bluuebunny/crossref_metadata_2025 huggingface dataset:
Rule learning in adolescents at clinical high risk for psychosis shows altered patterns of activation
Authors: Orr Joseph M. , Lopez Jesus , Imburgio Michael J. , Pelletier-Baldeli Andrea , Bernard Jessica A. , Mittal Vijay A.
Published: January 2020

Background

The ability to flexibly apply rules to novel situations is a critical aspect of adaptive human behavior. While executive function deficits are known to appear early in the course of psychosis, it is unclear which specific facets are affected. Identifying whether rule learning is impacted at the early stages of psychosis is necessary for truly understanding the etiology of psychosis and may be critical for designing novel treatments. Therefore, we examined rule learning in healthy adolescents and those meeting criteria for clinical high risk (CHR) for psychosis.

Methods

24 control and 22 CHR adolescents underwent rapid, high-resolution fMRI while performing a paradigm which required them to apply novel or practiced task rules.

Results

Previous work has suggested that practiced rules rely on rostrolateral prefrontal cortex (RLPFC) during rule encoding and dorsolateral prefrontal cortex (DLPFC) during task performance, while novel rules show the opposite pattern. We failed to replicate this finding, with greater activity for novel rules during performance. Comparing the HC and CHR group, there were no statistically significant effects, but an effect size analysis found that the CHR group showed less activation during encoding and greater activation during performance. This suggests the CHR group may use less efficient reactive control to retrieve task rules at the time of task performance, rather than proactively during rule encoding.

Conclusions

These findings suggest that flexibility may be altered in the clinical high risk state, however, more data is needed to determine whether these deficits predict disease progression.
Family Presence and Audience Effects on Cardiopulmonary Resuscitation: Perceptions of Pre-hospital Emergency Caregivers in Turkey
Authors: Erbay Hasan
Published: January 2020

Background

There have been many studies regarding family presence during cardiopulmonary resuscitation and most of them are about emergency services or intensive care units. However, the issue has not been studied enough in terms of pre-hospital emergency medicine and the perspective of pre-hospital emergency caregivers.

Aim

In this study, it is aimed to present the perceptions and attitudes of a group of pre-hospital emergency care professionals to family presence during cardiopulmonary resuscitation.

Method

The data for this descriptive research was collected between March-May 2015. The participants were 63 pre-hospital healthcares from a small city, Afyonkarahisar. The data was collected using a questionnaire and the responses summarized by using frequencies and percentages. Descriptive statistics were used to characterize the sample and each of the survey items.

Findings

Of the respondents, for demographic findings of each groups by highest rates; 38 (60.32%) were male, 31 (49.21%) were paramedics and 37 (58.73%) were 1-3 years work experienced. 65.07% were strongly opposed to the family presence during CPR. Among the total sample, 71.41% of participants did not agree with that the presence of press members positively affects their performance.

Conclusion

The presence of significant others during CPR affects pre-hospital emergency caregivers negatively. Disturbing effect on caregivers is related not only to the presence of family members or to other significant others but also related to the press and audience. Family presence causes health professionals to experience performance anxiety. Family presence and the audience effect are crucial issues that need more attention in pre-hospital cardiopulmonary resuscitation.
Comprehensive assessment of PINK1 variants in Parkinson’s disease
Authors: Krohn Lynne , Grenn Francis P. , Makarious Mary B. , Kim Jonggeol Jeffrey , Bandres-Ciga Sara , Roosen Dorien A. , Gan-Or Ziv , Nalls Mike A. , Singleton Andrew B. , Blauwendraat Cornelis
Published: January 2020

Multiple genes have been associated with monogenic Parkinson’s disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early onset Parkinson’s disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson’s disease. Here we comprehensively assess the role of PINK1 variants in Parkinson’s disease susceptibility using several large datasets totalling 376,558 individuals including: 13,708 Parkinson’s disease cases and 362,850 controls. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a risk factor for Parkinson’s disease.
A prospective evaluation of inter-rater agreement of routine medical records audits at a large general hospital in São Paulo, Brazil
Authors: Nunes Mafra Ana Carolina Cintra , Miraglia João Luiz , Basile Colugnati Fernando Antonio , Lourenço Padilha Gilberto Soares , Santos Tadeucci Renata Rafaella , Almeida Ederson , Bracco Mario Maia
Published: January 2020

Background

The quality of the patient’s medical records is strictly related to patient safety. Besides, its data are widely used in observational studies. However, the reliability of the information extracted from them is a matter of concern in audit processes to ensure inter-rater agreement (IRA). Thus, the objective of this study is to evaluate the IRA among members of the Patient’s Health Record Review Board (PHRRB), in routine auditing of medical records, and the impact of periodic discussions of results with raters.

