bluuebunny/crossref_metadata_2025 huggingface dataset:
Repeat computed tomography head scan is not indicated in trauma patients taking novel anticoagulation: A multicenter study
Authors: Cohan Caitlin M. , Beattie Genna , Bowman Jessica A. , Galante Joseph M. , Kwok Amy M. , Dirks Rachel C. , Kornblith Lucy Z. , Plevin Rebecca , Browder Timothy D. , Victorino Gregory P.
Published: April 2020

BACKGROUND

The number of trauma patients on prehospital novel oral anticoagulants (NOACs) is increasing. After an initial negative computed tomography of the head (CTH), practice patterns are variable for obtaining repeat CTH to evaluate for delayed intracranial hemorrhage (ICH-d). However, the risks and outcomes of ICH-d for patients on NOACs are unclear. We hypothesized that, for these patients, the incidence of ICH-d is low, similar to that of warfarin, and when it occurs, it does not result in clinically significant worse outcomes.

METHODS

Five level 1 trauma centers in Northern California participated in a retrospective review of anticoagulated trauma patients. Patients were included if their initial CTH was negative. Primary outcomes were incidence of ICH-d, neurosurgical intervention, and death. Patient factors associated with the outcome of ICH-d were determined by multivariable regression.

RESULTS

From 2016 to 2018, 777 patients met the inclusion criteria (NOAC, n = 346; warfarin, n = 431), 54% of whom received a repeat CTH. Delayed intracranial hemorrhage incidence was 2.3% in the NOAC group and 4% in the warfarin group (p = 0.31). No NOAC patient with ICH-d required neurosurgical intervention or died because of their head injury. Two warfarin patients received neurosurgical intervention, and three died from their head injury. Head Abbreviated Injury Scale ≥3 was associated with increased odds of developing ICH-d (adjusted odds ratio, 32.70; p < 0.01).

CONCLUSION

The incidence of ICH-d in patients taking NOAC is low. In this study, patients on NOACs who developed ICH-d after an initial negative CTH did not need neurosurgical intervention or die from their head injury. Repeat CTH in this patient population does not appear necessary.

LEVEL OF EVIDENCE

Prognostic/epidemiologic study, level III.

Therapeutic, level IV.
Training With Wii Balance Board for Dynamic Balance in Older Adults
Authors: García-Bravo Sara , García-Bravo Cristina , Molina-Rueda Francisco , Cuesta-Gómez Alicia
Published: April 2020

Background and Purpose:

Age-related muscle strength deterioration and decreased ability to react appropriately and regain balance after unexpected sudden disturbances and deficit they have in the use of responsible mechanisms to control the dynamic stability in response to a disturbance are important intrinsic risk factors for the fall. The main objective of this study is to verify the impact on the dynamic balance, through the Limits of Stability test, of a physical exercise program in older adults using the Nintendo Wii console.

Methods:

The sample consisted of a total of 12 patients. Pre and posttreatment measurements and assessments were carried out at the Laboratory of Motion Analysis, Biomechanics, Ergonomics and Motor Control (LAMBECOM) in the Faculty of Health Sciences of the Rey Juan Carlos University.

Results and Conclusions:

The results of this study show improvements in the scores of all the variables analyzed by Limits of Stability: RT, MVL, EPE, MXE and DCL. The results obtained seem to determine that the protocol used through training with the Nintendo Wii and its Wii Fit video game produced clinical improvements in postural control and dynamic balance and a positive impact on quality of life.
Randomized Controlled Trial of Aquatic Cycling for Treatment of Knee Osteoarthritis in Elderly People
Authors: Rezasoltani Zahra , Sanati Ehsan , Kazempour Mofrad Reza , Azizi Sirous , Dadarkhah Afsaneh , Najafi Sharif
Published: April 2020

Objective:

To assess the effects of aqua-cycling on pain, physical function, and muscle strength among elderly people with knee osteoarthritis.

Methods:

We performed a randomized controlled trial from November 2016 through July 2017 in an outpatient clinic of the Department of Physical Medicine and Rehabilitation at the University Hospital. Patients were 60 years and older and had knee osteoarthritis. Among 32 patients who were randomly allocated to the groups aqua-cycling and control, 30 completed the study. We used the Knee injury and Osteoarthritis Outcome Score to assess the patients' opinion about their knees and associated problems. The measurements were performed at the baseline, and after 4, 8, and 12 sessions of aqua-cycling. Participants in the intervention group performed aqua-cycling, 3 sessions per week for 4 weeks. Each session lasted 50 minutes including 10 minutes of warm-up, 30 minutes of cycling, and 10 minutes of cool-down exercises. Both groups used acetaminophen, if needed, and followed lifestyle recommendations for 4 weeks.

Results:

There were significant improvements in pain reduction, physical function, and muscle strength in favor of aqua-cycling (all P < .001). Within-group analyses showed that participants in the aqua-cycling group experienced significant pain reduction (P < .001), and improved in physical function (P < .001), quadriceps (P < .001), and hamstring muscle strength (P < .001). Within-group comparisons for the group control were not significant (all P > .05).

