Miracle-dz/UniFAR-FTUs huggingface dataset:
MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma

Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Methods: Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. Results: PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both in vitro and in vivo and the combined treatment resulted in an improved cytotoxicity on tumour cells. Conclusion: In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.
A Video-Based Introductory EEG Curriculum for Neurology Residents and Other EEG Learners

Introduction It is difficult to provide standardized formal education in EEG because of time limitations and the availability of expert teachers. Video-based miniature lectures are a useful way to standardize the foundational principles of EEG and support learning during EEG/epilepsy rotations. Methods A curriculum of 10 EEG teaching videos was developed based on concepts outlined in the Accreditation Council for Graduate Medical Education Neurology Milestones. The videos were short (6–17 minutes) and made available to residents rotating through an EEG/epilepsy rotation in two neurology residency programs. Residents were instructed to review the videos and then apply their newly learned skills during EEG reading sessions. A survey about the process was completed at the end of the year. Results Twenty-one residents participated in the curriculum, and 15 (71%) responded to the survey. Two-thirds of respondents (10/15) said that they watched all of the videos, and 87% (13/15) watched at least half of the videos. All of the respondents used the videos as introductions to EEG concepts, and approximately half of respondents returned to the videos as a refresher after the rotation was over. Nearly all respondents either agreed or strongly agreed that the curriculum was a useful component of the rotation and helped them to understand difficult concepts. All strongly agreed that they would recommend the curriculum to other residents. Discussion A video-based approach to EEG teaching could complement existing curricula and ensure that learners have access to foundational miniature lectures when and where they need them.
Bottlebrush-architectured poly(ethylene glycol) as an efficient vector for RNA interference in vivo

Bottlebrush-structured PEG substantially enhances the pharmacokinetics of conjugated siRNA and RNAi activity in vivo. Nonhepatic delivery of small interfering RNAs (siRNAs) remains a challenge for development of RNA interference–based therapeutics. We report a noncationic vector wherein linear poly(ethylene glycol) (PEG), a polymer generally considered as inert and safe biologically but ineffective as a vector, is transformed into a bottlebrush architecture. This topology provides covalently embedded siRNA with augmented nuclease stability and cellular uptake. Consisting almost entirely of PEG and siRNA, the conjugates exhibit a ~25-fold increase in blood elimination half-life and a ~19-fold increase in the area under the curve compared with unmodified siRNA. The improved pharmacokinetics results in greater tumor uptake and diminished liver capture. Despite the structural simplicity these conjugates efficiently knock down target genes in vivo without apparent toxic and immunogenic reactions. Given the benign biological nature of PEG and its widespread precedence in biopharmaceuticals, we anticipate the brush polymer–based technology to have a significant impact on siRNA therapeutics.
The impact of catheter ablation for atrial fibrillation in heart failure

Atrial fibrillation (AF) commonly co‐exists with systolic heart failure (SHF) and its presence is associated with a worse prognosis. Despite this, a rhythm control approach using antiarrhythmic drugs (AADs) to reduce AF burden has demonstrated no prognostic benefit. Catheter ablation (AFA) is more effective than AADs at reducing AF burden. We performed a meta‐analysis to evaluate the impact of AFA on outcomes in SHF. Electronic databases were systematically searched. We included only randomized controlled trials that examined the impact of AFA on clinical outcomes in patients with SHF (LVEF <50%). We included studies with any ablation strategy that incorporated pulmonary vein isolation and any control group. Seven studies (n = 858) were included with a mean follow‐up of 6‐38 months. In comparison to controls, AFA was associated with significant reductions in all‐cause mortality (relative risk [RR] 0.52, P = 0.0009) and unplanned or heart failure hospitalization (RR 0.58, P < 0.00001). Compared to controls, AFA was also associated with significant improvements in LVEF (mean difference 6.30%, P < 0.00001), Minnesota Living with Heart Failure Questionnaire score (mean difference 9.58, P = 0.0003), 6‐minute walk distance (mean difference 31.78 m, P = 0.003) and VO2 max (mean difference 3.17, P = 0.003). However, major procedure‐related complications occurred in 2.4%‐15% of ablation patients. In patients with AF and SHF, catheter ablation has significant benefits. Further work is needed to establish the role of ablation in the routine treatment of SHF patients with AF.
Fto Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota

