bluuebunny/crossref_metadata_2025 huggingface dataset:
Indeterminate Dendritic Cell Tumor: A Report of Two New Cases Lacking the ETV3-NCOA2 Translocation and a Literature Review
Authors: Davick Jonathan J. , Kim Jinah , Wick Mark R. , Gru Alejandro A.
Published: June 2018

Indeterminate dendritic cell tumor (IDCT) is a cutaneous proliferation of histiocytes that share morphologic and immunophenotypic properties with Langerhans cells. IDCT was recently included in the updated WHO classification of tumors of hematopoietic and lymphoid tissues. Recent studies have shown that some cases of IDCT demonstrate an ETV3-NCOA2 translocation, supporting the idea that IDCT is a clonal neoplasm. We report 2 new cases of IDCT at our institution lacking the ETV3-NCOA2 translocation. We also present a comprehensive review of reported cases of IDCT in the medical literature. Eighty-five cases of IDCT were reported in the literature between 1985 and 2016. The median age at diagnosis was 45 years. In contrast to Langerhans cell histiocytosis, IDCT is limited to the skin in the majority of cases (88%) and generally follows an indolent clinical course. Most reported lesions are cured with complete excision. However, the histologic features of IDCT and langerhans cell histiocytosis are similar. Conjoint immunostaining for CD1a and langerin is necessary for optimal classification.
Self-healing Cutaneous Mucinosis in Adulthood: The Adult Counterpart of the Juvenile Variant of the Disease?
Authors: Deza Gustavo , García-Martínez Pablo , Gallardo Fernando , Barranco Carlos , Pujol Ramon M.
Published: June 2018

Self-healing cutaneous mucinosis (SHCM) is an idiopathic localized cutaneous mucinosis mainly described in children and characterized clinically by an acute onset of papules and nodules that exhibit a spontaneous resolution in a period ranging from weeks to few months. Histologically, a diffuse mucin deposition in the dermis and/or hypodermis associated with a proliferation of spindle-shaped cells and some large epithelioid gangliocyte-like mononuclear cells is usually observed. An uncommon adult variant of SHCM has also been reported; however, the clinicopathological features described in these patients are extremely heterogeneous and differ significantly from the juvenile variant of the disease, often showing exclusively dermal involvement. We report a case of a 37-year-old female patient with multiple asymptomatic nodules located on the legs and arms that resolved spontaneously in a period of 2 years, showing the typical subcutaneous features of the juvenile variant of SHCM at the histological examination (ie, mucinous areas associated with dense bands of fibrosis containing arborizing thin-walled vessels, spindle-shaped fibroblasts, and some gangliocyte-like cells). To the best of our knowledge, this is the first report of SHCM showing the classic pattern of deep-seated subcutaneous involvement of the disease in an adult patient. We also review the cases of adult-onset SHCM reported in the literature.
Drivers of Seasonal Variation in Tuberculosis Incidence
Authors: Tedijanto Christine , Hermans Sabine , Cobelens Frank , Wood Robin , Andrews Jason R.
Published: June 2018

Background:

Seasonality in tuberculosis incidence has been widely observed across countries and populations; however, its drivers are poorly understood. We conducted a systematic review of studies reporting seasonal patterns in tuberculosis to identify demographic and ecologic factors associated with timing and magnitude of seasonal variation.

Methods:

We identified studies reporting seasonal variation in tuberculosis incidence through PubMed and EMBASE and extracted incidence data and population metadata. We described key factors relating to seasonality and, when data permitted, quantified seasonal variation and its association with metadata. We developed a dynamic tuberculosis natural history and transmission model incorporating seasonal differences in disease progression and/or transmission rates to examine magnitude of variation required to produce observed seasonality in incidence.

Results:

Fifty-seven studies met inclusion criteria. In the majority of studies (n=49), tuberculosis incidence peaked in spring or summer and reached a trough in late fall or winter. A standardized seasonal amplitude was calculated for 34 of the studies, resulting in a mean of 17.1% (range: 2.7–85.5%) after weighting by sample size. Across multiple studies, stronger seasonality was associated with younger patients, extrapulmonary disease, and latitudes farther from the Equator. The mathematical model was generally able to reproduce observed levels of seasonal case variation; however, substantial variation in transmission or disease progression risk was required to replicate several extreme values.

Conclusions:

We observed seasonal variation in tuberculosis, with consistent peaks occurring in spring, across countries with varying tuberculosis burden. Future research is needed to explore and quantify potential gains from strategically conducting mass screening interventions in the spring.
Twenty years of adverse drug reactions: a look back – part 2
Authors: Ferner Robin E. , Anton Christopher
Published: June 2018

After 20 years, Robin Ferner and Christopher Anton, who took on responsibility for the Adverse Drug Reaction Bulletin from its founder Professor Dai Davies, are handing over responsibility to Professor Kim Dalhoff and his colleague Dr Jon Andersen in Copenhagen. They take the opportunity to review some interesting, important, or unusual clinical aspects of adverse drug reactions encountered over the last twenty years.
Factors Associated With Long-term Intraocular Pressure Fluctuation in Primary Angle Closure Disease: The CUHK PACG Longitudinal (CUPAL) Study
Authors: Cheung Carol Y. , Li Sophia Ling , Chan Noel , Wong Mandy Oi-Man , Chan Poemen Pui-Man , Lai Isabel , Baig Nafees , Tan Shaoying , Man Xiaofei , Tang Fangyao , Wang Yu Meng , Tham Clement C.
Published: June 2018

Purpose:

To determine the demographic, ocular, and systemic factors associated with long-term intraocular pressure (IOP) fluctuation in primary angle closure disease (PACD).

