bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and cumulative incidence of cancer, and mortality in patients with Takotsubo syndrome with focus on the index event
Authors: Tornvall P , Collste O , Pettersson H
Published: July 2019

Background

It has been suggested that Takotsubo syndrome (TS) is associated with cancer but previous studies have limitations.

Aim

To make a comprehensive analysis of prevalence and cumulative incidence of cancer, and mortality among TS patients with focus on the index event.

Design

A register-based case–control study.

Methods

The first new cancer occurrences (International Classification of Diseases C00–C75, C81–C96) were compared between 505 patients with TS without obstructive coronary artery disease (CAD) and four age- and gender-matched controls comprising patients with acute coronary syndrome with obstructive CAD (CAD controls), respectively, with chest-pain without obstructive CAD at coronary angiography (controls without CAD).

Results

The prevalence of cancer before the index event was non-significantly (P = 0.052) higher in TS patients (15.8%) than in CAD controls (11.5%), respectively, higher (P = 0.028) than in controls without CAD (11.1%). There were no differences between the groups in cumulative incidence of cancer after the index event but a higher mortality in TS patients who developed cancer when compared with controls without CAD that developed cancer after the index event (P = 0.018).

Conclusions

There is an increased prevalence of first diagnosed cancer in TS patients before the index event but no increased cumulative incidence of cancer after the index event. The results does not support investigation for the possibility of a malignancy specifically in TS patients but in the event of cancer this patient group might need special care. However, if there is lack of a clear stressor it could be of importance to investigate the possibility of a malignancy.
Clinical course of acute deep vein thrombosis of the legs in Behçet’s syndrome
Authors: Ozguler Yesim , Hatemi Gulen , Cetinkaya Firat , Tascilar Koray , Hamuryudan Vedat , Ugurlu Serdal , Seyahi Emire , Yazici Hasan , Melikoglu Melike
Published: July 2019

Objectives

Lower extremity deep vein thrombosis (LEDVT) is a serious complication of Behçet’s syndrome. Management constitutes mainly of administration of immunosuppressives, but the predictors of relapse and the optimal choice of immunosuppressives remain unclear. In this prospective study, we aimed to detect the risk and predictors of relapse and treatment response to different modalities.

Methods

All Behçet’s syndrome patients who presented with a first episode of acute LEDVT between 2010 and 2014 were prospectively followed with a standard protocol. Acute LEDVT was confirmed by Doppler ultrasonography. Serial planned Doppler ultrasonography assessments were performed during follow-up and additionally repeated in case of clinical suspicion. Recanalization rate was assessed at each visit. Our first-line treatment strategy consisted of AZA and CSs. IFN-alpha was used in patients who were refractory to or could not tolerate AZA or had concomitant eye involvement requiring further treatment.

Results

Thirty-three patients with LEDVT (26 M/7 F) were prospectively followed for 40.7 ± 13.4 months. Among the 33 patients, 23 relapses were observed in 15 patients. Relapse rates were 29%, 37% and 45% at 6, 12 and 24 months, respectively. Among the possible predictors of relapse, poor recanalization was the only significant factor [hazard ratio 4.34 (95% CI 1.96, 10.0)]. Overall 29 patients were treated with AZA and 17 with IFN-alpha. The relapse rate was lower and recanalization rate was higher with IFN-alpha compared with AZA (12% vs 45% and 86% vs 45%).

Conclusion

The relapse rate for LEDVT in Behçet’s syndrome is high despite AZA treatment. IFN-alpha seems to be a promising agent for preventing LEDVT relapses and achieving good recanalization.
The trustee’s lien and the law of insolvency: the Twain Meet in the Australian High Court: a comment on Carter Holt Harvey Woodproducts Australia Pty Ltd v The Commonwealth
Authors: Nitikman Joel
Published: July 2019

As with many things trust, the equitable rules defining a trustee’s right to an indemnity for acting as a trustee are shrouded in mystery. In particular, the issue of whether that right confers on the trustee an actual proprietary, in rem, beneficial, interest in the trust’s assets or merely an equitable right to access those assets to pay the trust’s debts in priority to the beneficiaries receiving them, has never been addressed by the highest court in any Commonwealth country. In a recent decision involving a priority claim by two creditors over the remaining surplus arising from the insolvency of a trading trust, the High Court of Australia, by a slim majority of 4-3, has held that the trustee does have a proprietary right to the trust’s assets. Joel Nitikman suggests that the majority’s reasoning and the jurisprudential basis on which it rests is either weak or ambiguous; the minority’s reasoning, to the effect that the trustee has only a preferential claim to the assets, is to be preferred.
Benzophenone-3 Passes Through the Blood-Brain Barrier, Increases the Level of Extracellular Glutamate, and Induces Apoptotic Processes in the Hippocampus and Frontal Cortex of Rats
Authors: Pomierny Bartosz , Krzyżanowska Weronika , Broniowska Żaneta , Strach Beata , Bystrowska Beata , Starek-Świechowicz Beata , Maciejska Alicja , Skórkowska Alicja , Wesołowska Julita , Walczak Maria , Budziszewska Bogusława
Published: July 2019