Depression and obesity have high concurrence within individuals, which may be explained by sharing the same risk factors, including disruption of the intestinal microbiota. However, evidence that delineated the causal connections is extremely scarce. Methods: Mice lacking fat mass- and obesity-associated gene (Fto) were generated. Fto-deficient and wild-type control mice were subjected to novel conditions with or without chronic unpredictable mild stress (CUMS) for 6 weeks. Some mice were treated with antibiotics via their drinking water for 6 weeks in order to deplete their microbiota. Behavioral tests were performed to evaluate anxiety- and depression-like behaviors. 16S rRNA amplicon and metagenomic sequencing were employed to analyse fecal microbiota. Plasma levels of inflammatory cytokines and lipopolysaccharides (LPS) were also compared. Results: Deletion of Fto led to lower body weight and decreased anxiety- and depression-like behaviors, Fto+/- mice were also less susceptible to stress stimulation, highlighting the essential role of Fto in pathogenesis of depression. With regard to gut microbiota, Fto deficiency mice harbored specific bacterial signature of suppressing inflammation, characterized with higher abundance of Lactobacillus, lower Porphyromonadaceae and Helicobacter. Critically, behavioral alterations of Fto+/- mice are mediated by shift in gut microbiota, as such changes can be partially attenuated using antibiotics. Exposure to CUMS increased serum IL-6 level while Fto deficiency reduced its level, which may be explained by a lower LPS concentration. Conclusion: Together, our findings uncover the roles of Fto on depression and provide insights into microbiota-related biological mechanisms underlying the association between obesity and depression.
Microencapsulation of β-Carotene by Spray Drying: Effect of Wall Material Concentration and Drying Inlet Temperature

Carotenoids are a class of natural pigments found mainly in fruits and vegetables. Among them, β-carotene is regarded the most potent precursor of vitamin A. However, it is susceptible to oxidation upon exposure to oxygen, light, and heat, which can result in loss of colour, antioxidant activity, and vitamin activity. Thus, the objective of this work was to study the microencapsulation process of β-carotene by spray drying, using arabic gum as wall material, to protect it against adverse environmental conditions. This was carried out using the response surface methodology coupled to a central composite rotatable design, evaluating simultaneously the effect of drying air inlet temperature (110-200°C) and the wall material concentration (5-35%) on the drying yield, encapsulation efficiency, loading capacity, and antioxidant activity. In addition, morphology and particles size distribution were evaluated. Scanning electron microscopy images have shown that the particles were microcapsules with a smooth surface when produced at the higher drying temperatures tested, most of them having a diameter lower than 10 μm. The conditions that enabled obtaining simultaneously arabic gum microparticles with higher β-carotene content, higher encapsulation efficiency, and higher drying yield were a wall material concentration of 11.9% and a drying inlet temperature of 173°C. The systematic approach used for the study of β-carotene microencapsulation process by spray drying using arabic gum may be easily applied for other core and wall materials.
Radiologic and Intraoperative Finding of Intimal Tear in Type A Intramural Hematoma of the Aorta

Abstract Aortic intramural hematoma (IMH) is described as “dissection without intimal tear” due to rhexis of vasa vasorum, which results in bleeding within the tunica media in the absence of intimal disruption or blood flow communication. The aim of our study is to validate perioperative evidence of intimal entry tear in IMH patients and to suggest that this entity may represent a part of a disease and not a separate disease.
Identities and frequencies of variants in CYP1B1 causing primary congenital glaucoma in Pakistan

