bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpersonal Psychotherapy: A Scoping Review and Historical Perspective (1974–2017)
Authors: Ravitz Paula , Watson Priya , Lawson Andrea , Constantino Michael J. , Bernecker Samantha , Park Jamie , Swartz Holly A.
Published: March 2019

Background

Interpersonal Psychotherapy (IPT) is an affect- and relationally focused, time-limited treatment supported by research spanning >4 decades. IPT focuses on stressful interpersonal experiences of loss, life changes, disputes, and social isolation. It emphasizes the role of relationships in recovery. This scoping review describes, within a historical perspective, IPT’s evolution as an evidence-supported treatment of psychiatric disorders.

Methods

English-language publications (n = 1119) identified via EMBASE, MEDLINE, PsycINFO, and Web of Science databases (1974–2017), augmented with manual reference searches, were coded for clinical focus, population demographics, format, setting, publication type, and research type. Quantitative and qualitative analyses identified IPT publications’ characteristics and trends over four epochs of psychotherapy research.

Results

IPT literature primarily focused on depression (n = 772 articles; 69%), eating disorders (n = 135; 12%), anxiety disorders (n = 68; 6%), and bipolar disorder (n = 44; 4%), with rising publication rates and numbers of well-conducted randomized, controlled trials over time, justifying inclusion in consensus treatment guidelines. Research trends shifted from efficacy trials to effectiveness studies and population-based dissemination initiatives. Process research examined correlates of improvement and efficacy moderators. Innovations included global initiatives, prevention trials, and digital, web-based training and treatment.

Conclusion

Sparked by clinical innovations and scientific advances, IPT has evolved as an effective treatment of psychiatric disorders across the lifespan for diverse patients, including underserved clinical populations. Future research to elucidate mechanisms of change, improve access, and adapt to changing frameworks of psychopathology and treatment planning is needed. IPT addresses the universal centrality of relationships to mental health, which is as relevant today as it was over 40 years ago.
The Landscape of KMT2A‐PTD AML: Concurrent Mutations, Gene Expression Signatures, and Clinical Outcome
Authors: Hinai Adil S.A. Al , Pratcorona Marta , Grob Tim , Kavelaars François G. , Bussaglia Elena , Sanders Mathijs A. , Nomdedeu Josep , Valk Peter J.M.
Published: March 2019

Supplemental Digital Content is available in the text
Gab2 is Essential for Transformation by FLT3‐ITD in Acute Myeloid Leukemia
Authors: Sies Katharina , Spohr Corinna , Gründer Albert , Todorova Rumyana , Uhl Franziska Maria , Huber Julia , Zeiser Robert , Pahl Heike Luise , Becker Heiko , Aumann Konrad , Brummer Tilman , Halbach Sebastian
Published: March 2019

Supplemental Digital Content is available in the text
Solid Variant of a Proliferative Apocrine Hidrocystoma
Authors: Charles Norman C. , Patel Payal
Published: March 2019

A cystic lesion of the eyelid margin in a 37-year-old man was diagnosed clinically as an apocrine hidrocystoma, a common lesion in that location. Histopathologic examination confirmed the presence of a hidrocystoma but also disclosed an extensive proliferation of bland epithelial cells arising from the inner layer of the cyst. The authors further characterized this unique occurrence on the spectrum of Moll gland eyelid tumors by immunohistochemical analysis.
International Collaborative Assessment of the Validity of the EAONO-JOS Cholesteatoma Staging System
Authors: James Adrian L. , Tono Tetsuya , Cohen Michael S. , Iyer Arunachalam , Cooke Lynn , Morita Yuka , Matsuda Keiji , Yamamoto Yutaka , Sakagami Masafumi , Yung Matthew
Published: March 2019

Objective:

Assessment of validity of the Japanese Otological Society and the European Academy of Otology and Neurotology (EAONO–JOS) cholesteatoma staging system (EJS) through international collaboration to investigate: (a) feasibility of retrospectively staging previously acquired data, (b) strengths and weaknesses of the staging system.

Method:

Nine centers with prospective cholesteatoma databases were recruited. Cases were allocated to EJS Stage at each center using details from time of initial surgery. An independent rater also staged the cases and noted any discrepancies. At one center results from database staging were compared with staging based on contemporaneous operative records. Inter and intrarater reliabilities were calculated, and recidivism rates calculated according to Stage.

Results:

Of 1482 cases of cholesteatoma, 320 (22%) were Stage 1, 977 (67%) Stage 2, 153 (11%) Stage 3 and 4 (0.3%) Stage 4. No database contained details of all parameters required for accurate staging. Staging discrepancies occurred in >10% cases but inter and intrarater reliability of staging were high (Kappa 0.8; 95% confidence interval between 0.7–0.9). At 5 years, 11% had residual and 8% had recurrent cholesteatoma: rates increased with Stage but generally not significantly (Kaplan–Meier Log Rank analysis).

