bluuebunny/crossref_metadata_2025 huggingface dataset:
Approaches to Study Gap Junctional Coupling
Authors: Stephan Jonathan , Eitelmann Sara , Zhou Min
Published: March 2021

Astrocytes and oligodendrocytes are main players in the brain to ensure ion and neurotransmitter homeostasis, metabolic supply, and fast action potential propagation in axons. These functions are fostered by the formation of large syncytia in which mainly astrocytes and oligodendrocytes are directly coupled. Panglial networks constitute on connexin-based gap junctions in the membranes of neighboring cells that allow the passage of ions, metabolites, and currents. However, these networks are not uniform but exhibit a brain region-dependent heterogeneous connectivity influencing electrical communication and intercellular ion spread. Here, we describe different approaches to analyze gap junctional communication in acute tissue slices that can be implemented easily in most electrophysiology and imaging laboratories. These approaches include paired recordings, determination of syncytial isopotentiality, tracer coupling followed by analysis of network topography, and wide field imaging of ion sensitive dyes. These approaches are capable to reveal cellular heterogeneity causing electrical isolation of functional circuits, reduced ion-transfer between different cell types, and anisotropy of tracer coupling. With a selective or combinatory use of these methods, the results will shed light on cellular properties of glial cells and their contribution to neuronal function.
Early Venous Filling Following Thrombectomy: Association With Hemorrhagic Transformation and Functional Outcome
Authors: Elands Sophie , Casimir Pierre , Bonnet Thomas , Mine Benjamin , Lubicz Boris , Sjøgård Martin , Ligot Noémie , Naeije Gilles
Published: March 2021

Background and Purpose: Previous studies have noted the angiographic appearance of early venous filling (EVF) following recanalisation in acute ischemic stroke. However, the prognostic implications of EVF as a novel imaging biomarker remain unclear. We aimed to evaluate the correlation between EVF with (i) the risk of subsequent reperfusion hemorrhage (RPH) and (ii) the association of EVF on both the NIHSS score at 24 h and functional outcome as assessed with the Modified Rankin Scale (mRS) score at 90 days.

Methods: We conducted a retrospective cohort study of patients presenting with an acute ischemic stroke due to a proximal large-vessel occlusion of the anterior circulation treated by thrombectomy. Post-reperfusion digital subtraction angiography was reviewed to look for EVF as evidenced by the contrast opacification of any cerebral vein before the late arterial phase.

Results: EVF occurred in 22.4% of the 147 cases included. The presence of EVF significantly increased the risk of RPH (p = 0.0048), including the risk of symptomatic hemorrhage (p = 0.0052). The presence of EVF (p = 0.0016) and the absence of RPH (p = 0.0021) were independently associated with a better outcome as defined by the NIHSS difference at 24 h, most significantly in the EVF+RPH− group. No significant relationship was however found between either EVF or RPH and a mRS score ≤ 2 at 90 days.

Conclusion: Early venous filling on angiographic imaging is a potential predictor of reperfusion hemorrhage. The absence of subsequent RPH in this sub-group is associated with better outcomes at 24 h post-thrombectomy than in those with RPH.
Case Report: Multiple Chromosomal Translocations Including Novel CIITA-CREBBP Fusion and Mutations in a Follicular Lymphoma
Authors: Wang Huan-You , Sokol Ethan S. , Goodman Aaron M. , Feldman Andrew L. , Mulroney Carolyn M.
Published: March 2021

The pathogenesis of follicular lymphoma is a multi-step process, in which chromosomal translocation between immunoglobulin heavy chain (IgH) and anti-apoptotic B-cell lymphoma 2 (BCL2), namely IgH-BCL2, is an earliest step, followed by other genetic/genomic alterations including but not limited to mutation of CREB binding protein (CREBBP). MHC class II transactivator (CIITA) is a transcription regulator responsible for expression of MHC class II molecules including HLA-DR in human. We report herein a novel fusion gene involving CIITA and CREBBP in a patient with a low-grade follicular lymphoma (FL) but with high Ki-67 proliferation index. In addition, our patient also harbors CREBBP mutation. Together, we postulate that total loss of CREBBP function may contribute, in part, to the lymphoma genesis. Furthermore, this patient has addition rare (TBL1XR1-TP63) and common (IgH-BCL2) chromosomal translocations and multiple mutations including BCL2, BRAF, MUTYH, and STAT6.
A Pragmatic Non-Randomized Trial of Prehabilitation Prior to Cancer Surgery: Study Protocol and COVID-19-Related Adaptations
Authors: Santa Mina Daniel , Sellers Daniel , Au Darren , Alibhai Shabbir M. H. , Clarke Hance , Cuthbertson Brian H. , Darling Gail , El Danab Alaa , Govindarajan Anand , Ladha Karim , Matthew Andrew G. , McCluskey Stuart , Ng Karen A. , Quereshy Fayez , Karkouti Keyvan , Randall Ian M.
Published: March 2021

Background

Experimental data highlight the potential benefits and health system cost savings related to surgical prehabilitation; however, adequately powered randomized controlled trial (RCT) data remain nascent. Emerging prehabilitation services may be informed by early RCT data but can be limited in informing real-world program development. Pragmatic trials emphasize external validity and generalizability to understand and advise intervention development and implementation in clinical settings. This paper presents the methodology of a pragmatic prehabilitation trial to complement emerging phase III clinical trials and inform implementation strategies.

