bluuebunny/crossref_metadata_2025 huggingface dataset:
Corneal Topographical Changes After Müller’s Muscle-conjunctival Resection Surgery
Authors: Ozturk Karabulut Gamze , Fazil Korhan
Published: August 2018

Purpose:

To evaluate corneal refractive and topographical changes after Müller’s muscle conjunctival resection surgery on patients with mild ptosis.

Methods:

A total of 28 eyes of 28 patients with mild ptosis underwent Müller’s muscle conjunctival resection. Visual acuity, margin reflex distance, and cycloplegic refraction were analyzed preoperatively and at first, third, and sixth months postoperatively. Change in corneal topography was analyzed with Sirius System using parameters including corneal astigmatism (CYL), average simulated keratometry value (simK), apical keratometry front (AKf), symmetry index front (SIf), and central corneal thickness (CCT) at the same intervals.

Results:

Best-corrected visual acuity and cycloplegic refraction did not change significantly at all controls postoperatively. The mean change in corneal astigmatism, simK, SIf, and CCT did not show significant differences. Apical keratometry front showed a significant decrease at 3 and 6 months.

Conclusion:

The pressure of upper eyelid in patients with ptosis appeared to have resulted in steepening of the superior cornea along this axis. The surgical correction of ptosis induces flattening of superior cornea as shown by significant decrease in apical keratometry front value postoperatively and restores corneal topography to a more regular state.
Psychosocial factors associated with persistent pain in people with HIV: a systematic review with meta-analysis
Authors: Scott Whitney , Arkuter Chinar , Kioskli Kitty , Kemp Harriet , McCracken Lance M. , Rice Andrew S.C. , de C. Williams Amanda C.
Published: August 2018

Chronic pain remains a prevalent and disabling problem for people living with HIV in the current antiretroviral treatment era. Psychosocial treatments may have promise for managing the impact of this pain. However, research is needed to identify psychosocial processes to target through such treatments. The current systematic review and meta-analysis examined the evidence for psychosocial factors associated with pain, disability, and quality of life in people living with HIV and persistent pain. Observational and experimental studies reporting on the association between one or more psychosocial factors and one or more pain-related variables in an adult sample of people living with HIV and pain were eligible. Two reviewers independently conducted eligibility screening, data extraction, and quality assessment. Forty-six studies were included in the review and 37 of these provided data for meta-analyses (12,493 participants). “Some” or “moderate” evidence supported an association between pain outcomes in people with HIV and the following psychosocial factors: depression, psychological distress, posttraumatic stress, drug abuse, sleep disturbance, reduced antiretroviral adherence, health care use, missed HIV clinic visits, unemployment, and protective psychological factors. Surprisingly, few studies examined protective psychological factors or social processes, such as stigma. There were few high-quality studies. These findings can inform future research and psychosocial treatment development in this area. Greater theoretical and empirical focus is needed to examine the role of protective factors and social processes on pain outcomes in this context. The review protocol was registered with PROSPERO (CRD42016036329).
Nursing Diagnoses Panorama in a Swedish Forensic Psychiatric Setting Using NANDA-International Taxonomy
Authors: Åling Maria , Nilsson Evelina R. , Garpstål Björn , Strömberg Lars
Published: August 2018

More than 1,000 Swedish hospital beds are occupied by patients in forensic psychiatric settings; their average length of hospitalization is 3–7 years. In this context, nursing diagnoses could be extremely useful to make nursing care structured, measurable, and internationally comparable. The study aimed to describe nursing diagnoses in a Swedish forensic psychiatric setting.

Methods:

Data were collected from electronic patient records of 55 patients in a medium-secure forensic psychiatric setting in Sweden. Anonymized data were entered into a database where entries were transformed into figures. Descriptive statistics were used, and frequencies, means, and percentages were calculated. The variables employed were characteristics and related factors, according to NANDA-International (NANDA-I) and International Statistical Classification of Dieseases and Related Heatlh Problems, 10th Revision (ICD-10), diagnoses.

Results:

The patients had between 1 and 13 NANDA-I diagnoses each. Forty-one of the 55 patients had psychosis as the primary ICD-10 code. The identified nursing diagnoses described the patients' status upon arrival in the forensic psychiatric setting. Of the 55 patients, entries in the patient records describing 300 signs and symptoms (i.e., characteristics and related factors) were found. From these signs and symptoms, 371 entries that fit NANDA-I diagnoses were identified, representing 20 different NANDA-I diagnoses.

