bluuebunny/crossref_metadata_2025 huggingface dataset:
ATIM-49 (LTBK-01). AMG 596, A NOVEL ANTI-EGFRVIII BISPECIFIC T CELL ENGAGER (BITE®) MOLECULE FOR THE TREATMENT OF GLIOBLASTOMA (GBM): PLANNED INTERIM ANALYSIS IN RECURRENT GBM (RGBM)
Authors: Rosenthal Mark A , Balana Carmen , van Linde Myra E , Sayehli Cyrus , Fiedler Walter M , Wermke Martin , Massard Christophe , Mellinghoff Ingo K , Khasraw Mustafa , Ang Agnes , Rasmussen Erik , Kast Johannes , Stienen Sabine , Cloughesy Timothy F
Published: November 2019

OBJECTIVES

The class III variant of the epidermal growth factor receptor (EGFRvIII) represents the most common EGFR mutation in GBM. AMG 596 is a bispecific T cell engager (BiTE®) molecule designed to engage a patient’s own CD3-positive T cells to EGFRvIII-positive tumor antigens. This is the first clinical data readout for AMG 596.

METHODS

This phase 1, first-in-human, open-label, sequential dose-escalation/expansion study evaluates continuous intravenous AMG 596 in patients with EGFRvIII-positive GBM or malignant glioma in recurrent (Group 1) or newly diagnosed in maintenance treatment (Group 2) settings. Eligible patients: adults with EGFRvIII-positive GBM or malignant glioma; ≤2 mg/day dexamethasone, ECOG performance status ≤1; life expectancy ≥3 months; and acceptable renal, hematological, and hepatic function. The primary objective evaluates safety and tolerability. Additional assessments include objective response rate per modified Response Assessment in Neuro-Oncology (RANO) Criteria.

RESULTS

As of June 2019, 15 rGBM patients (Group 1) were enrolled; 14 patients received ≥1 dose AMG 596. 14/15 (93.3%) patients were evaluable at time of analysis (safety analysis set). Median age was 54.5 years (range, 44–68); 50% were male. Seven patients discontinued for progressive disease (PD). AEs occurred in all patients and were serious in 7/14 (50%). None resulted in discontinuation; two (14.3%) fatal AEs were related to PD. Headache and depressed consciousness (both n=2, 14.3%) were the most common grade ≥3 treatment emergent AEs. In patients with sufficient follow-up to assess response (n=8), 1 (12.5%) achieved partial response, 2 (25%) had stable disease, 4 (50%) had PD at initial scan, and 1 (12.5%) discontinued treatment for PD. Semi-quantitative EGFRvIII expression analysis revealed a median H-score of 115 (range, 8–280).

CONCLUSION

This interim analysis suggests a first indication that AMG 596 may be well-tolerated and offer anti-tumor activity in patients with rGBM. Enrollment is ongoing and additional data will be presented. NCT03296696.
Expectations Management and Stock Returns
Authors: Johnson Travis L , Kim Jinhwan , So Eric C
Published: November 2019

We establish a link between firms managing investors’ performance expectations, earnings announcement premiums, and cyclical patterns (i.e., seasonalities) in returns. Firms that are more likely to manage expectations toward beatable levels predictably earn lower returns before, and higher returns during, their earnings announcements. This pattern repeats across firms’ fiscal quarters, suggesting firms manufacture positive “surprises” by negatively biasing investors’ expectations ahead of announcing earnings. We corroborate these findings using non-price-based outcomes indicative of expectations management. Together, our findings are consistent with the pressure for firms to meet earnings targets shaping the cross-section of firms’ stock returns.
A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution
Authors: Radin Massimo , Schreiber Karen , Cecchi Irene , Bortoluzzi Alessandra , Crisafulli Francesca , de Freitas Cristiano M , Bacco Beatrice , Rubini Elena , Foddai Silvia G , Padovan Melissa , Gallo Cassarino Silvia , Franceschini Franco , Andrade Danieli , Benedetto Chiara , Govoni Marcello , Bertero Tiziana , Marozio Luca , Roccatello Dario , Andreoli Laura , Sciascia Savino
Published: November 2019

Objectives

To investigate fetal/perinatal and maternal outcomes from a large multicentre cohort of women diagnosed with UCTD.

Methods

This multicentre retrospective cohort study describes the outcomes of 224 pregnancies in 133 consecutive women with a diagnosis of UCTD, positive for ANA and aged <45 years old at study inclusion.

Results

Of the 224 pregnancies analysed, 177 (79%) resulted in live births, 45 (20.1%) in miscarriages (defined as pregnancy loss before 12 weeks’ gestation), 2 (0.9%) in stillbirths (pregnancy loss after 20 weeks’ gestation) and 6 (2.7%) cases showed intrauterine growth restriction. Miscarriages and stillbirths were strongly associated with the presence of aPL and ENA antibodies (P < 0.05). Maternal pregnancy complications were as follows: 5 (2.2%) cases developed pre-eclampsia, 11 (4.9%) cases gestational hypertension and 12 (5.4%) cases gestational diabetes. Joint involvement represented the most frequent clinical manifestation of the cohort (57.9%), followed by RP (40.6%), photosensitivity (32.3%) and haematological manifestations (27.1%). The rate of disease evolution of our cohort from a diagnosis of UCTD to a diagnosis of definite CTD was 12% within a mean time of 5.3 ± 2.8 years. With a total follow-up after first pregnancy of 1417 patient-years, we observed the evolution to a defined CTD in one out of every 88 patient- years.