Benzophenone-3 is the most commonly used UV filter. It is well absorbed through the skin and gastrointestinal tract. Its best-known side effect is the impact on the function of sex hormones. Little is known about the influence of BP-3 on the brain. The aim of this study was to show whether BP-3 crosses the blood-brain barrier (BBB), to determine whether it induces nerve cell damage in susceptible brain structures, and to identify the mechanism of its action in the central nervous system. BP-3 was administered dermally during the prenatal period and adulthood to rats. BP-3 effect on short-term and spatial memory was determined by novel object and novel location recognition tests. BP-3 concentrations were assayed in the brain and peripheral tissues. In brain structures, selected markers of brain damage were measured. The study showed that BP-3 is absorbed through the rat skin, passes through the BBB. BP-3 raised oxidative stress and induced apoptosis in the brain. BP-3 increased the concentration of extracellular glutamate in examined brain structures and changed the expression of glutamate transporters. BP-3 had no effect on short-term memory but impaired spatial memory. The present study showed that dermal BP-3 exposure may cause damage to neurons what might be associated with the increase in the level of extracellular glutamate, most likely evoked by changes in the expression of GLT-1 and xCT glutamate transporters. Thus, exposure to BP-3 may be one of the causes that increase the risk of developing neurodegenerative diseases.
mRNA-Sequencing Identifies Liver as a Potential Target Organ for Triphenyl Phosphate in Embryonic Zebrafish
Authors: Reddam Aalekhya , Mitchell Constance A , Dasgupta Subham , Kirkwood Jay S , Vollaro Alyssa , Hur Manhoi , Volz David C
Published: July 2019

Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer in the United States. Using zebrafish as a model, the overall objective of this study was to identify potential organs that might be targeted by TPHP during embryonic development. Based on mRNA-sequencing, TPHP exposure from 24 to 30 h post fertilization (hpf) and 24 to 48 hpf significantly affected the abundance of 305 and 274 transcripts, respectively, relative to vehicle (0.1% DMSO) controls. In addition to minor effects on cardiotoxicity- and nephrotoxicity-related pathways, ingenuity pathway analysis (IPA) of significantly affected transcripts within 30- and 48-hpf embryos revealed that hepatotoxicity-related pathways were strongly affected following exposure to TPHP-alone. Moreover, although pretreatment with fenretinide (a retinoic acid receptor agonist) mitigated TPHP-induced pericardial edema and liver enlargement at 72 and 128 hpf, respectively, IPA revealed that fenretinide was unable to block TPHP-induced effects on cardiotoxicity-, nephrotoxicity-, and hepatotoxicity-related pathways at 48 hpf, suggesting that TPHP-induced effects on the transcriptome were not associated with toxicity later in development. In addition, based on Oil Red O staining, we found that exposure to TPHP nearly abolished neutral lipids from the embryonic head and trunk and, based on metabolomics, significantly decreased the total abundance of metabolites—including betaine, a known osmoprotectant—at 48 and 72 hpf. Overall, our data suggest that, in addition to the heart, TPHP exposure during early development results in adverse effects on the liver, lipid utilization, and osmoregulation within embryonic zebrafish.
Jobs and Land Use within Cities: A Survey of Theory, Evidence, and Policy
Authors: Goswami Arti Grover , Lall Somik V
Published: July 2019

Over the last century, the urban spatial structure of cities has transformed dramatically from a traditional monocentric configuration to varying forms of decentralized organization. This paper reviews theory and empirical evidence to understand the urban morphology of jobs and land use within a city. Our survey highlights four broad insights: (i) The evolution of monocentric to polycentric centers have been accompanied by structural changes within the city. (ii) The internal geography of a city is an outcome of the trade-off between the pull from agglomeration economies and the push from congestion. (iii) The presence of externalities implies that the equilibrium spatial organization achieved by profit-maximizing firms may not necessarily be optimal. This justifies the role of public policy in addressing associated market failures. (iv) The productive edge and competitiveness of a city can be enhanced by introducing policies that increase the overall connectivity to take advantage of economic opportunities across the metropolitan area. The survey also puts together a wide range of policy instruments useful in closing the gap between equilibrium urban spatial structures and the optimal outcome.
Technical and Nontechnical Skills in Surgery
Authors: Pfandler Michael , Stefan Philipp , Mehren Christoph , Lazarovici Marc , Weigl Matthias
Published: July 2019

Study Design.

Observational simulation study.

Objective.

The goal of this study was to investigate the relationship between technical and nontechnical skills (NTS) in a simulated surgical procedure.

Summary of Background Data.

Although surgeons’ technical and NTS during surgery are crucial determinants for clinical outcomes, little literature is available in spine surgery. Moreover, evidence regarding how surgeons’ technical and NTS are related is limited.

Methods.

A mixed-reality and full-scale simulated operating room environment was employed for the surgical team. Eleven surgeons performed the vertebroplasty procedure (VP). Technical skills (TS) were assessed using Objective Structured Assessment of Technical Skill scores and senior expert-evaluated VP outcome assessment. NTS were assessed with the Observational Teamwork Assessment for Surgery. Kendall-Tau-b tests were performed for correlations. We further controlled the influence of surgeons′ experience (based on professional tenure and number of previous VPs performed).

Result.

Surgeons’ NTS correlated significantly with their technical performance (τ = 0.63; P = 0.006) and surgical outcome scores (τ = 0.60; P = 0.007). This association was attenuated when controlling for surgeons’ experience.