Conclusion:

Aqua-cycling is effective, and can be used alone or combined with other treatments in the management of osteoarthritis.
Validation of a Brief Cognitive Screening Examination in an Adult Acute Inpatient Rehabilitation Population
Authors: Parkhurst Drew , Wyatt Rebecca , Andary Michael , Sylvain Jim
Published: April 2020

Objective:

To establish validity of a Brief Cognitive Screening Examination (BCSE) to identify patients requiring further cognitive testing.

Methods:

A total of 100 adult inpatients at a university acute inpatient rehabilitation facility were given the Mini-Mental State Examination (MMSE), Clock Draw Test (CDT), and BCSE. The BCSE is a 2-minute test to assess registration, concentration, working memory, and calculation.

Results:

Univariate linear regression analysis demonstrated that BCSE scores of 16 predicted the MMSE score of 28 (P < .01) and BCSE of 12 or less predicted the MMSE less than 24 (P < .01).

Conclusion:

The BCSE is a valid, time-efficient, bedside cognitive screen that identifies patients who would benefit from further cognitive evaluation.
Technostress at work and mental health: concepts and research results
Authors: Dragano Nico , Lunau Thorsten
Published: April 2020

Purpose of review

The ongoing digitalization has profound consequences for work in modern economies. It is, therefore, important to investigate if digital technologies increase stress at work (i.e. ‘technostress’) and lead to impaired mental health. This article describes the concept of technostress and discusses possible risks and opportunities of digital technologies at work and their effect on mental health.

Recent findings

Studies report that the use of digital technologies is associated with specific psychosocial demands (e.g. higher workload, complexity, conflicts between work and other life domains) and resulting psychobiological stress reactions. It is, however, still unclear if this kind of technostress causes mental disorders because epidemiological studies are missing. Yet, an increasing number of studies suggests that well designed digital work may promote good health if it optimizes work organization or enables greater flexibility, and increases control and autonomy at work.

Digitalization of work seems to have both opportunities and risks for the mental health of employees. The number of studies is currently limited and further research is necessary to describe the advantages and disadvantages more precisely.
Distinguish Coronavirus Disease 2019 Patients in General Surgery Emergency by CIAAD Scale: Development and Validation of a Prediction Model Based on 822 Cases in China
Authors: Zhao Bangbo , Wei Yingxin , Sun Wenwu , Qin Cheng , Zhou Xingtong , Wang Zihao , Li Tianhao , Cao Hongtao , Wang Weibin , Wang Yujun
Published: April 2020

ABATRACT

IMPORTANCE

In the epidemic, surgeons cannot distinguish infectious acute abdomen patients suspected COVID-19 quickly and effectively.

OBJECTIVE

To develop and validate a predication model, presented as nomogram and scale, to distinguish infectious acute abdomen patients suspected coronavirus disease 2019 (COVID-19).

DESIGN

Diagnostic model based on retrospective case series.

SETTING

Two hospitals in Wuhan and Beijing, China.

PTRTICIPANTS

584 patients admitted to hospital with laboratory confirmed SARS-CoV-2 from 2 Jan 2020 to15 Feb 2020 and 238 infectious acute abdomen patients receiving emergency operation from 28 Feb 2019 to 3 Apr 2020.

METHODS

LASSO regression and multivariable logistic regression analysis were conducted to develop the prediction model in training cohort. The performance of the nomogram was evaluated by calibration curves, receiver operating characteristic (ROC) curves, decision curve analysis (DCA) and clinical impact curves in training and validation cohort. A simplified screening scale and managing algorithm was generated according to the nomogram.

RESULTS

Six potential COVID-19 prediction variables were selected and the variable abdominal pain was excluded for overmuch weight. The five potential predictors, including fever, chest computed tomography (CT), leukocytes (white blood cells, WBC), C-reactive protein (CRP) and procalcitonin (PCT), were all independent predictors in multivariable logistic regression analysis (p ≤0.001) and the nomogram, named COVID-19 Infectious Acute Abdomen Distinguishment (CIAAD) nomogram, was generated. The CIAAD nomogram showed good discrimination and calibration (C-index of 0.981 (95% CI, 0.963 to 0.999) and AUC of 0.970 (95% CI, 0.961 to 0.982)), which was validated in the validation cohort (C-index of 0.966 (95% CI, 0.960 to 0.972) and AUC of 0.966 (95% CI, 0.957 to 0.975)). Decision curve analysis revealed that the CIAAD nomogram was clinically useful. The nomogram was further simplified into the CIAAD scale.