Conclusion

In our multicentre cohort, women with UCTD had a live birth rate of 79%. Women with UCTD should be referred to specialist follow-up when planning a pregnancy. ENA profiling and aPL testing should be mandatory in this setting, and further therapeutic approaches and management should be planned accordingly.
Species delimitation, classical taxonomy and genome skimming: a review of the ground beetle genusLionepha(Coleoptera: Carabidae)
Authors: Maddison David R , Sproul John S
Published: November 2019

The western North American genus Lionepha is shown to contain at least 11 species through a combination of eight-gene species delimitation analyses and morphological study. In order to confirm the names of several species, we sequence DNA of primary types of several names, including a LeConte lectotype collected in the 1850s, using next-generation sequencing. We examine chromosomes of eight species, and show that all have 12 pairs of autosomes and an X0/XX sex-chromosome system. The following species are described as new: Lionepha australerasa, L. kavanaughi, L. lindrothi and L. tuulukwa. The name Lionepha erasa is shown to belong to a relatively rare, western species ranging from Oregon through Alaska; the common, widespread species previously known as Lionepha erasa now takes the name L. probata. Bembidion chintimini, B. lindrothellus and B. lummi are synonymized with L. erasa. We provide tools to identify specimens to species, including illustrations, diagnoses and distribution maps.
Autoinhibition can identify rare driver mutations and advise pharmacology
Authors: Nussinov Ruth , Tsai Chung‐Jung , Jang Hyunbum
Published: November 2019

Identification of protein mutations that drive cancer is a major challenge. A primary reason is that driver mutations are principally identified by their high frequency even though they can also be rare. Driver mutations can locate at functional (binding or active) sites. We dub these orthosteric drivers. However, often they are allosteric drivers. Identification is particularly formidable for rare allosteric drivers. Autoinhibition, where a segment of the protein covers its functional site, is a common allosteric regulation mechanism. A modest shift in the equilibrium can switch the system from the autoinhibited to the active state. This can suggest why (i) mutations are likely to evolve to target it; (ii) inhibitors can straightforwardly relieve the autoinhibition but not vice versa; and why (iii) mutations that relieve the autoinhibition are likely to be drivers—even if they are rare. We explain in simple terms the linkage between allosteric driver mutations, release of autoinhibition, free energy landscapes, and targeted pharmacology in precision medicine. We review the literature and propose new concepts in identification of rare drivers in this framework.
Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice
Authors: Annunziata Chiara , Lama Adriano , Pirozzi Claudio , Cavaliere Gina , Trinchese Giovanna , Di Guida Francesca , Nitrato Izzo Allegra , Cimmino Fabiano , Paciello Orlando , De Biase Davide , Murru Elisabetta , Banni Sebastiano , Calignano Antonio , Mollica Maria Pina , Mattace Raso Giuseppina , Meli Rosaria
Published: November 2019

Peroxisome proliferator‐activated receptor (PPAR)‐α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR‐α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high‐fat diet (HFD) in mice. Long‐term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate‐challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin‐resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP‐activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA‐induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload.
Macro-parasite transmission in dynamic seasonal environment: Basic Reproductive Number, endemicity, and control
Authors: Huang Q. , Gurarie D. , Ndeffo-Mbah M. , Li E. , King CH.
Published: November 2019

Seasonality of transmission environment, which includes snail populations and habitats, or human-snail contact patterns, can affect the dynamics of schistosomiasis infection, and control outcomes. Conventional modeling approaches often ignore or oversimplify it by applying ‘seasonal mean’ formulation. Mathematically, such ‘averaging’ is justified when model outputs/quantities of interest depend linearly on input variables. That is not generally the case for macroparasite transmission models, where model outputs are nonlinear functions of seasonality fashion.

Another commonly used approach for Schistosomiasis modeling is a reduction of coupled human-snail system to a single ‘human equation’, via quasi-stationary snail (intermediate host) dynamics. The basic questions arising from these approaches are whether such ‘seasonal averaging’ and ‘intermediate host reduction’ are suitable for highly variable/seasonal environments, and what implications these methods have on models’ predictive potential of control interventions.