Conclusion.

Our results suggest that spine surgeons with higher levels of TS also apply better communication, leadership, and coordination behaviors during the procedure. Yet, the role of surgeons′ experience needs further investigation for improving surgeons’ intraoperative performance during spine surgery.

Level of Evidence: 3
B-Mode Ultrasound Findings in a Patient With Suspected Pulmonary Gangrene
Authors: Echivard Mathieu , Lichtenstein Daniel A. , Lala Adrian , Sanchez Anais Perez , Girerd Nicolas
Published: July 2019

Objectives:

Lung ultrasound has shown increasing diagnostic value in many lung diseases and has become an efficient tool in the management of dyspnea. In the present case report, we describe a new ultrasound feature of potential interest.

Data Sources:

Clinical observation of a patient.

Study Selection:

Case report.

Data Extraction:

Data were extracted from medical records, after obtaining consent from the patient’s family. Illustrations were extracted from the imaging software and a video device.

Data Synthesis:

A 56-year-old man was admitted with pneumonia of adverse outcome. Lung ultrasound, a method increasingly considered as a bedside gold standard in critically ill patients due to its overwhelming advantages, was the only tool able to specify the lung injuries. We describe herein a distinctive sign unequivocally evoking a destructive process suggestive of pulmonary gangrene, a variant of the fractal sign combining a lung consolidation with an underlying heterogeneous free fluid.

Conclusions:

Lung ultrasound may help highlight pulmonary gangrene, a poorly-known disease, with this new ultrasonographic description. The next step will be to ascertain the relation between this new ultrasound feature and pulmonary gangrene and to assess how this bedside diagnosis could impact the prognosis of the disease.
Supply Chain Delays in Antimicrobial Administration After the Initial Clinician Order and Mortality in Patients With Sepsis*
Authors: Kashiouris Markos G. , Zemore Zachary , Kimball Zachary , Stefanou Christos , Fowler Alpha A. , Fisher Bernard , de Wit Marjolein , Pedram Sammy , Sessler Curtis N.
Published: July 2019

Objectives:

There is mounting evidence that delays in appropriate antimicrobial administration are responsible for preventable deaths in patients with sepsis. Herein, we examine the association between potentially modifiable antimicrobial administration delays, measured by the time from the first order to the first administration (antimicrobial lead time), and death among people who present with new onset of sepsis.

Design:

Observational cohort and case-control study.

Setting:

The emergency department of an academic, tertiary referral center during a 3.5-year period.

Patients:

Adult patients with new onset of sepsis or septic shock.

Interventions:

None.

Measurements and Main Results:

We enrolled 4,429 consecutive patients who presented to the emergency department with a new diagnosis of sepsis. We defined 0–1 hour as the gold standard antimicrobial lead time for comparison. Fifty percent of patients had an antimicrobial lead time of more than 1.3 hours. For an antimicrobial lead time of 1–2 hours, the adjusted odds ratio of death at 28 days was 1.28 (95% CI, 1.07–1.54; p = 0.007); for an antimicrobial lead time of 2–3 hours was 1.07 (95% CI, 0.85–1.36; p = 0.6); for an antimicrobial lead time of 3–6 hours was 1.57 (95% CI, 1.26–1.95; p < 0.001); for an antimicrobial lead time of 6–12 hours was 1.36 (95% CI, 0.99–1.86; p = 0.06); and for an antimicrobial lead time of more than 12 hours was 1.85 (95% CI, 1.29–2.65; p = 0.001).

Conclusions:

Delays in the first antimicrobial execution, after the initial clinician assessment and first antimicrobial order, are frequent and detrimental. Biases inherent to the retrospective nature of the study apply. Known biologic mechanisms support these findings, which also demonstrate a dose-response effect. In contrast to the elusive nature of sepsis onset and sepsis onset recognition, antimicrobial lead time is an objective, measurable, and modifiable process.
Efficacy, Patient-Reported Outcomes, and Safety in Male Subjects Treated With OnabotulinumtoxinA for Improvement of Moderate to Severe Horizontal Forehead Lines
Authors: Keaney Terrence C. , Cavallini Maurizio , Leys Christophe , Rossi Anthony , Drinkwater Adrienne , Manson Brown Stephanie , Garcia Julie K. , Mao Cheri
Published: July 2019

BACKGROUND

Men represent a growing segment of the facial aesthetic market.

OBJECTIVE

To evaluate investigator-assessed efficacy, patient-reported outcomes, and safety after onabotulinumtoxinA treatment of forehead lines (FHL) in men.

METHODS

Subjects with moderate to severe FHL received onabotulinumtoxinA (frontalis: 20 U; glabellar complex: 20 U, with/without 24 U in crow's feet regions) or placebo in 6-month, double-blind periods of 2 pivotal trials. Results for men were pooled.

RESULTS

Men comprised 12% (140/1,178) of subjects. Day 30 male responder rates for achieving at least 1-grade Facial Wrinkle Scale (FWS) improvement at maximum eyebrow elevation and at rest were 98.2% and 93.3%, respectively; a significant difference in responder rates was maintained versus placebo (p < .05) through Day 150. Despite men having proportionately more severe FHL at baseline, 81.8% and 79.8% achieved Day 30 FWS ratings of none or mild at maximum eyebrow elevation and at rest, respectively (p < .05); significance versus placebo was maintained through Day 120. Men reported high satisfaction rates and improved psychological impacts. No new safety signals were detected.

