bluuebunny/crossref_metadata_2025 huggingface dataset:
National Organization of Nurse Practitioner Faculties: A 40-year history of preparing nurse practitioners for practice
Authors: Pulcini Joyce , Hanson Charlene , Johnson Jean
Published: November 2019

This article provides a historic view of the development and accomplishments of the National Organization of Nurse Practitioner Faculties (NONPF). The authors explore the history leading up to the formalization of NONPF, noting the major factors leading to the creation of NONPF. Since its inception in 1980, NONPF has led efforts to provide resources to nurse practitioner program faculty, create standards and guidelines for quality programs, and most recently work to develop measurable competencies. This article tracks the achievement of the organization by decade and provides an education, practice, and policy context that informed and inspired the activities of NONPF.
Risk factors for perforation of gastric endoscopic submucosal dissection: a systematic review and meta-analysis
Authors: Ding Xiang , Luo Hesheng , Duan Houyu
Published: November 2019

The aim of this systematic review and meta-analysis was to identify significant risk factors for perforation in gastric endoscopic submucosal dissection. Studies published in the English language were searched for in Embase, WEB OF SCIENCE, Medline (PubMed and Ovid) and the Cochrane Central Register of Controlled Trials and Database of Systematic Reviews. Inclusion criteria and exclusion criteria were defined in advance in this work. Probable risk factors in a total of eighteen studies were evaluated, and the results are represented in the case of dichotomous variables as an odds ratio (with 95% confidence interval). Analysing the risk factors, the odds ratios were 1.98 (95% confidence interval: 1.02–3.85) for liver disease; 3.62 (95% confidence interval: 2.83–4.65) for vertical localization (the upper portion of the stomach); 1.42 (95% confidence interval: 1.03–1.96) for resected size (>20 mm); 3.05 (95% confidence interval: 1.80–5.17) for depth of invasion (submucosal); 4.12 (95% confidence interval: 1.63–10.39) for operation time (>2 hours); 1.59 (95% confidence interval: 1.25–2.01) for gross type of lesion (depressed or flat); and 3.88 (95% confidence interval: 2.69–5.60) for piecemeal resection. Liver disease, vertical localization (the upper portion of the stomach), resected size (>20 mm), depth of invasion (submucosal), operation time (>2 hours), gross type of lesion (flat or depressed), and piecemeal resection were verified to be risk factors for perforation of gastric endoscopic submucosal dissection.
Tandem repeat analysis for typing of Pseudomonas aeruginosa carrying resistance genes in southern Iran
Authors: Shokoohizadeh Leili , Alizade Hesam , rajabi Roya Ahmad , Namordizadeh Vahideh , Karmostaji Afsaneh
Published: November 2019

Pseudomonas aeruginosa is known to be one of the most important causes of nosocomial infections, with high antimicrobial resistance. Thus, the current study was conducted to evaluate usefulness of multiple-locus variable number of tandem repeat (VNTR) analysis (MLVA) plan for epidemiological studies and clustering of P. aeruginosa isolated in different wards of general hospital in Bandar Abbas, south of Iran, as well as assessment of presence of integrons and resistance genes in these strains.

A total of 72 clinical isolates of P. aeruginosa were isolated from the patients hospitalized in the hospital from December 2017 to June 2018 in Bandar Abbas, southern Iran. MLVA of seven VNTR markers was performed for differentiating and genetic relatedness of isolates. PCR amplification was conducted for detection of bla
HSV, bla

VEB
, int1 and int2 genes.

MLVA assay with seven loci resolved 36 different genotypes. Nearly all the isolates were classified into 6 different clonal complexes and 15 singletons.

High-level resistance rate was observed in ceftazidime (44; 61%). Nine (12.5%) of these isolates showed multiple drug resistance (MDR) phenotypes. Seven (9.7%), 5 (6.9%), 46 (63.8%) and 6 (8.3%) of isolates carried bla
HSV, bla

VEB
, int1 and int2 genes, respectively.

Seven VNTR markers used in this study provided a moderate discriminatory power and differentiated 36 genotypes among 72 isolates. In addition, presence of class 1 and class 2 integrons, bla
HSV and bla

VEB
in different clones indicated a high risk of spreading of MDR isolates among these clones. Results obtained from specification of different tandem repeats in the current study can be helpful to be used for MLVA in epidemiological surveillance of P. aeruginosa isolates in different regions.
Reactions to Solidarity Versus Normalcy Messages for Antistigma Campaigns
Authors: Corrigan Patrick W. , Al-Khouja Maya A.
Published: November 2019

This study considers two of many messages that are used in antistigma campaigns: normalcy, that mental illness is like most kinds of illness—“You are just like me,” and solidarity, that one's mental illness is accepted—“I stand with you.” This study examined how research participants rated message merit: understandable, effective, and compelling. We particularly examined how views on message merit varied by whether participants reported previous mental health experience. Three hundred seventy-three participants rated the merit of the two messages provided in random order. They also reported previous experience with mental health services. Overall, participants viewed solidarity messages with greater merit than normalcy. Participants with self-reported mental illness viewed the solidarity message even better than participants without mental illness; this pattern varied by specific mental health experience. Findings suggest a greater understanding of stigma reduction methods from those who are more likely to have experienced stigma.
Nosocomial Infections During Extracorporeal Membrane Oxygenation in Neonatal, Pediatric, and Adult Patients: A Comprehensive Narrative Review
Authors: MacLaren Graeme , Schlapbach Luregn J. , Aiken Alexander M.
Published: November 2019

Objectives:

Extracorporeal membrane oxygenation is increasingly used in critically ill patients with refractory cardiopulmonary failure. Nosocomial infection acquired during extracorporeal membrane oxygenation represents one of the most frequent complications but the available evidence on the risk of infection and its association with outcomes has not been comprehensively analyzed. We performed a narrative review examining the epidemiology of nosocomial infection during extracorporeal membrane oxygenation, association with clinical outcomes, and preventive strategies.

