bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone remodeling effect of a chitosan and calcium phosphate-based composite
Authors: Kjalarsdóttir Lilja , Dýrfjörd Arna , Dagbjartsson Atli , Laxdal Elín H , Örlygsson Gissur , Gíslason Jóhannes , Einarsson Jón M , Ng Chuen-How , Jónsson Halldór
Published: March 2019

Chitosan is a biocompatible polymer that has been widely studied for tissue engineering purposes. The aim of this research was to assess bone regenerative properties of an injectable chitosan and calcium phosphate-based composite and identify optimal degree of deacetylation (%DDA) of the chitosan polymer. Drill holes were generated on the left side of a mandible in Sprague-Dawley rats, and the hole was either left empty or filled with the implant. The animals were sacrificed at several time points after surgery (7–22 days) and bone was investigated using micro-CT and histology. No significant new bone formation was observed in the implants themselves at any time points. However, substantial new bone formation was observed in the rat mandible further away from the drill hole. Morphological changes indicating bone formation were found in specimens explanted on Day 7 in animals that received implant. Similar bone formation pattern was seen in control animals with an empty drill hole at later time points but not to the same extent. A second experiment was performed to examine if the %DDA of the chitosan polymer influenced the bone remodeling response. The results suggest that chitosan polymers with %DDA between 50 and 70% enhance the natural bone remodeling mechanism.
Narrow Incumbent Victories and Post-Election Conflict: Evidence from the Philippines
Authors: Crost Benjamin , Felter Joseph H , Mansour Hani , Rees Daniel I
Published: March 2019

Post-election violence is a common form of conflict, but its underlying mechanisms are not well understood. Using data from the 2007 Philippine mayoral elections, this paper provides evidence that post-election violence is particularly intense after narrow victories by incumbents. Using a density test, the study shows that incumbents were substantially more likely to win narrow victories than their challengers, a pattern consistent with electoral manipulation. There is no evidence that the increase in post-election violence is related to the incumbents’ political platform or their performance in past elections. These results provide support for the notion that post-election violence is triggered by election fraud or by the failure of democratic ways of removing unpopular incumbents from office.
Field Evaluation of Reduced Rate Brassicaceae Seed Meal Amendment and Rootstock Genotype on the Microbiome and Control of Apple Replant Disease
Authors: Wang Likun , Mazzola Mark
Published: March 2019

An orchard field trial was conducted to assess the utility of reduced rate Brassicaceae seed meal (SM) amendment in concert with specific rootstock genotypes for effective control of apple replant disease. Three amendment rates of a 1:1 formulation of Brassica juncea-Sinapis alba SM were compared with preplant 1,3-dichloropropene/chloropicrin soil fumigation for disease control efficacy. When applied at the highest rate (6.6 t ha−1) in the spring of planting, SM caused significant phytotoxicity and tree mortality, which was higher for Gala/M.26 than for Gala/G.41 but was not observed at SM application rates of 2.2 or 4.4 t ha−1. SM treatment resulted in growth and yield increases of Gala/M.26 and Gala/G.41 trees in a manner similar to the fumigation treatment and significantly greater than the no treatment control. Tree growth in soils treated with SM at 4.4 t ha−1was similar or superior to that obtained with SM at 6.6 t ha−1and superior to that attained at an SM application rate of 2.2 t ha−1. Soil fumigation and all SM treatments reduced Pratylenchus penetrans root infestation relative to the control treatment at the end of the initial growing season. Lesion nematode root densities in the fumigation treatment, but not SM treatments, rapidly recovered and were indistinguishable from the control at the end of the second growing season. Soil fumigation and all SM treatments significantly suppressed Pythium spp. root infection relative to the control. Trees grafted to rootstock G.41 possessed lower P. penetrans root densities relative to trees grafted to rootstock M.26. One year after planting, composition of microbial communities from SM-amended soils was distinct from those detected in control and fumigated soils, and the differences were amplified with increasing SM application rate. Specific fungal and bacterial phyla associated with suppression of plant pathogens were more abundant in SM-treated soil relative to the control, and they were similar in abundance in 4.4- and 6.6-t ha−1SM treatments. Findings from this study demonstrated that use of the appropriate apple rootstock genotype will allow for effective replant disease control at SM application rates significantly less than that utilized previously (6.6 t ha−1).
Disruption of Rapid Eye Movement Sleep Homeostasis in Adolescent Rats after Neonatal Anesthesia
Authors: Lunardi Nadia , Sica Ryan , Atluri Navya , Salvati Kathryn A. , Keller Caroline , Beenhakker Mark P. , Goodkin Howard P. , Zuo Zhiyi
Published: March 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Previous studies suggest that rapid eye movement sleep rebound and disruption of rapid eye movement sleep architecture occur during the first 24 h after general anesthesia with volatile anesthetics in adult rats. However, it is unknown whether rapid eye movement sleep alterations persist beyond the anesthetic recovery phase in neonatal rats. This study tested the hypothesis that rapid eye movement sleep disturbances would be present in adolescent rats treated with anesthesia on postnatal day 7.