Conclusion:

NANDA-I diagnoses individualize patient care, making care person centered. NANDA-I is used all over the world and has the potential to make nursing care structured, measurable, and internationally comparable.
Addressing Human Papillomavirus Prevention During Pediatric Acute Sexual Assault Care
Authors: Deutsch Stephanie Anne , Benyo Sarah , Xie Sherlly , Carlin Eileen , Andalaro Bridgett , Clagg Bernadette , De Jong Allan
Published: August 2018

Background/Objectives:

Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Pediatric sexual assault (SA) victims are a special population eligible for HPV vaccination at the age of 9 years. National clinical practice guidelines advise clinicians to address HPV during emergency department (ED)-based SA care and at follow-up. At our institution, addressing HPV among suspected SA victims was highly variable, and HPV counseling was subsequently recommended on an ED-based acute SA clinical pathway as standard care. The aim of this study was to determine the proportion of age-eligible SA victims who received HPV counseling, determine victim characteristics associated with addressing HPV during SA care, and identify barriers to addressing HPV in the ED.

Methods:

This study used a retrospective chart review of 448 pediatric SA victims presenting to the ED for acute postassault care.

Results:

HPV was discussed in 10 of 56 (18%) and 37 of 49 (76%) cases in the control versus intervention groups, respectively. To verify vaccination status, caregiver recall was relied upon for 32 of 56 patients in the control group (57%) and 24 of 49 patients in the intervention group (48.9%). Factors associated with failure to discuss HPV during postassault care were younger age at encounter (OR = 0.78, 95% CI [0.67, 0.90], p < 0.001), verbal report of vaccination status verification (OR = 2.98, 95% CI [1.51, 6.01]), and male gender of the victim (OR = 3.35, 95% CI [1.20, 11.94]).

Conclusions:

Significant barriers to addressing HPV in the ED setting exist, most significantly reliance on caregiver recall to guide vaccination administration, raising concern for overvaccination and undervaccination.
Evaluation of a Standardized Patient Simulation on Undergraduate Nursing Students’ Knowledge and Confidence Pertaining to Intimate Partner Violence
Authors: Blumling Amber , Kameg Kirstyn , Cline Thomas , Szpak Janene , Koller Cora
Published: August 2018

Introduction:

Intimate partner violence (IPV) is a serious and preventable public health problem. Nurses are at the front lines of assessing and intervening with patients subjected to IPV. Lack of training and confidence is cited as a major barrier to assessing for IPV.

Objective:

The purpose of this study was to evaluate a standardized patient (SP) simulation experience depicting a victim of IPV on undergraduate nursing student knowledge and confidence in assessment and intervention of IPV.

Methods:

The Physician Readiness to Manage Intimate Partner Violence Survey tool was adapted to measure confidence, and a 10-item multiple-choice test was developed to measure knowledge, completed pretest, postlecture, and post-SP simulation.

Results:

There was a statistically significant increase in confidence from pretest to postlecture, 14.04 (SD = 3.01) to 20.61 (SD = 2.39), F(1, 56) = 345, p < 0.001, to postsimulation, 14.04–21.93 (SD = 2.18), F(1, 56) = 21.1, p < 0.001. Only statistically significant increases in knowledge occurred from pretest to postlecture, 6.96 (SD = 1.36) to 7.95 (SD = 1.47), F(1,56) = 29.84, p < 0.001. Increase in knowledge from postlecture to postsimulation was not found to be statistically significant, 7.95 (SD = 1.47) to 8.05 (SD = 1.27), F(1,56) = 0.632, p > 0.10.

Conclusion:

Healthcare professionals need to be adequately educated and trained to screen for IPV. This study provides preliminary evidence that the addition of an SP simulation appears to enhance nursing student confidence and knowledge of assessing and intervening with victims of IPV.
Moving Into Action: The Master Key to Patient Education
Authors: FEREIDOUNI Zhila , SABET SARVESTANI Raheleh , HARIRI Gholamreza , KUHPAYE Seyed Amin , AMIRKHANI Mehdi , KALYANI Majid NAJAFI
Published: August 2018

Background:

Illness and hospitalization are situations that increase the need for assistance and education. Poor education is currently the most common source of patient complaints in the health sector in Iran.

Purpose:

The aim of this study was to explore the perspectives and recommendations of nurses to improve patient education.

Methods:

This research followed a qualitative exploratory design with a qualitative content analysis approach. The study participants, including eight head nurses and 16 staff nurses, were selected through purposive sampling. The data were collected through semistructured interviews, focus group sessions, and observations during 2016.

Results:

Coding and analysis of the data generated one main theme, two subthemes, and four categories. The subthemes were “strengthen total commitment” and “reconstructing the infrastructure,” and the categories were “developing motivational factors,” “facilitating change by every impetus,” “systematizing activities,” and “contextual promotion.”