Here we address these questions by using a combination of mathematical analysis and numerical simulation of two commonly used models for macroparasite transmission, MacDonald (MWB), and stratified worm burden (SWB) snail-human systems. We showed that predictions from ‘seasonal averaging’ models can depart significantly from those of quasi-stationary models. Typically, seasonality would lower endemicity and sustained infection, vs. stationary system with comparable transmission inputs. Furthermore, discrepancies between the two models (‘seasonal’ and its ‘stationary mean’) increase with amplitude (or variance) of seasonality. So sufficiently high variability can render infection unsustainable. Similar discrepancies were observed between coupled and reduced ‘single host’ models, with reduced model overpredicting sustained endemicity. Seasonal variability of transmission raises the question of optimal control timing. Using dynamic simulation, we show that optimal timing of repeated MDA is about half season past the snail peak, where snail population attains its minimal value. Compared to sub-optimal timing, such strategy can reduce human worm burden by factor 2 after 5-6 rounds of MDA. We also extended our models for dynamic snail populations, which allowed us to study the effect of repeated molluscicide, or combined strategy (MDA + molluscicide). The optimal time for molluscicide alone is the end or the start of season, and combined strategy can give additional reduction, and in some cases lead to elimination.

Overall, reduced sustainability in seasonal environment makes it more amenable to control interventions, compared to stationary environment.
No Association between HPV Vaccination and Infertility in U.S. Females 18-33 Years Old
Authors: Mooney Katherine E. , Schmuhl Nicholas B. , Zhang Xiao , Cooney Laura G. , Conway James H. , LoConte Noelle K.
Published: November 2019

Background

Human papillomavirus (HPV) vaccines have been recommended as primary prevention of HPV-related cancers for over 10 years in the United States, and evidence reveals decreased incidence of HPV infections following vaccination. However, concerns have been raised that HPV vaccines could decrease fertility. This study examined the relationship between HPV immunization and self-reported infertility in a nationally representative sample.

Methods

Data from the 2013-2016 National Health and Nutrition Examination Survey were analyzed to asses likelihood of self-reported infertility among women aged 20 to 33, who were young enough to have been offered HPV vaccines and old enough to have been queried about infertility (n=1,114). Two logistic regression models, stratified by marital history, examined potential associations between HPV vaccination and infertility. Model 1 assessed the likelihood of infertility among women who had never been pregnant or whose pregnancies occurred prior to HPV vaccination. Model 2 accounted for the possibility of latent and/or non-permanent post-vaccine infertility by including all women 20-33 years old.

Results

8.1% reported any infertility. Women who had ever been married and had received an HPV vaccine were less likely to report infertility (OR 0.04, 95% CI 0.01-0.57) in model 1. No other associations between HPV and infertility were found.

Conclusion

There was no evidence of increased infertility among women who received the HPV vaccine. These results provide further evidence of HPV vaccine safety and should give providers confidence in recommending HPV vaccination. Further research should explore protective effects of HPV vaccines on female and male fertility.

What is already known on this subject?

Despite evidence that HPV vaccines are safe and effective, concerns persist regarding a purported link between HPV vaccination and infertility. These concerns were refuted by a recent population-based cohort study that found no association between the HPV vaccine and primary ovarian insufficiency.

What this study adds?

This study broadens the existing evidence by exploring possible associations between HPV vaccination and any self-reported infertility. There was no evidence of infertility among women 20-33 years old who received one or more doses of HPV vaccine. This result provides further evidence of HPV vaccine safety, diminishing remaining concerns among clinicians and the public.
Cost-effectiveness of implementing objective diagnostic verification of asthma in the United States
Authors: Yaghoubi Mohsen , Adibi Amin , Zafari Zafar , FitzGerald J Mark , Aaron Shawn D. , Johnson Kate M. , Sadatsafavi Mohsen
Published: November 2019

Background

Asthma diagnosis in the community is often made without objective testing.

Objective

The aim of this study was to evaluate the cost-effectiveness of implementing a stepwise objective diagnostic verification algorithm among patients with community-diagnosed asthma in the United States (US).

Methods

We developed a probabilistic time-in-state cohort model that compared a stepwise asthma verification algorithm based on spirometry and methacholine challenge test against the current standard of care over 20 years. Model input parameters were informed from the literature and with original data analyses when required. The target population was US adults (≥15 y/o) with physician-diagnosed asthma. The final outcomes were costs (in 2018 $) and quality-adjusted life years (QALYs), discounted at 3% annually. Deterministic and probabilistic analyses were undertaken to examine the effect of alternative assumptions and uncertainty in model parameters on the results.

Results

In a simulated cohort of 10,000 adults with diagnosed asthma, the stepwise algorithm resulted in the removal of diagnosis in 3,366. This was projected to be associated with savings of $36.26 million in direct costs and a gain of 4,049.28 QALYs over 20 years. Extrapolating these results to the US population indicated an undiscounted potential savings of $56.48 billion over 20 years. Results were robust against alternative assumptions and plausible changes in values of input parameters.

Conclusion

Implementation of a simple diagnostic testing algorithm to verify asthma diagnosis might result in substantial savings and improvement in patients’ quality of life.

Key Messages

Compared with current standards of practice, the implementation of an asthma verification algorithm among US adults with diagnosed asthma can be associated with reduction in costs and gain in quality of life.

There is substantial room for improving patient care and outcomes through promoting objective asthma diagnosis.