CONCLUSIONS

We established an easy and effective screening model and scale for surgeons in emergency department to distinguish COVID-19 patients from infectious acute abdomen patients. The algorithm based on CIAAD scale will help surgeons manage infectious acute abdomen patients suspected COVID-19 more efficiently.
Outbreak dynamics of COVID-19 in Europe and the effect of travel restrictions
Authors: Linka Kevin , Peirlinck Mathias , Costabal Francisco Sahli , Kuhl Ellen
Published: April 2020

For the first time in history, on March 17,2020, the European Union closed all its external borders to contain the spreading of the coronavirus 2019, COVID-19. Throughout two past months, governments around the world have implemented massive travel restrictions and border control to mitigate the outbreak of this global pandemic. However, the precise effects of travel restrictions on the outbreak dynamics of COVID-19 remain unknown. Here we combine a global network mobility model with a local epidemiology model to simulate and predict the outbreak dynamics and outbreak control of COVID-19 across Europe. We correlate our mobility model to passenger air travel statistics and calibrate our epidemiology model using the number of reported COVID-19 cases for each country. Our simulations show that mobility networks of air travel can predict the emerging global diffusion pattern of a pandemic at the early stages of the outbreak. Our results suggest that an unconstrained mobility would have significantly accelerated the spreading of COVID-19, especially in Central Europe, Spain, and France. Ultimately, our network epidemiology model can inform political decision making and help identify exit strategies from current travel restrictions and total lockdown.
Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missenseFmr1mutant mouse model of Fragile X syndrome
Authors: Prieto Marta , Folci Alessandra , Poupon Gwénola , Schiavi Sara , Buzzelli Valeria , Pronot Marie , François Urielle , Pousinha Paula , Lattuada Norma , Abelanet Sophie , Castagnola Sara , Chafai Magda , Khayachi Anouar , Gwizdek Carole , Brau Frédéric , Deval Emmanuel , Francolini Maura , Bardoni Barbara , Humeau Yann , Trezza Viviana , Martin Stéphane
Published: April 2020

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in theFMR1gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model(Fmr1R138Q)expressing the FMRP-R138Q protein. We demonstrate that theFmr1R138Qhippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits inFmr1R138Qmice. These findings reveal that the R138Q mutation impacts the synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.
Epidemiological impact of SARS-CoV-2 vaccination: mathematical modeling analyses
Authors: Makhoul Monia , Ayoub Houssein H. , Chemaitelly Hiam , Seedat Shaheen , Mumtaz Ghina R , Al-Omari Sarah , Abu-Raddad Laith J.
Published: April 2020

Background

Several SARS-CoV-2 vaccine candidates are currently in the pipeline. This study aims to inform SARS-CoV-2 vaccine development, licensure, decision-making, and implementation by determining key preferred vaccine product characteristics and associated population-level impact.

Methods

Vaccination impact was assessed at various efficacies using an age-structured mathematical model describing SARS-CoV-2 transmission and disease progression, with application for China.

Results

A prophylactic vaccine with efficacy against acquisition (VES) of ≥70% is needed to eliminate this infection. A vaccine withVES<70% will still have a major impact, and may control the infection if it reduces infectiousness or infection duration among those vaccinated who acquire the infection, or alternatively if supplemented with a moderate social-distancing intervention (<20% reduction in contact rate), or complemented with herd immunity. Vaccination is cost-effective. For a vaccine withVESof 50%, number of vaccinations needed to avert one infection is only 2.4, one severe disease case is 25.5, one critical disease case is 33.2, and one death is 65.1. Gains in effectiveness are achieved by initially prioritizing those ≥60 years. Probability of a major outbreak is virtually zero with a vaccine withVES≥70%, regardless of number of virus introductions. Yet, an increase in social contact rate among those vaccinated (behavior compensation) can undermine vaccine impact.

Conclusions

Even a partially-efficacious vaccine can offer a fundamental solution to control SARS-CoV-2 infection and at high cost-effectiveness. In addition to the primary endpoint on infection acquisition, developers should assess natural history and disease progression outcomes and/or proxy biomarkers, since such secondary endpoints may prove critical in licensure, decision-making, and vaccine impact.
Optimizing COVID-19 surveillance in long-term care facilities: a modelling study
Authors: Smith David RM , Duval Audrey , Pouwels Koen B , Guillemot Didier , Fernandes Jérôme , Huynh Bich-Tram , Temime Laura , Opatowski Lulla
Published: April 2020

Background

Long-term care facilities (LTCFs) are vulnerable to COVID-19 outbreaks. Timely epidemiological surveillance is essential for outbreak response, but is complicated by a high proportion of silent (non-symptomatic) infections and limited testing resources.

Methods

We used a stochastic, individual-based model to simulate SARS-CoV-2 transmission along detailed inter-individual contact networks describing patient-staff interactions in real LTCF settings. We distributed nasopharyngeal swabs and RT-PCR tests using clinical and demographic indications, and evaluated the efficacy and resource-efficiency of a range of surveillance strategies, including group testing (sample pooling) and testing cascades, which couple (i) testing for multiple indications (symptoms, admission) with (ii) random daily testing.

