bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepTraSynergy: drug combinations using multimodal deep learning with transformers
Authors: Rafiei Fatemeh , Zeraati Hojjat , Abbasi Karim , Ghasemi Jahan B , Parsaeian Mahboubeh , Masoudi-Nejad Ali 
Published: July 2023

Abstract

Motivation
Screening bioactive compounds in cancer cell lines receive more attention. Multidisciplinary drugs or drug combinations have a more effective role in treatments and selectively inhibit the growth of cancer cells.

Results
Hence, we propose a new deep learning-based approach for drug combination synergy prediction called DeepTraSynergy. Our proposed approach utilizes multimodal input including drug–target interaction, protein–protein interaction, and cell–target interaction to predict drug combination synergy. To learn the feature representation of drugs, we have utilized transformers. It is worth noting that our approach is a multitask approach that predicts three outputs including the drug–target interaction, its toxic effect, and drug combination synergy. In our approach, drug combination synergy is the main task and the two other ones are the auxiliary tasks that help the approach to learn a better model. In the proposed approach three loss functions are defined: synergy loss, toxic loss, and drug–protein interaction loss. The last two loss functions are designed as auxiliary losses to help learn a better solution. DeepTraSynergy outperforms the classic and state-of-the-art models in predicting synergistic drug combinations on the two latest drug combination datasets. The DeepTraSynergy algorithm achieves accuracy values of 0.7715 and 0.8052 (an improvement over other approaches) on the DrugCombDB and Oncology-Screen datasets, respectively. Also, we evaluate the contribution of each component of DeepTraSynergy to show its effectiveness in the proposed method. The introduction of the relation between proteins (PPI networks) and drug–protein interaction significantly improves the prediction of synergistic drug combinations.

Availability and implementation
The source code and data are available at https://github.com/fatemeh-rafiei/DeepTraSynergy.
Rescuing women from the brinks of whiteness: Carceral restoration in a human trafficking court
Authors: Singh Rashmee 
Published: July 2023

Abstract
Research on gender-specific penal reform programs critique their failure to prioritize the socio-economic recovery of criminalized women. This paper draws on these insights to examine the Women’s Refuge Court (WRC), a human trafficking court for adult women criminalized for prostitution and drug offences in Ohio. Using ethnographic research, I illustrate the WRC’s rejection of bootstrapping and emphasis on material resourcing as a penal reform strategy. I argue that the WRC’s prioritization of socio-economic recovery derives from fears over the status decline of the impoverished white women who predominate as defendants. Court officials rely on evangelical Christian imaginings of prostitution as ‘modern day slavery’ to frame participants as ‘trafficking victims’. I identify the WRC’s response as a racially specific form of gender responsive programming called carceral restoration.
SCN1A-deficient excitatory neuronal networks display mutation-specific phenotypes
Authors: van Hugte Eline J H , Lewerissa Elly I , Wu Ka Man , Scheefhals Nicky , Parodi Giulia , van Voorst Torben W , Puvogel Sofia , Kogo Naoki , Keller Jason M , Frega Monica , Schubert Dirk , Schelhaas Helenius J , Verhoeven Judith , Majoie Marian , van Bokhoven Hans , Nadif Kasri Nael 
Published: July 2023

Abstract
Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioural problems and developmental delay. Eighty per cent of patients with Dravet syndrome have a mutation in SCN1A, encoding Nav1.1. Milder clinical phenotypes, such as GEFS+ (generalized epilepsy with febrile seizures plus), can also arise from SCN1A mutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. This clinical and genetic heterogeneity adds to the difficulties of predicting disease progression and tailoring the prescription of anti-seizure medication. Understanding the neuropathology of different SCN1A mutations may help to predict the expected clinical phenotypes and inform the selection of best-fit treatments. Initially, the loss of Na+-current in inhibitory neurons was recognized specifically to result in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated and might depend on the patient clinical phenotype or the specific SCN1A mutation.
To examine the genotype-phenotype correlations of SCN1A mutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harbouring various SCN1A mutations, along with a family in which the same mutation led to febrile seizures, GEFS+ or Dravet syndrome.
We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponds to seizurogenic network prediction patterns elicited by proconvulsive compounds. We found that excitatory neuronal networks were affected differently, depending on the type of SCN1A mutation, but did not segregate according to clinical severity. Specifically, loss-of-function mutations could be distinguished from missense mutations, and mutations in the pore domain could be distinguished from mutations in the voltage sensing domain. Furthermore, all patients showed aggravated neuronal network responses at febrile temperatures compared with controls. Finally, retrospective drug screening revealed that anti-seizure medication affected GEFS+ patient- but not Dravet patient-derived neuronal networks in a patient-specific and clinically relevant manner.
In conclusion, our results indicate a mutation-specific excitatory neuronal network phenotype, which recapitulates the foremost clinically relevant features, providing future opportunities for precision therapies.
Comparative phenotype of circulating versus tissue immune cells in human lung and blood compartments during health and disease
Authors: Colombo Stefano A P , Brown Sheila L , Hepworth Matthew R , Hankinson Jenny , Granato Felice , Kitchen Semra J , Hussell Tracy , Simpson Angela , Cook Peter C , MacDonald Andrew S 
Published: July 2023