CONCLUSION

Standard dosing and administration of onabotulinumtoxinA significantly improved static and dynamic FHL appearance, despite men having proportionately more severe FHL at baseline. Men reported high satisfaction and appearance-related psychological impact improvements.
Autoantibodies produce pain in complex regional pain syndrome by sensitizing nociceptors
Authors: Cuhadar Ulku , Gentry Clive , Vastani Nisha , Sensi Serena , Bevan Stuart , Goebel Andreas , Andersson David A.
Published: July 2019

Complex regional pain syndrome (CRPS) is a posttraumatic pain condition with an incompletely understood pathophysiological basis. Here, we have examined the cellular basis of pain in CRPS using behavioral and electrophysiological methods in mice treated with IgG from CRPS patients, in combination with a paw incision. Mice were subjected to a hind paw skin–muscle incision alone, or in combination with administration of IgG purified from either healthy control subjects or patients with persistent CRPS. Nociceptive function was examined behaviorally in vivo, and electrophysiologically in vitro using skin–nerve preparations to study the major classes of mechanosensitive single units. Administration of IgG from CRPS patients exacerbated and prolonged the postsurgical hypersensitivity to noxious mechanical, cold, and heat stimulation, but did not influence tactile sensitivity after a paw incision. Studies of IgG preparations pooled from patient cohorts (n = 26-27) show that pathological autoantibodies are present in the wider population of patients with persistent CRPS, and that patients with more severe pain have higher effective autoantibody titres than patients with moderate pain intensity. Electrophysiological investigation of skin–nerve preparations from mice treated with CRPS IgG from a single patient identified both a significantly increased evoked impulse activity in A and C nociceptors, and an increased spontaneous impulse rate in the intact saphenous nerve. Our results show that painful hypersensitivity in persistent CRPS is maintained by autoantibodies, which act by sensitizing A and C nociceptors.
Pancreatic ductal adenocarcinoma: the role of circulating tumor DNA
Authors: Habib Joseph R. , Yin Lingdi , Yu Jun
Published: July 2019

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans, and utilized treatments over the past decades have shown little evidence of improvement in survival. This lack of progress in PDAC treatment outcomes has largely been attributed to a variety of limitations in all phases of care. These limitations most notably include late diagnosis leading to limited treatment options and consequently poorer response to treatments and eventual outcomes. Clinical implications regarding the emergence of circulating tumor cells and DNA (ctDNA) have shown promise in augmenting each step in the management of PDAC. This paper will review the emergence of ctDNA and its value in detection of common PDAC DNA alterations, potential clinical implications and utility, followed by the current limitations and the next steps that need to be taken to translate its use into a standard of care.
Nonthyroidal illness in critically ill children
Authors: Jacobs An , Vanhorebeek Ilse , Van den Berghe Greet
Published: July 2019

Purpose of review

This review summarizes recent literature on nonthyroidal illness syndrome (NTI) and outcome of pediatric critical illness, to provide insight in pathophysiology and therapeutic implications.

Recent findings

NTI is typically characterized by lowered triiodothyronine levels without compensatory TSH rise. Although NTI severity is associated with poor outcome of pediatric critical illness, it remains unclear whether this association reflects an adaptive protective response or contributes to poor outcome. Recently, two metabolic interventions that improved outcome also altered NTI in critically ill children. These studies shed new light on the topic, as the results suggested that the peripheral NTI component, with inactivation of thyroid hormone, may represent a beneficial adaptation, whereas the central component, with suppressed TSH-driven thyroid hormone secretion, may be maladaptive. There is currently insufficient evidence for treatment of NTI in children. However, the recent findings raised the hypothesis that reactivation of the central NTI component could offer benefit, which should be tested in RCTs.

NTI in critically ill children can be modified by metabolic interventions. The peripheral, but not the central, component of NTI may be a beneficial adaptive response. These findings open perspectives for the development of novel strategies to improve outcome of critical illness in children.
Evaluation of Bleeding Phenotype of Inherited Factor VII Deficiency in Children With a Bleeding Assessment Tool and Global Assays
Authors: Toret Ersin , Ay Yilmaz , Karapinar Tuba H. , Oymak Yeşim , Kavakli Kaan , Vergin Raziye C.
Published: July 2019

Introduction:

Inherited factor VII (FVII) deficiency is the most common of the rare bleeding disorders and shows a heterogenous distribution of bleeding phenotypes independent of factor activity level. The bleeding score (BS) evaluates the phenotype of patients with rare bleeding disorders. Thromboelastography (TEG) and thrombin generation assays (TGAs) are 2 methods to evaluate global hemostasis, and controversially both tests are useful for identifying different bleeding tendency phenotypes. The purpose of this study was to investigate the use of the BS and global assays (TEG and TGAs) to predict the bleeding phenotype of inherited FVII deficiency.

Materials and Methods:

A total of 27 patients with FVII deficiency were evaluated with the BS and global hemostasis assays.