Capsule summary

Asthma ‘overdiagnosis’ is common among US adults. An objective, stepwise verification algorithm for re-evaluation of asthma diagnosis can result in substantial savings in costs and improvements in quality of life.
Projected Impact of Concurrently Available Long-Acting Injectable and Daily-Oral HIV Pre-Exposure Prophylaxis: A Mathematical Model
Authors: Maloney Kevin M. , Guillou Adrien Le , Driggers Robert A. , Sarkar Supriya , Anderson Emeli J. , Malik Amyn A. , Jenness Samuel M.
Published: November 2019

Background

Long-acting injectable HIV pre-exposure prophylaxis (LAI-PrEP) is reportedly efficacious, although full trial results have not been published. We used a dynamic network model of HIV transmission among men who have sex with men (MSM) to assess the population impact of LAI-PrEP when available concurrently with daily-oral (DO) PrEP.

Methods

The reference model represents the current HIV epidemiology and DO-PrEP coverage (15% among indicated) among MSM in the southeastern US. Primary analyses investigated varied PrEP uptake and proportion selecting LAI-PrEP. Secondary analyses evaluated uncertainty in pharmacokinetic efficacy and LAI-PrEP persistence relative to DO-PrEP.

Results

Compared to the reference scenario, if 50% chose LAI-PrEP, 4.3% (95% SI: −7.3%, 14.5%) of infections would be averted over 10 years. LAI-PrEP impact is slightly greater than the DO-PrEP only regimen based on assumptions of higher adherence and partial protection after discontinuation. If the total PrEP initiation rate doubled, 17.1% (95% SI: 6.7%, 26.4%) of infections would be averted. The highest population-level impact occurred when LAI-PrEP uptake and persistence improved.

Conclusions

If LAI-PrEP replaces DO-PrEP, its availability will modestly improve the population impact. LAI-PrEP will make a more substantial impact if its availability drives higher total PrEP coverage, or if persistence is greater for LAI-PrEP.

Long-acting injectable pre-exposure prophylaxis (LAI-PrEP) will modestly decrease HIV incidence if it replaces daily-oral PrEP use among men who have sex with men. LAI-PrEP will make a more substantial impact if its availability drives higher total PrEP coverage.
Global and Historical Distribution ofClostridioides difficilein the Human Diet (1981-2019): Systematic Review and Meta-Analysis of 21886 Samples Reveal Sources of Heterogeneity, High-Risk Foods, and Unexpected Higher Prevalence Towards the Tropic
Authors: Rodriguez-Palacios Alexander , Mo Kevin Q , Shah Bhavan U. , Msuya Joan , Bijedic Nina , Deshpande Abhishek , Ilic Sanja
Published: November 2019

Clostridioides difficile(CD) is a spore-forming bacterium that causes life-threatening intestinal infections in humans. Although formerly regarded as exclusively nosocomial, there is increasing genomic evidence that person-to-person transmission accounts for only <25% of cases, supporting the culture-based hypothesis that foods may be routine sources of CD-spore ingestion in humans.

To synthesize the evidence on the risk of CD exposure via foods, we conducted a systematic review and meta-analysis of studies reporting the culture prevalence of CD in foods between January 1981 and November 2019. Meta-analyses, risk-ratio estimates, and meta-regression were used to estimate weighed-prevalence across studies and food types to identify laboratory and geographical sources of heterogeneity.

In total, 21,886 food samples were tested for CD between 1981 and 2019 (232 food-sample-sets; 79 studies; 25 countries). Culture methodology, sample size and type, region, and latitude were significant sources of heterogeneity (p<0.05). Although non-strictly-anaerobic methods were reported in some studies, and we confirmed experimentally that improper anaerobiosis of media/sample-handling affects CD recovery in agar (Fisher, p<0.01), most studies (>72%) employed the same (one-of-six) culture strategy. Because the prevalence was also meta-analytically similar across six culture strategies reported, all studies were integrated using three meta-analytical methods. At the study level (n=79), the four-decade global cumulative-prevalence of CD in the human diet was 4.1% (95%CI=-3.71, 11.91). At the food-set level (n=232), the weighted prevalence ranged between 4.5% (95%CI=3-6%; all studies) and 8% (95%CI=7-8%; only CD-positive-studies). Risk-ratio ranking and meta-regression showed that milk was the least likely source of CD, while seafood, leafy green vegetables, pork, and poultry carried higher risks (p<0.05). Across regions, the risk of CD in foods for foodborne exposure reproducibly decreased with Earth latitude (p<0.001).

In conclusion, CD in the human diet is a global nonrandom-source of foodborne exposure that occurs independently of laboratory culture methods, across regions, and at variable level depending on food type and latitude. The latitudinal trend (high CD-food-prevalence towards tropic) is unexpectedly inverse to the epidemiological observations of CD-infections in humans (frequent in temperate regions). Findings suggests the plausible hypothesis that ecologically-richer microbiomes in the tropic might protect against intestinal CD colonization/infections despite CD ingestion.
Incidence and Prevalence of Hidradenitis Suppurativa: A Systematic Review and Meta-analysis
Authors: Gill N. , Gniadecki R.
Published: November 2019

Background

Hidradenitis is a chronic relapsing follicular occlusive disease with a widely variable reported prevalence. The exact prevalence and incidence of HS is unknown.

Objectives

To perform a systematic review and meta-analysis of the published literature to estimate the global incidence and prevalence of HS.