Methods

Prospective longitudinal study conducted between July of 2015 and April of 2016 at Hospital Municipal Dr. Moysés Deutsch, a large public hospital in São Paulo. The PHRRB was composed of 12 physicians, 9 nurses and 3 physiotherapists, who audited medical records, monthly, with the number of raters changing throughout the study. It was carried out PHRRB meetings to reach a consensus on criteria that the members have to rate in the auditing process. It was created a review chart that raters should verify the registry of patient’s secondary diagnosis, chief complaint, history of presenting complaint, past medical history, medication history, physical exam and diagnostic testing. It was obtained the IRA every three months. The Gwet’s AC1 coefficient and Proportion of Agreement (PA) were calculated to evaluate the IRA for each item over time.

Results

The study included 1884 items from 239 records with an overall full agreement among raters of 71.2%. A significant IRA increase by 16.5% (OR=1.17; 95% CI=1.03—1.32; p=0.014) was found in the routine PHRRB auditing, with no significant differences between the PA and the Gwet’s AC1, that showed a similar evolution over time. The PA decreased by 27.1% when at least one of the raters was absent from the review meeting (OR=0.73; 95% CI=0.53—1.00; p=0.048).

Conclusions

Medical record quality has been associated with the quality of care and could be optimized and improved by targeted interventions. The PA and the Gwet’s AC1 are suitable agreement coefficients that are feasible to be incorporated in the routine of PHRRB evaluation process.
Neural stimulation and recording performance in human somatosensory cortex over 1500 days
Authors: Hughes Christopher L. , Flesher Sharlene N. , Weiss Jeffrey M. , Downey John E. , Collinger Jennifer L. , Gaunt Robert A.
Published: January 2020

Objective

Intracortical microstimulation (ICMS) in somatosensory cortex can restore sensation to people who have lost it due to spinal cord injury or other conditions. One potential challenge for chronic ICMS is whether neural recording and stimulation can remain stable over many years. This is particularly relevant since the recording quality of implanted microelectrode arrays frequently experience degradation over time and stimulation safety has been considered a potential barrier to the clinical use of ICMS. Our objective is to evaluate stability of recordings on intracortical stimulated and non-stimulated electrodes in a human participant across a long period of implantation. Additionally, we would like to assess the ability to evoke sensations with ICMS over time.

Approach

In a study investigating intracortical implants for a bidirectional brain-computer interface, we implanted microelectrode arrays with sputtered iridium oxide tips in the somatosensory cortex of a human participant with a cervical spinal cord injury. We regularly stimulated through electrodes on these microelectrode arrays to evoke tactile sensations on the hand. Here, we quantify the stability of these electrodes in comparison to non-stimulated electrodes implanted in motor cortex over 1500 days in two ways: recorded signal quality and electrode impedances. Additionally, we quantify the perceptual stability of ICMS-evoked sensations with detection thresholds.

Main results

We found that recording quality, as assessed by the number of electrodes with high-amplitude waveform recordings (> 100 µV), peak-to-peak voltage, noise, and signal-to-noise ratio, generally decreased over time on stimulated and non-stimulated electrodes. However, stimulated electrodes were much more likely to continue to record high-amplitude signals than non-stimulated electrodes. Interestingly, the detection thresholds for stimulus-evoked tactile sensations decreased over time from a median of 31.5 μA at Day 100 to 10.4 μA at Day 1500, with the most substantial changes occurring between Day 100 and Day 500.

Significance

These results provide evidence that ICMS in human somatosensory cortex can be provided over long periods of time without deleterious effects on recording or stimulation capabilities. In fact, psychophysical sensitivity to stimulation improves over time and stimulation itself may promote more robust long-term neural recordings.
Drug susceptibility profiling of AustralianBurkholderiaspecies as models for developing melioidosis therapeutics
Authors: Amiss Anna S. , Webb Jessica R. , Mayo Mark , Currie Bart J. , Craik David J. , Henriques Sónia Troeira , Lawrence Nicole
Published: January 2020

Synopsis

Background

Melioidosis is a neglected tropical disease caused by the Gram-negative soil bacteriumBurkholderia pseudomallei.Current treatment regimens are prolonged and costly, and acquired antimicrobial resistance has been reported for all currently used antibiotics.

Objectives

Efforts to develop new treatments for melioidosis are hampered by the risks associated with handling pathogenicB. pseudomallei, which restricts research to facilities with Biosafety Level (BSL) 3 containment. Closely relatedBurkholderiaspecies that are less pathogenic can be investigated under less stringent BSL 2 containment. We hypothesized that near-neighbourBurkholderiaspecies could be used as model organisms for developing therapies that would also be effective againstB. pseudomallei.

Methods

We used microbroth dilution assays to compare the susceptibility of three AustralianB. pseudomalleiisolates and five near-neighbourBurkholderiaspecies –B. humptydooensis, B. thailandensis, B. oklahomensis, B territoriiandB. stagnalis –to antibiotics currently used to treat melioidosis, and general-use antibacterial agents. We also established the susceptibility profiles ofB. humptydooensisandB. territoriito 400 compounds from the Medicines for Malaria Venture Pathogen Box.