Conclusion:

The EJS Staging system provides an internationally agreed standard for collecting data to classify cholesteatoma severity. Although data can be applied retrospectively with reasonable reliability, prospective data collection would prevent inaccuracies that arise from missing data fields. To enhance validity of the EJS system, we propose clearer definitions of some categories. Refinements to definitions of stage may improve prognostic utility of the EJS but should be made using evidence powered by large-scale collaboration.
Management of Ménière's Disease: How Does the Coexistence of Vestibular Migraine Affect Outcomes?
Authors: Shin Chul Ho , Kim Yehree , Yoo Myung Hoon , Kim Tae Su , Park Jun Woo , Kang Byung Chul , Park Hong Ju
Published: March 2019

Objective:

To report the incidence of vestibular migraine (VM) in patients with Ménière's disease (MD) and investigate whether management outcomes of MD differ by the association of VM.

Study Design:

Retrospective cohort study.

Setting:

Tertiary care academic center.

Patients:

MD patients (n = 251) with/without VM who were managed for 5 years in a dizziness clinic.

Main Outcome Measures:

Influence of VM on management outcomes and hearing at the latest follow-up in stepwise management options.

Results:

Incidence of VM was 35% in MD patients. VM was more common in women than men (40 vs. 22%) and in probable MD than definite MD (43 vs. 29%). Bilateral MD was more frequent with coexistence of VM than without VM in definite MD (14 vs. 0%) as well as probable MD (24 vs. 7%). At the latest follow-up, preventive medications were effective in controlling vertigo in most (80%) patients (74%/90% in definite/probable MD). Additional intratympanic steroids were required in 16% (20%/10% in definite/probable MD) and intratympanic gentamicin or surgeries in 9 (6%) patients with intractable MD. The percentage of intractable MD did not differ with coexistence of VM, though definite MD showed a significantly higher percentage of intractable MD than probable MD (6 vs. 0%, respectively,p = 0.002). Worsening hearing was more frequent in definite MD than probable MD (19 vs. 4%), and association of VM did not influence the incidence of worsening hearing.

Conclusions:

Coexistence of VM was about 30 to 40% in definite and probable MD, especially frequent in bilateral MD (77%) and women with probable MD (50%), requiring identification of coexisting VM while managing MD patients. Management outcomes and worsening hearing in MD patients are not dependent on the coexistence of VM, when both are managed.
Platelet Indices Alterations in Children With Type 1 Diabetes Mellitus
Authors: Baghersalimi Adel , Koohmanaee Shaahin , Darbandi Bahram , Farzamfard Venus , Hassanzadeh Rad Afagh , Zare Roghaye , Tabrizi Manijeh , Dalili Setila
Published: March 2019

Platelet (PLT) hyperactivity is a key factor which contributes to cardiovascular complications in patients with type 2 diabetes mellitus even in preclinical stages of disease. To the best of our knowledge, there is limited researches in this regard among patients with type 1 diabetes. The aim of this study was to evaluate hematologic indices indicating PLT activity in children with type 1 diabetes. This was a case-control study which was conducted on 166 inpatients in 17 Shahrivar children hospital, Rasht, Iran during April 2016 to April 2017. Cases and controls were 83 children with type 1 diabetes mellitus and 83 children hospitalized for thorough assessment of short stature, respectively. Groups were matched for age and sex. Demographic characteristics and hematologic variables were assessed. The Shapiro-Wilk test was used to determine the normality of the distribution. Results for continuous and categorical variables were demonstrated as mean±SD and number and percent, respectively. Continuous variables without normal distribution were demonstrated as median (interquartile range). The χ2/Fisher’s exact test was used to compare categorical variables. The normal and non-normal distributed quantitative variables were respectively assessed by independent T-test or Mann-Whitney U test. P-value <0.05 noted statistical significance. The median (interquartile range) age of all children was 10 (6 to 13) years old. Thirty-five (42.2) of patients with diabetes and 35 (42.2) of control group were male individuals. There were positive correlation between age (r=0.370; P=0.001), hemoglobin (r=0.278; P=0.009), blood sugar (r=0.243; P=0.027), PLT distribution width (r=0.229; P=0.038), plateletcrit (PCT) (r=0.290; P=0.008), PLT to lymphocyte ratio (r=0.230; P=0.037) and glycosylated hemoglobin in children with diabetes. The cut-off point of PCT was 0.19 (sensitivity=87.8%, specificity=66.7%). Only increased PCT (>0.19) was related with poor metabolic control and can put the patients to the risk of future cardiovascular events. The authors recommend considering multiple PLT parameters, and not just one of them, and even designing a scoring system in terms of PLT parameters for type 1 diabetes mellitus management programs.
Negative Experiences in Childhood, Parental Style, and Resilience Among People Reporting Paranormal Experiences
Authors: Parra Alejandro
Published: March 2019

