnson Amy , Arnatkevičiūtė Aurina , Koh Justin , Chennu Srivas , Bekinschtein Tristan A.
Published: June 2017

Mapping the reports of awareness and its neural underpinnings is instrumental to understand the limits of human perception. The capacity to become aware of objects in the world may be studied by suppressing faint target stimuli with strong masking stimuli, or – alternatively – by manipulating the level of wakefulness from full alertness to mild drowsiness. By combining these two approaches, we studied how perceptual awareness is modulated by decreasing wakefulness. We found dynamic changes in behavioural and neural signatures of conscious access in humans between awake and drowsy states. Behaviourally, we show a decrease in the steepness of the psychophysical function for conscious access in drowsy trials. Neural mapping showed delayed processing of target-mask interaction as the consciousness transition progressed, suggesting that the brain resolution of conscious access shifts from early sensory/perceptual to decision-making stages of processing. Once the goal to report the awareness of a target is set, the system behaviourally adapts to rapid changes in wakefulness, revealing the flexibility of the neural signatures of conscious access, and its suppression, to maintain performance.

Significance statement

Maintaining full alertness for long periods of time in attentionally demanding situations is challenging and may lead to a decrease in performance. We show the effect of wakefulness fluctuations on behaviour and brain dynamics that humans use to maintain performance. We reveal the neural strategies we have to cope with drowsiness by shifting the weights to more flexible brain processes and relaxing the precision of the decisions we take.
Modelling of the Cardiopulmonary Responses to Maximal Aerobic Exercise in Patients with Cystic Fibrosis
Authors: Williams Craig A. , Wedgwood Kyle C. A. , Mohammadi Hossein , Tomlinson Owen W. , Tsaneva-Atanasova Krasimira
Published: June 2017

Cystic fibrosis (CF) is a debilitating chronic condition, which requires complex and expensive disease management. Exercise has now been recognised as a critical factor in improving health and quality of life in patients with CF. Hence, cardiopulmonary exercise testing (CPET) is used to determine aerobic fitness of young patients as part of the clinical management of CF. However, at present there is a lack of conclusive evidence for one limiting system of aerobic fitness for CF patients at an individual patient level.

Here, we perform detailed data analysis that allows us to identify important systems-level factors that affect aerobic fitness. We use patients’ data and principal component analysis to confirm the dependence of CPET performance on variables associated with ventilation and metabolic rates of oxygen consumption. We find that the time at which participants cross the anaerobic threshold (AT) is well correlated with their overall performance. Furthermore, we propose a predictive modelling framework that captures the relationship between ventilatory dynamics, lung capacity and function and performance in CPET within a group of children and adolescents with CF. Specifically, we show that using Gaussian processes (GP) we can predict AT at the individual patient level with reasonable accuracy given the small sample size of the available group of patients. We conclude by presenting future perspectives for improving and extending the proposed framework.

Our modelling and analysis have the potential to pave the way to designing personalised exercise programmes that are tailored to specific individual needs relative to patient’s treatment therapies.
Metabarcoding for the parallel identification of several hundred predators and their preys: application to bat species diet analysis
Authors: Galan Maxime , Pons Jean-Baptiste , Tournayre Orianne , Pierre Éric , Leuchtmann Maxime , Pontier Dominique , Charbonnel Nathalie
Published: June 2017