Results:

The BS was compatible with disease severity according to the FVII activity level (P<0.05) but the BS and bleeding grade of patients did not show a statistically significant correlation with factor activity level (P>0.05). No significant correlation was observed between the factor activity level and any TEG parameter (P>0.05). The factor activity level was negatively correlated with the lag time of the TGA on the contrary positively correlated with the peak thrombin time of the TGA (P<0.05).

Conclusions:

The global assays do not successfully predict the bleeding phenotype. The BS is a more suitable tool than conventional and global assays for predicting the bleeding phenotype.
Investing in Skilled Specialists to Grow Hospital Infrastructure for Quality Improvement
Authors: Padula William V. , Nagarajan Madhuram , Davidson Patricia M. , Pronovost Peter J.
Published: July 2019

Objectives

Hospitals can reduce labor costs by hiring lowest skill possible for the job, stretching clinical hours, and reducing staff not at bedside. However, these labor constraints designed to reduce costs may paradoxically increase costs. Specialty staff, such as board-certified clinicians, can redesign health systems to evaluate the needs of complex patients and prevent complications. The aim of the study was to evaluate whether investing in skilled specialists for supporting hospital quality infrastructure improves value and performance.

Methods

We evaluated pressure injury rates as an indicator of performance in a retrospective observational cohort of 55 U.S. academic hospitals from the Vizient clinical database between 2007 and 2012. Pressure injuries were defined by U.S. Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicator 3 (PSI-03) for stage 3, 4, and unstageable pressure injuries not present on admission in hospitalized adults. We compared ratios of board-certified wound care nurses per 1000 hospital beds to hospital-acquired pressure injury rates in these hospitals using mixed-effects regression of hospital quarters.

Results

High-performing hospitals invested in prevention infrastructure with skilled specialists and observed performance improvements. Regression indicated that by adding one board-certified wound care nurse per 1000 hospital beds, hospitals had associated decreases in pressure injury rates by −17.7% relative to previous quarters, controlling for other interruptions. Highest performers supplied fewer skilled specialists and achieve improved outcomes.

Conclusions

Skilled specialists bring important value to health systems as a representation of investment in infrastructure, and the proportion of these specialists could be scaled relative to the hospital’s patient capacity. Policy should support hospitals to make investments in infrastructure to drive down patient costs and improve quality.
Mandibular Distraction Osteogenesis
Authors: Sahoo Nanda Kishore , Issar Yuvraj , Thakral Ankur
Published: July 2019

Mandibular hypoplasia is a common dentofacial deformity requiring a combination of orthodontic and surgical treatment. Before the introduction of distraction osteogenesis various orthognathic surgical procedures were carried out to treat mandibular hypoplasia. Orthognathic procedures like corpus lengthening by bilateral sagittal split ramus osteotomy and genioplasty are commonly practised all over the world to address the high esthetic demands and functional problems. But hardly there are any established orthognathic surgical procedures to address the deficiency of the posterior part of the mandible that is ramus and condyle. Transverse mandibular deficiency is one of the most difficult problems to be addressed surgically.

With the advent of distraction osteogenesis there is a change in concept of addressing mandibular deficiency. Mandibular corpus distraction was first performed by McCarthy et al using an extraoral unidirectional distraction device. The precision of bone lengthening with extraoral distracters did not accurately match the device settings. Since then due to sustained research and design and collaboration with the manufacturers, clinicians have developed various devices to improve the results of mandibular lengthening. Distractor devices of various shape and size are developed for intraoral use in specific anatomical locations of mandible.

This presentation will focus on use of intraoral distraction devices on different anatomical locations of mandible. The surgical methods of corpus, ramus, ramuscondylar unit, and symphyseal distraction osteogenesis and associated complications will be discussed in detail.
One-Step Triple-Layer Reconstruction of an Exposed Calvarium in a Patient With Radiated Tinea Capitis
Authors: Shay Tamir , Har-Shai Lior , Cohen Avi A. , Ad-El Dean D.
Published: July 2019

Full-thickness large scalp defects with underlying exposed calvarium pose a significant reconstructive challenge. Traditional reconstructive techniques are usually not an option in patients with irradiated scalp with thin skin and reduced laxity.

Dermal substitutes-based reconstruction techniques have been described in recent years. A common approach is the staged methodology, with the initial application of skin substitute followed by a split-thickness skin graft few weeks later; however, this method involves a prolonged period of local wound management prior to skin grafting and is often associated with complications that interfere with wound healing.

This report describes a single-stage triple-layer technique for the reconstruction of a large scalp defect with exposed bone in a patient with a history of radiation treatment, using 3 turnover pericranial flaps in conjunction with a Matriderm dermal substitute and split-thickness skin graft. This immediate multilayered reconstruction provides a long-lasting structural and aesthetic outcome, with minimal donor site morbidity and reduced complications.
Frontal Sinus Preservation During Cerebrospinal Fluid Leak Repair
Authors: Bozkurt Gülpembe , Zocchi Jacopo , Russo Federico , Pietrobon Giacomo , Karligkiotis Apostolos , Elhassan Hassan Ahmed , Seyhun Nurullah , Bignami Maurizio , Castelnuovo Paolo
Published: July 2019

Background:

To validate the repair of frontal sinus cerebrospinal fluid (CSF) leaks with preservation of frontal sinus drainage pathway (FSDP), independently of the approach used, and to establish the indications and limits of the endoscopic approach.