Methods

This is a pilot pragmatic clinical trial conducted in a large academic hospital in Toronto, Ontario, Canada to assess feasibility of clinical implementation and derive estimates of effectiveness. Feasibility data include program referral rates, enrolment and attrition, intervention adherence and safety, participant satisfaction, and barriers and facilitators to programming. The study aims to receive 150 eligible referrals for adult, English-speaking, preoperative oncology patients with an identified indication for prehabilitation (e.g., frailty, deconditioning, malnutrition, psychological distress). Study participants undergo a baseline assessment and shared-decision making regarding the intervention setting: either facility-based prehabilitation or home-based prehabilitation. In both scenarios, participants receive an individualized exercise prescription, stress-reduction psychological support, nutrition counseling, and protein supplementation, and if appropriate, smoking cessation program referrals. Secondary objectives include estimating intervention effects at the week prior to surgery and 30 and 90 days postoperatively. Outcomes include surgical complications, postoperative length of stay, mortality, hospital readmissions, physical fitness, psychological well-being, and quality of life. Data from participants who decline the intervention but consent for research-related access to health records will serve as comparators. The COVID-19 pandemic required the introduction of a ‘virtual program’ using only telephone or internet-based communication for screening, assessments, or intervention was introduced.

Conclusion

This pragmatic trial will provide evidence on the feasibility and viability of prehabilitation services delivered under usual clinical conditions. Study amendments due to the COVID-19 pandemic are presented as strategies to maintain prehabilitation research and services to potentially mitigate the consequences of extended surgery wait times.
Use of 68Ga-PSMA-11 and 18F-FDG PET-CT Dual-Tracer to Differentiate Between Lymph Node Metastases and Ganglia
Authors: Shi Yiping , Xu Lian , Zhu Yinjie , Wang Yining , Chen Ruohua , Liu Jianjun
Published: March 2021

Purpose

Differentiating lymph node metastases (LNM) from peripheral ganglia by physiological prostate-specific membrane antigen (PSMA) uptake is challenging. Two tracers (68Ga-PSMA-11 and 18F-fluorodeoxyglucose [FDG]) metabolic uptake patterns were evaluated by positron emission tomography-computed tomography (PET-CT), searching for differences that could tell ganglia from LNM.

Methods

Dual 68Ga-PSMA-11 and 18F-FDG PET-CT data of 138 prostate cancer patients acquired from June 2018 to December 2019 were retrospectively evaluated. Ganglia and LNM with PSMA-11 uptake above local background were analyzed by the location and PSMA-11-PET and FDG-PET maximum standardized uptake value (SUVmax).

Results

PSMA-11-positive ganglia (n = 381) and LNM (n = 83) were identified in 138 and 58 patients, respectively. The LNM SUVmax of PSMA-11-PET (16.4 ± 14.8 vs 2.3 ± 0.7, P < 0.001) and FDG-PET (3.3 ± 3.2 vs 1.5 ± 0.5, P < 0.001) were higher than in ganglia. The probabilities of being an LNM in the low-potential (PSMA-11-PET SUVmax of <4.1 and FDG-PET SUVmax of <2.05), moderate-potential (PSMA-11-PET SUVmax of >4.1 and FDG-PET SUVmax of <2.05, or PSMA-11-PET SUVmax of <4.1 and FDG-PET SUVmax of >2.05), and high-potential (PSMA-11-PET SUVmax of >4.1 and FDG-PET SUVmax of >2.05) groups were 0.9% (3/334), 44.6% (37/83), and 91.5% (43/47), respectively (P < 0.001). The cervical and coeliac ganglia had higher PSMA-11 and FDG uptake than the sacral ganglia (P < 0.001 for all). LNM PSMA-11 and FDG uptake was similar in these three locations.

Conclusion

The FDG-PET and PSMA-11-PET SUVmax, especially when combined, could well differentiate LNM from ganglia. The tracers uptake differed between cervical/coeliac and sacral ganglia, so the lesion location should be considered during image assessment.
Risk of Second Primary Malignancies Based on the Histological Subtypes of Colorectal Cancer
Authors: Wu Meijuan , Huang Mengxi , He Chenglong , Chen Cheng , Li Huiyu , Wang Jing , Liu Mengyan , Fu Gongbo , Lei Zengjie , Chu Xiaoyuan
Published: March 2021

Background: Previous studies have revealed an increased risk of second primary malignancies (SPMs) after colorectal cancer (CRC); however, no previous investigation has quantified differences in the risk of SPMs based on the histological subtypes of first primary CRC.

Methods: Patients diagnosed with first primary CRC between 2000 and 2011 were identified from the Surveillance, Epidemiology, and End Results cancer registries. The patients were divided into three cohorts: classical adenocarcinoma (CA), mucinous adenocarcinoma (MA), and signet-ring cell carcinoma (SRCC). Standardized incidence ratios were calculated to assess the risk of SPMs among the patients.

Results: Overall risk of SPMs was significantly higher among patients with three histological subtypes of CRC than in the general population. The risk of esophagus cancer was significantly increased in SRCC. The risk of small intestine, colon and rectum, and corpus uteri cancers was high in three histological subtypes, with the highest risk observed in SRCC, followed by MA. Increased risks of second stomach, uterus, urinary bladder, kidney, and thyroid cancers were only observed in CA patients, while increased risk of second renal pelvis cancer was limited to MA patients. Furthermore, the high overall risk of SPMs in CA patients persisted regardless of clinicopathological factors. After surgery combined with chemotherapy treatment, CA patients were more prone to developing second small intestine, colon and rectum cancers than those treated with surgery only. A lower second prostate cancer risk was observed in rectal CA patients treated with surgery combined with radiotherapy than in patients treated with surgery only.