Abstract
The lung is a dynamic mucosal surface constantly exposed to a variety of immunological challenges including harmless environmental antigens, pollutants, and potentially invasive microorganisms. Dysregulation of the immune system at this crucial site is associated with a range of chronic inflammatory conditions including asthma and Chronic Pulmonary Obstructive Disease (COPD). However, due to its relative inaccessibility, our fundamental understanding of the human lung immune compartment is limited. To address this, we performed flow cytometric immune phenotyping of human lung tissue and matched blood samples that were isolated from 115 donors undergoing lung tissue resection. We provide detailed characterization of the lung mononuclear phagocyte and T cell compartments, demonstrating clear phenotypic differences between lung tissue cells and those in peripheral circulation. Additionally, we show that CD103 expression demarcates pulmonary T cells that have undergone recent TCR and IL-7R signalling. Unexpectedly, we discovered that the immune landscape from asthmatic or COPD donors was broadly comparable to controls. Our data provide a much-needed expansion of our understanding of the pulmonary immune compartment in both health and disease.
Spontaneously disappearing right atrial mass in a preterm infant: a case report
Authors: Klimek Jan , Culcer Mihaela , Veerappan Sundar 
Published: July 2023

Abstract

Background
There is currently a lack of evidence-based guidelines regarding ideal management of a neonate, specifically a preterm, with thrombo-embolus. There are no clear guidelines as to the time-frame of spontaneous resolution of a thrombo-embolus.

Case summary
A large pedunculated right atrial mass was identified on a clinician-performed cardiac ultrasound in a preterm neonate. The mass was smaller than half of the atrial size and was not causing obstruction. The mass disappeared spontaneously within 6 days and was retrospectively presumed to have been a thrombus. The neonate remained asymptomatic with no signs suggesting that the mass may have embolized.

Discussion
In this case of an incidentally identified asymptomatic intracardiac mass in a preterm infant, presumed to be a thrombus, our conservative ‘wait and watch’ approach was not associated with any adverse pulmonary or systemic effects.
The causal effects of education on adult health, mortality and income: evidence from Mendelian randomization and the raising of the school leaving age
Authors: Davies Neil M , Dickson Matt , Davey Smith George , Windmeijer Frank , van den Berg Gerard J 
Published: July 2023

Abstract

Background
On average, educated people are healthier, wealthier and have higher life expectancy than those with less education. Numerous studies have attempted to determine whether education causes differences in later health outcomes or whether another factor ultimately causes differences in education and subsequent outcomes. Previous studies have used a range of natural experiments to provide causal evidence. Here we compare two natural experiments: a policy reform, raising the school leaving age in the UK in 1972; and Mendelian randomization.

Methods
We used data from 334 974 participants of the UK Biobank, sampled between 2006 and 2010. We estimated the effect of an additional year of education on 25 outcomes, including mortality, measures of morbidity and health, ageing and income, using multivariable adjustment, the policy reform and Mendelian randomization. We used a range of sensitivity analyses and specification tests to assess the plausibility of each method’s assumptions.

Results
The three different estimates of the effects of educational attainment were largely consistent in direction for diabetes, stroke and heart attack, mortality, smoking, income, grip strength, height, body mass index (BMI), intelligence, alcohol consumption and sedentary behaviour. However, there was evidence that education reduced rates of moderate exercise and increased alcohol consumption. Our sensitivity analyses suggest that confounding by genotypic or phenotypic confounders or specific forms of pleiotropy are unlikely to explain our results.