There are relatively few studies examining the parental style, childhood trauma, and paranormal experiences/beliefs; therefore, the aim of this study is to measure the dominant parental style of those who have experienced paranormal events and their correlation with negative events in childhood and resilience. Four questionnaires were administered to 644 participants. The results showed high frequency of experiences such as sense of presence, premonitory dreams, telepathy, mystical experiences, apparitions, and out-of-body experiences, among others. The results confirmed three hypotheses that predict a positive and significant correlation between the paranormal experiences in adult life and negative experiences in childhood, such as abuse and neglect. One possible interpretation is that “flexible” parental style is the more permissive ones (greater openness and sensitivity to capture alternative realities), in contrast to “rigid” parental style (whose perspectives generate restrictions to capitalize on the unconventional experiences of their children).
Venoarterial Extracorporeal Life Support Utilization in a Pediatric Trauma Patient Following a Severe Dog Mauling
Authors: Puzio Thaddeus J. , Cools Katherine , Adamson William , Erickson Kimberly
Published: March 2019

According to the Centers for Disease Control and Prevention, approximately 4.5 million dog bites occur each year in the United States, and more than half of these cases affect children. An estimated 1 in 6 dog bites, representing more than 800,000 bite victims each year, requires some form of medical attention. Historically, pediatric trauma patients who suffer devastating injuries and cardiopulmonary collapse requiring heroic salvage efforts have poor outcomes. We present the first case of extracorporeal membrane oxygenation utilized in a pediatric trauma patient following a severe dog bite injury. This case is an extraordinary example of multidisciplinary care of the pediatric trauma patient. It highlights the public health burden of dog bite injuries and the scant literature on extracorporeal membrane oxygenation in pediatric trauma patients.
Adolescent Substance Abuse Risk
Authors: Chun Thomas H. , Chernick Lauren S. , Ahmad Fahd A. , Ranney Megan L. , Shenoi Rohit P. , Casper T. Charles , Fein Joel A. , Grupp-Phelan Jackie , McAninch B. , Powell Elizabeth C. , Bromberg Julie R. , Linakis James G. , Spirito Anthony ,   for the Pediatric Emergency Care Applied Research Network
Published: March 2019

Objectives

The aim of this study was to understand the prevalence of alcohol and other substance use among teenagers in generalized samples.

Methods

This study compared the alcohol and other substance use of adolescents enrolled in a screening study across 16 Pediatric Emergency Care Applied Research Network emergency departments (EDs) (ASSESS) with those sampled in 2 nationally representative surveys, the Youth Risk Behavior Surveillance System (YRBSS) and the National Survey of Drug Use and Health (NSDUH). The analysis includes 3362 ASSESS participants and 11,142 YRBSS and 12,086 NSDUH respondents.

Results

The ASSESS patients had a similar profile to the NSDUH sample, with small differences in marijuana and cocaine use and age at first tobacco smoking and smoking within the last 30 days and higher use of snuff or chewing tobacco. The YRBSS participants had higher rates of using marijuana, snuff/chewing tobacco, methamphetamine, and hallucinogens and higher smoking rates compared with ASSESS and NSDUH.

Conclusions

Adolescents visiting Pediatric Emergency Care Applied Research Network EDs have substantial rates of substance use, similar to other nationally representative studies on this topic, although not as high as a school-based survey. Future ED studies should continue to investigate adolescent substance use, including exploring optimal methods of survey administration.
Profiling Pediatric Potentially Avoidable Transfers Using Procedure and Diagnosis Codes
Authors: Rosenthal Jennifer L. , Lieng Monica K. , Marcin James P. , Romano Patrick S.
Published: March 2019

Objectives

While hospital-hospital transfers of pediatric patients are often necessary, some pediatric transfers are potentially avoidable. Pediatric potentially avoidable transfers (PATs) represent a process with high costs and safety risks but few, if any, benefits. To better understand this issue, we described pediatric interfacility transfers with early discharges.

Methods

We conducted a descriptive study using electronic medical record data at a single-center over a 12-month period to examine characteristics of pediatric patients with a transfer admission source and early discharge. Among patients with early discharges, we performed descriptive statistics for PATs defined as patient transfers with a discharge home within 24 hours without receiving any specialized procedures or diagnoses.

Results

Of the 2,415 pediatric transfers, 31.4% were discharged home within 24 hours. Among transferred patients with early discharges, 356 patients (14.7% of total patient transfers) received no specialized procedures or diagnoses. Direct admissions were categorized as PATs 1.9-fold more frequently than transfers arriving to the emergency department. Among transferred direct admissions, PAT proportions to the neonatal intensive care unit (ICU), pediatric ICU, and non-ICU were 5.1%, 17.3%, and 27.3%, respectively. Respiratory infections, asthma, and ill-defined conditions (eg, fever, nausea with vomiting) were the most common PAT diagnoses.

Conclusions

Early discharges and PATs are relatively common among transferred pediatric patients. Further studies are needed to identify the etiologies and clinical impacts of PATs, with a focus on direct admissions given the high frequency of PATs among direct admissions to both the pediatric ICU and non-ICU.
Functional Task Training Combined With Electrical Stimulation Improves Motor Capacity in Children With Unilateral Cerebral Palsy: A Single-Subject Design
Authors: Gonçalves Rejane Vale , Fonseca Sérgio Teixeira , de Araújo Priscila Albuquerque , Souza Thales Rezende , Resende Renan Alves , Mancini Marisa Cotta
Published: March 2019

Purpose:

Reduced propulsive capability can impact negatively on mobility activities of many children with spastic unilateral cerebral palsy (SUCP). This study investigated the effect of a task-oriented training program combined with functional electrical stimulation (FES) on the motor capacity of children with SUCP.