Conclusion: The present study revealed that the risk of developing SPMs after CRC varied based on the histological subtypes of the first primary CRC. Although the mechanisms underlying the observed patterns of SPM risk remain unknown, the study provided insights into future cancer surveillance based on the histological subtypes of CRC.
Cell Population Data (CPD) for Early Recognition of Sepsis and Septic Shock in Children: A Pilot Study
Authors: Biban Paolo , Teggi Martina , Gaffuri Marcella , Santuz Pierantonio , Onorato Diletta , Carpenè Giovanni , Gregori Dario , Lippi Giuseppe
Published: March 2021

Objectives: Innovative Cell Population Data (CPD) have been used as early biomarkers for diagnosing sepsis in adults. We assessed the usefulness of CPD in pediatric patients with sepsis/septic shock, in terms of early recognition and outcome prediction. We revised 54 patients (0–15 y) admitted to our Pediatric Intensive Care Unit (PICU) for sepsis/septic shock during a 4-year period. Twenty-eight patients were excluded, 26 septic patients were enrolled (G1). Forty children admitted for elective surgery served as controls (G2). Data on five selected CPD parameters, namely neutrophils fluorescence intensity (NE-SFL), monocytes cells complexity (MO-X), monocytes fluorescence intensity (MO-Y), monocytes complexity and width of dispersion of events measured (MO-WX), and monocytes cells size and width dispersion (MO-WZ), were obtained at time of PICU admission (t0) by a hematological analyzer (Sysmex XN 9000®). As the primary outcome we evaluated the relevance of CPD for diagnosing sepsis/septic shock on PICU admission. Furthermore, we investigated if CPD at t0 were correlated with C-reactive protein (CRP), patient survival, or complicated sepsis course.

Results: On PICU admission (t0), NE-SFL, MO-WX, and MO-Y were higher in sepsis/septic shock patients compared to controls. NE-SFL values were correlated with CRP values in G1 patients (r = 0.83). None of the five CPD parameters was correlated with survival or complicated sepsis course.

Conclusion: We found higher values of NE-SFL, MO-WX, and MO-Y in children with sepsis/septic shock upon PICU admission. These parameters may be a promising adjunct for early sepsis diagnosis in pediatric populations. Larger, prospective studies are needed to confirm our preliminary observations.
The Diversity of the Intestinal Flora Disturbed After Feeding Intolerance Recovery in Preterm Twins
Authors: Li Ying , Jia Chunhong , Lin Xiaojun , Lin Lili , Li Lizhen , Fan Xi , Huang Xiaoxia , Xu Zhanyuan , Wang Huixin , Wu Fan , Liu Guosheng
Published: March 2021

Background: Feeding intolerance (FI) is a common condition in premature infants that results in growth retardation and even necrotizing enterocolitis. The gut microbiome is linked to FI occurrence; however, the outcome after FI recovery is unclear.

Methods: Fecal samples were collected from 11 pairs of premature twins/triplets for 16S rRNA gene sequencing. Initial fecal samples were collected shortly after admission, and then every other week until 7 weeks or discharge.

Results: After FI recovery, there was no significant difference in the β-diversity of the intestinal flora between the FI group and the feeding tolerance (FT) group. By contrast, there was a significant difference in the β-diversity. Proteobacteria was the predominant phylum in the microbiome of the FI group, whereas Firmicutes was the predominant phylum in the microbiome of the FT group. The predominant bacteria with LDA >4 between the two groups at 13–15 days after birth, 19–28 days after birth, and at discharge were different, with the proportions of Bacillus, Clostridium butyricum, and Clostridium being highest in the FT group and Firmicutes, unidentified_Clostridiales, and Proteobacteria being highest in the FI group. Similarly, there were significant differences in the relative abundances of KEGG pathways, such as fatty acid metabolism, DNA repair and recombination proteins, energy metabolism, and amino acid metabolism, between the two groups (P < 0.01).

Conclusions: There was a significant difference in diversity of the intestinal flora after feeding intolerance recovery. Feeding intolerance may disturb the succession of the intestinal bacterial community.
Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
Authors: Tu Chengyi , Cunningham Nathan J. , Zhang Mao , Wu Joseph C.
Published: March 2021