Methods:

This prospective cohort study included 422 PACD eyes from 269 Chinese patients, including 274 primary angle closure glaucoma (PACG) eyes and 152 primary angle closure/primary angle closure suspect (PAC/PACS) eyes. Long-term IOP fluctuation defined as the SD of all IOP measurements over 2 years (at least 5 measurements in total). Chinese patients with PACD were recruited and followed up 3 monthly. Eyes with IOP-lowering surgery or lens extraction performed within the 2-year study period were excluded. Patient demographics, received treatments, ocular biometry, retinal nerve fiber layer thickness, and systemic factors (eg, hypertension, smoking) were evaluated. Generalized estimating equations adjusting for inter-eye correlation were used to determine the associations.

Results:

Eyes with PACG had significantly higher IOP fluctuation than PAC/PACS (2.4±1.2 versus 2.1±0.9 mm Hg; P=0.04). In the multivariate analysis with PACG eyes, higher baseline IOP (P<0.001), greater number of IOP-lowering medications (P<0.001), previous trabeculectomy (P=0.002), and current smoking (P=0.03) were significantly associated with larger IOP fluctuation, whereas diabetes mellitus was associated with lower IOP fluctuation (P=0.03). Among PAC/PACS eyes, younger age group (P<0.001), male sex (P=0.002), and higher baseline IOP (P<0.001) were significantly associated with larger IOP fluctuation.

Conclusions:

PACG eyes have greater IOP fluctuation than PAC/PACS eyes. Certain demographic, ocular, and systemic factors are associated with IOP fluctuation in PACD eyes.
Trabeculectomy Following Failed Ab Interno Gelatin Microstent: Case Series
Authors: Gizzi Corrado , Mohamed-Noriega Jibran , Elkarmouty Ahmed , Scott Andrew
Published: June 2018

Purpose:

The purpose of this study is to describe the outcomes of mitomycin C (MMC)-augmented trabeculectomy performed following a failed MMC-augmented XEN-45 implantation.

Design:

Retrospective case series.

Methods:

All consecutive cases of MMC-augmented trabeculectomy performed after MMC-augmented XEN-45 in the Glaucoma Service at Moorfields Eye Hospital between April 2015 and June 2017 were retrospectively reviewed.

Results:

We identified 8 patients who had a trabeculectomy following a failed XEN-45 implantation. The median intraocular pressure (IOP) before and after trabeculectomy was 29.0 mm Hg (12 to 45 mm Hg) and 7.5 mm Hg (2 to 12 mm Hg), respectively. At the last follow-up, 6 cases had a single-digit IOP and 2 of them developed hypotony-related complications (1 case of late choroidal detachment and 1 case of hypotony maculopathy). The median number of glaucoma drops and the median visual acuity (logMAR) before and after trabeculectomy were 2.5 (0 to 5), and 0 and 0.17 (0 to 0.3), and 0.3 (0.17 to 0.47), respectively. At the last follow-up, 3 cases showed an avascular bleb.

Conclusions:

Trabeculectomy following a failed XEN-45 implantation seems technically feasible; however, higher than expected number of cases with low IOP and avascular blebs were observed. This might be related to the cumulative effect of MMC in these cases.
Study of the influence of heme oxygenase 1 gene single nucleotide polymorphism (rs2071746) on esophageal varices among patients with cirrhosis
Authors: Ellakany Walid Ismail , Mahmoud MoheyEldin Khaled , Invernizzi Pietro , Mahmoud ElKady Ali , Eldin Fathy Abou Elkheir Hossam , Abdel Haleem Abo Elwafa Reham , Ellakany Ahmed
Published: June 2018

Introduction

Cirrhosis as a pathological term has some criteria known to be common in all cases of liver cirrhosis. Esophageal varices are portosystemic collaterals arising in the submucosa of the lower esophagus because of portal hypertension. Portal hypertension is defined as hepatic venous pressure gradient greater than 5 mmHg that arises often as a sequelae of mesenchymal dysfunction in a cirrhotic liver. This study was carried out on 120 personnel divided into three groups: group A included 50 cases of liver cirrhosis with esophageal varices, group B consisted of 50 cases of cirrhosis without esophageal varices, and group C had 20 healthy volunteers a control group.

Patients and methods

DNA was extracted from the peripheral blood of the study participants. Genotyping of the HO1 413A>T promoter SNP (rs2071746) was performed using TaqMan SNP genotyping assay according to the manufacturer’s protocol by RQ-PCR.

Results

Patients carrying T allele of HO1 promoter were found to have 5.46-fold increased risk of esophageal varices development than patients with cirrhosis carrying A allele. T allele was significantly higher in cirrhotics with esophageal varices compared with those without esophageal varices (P<0.001). Rates of esophageal varices development in patients with cirrhotic liver were 52, 40, and 8% for genotypes TT, AT, and AA, respectively.