Results

From these comparisons, we observed a high degree of similarity in the susceptibility profiles ofB. pseudomalleiand near-neighbour speciesB. humptydooensis, B. thailandensis, B. oklahomensisandB. territorii.

Conclusions

Less pathogenic AustralianBurkholderiaspeciesB. humptydooensis, B. thailandensis, B. oklahomensisandB. territoriiare excellent model organisms for developing potential new therapies for melioidosis.
To pool or not to pool samples for Sexually Transmitted Infections detection in Men who have Sex with Men? An evaluation of a new pooling method using the GeneXpert instrument in West-Africa
Authors: De Baetselier Irith , Vuylsteke Bea , Yaya Issifou , Dagnra Anoumou , Diandé Souba , Yaka Jeff , Kadanga Gérard , Traore Issa , Cuylaerts Vicky , Smet Hilde , Dah Elias , Mensah Ephrem , Anoma Camille , Koné Amadou , Dramane Diallo , Fayé-Ketté Hortense , Yeo Alain , Keita Bintou Dembélé , Laurent Christian , Crucitti Tania ,   for the CohMSM-PrEP study group
Published: January 2020

Background

Men who have sex with Men (MSM) using Pre-exposure prophylaxis (PrEP) are at risk for Sexually Transmitted Infections (STIs). Therefore, PrEP services should include regular screening for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) at urethra, anorectum and pharynx. However, financial and logistic challenges arise in low resource settings. We assessed a new STI sample pooling method using the GeneXpert instrument among MSM initiating PrEP in West-Africa.

Methods

Urine, anorectal and pharyngeal samples were pooled per individual for analysis. Unpooled samples were analyzed in case of an invalid or positive result of the pool, to identify the infection’s biological location. The results of two different pooling strategies were compared against a gold standard.

Results

We found a prevalence of 14.5% for chlamydia and 11.5% for gonorrhea, with a predominance of infections being extra-genital (77.6%). The majority of infections were asymptomatic (88.2%). The pooling strategy with unpooling of invalid results only, had a sensitivity, specificity and agreement for CT of 95.4%, 98.7% and 0.93, respectively; and 92.3%, 99.2% and 0.93 with additional unpooling of positive results. For NG, these figures were 88.9%, 97.7% and 0.85 for testing of invalid results, and 88.9%, 96.7% and 0.81 with unpooling of positive results.

Conclusion

West-African MSM have a high prevalence of extra-genital and asymptomatic STIs. The GeneXpert method provides an opportunity to move from syndromic towards etiological STI diagnosis in low income countries, as the platform is available in all African countries for tuberculosis testing. Pooling will reduce costs of triple site testing.
Global DNA hypomethylation in epithelial ovarian cancer: passive demethylation and association with genomic instability
Authors: Zhang Wa , Klinkebiel David , Barger Carter J , Pandey Sanjit , Guda Chittibabu , Miller Austin , Akers Stacey N. , Odunsi Kunle , Karpf Adam R.
Published: January 2020

A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been defined in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO(+) EOC was enriched for a proliferative gene expression signature, including CCNE1 and FOXM1 overexpression. DNA hypomethylation preferentially occurred within genomic blocks (hypomethylated blocks) overlapping late-replicating, lamina-associated domains, PRC2 binding, and H3K27me3. Increased proliferation coupled with hypomethylated block formation at late replicating regions suggested passive hypomethylation, which was further supported by the observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO(+) EOC, after normalization to proliferation markers. Importantly, GDHO(+) EOC showed elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at hypomethylated blocks. Together, these findings implicate a passive demethylation mechanism for GDHO that promotes genomic instability and poor prognosis in EOC.
Bayesian hierarchical modeling of joint spatiotemporal risk patterns for Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) in Kenya
Authors: Otiende Verrah A. , Achia Thomas N. , Mwambi Henry G.
Published: January 2020