Results

In the baseline scenario, randomly introducing SARS-CoV-2 into a 170-bed LTCF led to large outbreaks, with a cumulative 86 (6-224) infections after three weeks of unmitigated transmission. Efficacy of symptom-based screening was limited by (i) lags between infection and symptom onset, and (ii) silent transmission from asymptomatic and pre-symptomatic infections. Testing upon admission detected up to 66% of patients silently infected upon LTCF entry, but missed potential introductions from staff. Random daily testing was more effective when targeting patients than staff, but was overall an inefficient use of limited resources. At high testing capacity (>1 test/10 beds/day), cascades were most effective, with a 22-52% probability of detecting outbreaks prior to any nosocomial transmission, and 38-63% prior to first onset of COVID-19 symptoms. Conversely, at low capacity (<1 test/85 beds/day), pooling randomly selected patients in a daily group test was most effective (9-15% probability of detecting outbreaks prior to transmission; 30-44% prior to symptoms). The most efficient strategy compared to the reference was to pool individuals with any COVID-like symptoms, requiring only 5-7 additional tests and 17-24 additional swabs to detect outbreaks 5-6 days earlier, prior to an additional 14-18 infections.

Conclusions

Group testing is an effective and efficient COVID-19 surveillance strategy for resource-limited LTCFs. Cascades are even more effective given ample testing resources. Increasing testing capacity and updating surveillance protocols accordingly could facilitate earlier detection of emerging outbreaks, informing a need for urgent intervention in settings with ongoing nosocomial transmission.
Potential magnitude of COVID-19-induced healthcare resource depletion in Ontario, Canada
Authors: Barrett Kali , Khan Yasin A. , Mac Stephen , Ximenes Raphael , Naimark David MJ , Sander Beate
Published: April 2020

Background

The global spread of coronavirus disease 2019 (COVID-19) continues in several jurisdictions, causing significant strain to healthcare systems. The purpose of our study is to predict the impact of the COVID-19 pandemic on patient outcomes and the healthcare system in Ontario, Canada.

Methods

We developed an individual-level simulation to model the flow of COVID-19 patients through the Ontario healthcare system. We simulated different combined scenarios of epidemic trajectory and healthcare capacity. Outcomes include numbers of patients needing admission to the ward, Intensive Care Unit (ICU), and requiring ventilation; days to resource depletion; and numbers of patients awaiting resources and deaths associated with limited access to resources.

Findings

We demonstrate that with effective early public health measures system resources need not be depleted. For scenarios considering late or ineffective implementation of physical distancing, health system resources would be depleted within 14-26 days. Resource depletion was also avoided or delayed with aggressive measures to rapidly increase ICU, ventilator, and acute care hospital capacity.

Interpretation

We found that without aggressive physical distancing measures the Ontario healthcare system would have been inadequately equipped to manage the expected number of patients with COVID-19, despite the rapid capacity increase. This overall lack of resources would have led to an increase in mortality. By slowing the spread of the disease via ongoing public health measures and having increased healthcare capacity, Ontario may have avoided catastrophic stresses to its health care system.
A Bayesian analysis of the total number of cases of the COVID 19 when only a few data is available. A case study in the state of Goias, Brazil
Authors: Silva Renato Rodrigues , Velasco Wisley Donizetti , Silva Marques Wanderson da , Gonçalves Tibiriçá Carlos Augusto
Published: April 2020

The outbreak of COVID 19 has been provoking several problems to the health system around the world. One of the concerning is the crash of the health system due to the increasing demand suddenly. To avoid it, knowing the total number and daily new cases is crucial. In this study, we fitted curves growth models using a Bayesian approach. We extracted information obtained from some countries to build the prior distribution of the model. The total number of cases of the COVID 19 in the state of Goias was analyzed. Results from analysis indicated that the date of the outbreak peak is between 51 and 68 days after the beginning. Moreover, the total number of cases is around 3180 cases. The analysis did not take into consideration possibles changes in government control measures. We hope this study can provide some valuable information to public health management.
Seasonality and uncertainty in COVID-19 growth rates
Authors: Merow Cory , Urban Mark C.
Published: April 2020

The virus causing COVID-19 has spread rapidly worldwide and threatens millions of lives. It remains unknown if summer weather will reduce its continued spread, thereby alleviating strains on hospitals and providing time for vaccine development. Early insights from laboratory studies of related coronaviruses predicted that COVID-19 would decline at higher temperatures, humidity, and ultraviolet light. Using current, fine-scaled weather data and global reports of infection we developed a model that explained 36% of variation in early growth rates before intervention, with 17% based on weather or demography and 19% based on country-specific effects. We found that ultraviolet light was most strongly associated with lower COVID-19 growth rates. Projections suggest that, in the absence of intervention, COVID-19 will decrease temporarily during summer, rebound by autumn, and peak next winter. However, uncertainty remains high and the probability of a weekly doubling rate remained >20% throughout the summer in the absence of control. Consequently, aggressive policy interventions will likely be needed in spite of seasonal trends.
Spectral DQE of the Volta Phase Plate
Authors: Buijsse Bart , Trompenaars Piet , Altin Veli , Danev Radostin , Glaeser Robert M.
Published: April 2020