Data Sources:

We searched PubMed, Web of Science, EMBASE, and the Cochrane Library between 1972 and June 2018.

Study Selection:

We included any article which detailed nosocomial infection during extracorporeal membrane oxygenation. Articles were excluded if they were not written in English, detailed extracorporeal membrane oxygenation use for infections acquired prior to extracorporeal membrane oxygenation, or used other forms of extracorporeal support such as ventricular assist devices.

Data Extraction:

Two reviewers independently assessed eligibility and extracted data. We screened 984 abstracts and included 59 articles in the final review.

Data Synthesis:

The reported risk of nosocomial infection among patients receiving extracorporeal membrane oxygenation ranged from 3.5% to 64% per extracorporeal membrane oxygenation run, while the incidence of infection ranged from 10.1 to 116.2/1,000 extracorporeal membrane oxygenation days. Nosocomial infections during extracorporeal membrane oxygenation were consistently associated with longer duration of extracorporeal membrane oxygenation and, in several large multicenter studies, with increased mortality. Risk factors for nosocomial infection included duration of extracorporeal membrane oxygenation, mechanical and hemorrhagic complications on extracorporeal membrane oxygenation, and use of venoarterial and central extracorporeal membrane oxygenation. Biomarkers had low specificity for infection in this population. Few studies examined strategies on how to prevent nosocomial infection on extracorporeal membrane oxygenation.

Conclusions:

Nosocomial infections in extracorporeal membrane oxygenation patients are common and associated with worse outcomes. There is substantial variation in the rates of reported infection, and thus, it is possible that some may be preventable. The evidence for current diagnostic, preventive, and therapeutic strategies for infection during extracorporeal membrane oxygenation is limited and requires further investigation.
Achieving Sustainability in Reducing Unplanned Extubations in a Pediatric Cardiac ICU*
Authors: Censoplano Nina M. , Barrett Cindy S. , Ing Richard J. , Reichert Kelly , Rannie Michael , Kaufman Jon
Published: November 2019

Objectives:

To determine the incidence of unplanned extubations in a pediatric cardiac ICU in order to prove sustainability of our previously implemented quality improvement initiative. Additionally, we sought to identify risk factors associated with unplanned extubations as well as review the overall outcome of this patient population.

Design:

Retrospective chart review.

Setting:

Pediatric cardiac ICU at Children’s Hospital of Colorado on the Anschutz Medical Center of the University of Colorado.

Patients:

Intubated and mechanically ventilated patients in the cardiac ICU from July 2011 to December 2017.

Interventions:

None.

Measurements and Main Results:

A total of 2,612 hospitalizations for 2,067 patients were supported with mechanical ventilation. Forty-five patients had 49 episodes of unplanned extubations (four patients > 1 unplanned extubation). The average unplanned extubation rate per 100 ventilator days was 0.4. Patients who had an unplanned extubation were younger (0.09 vs 5.45 mo; p < 0.001), weighed less (unplanned extubation median weight of 3.0 kg [interquartile range, 2.5–4.5 kg] vs control median weight of 6.0 kg [interquartile range, 3.5–13.9 kg]) (p < 0.001), and had a longer length of mechanical ventilation (8 vs 2 d; p < 0.001). Patients who had an unplanned extubation were more likely to require cardiopulmonary resuscitation during their hospital stay (54% vs 18%; p < 0.001) and had a higher likelihood of in-hospital mortality (15% vs 7%; p = 0.001). There was a significant difference in surgical acuity as denoted by The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score and patients with an unplanned extubation had a higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category (p = 0.019). Contributing factors associated with unplanned extubation were poor endotracheal tube tape integrity, inadequate tube securement, and/or inadequate sedation. A low rate of unplanned extubation was maintained even in the setting of increasing patient complexity and an increase in patient volume.

Conclusions:

A low rate of unplanned extubation is sustainable even in the setting of increased patient volume and acuity. Additionally, early identification of patients at higher risk of unplanned extubation may also contribute to decreasing the incidence of unplanned extubation.
What Do Individuals With Borderline Personality Disorder Want From Treatment? A Study of Self-generated Treatment and Recovery Goals
Authors: NG FIONA Y.Y. , CARTER PHOEBE E. , BOURKE MARIANNE E. , GRENYER BRIN F.S.
Published: November 2019