Methods

Literature searches were performed on Medline, Embase, and Pubmed to identify studies reporting incidence and/or prevalence of HS. Pooled estimates of prevalence and incidence were calculated with a meta-analysis of proportions.

Results

In total, 12 studies were included (Australia, Brazil, Denmark, France, Germany, Ireland, Israel, UK, USA) comprising a total population of 53,805,690. Eleven studies reported prevalence. The pooled proportion of individuals in the general population with HS was 0.36% (95% CI 0.21 - 0.56). Self-reported HS gave a higher prevalence estimate than clinician-diagnosed HS. HS is more prevalent in women. Average annual incidence of HS was 28.5 cases/100,000 (95% CI 26.8 – 30.1).

Conclusions

We estimated the global prevalence of HS to be 0.36% with 3:2 female predominance and average annual incidence to be 28.5 cases/100,000.
Antimicrobial resistance trends from a hospital and diagnostic facility in Lahore, Pakistan: A five-year retrospective analysis (2014-2018)
Authors: Ching Carly , Nizamuddin Summiya , Rasheed Farah , Seager R.J. , Litvak Felix , Sultan Faisal , Zaman Muhammad
Published: November 2019

Objective

Observing antimicrobial resistance (AMR) trends is critical to identify emerging pathogens and potential disease outbreaks. Determining these trends also allows for policy evaluations and development of interventions. We performed a retrospective analysis of microbiological testing results from a hospital and diagnostic facility in Lahore, Pakistan that represents country-wide sampling. Within this analysis, data was disaggregated by nationality, as it has been suggested that migration increases the burden of AMR. We sought to determine any trends in AMR among populations, which are often at-risk, while contributing to AMR surveillance in Pakistan, which currently does not have a national surveillance network.

Methods

Retrospective analysis of antimicrobial susceptibility records from 2014 to 2018 from Shaukat Khanum Memorial Cancer Hospital & Research Centre (SKMCH&RC) in Lahore, Pakistan was performed. All positive microbiological cultures from patients was analyzed to assess antibiotic resistance rates of the most common bacterial isolates and incidence of ESKAPE pathogens and emerging outbreaks among adults and children.

Results

For all years, data for a total of 12,702 and 78,130 bacterial and fungal isolates from children and adults, respectively, with Pakistani nationality were analyzed. For all years, data for 597 and 2470 bacterial and fungal isolates for children and adults, respectively, with Afghan nationality were analyzed. AMR rates largely did not vary between populations, but rather followed similar trends. AMR rates also largely agreed with the World Health Organization Global Antimicrobial Surveillance System results for Pakistan.

Conclusion

Pakistan requires increased AMR surveillance to identify emerging resistance infections and outbreaks.
Temperature-related disasters in Europe – a cross-sectional analysis of the emergency events database from a pediatric perspective
Authors: Brennenstuhl Heiko , Will Manuel , Ries Elias , Mechler Konstantin , Garbade Sven , Ries Markus
Published: November 2019

This study investigates patterns of extreme temperature-related events in Europe and its significance for the public health, with a focus on the vulnerable pediatric population. A generalized additive model of average surface temperature development for the European countries is described and discussed with an in-depth analysis of the influence of temperature on evolutional and behavioral aspects.

Methods

Extreme temperature related events are recorded in the publicly available epidemiological database of Emergency Events (EM-DAT). A comparative and descriptive statistical analysis of this data was conducted with a focus on (prospective) records from 1988 onwards. Average surface temperature data was provided by the World Bank’s Climate Change Knowledge Portal. The criteria for strengthening the reporting of observational studies in epidemiology (STROBE) were respected.

Results

Within EM-DAT, extreme temperature-related disasters in Europe were categorized as either heat waves, drought, forest or land fires, or cold waves and severe winter conditions, accordingly. The most frequent type of event recorded were cold waves (36.2%). However, cold waves and severe winter conditions only accounted for about 6,460 casualties (4.4%), while heat waves were responsible for a total of 137,533 casualties (95.1%). During the prospective observational period of the EM-DAT database, heat waves in 2003, 2006, 2010, and 2015, claimed a total of 119,760 casualties. These most severe heatwaves were geographically distributed over Russia (2010), as well as France, Italy, Spain, and Germany, each in 2003. Accordingly, analysis of temperature data revealed an increasing average surface temperature for all assessed European countries, correlating with in an increasing frequency of extreme temperature-related events.