The Volta Phase Plate (VPP) consists of a heated, thin film that is placed in the same plane as the focused diffraction pattern of an electron microscope. A change in surface potential develops at the point irradiated by the intense, unscattered electron beam, and this altered surface potential produces, in turn, a phase shift between the unscattered and scattered parts of the electron wave. While the VPP thus increases the image contrast for weak-phase objects at low spatial frequencies, we report here that it also leads to the loss of an increasing fraction of the signal at higher resolution. The approximately linear dependence (with increasing resolution) of this loss has been quantified at 200 kV and 300 kV, using evaporated-carbon films of different thicknesses as Volta phase plates. In all cases, the loss of signal remains almost independent of variation of the conditions and parameters that were tested. In spite of having done a number or additional, discovery-based experiments, the cause of this loss of signal remains unexplained at this point.
Probing the structure-function relationship with neural networks constructed by solving a system of linear equations
Authors: Mininni Camilo J. , Zanutto B. Silvano
Published: April 2020

Neural network models are an invaluable tool to understand brain function, since they allow to connect the cellular and circuit levels with behaviour. Neural networks usually comprise a huge number of parameters, which must be chosen carefully such that networks reproduce anatomical, behavioural and neurophysiological data. These parameters are usually fitted with off-the-shelf optimization algorithms that iteratively change network parameters and simulate the network to evaluate the changes and improve fitting. Here we propose to invert the fitting process by proceeding from the network dynamics towards network parameters. Firing state transitions are chosen according to the transition graph followed by an agent when solving a given behavioural task. Then, a system of linear equations is constructed from the network firing states and membrane potentials, in such a way that system consistency in guarantee. This allows to uncouple the activity features of the model, like its neurons firing rate and correlation, from the connectivity features and from the task-solving algorithm implemented by the network, allowing to fit these three levels separately. We employed the method to probe the structure-function relationship in a stimuli sequence memory task, finding solution networks where commonly employed optimization algorithms failed. The constructed networks showed reciprocity and correlated firing patterns that recapitulated experimental observations. We argue that the proposed method is a complementary and needed alternative to the way neural networks are constructed to model brain function.
Complementation can maintain a quasispecies of drug sensitive and resistant HIV
Authors: Jackson Laurelle , Cele Sandile , Lustig Gila , Giandhari Jennifer , de Oliveira Tulio , Neher Richard A. , Sigal Alex
Published: April 2020

HIV exists as multiple genotypes in a single infected individual referred to as a quasispecies. Here we reproduced a quasispecies by moderate selective pressure using an HIV reverse transcriptase inhibitor. The drug resistant genotype never completely supplanted the drug sensitive genotype, which stabilized at about 20 percent of viral sequences. Single-cell sequencing showed that resistant genotype frequency plateaued when cells were co-infected with sensitive and resistant genotypes, suggesting a sharing of viral proteins in co-infected cells (complementation) which masks genotypic differences. To test if complementation can confer phenotypic drug resistance, we co-transfected fluorescently labelled molecular clones of sensitive and resistant HIV and observed that genotypically sensitive virus from co-transfected cells was drug resistant. Resistant virus preferentially infected cells in tandem with drug sensitive HIV, explaining how co-infections of sensitive and resistant genotypes were initiated. Modelling this effect, we observed that a stable quasispecies could form at the experimental multiplicities of infection for the drug resistant and drug sensitive virus, showing that complementation can lead to a quasispecies in an HIV evolution experiment.
A reduced order model of the spine to study pediatric scoliosis
Authors: Neelakantan Sunder , Purohit Prashant K. , Pasha Saba
Published: April 2020

The S-shaped curvature of the spine has been hypothesized as the underlying mechanical cause of adolescent idiopathic scoliosis. In earlier work we proposed a reduced order model in which the spine was viewed as an S-shaped elastic rod under torsion and bending. Here, we simulate the deformation of S-shaped rods of a wide range of curvatures and inflection points under a fixed mechanical loading. Our analysis determines three distinct axial projection patterns of these S-shaped rods: two loop (in opposite directions) patterns and one lemniscate pattern. We further identify the curve characteristics associated with each deformation pattern showing that for rods deforming in a loop 1 shape the position of the inflection point is the highest and the curvature of the rod is smaller compared to the other two types. For rods deforming in the loop 2 shape the position of the inflection point is the lowest (closer to the fixed base) and the curvatures are higher than the other two types. These patterns matched the common clinically observed scoliotic curves - Lenke 1 and Lenke 5. Our elastic rod model predicts deformations that are similar to those of a pediatric spine and it can differentiate between the clinically observed deformation patterns. This provides validation to the hypothesis that changes in the sagittal profile of the spine can be a mechanical factor in parthenogenesis of pediatric idiopathic scoliosis.
Searching through functional space reveals distributed visual, auditory, and semantic coding in the human brain
Authors: Kumar Sreejan , Ellis Cameron T. , O’Connell Thomas , Chun Marvin M , Turk-Browne Nicholas B.
Published: April 2020