Outcome measurement has progressed in the field of personality disorders. While the majority of trials have evaluated outcomes on the basis of symptom and diagnostic indices, what is considered a meaningful and valued outcome to individuals has seldom been investigated. Self-generated treatment goals were collected from 102 individuals seeking treatment for borderline personality disorder and independently coded by 2 raters. Responses were content-analyzed to determine the categories of goals people want for treatment. A total of 464 individual goal units across 4 main goal types emerged in the content analysis: reducing symptoms, improved well-being, better interpersonal relationships, and having a greater sense of self. Although the reduction of symptoms was the most commonly reported goal, 88.2% reported wanting better psychosocial functioning, including improvements in relationships, vocation, and self-understanding. The existence of the wide range of goals suggests that there is a need for clinicians to establish a collaborative formulation of treatment goals with individuals to ensure that treatment is personalized and meaningful.
Drug-drug Interactions in Psychiatric Practice, Part 4: Classification of Neuropsychiatric Medications Based on Their Principal Mechanisms of Action (With Updated Neuroscience-based Nomenclature)
Authors: PRESKORN SHELDON H. , GERMANN ALEXANDER
Published: November 2019

This column is the fourth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. This column discusses how drugs with multiple mechanisms of action have the potential to interact pharmacodynamically by the mechanism(s) mediating their therapeutic indication and for some drugs by other mechanisms (ie, drugs with multiple mechanisms of action). In this and the next column in this series, we present a classificatory system in the form of 2 tables that prescribers can use to predict the action of a neuropsychiatric drug when used alone as well as DDIs that can occur when it is used in combination with other drugs. The table in this column presents neuropsychiatric medications classified according to their mechanism(s) of action. The next column in this series will present a parallel table summarizing major types of pharmacodynamic DDIs based on mechanism of action and discuss strategies for minimizing adverse outcomes from such unintended DDIs. The authors recommend that health care providers’ knowledge of the drugs they frequently prescribe include both their generic and brand names (to avoid confusion leading to dispensing the wrong drugs), routinely used doses, pharmacokinetics including half-lives, pharmacodynamics including mechanism(s) of action and binding profile for specific receptor(s) (not specifically discussed here but available in other columns by the first author), adverse effect profiles, potential DDIs, and the evolving research literature on these agents.
Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 5: Major Types of Pharmacodynamic DDIs Based on Mechanism of Action (With Updated Neuroscience-based Nomenclature)
Authors: PRESKORN SHELDON H. , GERMANN ALEXANDER
Published: November 2019

This column is the fifth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. In the preceding column, a classificatory system based on mechanism of action was presented and a table was provided outlining the primary, known mechanism(s) of action of all commonly used psychiatric medications. This column presents a parallel table summarizing major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables to predict pharmacodynamically mediated DDIs. As discussed in the third column in this series, a classification scheme for drugs based on what enzymes, if any, are responsible for their biotransformation as a necessary step in their eventual elimination and whether a drug is an inhibitor or inducer of those enzymes can be used to predict pharmacokinetic DDIs mediated by cytochrome P450 enzymes, just as the mechanism-based classification system presented in this and the fourth column in this series can be used to predict pharmacodynamic-based DDIs. The ultimate intent of this series is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use >1 drug in combination to optimally treat a patient.
A Case Report of Neurosyphilis Limbic Encephalitis With Reversible Geschwind Syndrome and Mood Disorder
Authors: TOFFANIN TOMMASO , MIOLA ALESSANDRO , FOLLADOR HALIMA , FERRI GIOVANNI , SCUPOLA NADIA , MARTINO NICOLA , BARATTO ALESSANDRA , PERINI GIULIA IDA
Published: November 2019

Limbic encephalitis is an inflammatory process of the limbic structures, with polymorphic clinical features, caused by paraneoplastic and nonparaneoplastic conditions and infections. We describe a case of neurosyphilis limbic encephalitis, presenting with reversible Geschwind syndrome (hyperreligiosity and hypergraphia) and mood disorder due to the predominant involvement of left mesial temporal structures in a previously healthy 34-year-old, left-handed woman. Because neurosyphilis can mimic common neuropsychiatric syndromes, it should be included in the differential diagnosis of psychiatric disorders with suspected general medical causes. This case of nondominant limbic encephalopathy caused by syphilis infection highlights the relevance of a careful investigation for secondary psychotic, mood, and personality disorders when assessing new-onset psychiatric illness and the importance of a multidisciplinary approach to provide a better outcome in patients with neurosyphilis.
A Call for Caution in Prescribing Gabapentin to Individuals With Concurrent Polysubstance Abuse: A Case Report
Authors: MARTINEZ GABRIEL M. , OLABISI JENDAYI , RUEKERT LAURA , HASAN SYED
Published: November 2019

Gabapentin is an anticonvulsant medication with an indication from the US Food and Drug Administration for use in partial onset seizures and postherpetic neuralgia in the United States. Currently, gabapentin is only classified as a controlled substance subject to stricter prescribing and distributing regulations in certain states, as opposed to pregabalin, an anticonvulsant with a similar mechanism of action which is a considered a Schedule V medication under federal law. Gabapentin shares a structural similarity to pregabalin, and several case reports have suggested that gabapentin has a similar propensity for abuse. The mechanisms of the gabapentin reward pathway, addiction, and withdrawal, however, are not well known. This case report describes a patient with long-term polysubstance abuse and new onset gabapentin dependence and demonstrates the need for increased surveillance of gabapentin prescribing.
Commentary on “A Call for Caution in Prescribing Gabapentin to Individuals with Concurrent Polysubstance Abuse: A Case Report”
Authors: KAHN DAVID A.
Published: November 2019