Methods:

Single-case A-B design with follow-up. Gross motor function and biomechanical walking data of 4 children with SUCP were measured repeatedly across the baseline, intervention, and follow-up phases. Intervention was a task-oriented training program combined with FES applied on the gastrocnemius. Outcome variables included gait speed, impulsive torque, and ankle/hip power generation ratio. The 2-SD band and celeration line methods compared outcomes among the baseline, intervention, and follow-up periods.

Results:

One child improved walking speed. All children improved impulsive torque and ankle/hip power ratio of the affected leg. All children improved gross motor function.

Conclusion:

The intervention improved children's propulsive capability and positively influenced their mobility.
Multi-institutional Surgical Education Interventions
Authors: Salles Arghavan , Milam Laurel , Sevdalis Nick , Alseidi Adnan , Mellinger John , Stefanidis Dimitrios , Nahmias Jeffry , Kulaylat Afif N. , Kim Roger H. , Falcone John L. , Arora Tania K. , Phitayakorn Roy , Cochran Amalia
Published: March 2019

Objective:

The aim of the study was to identify and evaluate scholarship in multi-institutional interventional surgical education trials.

Summary Background Data:

Most research on interventions in surgical education occurs at individual institutions. These studies typically involve a small number of learners in a unique environment, thereby limiting their generalizability. The status of multi-institutional studies in surgical education remains unknown.

Methods:

We searched the Pubmed, ERIC, PsycINFO, SCOPUS, and CINAHL databases for all English language articles published from January 1, 2000 to December 31, 2015 using the keywords “medical education,” “surgical education,” “multi-institutional,” “multi-center,” and related terms. Articles published in an English language peer-reviewed journal that described an educational intervention conducted at more than one institution and involving surgeons were included.

Results:

Of 3511 identified articles, 53 met criteria for full-text review and inclusion in this review. The median number of institutional sites was 4, with a range of 2 to 54. The 2 most common areas of focus were technical skills (43% of studies) and clinical knowledge (32% of studies). These were also the 2 most commonly measured outcomes (technical skills 32% of studies, clinical knowledge 21% of studies). Thirteen percentage of studies measured only learner attitudes and perceptions rather than learning outcomes.

Conclusions:

Multi-institutional surgical education studies do not uniformly incorporate characteristics of high quality research, particularly related to study design, measurable outcomes, and assessment tools used. Coordinated support, including grant funding, that addresses the challenging nature of multi-institutional surgical education research may improve the quality of these studies.
The decision to move: response times, neuronal circuits and sensory memory in a simple vertebrate
Authors: Roberts Alan , Borisyuk Roman , Buhl Edgar , Ferrario Andrea , Koutsikou Stella , Li Wen-Chang , Soffe Stephen R.
Published: March 2019

All animals use sensory systems to monitor external events and have to decide whether to move. Response times are long and variable compared to reflexes, and fast escape movements. The complexity of adult vertebrate brains makes it difficult to trace the neuronal circuits underlying basic decisions to move. To simplify the problem, we investigate the nervous system and responses of hatchling frog tadpoles which swim when their skin is stimulated. Studying the neuron-by-neuron pathway from sensory to hindbrain neurons, where the decision to swim is made, has revealed two simple pathways generating excitation which sums to threshold in these neurons to initiate swimming. The direct pathway leads to short, and reliable delays like an escape response. The other includes a population of sensory processing neurons which extend firing to introduce noise and delay into responses. These neurons provide a brief, sensory memory of the stimulus, that allows tadpoles to integrate stimuli occurring within a second or so of each other. We relate these findings to other studies and conclude that sensory memory makes a fundamental contribution to simple decisions and is present in the brainstem of a basic vertebrate at a surprisingly early stage in development.
Leptin reduces pathology and increases adult neurogenesis in a transgenic mouse model of Alzheimer’s disease
Authors: Calió Michele Longoni , Salles Geisa Nogueira , Marinho Darci Souza , Fávero Mosini Amanda , Massinhani Fernando Henrique , Ko Gui Mi , Porcionatto Marimélia A.
Published: March 2019

Alzheimer’s disease (AD) is the most common dementia worldwide, and is characterized by the presence, in the brain tissue, of extracellular senile plaques formed by amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles of hyperphosphorylated Tau protein. These changes lead to progressive neuronal degeneration and dysfunction, resulting in severe brain atrophy and cognitive deficits. With the discovery that neurogenesis persists in the adult mammalian brain, including brain regions affected by AD, studies of the use of neural stem cells for treatment of neurodegenerative diseases in order to repair and/or prevent neuronal cell loss have increased. Here we show that leptin increases neurogenesis in the dentate gyrus of adult mice as well as in the subventricular zone both in wild type and AD transgenic mouse model. Chronic administration of leptin to young mice increased neural stem cell proliferation with significant effects on differentiation and survival of newborn cells. Expression of the long form of leptin receptor, LepRb, was detected in the neurogenic niches by reverse transcription-PCR and immunohistochemistry. Moreover, leptin modulated astrogliosis and the formation of senile plaques. Additionally, leptin led to attenuation of Aβ-induced neurodegeneration and superoxide anion production as revealed by Fluoro-Jade B and dihydroethidium (DHE) staining. Our study contributes to the understanding of the effects of leptin in the brain that may lead to the development of new therapies to treat Alzheimer’s disease.
Characterising memory loss in patients with autoimmune limbic encephalitis hippocampal lesions
Authors: Lad Meher , Mullally Sinéad L. , Houston Alexandra L. , Kelly Tom , Griffiths Timothy D.
Published: March 2019