Assessing diet variability is of main importance to better understand the biology of bats and design conservation strategies. Although the advent of metabarcoding has facilitated such analyses, this approach does not come without challenges. Biases may occur throughout the whole experiment, from fieldwork to biostatistics, resulting in the detection of false negatives, false positives or low taxonomic resolution. We detail a rigorous metabarcoding approach based on a short COI minibarcode and two-step PCR protocol enabling the ‘all at once’ taxonomic identification of bats and their arthropod preys for several hundreds of samples. Our study includes faecal pellets collected in France from 357 bats representing 16 species, as well as insect mock communities that mimic bat meals of known composition, negative and positive controls. All samples were analysed using three replicates. We compare the efficiency of DNA extraction methods and we evaluate the effectiveness of our protocol using identification success, taxonomic resolution, sensitivity, and amplification biases. Our parallel identification strategy of predators and preys reduces the risk of mis-assigning preys to wrong predators and decreases the number of molecular steps. Controls and replicates enable to filter the data and limit the risk of false positives, hence guaranteeing high confidence results for both prey occurrence and bat species identification. We validate 551 COI variants from arthropod including 18 orders, 117 family, 282 genus and 290 species. Our method therefore provides a rapid, resolutive and cost-effective screening tool for addressing evolutionary ecological issues or developing ‘chirosurveillance’ and conservation strategies.
The genetic basis and evolution of red blood cell sickling in deer
Authors: Esin Alexander , Therese Bergendahl L. , Savolainen Vincent , Marsh Joseph A. , Warnecke Tobias
Published: June 2017

Crescent-shaped red blood cells, the hallmark of sickle cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown, limiting the utility of deer as comparative models for sickling. Here, we determine the sequences of human β-globin orthologs in 15 deer species and identify a set of co-evolving, structurally related residues that distinguish sickling from non-sickling deer. Protein structural modelling indicates a sickling mechanism distinct from human sickle cell disease, coordinated by a derived valine (E22V) in the second alpha helix of the β-globin protein. The evolutionary history of deer β-globins is characterized by incomplete lineage sorting, episodes of gene conversion between adult and foetal β-globin paralogs, and the presence of a trans-species polymorphism that is best explained by long-term balancing selection, suggesting that sickling in deer is adaptive. Our results reveal structural and evolutionary parallels and differences in erythrocyte sickling between human and deer, with implications for understanding the ecological regimes and molecular architectures that favour the evolution of this dramatic change in erythrocyte shape.
A zebrafish model of developmental joint dysplasia: Manipulating the larval mechanical environment to drive the malformation and recovery of joint shape
Authors: Roddy Karen A , Skinner Roddy EH , Brunt Lucy H , Kague Erika , Cross Stephen , Rayfield Emily J , Hammond Chrissy L
Published: June 2017

Developmental dysplasia of the hip (DDH), a malformation of the acetabulum, is a frequent cause of early onset osteoarthritis. The disease encompasses a spectrum of severities, some of which are more amenable to treatment. Embryonic immobilisation significantly impairs the development of joint shape however the impact of this malformation to the function and growth of the joint in the short to medium term is unclear. We developed a novel model of developmental joint dysplasia using the zebrafish jaw joint to identify the mechanisms regulating cellular plasticity and ability to recover joint shape and function. Larval zebrafish were immobilised either pharmacologically or using targeted ablation of jaw muscles to induce an altered joint shape. Following restoration of muscle activity we dynamically monitored the joint shape and function in individuals at cellular resolution impossible in other vertebrate species. Reflecting the variability of the human condition we found a proportion of joints will recover both their shape and function, while others will not; despite coming from a genetically homogenous population. This allowed us to study what controls likelihood of recovery; we identified a number of cellular changes that predict likelihood of functional recovery, including position of precursor cells, and specific patterns of proliferation, migration and differentiation in joints and associated connective tissues. These factors together predict recovery better than severity of malformation alone. Using Finite Element Analysis we studied the mechanics of joints representative of ones that recover and those that fail to identify differences in patterns of strain that could explain the cellular behaviours that underpin likelihood of recovery. Thus, this model would enable the study of the short to long term impact of altered joint shape on function and could help to identify the changes that render an individual more receptive to treatment and therefore may potentially be indicative of long term joint health.
Combined social and spatial coding in a descending projection from the prefrontal cortex
Authors: Murugan M. , Park M. , Taliaferro J. , Jang H.J. , Cox J. , Parker N.F. , Bhave V. , Nectow A. , Pillow J.W. , Witten I.B.
Published: June 2017