Methods:

A retrospective evaluation of patients undergoing surgery for frontal sinus CSF leaks was performed. Demographics, indications for both endoscopic/combined endoscopic and open approaches, complications, methods for maintaining FSDP, and perioperative outcomes were examined.

Results:

Fifty-three patients (average age 45 years) with frontal sinus CSF leaks were treated surgically from 2000 to 2018. All CSF leak repairs were successful at the 1st attempt with a mean follow-up of 76.8 months (range 4–227 months). Etiology was spontaneous (14), traumatic (26), and iatrogenic (13). In 17 patients, a purely endoscopic approach was performed, while an endoscopic endonasal orbital transposition procedure was added in 4 out of this group. In 23 patients, a combined endoscopic and osteoplastic procedure was employed, while in 13 patients a combined craniotomy and endoscopic procedure was performed. All frontal sinuses remained patent except for 2 cranialization patients.

Conclusion:

With contemporary endoscopic instrumentation and techniques, endoscopic closure of frontal sinus CSF leaks even in the far superolateral wall is feasible in selected patients. However, the surgeon should consider the option of combining an external approach when required. Preserving the FSDP should be the main aim regardless of the approach.
Pancreas Retransplant After Pancreas Graft Failure in Simultaneous Pancreas-kidney Transplants Is Associated With Better Kidney Graft Survival
Authors: Parajuli Sandesh , Arunachalam Annamalai , Swanson Kurtis J. , Aziz Fahad , Garg Neetika , Bath Natalie , Redfield Robert R. , Kaufman Dixon , Djamali Arjang , Odorico Jon , Mandelbrot Didier A.
Published: July 2019

Background.

Simultaneous pancreas-kidney (SPK) transplant is usually the best option for the diabetic end-stage renal disease patient. There is limited information about kidney graft outcomes in SPK recipients with isolated pancreas graft failure who do versus do not undergo pancreas retransplantation.

Methods.

Patients were divided into 2 groups based on whether they underwent pancreas retransplant (ReTx+) or not (ReTx−). Kidney graft function and survival were the primary endpoints.

Results.

One hundred and nine patients satisfied our selection criteria, 25 in ReTx+ and 84 in ReTx−. Mean interval from SPK to pancreas failure was significantly shorter in the ReTx+ compared with the ReTx− group, 19.3 ± 36.7 versus 45.7 ± 47.0 months (P = 0.01), respectively. There was no significant difference in kidney graft follow-up post SPK between 2 groups (P = 0.48). At last follow-up, 15 of the 25 (60%) of the repeat pancreas graft had failed, with a mean graft survival among these failed pancreas graft of 2.6 ± 2.7 years, ranging from 0 to 8.1 years. Uncensored kidney graft failure was significantly lower in the ReTx+ group compared with the ReTx− group, 44% versus 67% (P = 0.04). Death-censored kidney graft failure was also lower in the ReTx+ group, 24% versus 48% (P = 0.04). The difference in patient survival did not reach statistical significance. In adjusted Cox regression analysis, rejection as a cause of pancreas failure was associated with increased risk of death-censored kidney graft failure, and pancreas retransplantation was associated with decreased risk of kidney graft failure. A similar pattern was seen after 1:1 matching for the interval between SPK and pancreas graft failure.

Conclusions.

Even though ReTx+ patients accept the risks associated with repeat pancreas surgery, providers should consider this option in suitable otherwise healthy patients.
Early-Career Coordinated Distributed Experiments: Empowerment Through Collaboration
Authors: Pastor Ada , Hernández-del Amo Elena , Giménez-Grau Pau , Fillol Mireia , Pereda Olatz , Flores Lorea , Sanpera-Calbet Isis , Bravo Andrea G. , Martín Eduardo J. , Poblador Sílvia , Arroita Maite , Rasines-Ladero Rubén , Ruiz Celia , del Campo Rubén , Abril Meritxell , Reyes Marta , Casas-Ruiz Joan Pere , Fernández Diego , de Castro-Català Núria , Tornero Irene , Palacin-Lizarbe Carlos , Arce María Isabel , Mora-Gómez Juanita , Gómez-Gener Lluís , Monroy Silvia , Freixa Anna , Lupon Anna , González-Ferreras Alexia María , Estévez Edurne , Rodríguez-Lozano Pablo , Solagaistua Libe , Rodríguez-Castillo Tamara , Aristi Ibon , Martínez Aingeru , Catalán Núria
Published: July 2019

Coordinated distributed experiments (CDEs) enable the study of large-scale ecological patterns in geographically dispersed areas, while simultaneously providing broad academic and personal benefits for the participants. However, the effective involvement of early-career researchers (ECRs) presents major challenges. Here, we analyze the benefits and challenges of the first CDE exclusively led and conducted by ECRs (i.e. ECR-CDE), which sets a baseline for similar CDEs, and we provide recommendations for successful CDE execution. ECR-CDEs achieve most of the outcomes identified in conventional CDEs as well as extensive benefits for the young cohort of researchers, including: (i) receiving scientific credit, (ii) peer-training in new concepts and methods, (iii) developing leadership and communication skills, (iv) promoting a peer network among ECRs, and (v) building on individual engagement and independence. We also discuss the challenges of ECR-CDEs, which are mainly derived from the lack of independence and instability of the participants, and we suggest mechanisms to address them, such as resource re-allocation and communication strategies.
Principles of Cell Circuits for Tissue Repair and Fibrosis
Authors: Adler Miri , Mayo Avi , Zhou Xu , Franklin Ruth , Meizlish Matthew , Medzhitov Ruslan , Kallenberger Stefan , Alon Uri
Published: July 2019