Evaluation of potential vascular injury is an essential part of the safety study during pharmaceutical development. Vascular liability issues are important causes of drug termination during preclinical investigations. Currently, preclinical assessment of vascular toxicity primarily relies on the use of animal models. However, accumulating evidence indicates a significant discrepancy between animal toxicity and human toxicity, casting doubt on the clinical relevance of animal models for such safety studies. While the causes of this discrepancy are expected to be multifactorial, species differences are likely a key factor. Consequently, a human-based model is a desirable solution to this problem, which has been made possible by the advent of human induced pluripotent stem cells (iPSCs). In particular, recent advances in the field now allow the efficient generation of a variety of vascular cells (e.g., endothelial cells, smooth muscle cells, and pericytes) from iPSCs. Using these cells, different vascular models have been established, ranging from simple 2D cultures to highly sophisticated vascular organoids and microfluidic devices. Toxicity testing using these models can recapitulate key aspects of vascular pathology on molecular (e.g., secretion of proinflammatory cytokines), cellular (e.g., cell apoptosis), and in some cases, tissue (e.g., endothelium barrier dysfunction) levels. These encouraging data provide the rationale for continuing efforts in the exploration, optimization, and validation of the iPSC technology in vascular toxicology.
Effectiveness of a Virtual Exercise Program During COVID-19 Confinement on Blood Pressure Control in Healthy Pregnant Women
Authors: Silva-Jose Cristina , Sánchez-Polán Miguel , Diaz-Blanco Ángeles , Coterón Javier , Barakat Ruben , Refoyo Ignacio
Published: March 2021

Background

The situation caused by COVID-19 has led to movement restrictions for the majority of the population due to the confinement established by the health authorities. This new situation has changed people’s habits and significantly affected the pregnant population. Decreased exercise and increased psychophysical stress are associated with excessive weight gain, diabetes, and gestational cardiovascular complications that affect the mother, fetus, and newborn. Recent research shows that the dynamics of maternal blood pressure is one of the most important control factors during pregnancy. Thus, prevention of these type of pathologies through interventions without maternal-fetal risks is important.

Objectives

To examine the influence of a virtual exercise program on maternal blood pressure during pregnancy.

Materials and Methods

A randomized clinical trial design was used (NCT04563065). Data from 72 pregnant women without obstetric contraindications under confinement conditions in the Madrid area were collected. Women were randomly assigned to the intervention (IG) or control group (CG). They previously signed informed consent forms. A moderate exercise program was performed as an intervention from 8–10 to 38–39 weeks of pregnancy. Systolic (SBP) and diastolic (DBP) maternal blood pressure were measured during the first, second and third trimesters of pregnancy, as well as before and immediately after delivery in both study groups.

Results

No differences in systolic and diastolic blood pressure during the first, second and third trimesters were found between groups. Significant differences in SBP were found immediately before delivery (IG = 119.83 ± 10.16 vs. CG = 125.6 ± 10.91; p = 0.047) and immediately after delivery (IG = 115.00 ± 11.18 vs. CG = 122.24 ± 15.71; p = 0.045).

Conclusions

Results show lower SBP values for the IG during delivery than CG. A virtual exercise program throughout pregnancy during COVID-19 confinement can help to control systolic blood pressure before and immediately after delivery in healthy pregnant women.
Behavioral Changes After the COVID-19 Lockdown in Italy
Authors: Cucchiarini Veronica , Caravona Laura , Macchi Laura , Perlino Federico L. , Viale Riccardo
Published: March 2021

This study aims at identifying the tools necessary for COVID-19 health emergency management, with particular reference to the period following the first lockdown, a crucial phase in which it was important to favor the maintenance of protective behaviors. It also aims at identifying the messages and sources that were most effective in managing communication correctly in such a crucial phase that is likely characterized by a fall in perceived health risk (due to the flattening of the epidemic curve) and a simultaneous rise in perceived economic and social risks (due to the enduring calamity). Knowing what source will be most effective to convey a specific message is fundamental in enabling individuals to focus on and comply with the rules. At the same time, it is necessary to understand how the message should be presented, and the relationships between messages, sources and targets. To meet these goals, data were collected through a self-administered online questionnaire submitted to a sample of undergraduate students from a University in Lombardy–the region most affected by the pandemic in the first wave- (Study 1), and to a national sample composed of Italian citizens (Study 2). Through our first manipulation which explored the effectiveness of social norms in relation to different sources, we found that, in the national sample, the injunctive norm conveyed by the government was the most effective in promoting behavioral intentions. By contrast, among the students, results showed that for the critical group with a lower risk perception (less inclined to adopt prevention behavior) descriptive norms, which implicitly convey the risk perception of peers, were as effective as the government injunctive norm. Our second manipulation, identical in Study 1 and 2, compared four types of communication (emotional, exponential growth, both of them, or neutral). The neutral condition was the most memorable, but no condition was more effective than the others. Across all message types there was a high intention to adopt protective behaviors. The results indicate possible applicative implications of the adopted communicative tools.
Clinical Correlates of Health-Related Quality of Life in Adults With Chronic Tic Disorder
Authors: Isaacs David A. , Riordan Heather R. , Claassen Daniel O.
Published: March 2021