Social interactions are crucial to the survival and well-being of all mammals, including humans. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant, nor how they contribute. We found that the PL contains anatomically and molecularly distinct subpopulations of neurons that target 3 downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), the amygdala, and the ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased preference for a social target, suggesting an unique contribution of this population to social behavior. To determine what information PL-NAc neurons convey, we recorded selectively from them, and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially-specific inhibition of these neurons prevented the formation of a social-spatial association at the inhibited location. In contrast, spatially nonspecific inhibition did not affect social behavior. Thus, the unexpected combination of social and spatial information within the PL-NAc population appears to support socially motivated behavior by enabling the formation of social-spatial associations.
Fluidic microactuation of flexible electrodes for neural recording
Authors: Vitale Flavia , Vercosa Daniel G. , Rodriguez Alexander V. , Pamulapati Sushma Sri , Seibt Frederik , Lewis Eric , Yan J. Stephen , Badhiwala Krishna , Adnan Mohammed , Royer-Carfagni Gianni , Beierlein Michael , Kemere Caleb , Pasquali Matteo , Robinson Jacob T.
Published: June 2017

Ultra-flexible microelectrodes that can bend and flex with the natural movement of the brain reduce the inflammatory response and improve the stability of long-term neural recordings.1-5However, current methods to implant these highly flexible electrodes rely on temporary stiffening agents that increase the electrode size6-10thus aggravating neural damage during implantation, which leads to cell loss and glial activation that persists even after the stiffening agents are removed or dissolve.11-13A method to deliver thin, ultra-flexible electrodes deep into neural tissue without increasing the stiffness or size of the electrodes will enable minimally invasive electrical recordings from within the brain. Here we show that specially designed microfluidic devices can apply a tension force to ultra-flexible electrodes that prevents buckling without increasing the thickness or stiffness of the electrode during implantation. Additionally, these “fluidic microdrives” allow us to precisely actuate the electrode position with micron-scale accuracy. To demonstrate the efficacy of our fluidic microdrives, we used them to actuate highly flexible carbon nanotube fiber (CNTf) microelectrodes11,14for electrophysiology. We used this approach in three proof-of-concept experiments. First, we recorded compound action potentials in a soft model organism, the small cnidarianHydra. Second, we targeted electrodes precisely to the thalamic reticular nucleus in brain slices and recorded spontaneous and optogenetically-evoked extracellular action potentials. Finally, we inserted electrodes more than 4 mm deep into the brain of rats and detected spontaneous individual unit activity in both cortical and subcortical regions. Compared to syringe injection, fluidic microdrives do not penetrate the brain and prevent changes in intracranial pressure by diverting fluid away from the injection site during insertion and actuation. Overall, the fluidic microdrive technology provides a robust new method to implant and actuate ultra-flexible neural electrodes.
Delineating the macroscale areal organization of the macaque cortex in vivo
Authors: Xu Ting , Falchier Arnaud , Sullivan Elinor L. , Linn Gary , Ramirez Julian , Ross Deborah , Feczko Eric , Opitz Alexander , Bagley Jennifer , Sturgeon Darrick , Earl Eric , Miranda-Domínguez Oscar , Perrone Anders , Craddock R. Cameron , Schroeder Charles , Colcombe Stan , Fair Damien , Milham Michael P.
Published: June 2017

Complementing longstanding traditions centered around histology, fMRI approaches are rapidly maturing in delineating brain areal organization at the macroscale. The non-human primate (NHP) provides the opportunity to overcome critical barriers in translational research. Here, we establish the data and scanning conditions for achieving reproducible, stable and internally valid areal parcellations in individuals. We demonstrate that these functional boundaries serve as a functional fingerprint of the individual animals, and can be achieved under anesthesia or awake conditions (rest, naturalistic viewing), though differences between awake and anesthetized states precluded the detection of individual differences across states. Comparison of awake and anesthetized states suggested a more nuanced picture of changes in connectivity for higher order association areas, as well as visual and motor cortex. These results establish feasibility and data requirements for the generation of reproducible individual-specific parcellations in NHP, as well as provide insights into the impact of scan state and motivate efforts toward harmonizing protocols.