Miracle-dz/UniFAR-FTUs huggingface dataset:
Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

Simple Summary Colorectal cancer (CRC) is among the most common cancers and the third leading cause of cancer deaths worldwide. Despite the identification of alterations in DNA repair genes and the resulting genomic instability in sub-populations of CRC, therapies that exploit defects in DNA repair pathways or high level of replicative stress have been explored only in breast, ovarian, and other tumor types, but not yet systematically in CRC. Here, we discuss how targeting genes involved in the responses to replication stress and the repair of DNA double-strand breaks (DSBs) could provide new therapeutic opportunities to treat CRCs and have the potential to confer increased sensitivity to current chemotherapy regimens, thus, expanding the spectrum of therapy options, and potentially improving clinical outcomes for CRC patients. Abstract Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies.
How Do Patients with Life-Limiting Illness and Caregivers Want End-Of-Life Prognostic Information Delivered? A Pilot Study

We aimed to identify the level of prognostic disclosure, type of prognostic information and delivery format of prognostic communication that older adults diagnosed with a life-limiting illness or caregivers prefer to receive. We developed and pilot tested an open-ended survey to 15 older patients and caregivers who had experience in health services for life-limiting illness either for a relative, friend or themselves. Five hypothetical clinical scenarios of prognostic options were presented to ascertain preferences. The preferred format to receive prognostic information was verbal delivery by the clinician with a written summary. Photos and videos were less favoured, and a table with numbers/percentages was least preferred. Distress levels to the prognostic scenarios were low, with the exception of a photo. We conclude that older patients/caregivers want end-of-life prognostic information delivered the traditional way, verbally by clinicians. Options to deliver prognostic information may vary across patient groups but empower clinicians in introducing end-of-life discussions with patients/caregivers. Our study illustrates the feasibility of involving terminal patients and caregivers in research that contributes to eliciting prognostic preferences. Further research is needed to understand whether the prognostic preferences of hospitalized patients with life-limiting illness differ.
Fracture Behavior of Short Fiber-Reinforced Direct Restorations in Large MOD Cavities

The aim of this research was to study the impact of using a short fiber-reinforced composite (SFRC) core on the fatigue performance and fracture behavior of direct large posterior composite restorations. Moreover, the influence of the consistency (flowable or packable) of occlusal composite coverage was assessed. A total of 100 intact molars were collected and randomly distributed into five groups (n = 20). Deep mesio-occlusal-distal (MOD) cavities were prepared in all groups. After adhesive treatment and rebuilding the missing interproximal walls with conventional composite, the specimens in four experimental groups were restored by an SFRC core (everX Flow), which was applied and cured either in bulk or in oblique layers (each 2 mm thick). Packable (G-aenial Posterior) or flowable (G-aenial Injectable) conventional composites were used as a final occlusal layer. The control group was restored with only packable conventional composite. Fatigue survival was measured for all specimens using a cyclic loading machine until a fracture occurred or a total of 25,000 cycles was achieved. Kaplan–Meyer survival analyses were conducted, followed by pairwise log-rank post hoc comparisons. The static load-bearing capacity of surviving teeth was tested using a universal testing machine. Fracture patterns were evaluated visually. There was no statistically significant (p > 0.05) difference in terms of survival between the tested groups. All groups for which flowable SFRC was used showed statistically significantly higher load-bearing capacities compared to the control group (p < 0.05). There were no significant differences regarding fracture resistance among the fiber-reinforced study groups. Regarding the fracture pattern during the survival analysis, all specimens that received SFRC showed a dominantly restorable type of fracture, while the control specimens presented a dominantly non-restorable type. The use of flowable SFRC as a reinforcing core for large MOD direct restorations showed promising achievements regarding fracture behavior.
Knowledge, Attitude, and Practices on Antimicrobial Use and Antimicrobial Resistance among Commercial Poultry Farmers in Bangladesh