Methods

Forty-four neonatal rats were randomly allocated to treatment with anesthesia consisting of midazolam, nitrous oxide, and isoflurane or control conditions for 2 h or 6 h. Electroencephalographic and electromyographic electrodes were implanted and recordings obtained between postnatal days 26 and 34. The primary outcome was time spent in rapid eye movement sleep. Data were analyzed using two-tailed unpaired t tests and two-way repeated measures analysis of variance.

Results

Rats treated with midazolam, nitrous oxide, and isoflurane exhibited a significant increase in rapid eye movement sleep three weeks later when compared with control rats, regardless of whether they were treated for 2 h (174.0 ± 7.2 min in anesthetized, 108.6 ± 5.3 in controls, P < 0.0001) or 6 h (151.6 ± 9.9 min in anesthetized, 108.8 ± 7.1 in controls, P = 0.002).

Conclusions

Treatment with midazolam, nitrous oxide, and isoflurane on postnatal day 7 increases rapid eye movement sleep three weeks later in rats.
Effect of Documenting Prognosis on the Information Provided to ICU Proxies: A Randomized Trial*
Authors: Turnbull Alison E. , Hayes Margaret M. , Brower Roy G. , Colantuoni Elizabeth , Basyal Pragyashree Sharma , White Douglas B. , Curtis J. Randall , Needham Dale M.
Published: March 2019

Objectives:

The Critical Care Choosing Wisely Task Force recommends that intensivists offer patients at high risk for death or severe functional impairment the option of pursuing care focused on comfort. We tested the a priori hypothesis that intensivists who are prompted to document patient prognosis are more likely to disclose prognosis and offer comfort-focused care.

Design:

Randomized controlled trial (clinicaltrials.gov: NCT02721810).

Setting:

High-fidelity Simulation Center in Baltimore, MD.

Participants:

One hundred sixteen intensivists from 17 states.

Intervention:

All intensivists reviewed a paper-based medical record for a hypothetical patient on ICU day 3 and answered four survey questions about the patient’s medical management. Intensivists randomized to the intervention group answered three additional questions about patient prognosis. Thereafter, each intensivist participated in a standardized, video-recorded, simulated family meeting with an actor performing a standardized portrayal of the patient’s daughter.

Measurements and Main Results:

Two blinded intensivists reviewed deidentified written transcripts of all simulated family meetings. The primary outcome was the blinded reviewers’ assessment that the intensivist had presented the option of care focused entirely on comfort. Secondary outcomes included disclosing risk of death. All outcomes were planned prior to data collection. Among the 63 intensivists randomized to the intervention, 50 (79%) expected the patient to die during the hospitalization and 58 (92%) expected the patient to have new functional impairments preventing independent living. Intensivists in the intervention versus control group were no more likely to offer the option of care focused on comfort (13% vs 13%; 95% CI, –13% to 12%; p = 1.0) but were more likely to inform the daughter that her father was sick enough to die (68% vs 43%; 95% CI, 5–44%; p = 0.01).

Conclusions:

Documenting prognosis may help intensivists disclose prognosis to ICU proxies, but in isolation, it is unlikely to change the treatment options offered during initial family meetings.
Inflammatory side effects of BRAF and MEK inhibitors
Authors: Mackin Anna G. , Pecen Paula E. , Dinsmore Amanda L. , Patnaik Jennifer L. , Gonzalez Rene , Robinson William A. , Palestine Alan G.
Published: March 2019

The aim of this study was to describe inflammatory side effects in patients treated with BRAF and MEK inhibitors at a single tertiary care institution. This was a retrospective chart review of patients prescribed single-agent or combination BRAF and MEK inhibitors from January 2010 until May 2015. The primary outcome was the presence of inflammatory side effects. Among 124 patients, 56.4% were male, the median age was 59 years, and most (91.1%) were treated for metastatic melanoma. Most patients (74.2%) developed inflammatory side effects, some with multiple occurrences, for a total of 211 occurrences. The overall prevalence of inflammatory side effects did not differ across therapies. In a subanalysis, patients treated with both single-agent and combination therapies were more likely to experience an inflammatory side effect on single-agent therapy (P = 0.0126 for BRAF inhibitor, P = 0.0833 for MEK inhibitor). The most common inflammatory side effects for the entire cohort included arthralgias/myalgias (32.9%), nonacneiform rash (28.0%), pyrexia (25.5%), and erythema nodosum (11.2%), although side effects differed across the class of therapy. Corticosteroids were initiated in 73 side effect instances among 47 patients. Drug interruption or dose reduction was reported in 78 side effect instances in 50 patients. Fifteen side effect instances led to treatment termination. There is a high prevalence of inflammatory side effects encompassing all organ systems in patients treated with BRAF and MEK inhibitors. There is no significant difference in the prevalence of inflammatory side effects in patients treated with single-agent versus combination therapies, however, side effect profile differs across agents.
Quality of Life After Curative Resection for Rectal Cancer in Patients Treated With Adjuvant Chemotherapy Compared With Observation: Results of the Randomized Phase III SCRIPT Trial
Authors: van der Valk Maxime J.M. , Hilling Denise E. , Meershoek-Klein Kranenbarg Elma , Peeters Koen C.M.J. , Kapiteijn Ellen , Tsonaka Roula , van de Velde Cornelis J.H. , Marang-van de Mheen Perla J.
Published: March 2019

BACKGROUND:

Adjuvant chemotherapy after curative resection for rectal cancer is the standard of care in several American and European guidelines.