Tics are the hallmark feature of Tourette syndrome (TS), but psychiatric and sensory symptoms are widely prevalent and increasingly recognized as core manifestations of the disorder. Accumulating evidence suggests that these psychiatric and sensory symptoms exert greater influence on quality of life (QOL) than tics themselves. However, much remains uncertain about determinants of QOL in TS due to the complexity of the clinical presentation. Here, we sought to clarify the association between health-related QOL (HRQOL) and common psychiatric and sensory symptoms in adults with TS and other chronic tic disorders. To do so, we prospectively recruited 52 patients from a tertiary care clinic to complete self-report measures assessing HRQOL (Gilles de la Tourette-Quality of Life Scale, GTS-QOL), depression (Patient Health Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder Scale-7, GAD-7), obsessive-compulsive symptoms (Dimensional Obsessive-Compulsive Scale, DOCS), attention deficit hyperactivity disorder symptoms (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-V), and premonitory urge (Premonitory Urge to Tic Scale, PUTS). All participants were also administered the Yale Global Tic Severity Scale (YGTSS) to quantify tic severity. Using correlational analysis and multivariable linear regression modeling, we found that GTS-QOL score was significantly associated with scores from all other rating scales, with the exception of the PUTS. GTS-QOL was most strongly associated with PHQ-9, followed by ASRS-V, GAD-7, DOCS, and YGTSS total tic score. The regression model including these five independent variables, as well as sex, explained 79% of GTS-QOL score variance [F(6,40) = 29.6, p < 0.001]. Specific psychiatric symptoms differentially impacted physical, psychological, and cognitive HRQOL. Systematic assessment of psychiatric comorbidities is imperative for clinical care and clinical research efforts directed at improving QOL in adults with chronic tic disorders.
Anxiety and Its Associated Factors During the Initial Phase of the COVID-19 Pandemic in Indonesia
Authors: Anindyajati Gina , Wiguna Tjhin , Murtani Belinda Julivia , Christian Hans , Wigantara Ngurah Agung , Putra Anggi Aviandri , Hanafi Enjeline , Minayati Kusuma , Ismail Raden Irawati , Kaligis Fransiska , Savitri Ary I. , Uiterwaal Cuno S. P. M. , Diatri Hervita
Published: March 2021

Introduction: Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus which has not been identified previously in humans. The disease leads to respiratory problems, systemic disorders, and death. To stop the virus transmission, physical distancing was strongly implemented, including working and school from home (WFH & SFH). The limitation altered daily routines and needs advanced to adapt. Many have felt uncomfortable and this could have triggered anxiety symptoms. This study aimed to evaluate the proportion of significant anxiety symptoms and its association with COVID-19-related situations in an Indonesian context during the initial months of the pandemic.

Methods: An online community survey was distributed through social media and communication platforms, mainly WhatsApp, targeting people >18 years old in Indonesia. Anxiety symptoms were assessed using Generalized Anxiety Disorder-7 (Indonesian Version). Demographical data and information on social situation related to the COVID-19 pandemic were collected. The proportion of clinically significant anxiety symptoms was calculated and the association with demographic and social factors was assessed using chi square test (χ2) and logistic regression for multivariate analysis.

Results: Out of 1215 subjects that completed the survey, 20.2% (n = 245) exhibited significant anxiety symptoms. Several factors, such as age (AOR = 0.933 CI 95% = 0.907–0.96), sex (AOR = 1.612 CI 95% = 1.097–2.369), medical workers (AOR = 0.209 CI 95% = 0.061–0.721), suspected case of COVID-19 (AOR = 1.786 CI 95% = 1.001–3.186), satisfaction level of family support (AOR = 3.052 CI 95% = 1.883–4.946), and satisfaction level of co-workers (AOR = 2.523 CI 95% = 1.395–4.562), were associated with anxiety.

Conclusion: One out of five Indonesian people could have suffered from anxiety during the COVID-19 pandemic. The riskiest group being young females, people who had suspected cases of COVID-19, and those with less satisfying social support. Nevertheless, health workers were found to have a lesser risk of developing anxiety. Accessible information and healthcare, social connection, supportive environment, and mental health surveillance are important to prevent bigger psychiatric problems post-pandemic.
“It’s all About the Colors:” How do Mexico City Youth Perceive Cigarette Pack Design
Authors: Grilo Graziele , Lagasse Lisa P. , Cohen Joanna E. , Moran Meghan B. , Reynales-Shigematsu Luz Myriam , Smith Katherine C.
Published: March 2021

Objectives: Cigarette packs are relevant to branding strategies, designed to appeal to specific groups. There is little research on how pack features increase product appeal among key constituents such as youth in low- and middle-income countries.

Methods: We conducted 10 focus group discussions (FGDs) with adolescents and 5 FGDs with young adult smokers in Mexico City, separated by age, gender, smoking, and socioeconomic status. Participants separated 23 cigarette packs into “appealing” and “unappealing” groups, and were asked to explain their decisions, describing the features that supported their views. FGDs were video-recorded, transcribed in Spanish, translated into English, and subjected to thematic analysis.

Results: Pack groupings did not differ greatly across FGDs; bold, contrasting colors and elements communicating flavor and promotion increased cigarette pack appeal and desire to try. Participants perceived packs with these features to be used by and designed for youth, like themselves.

Conclusion: Our findings reinforce the importance of packaging design in attracting new consumers and maintaining current ones. Mexico should consider stronger tobacco advertising policies that include packaging color and depiction of flavor to reduce product appeal.
Comparative Analysis between Daily Extreme Temperature and Precipitation Values Derived from Observations and Gridded Datasets in North-Western Romania
Authors: Sidău Mugurel Raul , Croitoru Adina-Eliza , Alexandru Diana-Elena
Published: March 2021