Conclusions:

Study findings provide a complete picture of patient education and challenge managers to develop new strategies to plan and implement appropriate changes.
Lack of Benefit of Lactobacillus reuteri DSM 17938 as an Addition to the Treatment of Functional Constipation
Authors: Jadrešin Oleg , Sila Sara , Trivić Ivana , Mišak Zrinjka , Hojsak Iva , Kolaček Sanja
Published: August 2018

The aim of this study was to investigate the role of Lactobacillus reuteri DSM 17983 in the treatment of functional constipation in children. The trial was a single‐center randomized, double‐blind, placebo‐controlled study. Patients were allocated into the 2 groups; intervention group which received L reuteri DSM 17983 and lactulose and placebo group which received placebo and lactulose. Due to small recruitment rate study was terminated prematurely; therefore, only 33 children (12 girls, median age 4.5 years, range 2–16) were randomized. There was no difference between groups in the stool frequency, stool consistency, pain, soiling rate and dose of the lactulose. This study found that L reuteri DSM 17938 adds no benefit to the treatment of constipation in children. Due to small sample size, these results, however, should be interpreted with caution.
Iron Refractory Iron Deficiency Anemia Due to 374 Base Pairs Deletion in the TMPRSS6 Gene
Authors: Çakmakli Seda , Acipayam Can , Yenmiş İnan Merve N. , Doğan Haldun
Published: August 2018

Iron refractory iron deficiency anemia is an autosomal recessive disorder arising from defects in iron metabolism that cause microcytic anemia to grow resistant to treatment. The patients usually do not respond to orally administered iron treatment and partially respond to intravenous iron administration. Mutations of TMPRSS6 gene which encodes matriptase-2 are the main cause of the disorder. Here, we describe the case of a 6-month-old Syrian boy who had hypochromic-microcytic anemia and normal ferritin levels at presentation. The patient did not respond to 1 month of iron therapy and his hemoglobin levels increased only after red blood cell transfusion. Mutation analysis demonstrated a novel 374 base pairs homozygote deletion spanning exon 15 of TMPRSS6 gene. Our results expand the mutation spectrum of TMPRSS6 gene in iron refractory iron deficiency anemia.
Student Perceptions of Classic and Game-Based Online Student Response Systems
Authors: Wang Weiwen , Sun Ran , Huang Linda , Swigart Valerie
Published: August 2018

Background

Online student response systems (OSRSs), driven by the Internet and cell phone technology, provide a free, easily accessible method to increase student engagement, facilitate active learning, and provide learners and teachers with instant feedback about learning progress.

Purpose

This article describes undergraduate nursing students' use of 2 OSRSs and their perceptions of the impact of the tools on class participation and engagement.

Methods

Students used their own mobile phones or computers to access 2 types of OSRSs: a classic and a game-based OSRS.

Results

Students indicated that both systems increased participation and engagement. The game-based OSRS was favored over the classic OSRS. The potential for use of the game-based OSRS for assessing rapid-answer fact-based knowledge and the classic OSRS for assessing more complex learning tasks is discussed.

Conclusion

Nurse educators are encouraged to consider integrating online response system technology into their classroom teaching.
A Traumatic Quinceañera
Authors: Russell Eric A. , Braverman Richard M. , Vasudevan Sanjeev A. , Patel Binita
Published: August 2018

A 15-year-old girl presented with 3 days of progressive abdominal distention, pain, and bilious hematemesis. Her symptoms began after her quinceañera, during which she wore a tight corset. On examination, she was thin and had significant abdominal distention and pain. A computed tomography revealed a massively dilated stomach and proximal duodenum to the region of the superior mesenteric artery (SMA) with distal decompression. An upper gastrointestinal fluoroscopy demonstrated marked dilation of the stomach through the mid third portion of the duodenum with distal decompression and an associated linear compression on her duodenal wall. We believe that she developed acute SMA syndrome. Superior mesenteric artery syndrome is a partial bowel obstruction caused when the third portion of the duodenum is compressed as it passes between the SMA and the aorta. Although the SMA syndrome is most commonly described as a condition associated with chronic, severe weight loss resulting in a narrowing of the SMA to aorta angle and subsequent duodenal compression, it can present acutely from causes such as a postoperative complication, blunt trauma, or external compression. Previously described acute SMA syndrome from external compression has been the result of medically necessary causes, such as body casting. In this case, the tight gown was likely the inciting factor for her development of SMA syndrome; however, she was placed at high risk for the condition by being underweight at baseline and experiencing food restriction for several days preceding her quinceañera. She was treated conservatively with nasogastric decompression and parenteral nutrition, and has since completely recovered.
Expression of Immunomodulatory Molecules PD-1, PD-L1, and PD-L2, and their Relationship With Clinicopathologic Characteristics in Endometrial Cancer
Authors: Sungu Nuran , Yildirim Melahat , Desdicioglu Raziye , Başaran Aydoğdu Özge , Kiliçarslan Aydan , Tatli Doğan Hayriye , Kiliç Yazgan Aylin , Akyol Mesut , Erdoğan Fazli
Published: August 2018