Tissue-repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue-repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound-healing, including the accumulation of scar-forming extracellular matrix. We find that fibrosis results from multistability between three outcomes, which we term ‘hot fibrosis’ characterized by many macrophages, ‘cold fibrosis’ lacking macrophages, and normal wound-healing. The cell-circuit framework clarifies several unexplained phenomena including the paradoxical effect of macrophage depletion, the limited time-window in which removing inflammation leads to healing, the effects of cellular senescence, and why scar maturation takes months. We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis.
Plant defense resistance in natural enemies of a specialist insect herbivore
Authors: Zhang Xi , van Doan Cong , Arce Carla C.M. , Hu Lingfei , Gruenig Sandra , Parisod Christian , Hibbard Bruce E. , Hervé Maxime , Robert Christelle A.M. , Machado Ricardo A.R. , Erb Matthias
Published: July 2019

Plants defend themselves against herbivores through the production of toxic and deterrent metabolites. Adapted herbivores can tolerate and sequester these metabolites, allowing them to feed on defended plants and become toxic to their own enemies. Can herbivore natural enemies overcome sequestered plant defense metabolites to prey on adapted herbivores? To address this question, we studied how entomopathogenic nematodes cope with benzoxazinoid defense metabolites that are produced by grasses and sequestered by a specialist maize herbivore, the western corn rootworm. We find that nematodes from US maize fields in regions in which the western corn rootworm was present over the last 50 years are behaviorally and metabolically resistant to sequestered benzoxazinoids and more infective towards the western corn rootworm than nematodes from other parts of the world. Exposure of a benzoxazinoid-susceptible nematode strain to the western corn rootworm for five generations results in higher behavioral and metabolic resistance and benzoxazinoid-dependent infectivity towards the western corn rootworm. Thus, herbivores that are exposed to a plant defense sequestering herbivore can evolve both behavioral and metabolic resistance to plant defense metabolites, and these traits are associated with higher infectivity towards a defense sequestering herbivore. We conclude that plant defense metabolites that are transferred through adapted herbivores may result in the evolution of resistance in herbivore natural enemies. Our study also identifies plant defense resistance as a novel target for the improvement of biological control agents.
Enhanced targeted resequencing by optimizing the combination of enrichment technology and DNA fragment length
Authors: Iadarola Barbara , Xumerle Luciano , Lavezzari Denise , Paterno Marta , Marcolungo Luca , Beltrami Cristina , Fortunati Elisabetta , Mei Davide , Vetro Annalisa , Guerrini Renzo , Parrini Elena , Rossato Marzia , Delledonne Massimo
Published: July 2019

Whole-exome sequencing (WES) enrichment platforms are usually evaluated by measuring the depth of coverage at target regions. However, variants called in WES are reported in the variant call format (VCF) file, which is filtered by minimum site coverage and mapping quality. Therefore, genotypability (base calling calculated by combining depth of coverage with the confidence of read alignment) should be considered as a more informative parameter to assess the performance of WES. We found that the mapping quality of reads aligned to difficult target regions was improved by increasing the DNA fragment length well above the average exon size. We tested three different DNA fragment lengths using four major commercial WES platforms and found that longer DNA fragments achieved a higher percentage of callable bases in the target regions and thus improved the genotypability of many genes, including several associated with clinical phenotypes. DNA fragment size also affected the uniformity of coverage, which in turn influences genotypability, indicating that different platforms are optimized for different DNA fragment lengths. Finally, we found that although the depth of coverage continued to increase in line with the sequencing depth (overall number of reads), base calling reached saturation at a depth of coverage that depended on the enrichment platform and DNA fragment length. This confirmed that genotypability provides better estimates for the optimal sequencing depth of each fragment size/enrichment platform combination.
Actin modulates shape and mechanics of tubular membranes
Authors: Allard A. , Bouzid M. , Betz T. , Simon C. , Abou-Ghali M. , Lemière J. , Valentino F. , Manzi J. , Brochard-Wyart F. , Guevorkian K. , Plastino J. , Lenz M. , Campillo C. , Sykes C.
Published: July 2019

The actin cytoskeleton shapes cells and also organizes internal membranous compartments. In particular, it interacts with membranes in intracellular transport of material in mammalian cells, yeast or plant cells. Tubular membrane intermediates, pulled along microtubule tracks, are involved during these processes, and destabilize into vesicles. While the role of actin in this destabilization process is still debated, literature also provide examples of membranous structures stabilization by actin. To directly address this apparent contradiction, we mimic the geometry of tubular intermediates with preformed membrane tubes. The growth of an actin sleeve at the tube surface is monitored spatio-temporally. Depending on network cohesiveness, actin is able to stabilize, or maintain membrane tubes under pulling. Indeed, on a single tube, thicker portions correlate with the presence of actin. Such structures relax over several minutes, and may provide enough time and curvature geometries for other proteins to act on tube stability.
Global Analysis of Human mRNA Folding Disruptions in Synonymous Variants Demonstrates Significant Population Constraint
Authors: Gaither Jeffrey B.S. , Lammi Grant E. , Li James L. , Gordon David M. , Kuck Harkness C. , Kelly Benjamin J. , Fitch James R. , White Peter
Published: July 2019