OBJECTIVE:

The aim of this study was to examine the differences in health-related quality of life over time between patients with rectal cancer who were treated with adjuvant chemotherapy or observation.

DESIGN:

This is a randomized controlled phase III trial.

SETTINGS:

Health-related quality-of-life assessments were conducted in Dutch patients from 43 institutes.

PATIENTS:

Patients with stage II or III rectal cancer who underwent preoperative (chemo)radiotherapy followed by curative surgery (the SCRIPT trial) were included.

INTERVENTIONS:

Patients were randomly assigned to adjuvant capecitabine monotherapy for 8 cycles or observation. Health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer C30 and CR38 questionnaires at 1 month after surgery (before the start of chemotherapy), and 3, 6, and 12 months after surgery.

MAIN OUTCOME MEASURES:

The primary outcome measure was the difference in quality of life at 6 months after surgery, just after completion of adjuvant chemotherapy for patients in the treatment group. Second, the difference in health-related quality of life at 12 months after surgery was examined. A statistically significant difference of 5 points was considered clinically relevant.

RESULTS:

Health-related quality-of-life results of 226 of 233 patients were available. At T3, overall quality of life (C30 summary score) was worse for patients treated with chemotherapy compared with observation (mean 82.3 versus 86.9, p = 0.006), but the difference was not clinically relevant. Patients treated with adjuvant chemotherapy reported clinically relevant worse physical functioning (mean 78.3 versus 87.0, p < 0.001) and more reports of fatigue and dyspnea (35.7 versus 21.0 and 17.1 versus 6.7, p < 0.001). All differences were resolved at 12 months postsurgery.

LIMITATIONS:

A selection of relatively fit patients willing to be randomly assigned may limit the generalizability of the results.

CONCLUSIONS:

Although inferior health-related quality of life was reported just after completion of adjuvant chemotherapy, no persistent deterioration in quality of life was detected. See Video Abstract at http://links.lww.com/DCR/A907.
How Reliable Is CT Scan in Staging Right Colon Cancer?
Authors: Fernandez Laura M. , Parlade Albert J. , Wasser Elliot J. , Dasilva Giovanna , de Azevedo Rafael U. , Ortega Cinthia D. , Perez Rodrigo O. , Habr-Gama Angelita , Berho Mariana , Wexner Steven D.
Published: March 2019

BACKGROUND:

The observation of inferior oncologic outcomes after surgery for proximal colon cancers has led to the investigation of alternative treatment strategies, including surgical procedures and neoadjuvant systemic chemotherapy in selected patients.

OBJECTIVE:

The purpose of this study was to determine the accuracy of CT staging in proximal colon cancer in detecting unfavorable pathologic features that may aid in the selection of ideal candidates alternative treatment strategies, including extended lymph node dissection and/or neoadjuvant chemotherapy.

DESIGN:

This was a retrospective consecutive series.

SETTINGS:

Trained abdominal radiologists from 2 centers performed a blinded review of CT scans obtained to locally stage proximal colon cancer according to previously defined prognostic groups, including T1/2, T3/4, N+, and extramural venous invasion. CT findings were compared with histopathologic results as a reference standard. Unfavorable pathologic findings included pT3/4, pN+, or extramural venous invasion.

PATIENTS:

Consecutive patients undergoing right colectomy in 2 institutions between 2011 and 2016 were retrospectively reviewed from a prospectively collected database.

MAIN OUTCOME MEASURES:

T status, nodal status, and extramural venous invasion status comparing CT with final histologic findings were measured.

RESULTS:

Of 150 CT scans reviewed, CT failed to identify primary cancer in 18%. Overall accuracy of CT to identify unfavorable pathologic features was 63% with sensitivity, specificity, positive predictive value, and negative predictive value of 63% (95% CI, 54%–71%), 63% (95% CI, 46%–81%), 87% (95% CI, 80%–94%) and 30% (95% CI, 18%–41%). Only cT3/4 (55% vs 45%; p = 0.001) and cN+ (42% vs 58%; p = 0.02) were significantly associated with correct identification of unfavorable features at final pathology. CT scans overstaged and understaged cT in 23.7% and 48.3% and cN in 28.7% and 53.0% of cases.

LIMITATIONS:

The study was limited by its retrospective design, relatively small sample size, and heterogeneity of CT images performed in different institutions with variable equipment and technical details.