Climate gridded datasets are highly needed and useful in conducting data analysis for research and practical purposes. They provide long-term information on various climatic variables for large areas worldwide, making them suitable for use at any spatial level. It is essential to assess the accuracy of gridded data by comparing the data to measured values, especially when they are used as input parameters for hydro-climatic models. From the multitude of databases available for North-western Romania, we selected three, particularly the European Climate Assessment and Dataset (E-OBS), the Romanian Climatic Dataset (ROCADA), and the Climate of the Carpathian Region (CARPATCLIM). In this paper, we analyse the extreme precipitation and temperature data derived from the above-mentioned datasets over a common 50-year period (1961–2010) and compare the data with raw values to estimate the degree of uncertainty for each set of data. The observation data, recorded at two meteorological stations located in a complex topography region, were compared to the output of the gridded datasets, by using descriptive statistics for the mean and extreme annual and seasonal temperature and precipitation data, and trend analyses. The main findings are: the high suitability of the ROCADA gridded database for climate trend analysis and of the E-OBS gridded database for extreme temperature and precipitation analysis.
Evaluation of ENSO Prediction Skill Changes since 2000 Based on Multimodel Hindcasts
Authors: Zhang Shouwen , Wang Hui , Jiang Hua , Ma Wentao
Published: March 2021

In this study, forecast skill over four different periods of global climate change (1982–1999, 1984–1996, 2000–2018, and 2000–2014) is examined using the hindcasts of five models in the North American Multimodel Ensemble. The deterministic evaluation shows that the forecasting skills of the Niño3.4 and Niño3 indexes are much lower during 2000–2018 than during 1982–1999, indicating that the previously reported decline in forecasting skill continues through 2018. The decreases in skill are most significant for the target months from May to August, especially for medium to long lead times, showing that the forecasts suffer more from the effect of the spring predictability barrier (SPB) post-2000. Relationships between the extratropical Pacific signal and the El Niño-Southern Oscillation (ENSO) weakened after 2000, contributing to a reduction in inherent predictability and skills of ENSO, which may be connected with the forecasting skills decline for medium to long lead times. It is a great challenge to predict ENSO using the memory of the local ocean itself because of the weakening intensity of the warm water volume (WWV) and its relationship with ENSO. These changes lead to a significant decrease in the autocorrelation coefficient of the persistence forecast for short to medium lead months. Moreover, for both the Niño3.4 and Niño3 indexes, after 2000, the models tend to further underestimate the sea surface temperature anomalies (SSTAs) in the El Niño developing year but overestimate them in the decaying year. For the probabilistic forecast, the skills post-2000 are also generally lower than pre-2000 in the tropical Pacific, and in particular, they decayed east of 120° W after 2000. Thus, the advantages of different methods, such as dynamic modeling, statistical methods, and machine learning methods, should be integrated to obtain the best applicability to ENSO forecasts and to deal with the current low forecasting skill phenomenon.
Distribution of Visual and Oculomotor Alterations in a Clinical Population of Children with and without Neurodevelopmental Disorders
Authors: Bilbao Carmen , Piñero David Pablo
Published: March 2021

A prospective, non-randomized comparative study was conducted to compare the distribution of oculomotor and visual alterations in children with neurodevelopmental disorders and healthy children without such disorders. Sixty-nine children (aged 6–13 years) were enrolled and divided into three groups: a control group (CG) of 23 healthy children; a group of 18 healthy children with oculomotor abnormalities (OAG); and a group of 28 children with a neurodevelopmental disorder (NDDG), with 15 cases of dyslexia, 7 cases of developmental coordination disorder (DCD) and 6 cases of attention deficit/hyperactivity disorder (ADHD). Significantly worse near stereopsis was found in NDDG compared with CG (p < 0.001) and OAG (p = 0.001). Likewise, a significantly lower amplitude of accommodation was found in NDDG compared with CG in both the right (p = 0.001) and left eyes (p < 0.001). No statistically significant differences between groups were found in the measurement of near and distance phoria (p ≥ 0.557), near point of convergence (p = 0.700) and fusional vergences (p ≥ 0.059). Significantly impaired oculomotor test scores were found in NDDG compared with CG (p < 0.001), with no significant differences between OAG and NDDG (p ≥ 0.063). The comparison between the three types of neurodevelopmental disorders included revealed the presence of a significantly lower amplitude of accommodation in children with DCD compared with dyslexics. Furthermore, less exophoria at near was present in children with dyslexia compared with children with ADHD (p = 0.018) and DCD (p = 0.054). In conclusion, children with dyslexia, ADHD and DCD show an altered oculomotor pattern and a more reduced amplitude of accommodation, not always compatible with the diagnostic criteria of an accommodative insufficiency. Accommodative and binocular vision problems are not always present in these children and cannot be considered an etiologic factor.
A Brief Executive Language Screen for Frontal Aphasia
Authors: Robinson Gail A. , Shi Lucy , Nott Zoie , Ceslis Amelia
Published: March 2021

Aphasia assessment tools have primarily focused on classical aphasia type and severity, with minimal incorporation of recent findings that suggest a significant role of executive control operations in language generation. Assessment of the interface between language and executive functions is needed to improve detection of spontaneous speech difficulties. In this study we develop a new Brief Executive Language Screen (BELS), a brief tool specifically designed to assess core language and executive functions shown to be involved in spontaneous generation of language. Similar to other measures of aphasia, the BELS assesses articulation and core language skills (repetition, naming and comprehension). Unique additions to the BELS include assessments of spontaneous connected speech, word fluency (phonemic/semantic) and sentence completion (verbal initiation, inhibition and selection). One-hundred and eight healthy controls and 136 stroke patients were recruited. Confirmatory factor analysis was used to determine construct validity and logistic regression was used to evaluate the discriminative validity, informing the final version of the BELS. The results showed that the BELS is sensitive for articulation and nominal language deficits, and it measures executive aspects of spontaneous language generation, which is a hallmark of frontal dynamic aphasia. The results have encouraging theoretical and practical implications.
The Use and Impact of Cognitive Enhancers among University Students: A Systematic Review
Authors: Sharif Safia , Guirguis Amira , Fergus Suzanne , Schifano Fabrizio
Published: March 2021