Gabapentin is an anticonvulsant medication with an indication from the US Food and Drug Administration for use in partial onset seizures and postherpetic neuralgia in the United States. Currently, gabapentin is only classified as a controlled substance subject to stricter prescribing and distributing regulations in certain states, as opposed to pregabalin, an anticonvulsant with a similar mechanism of action which is a considered a Schedule V medication under federal law. Gabapentin shares a structural similarity to pregabalin, and several case reports have suggested that gabapentin has a similar propensity for abuse. The mechanisms of the gabapentin reward pathway, addiction, and withdrawal, however, are not well known. This case report describes a patient with long-term polysubstance abuse and new onset gabapentin dependence and demonstrates the need for increased surveillance of gabapentin prescribing.
Are We Missing Subtle Forms of Anti-N-Methyl-D-Aspartate Encephalitis With the Current Diagnostic Approach? A Case Report
Authors: BAYLISS LEO , RESTREPO-MARTÍNEZ MIGUEL , DUARTE ALFONSO , BORJA CESAR C. , ESPINOLA-NADURILLE MARIANA
Published: November 2019

Encephalitis related to antibodies against the N-methyl-D-aspartate receptor (NMDAr) is a recently described clinical entity in which IgG autoantibodies against the NR1 subunit of the NMDAr lead to the appearance of complex neuropsychiatric symptoms. As psychiatric symptoms predominate in early stages, anti-NMDAr encephalitis is frequently mistaken as a primary psychiatric disorder which delays treatment and has serious consequences for patients. This report presents the case of a 24-year-old woman with a subacute onset of psychotic and catatonic symptoms in whom current diagnostic criteria for probable anti-NMDAr encephalitis were not fulfilled. On the basis of the red flags that have been proposed to raise suspicion of anti-NMDAr encephalitis, a study of fluorodeoxyglucose positron emission tomography was requested and demonstrated bilateral occipital hypometabolism consistent with clinical suspicion of anti-NMDAr encephalitis. Once the appropriate treatment was established, the patient recovered completely. This case supports the need to maintain clinical suspicion of anti-NMDAr encephalitis, even when conventional diagnostic tests have been normal. Psychiatrists should be familiar with this entity to promote timely diagnosis and prompt treatment.
Personality as a Predictor of Treatment Response to Escitalopram in Adults With Body Dysmorphic Disorder
Authors: FANG ANGELA , PORTH RACHEL , PHILLIPS KATHARINE A. , WILHELM SABINE
Published: November 2019

Objective:

Serotonin reuptake inhibitors (SRIs) are the first-line pharmacotherapy for body dysmorphic disorder (BDD), a common and severe disorder. However, predictors and correlates of treatment response are not well understood. A closer examination of baseline personality dimensions and disorders and of changes in personality during SRI treatment is needed to advance knowledge of this clinically important issue.

Method:

We conducted a secondary analysis of data from a pharmacotherapy relapse prevention trial of the SRI escitalopram in adults with BDD to examine personality dimensions and traits, as well as whether these variables predict and correlate with treatment response. A total of 65 participants with BDD completed the Revised NEO Personality Inventory (NEO PI-R) before starting open-label treatment with escitalopram and 42 participants completed the NEO PI-R after treatment.

Results:

At baseline, participants with BDD displayed higher levels of neuroticism and lower levels of extraversion than a normed reference group. Higher baseline neuroticism was a significant predictor of nonresponse to escitalopram treatment, even when baseline depression severity was controlled for. Changes in neuroticism were not associated with treatment response.

Conclusion:

Our findings underscore the relationship between BDD and neuroticism, and they suggest a link between neuroticism and SRI treatment response.
Chicken or the Egg: A Case Report of Endoscopic-Assisted Treatment of Concomitant Sagittal Craniosynostosis With Calcified Cephalohematoma
Authors: Başağaoğlu Berkay , St Cyr Grace , Dempsey Robert F. , Dauser Robert C. , Lam Sandi , Maricevich Renata S.
Published: November 2019

Nonsyndromic craniosynostosis results in premature fusion of cranial sutures and is rarely found in the context of other craniofacial abnormalities. Here the authors present the case of a 3-month-old male infant with a rare presentation of sagittal craniosynostosis and concomitant calcified cephalohematoma repaired by endoscopic-assisted sagittal strip craniectomy with good cosmetic and functional outcomes. The authors discuss the advantages of endoscopic repair of craniosynostosis when found in the presence of a cephalohematoma and the need for further research to investigate a possible causal relationship between these 2 pathologies.
Using Dehydrated Amniotic Membrane Skin Substitute in Facial Burns: Is There a Outcome Difference Between Adult and Pediatric Patients?
Authors: Puyana Salomon , Ruiz Samuel , Elkbuli Adel , Bernal Eileen , McKenney Mark , Lim Rizal , Askari Morad , Mir Haaris
Published: November 2019

Introduction:

Facial burns have significant physical and psychological effects on patients, and minimizing morbidity continues to be a challenge for reconstructive surgeons. Advancements have allowed the development of various skin substitutes. Among these, human dehydrated amniotic skin substitutes represent novel technology, yet their outcome has not been sufficiently studied to guide practice. The objective of our study is to compare the safety of amniotic membrane skin substitutes in the treatment of adult and pediatric facial burns.