CONCLUSIONS:

Accuracy of CT scan for identification of pT3/4, pN+, or extramural venous invasion was insufficient to allow for proper identification of patients at high risk for local recurrence and/or in whom to consider alternative treatment strategies. Locoregional overstaging and understaging resulted in inappropriate treatment strategies in <48%. See Video Abstract at http://links.lww.com/DCR/A935.
Emissions From Smart Meters and Other Residential Radiofrequency Sources
Authors: Aerts Sam , Verloock Leen , Van den Bossche Matthias , Martens Luc , Vergara Ximena , Joseph Wout
Published: March 2019

The advent of the Internet of things comes with a huge increase in wirelessly communicating devices in our environment. For example, smart energy-consumption meters are being widely deployed in residences from which they communicate their state using radiofrequency networks. Accurate characterization of the radiofrequency emissions from emerging residential wireless solutions is important to inform the public about the potential impact on their exposure to radiofrequency electromagnetic fields. A new measurement procedure to determine the exposure from residential radiofrequency devices is proposed by assessing the peak emitted fields at various distances and the proportion of time they transmit (duty cycle). Radiofrequency emissions from 55 residential devices were measured in 10 residences (Belgium and France) and compared to environmental levels, emissions from 41 mobile phones, and international standards. Overall, residential levels of radiofrequency electromagnetic field exposure are low. In addition to the continuous environmental exposure, wireless access points (due to frequent use) and especially mobile phones and other personal communication devices (due to their use close to the body) continue to represent the bulk of the radiofrequency electromagnetic field exposure in the smart home. However, some residential devices can significantly increase the exposure if their duty cycles are high enough (>10%), especially when held or used close to the body. Individual smart meters, on the other hand, will contribute only little in general, despite emissions of up to 20 V m−1 at 50 cm, due to their low duty cycles (maximum 1%) and locations.
Brain Tumor Classification Using Principal Component Analysis and Artificial Neural Network
Authors: Abdalla Sheroug A. , Mustafa Zeinab A. , Abrahim Banazier A.
Published: March 2019

The abnormal growth of cells in the brain is known as brain tumor. A brain tumor is a kind of disease that can hit children, adults, and older adults. In this work, a proposed method for brain tumor detection and classification using MATLAB and based on magnetic resonance imaging plays an essential role in the brain-tumor disease diagnostic application that is based on manual and automatic detection. Moreover, various kinds of tumors exist so it is complicated to detect, and thus it is hard to make decisions. Correct segmentation and image enhancement give an accurate classification of brain tumor types. A probabilistic neural network was applied for classification. Two steps were used for making the correct decision: first is feature extraction based on principal component analysis, and second is the classification done using a probabilistic neural network. The known classifications are “normal,” “benign,” and “malignant.”
Clinicopathological study of occult hepatitis B virus infection in hepatitis C virus-associated hepatocellular carcinoma
Authors: El-Maksoud Mohamed A. , Habeeb Maha R. , Ghazy Hayam F. , Nomir Manal M. , Elalfy Hatem , Abed Sally , Zaki Maysaa E.S.
Published: March 2019

Background

Occult hepatitis B virus infection (OBI) frequently occurs in patients with chronic hepatitis C (CHC) infection, but the influence of OBI on CHC outcome is still uncertain. The aim of the present study was to clarify the clinical and pathological characteristics of OBI in CHC-related hepatocellular carcinoma (HCC).

Patients and methods

DNA was obtained from serum and tumor tissue of patients with hepatitis C virus (HCV)-related HCC with negative HBsAg and from patients with HCV-related liver cirrhosis. HBV-DNA was detected using qPCR. Clinicopathological features were compared between patients with HCC with and without OBI.

Results

On the basis of positive serum and tissue HBV-DNA typing, the overall frequency of OBI was 50% in patients with HCV-related HCC. HBV genotype D was the most dominant, constituting 35.3% of HCC cases. Almost 80% of patients with OBI had anti-HBc, whereas 20% of patients had no serological markers. Tissue HBV-DNA showed significant association with positive serum HBV-DNA, anti-HBc, and genotype D. There were no clinical differences between patients with HCC with and without OBI; however, patients with OBI tended to be younger. HCC cases with positive OBI were significantly associated with positive anti-HBc antibodies and late histological grades (3–4). Multivariate logistic regression analysis revealed that the presence of OBI was a predictor of more advanced HCC histological grades in patients with HCV infection.

Conclusion

OBI was detected in 50% of HCV-infected patients with HCC. OBI was strongly associated with the presence of anti-HBc antibodies. Patients with HCC with positive OBI were younger and had more advanced HCC histological grades.
An update on the medical consequences of anorexia nervosa
Authors: Chidiac Carole Wehbe
Published: March 2019

Purpose of review

The diagnosis of anorexia nervosa is associated with the highest mortality rate of any psychiatric disorder, mainly caused by medical complications.

The purpose of this article is to review the common medical consequences of anorexia nervosa focusing on the special considerations related to children and adolescents and recent updates on the pathophysiology of these complications and their prognosis significance.

Recent findings

The main findings were related to the diagnostic and prognostic value of hypokalaemia, QTc prolongation, hypoglycaemia and orthostatic changes. A new modality to evaluate the heart in anorexia nervosa was explored (2DSTE) as well. Bone mineral density (BMD) loss is one of the few nonreversible consequences of anorexia nervosa. BMD loss does not seem to be significantly related to sex or to cut-off low-weight parameters in teenagers with anorexia nervosa, but rather to the amount of weight loss they have experienced. Brain volume deficits might be another irreversible complication in adolescents with anorexia nervosa.