Chemotherapeutic agents are not very effective in treating advanced endometrial cancers (ECs). Recent studies have demonstrated the immune evasion mechanism of tumors and possible remedies. Programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and programmed death ligand 2 (PD-L2) are immunomodulator molecules that have been the focus of research in lung cancer, melanoma, and renal cell cancer. However, there are few studies concerning EC. This retrospective study aimed to determine PD-1, PD-L1, and PD-L2 expression immunohistochemically in EC, and to study their correlation with clinicopathologic tumor characteristics. This study comprised 127 patients with EC. Anti PD-1, PD-L1, and PD-L2 antibodies were examined immunohistochemically on sections obtained from tissue microarray paraffin blocks. No staining with PD-1 in tumor cells was seen; however, we found positive staining in tumor cells at 36.2% with PD-L1 and 64.4% with PD-L2, and at 61.6% with PD-1, 36.2% with PD-L1, and 93.2% with PD-L2 in immune cells. When comparing staining and clinicopathologic findings, most of the PD-L1 negative tumors (both in tumor and immune cells) were FIGO Stage I, which was significantly higher than stage II-III-IV tumors (P<0.05). There was a statistically significant association between the FIGO grade and the PD-L1 score in immune cells (P=0.009), and between staining of PD-1, PD-L1, and PD-L2 and age (P=0.004, 0.013, and 0.043, respectively). Interaction between PD-1, PD-L1, and PD-L2 may be a potential target for immunotherapy in elderly and advanced stage EC patients.
Targeted Genomic Profiling of Female Adnexal Tumors of Probable Wolffian Origin (FATWO)
Authors: Mirkovic Jelena , Dong Fei , Sholl Lynette M. , Garcia Elizabeth , Lindeman Neal , MacConaill Laura , Crum Christopher P. , Nucci Marisa R. , McCluggage W. Glenn , Howitt Brooke E.
Published: August 2018

Female adnexal tumor of probable Wolffian origin (FATWO) is a rare gynecologic neoplasm of low-malignant potential presumed to be derived from mesonephric remnants in the upper female genital tract. Similarly, mesonephric remnants in the lower female genital tract are thought to be the origin for mesonephric carcinoma. Although the molecular alterations in mesonephric carcinoma have been recently reported, the pathogenesis of and molecular alterations in FATWO are not well understood. The aims of this study were to examine the molecular alterations in FATWO and to establish whether these neoplasms are molecularly similar to mesonephric carcinoma. Eight FATWOs underwent massively parallel sequencing to detect single nucleotide variations, copy number variations, and structural variants by surveying exonic DNA sequences of 300 cancer genes and 113 introns across 35 genes. Good quality DNA was isolated from 7 of 8 cases. Novel KMT2D variants (1 frameshift, 3 missense) were identified in 4 of 7 cases (57%), but were variants of uncertain biologic significance. STK11 mutations (both frameshift) were identified in 2 of 7 cases (29%); one of these was in a patient with a known history of Peutz-Jeghers syndrome. A mutation in the chromatin remodeling gene ARID1B was identified in 1 of 7 cases (14%). No cases harbored KRAS, NRAS, TP53, PIK3CA, PTEN, or DICER1 mutations. There were relatively low numbers of copy number variations, and no recurrent copy number variations were identified. One case demonstrated moderate copy gain of CCND1. No structural variants were identified. In summary, FATWO is characterized molecularly by the absence of KRAS/NRAS mutations (characteristic of mesonephric carcinoma), absence of DICER1 mutations (characteristic of Sertoli-Leydig cell tumor) and frequent KMT2D mutations of unknown biologic significance. FATWOs exhibit a limited number of molecular aberrations that are significantly different from those reported in tumors in the differential diagnosis, and our results question the relationship of mesonephric carcinoma with FATWO. Disease-defining molecular alterations for FATWO have yet to be discovered.
Dechelation (Transmetalation)
Authors: Runge Val M.
Published: August 2018

The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.