Conclusion

This study shows that according to EM-DAT data extreme temperatures are an increasingly important public health threat to the European population as the average European surface temperatures are rising. Although cold waves are more frequently reported in EM-DAT, heat waves are the major cause for temperature-related casualties. Therefore, we conclude that evolutional and cultural resilience against cold and drought is significantly higher than it is against heat. Our results project that the frequency, duration and intensity of heat waves will further increase due to current climatic changes and become a more prevalent problem for future generations. Hence, we propose an emergency plan to inform the public and authorities about measurements to be taken in such extreme heat conditions to overcome the prevailing lack of information available to the public.
Aberrant effective connectivity is associated with positive symptoms in first-episode schizophrenia
Authors: Dietz Martin J. , Zhou Yuan , Veddum Lotte , Frith Christopher D. , Bliksted Vibeke F.
Published: November 2019

Schizophrenia is a tenacious psychiatric disorder thought to result from synaptic dysfunction. While symptomatology is traditionally divided into positive and negative symptoms, abnormal social cognition is now recognized a key component of schizophrenia. Nonetheless, we are still lacking a mechanistic understanding of how aberrant synaptic connectivity is expressed in schizophrenia during social perception and how it relates to positive and negative symptomatology. We used fMRI and dynamic causal modelling (DCM) to test for abnormalities in synaptic efficacy in twenty-four patients with first-episode schizophrenia (FES) compared to twenty-five matched controls performing the Human Connectome Project (HCP) social cognition paradigm. Patients had not received regular therapeutic antipsychotics, but were not completely drug naïve. Our data reveal an increase in excitatory feedforward connectivity from motion-sensitive V5 to posterior superior temporal sulcus (pSTS) in patients compared to matched controls. At the same time, were less accurate than controls in judging social stimuli from non-social stimuli. Crucially, patients with a higher degree of positive symptoms had more disinhibition within pSTS, a region computationally involved in Theory of Mind. We interpret these within a predictive coding framework where increased feedforward connectivity may encode aberrant prediction errors from V5 to hierarchically higher pSTS and local disinhibition within pSTS may reflect aberrant encoding of the precision of cortical representations about social stimuli.
Stereotactic arrhythmia radioablation for refractory scar-related ventricular tachycardia
Authors: Gianni Carola , Rivera Douglas , Burkhardt J David , Pollard Brad , Gardner Edward , Maguire Patrick , Zei Paul C , Natale Andrea , Al-Ahmad Amin
Published: November 2019

Background

Stereotactic radiosurgery is a form of radiotherapy that is performed in a single session and focuses high-dose ionizing radiation beams from a collimated radiation source to a small, localized area of the body. Recently, stereotactic radiosurgery has been applied to arrhythmias (stereotactic arrhythmia radioablation - STAR), with promising results reported in patients with refractory, scar-related ventricular tachycardia (VT), a cohort with known high morbidity and mortality.

Objective

Herein, we describe our experience with the use of CyberKnife, a frameless image-guided linear accelerator stereotactic radiosurgery system, in conjunction with CardioPlan, a cardiac specific radiotherapy planning software, to treat patients with scar-related VT, detailing its early and mid-to long-term results.

Methods

This is a pilot, prospective study of patients undergoing STAR for refractory VT. The anatomical target for radioablation was defined based on the clinical VT morphology, electroanatomical mapping, and study-specific pre-procedural imaging with cardiac computed tomography. The target volume delineated with the aid of CardioPlan was treated with a prescription radiation dose of 25 Gy delivered in a single fraction by CyberKnife in an outpatient setting. Ventricular arrhythmias and radiation-related adverse events were monitored at follow-up to determine STAR efficacy and safety.

Results

Five patients (100 % male, 63 ± 12 years old, 80 % ischemic cardiomyopathy, left ventricular ejection fraction 34 ± 15 %) with refractory VT underwent STAR between January and June 2018. Radioablation was delivered in 82 ± 11 minutes without acute complications. During a mean follow-up of 12 ± 2 months, all patients experienced clinically significant mid-to late-term ventricular arrhythmia recurrence; two patients died of complications associated with their advanced heart failure. There were no clinical or imaging evidence of radiation necrosis or other radiation-induced complications in the organs at risk surrounding the scar targeted by radioablation.

Conclusion

Despite good initial results, STAR did not result in effective ventricular arrhythmia control in the long term in a selected, high-risk population of patients with scar-related VT. The safety profile was confirmed to be favorable, with no radiation-related complications observed during follow-up. Further studies are needed to explain these disappointing results.
Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7
Authors: Greer Stephanie U. , Ogmundsdottir Margret H. , Chen Jiamin , Lau Billy T. , Delacruz Richard Glenn C. , Sandoval Imelda T. , Kristjansdottir Sigrun , Jones David A. , Haslem Derrick S. , Romero Robin , Fulde Gail , Bell John M. , Jonasson Jon G. , Steingrimsson Eirikur , Ji Hanlee P. , Nadauld Lincoln D.
Published: November 2019