Conclusion

The T allele of heme oxygenase 1 gene SNP polymorphism (rs2071746) is a risk factor for esophageal varices development in cirrhotics.
Approaches to Address Premature Death of Patients When Assessing Patterns of Use of Health Care Services After an Index Event
Authors: Bush Montika , Simpson Ross J. , Kucharska-Newton Anna , Fang Gang , Stürmer Til , Brookhart M. Alan
Published: June 2018

Background:

Studies of the use of health care after the onset of disease are important for assessing quality of care, treatment disparities, and guideline compliance. Cohort definition and analysis method are important considerations for the generalizability and validity of study results. We compared different approaches for cohort definition (restriction by survival time vs. comorbidity score) and analysis method [Kaplan-Meier (KM) vs. competing risk] when assessing patterns of guideline adoption in elderly patients.

Methods:

Medicare beneficiaries aged 65–95 years old who had an acute myocardial infarction (AMI) in 2008 were eligible for this study. Beneficiaries with substantial frailty or an AMI in the prior year were excluded. We compared KM with competing risk estimates of guideline adoption during the first year post-AMI.

Results:

At 1-year post-AMI, 14.2% [95% confidence interval (CI), 14.0%–14.5%) of beneficiaries overall initiated cardiac rehabilitation when using competing risk analysis and 15.1% (95% CI, 14.8%–15.3%) from the KM analysis. Guideline medication adoption was estimated as 52.3% (95% CI, 52.0%–52.7%) and 53.4% (95% CI, 53.1%–53.8%) for competing risk and KM methods, respectively. Mortality was 17.0% (95%CI, 16.8%–17.3%) at 1 year post-AMI. The difference in cardiac rehabilitation initiation at 1-year post-AMI from the overall population was 0.1%, 1.7%, and 1.9% compared with 30-day survivor, 1-year survivor, and comorbidity-score restricted populations, respectively.

Conclusions:

In this study, the KM method consistently overestimated the competing risk method. Competing risk approaches avoid unrealistic mortality assumptions and lead to interpretations of estimates that are more meaningful.
The Role of Inflammation on Vitamin D Levels in a Cohort of Pediatric Patients With Inflammatory Bowel Disease
Authors: Strisciuglio Caterina , Cenni Sabrina , Giugliano Francesca Paola , Miele Erasmo , Cirillo Grazia , Martinelli Massimo , Vitale Alessandra , Tolone Carlo , Staiano Annamaria , Miraglia Del Giudice Emanuele , Perrone Laura
Published: June 2018

Objectives:

Existing studies usually do not measure the free vitamin D in pediatric patients with inflammatory bowel disease (IBD) and not consider the effect of inflammation on vitamin D levels. The aim of our study was to evaluate the concentrations of vitamin D–binding protein (VDBP), total and free 25‐hydroxyvitamin‐D (25(OH)D), and to correlate these values with the disease activity markers.

Methods:

Newly diagnosed children with IBD and a group of healthy controls (HCs) were enrolled. VDBP and total and free 25(OH)D levels were measured by enzyme‐linked immunosorbent assay and compared using the Student t test. In each patient with IBD, the activity scores of disease and the main inflammation markers were correlated to total and free 25(OH)D levels. C‐reactive protein was also measured in the control group, and it was related to VDBP by a linear regression test for all the groups.

Results:

Fifty‐one consecutive children were enrolled: IBD = 33, HC = 18. Levels of total 25(OH)D were higher in HC than in patients with IBD (P = 0.01). The free/total 25(OH)D ratio was, however, higher in patients with IBD compared to HC (P < 0.001). Finally, levels of VDBP were lower in patients with IBD than in HC (P = 0.001). A significant direct correlation was found between the free/total 25(OH)D ratio and the activity index of disease (r2: 0.17; P = 0.01). Moreover, in patients with IBD and controls we found a significant indirect correlation between VDBP and C‐reactive protein (r2: 0.12; P = 0.01).

Conclusions:

Inflammation inversely correlates to VDBP concentrations and patients with IBD, despite their deficiency in total 25(OH)D, have normal or even higher levels of free 25(OH)D.
Patient Experience
Authors: Niederhauser Victoria , Wolf Jason
Published: June 2018

Health care organizations recognize that it is difficult to achieve consistent excellence in patient experience. Nursing leaders cannot underestimate the importance of the role they play in efforts to improve the patient experience. This article outlines a call to action for nurse leaders to consider reframing the patient experience as a focal point for the entire organization's strategic approach and tactics. This involves facilitating a dialogue about the organization's patient experience definition; building a strong, positive organization culture; creating processes to ensure the engagement of all voices; ensuring a focus across the continuum of care; and addressing the key drivers of patient experience excellence.
Role of the Chief Nurse Officer in Ensuring Person- and Family-Centered Care
Authors: Barnsteiner Jane , Disch Joanne
Published: June 2018

Person- and family-centered care (PFCC) is a philosophy that has been espoused for decades and yet is rarely embedded in health care organizations. Difficulties dispelling the numerous myths about what PFCC is, as well as daunting challenges to designing and implementing it, have hindered progress. The chief nurse officer is well-positioned to assume organizational leadership in successfully navigating this effort. This article provides 9 specific steps a chief nurse officer should take to create a culture, with supportive systems and an environment, to ensure authentic PFCC.
What Do Patients Want, Need, and Have the Right to Expect?
Authors: Mastors Pat
Published: June 2018