Methods:

The authors performed a retrospective review of our institutional burn registry, with 90 burn patients meeting the inclusion criteria. Demographic and outcome measures included age, percentage of total body surface area (TBSA), Injury Severity Score (ISS), and complications (eg, pigmentation, hypertrophic scar, infection, and delayed healing). Paired sample t test and Chi-squared test were used, with significance defined as P < 0.05.

Results:

Seventy-seven adults and 13 pediatric patients with facial burns who had received dehydrated amniotic membrane skin substitutes were included in the analysis. The mean age was 40.8 years for adults and 5.6 years for children. Mean TBSA was similar, with 9.6% (1−57%) in adults and 6.0% (2−14%) in children. The mean ISS did not significantly differ between groups (4.0 versus 2.2, P = ns). Pediatric patients with facial burns treated with amniotic membranes had a higher incidence of dyspigmentation relative to adult patients (46.2% versus 9.1%, P ≤ 0.05). Remaining morbidities were not significantly different between adult and pediatric patients. All patients, irrespective of group, healed by the second post-operative week.

Conclusion:

Dehydrated amniotic membrane skin substitutes are a safe alternative in the treatment of facial burns across all ages.
Nasal Septum Actinomycosis Mimicking Mucocele
Authors: Lee Dong Hoon , Yoon Tae Mi , Lee Joon Kyoo , Lim Sang Chul
Published: November 2019

Actinomycosis commonly occurs in the cervicofacial region, but rarely in the paranasal sinus. The authors report an unusual case of nasal septum actinomycosis that was mistaken for a mucocele. The patient was treated accordingly using antibiotic therapy after endoscopic sinus surgery was performed. It is noteworthy that actinomycosis of the nasal septum could appear as a mucocele without central calcification or bony destruction in imaging studies.
Interacting With Persons Who Have ALS
Authors: Fulcher-Rood Katrina , Higginbotham Jeff
Published: November 2019

Individuals with amyotrophic lateral sclerosis (ALS) in later stages may rely on a variety of modalities to communicate. The current study used conversational analysis techniques to examine naturalistic face-to-face interaction between a man with late-stage ALS and his wife to understand the types of accommodations they made to ensure that successful meaning was established. Three extracts of talk were selected from a corpus of 30 videotaped interactions between a man with ALS interacting either with his wife or the first author of the study. The extracts were examined for the type of communicative resources used and the ways in which conversants worked together to maintain the temporal–sequential demands of in-person interaction. Conversants used a variety of communication modalities during their social interactions including voice, body, gestures, a speech-generating device (SGD), and the SGD screen to construct utterances for one another, establish meaning, and stay in-time. The pair were successful and maintained conversation expectations in many ways similar to those with nonimpaired voices and bodies. Conversations including an SGD are a highly coordinated and interactive affair that is experienced jointly by all conversants. In this study, the conversational partners were aware of, and sensitive to, the temporal–sequential demands of in-person interaction and the modality restrictions associated with SGD use. Clinical and device design recommendations are discussed.
Update on posterior cortical atrophy
Authors: Holden Samantha K. , Bettcher Brianne M. , Pelak Victoria S.
Published: November 2019

Purpose of review

Non-amnestic (or atypical) presentations of neurodegenerative dementias are underrecognized and underdiagnosed, including posterior cortical atrophy (PCA) syndrome, which is characterized by prominent visuospatial and visuoperceptual dysfunction at presentation. It is most commonly due to Alzheimer's disease pathology, while Lewy body disease, corticobasal degeneration, and prion disease are neuropathological entities that are less frequently associated with PCA. The diagnosis of PCA is often delayed, to the detriment of the patient, and awareness and understanding of PCA will improve detection, prognostication, and treatment.

Recent findings

The natural history of PCA appears to be distinct from typical Alzheimer's disease and significant heterogeneity exists within the PCA syndrome, with the underlying causes of this heterogeneity beginning to be explored. Functional and molecular imaging can assist in better understanding PCA, particularly assessment of network disruptions that contribute to clinical phenotypes. Cerebrospinal fluid biomarkers are useful to detect underlying pathology, but measures of retinal thickness are less promising. There are currently no adequate treatment options for PCA.

Continued efforts to characterize PCA are needed, and greater awareness and understanding of atypical presentations of neurodegenerative dementias could serve to elucidate pathobiological mechanisms of underlying disease.
Mind the Outgroup: Influence of Taxon Sampling on Total-Evidence Dating of Pimpliform Parasitoid Wasps (Hymenoptera, Ichneumonidae)
Authors: Spasojevic Tamara , Broad Gavin R. , Sääksjärvi Ilari E. , Schwarz Martin , Ito Masato , Korenko Stanislav , Klopfstein Seraina
Published: November 2019