The extent to which brain functions are localized or distributed is a foundational question in neuroscience. In the human brain, common fMRI methods such as cluster correction, atlas parcellation, and anatomical searchlight are biased by design toward finding localized representations. Here we introduce the functional searchlight approach as an alternative to anatomical searchlight analysis, the most commonly used exploratory multivariate fMRI technique. Functional searchlight removes any anatomical bias by grouping voxels based only on functional similarity and ignoring anatomical proximity. We report evidence that visual and auditory features from deep neural networks and semantic features from a natural language processing model are more widely distributed across the brain than previously acknowledged. This approach provides a new way to evaluate and constrain computational models with brain activity and pushes our understanding of human brain function further along the spectrum from strict modularity toward distributed representation.
Modeling the COVID-19 epidemic in Okinawa
Authors: Pigolotti Simone , Chiuchiu Davide , Martin Paula Villa , Bhat Deepak
Published: April 2020

We analyze current data on the COVID-19 spreading in Okinawa, Japan. We find that the initial spread is characterized by a doubling time of about 5 days. We implement a model to forecast the future spread under different scenarios. The model predicts that, if significant containment measures are not taken, a large fraction of the population will be infected with COVID-19, with the peak of the epidemic expected at the end of May and intensive care units having largely exceeded capacity. We analyzed scenarios implementing strong containment measures, similar to those imposed in Europe. The model predicts that an immediate implementation of strong containment measures (on the 19th of April) will significantly reduce the death count. We assess the negative consequences of these measures being implemented with a delay, or not being sufficiently stringent.
IER5, a DNA-damage response gene, is required for Notch-mediated induction of squamous cell differentiation
Authors: Pan Li , Lemieux Madeleine E. , Thomas Tom , Rogers Julia M. , Lee Winston , Johnson Carl , Sholl Lynette , South Andrew P. , Marto Jarrod A. , Adelmant Guillaume O. , Blacklow Stephen C. , Aster Jon C.
Published: April 2020

Notch signaling regulates normal squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is a key tumor suppressive pathway. To identify the direct targets of Notch that produce these phenotypes, we introduced a conditional Notch transgene into squamous cell carcinoma cell lines, which respond to Notch activation in 2D culture and in organoid cultures by undergoing differentiation. RNA-seq and ChIP-seq analyses show that in squamous cells Notch activates a context-specific program of gene expression that depends on lineage-specific regulatory elements, most of which lie in long- range enhancers. Among the direct Notch target genes are multiple DNA damage response genes, includingIER5, which is regulated by Notch through several enhancer elements. We show thatIER5is required for Notch-induced differentiation in squamous carcinoma cells and in TERT-immortalized keratinocytes. Its function is epistatic toPPP2R2A, which encodes the B55αsubunit of PP2A, and IER5 interacts with B55αin cells and in purified systems. These results show that Notch and DNA-damage response pathways converge in squamous cells and that some components of these pathways promote differentiation, which may serve to eliminate DNA-damaged cells from the proliferative pool in squamous epithelia. Crosstalk involving Notch and PP2A may enable Notch signaling to be tuned and integrated with other pathways that regulate squamous differentiation. Our work also suggests that squamous cell carcinomas remain responsive to Notch signaling, providing a rationale for reactivation of Notch as a therapeutic strategy in these cancers.

Impact

Our findings highlight context-specific crosstalk between Notch, DNA damage response genes, and PP2A, and provide a roadmap for understanding how Notch induces the differentiation of squamous cells.
Strain background, species frequency and environmental conditions are important in determining population dynamics and species co-existence betweenPseudomonas aeruginosaandStaphylococcus aureus
Authors: Niggli Selina , Kümmerli Rolf
Published: April 2020

Bacterial communities in the environment and in infections are typically diverse, yet we know little about the factors that determine interspecies interactions. Here, we apply concepts from ecological theory to understand how biotic and abiotic factors affect interaction patterns between the two opportunistic human pathogensPseudomonas aeruginosaandStaphyloccocus aureus, which often co-occur in polymicrobial infections. Specifically, we conducted a series of short- and long-term competition experiments betweenP. aeruginosaPAO1 (as our reference strain) and three differentS. aureusstrains (Cowan I, 6850, JE2) at three starting frequencies and under three environmental (culturing) conditions. We found that the competitive ability ofP. aeruginosastrongly depended on the strain background ofS. aureus, wherebyP. aeruginosadominated against Cowan I and 6850, but not against JE2. In the latter case, both species could end up as winners depending on conditions. Specifically, we observed strong frequency-dependent fitness patterns, including positive frequency dependence, whereP. aeruginosacould dominate JE2 only when common, but not when rare. Finally, changes in environmental (culturing) conditions fundamentally altered the competitive balance between the two species, in a way thatP. aeruginosadominance increased when moving from shaken to static environments. Altogether, our results highlight that ecological details can have profound effects on the competitive dynamics between co-infecting pathogens, and determine whether two species can co-exist or invade each others’ populations from rare. Moreover, our findings might parallel certain dynamics observed in chronic polymicrobial infections.