Purpose Primary congenital glaucoma (PCG) is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic causes of PCG segregating in 36 large consanguineous Pakistani families. Methods Ophthalmic examination including fundoscopy, or slit-lamp microscopy was performed to clinically characterize the PCG phenotype. Genomic nucleotide sequences of the CYP1B1 and LTBP2 genes were analyzed with either Sanger or whole exome sequencing. In silico prediction programs were used to assess the pathogenicity of identified alleles. ClustalW alignments were performed to determine evolutionary conservation, and three-dimensional (3D) modeling was performed using HOPE and Phyre2 software. Results Among the known loci, mutations in CYP1B1 and LTBP2 are the common causes of PCG. Therefore, we analyzed the genomic nucleotide sequences of CYP1B1 and LTBP2, and detected probable pathogenic variants cosegregating with PCG in 14 families. These included the three novel (c.542T>A, c.1436A>G, and c.1325delC) and five known (c.868dupC, c.1168C>T, c.1169G>A, c.1209InsTCATGCCACC, and c.1310C>T) variants in CYP1B1. Two of the novel variants are missense substitutions [p.(Leu181Gln), p.(Gln479Arg)], which replaced evolutionary conserved amino acids, and are predicted to be pathogenic by various in silico programs, while the third variant (c.1325delC) is predicted to cause reading frameshift and premature truncation of the protein. A single mutation, p.(Arg390His), causes PCG in six (~43%) of the 14 CYP1B1 mutations harboring families, and thus, is the most common variant in this cohort. Surprisingly, we did not find any LTBP2 pathogenic variants in the families, which further supports the genetic heterogeneity of PCG in the Pakistani population. Conclusions In conclusion, results of the present study enhance our understanding of the genetic basis of PCG, support the notion of a genetic modifier of CYP1B1, and contribute to the development of genetic testing protocols and genetic counseling for PCG in Pakistani families.
Assent and consent in pediatric and adolescent research: school children’s perspectives

Background School students’ views and perceptions of informed parental consent and child assent about child participation in research in the Middle East are not known. Methods Focus group interviews were conducted to understand high school students’ perspectives toward child and adolescent assents and consents in research including the importance of, and depth of information needed in consent and assent, and perception toward written vs verbal consent and assent. Results The majority of students agreed that it is necessary to take parental approval and that they would not participate in research if their parents refused. Furthermore, the majority of male students agreed that if the research requires only questionnaires to be completed, then child’s approval is sufficient whereas measures, such as blood sugar screening required approval from both the parent and child. Females believed it is enough to provide parental consent to participate in research unless information provided is adequate, then child approval is enough. All students stressed the importance of including detailed information; however, parental consent needs to have more detailed information than child assent. Conclusion Parts of the students’ perceptions were congruent, whereas other views were not congruent with proper conduct of pediatric research. Such a situation warrants further research and actions.
A Retrospective Analysis of Softball-Related Head and Facial Injuries Treated in United States Emergency Departments, 2013-2017

Background: Softball is a popular sport played through both competitive and recreational leagues. While head and facial injuries are a known problem occurring from games, little is known about the frequency or mechanisms by which they occur. Purpose: To analyze head/face injury diagnoses and to identify the mechanisms associated with such injuries. Study Design: Descriptive epidemiological study. Methods: A public database was used to query data related to head/facial injuries sustained in softball. Data including age, sex, race/ethnicity, injury diagnosis, affected body parts, disposition, incident location, and narrative descriptions were collected and analyzed. Results: A total of 3324 head and face injuries were documented in the database over the time span of 2013 to 2017, resulting in a nationwide weighted estimate of 121,802 head/face injuries occurring annually. The mean age of the players was 21.5 ± 14.4 years; 72.1% of injured players were female, while 27.9% were male. The most common injury diagnoses were closed head injuries (22.0%), contusions (18.7%), concussions (17.7%), lacerations (17.1%), and fractures (15.1%). The overwhelming majority of injuries involved being struck by a ball (74.3%), followed by colliding with another player (8.3%), colliding with the ground or a fixed object (5.0%), or being struck by a bat (2.8%). For those injuries caused by a struck-by-ball incident, most occurred from defensive play (83.7% were fielders struck by a hit or thrown ball) as opposed to offensive play (12.3% were players hit by a pitch or runners struck by a ball). Although helmet usage was poorly tracked in the database, female players (1.3%) were significantly more likely to have been wearing a helmet at the time of injury than were male players (0.2%) (P = .002). Conclusion: The present study demonstrates that a large number of head and face injuries occur annually within the United States as a result of softball play. A variety of injuries were observed, with the majority involving defensive players being struck by the ball, which highlights the need for more focus on player safety by stronger adherence to protective headgear usage and player health monitoring.
Novel genetic alterations and their impact on target therapy response in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is highly variable by tumor site, histologic type, molecular characteristics, and clinical outcome. During recent years, emerging targeted therapies have been focused on driver genes. HNSCC involves several genetic alterations, such as co-occurrence, multiple feedback loops, and cross-talk communications. These different kinds of genetic alterations interact with each other and mediate targeted therapy response. In the current review, it is emphasized that future treatment strategy in HNSCC will not solely be based on “synthetic lethality” approaches directed against overactivated genes. More importantly, biologic, genetic, and epigenetic alterations of HNSCC will be taken into consideration to guide the therapy. The emerging genetic alterations in HNSCC and its effect on targeted therapy response are discussed in detail. Hopefully, novel combination regimens for the treatment of HNSCC can be developed.
Multiple facets of stream macroinvertebrate alpha diversity are driven by different ecological factors across an extensive altitudinal gradient