Antimicrobial resistance (AMR) has become an emerging health issue globally, posing a threat to zoonotic pathogens and foodborne diseases. In Bangladesh, the poultry sector supplies the majority of the demand for animal-source protein. The irrational and excessive use of antimicrobials (AMU) has been observed in the poultry sector. The development of AMR is associated with many factors, including the knowledge and attitudes of poultry farmers. Therefore, AMR reduction requires intervention from all the stockholders, including the farmers who are considered as end users of antimicrobials. This current research conducted a cross-sectional study to assess the knowledge, attitudes, and practices (KAP) of poultry farmers on AMU and AMR in Bangladesh. We determined the KAP of poultry farmers (broiler and layer farmers) of some selected districts of the country using a tested and paper-based questionnaire. The results demonstrated that most of the respondents have insufficient KAP regarding AMU and AMR. The respondents used a variety of antimicrobials primarily in the treatment of various diseases in poultry. One-third of the farmers did not seek antimicrobials from registered vets. Instead, they depended on others or themselves. The factor score analysis further revealed that the farmers’ demographic and socioeconomic variables were significant factors influencing the KAP. An adjusted logistic regression analysis showed that older farmers with 9–12 years of farming experience and graduate-level education, engaging in medium-sized layer farming, were more likely to have correct KAP on AMU and AMR. Further, farmers from the Cox’s Bazar region showed correct knowledge, whereas farmers of the Chattogram region showed a correct attitude towards AMU and AMR. A Spearman’s rank-order correlation revealed a positive association between knowledge–attitudes and knowledge–practices. The findings of the current investigation provide baseline evidence about the KAP of poultry farmers from low-income resources and offer insights into designing interventions and policies for the use of AMU and AMR in Bangladesh.
Using Artificial Neural Network Modeling to Analyze the Thermal Protective and Thermo-Physiological Comfort Performance of Textile Fabrics Used in Oilfield Workers’ Clothing

Most of the fatalities and injuries of oilfield workers result from inadequate protection and comfort by their clothing under various work hazards and ambient environments. Both the thermal protective performance and thermo-physiological comfort performance of textile fabrics used in clothing significantly contribute to the mitigation of workers’ skin burns and heat-stress-related deaths. This study aimed to apply the ANN modeling approach to analyze clothing performance considering the wearers’ sweat moisture and the microclimate air gap that is generated in between their body and clothing. Firstly, thermal protective and thermo-physiological comfort performance of fire protective textiles used in oilfield workers’ clothing were characterized. Different fabric properties (e.g., thickness, weight, fabric count), thermal protective performance, and thermo-physiological comfort performance were measured. The key fabric property that affects thermal protective and thermo-physiological performance was identified as thickness by statistical analysis. The ANN modeling approach could be successfully implemented to analyze the performance of fabrics in order to predict the performance more conveniently based on the fabric properties. It is expected that the developed models could inform on-duty oilfield workers about protective and thermo-physiological comfort performance and provide them with occupational health and safety.
Integration of NRP1, RGS5, and FOXM1 expression, and tumour necrosis, as a postoperative prognostic classifier based on molecular subtypes of clear cell renal cell carcinoma

Molecular mechanisms of progression of clear cell renal cell carcinoma (ccRCC) have been proven with recent genomic or transcriptional analyses. However, it is still difficult to apply these analyses to daily clinical practice owing to economical and practical issues. Here, we established a pathology‐based, postoperative prognostic classification based on the well‐validated transcriptional classifier, ClearCode34, in ccRCC. A total of 342 cases with available tissue were identified and randomly allocated into a discovery cohort (n = 138) and a validation cohort (n = 204). Levels of mRNA were quantified using a nCounter Digital Analyzer, and the ccA/ccB subtypes were determined. Histological and immunohistochemistry (IHC) analyses were subsequently performed to establish a pathology‐based classification based on the mRNA levels. Finally, the prognostic ability of the new classifier was evaluated in both the discovery and validation cohorts. Of 138 cases in the discovery cohort, 78 (56.5%) and 60 (43.5%) were assigned to the ccA and ccB subtypes, respectively. Proangiogenic genes, neuropilin 1 (NRP1) and regulator of G protein signalling 5 (RGS5), were especially overexpressed in all ccRCC samples and were enriched in ccA‐assigned tumours. Histologically, tumour necrosis and the sarcomatoid feature were associated with the ccB subtype. In IHC analyses, expression of NRP1, RGS5, and forkhead box M1 (FOXM1), an epithelial–mesenchymal transition‐related factor, significantly correlated with the ccA/ccB subtypes. Combining these three IHC factors and tumour necrosis, we developed the IHC/histology‐based classifier, which showed good concordance with the ClearCode34 classifier with an accuracy of 0.80. The established classification significantly stratified relapse‐free, cancer‐specific, and overall survival rates in both the discovery and validation cohorts. The novel molecular pathology classifier integrating NRP1, RGS5, FOXM1, and tumour necrosis may enable the stratification of oncological outcomes for patients with ccRCC undergoing resection surgery.
COVID-19 Antibody Detecting Rapid Diagnostic Tests Show High Cross-Reactivity When Challenged with Pre-Pandemic Malaria, Schistosomiasis and Dengue Samples