Note from the Editor: This article is written by Pat Mastors, founder of the Patients' View Institute. While we traditionally publish articles by nurse leaders for nurse leaders, Ms Mastors offers us a view of hospital care from patients and families. We are publishing this as a gift to our readers because who can better tell us what is most important to those who receive our care than the recipients themselves.
The Impact of Nurse Engagement on Quality, Safety, and the Experience of Care
Authors: Dempsey Christina , Assi Mary Jo
Published: June 2018

To lead others in achieving exemplary outcomes, nurse leaders need to understand the vital and interdependent connection between quality, safety, the patient and RN experience of care, and RN engagement. The triple aim of improving population health, enhancing patient experience, and reducing cost cannot be accomplished without a robust and engaged workforce that finds joy and meaning in its work. This is especially true for the nursing workforce. The vital connection of nurse engagement to the experience of care, and ultimately to nurse and patient outcomes, is clear. Quality improvement efforts that equally emphasize initiatives to improve patient experience and create and sustain a highly engaged nursing workforce are key to achieving desired outcomes.
Economic Assessment of Reverse Algorithm Syphilis Screening in a High Prevalence Population
Authors: Buono Sean A. , Basurto-Davila Ricardo , Godwin Hilary A. , Green Nicole M.
Published: June 2018

Background

More laboratories are screening for syphilis with automated treponemal immunoassays. We compared direct costs and downstream consequences when a local public health laboratory switches from a traditional algorithm (nontreponemal screening) to a reverse algorithm (treponemal screening).

Methods

We created a decision analysis model based on laboratory and surveillance data to estimate the cost-effectiveness of a reverse syphilis-screening algorithm from the perspectives of the Los Angeles County Public Health Laboratory and the Los Angeles County Department of Public Health (laboratory + STD Program costs) in 2015 US dollars.

Results

The estimated total costs for the Department (Public Health Laboratories) were $2,153,225 ($367,119) for the traditional algorithm and $2,197,478 ($239,855) for the reverse algorithm. Reverse algorithm screening was estimated to detect an additional 626 cases of syphilis, 9.7% more than the traditional algorithm. The incremental cost-effectiveness ratio for the reverse algorithm from the Public Health Department's perspective was $39 per additional syphilis case detected. Cost of follow-up, screening test costs, positivity rates, and frequency of repeat infections most affected the cost-effectiveness of reverse algorithm. Costs were significantly higher for the reverse algorithm when the enzyme Immunoassay/chemiluminescence immunoassay screening test cost was the same as the published Centers for Medicaid Services treponemal test cost.

Conclusions

Using the reverse algorithm would have been slightly more expensive for the Los Angeles County Department of Public Health, but would have identified more syphilis cases and would have resulted in lower laboratory costs.
Counterclockwise Craniofacial Distraction Osteogenesis for Tracheostomy-Dependent Children with Treacher Collins Syndrome
Authors: Hopper Richard A. , Kapadia Hitesh , Susarla Srinivas , Bly Randall , Johnson Kaalan
Published: June 2018

Background:

The craniofacial rotation deformity in Treacher Collins syndrome results in airway compression that is not addressed by isolated mandibular distraction osteogenesis. Our purpose is to present a surgical technique—counterclockwise craniofacial distraction osteogenesis—that improves airway morphology and occlusal rotation in tracheostomy-dependent patients with this condition.

Methods:

All patients underwent subcranial Le Fort II osteotomies with simultaneous mandibular osteotomies, followed by coordinated maxillomandibular distraction with counterclockwise rotation. We reviewed pretreatment, posttreatment, and end-treatment cephalograms. Airway changes were assessed using polysomnography, sleep endoscopy, and direct laryngoscopy. Bivariate statistics were computed to compare pretreatment and posttreatment measures.

Results:

Five subjects (age range, 4.5 to 12.1 years) underwent this new procedure; three had previously undergone mandibular distraction. The average palatal plane rotation was 17 degrees, the effective mandible length increase was 18 mm, and the facial plane relative to skull base rotation was 14 degrees. There was a symmetric 30 percent relapse of rotation with maintained occlusion in the first 9 months of follow-up that then stabilized. Four patients were successfully decannulated following counterclockwise craniofacial distraction osteogenesis following polysomnography. Sleep endoscopy available on two patients demonstrated resolution of the upper airway obstruction.

Conclusions:

Counterclockwise craniofacial distraction osteogenesis provided greater palatal rotation than previous techniques. The resulting improvement in airway anatomy allowed for decannulation in four of five tracheotomized patients. Stability of the counterclockwise rotation is comparable to that of related orthognathic operations, despite substantially greater magnitude.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
18F-FDG PET Brain in a Patient With Fatal Familial Insomnia
Authors: Tham Wei Ying , Thian Yee-Liang , Ratnagopal Pavanni , Xie Wanying
Published: June 2018