Taxon sampling is a central aspect of phylogenetic study design, but it has received limited attention in the context of molecular dating and especially in the framework of total-evidence dating, a widely used dating approach that directly integrates molecular and morphological information from extant and fossil taxa. We here assess the impact of different outgroup sampling schemes on age estimates in a total-evidence dating analysis under the uniform tree prior. Our study group are Pimpliformes, a highly diverse, rapidly radiating group of parasitoid wasps of the family Ichneumonidae. We cover 201 extant and 79 fossil taxa, including the oldest fossils of the family from the Early Cretaceous and the first unequivocal representatives of extant subfamilies from the mid Paleogene. Based on newly compiled molecular data from ten nuclear genes and a morphological matrix that includes 222 characters, we show that age estimates become both older and less precise with the inclusion of more distant and more poorly sampled outgroups. In addition, we discover an artefact that might be detrimental for total-evidence dating: “bare-branch attraction”, namely high attachment probabilities of, especially, older fossils to terminal branches for which morphological data are missing. After restricting outgroup sampling and adding morphological data for the previously attracting, bare branches, we recover a Middle and Early Jurassic origin for Pimpliformes and Ichneumonidae, respectively. This first age estimate for the group not only suggests an older origin than previously thought, but also that diversification of the crown group happened before the Cretaceous-Paleogene boundary. Our case study demonstrates that in order to obtain robust age estimates, total-evidence dating studies need to be based on a thorough and balanced sampling of both extant and fossil taxa, with the aim of minimizing evolutionary rate heterogeneity and missing morphological information.
Contextual flexibility inPseudomonas aeruginosacentral carbon metabolism during growth in single carbon sources
Authors: Dolan Stephen K. , Kohlstedt Michael , Trigg Stephen , Ramirez Pedro Vallejo , Wittmann Christoph , Kaminski Clemens F. , Welch Martin
Published: November 2019

Pseudomonas aeruginosais an opportunistic human pathogen, particularly noted for causing infections in the lungs of people with cystic fibrosis (CF). Previous studies have shown that the gene expression profile ofP. aeruginosaappears to converge towards a common metabolic program as the organism adapts to the CF airway environment. However, at a systems level, we still have only a limited understanding of how these transcriptional changes impact on metabolic flux. To address this, we analysed the transcriptome, proteome and fluxome ofP. aeruginosagrown on glycerol or acetate. These carbon sources were chosen because they are the primary breakdown products of airway surfactant, phosphatidylcholine, which is known to be a major carbon source forP. aeruginosain the CF airways. We show that the flux of carbon through central metabolism is radically different on each carbon source. For example, the newly-recognised EDEMP cycle plays an important role in supplying NADPH during growth on glycerol. By contrast, the EDEMP cycle is attenuated during growth on acetate, and instead, NADPH is primarily supplied by the isocitrate dehydrogenase(s)-catalyzed reaction. Perhaps more importantly, our proteomic and transcriptomic analyses reveal a global remodelling of gene expression during growth on the different carbon sources, with unanticipated impacts on aerobic denitrification, electron transport chain architecture, and the redox economy of the cell. Collectively, these data highlight the remarkable metabolic plasticity ofP. aeruginosa; a plasticity which allows the organism to seamlessly segue between different carbon sources, maximising the energetic yield from each.

Importance

Pseudomonas aeruginosais an opportunistic human pathogen, well-known for causing infections in the airways of people with cystic fibrosis. Although it is clear thatP. aeruginosais metabolically well-adapted to life in the CF lung, little is currently known about how the organism metabolises the nutrients available in the airways. In this work, we use a combination of gene expression and isotope tracer (“fluxomic”) analyses to find out exactly where the input carbon goes during growth on two CF-relevant carbon sources, acetate and glycerol (derived from the breakdown of lung surfactant). We find that carbon is routed (“fluxed”) through very different pathways during growth on these substrates, and that this is accompanied by an unexpected remodelling of the cell’s electron transfer pathways. Having access to this “blueprint” is important because the metabolism ofP. aeruginosais increasingly being recognised as a target for the development of much-needed antimicrobial agents.
Brainstem organoids from human pluripotent stem cells contain neural crest population
Authors: Eura Nobuyuki , Matsui Takeshi K. , Luginbühl Joachim , Matsubayashi Masaya , Nanaura Hitoki , Shiota Tomo , Kinugawa Kaoru , Iguchi Naohiko , Kiriyama Takao , Zheng Canbin , Kouno Tsukasa , Lan Yan Jun , Kongpracha Pornparn , Wiriyasermkul Pattama , Sakaguchi Yoshihiko M. , Nagata Riko , Komeda Tomoya , Morikawa Naritaka , Kitayoshi Fumika , Jong Miyong , Kobashigawa Shinko , Nakanishi Mari , Hasegawa Masatoshi , Saito Yasuhiko , Shiromizu Takashi , Nishimura Yuhei , Kasai Takahiko , Takeda Maiko , Kobayashi Hiroshi , Inagaki Yusuke , Tanaka Yasuhito , Makinodan Manabu , Kishimoto Toshifumi , Kuniyasu Hiroki , Nagamori Shushi , Muotri Alysson R. , Shin Jay W. , Sugie Kazuma , Mori Eiichiro
Published: November 2019