Since the publication of Scoville and Milner’s (1957) seminal paper, the precise functional role played by the hippocampus in support of human memory has been fiercely debated. For instance, the single question of whether the hippocampus plays a time-limited or an indelible role in the recollection of personal memories led to a deep and tenacious schism within the field. Similar polarisations arose between those who debated the precise nature of the role played by the hippocampus in support of semantic relative to episodic memories and in recall/recollection relative to familiarity-based recognition. At the epicentre of these divisions lies conflicting neuropsychological findings. These differences likely arise due to the consistent use of heterogeneous patient populations to adjudicate between these positions. Here we utilised traditional neuropsychological measures in a homogenous patient population with a highly discrete hippocampal lesion (i.e. patients with voltage-gated potassium channel complex antibody associated limbic encephalitis (VGKC-LE)). We observed impairment of recent but not remote episodic memory, a preservation of semantic memory, and recall but not recognition memory deficits. We conclude that this increasingly well-characterised group of patients may represent an important homogeneous population in which the functional role played by the hippocampus may be more precisely delineated.
Gut-innervating nociceptor neurons protect against enteric infection by modulating the microbiota and Peyer’s patch microfold cells
Authors: Lai Nicole Y. , Musser Melissa A. , Pinho-Ribeiro Felipe A. , Baral Pankaj , Ma Pingchuan , Potts David E. , Chen Zuojia , Paik Donggi , Soualhi Salima , Shi Hailian , Misra Aditya , Goldstein Kaitlin , Sivanathan Kisha N. , Jacobson Amanda , Wallrapp Antonia , Lagomarsino Valentina , Kuchroo Vijay K. , Nowarski Roni , Starnbach Michael N. , Surana Neeraj K. , An Dingding , Wu Chuan , Huh Jun R. , Rao Meenakshi , Chiu Isaac M.
Published: March 2019

Gut-innervating nociceptor sensory neurons respond to noxious/tissue-damaging stimuli by initiating protective responses and releasing mediators that regulate tissue inflammation, gastrointestinal secretion, and motility. The role of nociceptors in host defense against enteric pathogens is unclear. Here, we found that gut-extrinsic nociceptor neurons are critical in protecting the host against Salmonella typhimurium (STm) infection. Nociceptors responded to STm by releasing the neuropeptide calcitonin gene-related peptide (CGRP). Targeted depletion of Nav1.8 and TRPV1 neurons from gut-extrinsic dorsal root ganglia and vagal ganglia increased STm colonization, invasion, and dissemination. Nociceptors regulated the gut microbiota at homeostasis, specifically segmented filamentous bacteria (SFB) levels in the ileum, which protected against STm by colonization resistance. Nociceptors also regulated the density of microfold epithelial cells in the Peyer’s patch via CGRP to limit points of entry for STm invasion into host tissues. Understanding how host sensory neurons crosstalk with pathogenic bacteria may impact treatments for enteric infections.

HIGHLIGHTS

Nav1.8 and TRPV1 nociceptors defend against Salmonella typhimurium (STm) infection

Nociceptors shape the gut microbiota and SFB levels which resist pathogen colonization

Nociceptors suppress Peyer’s patch microfold cell density to limit pathogen invasion

Neurons sense STm and release CGRP to modulate microfold cells and host defense
lionessR: single-sample network reconstruction in R
Authors: Kuijjer Marieke L. , Quackenbush John , Glass Kimberly
Published: March 2019

We recently developed LIONESS (Linear Interpolation to Obtain Network Estimates for Single Samples), a method that can be used together with network reconstruction algorithms to extract networks for individual samples in a population. LIONESS was originally made available as a function within the PANDA (Passing Attributes between Networks for Data Assimilation) regulatory network reconstruction framework. In this application note, we describe lionessR, an R implementation of LIONESS that can be applied to any network reconstruction method in R that outputs a complete, weighted adjacency matrix. As an example, we use lionessR to model single-sample co-expression networks on a bone cancer dataset, and show how lionessR can be used to identify differential co-expression between two groups of patients.

Availability and implementation

The lionessR open source R package, which includes a vignette of the application, is freely available athttps://github.com/mararie/lionessR.