A 57-year-old woman presented with a 3-month history of cognitive impairment, daytime somnolence, and violent sleep behavior. Her first- and second-degree relatives had similar symptoms prior to their premature deaths. Her MRI scan of the brain showed no significant abnormality. Electroencephalogram showed loss of slow-wave activity. Functional brain imaging performed with 18F-FDG PET was fused with her MRI scans. This demonstrated profound hypometabolism in bilateral thalami and the posterior cingulate cortex, which is pathognomonic for familial fatal insomnia. Hypometabolism in the temporal lobes suggests a long-standing course of the disease. Genetic testing confirmed a mutation of the prion-protein gene (PRNP).
Prognostic Significance of Interim 11C-Methionine PET/CT in Primary Central Nervous System Lymphoma
Authors: Ahn Seo-Yeon , Kwon Seong Young , Jung Sung-Hoon , Ahn Jae-Sook , Yoo Su Woong , Min Jung-Joon , Bom Hee-Seung , Ki So Yeon , Kim Hyeoung-Joon , Lee Je-Jung , Song Sang Yun , Yang Deok-Hwan
Published: June 2018

Purpose

Primary central nervous system lymphoma (PCNSL) has a poor prognosis. There has been limited study evaluating the role of interim PET/CT in PCNSL. This prospective study investigated the interim response using sequential brain PET/CT with 11C-methionine (11C-MET) to provide prognostic information during the treatment of PCNSL.

Materials and Methods

A total of 26 immunocompetent patients recently diagnosed with PCNSL were evaluated. Brain MRI and 11C-MET PET/CT were performed at the time of diagnosis and after 4 cycles of high-dose methotrexate-based induction chemotherapy. Tumor-to-normal tissue (T/N) ratio and MTV were used to assess the interim response.

Results

All patients had diffuse large B-cell lymphoma. No differences were observed in initial tumor volume or quantitative uptake among the International Extranodal Lymphoma Study Group groups. Higher International Extranodal Lymphoma Study Group risk scores were associated with higher median values for interim MTV and T/N ratios, as well as poor outcomes. After a median follow-up of 21 months, interim 11C-MET PET/CT assessments based on the quantitative T/N ratio and MTV predicted progression-free survival and overall survival, respectively. A high interim T/N ratio was significantly associated with decreased progression-free survival (hazards ratio, 3.68; P = 0.044).

Conclusions

Response assessments based on interim 11C-MET PET/CT could predict the therapeutic outcome of PCNSL.
Multidisciplinary Diagnostic and Surgical Management of Adenocarcinoma Gingival Metastases
Authors: Di Stasio Dario , Montella Marco , Cozzolino Immacolata , Cicciù Marco , Cervino Gabriele , Paparella Renato Silvio , Serpico Rosario , Laino Luigi
Published: June 2018

Colon cancer is the third leading cause of cancer-related mortality worldwide and colon cancer metastases in rare sites, such as the oral cavity, lead to a worse prognosis. Oral metastasis is a rare clinical condition and it represents only the 1% among all oral cavity neoplasms. A multidisciplinary approach is recommended to carry out a correct diagnostic procedure that allows distinguishing between metastatic and primitive lesions of the oral cavity. Quick diagnosis and management are fundamental to take an appropriate action as early as possible, as usually the prognosis in patients with oral metastases of colon carcinoma is poor. Aim of this brief clinical report is to underline how the quick diagnosis and management of gingival lesions can be crucial for the correct management of those uncommon oral diseases and for having a better prognosis of the primary cancer.
Changes in Cervical Lordosis After Orthognathic Surgery in Skeletal Class III Patients
Authors: Andriola Fernando de Oliveira , Kulczynski Fernando Zugno , Deon Pedro Henrique , Melo Denizar Alberto da Silva , Zanettini Leonardo Matos Santolim , Pagnoncelli Rogério Miranda
Published: June 2018

The purpose of this study was to evaluate cervical lordosis and head posture changes using lateral cephalographs after bimaxillary orthognathic surgery for mandibular prognatism by null hypothesis. Twenty-five patients with skeletal class III dentofacial deformities (10 men, 15 women; mean age, 29.28 ± 8.23 years; range 18–48 years) were included in this prospective clinical study. Lateral cephalographs were taken in natural head position (NHP) 2 weeks before and 6 months after orthognathic surgery. The reproducibility of the radiographer's technique of taking radiographs in NHP was investigated using a photographic method and found to be acceptable. All measurements for cervical lordosis (CV1/CV2; CV3/CV7; CV1/CV7), head posture (NSL/OPT; NSL/VER), and other cephalometric values (NSL/Go-Gn; NSL/OCL; Overjet) were repeated 3 times by the same blinded investigator at 2-week intervals and the average values of the 3 measurements were calculated to use in statistical analysis. Intraclass correlation coefficients (ICC) ranged between 0.996 and 1.000, demonstrating a high reliability of the measures. Statistically significant differences were found for CV3/CV7 (P = 0.006) and CV1/CV7 (P = 0.005) and no significant differences were identified in head posture for both cranio-cervical and cranio-vertical angles. The null hypothesis was rejected. Orthognathic surgery resulted in significant cervical lordosis extension, and a tendency for head extension could also be observed.
Premise for Standardized Sepsis Models
Authors: Remick Daniel G. , Ayala Alfred , Chaudry Irshad H. , Coopersmith Craig M. , Deutschman Clifford , Hellman Judith , Moldawer Lyle , Osuchowski Marcin F.
Published: June 2018