Conclusions
Previous studies have suggested that the differences in outcomes associated with education may be due to confounding. However, the two independent sources of exogenous variation we exploit largely imply consistent causal effects of education on outcomes later in life.
Low-dose perinatal supplementation with Enterococcus faecalis increases concentrations of short-chain fatty acids in the offspring but does not protect against allergic asthma
Authors: Arntz Jeanne L , Alhasan Moumen M , Datye Swarali , Kahhaleh Fariz G , Almousa Yahia , Barrientos Gabriela , Schwiertz Andreas , Conrad Melanie L 
Published: July 2023

Abstract
Childhood allergic asthma is associated with a dysbiotic gut microbiome in early life, and maternal perinatal treatment with probiotics is a potential way alter the infant microbiome, which may improve asthma outcomes. This study used a mouse model to examine the effect of maternal supplementation with the probiotic Enterococcus faecalis on faecal short-chain fatty acid (SCFA) concentrations and asthma risk in the offspring. Pregnant/lactating mice were treated daily, from gestation day 6 to postnatal day 21, with an oral suspension of 106, 107 or 108 colony-forming units of a live preparation of the probiotic E. faecalis (Symbioflor®1). At weaning, offspring were subjected to an ovalbumin-induced experimental asthma protocol. Faeces were collected from the mothers and offspring at several different time points to determine SCFA concentrations. It was found that maternal supplementation with E. faecalis did not alter litter size, sex ratio or offspring weight, and was associated with an increase in SCFAs in offspring faeces at weaning and after allergy induction. However, allergic offspring from E. faecalis supplemented mothers showed no difference in asthma severity when compared with allergic offspring from control mothers. In conclusion, although maternal perinatal supplementation with low-dose E. faecalis was associated with increased faecal SCFAs in the offspring, it did not protect against offspring asthma. This is may be because SCFA concentrations were not increased to an immunoprotective level. We recommend that future studies concentrate on probiotic supplementation in high-risk cases, for instance, to repair gut dysbiosis resulting from antibiotic use in pregnant mothers or their infants.
Semi-parametric estimation of treatment effects in randomised experiments
Authors: Athey Susan , Bickel Peter J , Chen Aiyou , Imbens Guido W , Pollmann Michael 
Published: July 2023

Abstract
We develop new semi-parametric methods for estimating treatment effects. We focus on settings where the outcome distributions may be thick tailed, where treatment effects may be small, where sample sizes are large, and where assignment is completely random. This setting is of particular interest in recent online experimentation. We propose using parametric models for the treatment effects, leading to semi-parametric models for the outcome distributions. We derive the semi-parametric efficiency bound for the treatment effects for this setting, and propose efficient estimators. In the leading case with constant quantile treatment effects, one of the proposed efficient estimators has an interesting interpretation as a weighted average of quantile treatment effects, with the weights proportional to minus the second derivative of the log of the density of the potential outcomes. Our analysis also suggests an extension of Huber’s model and trimmed mean to include asymmetry.
Large-scale structures in the stellar wind of fast-rotating stars spawned by the presence of Earth-like planets
Authors: Canet Ada , Gómez de Castro Ana I 
Published: July 2023

ABSTRACT
Forming planets around young, fast-rotating solar-like stars are exposed to an intense X-ray/extreme ultraviolet radiation field and strongly magnetized stellar winds, as a consequence of the high magnetic activity of these stars. Under these conditions, Earth-like exoplanets may experience a rapid loss of their primordial hydrogen atmospheres, resulting in atmosphereless rocky obstacles for the stellar winds. The interaction of stellar winds with those planets leads to the formation of potentially observable structures due to the formation of large-scale magnetic field and density disturbances in the vicinity of these planets, such as bow shocks, induced magnetospheres, and comet-like tails. In this work, we study the interaction between the stellar winds of active, fast-rotating solar-like stars in the superfast-magnetosonic regime with Earth-like, unmagnetized, tenuous atmosphere, planetary obstacles through numerical three-dimensional simulations using the pluto magnetohydrodynamical code. The properties of AB Doradus, a nearby young star with a small rotation period (0.51 d) and a strong flaring activity, have been used to parametrize this early wind state. Bow shock and induced magnetosphere formation are characterized through the Alfvénic Mach number MA of the wind, for different stellar wind configurations. Large bow shocks, up to an extension of ∼7.0 planetary radii, are found for low-MA winds. The general increase of density, temperature, and magnetic field in these large-scale structures formed around planets may result in potentially detectable spectral signatures.
Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas
Authors: Holdhoff Matthias , Nicholas M Kelly , Peterson Richard A , Maraka Stefania , Liu Li C , Fischer James H , Wefel Jeffrey S , Fan Timothy M , Vannorsdall Tracy , Russell Meredith , Iacoboni Michaella , Tarasow Theodore M , Hergenrother Paul J , Dudek Arkadiusz Z , Danciu Oana C 
Published: July 2023

Abstract

Background
Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas.

Methods
A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1–21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study.

Results
Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF.