The spatiotemporal modeling of multiple diseases simultaneously is a recent extension that advances the space-time analysis to model multiple related diseases simultaneously. This approach strengthens inferences by borrowing information between related diseases. Numerous research contributions to spatiotemporal modeling approaches exhibit their strengths differently with increasing complexity. However, contributions that combine spatiotemporal approaches to modeling of multiple diseases simultaneously are not so common. We present a full Bayesian hierarchical spatio-temporal approach to the joint modeling of Human Immunodeficiency Virus and Tuberculosis incidences in Kenya. Using case notification data for the period 2012 - 2017, we estimated the model parameters and determined the joint spatial patterns and temporal variations. Our model included specific and shared spatial and temporal effects. The specific random effects allowed for departures from the shared patterns for the different diseases. The space-time interaction term characterized the underlying spatial patterns with every temporal fluctuation. We assumed the shared random effects to be the structured effects and the disease-specific random effects to be unstructured effects. We detected the spatial congruence in the distribution of Tuberculosis and Human Immunodeficiency Virus in approximately 29 counties around the western, central and southern regions of Kenya. The distribution of the shared relative risks had minimal difference with the Human Immunodeficiency Virus disease-specific relative risk whereas that of Tuberculosis presented many more counties as high-risk areas. The flexibility and informative outputs of Bayesian Hierarchical Models enabled us to identify the similarities and differences in the distribution of the relative risks associated with each disease. Estimating the Human Immunodeficiency Virus and Tuberculosis shared relative risks provide additional insights towards collaborative monitoring of the diseases and control efforts.
microRNA-based predictor for diagnosis of frontotemporal dementia
Authors: Magen Iddo , Yacovzada Nancy-Sarah , Warren Jason D. , Heller Carolin , Swift Imogen , Bobeva Yoana , Malaspina Andrea , Rohrer Jonathan D. , Fratta Pietro , Hornstein Eran
Published: January 2020

BACKGROUND

Frontotemporal dementia (FTD) is an early onset dementia that is diagnosed in ∼20% of the progressive dementia cases. Heterogeneity in FTD clinical presentation too often delays clinical diagnosis and calls for molecular biomarkers to assist diagnosis, including cell free microRNAs (miRNA). However, nonlinearity in the relationship of miRNAs to clinical states and underpowered cohorts has limited research in this domain.

METHODS

We initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls).

RESULTS

Based on cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a nonlinear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ∼90% of cases.

DISCUSSION

The fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.
Perceived facilitators and barriers among physical therapists and orthopedic surgeons to pre-operative home-based exercise withoneexercise-only in patients with severe knee osteoarthritis: A qualitative interview study nested in the QUADX-1 trial
Authors: Husted Rasmus Skov , Bandholm Thomas , Rathleff Michael Skovdal , Troelsen Anders , Kirk Jeanette
Published: January 2020

Aim

Clinical guidelines recommend non-surgical treatment before surgery is considered in patients eligible for knee replacement (KR). Surgical treatment is provided by orthopedic surgeons and exercise therapy is provided by physical therapists. This study aimed to investigate key stakeholder perspectives on pre-operative, home-based exercise therapy withoneexercise-only in patients eligible for KR.

Methods

This qualitative study is embedded within the QUADX-1 randomized trial that investigates a model of coordinated non-surgical and surgical treatment for patients eligible for KR. Physical therapists and orthopedic surgeons working with patients with knee osteoarthritis in their daily clinical work were interviewed (one focus group and four single interviews) to explore their perceived facilitators and barriers related to pre-operative home-based exercise therapy withoneexercise-only in patients eligible for KR. Interviews were analyzed using content analysis.

Results

From the content analysis three main themes emerged: 1)Physical therapists’ and orthopedic surgeons’ ambivalence in their professional roles, 2)Orthopedic surgeons view on exercise, and 3)Coordinated non-surgical and surgical care.

Conclusion

We found that the pre-operative exercise intervention created ambivalence in the professional role of both the physical therapists and orthopedic surgeons. The physical therapists were skeptical towards over-simplified exercise therapy. The orthopedic surgeons were skeptical towards the potential lack of (long-term) effect of exercise therapy in patients eligible for KR. The consequence of these barriers and ambivalence in the professional role is important to consider when planning implementation of the model of coordinated non-surgical and surgical treatment.

Trial registration

ClinicalTrials.gov, ID:NCT02931058.
The modified arterial reservoir: an update with consideration of asymptotic pressure (P∞) and zero-flow pressure (Pzf)
Authors: Hughes Alun D , Parker Kim H
Published: January 2020

This article describes the modified arterial reservoir in detail. The modified arterial reservoir makes explicit the wave nature of both reservoir (Pres) and excess pressure (Pxs). The mathematical derivation and methods for estimatingPresin the absence of flow velocity data are described. There is also discussion of zero-flow pressure (Pzf), the pressure at which flow through the circulation ceases; its relationship to asymptotic pressure (P∞) estimated by the reservoir model; and the physiological interpretation ofPzf. A systematic review and meta-analysis provides evidence thatPzfdiffers from mean circulatory filling pressure.
FDA and EMA clinical research guidelines: Assessment of trial design recommendations for pivotal psychiatric drug trials (Protocol)
Authors: Boesen Kim , Gøtzsche Peter C , Ioannidis John PA
Published: January 2020

This is a protocol for the project entitled "FDA and EMA clinical research guidelines: Assessment of trial design recommendations for pivotal psychiatric drug trials".
Integrated genomics identify novel immunotherapy targets for malignant mesothelioma
Authors: Nastase Anca , Mandal Amit , Lu Shir Kiong , Anbunathan Hima , Morris-Rosendahl Deborah , Zhang Yu Zhi , Sun Xiao-Ming , Gennatas Spyridon , Rintoul Robert C , Edwards Matthew , Bowman Alex , Chernova Tatyana , Benepal Tim , Lim Eric , Taylor Anthony Newman , Nicholson Andrew G , Popat Sanjay , Willis Anne E , MacFarlane Marion , Lathrop Mark , Bowcock Anne M , Moffatt Miriam F , Cookson William OCM
Published: January 2020

Background

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.