Sepsis morbidity and mortality exacts a toll on patients and contributes significantly to healthcare costs. Preclinical models of sepsis have been used to study disease pathogenesis and test new therapies, but divergent outcomes have been observed with the same treatment even when using the same sepsis model. Other disorders such as diabetes, cancer, malaria, obesity, and cardiovascular diseases have used standardized, preclinical models that allow laboratories to compare results. Standardized models accelerate the pace of research and such models have been used to test new therapies or changes in treatment guidelines. The National Institutes of Health mandated that investigators increase data reproducibility and the rigor of scientific experiments and has also issued research funding announcements about the development and refinement of standardized models. Our premise is that refinement and standardization of preclinical sepsis models may accelerate the development and testing of potential therapeutics for human sepsis, as has been the case with preclinical models for other disorders. As a first step toward creating standardized models, we suggest standardizing the technical standards of the widely used cecal ligation and puncture model and creating a list of appropriate organ injury and immune dysfunction parameters. Standardized sepsis models could enhance reproducibility and allow comparison of results between laboratories and may accelerate our understanding of the pathogenesis of sepsis.
Immunogenicity of propagation-restricted vesicular stomatitis virus encoding Ebola virus glycoprotein in guinea pigs
Authors: Locher Samira , Schweneker Marc , Hausmann Jürgen , Zimmer Gert
Published: June 2018

Vesicular stomatitis virus (VSV) expressing the Ebola virus (EBOV) glycoprotein (GP) in place of the VSV glycoprotein G (VSV/EBOV-GP) is a promising EBOV vaccine candidate which has already entered clinical phase 3 studies. Although this chimeric virus was tolerated overall by volunteers, it still caused viremia and adverse effects such as fever and arthritis, suggesting that it might not be sufficiently attenuated. In this study, the VSV/EBOV-GP vector was further modified in order to achieve attenuation while maintaining immunogenicity. All recombinant VSV constructs were propagated on VSV G protein expressing helper cells and used to immunize guinea pigs via the intramuscular route. The humoral immune response was analysed by EBOV-GP-specific fluorescence-linked immunosorbent assay, plaque reduction neutralization test and in vitro virus-spreading inhibition test that employed recombinant VSV/EBOV-GP expressing either green fluorescent protein or secreted Nano luciferase. Most modified vector constructs induced lower levels of protective antibodies than the parental VSV/EBOV-GP or a recombinant modified vaccinia virus Ankara vector encoding full-length EBOV-GP. However, the VSV/EBOV-GP(F88A) mutant was at least as immunogenic as the parental vaccine virus although it was highly propagation-restricted. This finding suggests that VSV-vectored vaccines need not be propagation-competent to induce a robust humoral immune response. However, VSV/EBOV-GP(F88A) rapidly reverted to a fully propagation-competent virus indicating that a single-point mutation is not sufficient to maintain the propagation-restricted phenotype.
BIOLOGICAL SCIENCES: Neuroscience, cell biology MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias
Authors: Brown Alexander S. , Meera Pratap , Altindag Banu , Chopra Ravi , Perkins Emma , Paul Sharan , Scoles Daniel R. , Tarapore Eric , Jackson Mandy , Shakkottai Vikram G. , Otis Thomas S. , Pulst Stefan M. , Atwood Scott X. , Oro Anthony E.
Published: June 2018

The genetically heterogeneous Spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically-approved Src inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

Significance Statement

The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system function, and may contribute to neurodegeneration. Spinocerebellar ataxias (SCAs) are neurodegenerative diseases where Purkinje neurons fire irregularly and degenerate leading to motor problems. We show that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia gene that links multiple SCAs. MTSS1 loss results in increased SFK activity, degenerating Purkinje neurons with low basal firing rates, and cell death. Surprisingly, mouse models for three different SCAs show elevated SFK activity, with SCA1 and SCA2 models displaying dramatically reduced MTSS1 protein levels. Treatment of each SCA model with SFK inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common link among disparate neurodegenerative diseases.
Exhaustive exploration of the conformational landscape of small cyclic peptides using a robotics approach
Authors: Jusot Maud , Stratmann Dirk , Vaisset Marc , Chomilier Jacques , Cortés Juan
Published: June 2018

Small cyclic peptides represent a promising class of therapeutic molecules with unique chemical properties. However, the poor knowledge of their structural characteristics makes their computational design and structure prediction a real challenge. In order to better describe their conformational space, we developed a method, named EGSCyP, for the exhaustive exploration of the energy landscape of small head-to-tail cyclic peptides. The method can be summarized by (i) a global exploration of the conformational space based on a mechanistic representation of the peptide and the use of robotics-based algorithms to deal with the closure constraint, (ii) an all-atom refinement of the obtained conformations. EGSCyP can handle D-form residues and N-methylations. Two strategies for the side-chains placement were implemented and compared. To validate our approach, we applied it to a set of three variants of cyclic RGDFV pentapeptides, including the drug candidate Cilengitide. A comparative analysis was made with respect to replica exchange molecular dynamics simulations in implicit solvent. It results that the EGSCyP method provides a very complete characterization of the conformational space of small cyclic pentapeptides.
Automatic Removal of False Connections in Diffusion MRI Tractography Using Topology-Informed Pruning (TIP)
Authors: Yeh Fang-Cheng , Panesar Sandip , Barrios Jessica , Fernandes David , Abhinav Kumar , Meola Antonio , Fernandez-Miranda Juan C.
Published: June 2018