Introduction: Cognitive enhancers (CEs), also known as “smart drugs”, “study aids” or “nootropics” are a cause of concern. Recent research studies investigated the use of CEs being taken as study aids by university students. This manuscript provides an overview of popular CEs, focusing on a range of drugs/substances (e.g., prescription CEs including amphetamine salt mixtures, methylphenidate, modafinil and piracetam; and non-prescription CEs including caffeine, cobalamin (vitamin B12), guarana, pyridoxine (vitamin B6) and vinpocetine) that have emerged as being misused. The diverted non-prescription use of these molecules and the related potential for dependence and/or addiction is being reported. It has been demonstrated that healthy students (i.e., those without any diagnosed mental disorders) are increasingly using drugs such as methylphenidate, a mixture of dextroamphetamine/amphetamine, and modafinil, for the purpose of increasing their alertness, concentration or memory. Aim: To investigate the level of knowledge, perception and impact of the use of a range of CEs within Higher Education Institutions. Methodology: A systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Whilst 1400 studies were identified within this study through a variety of electronic databases (e.g., 520 through PubMed, 490 through Science Direct and 390 through Scopus), 48 papers were deemed relevant and were included in this review. Results: The most popular molecules identified here included the stimulant CEs, e.g., methylphenidate, modafinil, amphetamine salt mixtures and caffeine-related compounds; stimulant CEs’ intake was more prevalent among males than females; drugs were largely obtained from friends and family, as well as via the Internet. It is therefore suggested that CEs are increasingly being used among healthy individuals, mainly students without any diagnosed cognitive disorders, to increase their alertness, concentration, or memory, in the belief that these CEs will improve their performance during examinations or when studying. The impact of stimulant CEs may include tolerance, dependence and/or somatic (e.g., cardiovascular; neurological) complications. Discussion: The availability of CEs for non-medical indications in different countries is influenced by a range of factors including legal, social and ethical factors. Considering the risk factors and motivations that encourage university students to use CE drugs, it is essential to raise awareness about CE-related harms, counteract myths regarding “safe” CE use and address cognitive enhancement in an early stage during education as a preventative public health measure.
Pan-Cancer Analysis of Human Kinome Gene Expression and Promoter DNA Methylation Identifies Dark Kinase Biomarkers in Multiple Cancers
Authors: Southekal Siddesh , Mishra Nitish Kumar , Guda Chittibabu
Published: March 2021

Kinases are a group of intracellular signaling molecules that play critical roles in various biological processes. Even though kinases comprise one of the most well-known therapeutic targets, many have been understudied and therefore warrant further investigation. DNA methylation is one of the key epigenetic regulators that modulate gene expression. In this study, the human kinome’s DNA methylation and gene expression patterns were analyzed using the level-3 TCGA data for 32 cancers. Unsupervised clustering based on kinome data revealed the grouping of cancers based on their organ level and tissue type. We further observed significant differences in overall kinase methylation levels (hyper- and hypomethylation) between the tumor and adjacent normal samples from the same tissue. Methylation expression quantitative trait loci (meQTL) analysis using kinase gene expression with the corresponding methylated probes revealed a highly significant and mostly negative association (~92%) within 1.5 kb from the transcription start site (TSS). Several understudied (dark) kinases (PKMYT1, PNCK, BRSK2, ERN2, STK31, STK32A, and MAPK4) were also identified with a significant role in patient survival. This study leverages results from multi-omics data to identify potential kinase markers of prognostic and diagnostic importance and further our understanding of kinases in cancer.
Photodynamic Therapy as a Potent Radiosensitizer in Head and Neck Squamous Cell Carcinoma
Authors: Cho Won Jin , Kessel David , Rakowski Joseph , Loughery Brian , Najy Abdo J. , Pham Tri , Kim Seongho , Kwon Yong Tae , Kato Ikuko , Kim Harold E. , Kim Hyeong-Reh C.
Published: March 2021

Despite recent advances in therapeutic modalities such as radiochemotherapy, the long-term prognosis for patients with advanced head and neck squamous cell carcinoma (HNSCC), especially nonviral HNSCC, remains very poor, while survival of patients with human papillomavirus (HPV)-associated HNSCC is greatly improved after radiotherapy. The goal of this study is to develop a mechanism-based treatment protocol for high-risk patients with HPV-negative HNSCC. To achieve our goal, we have investigated molecular mechanisms underlying differential radiation sensitivity between HPV-positive and -negative HNSCC cells. Here, we found that autophagy is associated with radioresistance in HPV-negative HNSCC, whereas apoptosis is associated with radiation sensitive HPV-positive HNSCC. Interestingly, we found that photodynamic therapy (PDT) directed at the endoplasmic reticulum (ER)/mitochondria initially induces paraptosis followed by apoptosis. This led to a substantial increase in radiation responsiveness in HPV-negative HNSCC, while the same PDT treatment had a minimal effect on HPV-positive cells. Here, we provide evidence that the autophagic adaptor p62 mediates signal relay for the induction of apoptosis, promoting ionizing radiation (XRT)-induced cell death in HPV-negative HNSCC. This work proposes that ER/mitochondria-targeted PDT can serve as a radiosensitizer in intrinsically radioresistant HNSCC that exhibits an increased autophagic flux.
DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients
Authors: Bold Ioan T. , Specht Ann-Kathrin , Droste Conrad F. , Zielinski Alexandra , Meyer Felix , Clauditz Till S. , Münscher Adrian , Werner Stefan , Rothkamm Kai , Petersen Cordula , Borgmann Kerstin
Published: March 2021

Aneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score was established. We observed an association of CIN70 score and survival in 519 HNSCC patients in the TCGA dataset; the 15% patients with the lowest CIN70 score showed better survival (p = 0.11), but association was statistically non-significant. This correlated with the expression of 39 proteins of the major repair complexes. A positive association with survival was observed for MSH2, XRCC1, MRE11A, BRCA1, BRCA2, LIG1, DNA2, POLD1, MCM2, RAD54B, claspin, a negative for ERCC1, all related with replication. We hypothesized that expression of these factors leads to protection of replication through efficient repair and determines survival and resistance to therapy. Protein expression differences in HNSCC cell lines did not correlate with cellular sensitivity after treatment. Rather, it was observed that the stability of the DNA replication fork determined resistance, which was dependent on the ATR/CHK1-mediated S-phase signaling cascade. This suggests that it is not the expression of individual DNA repair proteins that causes therapy resistance, but rather a balanced expression and coordinated activation of corresponding signaling cascades.
TAM Receptor Inhibition–Implications for Cancer and the Immune System
Authors: Aehnlich Pia , Powell Richard Morgan , Peeters Marlies J. W. , Rahbech Anne , thor Straten Per
Published: March 2021

Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 (Gas6) which act as bridging molecules for binding of phosphatidyl serine (PtdSer) exposed on apoptotic cell membranes. Upon clearance of apoptotic cell material, TAM receptor activation on innate cells suppresses proinflammatory functions, thereby ensuring the immunologically silent removal of apoptotic material in the absence of deleterious immune responses. However, in T cells, MerTK signaling is costimulatory and promotes activation and functional output of the cell. MerTK and Axl are also aberrantly expressed in a range of both hematological and solid tumor malignancies, including breast, lung, melanoma and acute myeloid leukemia, where they have a role in oncogenic signaling. Consequently, TAM receptors are being investigated as therapeutic targets using small molecule inhibitors and have already demonstrated efficacy in mouse tumor models. Thus, inhibition of TAM signaling in cancer cells could have therapeutic value but given the opposing roles of TAM signaling in innate cells and T cells, TAM inhibition could also jeopardize anticancer immune responses. This conflict is discussed in this review, describing the effects of TAM inhibition on cancer cells as well as immune cells, while also examining the intricate interplay of cancer and immune cells in the tumor microenvironment.
Excision Repair Cross-Complementation Group 6 Gene Polymorphism Is Associated with the Response to FOLFIRINOX Chemotherapy in Asian Patients with Pancreatic Cancer
Authors: Choi Young Hoon , Lim Younggyun , Ryu Ji Kon , Paik Woo Hyun , Lee Sang Hyub , Kim Yong-Tae , Kim Ju Han
Published: March 2021

FOLFIRINOX is currently one of the standard chemotherapy regimens for pancreatic cancer patients, but little is known about the factors that can predict a response to it. We performed a study to discover novel DNA damage repair (DDR) gene variants associated with the response to FOLFIRINOX chemotherapy in patients with pancreatic cancer. We queried a cohort of pancreatic cancer patients who received FOLFIRINOX chemotherapy as the first treatment and who had tissue obtained through an endoscopic ultrasound-guided biopsy that was suitable for DNA sequencing. We explored variants of 148 DDR genes based on whole exome sequencing and performed multivariate Cox regression to find genetic variants associated with progression-free survival (PFS). Overall, 103 patients were included. Among 2384 variants of 141 DDR genes, 612 non-synonymous variants of 123 genes were selected for Cox regression analysis. The multivariate Cox model showed that rs2228528 in ERCC6 was significantly associated with improved PFS (hazard ratio 0.54, p = 0.001). The median PFS was significantly longer in patients with rs2228528 genotype AA vs. genotype GA and GG (23.5 vs. 16.2 and 8.6 months; log-rank p < 0.001). This study suggests that rs2228528 in ERCC6 could be a potential predictor of response to FOLFIRINOX chemotherapy in patients with pancreatic cancer.
Subsequent Malignant Neoplasms in Retinoblastoma Survivors
Authors: Fabius Armida W. M. , van Hoefen Wijsard Milo , van Leeuwen Flora E. , Moll Annette C.
Published: March 2021

Retinoblastoma (Rb) is a pediatric malignant eye tumor. Subsequent malignant neoplasms (SMNs) and trilateral Rb (TRb) are the leading cause of death in heritable Rb patients in developed countries. The high rate of SMNs in heritable Rb patients is attributed to the presence of a mutation in the RB1 tumor suppressor gene. In addition, Rb therapy choices also influence SMN incidence in this patient group. The incidence rates and age of occurrence for the most frequent SMNs and TRb will be discussed. In addition, the impact of genetic predisposition and Rb treatments on the development of SMNs will be evaluated. Furthermore, screening and other prevention methods will be reviewed.