Methods

In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.

Results

Previously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.

Conclusions

Our results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.
Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets
Authors: Kurozumi Sasagu , Alsaleem Mansour , Monteiro Cíntia J. , Bhardwaj Kartikeya , Joosten Stacey E. P. , Fujii Takaaki , Shirabe Ken , Green Andrew R. , Ellis Ian O. , Rakha Emad A. , Mongan Nigel P. , Heery David M. , Zwart Wilbert , Oesterreich Steffi , Johnston Simon J.
Published: January 2020

Background

Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets.

Methods

We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N=279) and invasive ductal carcinoma (IDC, N=1,301) using METABRIC, TCGA and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in-silico model of response to neratinib derived from breast cancer cell lines.

Results

ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC versus IDC cases (5.7%, N=16 vs. 1.4%, N=18, p<0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N=3 vs. 1.8%, N=23; p=0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months versus 211 months for ERBB2 wild-type (p=0.0001), and 159 vs. 166 months (p=0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS – but only in ILC (hazard ratio, HR=3.7, 95% CI 1.2–11.0; p=0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC=2.3, 95% CI 1.04–5.05; p=0.040).

Conclusions

Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.
Unpublished clinical studies in pediatric emergence delirium – a cross sectional analysis
Authors: Meyburg Jochen , Ries Markus
Published: January 2020

Objectives

Emergence delirium (ED) is a frequent and potentially serious complication of general anesthesia in children. Although there are various treatment strategies, no general management recommendations can be made. Selective reporting of study results may impair clinical decision making. We therefore analyzed whether the results of completed registered clinical studies in patients with pediatric ED are publically available or remain unpublished.

Design

Cross sectional analysis.

Setting

ClinicalTrials.gov and ClinicalTrialsRegister.eu

Participants and outcome measures

We determined the proportion of published and unpublished studies registered at ClinicalTrials.gov and ClinicalTrialsRegister.eu that were marked as completed by September 1st 2018. The major trial and literature databases were used to search for publications. In addition, the study investigators were contacted directly.

Results

Of the 44 registered studies on pediatric ED, only 24 (54%) have been published by September 2019. Published trials contained data from n=2556 patients, whereas n=1644 patients were enrolled in unpublished trials. Median time to publication was 19 months. Studies completed in recent years were published faster, but still only 9 of 25 trials were published within 12 months after completion.

Conclusion

There is a distinct publication gap in clinical research in pediatric ED that may have an impact on meta-analyses and clinical practice.

Strengths and limitations of this study

This study quantitates the amount of research waste in pediatric emergence delirium assessed as a) the number and b) sample sizes of published and unpublished completed clinical studies

The precise reasons for non-publication of the studies included in this analysis remain unknown

Strengths of findings as well as directions of individual unpublished studies remain unknown

Study registers other than ClinicalTrials.gov and ClinicalTrialsRegister.eu were not analyzed

Funding statement

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Temporal selectivity declines in the aging human auditory cortex
Authors: Erb Julia , Schmitt Lea-Maria , Obleser Jonas
Published: January 2020

Current models successfully describe the auditory cortical response to natural sounds with a set of spectra-temporal features. However, these models have hardly been linked to the ill-understood neurobiological changes that occur in the aging auditory cortex. Modelling the hemodynamic response to a rich natural sound mixture in N=64 listeners of varying age, we here show that in older listeners’ auditory cortex, the key feature of temporal rate is represented with a markedly broader tuning. This loss of temporal selectivity is most prominent in primary auditory cortex and planum temporale, with no such changes in adjacent auditory or other brain areas. Amongst older listeners, we observe a direct relationship between chronological age and temporal-rate tuning, unconfounded by auditory acuity or model goodness of fit. In line with senescent neural dedifferentiation more generally, our results highlight decreased selectivity to temporal information as a hallmark of the aging auditory cortex.

Impact Statement

Age-dependent broadening of tuning to temporal modulation rate in older humans’ cortical sound representations highlights decreased temporal selectivity as an anatomically and functionally specific hallmark of the aging auditory cortex.
Time-varying transmission dynamics of Novel Coronavirus Pneumonia in China
Authors: Liu Tao , Hu Jianxiong , Xiao Jianpeng , He Guanhao , Kang Min , Rong Zuhua , Lin Lifeng , Zhong Haojie , Huang Qiong , Deng Aiping , Zeng Weilin , Tan Xiaohua , Zeng Siqing , Zhu Zhihua , Li Jiansen , Gong Dexin , Wan Donghua , Chen Shaowei , Guo Lingchuan , Li Yan , Sun Limei , Liang Wenjia , Song Tie , He Jianfeng , Ma Wenjun
Published: January 2020

Rationale

Several studies have estimated basic production number of novel coronavirus pneumonia (NCP). However, the time-varying transmission dynamics of NCP during the outbreak remain unclear.