Diffusion MRI fiber tracking provides a non-invasive method for mapping the trajectories of human brain connections, but its false connection problem has been a major challenge. This study introduces topology-informed pruning (TIP), a method that automatically identifies singular tracts and eliminates them to improve the tracking accuracy. The accuracy of the tractography with and without TIP was evaluated by a team of 6 neuroanatomists in a blinded setting to examine whether TIP could improve the accuracy. The results showed that TIP improved the tracking accuracy by 11.93% in the single-shell scheme and by 3.47% in the grid scheme. The improvement is significantly different from a random pruning (p-value < 0.001). The diagnostic agreement between TIP and neuroanatomists was comparable to the agreement between neuroanatomists. The proposed TIP algorithm can be used to automatically clean up noisy fibers in deterministic tractography, with a potential to confirm the existence of a fiber connection in basic neuroanatomical studies or clinical neurosurgical planning.
Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells
Authors: Jacobson Elsie C. , Perry Jo K. , Long David S. , Olins Ada L. , Olins Donald E. , Wright Bryon E. , Vickers Mark H. , O’Sullivan Justin M.
Published: June 2018

Background

Mammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. Their nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through constricted space, where the nuclear shape must change in order to fit through the constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration.

Results

Total RNA-sequencing identified that neutrophil migration through 5 or 14μm pores was associated with changes in the transcript levels of inflammation and chemotaxis-related genes, when compared to unmigrated cells. Differentially expressed transcripts specific to migration with constriction were enriched for groups of genes associated with cytoskeletal remodeling.

Hi-C was used to capture the genome organization in control and migrated cells. Minimal switching was observed between the active (A) and inactive (B) compartments after migration. However, global depletion of short range contacts was observed following migration with constriction compared to migration without constriction. Regions with disrupted contacts, TADs, and compartments were enriched for inactive chromatin.

Conclusion

Short range genome organization is preferentially altered in inactive chromatin, possibly protecting transcriptionally active contacts from the disruptive effects of migration with constriction. This is consistent with current hypotheses implicating heterochromatin as the mechanoresponsive form of chromatin. Further investigation concerning the contribution of heterochromatin to stiffness, flexibility, and protection of nuclear function will be important for understanding cell migration in human health and disease.
Improved performance of microbial fuel cells through addition of trehalose lipids
Authors: Cheng Peng , Shan Rui , Yuan Hao-Ran , Dong Ge , Deng Li-fang , Chen Yong
Published: June 2018

Electron transfer from microorganisms to the electrode is the key process in microbial fuel cells (MFCs). In this study, a trehalose lipid was added to a Rhodococcus pyridinivorans-inoculated MFC to improve the power output by enhancing electron transfer. Upon trehalose lipid addition, the current density and maximum power density were increased by 1.83 times and 5.93 times, respectively. Cyclic voltammetry analysis revealed that the addition of trehalose lipid increased the electron transfer performance, while electrochemical impedance spectroscopy results proved a decrease in internal resistance. Microscopy images showed that the trehalose lipid-treated bacteria interacted more closely with various fagellum-like contacts, while in the pure trehalose lipid (200 mg/L), pores were obviously observed in the cell surface.

Importance

Improving the power output of microbial fuel cells by the addition of bio-surfactants have been proved to be a novel method. However, only rhamnolipid and sophorolipid are certified to be effective. Trehalose lipid is a common material in cosmetic and bio-medicine industry. Our research broaden the application of bio-surfactant in MFC and preliminarily explain the mechanism.

Highlights

Trehalose lipid enhanced MFC power generation

Trehalose lipid decrease MFC internal resistance

Pores were observed with the addition of trehalose lipid

Addition of bio-surfactant is a promising way to increase MFC performance
A command-like descending neuron that coordinately activates backward and inhibits forward locomotion
Authors: Carreira-Rosario Arnaldo , Zarin Aref Arzan , Clark Matthew Q. , Manning Laurina , Fetter Richard , Cardona Albert , Doe Chris Q.
Published: June 2018

Command-like descending neurons can induce many behaviors, such as backward locomotion, escape, feeding, courtship, egg-laying, or grooming. In most animals it remains unknown how neural circuits switch between these antagonistic behaviors: via top-down activation/inhibition of antagonistic circuits or via reciprocal inhibition between antagonistic circuits. Here we use genetic screens, intersectional genetics, circuit reconstruction by electron microscopy, and functional optogenetics to identify a bilateral pair of larval “mooncrawler descending neurons” (MDNs) with command-like ability to coordinately induce backward locomotion and block forward locomotion; the former by activating a backward-specific premotor neuron, and the latter by disynaptic inhibition of a forward-specific premotor neuron. In contrast, direct reciprocal inhibition between forward and backward circuits was not observed. Thus, MDNs coordinate a transition between antagonistic larval locomotor behaviors. Interestingly, larval MDNs persist into adulthood, where they can trigger backward walking. Thus, MDNs induce backward locomotion in both limbless and limbed animals.