Contact

marieke.kuijjer@ncmm.uio.no
Loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients
Authors: Ravi Anuradha , Halstead Fenella D , Bamford Amy , Casey Anna , Thomson Nicholas M. , van Schaik Willem , Snelson Catherine , Goulden Robert , Foster-Nyarko Ebenezer , Savva George M. , Whitehouse Tony , Pallen Mark J. , Oppenheim Beryl A.
Published: March 2019

Background

For long-stay patients on the adult intensive care unit, the gut microbiota plays a key role in determining the balance between health and disease. However, it remains unclear which ICU patients might benefit from interventions targeting the gut microbiota or the pathogens therein.

Methods

We undertook a prospective observational study of twenty-four ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses.

Results

Two-thirds of patients experienced a marked drop in gut microbial diversity (to an inverse Simpson’s index of <4) at some stage during their stay in ICU, often accompanied by absence or loss of beneficial commensal bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but administration of other antibiotics, including piperacillin-tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission ofEnterococcus faecium. In some patients we also saw domination of the gut microbiota by commensal organisms, such asMethanobrevibacter smithii.

Conclusions

Our results support a role for metagenomic surveillance of the gut microbiota and pave the way for patient-specific interventions that maintain or restore gut microbial diversity in the ICU.
Population history from the Neolithic to present on the Mediterranean island of Sardinia: An ancient DNA perspective
Authors: Marcus Joseph H. , Posth Cosimo , Ringbauer Harald , Lai Luca , Skeates Robin , Sidore Carlo , Beckett Jessica , Furtwängler Anja , Olivieri Anna , Chiang Charleston , Al-Asadi Hussein , Dey Kushal , Joseph Tyler A. , Der Sarkissian Clio , Radzevičiūtė Rita , Gradoli Maria Giuseppina , Haak Wolfgang , Reich David , Schlessinger David , Cucca Francesco , Krause Johannes , Novembre John
Published: March 2019

Recent ancient DNA studies of western Eurasia have revealed a dynamic history of admixture, with evidence for major migrations during the Neolithic and Bronze Age. The population of the Mediterranean island of Sardinia has been notable in these studies – Neolithic individuals from mainland Europe cluster more closely with Sardinian individuals than with all other present-day Europeans. The current model to explain this result is that Sardinia received an initial influx of Neolithic ancestry and then remained relatively isolated from expansions in the later Neolithic and Bronze Age that took place in continental Europe. To test this model, we generated genome-wide capture data (approximately 1.2 million variants) for 43 ancient Sardinian individuals spanning the Neolithic through the Bronze Age, including individuals from Sardinia’s Nuragic culture, which is known for the construction of numerous large stone towers throughout the island. We analyze these new samples in the context of previously generated genome-wide ancient DNA data from 972 ancient individuals across western Eurasia and whole-genome sequence data from approximately 1,500 modern individuals from Sardinia. The ancient Sardinian individuals show a strong affinity to western Mediterranean Neolithic populations and we infer a high degree of genetic continuity on the island from the Neolithic (around fifth millennium BCE) through the Nuragic period (second millennium BCE). In particular, during the Bronze Age in Sardinia, we do not find significant levels of the “Steppe” ancestry that was spreading in many other parts of Europe at that time. We also characterize subsequent genetic influx between the Nuragic period and the present. We detect novel, modest signals of admixture between 1,000 BCE and present-day, from ancestry sources in the eastern and northern Mediterranean. Within Sardinia, we confirm that populations from the more geographically isolated mountainous provinces have experienced elevated levels of genetic drift and that northern and southwestern regions of the island received more gene flow from outside Sardinia. Overall, our genetic analysis sheds new light on the origin of Neolithic settlement on Sardinia, reinforces models of genetic continuity on the island, and provides enhanced power to detect post-Bronze-Age gene flow. Together, these findings offer a refined demographic model for future medical genetic studies in Sardinia.
An image-computable model for the stimulus selectivity of gamma oscillations
Authors: Hermes Dora , Petridou Natalia , Kay Kendrick , Winawer Jonathan
Published: March 2019

Gamma oscillations in visual cortex have been hypothesized to be critical for perception, cognition, and information transfer. However, observations of these oscillations in visual cortex vary widely; some studies report little to no stimulus-induced narrowband gamma oscillations, others report oscillations for only some stimuli, and yet others report large oscillations for most stimuli. To reconcile these findings and better understand this signal, we developed a model that predicts gamma responses for arbitrary images and validated this model on electrocorticography (ECoG) data from human visual cortex. The model computes variance across the outputs of spatially pooled orientation channels, and accurately predicts gamma amplitude across 86 images. Gamma responses were large for a small subset of stimuli, differing dramatically from fMRI and ECoG broadband (non-oscillatory) responses. We suggest that gamma oscillations in visual cortex serve as a biomarker of gain control rather than being a fundamental mechanism for communicating visual information.
Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification
Authors: Gliddon Harriet D. , Kaforou Myrsini , Alikian Mary , Habgood-Coote Dominic , Zhou Chenxi , Oni Tolu , Anderson Suzanne T. , Brent Andrew J. , Crampin Amelia C. , Eley Brian , Kern Florian , Langford Paul R. , Ottenhoff Tom H. M. , Hibberd Martin L. , French Neil , Wright Victoria J. , Dockrell Hazel M. , Coin Lachlan J. , Wilkinson Robert J. , Levin Michael ,   on behalf of the ILULU Consortium
Published: March 2019

Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate the development of diagnostic tests.