Objectives

We aimed to estimate the basic and time-varying transmission dynamics of NCP across China, and compared them with SARS.

Methods

Data on NCP cases by February 7, 2020 were collected from epidemiological investigations or official websites. Data on severe acute respiratory syndrome (SARS) cases in Guangdong Province, Beijing and Hong Kong during 2002-2003 were also obtained. We estimated the doubling time, basic reproduction number (R0) and time-varying reproduction number (Rt) of NCP and SARS.

Measurements and main results

As of February 7, 2020, 34,598 NCP cases were identified in China, and daily confirmed cases decreased after February 4. The doubling time of NCP nationwide was 2.4 days which was shorter than that of SARS in Guangdong (14.3 days), Hong Kong (5.7 days) and Beijing (12.4 days). TheR0of NCP cases nationwide and in Wuhan were 4.5 and 4.4 respectively, which were higher thanR0of SARS in Guangdong (R0=2.3), Hongkong (R0=2.3), and Beijing (R0=2.6). TheRtfor NCP continuously decreased especially after January 16 nationwide and in Wuhan. TheR0for secondary NCP cases in Guangdong was 0.6, and theRtvalues were less than 1 during the epidemic.

Conclusions

NCP may have a higher transmissibility than SARS, and the efforts of containing the outbreak are effective. However, the efforts are needed to persist in for reducing time-varying reproduction number below one.

At a Glance Commentary

Scientific Knowledge on the Subject

Since December 29, 2019, pneumonia infection with 2019-nCoV, now named as Novel Coronavirus Pneumonia (NCP), occurred in Wuhan, Hubei Province, China. The disease has rapidly spread from Wuhan to other areas. As a novel virus, the time-varying transmission dynamics of NCP remain unclear, and it is also important to compare it with SARS.

What This Study Adds to the Field

We compared the transmission dynamics of NCP with SARS, and found that NCP has a higher transmissibility than SARS. Time-varying production number indicates that rigorous control measures taken by governments are effective across China, and persistent efforts are needed to be taken for reducing instantaneous reproduction number below one.
Interleukin-11 is a Marker for Both Cancer- and Inflammation-Associated Fibroblasts that Contribute to Colorectal Cancer Progression
Authors: Nishina Takashi , Deguchi Yutaka , Takeda Wakami , Ohtsuka Masato , Ohshima Daisuke , Yamazaki Soh , Kawauchi Mika , Nakamura Eri , Nishiyama Chiharu , Kojima Yuko , Adachi-Akahane Satomi , Hasegawa Mizuho , Nakayama Mizuho , Oshima Masanobu , Yagita Hideo , Shibuya Kazutoshi , Mikami Tetuo , Inohara Naohiro , Tada Norihiro , Nakano Hiroyasu
Published: January 2020

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+cellsin vivo, we generatedIl11reporter mice. IL-11+cells appeared in the colon of three murine tumor models, and a murine acute colitis model.Il11ra1orIl11deletion attenuated the development of colitis-associated colorectal cancer. IL-11+cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, suggesting the activation of IL-11+fibroblasts. Analysis using the human cancer database revealed that genes enriched in IL-11+fibroblasts were elevated in human colorectal cancer, and correlated with reduced disease-free survival. Together, our results suggested that tumor cells induced IL-11+fibroblasts, and that a feed-forward loop between IL-11 and IL-11+fibroblasts might contribute to tumor development.
Epigenetic engineering of yeast reveals dynamic molecular adaptation to methylation stress and genetic modulators of specific DNMT3 family members
Authors: Finnegan Alex I. , Kim Somang , Jin Hu , Gapinske Michael , Woods Wendy S. , Perez-Pinera Pablo , Song Jun S.
Published: January 2020