Highlights

MDN command-like descending neuron induces backward larval locomotion

MDN neurons coordinately regulate antagonistic behaviors (forward/backward locomotion)

MDN-motor circuit validated at structural (TEM) and functional (optogenetic) levels

MDN neurons induce backward locomotion in both limbless larva and limbed adult
AQ-seq: Accurate quantification of microRNAs and their variants
Authors: Kim Haedong , Kim Jimi , Kim Kijun , Chang Hyeshik , You Kwontae , Kim V. Narry
Published: June 2018

MicroRNAs (miRNAs) modulate diverse biological and pathological processes via post-transcriptional gene silencing. High-throughput small RNA sequencing (sRNA-seq) has been widely adopted to investigate the functions and regulatory mechanisms of miRNAs. However, accurate quantification has been limited owing to the severe ligation bias in conventional sRNA-seq methods. Here we present a high-throughput protocol, termed AQ-seq (accurate quantification by sequencing), that utilizes adapters with terminal degenerate sequences and a high concentration of polyethylene glycol (PEG), which removes the ligation bias during library preparation. By accurately measuring miRNAs and their variants (known as isomiRs), we identify alternatively processed miRNAs and correct the 5′ end usage and strand preference that have been misannotated. We also uncover highly modified miRNAs that are uridylated and adenylated. Taken together, AQ-seq reveals the complexity of the miRNA isoform landscape, allowing us to refine miRNA annotation and to advance our understanding of miRNA regulation. Furthermore, AQ-seq can be adopted to improve other ligation-based sequencing methods including crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome profiling (Ribo-seq).
How adaptive plasticity evolves when selected against
Authors: Rago Alfredo , Kouvaris Kostas , Uller Tobias , Watson Richard
Published: June 2018

Adaptive plasticity allows organisms to cope with environmental change, thereby increasing the population’s long-term fitness. However, individual selection can only compare the fitness of individuals within each generation: if the environment changes more slowly than the generation time (i.e., a coarse-grained environment) a population will not experience selection for plasticity even if it is adaptive in the long-term. How does adaptive plasticity then evolve? One explanation is that, if competing alleles conferring different degrees of plasticity persist across multiple environments, natural selection between lineages carrying those alleles could select for adaptive plasticity (lineage selection).

We show that adaptive plasticity can evolve even in the absence of such lineage selection. Instead, we propose that adaptive plasticity in coarse-grained environments evolves as a by-product of inefficient short-term natural selection. In our simulations, populations that can efficiently respond to selective pressures follow short-term, local, optima and have lower long-term fitness. Conversely, populations that accumulate limited genetic change within each environment evolve long-term adaptive plasticity even when plasticity incurs short-term costs. These results remain qualitatively similar regardless of whether we decrease the efficiency of natural selection by increasing the rate of environmental change or decreasing mutation rate, demonstrating that both factors act via the same mechanism. We demonstrate how this mechanism can be understood through the concept of learning rate.

Our work shows how plastic responses that are costly in the short term, yet adaptive in the long term, can evolve as a by-product of inefficient short-term selection, without selection for plasticity at either the individual or lineage level.
Phosphorylation of a Toxoplasma gondii tyrosine transporter by calcium-dependent kinase 3 is important for parasite fitness
Authors: Wallbank Bethan A. , Dominicus Caia S. , Broncel Malgorzata , Legrave Nathalie , MacRae James I. , Staines Henry M. , Treeck Moritz
Published: June 2018

Toxoplasma gondii parasites rapidly exit their host cell when exposed to calcium ionophores. The calcium-dependent protein kinase 3 (TgCDPK3) was previously identified as a key mediator in this process, as TgCDPK3 knockout (Δcdpk3) parasites fail to egress in a timely manner. Phosphoproteomic analysis comparing WT with Δcdpk3 parasites revealed changes in the TgCDPK3-dependent phosphoproteome that included proteins important for regulating motility, but also metabolic enzymes, indicating that TgCDPK3 controls processes beyond egress. Here we have investigated a predicted direct target of TgCDPK3, a putative transporter of the major facilitator superfamily (MFS) and show that it is rapidly phosphorylated after induction of calcium signalling. Conditional knockout (KO) of the transporter reveals an essential role in the lytic cycle during intracellular growth with a transcriptome signature of amino acid-starved parasites. Using a combination of metabolomics and heterologous expression, we confirmed a primary role in tyrosine import. Complementation with phosphorylation site mutants shows that phosphorylation of serine 56 (S56) by TgCDPK3 gives the parasites a growth benefit in competition assays. Collectively, these findings validate an important, albeit non-essential role for TgCDPK3 in the regulation of metabolic processes, in addition to motility.

Author summary

Toxoplasma gondii is an obligate intracellular parasite. To survive and spread throughout the host it must repeatedly infect, replicate within and exit, host cells. These recurring cycles of infection and egress rely on signalling pathways that allow the parasites to sense and respond rapidly to their environment. While some key kinases and secondary messengers within these pathways have been identified, functional analysis of non-kinases has been very limited. This is especially true for candidates that are not predicted to play a role in active motility or are not known to function in established signalling pathways. Here we have followed up on an unexpected target of the T. gondii calcium-dependent kinase 3 (TgCDPK3), a plant-like calcium dependent kinase, that was previously shown to play an important role in calcium-mediated exit from the host cell. We show that, in addition to controlling motility of the parasite (as previously shown), TgCDPK3 phosphorylates an essential tyrosine transporter in the plasma membrane. Mutational analysis of the phosphorylation sites demonstrates an important role in maintaining parasite fitness, thus demonstrating that TgCDPK3 plays a pleiotropic role in controlling both egress and metabolism.