Conclusions
Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.
Surgery versus radiosurgery for vestibular schwannoma: Shared decision making in a multidisciplinary clinic
Authors: Colombo Francesca , Maye Helen , Rutherford Scott , King Andrew , Hammerbeck-Ward Charlotte , Whitfield Gillian A , McBain Catherine , Colaco Rovel , Entwistle Helen , Wadeson Andrea , Lloyd Simon , Freeman Simon , Pathmanaban Omar N 
Published: July 2023

Abstract

Background
Our neurosurgical unit adopted a model of shared decision-making (SDM) based on multidisciplinary clinics for vestibular schwannoma (VS). A unique feature of this clinic is the interdisciplinary counseling process with a surgeon presenting the option of surgery, an oncologist radiosurgery or radiotherapy, and a specialist nurse advocating for the patient.

Methods
This is a retrospective cohort study. All new patients seen in the combined VS clinic and referred from the skull base multidisciplinary team (MDT) from beginning of June 2013 to end of January 2019 were included. Descriptive statistics and frequency analysis were carried out for the full cohort.

Results
Three hundred and fifty-four patients presenting with new or previously untreated VS were included in the analysis. In our cohort, roughly one-third of patients fall into each of the treatment strategies with slightly smaller numbers of patients undergoing surgery than watch, wait and rescan (WWR) ,and SRS (26.6% vs. 32.8% and 37.9%, respectively).

Conclusion
In our experience, the combined surgery/oncology/specialist nurse clinic streamlines the patient experience for those with a VS suitable for either microsurgical or SRS/radiotherapy treatment. Decision-making in this population of patients is complex and when presented with all treatment options patients do not necessarily choose the least invasive option as a treatment. The unique feature of our clinic is the multidisciplinary counseling process with a specialist nurse advocating and guiding the patient. Treatment options are likely to become more rather than less complex in future years making combined clinics more valuable than ever in the SDM process.
Changes in E-cigarette Use, Cigarette Smoking, and Dual-Use Among the Youth (13–15 Years) in 10 Countries (2013–2019)—Analyses of Global Youth Tobacco Surveys
Authors: Sreeramareddy Chandrashekhar T , Acharya Kiran , Manoharan Anusha , Oo Phyu Synn 
Published: July 2023

Abstract

Introduction
The increasing use of e-cigarettes among the youth is a public health problem that needs surveillance. We report changes in e-cigarette use, cigarette smoking, and “dual use” among youth in 10 countries.

Aims and Methods
Global Youth Tobacco Survey (GYTS)s from Georgia, Iraq, Italy, Latvia, Montenegro, Paraguay, Peru, Qatar, Romania, and San Marino were analyzed. Changes in prevalence of “awareness of e-cigarettes,” “ever use” (even tried a few puffs) and “current use” (during last 30 days) of e-cigarettes and cigarette smoking, and “dual use” (both e-cigarette and cigarette smoking) between baseline (2013 and 2014) and most recent (2017–2019) surveys were estimated.

Results
“Awareness of e-cigarettes” and “ever e-cigarette use” significantly increased (p &lt; .001). “Ever e-cigarette use” was highest in Italy, 93% (95% CI 90.9, 94.4). “Current e-cigarette use” significantly (p &lt; .05) increased by &gt; 50% in most countries. During the most recent surveys, “current e-cigarette” use was &gt; 10% in five countries Italy (18.3%) and Latvia (18.5%) being the highest. Cigarette smoking significantly declined in Italy, Latvia, Peru, and San Marino (p &lt; .05) but remains unchanged in other countries. “Dual use” (both electronic and conventional cigarettes) significantly increased in all countries (p &lt; .001). During the most recent surveys “dual use” was highest in Italy (10%, 95% CI 8.1, 12.2) and Latvia (8.6%, 95% CI 7.2, 10.2). Youth aged 14 and ≥15 years the smokers, were more likely to be e-cigarette users.

Conclusions
Awareness and use of e-cigarettes and “dual use” among youth have increased. Closer monitoring of tobacco use among youths and comprehensive tobacco control policies inclusive of e-cigarettes are needed.

Implications
Secondary data analyses of serial GYTSs in 10 countries showed that both awareness of e-cigarette and e-cigarette use has increased among school-going youth aged 13–15 years. A concurrent increase in “dual use” of e-cigarettes and cigarette smoking during the last 30 days in all 10 countries indicates continued cigarette smoking in the absence of e-cigarettes because of the common risk construct of tobacco product use. Results call for continued surveillance of both e-cigarettes and cigarette smoking among school-going youth. Comprehensive tobacco control measures inclusive of e-cigarettes should be implemented to reduce tobacco use among the youth.