It is crucial for any healthcare provider to be informed about the medical consequences of anorexia nervosa, not only because they can be devastating, but also because they can play an essential role in motivating patients to get treated.
Early Identification of Risk Factors for Mobility Decline Among Hospitalized Older Patients
Authors: Lee Yejin , Lee Hyun-Haeng , Uhm Kyeong Eun , Jung Ho Joong , Kim Yoon-Sook , Shin Jinyoung , Choi Jaekyung , Han Seol-Heui , Lee Jongmin
Published: March 2019

Objective

The aim of the study was to identify the risk factors for mobility decline among hospitalized older patients early.

Design

This is a prospective cohort study. A total of 875 older patients were divided into two groups: older patients with and without mobility decline. The mobility level was measured using the item of functional mobility in the Geriatric Screening for Care 10. The change in mobility between admission and discharge was determined as the dependent variable. There were a total of 18 independent variables, which consisted of three demographic variables, 10 most problematic domains of geriatric care, and five other health-related variables. A multivariable logistic regression analysis was conducted to identify the risk factors for mobility decline during hospitalization.

Results

Of the 875 older patients, 135 (15.4%) experienced mobility decline during hospitalization. The multivariable logistic regression analysis revealed female sex, cognitive impairment, and underweight as the risk factors for mobility decline during hospitalization.

Conclusions

The identified risk factors should be considered to identify patients at a risk of mobility decline early and to provide targeted interventions, which can prevent mobility decline.
Infected Lingual Thyroglossal Duct Cyst Mimicking Supraglottitis
Authors: Hsiao Jen-Hao , Chao Wei-Chieh , Lee Yi-Chan
Published: March 2019

A thyroglossal duct cyst (TGDC) is a common embryological remnant that typically presents as an anterior neck mass; however, this malformation can occur in any adjacent area, including the tongue base (lingual type), along the migration path of the thyroid during embryonic development. Lingual TGDC is often quiescent until infection occurs. Supraglottitis or inflammation of the supraglottis, is a potentially life-threatening disease. Because of the anatomical proximity of lingual TGDC to the supraglottis, lingual TGDC infection might be related to a presentation of supraglottitis. A 49-year-old male initially presented with clinical symptoms of acute supraglottitis. After intensive medical treatment resulting in no improvement, a computed tomography scan was performed. The result raised the suspicion of an infected lingual TGDC. Transoral marsupialization using a rigid laryngoscope was performed to drain the abscess inside the cyst. A diagnosis of lingual TGDC was made based on the characteristic histological pattern of the lesion. After treatment, a follow-up computed tomography scan showed no evidence of recurrence. To the authors’ knowledge, only a few reports have pointed out similarities in the clinical and radiological findings between acute supraglottitis and an infected lingual TGDC. Clinicians should consider lingual TGDC during the differential diagnosis of supraglottitis, especially in patients with poor response to medical treatment.
Use of Parotid Gland Fascia in the Prevention of Frey Syndrome After Parotidectomy
Authors: Ogino Akihiro , Onishi Kiyoshi , Nakamichi Miho , Okaneya Tetsuya
Published: March 2019

Background:

Superficial parotidectomy is standard surgical procedure for parotid gland tumor, and Frey syndrome and depressed deformity of the region are often seen as complications. In this study, we performed prevention of Frey syndrome by covering the residual parotid gland defect with the parotid gland fascia flap.

Method:

The subjects were 5 patients with parotid gland tumor. Tumor was localized in the inferior and superior poles of the parotid gland in 3 and 2 patients, respectively, and it was confirmed on preoperative diagnostic imaging that the tumor and parotid gland fascia were not present in close proximity. Through Lazy-S incision, main trunk of facial nerve was identified and conserved following the surgical procedure of normal superficial parotidectomy, and the superficial parotid gland containing tumor was elevated. A parotid gland fascia flap with a pedicle on the nasal side was prepared and the defect after superficial parotidectomy was covered with it.

Results:

The facial nerve and resected parotid gland stump could be sufficiently covered with the parotid gland fascia flap in all patients. The mean duration of postoperative follow-up was 36 months (10 months-4 years and 5 months), and there were no complications such as tumor recurrence, Frey syndrome, salivary gland fistula, or severe concavity in the parotid region.

Conclusion:

Although application of the present procedure is limited to patients in whom the parotid gland fascia and tumor are not located in close proximity, it may be useful to prevent Frey syndrome because extension of incision is not necessary, the surrounding tissue is not sacrificed, the flap can be easily elevated, and the parotid gland stump can be sufficiently covered.
Concomitant chest trauma and traumatic brain injury, biomarkers correlate with worse outcomes
Authors: Crawford Angela M. , Yang Shiming , Hu Peter , Li Yao , Lozanova Petya , Scalea Thomas M. , Stein Deborah M.
Published: March 2019

BACKGROUND

Clinical data are lacking on the influence of chest trauma on the secondary injury process after traumatic brain injury (TBI), with some data suggesting that multiple trauma may worsens brain injury. Blunt chest trauma and TBI represent the two major single injury entities with the highest risk of complications and are potential biomarker targets.