Cholangiocarcinoma is an aggressive cancer originating from the bile duct. Although cholangiocarcinoma does occur in families, to date no specific causative gene has been identified. We identified ATG7 as a cancer susceptibility gene using a joint genetic analysis of an extended pedigree with familial cholangiocarcinoma in combination with a population genetic association study. Affected family members had a germline mutation (c.2000C>T [p.Arg659*]) in the autophagy related gene, ATG7, and all of the affected individuals had cholangiocarcinoma tumors harboring somatic genomic deletions of ATG7. From a population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G [p.Asp522Glu]) associated with increased risk of cholangiocarcinoma. The autophagy substrate p62 demonstrated a higher accumulation in tumors of p.Asp522Glu carriers compared with non-carriers indicating defective autophagy. To determine whether the germline ATG7 mutation had functional consequences, we developed an ATG7-deficient cholangiocyte cell line, derived from human bile duct, to test for autophagy-mediated lipidation activity. The germline mutation from the familial cholangiocarcinoma demonstrated a lack of lipidation activity compared to the wildtype ATG7. Moreover, in zebrafish embryos depleted of atg7, a reproducible necrotic head phenotype was rescued by injection of wildtype ATG7 but not mutant ATG7. Our findings point to ATG7 as a causative genetic risk factor for cholangiocarcinoma and implicate autophagy as a novel cancer driver mechanism.
Simultaneous fluorescence imaging of tilted focal planes at two depths in thick neural tissue: Implementation with remote focus in a widefield electrophysiological microscope
Authors: Lagarde Bruno , Russell Noah , Esposito Elric , Desban Laura , Wyart Claire , Ogden David
Published: November 2019

Wide-field imaging conventionally results in a single image plane oriented perpendicular to the optical axis. However, in brain slice or in vivo recording, neuronal or circuit morphologies lie in arbitrarily tilted planes. Consequently the spatiotemporal advantages of wide-field non-scanned imaging are lost because of the time required for stepwise focal readjustments to view an entire neuron or network. We describe an application of remote focus that views simultaneously two planes separated by up to 100 µm, each with variable tilt from the conventional image plane. This permits fluorescence detection of ion fluxes or membrane potential across neuronal compartments and their correlation with electrical activity. Further, two fluorophores can be viewed simultaneously in each plane.

We show (i) neuronal images tilted to optimise simultaneous aquisition of somatic, dendritic and axonal compartments; (ii) networks viewed simultaneously at 2 depths separated by up to 100 µm, (iii) widefield imaging at 30 Hz of Gcamp5 fluorescence during spontaneous spiking in motoneuron layers of zebrafish spinal cord separated by 30-40 microns.
To dereplicate or not to dereplicate?
Authors: Evans Jacob T. , Denef Vincent J.
Published: November 2019

Our ability to reconstruct genomes from metagenomic datasets has rapidly evolved over the past decade, leading to publications presenting 1,000s, and even more than 100,000 metagenome-assembled genomes (MAGs) from 1,000s of samples. While this wealth of genomic data is critical to expand our understanding of microbial diversity, evolution, and ecology, various issues have been observed in some of these datasets that risk obfuscating scientific inquiry. In this perspective we focus on the issue of identical or highly similar genomes assembled from independent datasets. While obtaining multiple genomic representatives for a species is highly valuable, multiple copies of the same or highly similar genomes complicates downstream analysis. We analyzed data from recent studies to show the levels of redundancy within these datasets, the highly variable performance of commonly used dereplication tools, and to point to existing approaches to account and leverage repeated sampling of the same/similar populations.
The genome sequence of the octocoral Paramuricea clavata – a key resource to study the impact of climate change in the Mediterranean
Authors: Ledoux Jean-Baptiste , Cruz Fernando , Gomez-Garrido Jèssica , Antoni Regina , Blanc Julie , Gómez-Gras Daniel , López-Sendino Paula , Antunes Agostinho , Linares Cristina , Gut Marta , Alioto Tyler , Garrabou Joaquim
Published: November 2019

The octocoral, Paramuricea clavata, is a habitat-forming anthozoan with a key ecological role in rocky benthic and biodiversity-rich communities in the Mediterranean and Eastern Atlantic. Shallow populations of P. clavata in the North-Western Mediterranean are severely affected by warming-induced mass mortality events (MMEs). These MMEs have differentially impacted individuals and populations of P. clavata (i.e. varied levels of tissue necrosis and mortality rates) over thousands of kilometers of coastal areas. The eco-evolutionary processes and genetic factors contributing to these differential responses remain to be characterized. Here, we sequenced a P. clavata individual with short and long read technologies, producing 169.98 Gb of Illumina paired-end and 3.55 Gb of Oxford Nanopore Technologies (ONT) reads. We obtained a de novo hybrid assembly accounting for 712.4 Mb and 107,682 scaffolds. The contig and scaffold N50 are 15.85 Kb and 17.01 Kb, respectively. Despite of the low contiguity of the assembly, the gene completeness was relatively high, including 86% of the 978 metazoan genes contained in the metazoa_odb9 database. A total of 76,508 protein-coding genes and 85,763 transcripts have been annotated. This assembly is one of the few octocoral genomes currently available. This is undoubtedly a valuable resource for characterizing the genetic bases of the differential responses to thermal stress and for the identification of thermo-resistant individuals and populations. Overall, the genome of P. clavata will help to understand various aspects of its evolutionary ecology and to elaborate effective conservation plans such as active restoration actions to overcome the threats of global change.
SVJedi: Genotyping structural variations with long reads
Authors: Lecompte Lolita , Peterlongo Pierre , Lavenier Dominique , Lemaitre Claire
Published: November 2019

Motivation

Studies on structural variants (SV) are expanding rapidly. As a result, and thanks to third generation sequencing technologies, the number of discovered SVs is increasing, especially in the human genome. At the same time, for several applications such as clinical diagnoses, it is important to genotype newly sequenced individuals on well defined and characterized SVs. Whereas several SV genotypers have been developed for short read data, there is a lack of such dedicated tool to assess whether known SVs are present or not in a new long read sequenced sample, such as the one produced by Pacific Biosciences or Oxford Nanopore Technologies.