COVID-19 Antibody Detecting Rapid Diagnostic Tests (COVID-19 Ab RDTs) are the preferred tool for SARS-CoV-2 seroprevalence studies, particularly in low- and middle-income countries. The present study challenged COVID-19 Ab RDTs with pre-pandemic samples of patients exposed to tropical pathogens. A retrospective study was performed on archived serum (n = 94) and EDTA whole blood (n = 126) samples obtained during 2010–2018 from 196 travelers with malaria (n = 170), schistosomiasis (n = 25) and dengue (n = 25). COVID-19 Ab RDTs were selected based on regulatory approval status, independent evaluation results and detecting antigens. Among 13 COVID-19 Ab RDT products, overall cross-reactivity was 18.5%; cross-reactivity for malaria, schistosomiasis and dengue was 20.3%, 18.1% and 7.5%, respectively. Cross-reactivity for current and recent malaria, malaria antibodies, Plasmodium species and parasite densities was similar. Cross-reactivity among the different RDT products ranged from 2.7% to 48.9% (median value 14.5%). IgM represented 67.9% of cross-reactive test lines. Cross-reactivity was not associated with detecting antigens, patient categories or disease (sub)groups, except for schistosomiasis (two products with ≥60% cross-reactivity). The high cross-reactivity for malaria, schistosomiasis and—to a lesser extent—dengue calls for risk mitigation when using COVID-19 Ab RDTs in co-endemic regions.
MMPs and TIMPs Expression Levels in the Periodontal Ligament during Orthodontic Tooth Movement: A Systematic Review of In Vitro and In Vivo Studies

Background: During orthodontic tooth movement (OTM), applied orthodontic forces cause an extensive remodeling of the extracellular matrix (ECM) in the periodontal ligament (PDL). This is mainly orchestrated by different types of matrix metalloproteinases (MMPs) and their tissue inhibitors of matrix metalloproteinases (TIMPs), which are both secreted by periodontal ligament (PDL) fibroblasts. Multiple in vitro and in vivo studies already investigated the influence of applied orthodontic forces on the expression of MMPs and TIMPs. The aim of this systematic review was to explore the expression levels of MMPs and TIMPs during OTM and the influence of specific orthodontic force-related parameters. Methods: Electronic article search was performed on PubMed and Web of Science until 31 January 2021. Screenings of titles, abstracts and full texts were performed according to PRISMA, whereas eligibility criteria were defined for in vitro and in vivo studies, respectively, according to the PICO schema. Risk of bias assessment for in vitro studies was verified by specific methodological and reporting criteria. For in vivo studies, risk of bias assessment was adapted from the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross-sectional study. Results: Electronic article search identified 3266 records, from which 28 in vitro and 12 in vivo studies were included. The studies showed that orthodontic forces mainly caused increased MMPs and TIMPs expression levels, whereas the exact effect may depend on various intervention and sample parameters and subject characteristics. Conclusion: This systematic review revealed that orthodontic forces induce a significant effect on MMPs and TIMPs in the PDL. This connection may contribute to the controlled depletion and formation of the PDLs’ ECM at the compression and tension site, respectively, and finally to the highly regulated OTM.
The Impact of Nursing on Trauma Patient Satisfaction: An Analysis of HCAHPS From 112,283 Patients

Background: Assessment of patient satisfaction is central to understanding and improving system performance with the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) national standard survey. However, no large, multi-institutional study exists, which examines the role of nurses in trauma patient satisfaction. Objective: To assess the impact of nurses on trauma patient satisfaction. Methods: This retrospective, descriptive study of Level I–IV trauma centers in a multistate hospital system evaluated patients 18 years and older admitted with at least an overnight stay. Data were obtained electronically for patients discharged in 2018–2019 who returned an HCAHPS survey. Surveys were linked by an honest broker to demographic and injury data from the trauma registry, and then anonymized prior to analysis. Patients were categorized as “trauma” per the National Trauma Data Standard (NTDS) definition or as “medical” or “surgical” per the HCAHPS definition. Results: Of 112,283 surveys from 89 trauma centers, “trauma” patients (n = 5,126) comprised 4.6%, “surgical” 39.0% (n = 43,763), and “medical” 56.5% (n = 63,394). Nurses had an overwhelming impact on “trauma” patient satisfaction, accounting for 63.9% (p < .001) of the variation (adjusted R2) in the overall score awarded the institution—larger than for “surgery” (59.6%; p < .001) or “medical” (58.4%; p < .001) patients. The most important individual domain contributor to the overall rating of a facility was “nursing communication. ” Conclusions: The magnitude of the effect of trauma nurses was noteworthy, with their communication ability being the single biggest driver of institutional ratings. These data provide insight for future performance benchmark development and emphasize the critical impact of trauma nurses on the trauma patient experience.
Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