METHODS

Trauma patients with severe TBI were enrolled. Serum biomarker levels were obtained every 6 hours for 72 hours. Baseline, 6 hours and 24 hours CT head scans were evaluated. Neurologic worsening was defined as increased contusions, ischemia, compression of basal cisterns, and/or midline shift. The TBI patients with chest injury (Abbreviated Injury Scale chest score ≥1) and those without chest injury were compared. Wilcoxon rank sum test, univariate logistic regression and receiver operating characteristic were reported.

RESULTS

Fifty-seven patients. Mean age of 40.5 years. Median motor Glasgow Coma Scale score at admission and 24 hours was 3 (interquartile range, 1–5) and 5 (interquartile range, 3–5). Of the patients enrolled, 12.2% patients underwent craniotomy within 6 hours from the time of admission and 22.8% within 12 hours. Patients with chest trauma, 24.5% had a chest Abbreviated Injury Scale score of 3 or greater, and 73.6% sustained blunt chest trauma. Stratifying TBI patients with and without chest injury revealed higher mean levels of IL-4, IL-5, IL-8, and IL-10 and lower mean IFN-γ and IL-7 levels in patient with chest injury. IL-7 levels adjusted for chest injury predicted neurological worsening with area under the receiver operating characteristic of 0.59 (p value = 0.011). The TBI and chest trauma patients' IL-4 and neuron-specific enolase levels were predictive of mortality (area under the receiver operating characteristic of 0.67 and 0.63, p = 0.0001, 0.003), respectively.

CONCLUSION

Utilizing biomarkers for early identification of patients with TBI and chest trauma has the capability of modifying adverse factors affecting morbidity and mortality in this subset of TBI patients.

LEVEL OF EVIDENCE

Level III.
Transplant Recipients and Anal Neoplasia Study: Design, Methods, and Participant Characteristics of a Prevalence Study
Authors: Rosales Brenda Maria , Langton-Lockton Julian , Cornall Alyssa M. , Roberts Jennifer M. , Hillman Richard J. , Webster Angela Claire
Published: March 2019

Kidney recipients have anal cancer rates 3 times higher than the general population in Australia and New Zealand. High-risk human papillomavirus (HPV) genotypes are implicated in the majority of anal cancers. Establishing the epidemiology of anal HPV infection and precursors of anal cancer in transplant recipient populations is 1 consideration in any potential screening program. The Transplant and Anal Neoplasia Study is a cross-sectional study of the prevalence of anal cytological abnormalities and HPV deoxyribonucleic acid in kidney transplant recipients, as well as evaluating the acceptability of an anal cancer screening intervention. The study aims to recruit 100 kidney transplant recipients, older than 18 years, in Australia. Transplant recipients attending for a protocol biopsy at 3 and 12 months and annually posttransplant are approached to participate. Participants undergo an anal swab, which is then analyzed using liquid-based cytological examination and tested for the detection of 37 anogenital HPV deoxyribonucleic acid genotypes. Participants also complete a demographic and behavioral questionnaire that covers sexual behavior, history of anal symptoms, and possible anal cancer risk factors. Associations will be tested using multiple regression analysis. Recruitment for the study began in 2015 and is ongoing. To date, 96 (77%) of 125 kidney transplant recipients approached have consented to the study. The mean age is 48 (median, 47 y; range, 20–76 y), 59% are male, and Northwest European (58%) represented the largest ethnic group. No participants self-identified as Aboriginal or Torres Strait Islander. High consent rates and positive qualitative results suggest that a larger screening program may be well received by kidney transplant recipients, with increased resources and some modification to the timing of approach. Further results of the study will inform the possible implementation of a larger screening trial for prevention of anal cancers in kidney and other solid organ transplant recipients.
Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish
Authors: Chhabria K. , Vouros A. , Gray C. , MacDonald R.B. , Jiang Z. , Wilkinson R.N. , Plant K , Vasilaki E. , Howarth C. , Chico T.J.A.
Published: March 2019

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood, and currently no treatment exists to prevent these negative effects. We previously found that the NO donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish and the ability of SNP to prevent these.

We incubated 4 days post fertilisation (dpf) zebrafish embryos in 20mM glucose or mannitol for five days until 9dpf, with or without 0.1mM SNP co-treatment for 24h (8-9dpf), and quantified vascular nitric oxide reactivity, vascular mural cell number, expression of aklf2areporter, glial fibrillary acidic protein (GFAP) and TRPV4, as well as spontaneous neuronal activation at 9dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies.

We find that glucose exposure significantly reduced nitric oxide reactivity,klf2areporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour we found glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure.

Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype, and function of the optic tectum and on whole organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.
Comparative analysis of novel MGISEQ-2000 sequencing platform vs Illumina HiSeq 2500 for whole-genome sequencing
Authors: Korostin Dmitriy , Kulemin Nikolay , Naumov Vladimir , Belova Vera , Kwon Dmitriy , Gorbachev Alexey
Published: March 2019

Background

MGISEQ-2000 developed by MGI Tech Co. Ltd. (a subsidiary of the BGI Group) is a new competitor of such next-generation sequencing platforms as NovaSeq and HiSeq (Illumina). Its sequencing principle is based on the DNB and cPAS technologies, which were also used in the previous version of the BGISEQ-500 device. However, the reagents for MGISEQ-2000 have been refined and the platform utilizes updated software. The cPAS method is an advanced technology based on cPAL previously created by Complete Genomics.