Cytosine methylation is a ubiquitous modification in mammalian DNA generated and maintained by several DNA methyltransferases (DNMTs) with partially overlapping functions and genomic targets. To systematically dissect the factors specifying each DNMT’s activity, we engineered combinatorial knock-in of human DNMT genes inKomagataella phaffii, a yeast species lacking endogenous DNA methylation. Time-course expression measurements captured dynamic network-level adaptation of cells to DNMT3B1-induced DNA methylation stress and showed that coordinately modulating the availability of S-adenosyl methionine (SAM), the essential metabolite for DNMT-catalyzed methylation, is an evolutionarily conserved epigenetic stress response, also implicated in several human diseases. Convolutional neural networks trained on genome-wide CpG-methylation data learned distinct sequence preferences of DNMT3 family members. A simulated annealing interpretation method resolved these preferences into individual flanking nucleotides and periodic poly(A) tracts that rotationally position highly methylated cytosines relative to phased nucleosomes. Furthermore, the nucleosome repeat length defined the spatial unit of methylation spreading. Gene methylation patterns were similar to those in mammals, and hypo- and hypermethylation were predictive of increased and decreased transcription relative to control, respectively, in the absence of mammalian readers of DNA methylation. Introducing controlled epigenetic perturbations in yeast thus enabled characterization of fundamental genomic features directing specific DNMT3 proteins.
Stoichiometric Analysis of Protein Complexes by Cell Fusion and Single Molecule Imaging
Authors: Singh Avtar , Van Slyke Alexander L. , Sirenko Maria , Song Alexander , Kammermeier Paul J. , Zipfel Warren R.
Published: January 2020

The composition, stoichiometry and interactions of supramolecular protein complexes are a critical determinant of biological function. Several techniques have been developed to study molecular interactions and quantify subunit stoichiometry at the single molecule level; however, these typically require artificially low expression levels to achieve the low fluorophore concentration required for single molecule imaging, or use of detergent isolation of complexes that may perturb native subunit interactions. Here we present an alternative approach where protein complexes are assembled at physiological concentrations and subsequently dilutedin situfor single-molecule level observations while preserving them in a near-native cellular environment. We show that coupling thisin situdilution strategy with single molecule techniques such asin vivoFluorescence Correlation Spectroscopy (FCS), bleach step counting for quantifying protein complex stoichiometry, and two-color single molecule colocalization, improves the quality of data obtained using these single molecule fluorescence methods. Single Protein Recovery After Dilution (SPReAD) is a simple and versatile means of extending the concentration range of single molecule measurements into the cellular regime while minimizing potential artifacts and perturbations of protein complex stoichiometry.

SIGNIFICANCE STATEMENT

Quantifying the composition and stoichiometry of protein complexes in live cells is critical to understanding mechanisms involved in their function. Here we detail a method in which protein complexes are assembled intracellularly at physiological concentrations, but then diluted to levels suitable for single-molecule fluorescence observations while still within a cellular environment. The technique permits the use of common single molecule analysis techniques such as stepwise photobleaching quantification and fluorescence correlation spectroscopy to determine stoichiometry and functional interactions while avoiding artifacts that may occur from the use of detergent isolation methods or from the artificially low expression levels sometimes used to attain single molecule observation levels.
Generation of cell-free matrices that support human NK cell migration and differentiation
Authors: Lee Barclay J. , Mace Emily M.
Published: January 2020

Human natural killer cells are effectors of the innate immune system that originate from hematopoietic precursors in the bone marrow. While feeder cell lines that support NK cell development from hematopoietic precursors are often used to generate mature NK cells from lymphoid precursors in vitro, the nature of contributing factors of these stromal cells to the generation of functionally mature NK cells has been poorly described. Previous studies have shown that developing NK cells adhere to, and migrate on, developmentally supportive stroma. Here, we describe the generation of cell-derived matrices (CDMs) from a commonly used murine fetal liver stromal cell line. These CDMs are derived directly from the same EL08.1D2 stromal cell line known to support NK cell differentiation and contain ECM structural components fibronectin and collagen. We demonstrate that CDMs support NK cell adhesion and migration with similar properties as intact cells. Further, we show that CDMs support NK cell maturation from lymphoid precursors in vitro, albeit with reduced cell survival compared to intact cell-based differentiation. Together, these results describe a cell-free system that supports NK cell development and that can serve as a useful model for studying the nature of the biochemical interactions between NK cell developmental intermediates and developmentally supportive substrates.
Non-invasive red-light optogenetic control ofDrosophilacardiac function
Authors: Men Jing , Li Airong , Jerwick Jason , Li Zilong , Tanzi Rudolph E. , Zhou Chao
Published: January 2020

Drosophila is a powerful genetic model system for cardiovascular studies. Recently, optogenetic pacing tools have been developed to controlDrosophilaheart rhythm noninvasively with blue light, which has a limited penetration depth. Here we developed both a red-light sensitive opsin expressingDrosophilasystem and an integrated red-light stimulation and optical coherence microscopy (OCM) imaging system. We demonstrated noninvasive control ofDrosophilacardiac rhythms, including simulated tachycardia in ReaChR-expressing flies and bradycardia and cardiac arrest in halorhodopsin (NpHR)-expressing flies at multiple developmental stages. By using red excitation light, we were able to pace flies at higher efficiency and with lower power than with equivalent blue light excitation systems. The recovery dynamics after red-light stimulation of NpHR flies were observed and quantified. The combination of red-light stimulation, OCM imaging, and transgenicDrosophilasystems provides a promising and easily manipulated research platform for noninvasive cardiac optogenetic studies.
Thm2interacts with paralog,Thm1, and sensitizes to Hedgehog signaling in postnatal skeletogenesis
Authors: Allard Bailey A , Wang Wei , Pottorf Tana S , Mumtaz Hammad , Silva Luciane M , Jacobs Damon T , Wang Jinxi , Bumann Erin E , Tran Pamela V
Published: January 2020