The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis–like symptoms—including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).
Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial
Authors: Maffi Paola , Nano Rita , Monti Paolo , Melzi Raffaella , Sordi Valeria , Mercalli Alessia , Pellegrini Silvia , Ponzoni Maurilio , Peccatori Jacopo , Messina Carlo , Nocco Angela , Cardillo Massimo , Scavini Marina , Magistretti Paola , Doglioni Claudio , Ciceri Fabio , Bloem Stef J. , Roep Bart O. , Secchi Antonio , Piemonti Lorenzo
Published: August 2018

Background.

Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation.

Methods.

We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n = 4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n = 6) or BM (n = 3) to evaluate islet transplant function and survival.

Results.

We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity.

Conclusions.

Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.
Temporal Changes in the Impact of HLA Mismatching Among Pediatric Kidney Transplant Recipients
Authors: Ruck Jessica M. , Jackson Annette M. , Massie Allan B. , Segev Dorry L. , Desai Niraj , Garonzik-Wang Jacqueline
Published: August 2018

Background.

Allocation for pediatric deceased-donor kidney transplantation (pDDKT) in the United States now de-emphasizes HLA matching to improve equality in access to transplantation, but other national systems still consider HLA matching due to concerns about graft survival. We hypothesized that the impact of HLA mismatching has decreased over time due to advances including improved immunosuppression.

Methods.

Using Scientific Registry of Transplant Recipient data, we analyzed whether the association between the number of HLA mismatches and outcomes of first-time pDDKTs changed between 2 eras: 1995 to 2004 (N = 2854) and 2005 to 2014 (N = 4643).

Results.

Between eras, the median number of mismatches increased from 4 to 5 (P < 0.001). Overall graft failure risk was higher among HLA-mismatched versus HLA-matched transplants (adjusted hazard ratio 1.211.431.69 for 3–6 versus 0–2 mismatches; P < 0.001), and this association was similar pre-2005 and post-2005 (P
interaction = 0.5). Median panel-reactive antibody change at relisting increased from 79 to 85 (P = 0.01), but the association between number of HLA mismatches and panel-reactive antibody change was similar between eras (P
interaction = 0.6).

Conclusions.

Our finding that increased HLA mismatching continues to impact graft survival, with 43% higher risk of graft failure, highlights the tradeoff between transplant access equity and outcomes and calls into question the deemphasis on HLA matching in pDDKT allocation in the United States.
Treatment of Myasthenia Gravis With High-Dose Cholinesterase Inhibitors and Calcineurin Inhibitors Caused Spontaneous Muscle Cramps in Patients
Authors: Masuda Masayuki , Utsumi Hiroya , Tanaka Sachiko , Maeno Akemi , Yamamoto Mamiko , Sugiyama Kentaro , Hirano Toshihiko , Aizawa Hitoshi
Published: August 2018

Objectives

The objective of this study was to investigate the influence of treatment with cholinesterase inhibitors (ChEIs) and calcineurin inhibitors (CNIs) on the occurrence of cramps in myasthenia gravis (MG) patients.

Methods

The frequency and duration of cramp and serum electrolytes were evaluated in 81 patients with MG. The patients were classified using Myasthenia Gravis Foundation of America postintervention status scores based on the treatment and the responsiveness to the treatment. Quantitative MG score, MG activities of daily living score, MG composite score, or MG quality of life 15 score was used to assess the health-related quality of life (QOL).

Results

Muscle cramps developed in 44 (54.3%) of 81 MG patients. The scores of MG activities of daily living, MG composite, or MG-QOL 15-item questionnaire in patients with cramp were significantly higher than those in patients without cramps (P = 0.002, P = 0.01, or P = 0.0022, respectively). The serum magnesium concentrations were lower in patients treated with CNI (n = 16) than in those not treated with CNI (n = 65) (P = 0.002). The probability of cramps was significantly higher in patients treated with ChEIs (≥180 mg/d) in addition to CNI than in patients who were treated with a low dose of ChEIs (≤60 mg/d) without concomitant CNI treatment (P = 0.017).

Conclusions

Our data suggested that treatment with a high dose of ChEI and CNI accelerated the probability of cramps and reduced the QOL in MG patients.
Increased rates of genomic mutation in a biofilm co-culture model of Pseudomonas aeruginosa and Staphylococcus aureus
Authors: Frapwell C.J. , Howlin R.P. , Soren O. , McDonagh B.T. , Duignan C.M. , Allan R.N. , Horswill A.R. , Stoodley P. , Hu Y. , Coates A.R.M. , Webb J. S.
Published: August 2018

Biofilms are major contributors to disease chronicity and are typically multi-species in nature. Pseudomonas aeruginosa and Staphylococcus aureus are leading causes of morbidity and mortality in a variety of chronic diseases but current in vitro dual-species biofilms models involving these pathogens are limited by short co-culture times (24 to 48 hours). Here, we describe the establishment of a stable (240 hour) co-culture biofilm model of P. aeruginosa and S. aureus that is reproducible and more representative of chronic disease.