To identify minimal transcript signatures, we applied a novel transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were validated using reverse transcriptase (RT) - digital PCR (dPCR).

A four-transcript signature (GBP6, TMCC1, PRDM1, ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2 – 100%). A three-transcript signature (FCGR1A, ZNF296, C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3 – 100%), regardless of HIV.

These signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.
TheC. elegansSET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations
Authors: Robert Valérie J. , Knutson Andrew K. , Rechtsteiner Andreas , Yvert Gaël , Strome Susan , Palladino Francesca
Published: March 2019

Chromatin factors contribute to germline maintenance by preserving a germline-appropriate transcriptional program. In the absence of the conserved histone H3 Lys4 (H3K4) methyltransferase SET-2,C. elegansgerm cells progressively lose their identity over generations, leading to sterility. How this transgenerational loss of fertility results from the absence of SET-2 is unknown. Here we performed expression profiling across generations on germlines from mutant animals lacking SET-2 activity. We found that gene deregulation occurred in 2 steps: a priming step in early generations progressing to loss of fertility in later generations. By performing Within-Class Analysis (WCA), a derivative of Principal Component Analysis, we identified transcriptional signatures associated with SET-2 inactivation, both at the priming step and later on during loss of fertility. Further analysis showed that repression of germline genes, derepression of somatic programs, and X-chromosome desilencing through interference with PRC2-dependent repression, are priming events driving loss of germline identity in the absence of SET-2. Decreasing expression of identified priming genes, including the C/EBP homologuecebp-1and TGF-β pathway components, was sufficient to delay the onset of sterility, suggesting that they individually contribute to the loss of germ cell fate. Altogether, our findings illustrate how the loss of a chromatin regulator at one generation can progressively deregulate multiple transcriptional and signaling programs, ultimately leading to loss of appropriate cell fate.
ThePax6master control gene initiates spontaneous retinal development via a self-organising Turing network
Authors: Grocott Timothy , Lozano-Velasco Estefania , Mok Gi Fay , Münsterberg Andrea E
Published: March 2019

Understanding how complex organ systems are assembled from simple embryonic tissues is a major challenge. Across the animal kingdom a great diversity of visual organs are initiated by a ‘master control gene’ calledPax6, which is both necessary and sufficient for eye development1–6. Yet precisely howPax6achieves this deeply homologous function is poorly understood. Here we show that vertebratePax6interacts with a pair of morphogen-coding genes,Tgfb2andFst, to form a putative Turing network7, which we have computationally modelled. Computer simulations suggest that this gene network is sufficient to spontaneously polarise the developing retina, establishing the eye’s first organisational axis and prefiguring its further development. Our findings reveal how retinal self-organisation may be initiated independent of the highly ordered tissue interactions that help to assemble the eyein vivo. These results help to explain how stem cell aggregates spontaneously self-organise into functional eye-cupsin vitro8. We anticipate these findings will help to underpin retinal organoid technology, which holds much promise as a platform for disease modelling, drug development and regenerative therapies.
The crustaceanArmadillidium vulgare(Latreille, 1804) (Isopoda: Oniscoidea), a new promising model for the study of cellular senescence
Authors: Depeux Charlotte , Samba-Louaka Ascel , Becking Thomas , Braquart-Varnier Christine , Moreau Jérôme , Lemaître Jean-François , Laverre Tiffany , Paulhac Hélène , Dechaume-Moncharmont François-Xavier , Gaillard Jean-Michel , Beltran-Bech Sophie
Published: March 2019

Senescence, the decline of physiological parameters with increasing age, is a quasi-ubiquitous phenomenon in the living world. The observed patterns of senescence, however, can markedly differ across species and populations, between sexes, and even among individuals. To identify the drivers of this variation in senescence, experimental approaches are essential and involve the development of tools and new study models. Current knowledge of the senescence process is mostly based on studies on vertebrates and main information about senescence in invertebrates is mostly limited to model organisms such asCaenorhabditis elegansorDrosophila melanogaster. In this context, we tested whether biomarkers of vertebrate ageing could be used to study senescence in a new invertebrate model: the common woodlouseArmadillidium vulgare(Latreille, 1804). More specifically, we looked for the effect of age in woodlouse on three well-established physiological biomarkers of ageing in vertebrates: immune cells (cell size, density, and viability), β-galactosidase activity, and the gene expression of telomerase reverse transcriptase (TERT), an essential subunit of telomerase protein. We found that the size of immune cells was higher in older individuals, whereas their density and viability decreased, and that the β-galactosidase activity increased with age, whereas the TERT gene expression decreased. These findings demonstrate that woodlouse displays age-related changes in biomarkers of vertebrate senescence, with different patterns depending on gender. The tools used in studies of vertebrate senescence can thus be successfully used in studies of senescence of invertebrates such as the woodlouse. The application of commonly used tools to new biological models offers a promising approach to assess the diversity of senescence patterns across the tree of life.
Extensive memory testing improves prediction of progression to MCI in late middle age
Authors: Gustavson Daniel E. , Elman Jeremy A. , Sanderson-Cimino Mark , Franz Carol E. , Panizzon Matthew S. , Jak Amy J. , Reynolds Chandra A. , Neale Michael C. , Lyons Michael J. , Kremen William S.
Published: March 2019

INTRODUCTION

Predicting risk for Alzheimer’s disease when most people are likely still biomarker negative would aid earlier identification. We hypothesized that combining multiple memory tests and scores in middle-aged adults would provide useful, and non-invasive, prediction of 6-year progression to MCI.