Result

In this paper, the authors compare the results of the whole-genome sequencing of a DNA sample from a Russian female donor performed on MGISEQ-2000 and Illumina HiSeq 2500 (both PE150). Two platforms were compared in terms of sequencing quality, number of errors and performance. Additionally, we performed variant calling using four different software packages: Samtools mpileaup, Strelka2, Sentieon, and GATK. The accuracy of single nucleotide polymorphism (SNP) detection was similar in the data generated by MGISEQ-2000 and HiSeq 2500, which was used as a reference. At the same time, a separate indel analysis of the overall error rate revealed similar FPR values and lower sensitivity.

Conclusions

it may be concluded with confidence that the data generated by the analyzed sequencing systems is characterized by comparable magnitudes of error and that MGISEQ-2000 can be used for a wide range of research tasks on par with HiSeq 2500.
Pattern separation is the key driver of expectation-modulated memory
Authors: Frank Darya , Montaldi Daniela
Published: March 2019

The hippocampus uses pattern separation and pattern completion in a continuous manner to successfully encode and retrieve memories1,2. However, whether and how cognitive factors might modulate the dynamics between these types of computation is not well understood. Here we examine the role of expectation in shifting the hippocampus to perform pattern separation. Expectation can be built up through multiple contextual exposures leading to prediction (as in a learnt contingency) or through logical deduction based on a previous mnemonic response. Participants first learned a contingency between a cue and an object’s category (man-made or natural). Then, at encoding, one third of the cues that preceded the to-be-memorised objects violated the studied rule. At test, participants performed an old/new recognition task with old items (targets) and a set of parametrically manipulated (very similar to dissimilar) new foils for each object. We explored the effects of both contextual expectation, manipulated at initial encoding, and mnemonic-attribution expectation, driven by the mnemonic decisions taken on previous retrieval trials. For example, a target would be unexpected if in a previous trial a similar foil had been erroneously accepted as old. Memory was found to be better for foils of high and mid similarity to contextually unexpected targets at encoding, compared to expected ones. Additionally, violations of mnemonic-attribution expectation also yielded improved memory performance when the level of foil similarity was high. These results suggest that violations of both contextual expectation and mnemonic-attribution expectation engage pattern separation, resulting in better discrimination performance for these items. Importantly, this mechanism is engaged when input differentiation is required in order to make a correct recognition decision.
Age Differences in Hemispheric Lateralization in Spatial and Verbal Visual Working Memory
Authors: Sander Myriam C. , Maier Patrizia M. , Napiórkowski Natan , Finke Kathrin , Töllner Thomas , Müller Hermann J. , Lindenberger Ulman , Werkle-Bergner Markus , Wiegand Iris
Published: March 2019

Due to hemispheric specialization of the human brain, neural signatures of visual working memory (WM) performance are expected to differ between tasks involving verbal versus spatial memoranda. Theories of cognitive aging suggest a reduction of hemispheric specialization in older adults. Using behavioral and neural WM capacity markers, we assessed hemispheric lateralization in younger and older adults performing a spatial or verbal visual WM task. Participants encoded information presented in the left or right hemifield. We observed behavioral advantages for spatial stimuli processed in the right hemisphere and for verbal stimuli processed in the left hemisphere. While younger adults showed lateralization in both tasks, older adults showed lateralization only in the verbal task. Lateralization was assessed by the contralateral delay activity (CDA) on the neural level. CDA amplitudes displayed hemispheric lateralization for verbal versus spatial material, but this effect was age-invariant. While our findings support right-hemispheric specialization for spatial information maintenance, and left-hemispheric specialization for verbal information maintenance, we could not confirm a generalized reduction in hemispheric lateralization at older ages.
Host metabolic reprogramming of Pseudomonas aeruginosa by phage-based quorum sensing modulation
Authors: Hendrix H. , Kogadeeva M. , Zimmermann M. , Sauer U. , De Smet J. , Muchez L. , Lissens M. , Staes I. , Voet M. , Wagemans J. , Ceyssens P-J. , Noben J-P. , Aertsen A. , Lavigne R.
Published: March 2019

The Pseudomonas quinolone signal (PQS) is a multifunctional quorum sensing molecule of key importance to the P. aeruginosa metabolism. We here describe that the lytic Pseudomonas bacterial virus LUZ19 targets this population-density-dependent signaling system by expressing quorum sensing-associated acyltransferase (Qst) during early infection. Qst interacts with a key biosynthesis pathway enzyme PqsD, resulting in decreased metabolites levels of PQS and its precursor 2-heptyl-4(1H)-quinolone. The lack of a functional PqsD enzyme impairs the normal LUZ19 infection but is restored by external supplementation of 2-heptyl-4(1H)-quinolone, showing that LUZ19 exploits PQS to successfully achieve its infection. A functional interaction network, which includes enzymes of the central carbon metabolism (CoaC/ThiD) and a novel non-ribosomal peptide synthetase pathway (PA1217), suggests a broader functional context for Qst, which blocks P. aeruginosa cell division. Qst represents an exquisite example of intricate reprogramming of the bacterium, which may be exploited towards antibiotic target discovery for this bacterial pathogen.
Resilience Analysis for Competing Populations
Authors: César Fassoni Artur , de Carvalho Braga Denis
Published: March 2019