The ability of two P. aeruginosa strains, (PAO1 and a cystic fibrosis isolate, PA21), to form co-culture biofilms with S. aureus was investigated. Co-culture was stable for longer periods using P. aeruginosa PA21 and S. aureus viability within the model improved in the presence of exogenous hemin. Biofilm co-culture was associated with increased tolerance of P. aeruginosa to tobramycin and increased susceptibility of S. aureus to tobramycin and a novel antimicrobial, HT61, previously shown to be more effective against non-dividing cultures of Staphylococcal spp. Biofilm growth was also associated with increased short-term mutation rates; 10-fold for P. aeruginosa and 500-fold for S. aureus.

By describing a reproducible 240 hour co-culture biofilm model of P. aeruginosa and S. aureus, we have shown that interspecies interactions between these organisms may influence short-term mutation rates and evolution, which could be of importance in understanding the adaptive processes that lead to the development of antimicrobial resistance.
Selecting causal risk factors from high-throughput experiments using multivariable Mendelian randomization
Authors: Zuber Verena , Colijn Johanna Maria , Klaver Caroline , Burgess Stephen
Published: August 2018

Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors.

Here, we propose a novel approach to two-sample multivariable MR based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.
Circadian control of lung inflammation in influenza infection
Authors: Sengupta Shaon , Tang Soon Yew , Devine Jill , Nayak Soumyashant , Zhang Shirley , Valenzuela Alex , Lopez Carolina B. , Grant Gregory , FitzGerald Garret A.
Published: August 2018

Influenza is a leading cause of respiratory mortality and morbidity. While inflammation is necessary for fighting infection, a fine balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been known to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms influence the cellular response to infection in bronchoalveolar lavage (BAL), the pulmonary transcriptomic profile and lesional histology. This time dependent variability does not reflect alterations in viral replication. Rather, we found that better time-dependent outcomes were associated with a preponderance of NK and NKT cells and lower proportion of monocytes in the lung. Thus, host tolerance, rather than viral burden underlies the diurnal gating of influenza induced lung injury.

Significance statement

Our work demonstrates the importance of circadian rhythms in influenza infection --a condition with significant public health implications. Our findings, which establish the role of the circadian rhythms in maintaining the balance between host tolerance pathways and anti-viral responses confers a new framework for evaluating the relevance of circadian influences on immunity.
Macroevolutionary diversification rates show time-dependency
Authors: Henao Diaz Luis Francisco , Harmon Luke J. , Sugawara Mauro T.C. , Miller Eliot I , Pennell Matthew W.
Published: August 2018

For centuries, biologists have been captivated by the vast disparity in species richness between different groups of organisms. Variation in diversity is widely attributed to differences between groups in how fast they speciate or go extinct. Such macroevolutionary rates have been estimated for thousands of groups and have been correlated with an incredible variety of organismal traits. Here we analyze a large collection of phylogenetic trees and fossil time series and describe a hidden generality amongst these seemingly idiosyncratic results: speciation and extinction rates follow a scaling law where both depend on the age of the group in which they are measured, with the fastest rates in the youngest clades. Using a series of simulations and sensitivity analyses, we demonstrate that the time-dependency is unlikely to be a result of simple statistical artifacts. As such, this time-scaling is likely a genuine feature of the Tree of Life -- hinting that the dynamics of biodiversity over deep time may be driven, in part, by surprisingly simple and general principles.
Streptomycesvolatile compounds influence exploration and microbial community dynamics by altering iron availability
Authors: Jones Stephanie E. , Pham Christine A. , McKillip Joseph , Zambri Matthew , Carlson Erin E. , Elliot Marie A.
Published: August 2018

Bacteria and fungi produce a wide array of volatile organic compounds (VOCs), and these can act as infochemicals or as competitive tools. Recent work has shown that the VOC trimethylamine (TMA) can promote a new form ofStreptomycesgrowth, termed ‘exploration’. Here, we report that TMA also serves to alter nutrient availability in the area surrounding exploring cultures: TMA dramatically increases the environmental pH, and in doing so, reduces iron availability. This, in turn, compromised the growth of other soil bacteria and fungi. In contrast,Streptomycesthrives in these iron-depleted niches by secreting a suite of differentially modified siderophores, and by upregulating genes associated with siderophore uptake. Further reducing iron levels by siderophore piracy, limiting siderophore uptake, or growing cultures in the presence of iron chelators, unexpectedly enhanced exploration. Our work reveals a new role for VOCs in modulating iron levels in the environment, and implies a critical role for VOCs in modulating the behaviour of microbes and the makeup of their communities.
Zebrafish Otolith Biomineralization Requires Polyketide Synthase
Authors: Thiessen Kevin D. , Grzegorski Steven J. , Higuchi Lisa , Shavit Jordan A. , Kramer Kenneth L.
Published: August 2018