We report the results of calculations of the Gibbs energy profiles of the guanosine triphosphate (GTP) hydrolysis by the Arl3-RP2 protein complex using molecular dynamics (MD) simulations with ab initio type QM/MM potentials. The chemical reaction of GTP hydrolysis to guanosine diphosphate (GDP) and inorganic phosphate (Pi) is catalyzed by GTPases, the enzymes, which are responsible for signal transduction in live cells. A small GTPase Arl3, catalyzing the GTP → GDP reaction in complex with the activating protein RP2, constitute an essential part of the human vision cycle. To simulate the reaction mechanism, a model system is constructed by motifs of the crystal structure of the Arl3-RP2 complexed with a substrate analog. After selection of reaction coordinates, energy profiles for elementary steps along the reaction pathway GTP + H2O → GDP + Pi are computed using the umbrella sampling and umbrella integration procedures. QM/MM MD calculations are carried out, interfacing the molecular dynamics program NAMD and the quantum chemistry program TeraChem. Ab initio type QM(DFT)/MM potentials are computed with atom-centered basis sets 6-31G** and two hybrid functionals (PBE0-D3 and ωB97x-D3) of the density functional theory, describing a large QM subsystem. Results of these simulations of the reaction mechanism are compared to those obtained with QM/MM calculations on the potential energy surface using a similar description of the QM part. We find that both approaches, QM/MM and QM/MM MD, support the mechanism of GTP hydrolysis by GTPases, according to which the catalytic glutamine side chain (Gln71, in this system) actively participates in the reaction. Both approaches distinguish two parts of the reaction: the cleavage of the phosphorus-oxygen bond in GTP coupled with the formation of Pi, and the enzyme regeneration. Newly performed QM/MM MD simulations confirmed the profile predicted in the QM/MM minimum energy calculations, called here the pathway-I, and corrected its relief at the first elementary step from the enzyme–substrate complex. The QM/MM MD simulations also revealed another mechanism at the part of enzyme regeneration leading to pathway-II. Pathway-II is more consistent with the experimental kinetic data of the wild-type complex Arl3-RP2, whereas pathway-I explains the role of the mutation Glu138Gly in RP2 slowing down the hydrolysis rate.
The Accuracy of Causal Learning Over Long Timeframes: An Ecological Momentary Experiment Approach

The ability to learn cause-effect relations from experience is critical for humans to behave adaptively - to choose causes that bring about desired effects. However, traditional experiments on experience-based learning involve events that are artificially compressed in time so that all learning occurs over the course of minutes. These paradigms therefore exclusively rely upon working memory. In contrast, in real-world situations we need to be able to learn cause-effect relations over days and weeks, which necessitates long-term memory. 413 participants completed a smartphone study, which compared learning a cause-effect relation one trial per day for 24 days versus the traditional paradigm of 24 trials back- to- back. Surprisingly, we found few differences between the short versus long timeframes. Subjects were able to accurately detect generative and preventive causal relations, and they exhibited illusory correlations in both the short and long timeframe tasks. These results provide initial evidence that experience-based learning over long timeframes exhibits similar strengths and weaknesses as in short timeframes. However, learning over long timeframes may become more impaired with more complex tasks.
Interactions between Personality and Types of Mindfulness Practice in Reducing Burnout in Mental Health Professionals

Research on mindfulness-based interventions reports mainly on improvements at the group level. Thus, there is a need to elaborate on the individual differences in their effectiveness. The aim of this study was twofold: (1) to examine which personality factors could influence burnout reduction associated with different types of mindfulness practice and (2) to evaluate the interaction between personality factors and the amount of home practice; both aims were controlled for sociodemographic characteristics. A total of 104 Cuban mental health professionals, who participated in a crossover trial, were included. The effect of personality (Cattell’s 16 Personality Factors) was analyzed through regression analysis. First, the results revealed that Emotional Stability and Vigilance could negatively moderate the effectiveness of mindfulness-based interventions. Second, participants who scored low in Sensitivity or Vigilance could benefit more from the body-centered practices (i.e., body scan and Hatha yoga practices), but no significant results for the mind-centered practices (i.e., classical meditation) were found. Third, participants who scored high in Self-reliance could benefit more from informal practice. Other personality factors did not appear to moderate the effect of the interventions, though previous experience in related techniques must be considered. Recommendations and clinical implications are discussed. Trial registration number is NCT03296254 (clinicaltrials.gov).