Importance

Bacterial infections are frequently caused by more than one species and such polymicrobial infections are often considered more virulent and more difficult to treat than the respective monospecies infections.Pseudomonas aeruginosaandStaphyloccocus aureusare among the most important pathogens in polymicrobial infections and their co-occurrence is linked to worse disease outcome. There is great interest in understanding how these two species interact with each other and what the consequences for the host are. While previous studies have mainly looked at molecular mechanisms implicated in interactions betweenP. aeruginosaandS. aureus, here we show that ecological factors such as strain background, species frequency and environmental conditions are important elements determining population dynamics and species co-existence patterns. We propose that the uncovered principles may also play major roles in infections, and therefore proclaim that an integrative approach combining molecular and ecological aspects is required to fully understand polymicrobial infections.
The lemur baseline: How lemurs compare to monkeys and apes in the Primate Cognition Test Battery
Authors: Fichtel Claudia , Dinter Klara , Kappeler Peter M.
Published: April 2020

Primates have relatively larger brains than other mammals even though brain tissue is energetically costly. Comparative studies of variation in cognitive skills allow testing of evolutionary hypotheses addressing socioecological factors driving the evolution of primate brain size. However, data on cognitive abilities for meaningful interspecific comparisons are only available for haplorhine primates (great apes, Old- and New World monkeys) although strepsirrhine primates (lemurs and lorises) serve as the best living models of ancestral primate cognitive skills, linking primates to other mammals. To begin filling this gap, we tested members of three lemur species (Microcebus murinus, Varecia variegata, Lemur catta) with the Primate Cognition Test Battery, a comprehensive set of experiments addressing physical and social cognitive skills that has previously been used in studies of haplorhines. We found no significant differences in cognitive performance among lemur species and, surprisingly, their average performance was not different from that of haplorhines in many aspects. Specifically, lemurs’ overall performance was inferior in the physical domain but matched that of haplorhines in the social domain. These results question a clear-cut link between brain size and cognitive skills, suggesting a more domain-specific distribution of cognitive abilities in primates, and indicate more continuity in cognitive abilities across primate lineages than previously thought.
FORCAST: a fully integrated and open source pipeline to design Cas-mediated mutagenesis experiments
Authors: Elrick Hillary , Nelakuditi Viswateja , Clark Greg , Brudno Michael , Ramani Arun K. , Nutter Lauryl M.J.
Published: April 2020

Cas-mediated genome editing has enabled researchers to perform mutagenesis experiments with relative ease. Effective genome editing requires tools for guide RNA selection, off-target prediction, and genotyping assay design. While independent tools exist for these functions, there is still a need for a comprehensive platform to design, view, evaluate, store, and catalogue guides and their associated primers. The Finding Optimizing and Reporting Cas Targets (FORCAST) application integrates existing open source tools such as JBrowse, Primer3, BLAST, bwa, and Silica to create a complete allele design and quality assurance pipeline. FORCAST is a fully integrated software that allows researchers performing Cas-mediated genome editing to generate, visualize, store, and share information related to guides and their associated experimental parameters. It is available from a public GitHub repository and as a Docker image, for ease of installation and portability.
Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition
Authors: Bertels Zachariah , Singh Harinder , Dripps Isaac , Siegersma Kendra , Tipton Alycia F , Witkowski Wiktor , Sheets Zoie , Shah Pal , Conway Catherine , Petukhova Valentina , Karumudi Bhargava , Petukhov Pavel A. , Baca Serapio M. , Rasenick Mark M , Pradhan Amynah A
Published: April 2020

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.
Tgfbr2 in dental pulp cells guides sensory innervation in developing teeth
Authors: Barkley Courtney , Serra Rosa , Nguyen Kevin , Peters Sarah B.
Published: April 2020

Transforming growth factor β (TGFβ) plays an important role in tooth morphogenesis and mineralization. Our laboratory established a mouse model in which Tgfbr2 was conditionally deleted in the dental pulp (DP) mesenchyme using an Osterix promoter-driven Cre recombinase (Tgfbr2cko). These mice survived postnatally, but had significant defects in bones and teeth, including reduced mineralization and short roots. H&E staining revealed reduced axon-like structures in the mutant mice. Reporter imaging demonstrated that Osterix-Cre activity was localized within the tooth and was active in the DP and derivatives, but not in neurons. Previous research has established that paracrine signals from the dental pulp attract trigeminal axons toward and into the tooth during postnatal development, yet very little is known about the signals that regulate tooth innervation. Immunofluorescent staining for a neuronal marker, β3 tubulin, was performed on serial cryosections from control and mutant molars at two different postnatal stages. Confocal imaging and pixel quantification of β3 tubulin demonstrated reduced innervation in P7 and P24 Tgfbr2ckofirst molars compared to controls, indicating that the signals necessary to promote neurite outgrowth were disrupted by Tgfbr2 deletion. Quantitative real time PCR showed that the mRNA expression levels of several neuronal genes were reduced. Lastly, trigeminal neurons were co-cultured atop Transwell filters overlying primary Tgfbr2f/fDP cells. Tgfbr2 in the DP was deleted with an adenovirus expressing Cre recombinase. Confocal imaging of axons through the filter pores showed increased axonal sprouting from neurons cultured in the presence of Tgfbr2-positive DP cells compared to neurons cultured alone. Further, axon sprouting was reduced when Tgfbr2 was knocked down in the DP cells. These results indicate that Tgfbr2 in the DP mesenchyme regulates paracrine signals that guide sensory innervation of the tooth.