The brainstem controls heartbeat, blood pressure and respiration, which are life-sustaining functions, therefore, disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models have limitations, hampering the elucidation of diseases affecting specific components of the brain. Here, we developed a method to generate human brainstem organoids (hBSOs), containing neural crest stem cells as well as midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, and dopaminergic neurons, demonstrated by specific electrophysiological signatures. Single-cell RNA sequence analysis, together with proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem and neural crest, which raises the possibility of making use of hBSOs in grafting for transplantation, efficient drug screenings and modeling the neural crest diseases.
Subcellular mRNA localization regulates ribosome biogenesis in migrating cells
Authors: Dermit Maria , Dodel Martin , Lee Flora C. Y. , Azman Muhammad S. , Schwenzer Hagen , Jones J. Louise , Blagden Sarah P. , Ule Jernej , Mardakheh Faraz K.
Published: November 2019

Translation of Ribosomal Protein-coding mRNAs (RP-mRNAs) constitutes a key step in ribosome biogenesis, but the mechanisms which modulate RP-mRNAs translation in coordination with other cellular processes are poorly defined. Here we show that the subcellular localization of RP-mRNAs acts as a key regulator of their translation during cell migration. As cells migrate into their surroundings, RP-mRNAs localize to actin-rich protrusions at the front the cells. This localization is mediated by La-related protein 6 (LARP6), an RNA binding protein that is enriched in protrusions. Protrusions act as hotspots of translation for RP-mRNAs, resulting in enhancement of ribosome biogenesis and overall protein synthesis, which is required for sustained migration. In human breast carcinomas, Epithelial to Mesenchymal Transition (EMT) upregulates LARP6 expression to enhance ribosome biogenesis and support invasive growth. Our findings reveal LARP6 mediated mRNA localization as a key regulator of ribosome biogenesis during cell migration, and demonstrate a role for this process in cancer progression downstream of EMT.
Diversification of Reprogramming Trajectories Revealed by Parallel Single-cell Transcriptome and Chromatin Accessibility Sequencing
Authors: Xing Qiaorui , Farran Chadi El , Gautam Pradeep , Chuah Yu Song , Warrier Tushar , Toh Cheng-Xu Delon , Kang Nam-Young , Sugii Shigeki , Chang Young-Tae , Xu Jian , Collins James , Daley George , Li Hu , Zhang Li-Feng , Loh Yuin-Han
Published: November 2019

To unravel the mechanism of human cellular reprogramming process at single-cell resolution, we performed parallel scRNA-Seq and scATAC-Seq analysis. Our analysis reveals that the cells undergoing reprogramming proceed in an asynchronous trajectory and diversify into heterogeneous sub-populations. BDD2-C8 fluorescent probe staining and negative staining for CD13, CD44 and CD201 markers, could enrich for the GDF3+ early reprogrammed cells. Combinatory usage of the surface markers enables the fine segregation of the early-intermediate cells with diverse reprogramming propensities. scATAC-Seq analysis further uncovered the genomic partitions and transcription factors responsible for the regulatory phasing of reprogramming process. Binary choice between a FOSL1 or a TEAD4-centric regulatory network determines the outcome of a successful reprogramming. Altogether, our study illuminates the multitude of diverse routes transversed by individual reprogramming cells and presents an integrative roadmap for identifying the mechanistic part-list of the reprogramming machinery.
A 2-Compartment Bone Tumor Model for Testing the Efficacy of Cancer Drugs
Authors: Komez Aylin , Buyuksungur Arda , Antmen Ezgi , Swieszkowski Wojciech , Hasirci Nesrin , Hasirci Vasif
Published: November 2019

We produced a three dimensional (3D) bone tumor model (BTM) to study the interactions between healthy and tumor cells in a tumor tissue microenvironment, migration of the tumor cells and the efficacy of an anticancer drug, Doxorubicin, for personalized medicine applications. The model consisted of two compartments: (a) a healthy bone tissue mimic, poly(lactic acid-co-glycolic acid) (PLGA)/beta-tricalcium phosphate (β-TCP) sponge that was seeded with human fetal osteoblastic cells (hFOB) and human umbilical vein endothelial cells (HUVECs), and (b) a tumor mimic, a lyophilized collagen sponge that was seeded with human osteosarcoma cells (Saos-2). The tumor component was introduced to a central cavity created in the healthy bone mimic and together they constituted the total 3D model (3D-BTM). The scaffolds were characterized by determining their mechanical properties, studying their topography and stability with compression tests, microCT, SEM, confocal microscopy and gravimetry. Porosities of the sponges were determined from µCT data as 96.7% and 86% for PLGA/TCP and collagen sponges, respectively. The average diameters of the pores were measured by using ImageJ (NIH, USA) as 199±52 µm for PLGA/TCP and 50-150 μm for collagen scaffolds. Young’ modulus of the PLGA/TCP and collagen sponges were determined as 4.76MPa and 140kPa, respectively. Cells seeded on the two sponges were studied independently and together on the BTM. Cell proliferation, morphology, calcium phosphate forming capacity and ALP production were studied on both healthy bone and tumor mimics. All types of cells showed cellular extensions and spread on and in the scaffolds indicating good cell-material interactions. Angiogenic developments in BTM were studied along with migration of cells between the components with immunocytochemistry, SEM, microCT, qRT-PCR and agarose gel electrophoresis. Confocal microscopy showed that a direct contact was established between the cells present in different parts of the BTM; and the HUVEC cells within the healthy bone mimic were observed to migrate into the tumor mimic. This was confirmed by the increase in the levels of angiogenic factors VEGF, bFGF, and IL-8 in the tumor component. The IC50 of Doxorubicin on Saos-2 cells was determined as 0.1876 µg.mL−1. Doxorubicin was administered to the BTM at 2.7 µg.mL−1 concentration and after allowing one day for interaction, the cell number was determined with Alamar Blue cell viability test as 7-fold lesser compared to 24 h earlier. Apoptosis of the osteosarcoma cells was measured by caspase-3 enzyme activity assay. These results demonstrate the suitability of the 3D BTM model for use in the investigation of activities and migrations of cells in a tumor tissue. These will be very useful in studying metastatic capabilities of cells in addition to personalized drug treatments.
Comparison of in vitro and in planta toxicity of Vip3A for lepidopteran herbivores
Authors: Khan Muhammad Hassaan , Jander Georg , Mukhtar Zahid , Arshad Muhammad , Sarwar Muhammad , Asad Shaheen
Published: November 2019