METHODS

We examined 849 men who were cognitively normal at baseline (mean age=55.69±2.45).

RESULTS

California Verbal Learning Test learning trials was the best individual predictor of amnestic MCI (OR=4.75). A latent factor incorporating 7 measures across 3 memory tests provided much stronger prediction (OR=9.88). This compared favorably with biomarker-based prediction in a study of much older adults.

DISCUSSION

Neuropsychological tests are sensitive and early indicators of Alzheimer’s disease risk at an age when few individuals are likely to have yet become biomarker positive. Single best measures may appear time- and cost-effective, but 30 additional minutes of testing, and use of multiple scores within tests, provides substantially improved prediction
microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory
Authors: Jones Meghan E , Sillivan Stephanie E. , Jamieson Sarah , Rumbaugh Gavin , Miller Courtney A.
Published: March 2019

microRNAs (miRNAs) have emerged as potent regulators of learning, recent memory and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memory, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue to identify miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was downregulated in the BLA. Further decreasing BLA mir-598-3p levels did not alter the expression or extinction of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 days post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton.
Levels of sdRNAs in cytoplasm and their association with ribosomes are dependent upon stress conditions but independent from snoRNA expression
Authors: Mleczko Anna M. , Machtel Piotr , Walkowiak M. , Wasilewska A. , Bąkowska-Żywicka K.
Published: March 2019

In recent years, a number of small RNA molecules derived from snoRNAs have been observed. Findings concerning the functions of sdRNAs in cells are limited primarily to their involvement in microRNA pathways. However, similar molecules have been observed inSaccharomyces cerevisiae, which is an organism lacking miRNA machinery. Considering our previous observations, we examined the subcellular localization of sdRNAs in yeast. Our findings reveal that both sdRNAs and their precursors, snoRNAs, are present in the cytoplasm at levels dependent upon stress conditions. Moreover, both sdRNAs and snoRNAs interact with translating ribosomes in a stress-dependent manner. As a consequence of binding to ribosomes, yeast sdRNAs exhibit inhibitory activity on translation. However, observed levels of sdRNAs and snoRNAs in the cytoplasm and their association with ribosomes suggest independent regulation of these molecules by yet unknown factors.
Single trial dynamics of attentional intensity in visual area V4
Authors: Ghosh Supriya , Maunsell John H.R.
Published: March 2019

Understanding how activity of visual neurons represents distinct components of attention and their dynamics that account for improved visual performance remains elusive because single-unit experiments have not isolated the intensive aspect of attention from attentional selectivity. We isolated attentional intensity and its single trial dynamics as determined by spatially non-selective attentional performance in an orientation discrimination task while recording from neurons in monkey visual area V4. We found that attentional intensity is a distinct cognitive signal that can be distinguished from spatial selectivity, reward expectations and motor actions. V4 spiking on single trials encodes a combination of sensory and cognitive signals on different time scales. Attentional intensity and the detection of behaviorally relevant sensory signals are well represented, but immediate reward expectation and behavioral choices are poorly represented in V4 spiking. These results provide a detailed representation of perceptual and cognitive signals in V4 that are crucial for attentional performance.
The yeast proteases Ddi1 and Wss1 are both involved in the DNA replication stress response
Authors: Svoboda Michal , Konvalinka Jan , Trempe Jean-François , Saskova Klara Grantz
Published: March 2019

Genome integrity and cell survival are dependent on proper replication stress response. Multiple repair pathways addressing obstacles generated by replication stress arose during evolution, and a detailed understanding of these processes is crucial for treatment of numerous human diseases. Here, we investigated the strong negative genetic interaction between two proteases involved in the DNA replication stress response, yeast Wss1 and Ddi1. While Wss1 proteolytically acts on DNA-protein crosslinks, mammalian DDI1 and DDI2 proteins remove RTF2 from stalled forksviaa proposed proteasome shuttle hypothesis. We show that the double-deleted Δddi1, Δwss1 yeast strain is hypersensitive to the replication drug hydroxyurea and that this phenotype can be complemented only by catalytically competent Ddi1 protease. Furthermore, our data show the key involvement of the helical domain preceding the Ddi1 protease domain in response to replication stress caused by hydroxyurea, offering the first suggestion of this domain’s biological function. Overall, our study provides a basis for a novel dual protease-based mechanism enabling yeast cells to counteract DNA replication stress.