Deflecting biomineralized crystals attached to vestibular hair cells are necessary for maintaining balance. Zebrafish (Danio rerio) are useful organisms to study these biomineralized crystals called otoliths, as many required genes are homologous to human otoconial development. We sought to identify and characterize the causative gene in a trio of mutants,no content (nco)andcorkscrew (csr), andvanished (vns), which fail to develop otoliths during early ear development. We show thatnco, csr, andvnshave potentially deleterious mutations in polyketide synthase (pks1), a multi-modular protein that has been previously implicated in biomineralization events in chordates and echinoderms. We found that Otoconin-90 (Oc90) expression within the otocyst is normal inncoandcsr; therefore, it is not sufficient for otolith biomineralization in zebrafish. Similarly, normal localization of Otogelin, a protein required for otolith tethering in the otolithic membrane, is not sufficient for Oc90 attachment. Furthermore, eNOS signaling and Endothelin-1 signaling were the most up- and down-regulated pathways during otolith agenesis innco, respectively. Our results demonstrate distinct processes for otolith nucleation and biomineralization in vertebrates and will be a starting point for models that are independent of Oc90-mediated seeding. This study will serve as a basis for investigating the role of eNOS signaling and Endothelin-1 signaling during otolith formation.
Divine: Prioritizing Genes for Rare Mendelian Disease in Whole Exome Sequencing Data
Authors: Hong Changjin , Clemenceau Jean R. , Yeu Yunku , Hwang TaeHyun
Published: August 2018

Motivation

Recent studies showed that a phenotype-driven analysis of whole exome sequencing (WES) could provide more accurate and clinically relevant genetic variants.

Results

We develop a computational tool called Divine that integrates patients’ phenotype(s) and WES data with 30 prior biological knowledge (e.g., human phenotype ontology, gene ontology, pathway database, protein-protein interaction networks, pathogenicity by the amino acid change due to polymorphism, and hot-spot protein domains) to prioritize potential disease-causing genes. In a retrospective study with 22 real and four simulated data set, Divine ranks the same pathogenic genes confirmed by the original studies 5th on average out of a thousand of mutated genes and outperforms existing state-of-the-art methods.

Availability

https://github.com/hwanglab/divine

Contact

hwangt@ccf.org

Supplementary information

Supplementary Document is attached at the end of the page.
Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome
Authors: Booker Sam A. , Domanski Aleksander P.F. , Dando Owen R. , Jackson Adam D. , Isaac John T.R. , Hardingham Giles E. , Wyllie David J.A. , Kind Peter C.
Published: August 2018

Cellular and circuit hyperexcitability are core features of Fragile X Syndrome and related autism spectrum disorder models. However, a synaptic basis for this hyperexcitability has proved elusive. We show in a mouse model of Fragile X Syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, near-simultaneous uncaging at multiple spines revealed fewer spines are required to trigger an action potential. This arose, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents. Super-resolution microscopy revealed no change in dendritic spine morphology, pointing to an absence of a structure-function relationship. However, ultrastructural analysis revealed a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine excitatory currents following glutamate uncaging. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.
A neuromechanistic model for rhythmic beat generation
Authors: Bose Amitabha , Byrne Áine , Rinzel John
Published: August 2018

When listening to music, humans can easily identify and move to the beat. Numerous experimental studies have identified brain regions that may be involved with beat perception and representation. Several theoretical and algorithmic approaches have been proposed to account for this ability. Related to, but different from the issue of how we perceive a beat, is the question of how we learn to generate and hold a beat. In this paper, we introduce a neuronal framework for a beat generator that is capable of learning isochronous rhythms over a range of frequencies that are relevant to music and speech. Our approach combines ideas from error-correction and entrainment models to investigate the dynamics of how a biophysically-based neuronal network model synchronizes its period and phase to match that of an external stimulus. The model makes novel use of on-going faster gamma rhythms to form a set of discrete clocks that provide estimates, but not exact information, of how well the beat generator spike times match those of a stimulus sequence. The beat generator is endowed with plasticity allowing it to quickly learn and thereby adjust its spike times to achieve synchronization. Our model makes generalizable predictions about the existence of asymmetries in the synchronization process, as well as specific predictions about resynchronization times after changes in stimulus tempo or phase. Analysis of the model demonstrates that accurate rhythmic time keeping can be achieved over a range of frequencies relevant to music, in a manner that is robust to changes in parameters and to the presence of noise.