Note: A list of abbreviations is included in the appendix.
Genomic regions linked to soft sweeps approximate neutrality when inferring population history from site pattern frequencies
Authors: Harris Nathan S. , Rogers Alan R.
Published: April 2020

Recent studies have suggested that selection is widespread throughout the genome and largely uncompensated for in inferences of population history. To address this potential issue, we estimated site pattern frequencies for neutral and selection associated areas of the genome. There are notable differences in these frequencies between neutral regions and those affected by selection. However, these differences have relatively small effects when inferring population history.
Hyperexcitability and loss of feedforward inhibition in theFmr1KO lateral amygdala
Authors: Guthman E. Mae , Svalina Matthew N. , Cea-Del Rio Christian A. , Kushner J. Keenan , Baca Serapio M. , Restrepo Diego , Huntsman Molly M.
Published: April 2020

Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorders (ASDs), and anxiety disorders. The disruption in the function of theFMR1gene results in a range of alterations in cellular and synaptic function. Previous studies have identified dynamic alterations in inhibitory neurotransmission in early postnatal development in the amygdala of the mouse model of FXS. Yet little is known how these changes alter microcircuit development and plasticity in the lateral amygdala (LA). Using whole-cell patch clamp electrophysiology, we demonstrate that principal neurons (PNs) in the LA exhibit hyperexcitability with a concomitant increase in the synaptic strength of excitatory synapses in the BLA. Further, reduced feed-forward inhibition appears to enhance synaptic plasticity in the FXS amygdala. These results demonstrate that plasticity is enhanced in the amygdala of the juvenileFmr1KO mouse and that E/I imbalance may underpin anxiety disorders commonly seen in FXS and ASDs.
Simplicity in numbers: Implications of diversity for the community Bioturbation Potential (BPc)
Authors: Neumann Andreas , Wrede Alexa
Published: April 2020

The mobility of particles and solutes within aquatic sediment is substantially impacted by faunal bioturbation activities such as bioirrigation and sediment reworking. The non-quantitative community bioturbation potential (BPc) aims to estimate the potential of a given benthic community for bioturbation activities, based on the functional traits of the species within that community. We argue that in sufficiently diverse communities, the characteristics of individual species, expressed as traits scores, average each other out, and approach a universal constant. This enables to derive a simpler community bioturbation potential (BPs), which may be applied in cases when taxonomic expertise or trait data are not available. As a proof of concept, we evaluated a dataset of 84 benthos assemblages, and found a high degree of agreement of full BPc and simplified BPs.
T2 heterogeneity provides a sensitive measure of early tumor response to radiotherapy
Authors: Tomaszewski Michal R. , Dominguez-Viqueira William , Ortiz Antonio , Shi Yu , Costello James R. , Enderling Heiko , Rosenberg Stephen A. , Gillies Robert J.
Published: April 2020

Purpose

External beam radiotherapy (XRT) is a widely used cancer treatment, yet responses vary dramatically between patients. These differences are not accounted for in clinical practice, in part due to a lack of sensitive biomarkers of early response. In this work, we test the hypothesis that quantification of intratumor heterogeneity is a sensitive and robust biomarker of early response to XRT. A novel Magnetic Resonance Imaging (MRI) approach is proposed, utilizing histogram analysis of clinically-used T2 relaxation measurements to assess early changes in the tumor heterogeneity following irradiation in murine models of pancreatic cancer, indicative of radiotherapy response.

Methods and Materials

Dynamic Magnetic Resonance T2 relaxation imaging was performed every 72h following 10 Gy dose XRT in two murine models of pancreatic cancer. Proposed biomarker of radiotherapy response was compared with tumor growth kinetics, and biological validation was performed through quantitative histology analysis.

Results

Quantification of tumor T2 interquartile range (IQR) as a measure of histogram width showed excellent sensitivity for detection of XRT-induced tumor changes as early as 72h after treatment, outperforming whole tumor T2 and Diffusion weighted MRI metrics. This response was observed both in quantitative T2 maps and in T2-weighted images that are routine in clinical practice. Histological comparison revealed the T2 IQR provides a measure of spatial heterogeneity in tumor cell density, related to radiation-induced necrosis. The early IQR changes were found to presage subsequent tumor volume changes in two distinct pancreatic models, suggesting promise for treatment response prediction. The metric showed excellent test-retest robustness.

Conclusions

Our preclinical findings indicate that spatial heterogeneity analysis of T2 MRI can provide a sensitive and readily translatable method for early radiotherapy response assessment in pancreatic cancer. We propose that this will be useful in adaptive radiotherapy, specifically in MRI-guided treatment paradigms.