Results

We present a novel method to genotype known SVs from long read sequencing data. The method is based on the generation of a set of reference sequences that represent the two alleles of each structural variant. Long reads are aligned to these reference sequences. Alignments are then analyzed and filtered out to keep only informative ones, to quantify and estimate the presence of each SV allele and the allele frequencies. We provide an implementation of the method, SVJedi, to genotype insertions and deletions with long reads. The tool has been applied to both simulated and real human datasets and achieves high genotyping accuracy. We also demonstrate that SV genotyping is considerably improved with SVJedi compared to other approaches, namely SV discovery and short read SV genotyping approaches.

Availability

https://github.com/llecompte/SVJedi.git

Contact

lolita.lecompte@inria.fr
Mental travel in the social domain
Authors: Hayman Mordechai , Arzy Shahar
Published: November 2019

“Mental travel” is the ability to imagine oneself in different places and times and to adopt other people’s point of view (POV), also termed “Theory of Mind (ToM)”. While ToM has been extensively investigated, self-projection with respect to ones’ own and others’ social networks has yet to be systematically studied.

Here we asked participants to “project” themselves to four different POVs: a significant other, a non-significant other, a famous-person, and their own-self. From each POV they were asked to rate the level of affiliation (closeness) to different individuals in the respective social network while undergoing functional MRI.

Participants were always faster making judgments from their own POV compared to other POVs (self-projection effect) and for people who were personally closer to their adopted POV (self-reference effect). Brain activity at the medial prefrontal and anterior cingulate cortex in the self POV condition was found to be higher compared to all other conditions. Activity at the right temporoparietal junction and medial parietal cortex was found to distinguish between the personally related (self, significant- and non-significant others) and unrelated (famous-person) individuals within the social network. Regardless of the POV, the precuneus, anterior cingulate cortex, prefrontal cortex, and temporoparietal junction distinguished between relatively closer and distant people. Representational similarity analysis (RSA) implicated the left retrosplenial cortex as crucial for social distance processing across all POVs.
Stimulus contrast information modulates sensorimotor decision making in goldfish
Authors: Coronel Santiago Otero , Martorell Nicolás , de Astrada Martín Berón , Medan Violeta
Published: November 2019

Animal survival relays on environmental information gathered by their sensory systems. We found that contrast information of a looming stimulus biases the type of defensive behavior goldfish (Carassius auratus) perform. Low contrast looms only evoke subtle alarm reactions whose probability is independent of contrast. As looming contrast increases, the probability of eliciting a fast escape maneuver, the C-start response, increases dramatically. Contrast information also modulates the decision of when to escape. Although looming retinal size is determinant of response latency, we found that contrast acts as an additional parameter influencing this decision. When presented progressively higher contrast stimuli, animals need shorter periods of stimulus integration to initiate the response. Our results comply the notion that the decision to escape is a flexible process initiated with stimulus detection and followed by assessment of the perceived risk posed by the stimulus. Highly disruptive behaviors as the C-start are only observed when a multifactorial threshold that includes stimulus contrast is surpassed.

Summary statement

This study highlights that in fish, the decision of what to do after threat detection is a multifactorial non-binary process that includes assessing the relative contrast of the potential threat. Increasingly higher contrast stimuli produce a progressive increase in C-start escape probability and a decrease in response latency. More subtle alarm reactions are, on the contrary, mostly insensitive to changes in contrast. This might reflect that while subtle reactions have lower thresholds to be executed, disruptive behaviors as the C-start must surpass higher saliency thresholds that integrate multiple aspects including contrast.
Electron beam lithography fabrication of SU-8 polymer structures for cell studies
Authors: Vinje Jakob , Beckwith Kai S. , Sikorski Pawel
Published: November 2019

Flat surfaces decorated with micro- and nanostructures are important tools in biomedical research used to control cellular shape, in studies of mechanotransduction, membrane mechanics, cell migration and cellular interactions with nanostructured surfaces. Existing methods to fabricate surface-bound nanostructures are typically limited either by resolution, aspect ratio or throughput. In this work, we explore electron beam lithography based structuring of the epoxy resist SU-8 on glass substrate. We focus on a systematic investigation of the process parameters and determine limits of the fabrication process, both in terms of spatial resolution, structure aspect ration and fabrication throughput. The described approach is capable of producing high-aspect ratio, surface bound nanostructures with height ranging from 100 nm to 4000 nm and with in-plane resolution below 100 nm directly on a transparent substrate. Fabricated nanostructured surfaces can be integrated with common techniques for biomedical research, such as high numerical aperture optical microscopy. Further more, we show how the described approach can be used to make nanostructures with multiple heights on the same surface, something which is not readily achievable using alternative fabrication approaches. Our research paves an alternative way of manufacturing nanostructured surfaces with applications in life science research.