Author summary

Music is integral to human experience and is appreciated across a wide range of cultures. Although many features distinguish different musical traditions, rhythm is central to nearly all. Most humans can detect and move along to the beat through finger or foot tapping, hand clapping or other bodily movements. But many people have a hard time “keeping a beat”, or say they have “no sense of rhythm”. There appears to be a disconnect between our ability to perceive a beat versus our ability to produce a beat, as a drummer would do as part of a musical group. Producing a beat requires beat generation, the process by which we learn how to keep track of the specific time intervals between beats, as well as executing the motor movement needed to produce the sound associated with a beat. In this paper, we begin to explore neural mechanisms that may be responsible for our ability to generate and keep a beat. We develop a computational model that includes different neurons and shows how they cooperate to learn a beat and keep it, even after the stimulus is removed, across a range of frequencies relevant to music. Our dynamical systems model leads to predictions for how the brain may react when learning a beat. Our findings and techniques should be widely applicable to those interested in understanding how the brain processes time, particularly in the context of music.
Long fragments achieve lower base quality in Illumina paired-end sequencing
Authors: Tan Ge , Opitz Lennart , Schlapbach Ralph , Rehrauer Hubert
Published: August 2018

Illumina’s technology provides high quality reads of DNA fragments with error rates below 1/1000 per base. Runs typically generate a millions of reads where the vast majority of the reads has also an average error rate below 1/1000. However, some paired-end sequencing data show the presence of a subpopulation of reads where the second read has lower average qualities. We show that the fragment length is a major driver of increased error rates in the R2 reads. Fragments above 500 nt tend to yield lower base qualities and higher error rates than shorter fragments. We demonstrate the fragment length dependency of the R2 read qualities using publicly available Illumina data generated by various library protocols, in different labs and using different sequencer models. Our finding extends the understanding of the Illumina read quality and has implications on error models for Illumina reads. It also sheds a light on the importance of the fragmentation during library preparation and the resulting fragment length distribution.
A spike-timing-dependent plasticity rule for single, clustered and distributed dendritic spines
Authors: Tazerart Sabrina , Mitchell Diana E. , Miranda-Rottmann Soledad , Araya Roberto
Published: August 2018

Spike-timing-dependent plasticity (STDP) has been extensively studied in cortical pyramidal neurons, however, the precise structural organization of excitatory inputs that supports STDP, as well as the structural, molecular and functional properties of dendritic spines during STDP remain unknown. Here we performed a spine STDP protocol using two-photon glutamate uncaging to mimic presynaptic glutamate release (pre) paired with somatically generated postsynaptic spikes (post). We found that the induction of STDP in single spines follows a classical Hebbian STDP rule, where pre-post pairings at timings that trigger LTP (t-LTP) produce shrinkage of the activated spine neck and a concomitant increase in its synaptic strength; and post-pre pairings that trigger LTD (t-LTD) decrease synaptic strength without affecting the activated spine shape. Furthermore, we tested whether the single spine-Hebbian STDP rule could be affected by the activation of neighboring (clustered) or distant (distributed) spines. Our results show that the induction of t-LTP in two clustered spines (<5 μm apart) enhances LTP through a mechanism dependent on local spine calcium accumulation and actin polymerization-dependent neck shrinkage, whereas t-LTD was disrupted by the activation of two clustered spines but recovered when spines were separated by >40 μm. These results indicate that synaptic cooperativity, induced by the co-activation of only two clustered spines, provides local dendritic depolarization and local calcium signals sufficient to disrupt t-LTD and extend the temporal window for the induction of t-LTP, leading to STDP only encompassing LTP.
A Tumor Suppressor-Regulated Cell Cycle Derived Gene Signature is Prognostic of Recurrence Risk in Prostate Cancer
Authors: Georgescu Constantin , Corbin Joshua M. , Thibivilliers Sandra , Webb Zachary D. , Zhao Yan D. , Koster Jan , Fung Kar-Ming , Asch Adam S. , Wren Jonathan D. , Ruiz-Echevarría Maria J.
Published: August 2018

Background

The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.

Methods

We used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated withTmeff2,an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analysis were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SIgCheck software.

Results

Low levels of Tmeff2 mRNA significantly (p<0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9≤HR≥4.1; p≤0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96≤HR≥4.28; p≤0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017).

Conclusions

This study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, likeTmeff2, as guides to discover prognostic indicators, and suggests the possibility that lowTmeff2expression marks a distinct subclass of PCa.