Agricultural pest infestation is as old as domestication of food crops and contributes a major share to the cost of crop production. Transgenic production of Vip3A, an insecticidal protein from Bacillus thuringiensis, effectively controls lepidopteran pests. A synthetic vip3A gene was evaluated its efficacy against Spodoptera litura (cotton leafworm), Spodoptera exigua (beet armyworm), Spodoptera frugiperda (fall armyworm), Helicoverpa armigera (cotton bollworm), Helicoverpa zea (corn earworm), Heliothis virescens (tobacco budworm), and Manduca sexta (tobacco hornworm). In artificial diet assays, the Vip3A concentration causing 50% mortality was H. zea > H. virescens > S. exigua > H. armigera > M. sexta > S. frugiperda > S. litura. In contrast, on vip3A transgenic tobacco the order of resistance (time until 50% lethality) was M. sexta > H. virescens > S. litura > H. zea > H. armigera > S. exigua > S. frugiperda. There was no significant correlation between the artificial diet and transgenic tobacco effects. Notably, the two insect species that are best-adapted for growth on tobacco, M. sexta and H. virescens, showed the greatest tolerance of vip3A-transgenic tobacco. This may indicate synergistic effects of Vip3A and endogenous plant defense mechanisms, e.g. nicotine, to which M. sexta and H. virescens would have greater resistance. Together, our results show that artificial diet assays are a poor predictor of Vip3A efficacy in transgenic plants, lepidopteran species vary in their sensitivity to Vip3A in diet-dependent manner, and that host plant adaptation of the targeted herbivores should be considered when designing transgenic plants for pest control.
Dynamic neurotransmitter specific transcription factor expression profiles duringDrosophiladevelopment
Authors: Estacio-Gómez Alicia , Hassan Amira , Walmsley Emma , Le Lily Wong , Southall Tony D.
Published: November 2019

The remarkable diversity of neurons in the nervous system is generated during development, when properties such as cell morphology, receptor profiles and neurotransmitter identities are specified. In order to gain a greater understanding of neurotransmitter specification we profiled the transcription state of cholinergic, GABAergic and glutamatergic neuronsin vivoat three developmental time points. We identified 86 differentially expressed transcription factors that are uniquely enriched, or uniquely depleted, in a specific neurotransmitter type. Some transcription factors show a similar profile across development, others only show enrichment or depletion at specific developmental stages. Profiling of Acj6 (cholinergic enriched) and Ets65A (cholinergic depleted) binding sitesin vivoreveals that they both directly bind theChATlocus, in addition to a wide spectrum of other key neuronal differentiation genes. We also show that cholinergic enriched transcription factors are expressed in mostly non-overlapping populations in the adult brain, implying the absence of combinatorial regulation of neurotransmitter fate in this context. Furthermore, our data underlines that, similar toC. elegans, there are no simple transcription factor codes for neurotransmitter type specification.
Mitochondrial clearance of Ca2+controls insulin secretion
Authors: Vishnu N , Hamilton A , Bagge A , Wernersson A , Cowan E , Barnard H , Sancak Y , Kamer K.J. , Spégel P , Fex M , Tengholm A , Mootha V.K. , Nicholls DG , Mulder H
Published: November 2019

Transport of Ca2+from the cytosol to the mitochondrial matrix of insulin-secreting pancreatic β-cells facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. The establishment of the molecular identity of the mitochondrial Ca2+uniporter (MCU) and associated proteins has allowed mitochondrial Ca2+transport to be modified in intact cells. We examined the consequences of deficiency of the accessory protein, MICU2, in rat and human insulin-secreting cell lines as well as in mouse islets. Glucose-induced mitochondrial Ca2+elevation and inner membrane hyperpolarization were reduced, together with cytosolic ATP/ADP-ratios and insulin secretion. Insulin secretion inMicu2knock out mice was attenuatedin vitroas well asin vivo. While KCl-evoked sub-plasmalemmal Ca2+increases were more pronounced, the global cytosolic Ca2+response was, surprisingly, diminished inMICU2-deficient cells. These findings were supported by selective inhibition of mitochondrial Ca2+uptake by mitochondrial depolarization. It is concluded that mitochondrial Ca2+transport plays an additional and hitherto unrecognized role in stimulated β-cells by regulating net Ca2+entry across the plasma membrane. This is likely accounted for by clearing of sub-plasmalemmal Ca2+levels by mitochondria located near the plasma membrane.