Ciliopathies are genetic syndromes that link osteochondrodysplasias to dysfunction of primary cilia. Primary cilia extend from the surface of bone and cartilage cells, to receive extracellular cues and mediate signaling pathways. Mutations in several genes that encode components of the intraflagellar transport-A ciliary protein complex have been identified in skeletal ciliopathies, includingTHM1. Here, we report a role for genetic interaction betweenThm1and its paralog,Thm2,in skeletogenesis. THM2 localizes to the ciliary axoneme, but unlike its paralog,Thm2deficiency does not affect ciliogenesis andThm2-null mice survive into adulthood. Since paralogs often have redundant functions, we crossed aThm1null (aln) allele into theThm2colony. After 5 generations of backcrossing the colony onto a C57BL6/J background, we observed that by postnatal day 14,Thm2-/-; Thm1aln/+mice are smaller than control littermates.Thm2-/-; Thm1aln/+mice exhibit shortened long bones, narrow ribcage, shortened cranium and mandibular defects. Mutant mice also show aberrant architecture of the tibial growth plate, with an expanded proliferation zone and diminished hypertrophic zone, indicating impaired chondrocyte differentiation. Using microcomputed tomography,Thm2-/-; Thm1aln/+tibia were revealed to have reduced cortical and trabecular bone mineral density. Deletion of one allele ofGli2, a major transcriptional activator of the Hedgehog (Hh) pathway, exacerbated the small phenotype ofThm2-/-; Thm1aln/+mice and caused small stature inThm2-null mice. Together, these data revealThm2as a novel locus that sensitizes to Hh signaling in skeletal development. Further,Thm2-/-; Thm1aln/+mice present a new postnatal ciliopathy model of osteochondrodysplasia.
A Multivariate View of Parallel Evolution
Authors: De Lisle Stephen P. , Bolnick Daniel I.
Published: January 2020

A growing number of empirical studies have quantified the degree to which evolution is geometrically parallel, by estimating and interpreting pairwise angles between evolutionary change vectors in multiple replicate lineages. Similar comparisons, of distance in trait space, are used to assess the degree of convergence. These approaches amount to element-by-element interpretation of distance matrices, and can fail to capture the true extent of multivariate parallelism when evolution involves multiple traits sampled across multiple lineages. We suggest an alternative set of approaches, co-opted from evolutionary quantitative genetics, involving eigen analysis and comparison of among-lineage covariance matrices. Such approaches not only allow the full extent of multivariate parallelism to be revealed and interpreted, but also allow for the definition of biologically tenable null hypotheses against which empirical patterns can be tested. Reanalysis of a dataset of multivariate evolution across a replicated lake/stream gradient in threespine stickleback reveals that most of the variation in the direction of evolutionary change can be captured in just a few dimensions, indicating a greater extent of parallelism than previously appreciated. We suggest that applying such multivariate approaches may often be necessary to fully understand the extent and form of parallel and convergent evolution.
Mapping Functional Protein Neighborhoods in the Mouse Brain
Authors: Liebeskind Benjamin J. , Young Rebecca L. , Halling D. Brent , Aldrich Richard W. , Marcotte Edward M.
Published: January 2020

New proteomics methods make it possible to determine protein interaction maps at the proteome scale without the need for genetically encoded tags, opening up new organisms and tissue types to investigation. Current molecular and computational methods are oriented towards protein complexes that are soluble, stable, and discrete. However, the mammalian brain, among the most complicated and most heavily studied tissue types, derives many of its unique functions from protein interactions that are neither discrete nor soluble. Proteomics investigations into the global protein interaction landscape of the brain have therefore leveraged non-proteomics datasets to supplement their experiments. Here, we develop a novel, integrative proteomics pipeline and apply it to infer a global map of functional protein neighborhoods in the mouse brain without the aid of external datasets. By leveraging synaptosome enrichment and interactomics methods that target both soluble and insoluble protein fractions, we resolved protein interactions for key neural pathways, including those from refractory subcellular fractions such as the membrane and cytoskeleton. In comparison to external datasets, our observed interactions perform similarly to hand-curated synaptic protein interactions while also suggesting thousands of novel connections. We additionally employed cleavable chemical cross-linkers to detect direct binding partners and provide structural context. Our combined map suggests new protein pathways and novel mechanisms for proteins that underlie neurological diseases, including autism and epilepsy. Our results show that proteomics methods alone are sufficient to determine global interaction maps for proteins that are of broad interest to neuroscience. We anticipate that our map will be used to prioritize new research avenues and will pave the way towards future proteomics techniques that resolve protein interactions at ever greater resolution.