Background

In most organisms the structure of an mRNA molecule is crucial in determining speed of translation, half-life, splicing propensities and final protein configuration. Synonymous variants which distort this wildtype mRNA structure may be pathogenic as a consequence. However, current clinical guidelines classify synonymous or “silent” single nucleotide variants (sSNVs) as largely benign unless a role in RNA splicing can be demonstrated.

Results

We developed novel software to conduct a global transcriptome study in which RNA folding statistics were computed for 469 million SNVs in 45,800 transcripts using an Apache Spark implementation of ViennaRNA in the cloud. Focusing our analysis on the subset of 17.9 million sSNVs, we discover that variants predicted to disrupt mRNA structure have lower rates of incidence in the human population. Given that the community lacks tools to evaluate the potential pathogenic impact of sSNVs, we introduce a “Structural Predictivity Index” (SPI) to quantify this constraint due to mRNA structure.

Conclusions

Our findings support the hypothesis that sSNVs may play a role in genetic disorders due to their effects on mRNA structure. Our RNA-folding scores provide a means of gauging the structural constraint operating on any sSNV in the human genome. Given that the majority of patients with rare or as yet to be diagnosed disease lack a molecular diagnosis, these scores have the potential to enable discovery of novel genetic etiologies. Our RNA Stability Pipeline as well as ViennaRNA structural metrics and SPI scores for all human synonymous variants can be downloaded from GitHub https://github.com/nch-igm/rna-stability.
Aerobic methoxydotrophy: growth on methoxylated aromatic compounds by Methylobacterium
Authors: Lee Jessica A. , Stolyar Sergey , Marx Christopher J.
Published: July 2019

Pink-pigmented facultative methylotrophs have long been studied for their ability to grow on reduced single-carbon (C1) compounds. The C1 groups that support methylotrophic growth may come from a variety of sources. Here, we describe a group of Methylobacterium strains that can engage in methoxydotrophy: they can metabolize the methoxy groups from several aromatic compounds that are commonly the product of lignin depolymerization. In addition, these organisms can utilize the full aromatic ring as a growth substrate, a phenotype that has rarely been described in Methylobacterium. We demonstrated growth on p-hydroxybenzoate, protocatechuate, vanillate, and ferulate in laboratory culture conditions. We also used comparative genomics to explore the evolutionary history of this trait, finding that the capacity for aromatic catabolism is likely ancestral to two clades of Methylobacterium, but has also been acquired horizontally by closely related organisms. In addition, we surveyed the published metagenome data to find that the most abundant group of aromatic-degrading Methylobacterium in the environment is likely the group related to M. nodulans, and they are especially common in soil and root environments. The demethoxylation of lignin-derived aromatic monomers in aerobic environments releases formaldehyde, a metabolite that is a potent cellular toxin but that is also a growth substrate for methylotrophs. We found that, whereas some known lignin-degrading organisms excrete formaldehyde as a byproduct during growth on vanillate, Methylobacterium do not. This observation is especially relevant to our understanding of the ecology and the bioengineering of lignin degradation.
Habitat affinity and density-dependent movement as indicators of fish habitat restoration efficacy
Authors: Polivka Carlos M.
Published: July 2019

Conceptual and methodological tools from behavioral ecology can inform studies of habitat quality and their potential for evaluating habitat restoration in conservation efforts is explored here. Such approaches provide mechanistic detail in understanding the relationship between organisms and their habitats and are thus more informative than correlations between density and habitat characteristics. Several Pacific salmon species have been the target of habitat restoration efforts for the past 2-3 decades, but most post-restoration effectiveness studies have been limited to correlative data described above. In mark-recapture assays from four different study years, the affinity of sub-yearling Chinook salmon (Oncorhynchus tschawytscha) and steelhead (O. mykiss) for stream pools restored with or created by engineered log structures was greater than that for pools without restoration, though with high interannual variability. From corresponding distribution and density data, it was clear that habitat affinity data are not always concordant with single observations of density. The same was true of the correlation between either affinity or density and physical characteristics of pools, although depth and current velocity had some explanatory power for both responses in Chinook. Movement into pools by Chinook during the assays indicated that restored pools can support more immigrants at a given density than can unrestored pools; however no such pattern emerged for steelhead. Variation among individuals in body condition has implications for population-wide fitness, and such low variation was correlated with stronger affinity for pools in Chinook regardless of restoration status. This suggests that pools may mediate habitat-related trade-offs and that restoring them might have a positive effect on fitness. Thus affinity, immigration, and condition data give much-needed mechanistic indication of habitat selection for restored habitat via an apparent capacity increase and those potential fitness benefits. This is stronger support for restoration effectiveness than density differences alone because density data 1) may simply indicate redistribution of fish from poor to good habitats and 2) are not adequate to show correlations between restoration and positive change in traits correlated with fitness.