Ecological resilience refers to the ability of a system to retain its state when subject to state variables perturbations or parameter changes. While understanding and quantifying resilience is crucial to anticipate the possible regime shifts, characterizing the influence of the system parameters on resilience is the first step towards controlling the system to avoid undesirable critical transitions. In this paper, we apply tools of qualitative theory of differential equations to study the resilience of competing populations as modeled by the classical Lotka-Volterra system. Within the high interspecific competition regime, such model exhibits bistability, and the boundary between the basins of attraction corresponding to exclusive survival of each population is the stable manifold of a saddle-point. Studying such manifold and its behavior in terms of the model parameters, we characterized the populations resilience: while increasing competitiveness leads to higher resilience, it is not always the case with respect to reproduction. Within a pioneering context where both populations initiate with few individuals, increasing reproduction leads to an increase in resilience; however, within an environment previously dominated by one population and then invaded by the other, an increase in resilience is obtained by decreasing the reproduction rate. Besides providing interesting insights for the dynamics of competing population, this work brings near to each other the theoretical concepts of ecological resilience and the mathematical methods of differential equations and stimulates the development and application of new mathematical tools for ecological resilience.
Short-Term Synaptic Dynamics Control the Activity Phase of Neurons in an Oscillatory Network
Authors: Martinez Diana , Anwar Haroon , Bose Amitabha , Bucher Dirk , Nadim Farzan
Published: March 2019

In oscillatory systems, neuronal activity phase is often independent of network frequency. Such phase maintenance requires adjustment of synaptic input with network frequency, a relationship that we explored using the crab,Cancer borealis, pyloric network. The burst phase of pyloric neurons is relatively constant despite a >2-fold variation in network frequency. We used noise input to characterize how input shape influences burst delay of a pyloric neuron, and then used dynamic clamp to examine how burst phase depends on the period, amplitude, duration, and shape of rhythmic synaptic input. Phase constancy across a range of periods required a proportional increase of synaptic duration with period. However, phase maintenance was also promoted by an increase of amplitude and peak phase of synaptic input with period. Mathematical analysis shows how short-term synaptic plasticity can coordinately change amplitude and peak phase to maximize the range of periods over which phase constancy is achieved.
Hearing impairment due toMir183/96/182mutations suggests both loss and gain of function effects
Authors: Lewis Morag A. , Di Domenico Francesca , Ingham Neil J. , Prosser Haydn M. , Steel Karen P.
Published: March 2019

The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss.Mir96is expressed in sensory cells along withMir182andMir183, but the roles of these closely-linked microRNAs are as yet unknown. Here we analyse mice carrying null alleles ofMir182, and ofMir183andMir96together to investigate their roles in hearing. We found thatMir183/96heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at four weeks old.Mir182knockout mice developed normal hearing then exhibited progressive hearing loss. Our transcriptional analyses revealed significant changes in a range of other genes, but surprisingly there were fewer genes with altered expression in the organ of Corti ofMir183/96null mice compared with our previous findings inMir96Dmdomutants, which have a point mutation in the miR-96 seed region. This suggests the more severe phenotype ofMir96Dmdomutants compared withMir183/96mutants, including progressive hearing loss inMir96Dmdoheterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets. We propose three mechanisms of action of mutant miRNAs; loss of targets that are normally completely repressed, loss of targets whose transcription is normally buffered by the miRNA, and gain of novel targets. Any of these mechanisms could lead to a partial loss of a robust cellular identity and consequent dysfunction.
Efficient parameterization of large-scale dynamic models based on relative measurements
Authors: Schmiester Leonard , Schälte Yannik , Fröhlich Fabian , Hasenauer Jan , Weindl Daniel
Published: March 2019

Motivation

Mechanistic models of biochemical reaction networks facilitate the quantitative understanding of biological processes and the integration of heterogeneous datasets. However, some biological processes require the consideration of comprehensive reaction networks and therefore large-scale models. Parameter estimation for such models poses great challenges, in particular when the data are on a relative scale.

Results

Here, we propose a novel hierarchical approach combining (i) the efficient analytic evaluation of optimal scaling, offset, and error model parameters with (ii) the scalable evaluation of objective function gradients using adjoint sensitivity analysis. We evaluate the properties of the methods by parameterizing a pan-cancer ordinary differential equation model (>1000 state variables,>4000 parameters) using relative protein, phospho-protein and viability measurements. The hierarchical formulation improves optimizer performance considerably. Furthermore, we show that this approach allows estimating error model parameters with negligible computational overhead when no experimental estimates are available, pro-viding an unbiased way to weight heterogeneous data. Overall, our hierarchical formulation is applicable to a wide range of models, and allows for the efficient parameterization of large-scale models based on heterogeneous relative measurements.

Contact

jan.hasenauer@helmholtz-muenchen.de

Supplementary information

Supplementary information are available atbioRxivonline. Supplementary code and data are available online athttp://doi.org/10.5281/zenodo.2593839andhttp://doi.org/10.5281/zenodo.2592186.