Abstract Environmental filtering and spatial structuring are important ecological processes for the generation and maintenance of biodiversity. However, the relative importance of these ecological drivers for multiple facets of diversity is still poorly understood in highland streams. Here, we examined the responses of three facets of stream macroinvertebrate alpha diversity to local environmental, landscape‐climate and spatial factors in a near‐pristine highland riverine ecosystem. Taxonomic (species richness, Shannon diversity, and evenness), functional (functional richness, evenness, divergence, and Rao's Quadratic entropy), and a proxy of phylogenetic alpha diversity (taxonomic distinctness and variation in taxonomic distinctness) were calculated for macroinvertebrate assemblages in 55 stream sites. Then Pearson correlation coefficient was used to explore congruence of indices within and across the three diversity facets. Finally, multiple linear regression models and variation partitioning were employed to identify the relative importance of different ecological drivers of biodiversity. We found most correlations between the diversity indices within the same facet, and between functional richness and species richness were relatively strong. The two phylogenetic diversity indices were quite independent from taxonomic diversity but correlated with functional diversity indices to some extent. Taxonomic and functional diversity were more strongly determined by environmental variables, while phylogenetic diversity was better explained by spatial factors. In terms of environmental variables, habitat‐scale variables describing habitat complexity and water physical features played the primary role in determining the diversity patterns of all three facets, whereas landscape factors appeared less influential. Our findings indicated that both environmental and spatial factors are important ecological drivers for biodiversity patterns of macroinvertebrates in Tibetan streams, although their relative importance was contingent on different facets of diversity. Such findings verified the complementary roles of taxonomic, functional and phylogenetic diversity, and highlighted the importance of comprehensively considering multiple ecological drivers for different facets of diversity in biodiversity assessment.
Loss of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) in the Diabetic Retina: Role of Matrix Metalloproteinases

Purpose To test the hypothesis that high glucose and matrix metalloproteinases (MMPs) contribute to the diabetes-induced loss of platelet endothelial cell adhesion molecule-1 (PECAM-1) in the retinal microvasculature. Methods PECAM-1 and MMP protein, activity, and interactions with PECAM-1 were assessed using western blotting, zymography, immunofluorescence, or coimmunoprecipitation assays. These assays were conducted using primary rat retinal microvascular endothelial cells (RRMECs) grown either in normal glucose (5 mM) or high glucose (25 mM) conditions and using retinas collected from streptozotocin-induced diabetic or control rats. The broad-spectrum MMP inhibitor GM6001 was administered in vivo and in vitro to ascertain the role of MMPs in the hyperglycemia-induced loss of PECAM-1. Results A dramatic decrease in PECAM-1 (western blotting, immunofluorescence) was observed in both the diabetic retina and in hyperglycemic RRMECs. The decrease in PECAM-1 was accompanied by a significant increase in the presence and activity of matrix metalloproteinase-2 (MMP-2) (but not matrix metalloproteinase-9 [MMP-9]) in the diabetic plasma (P < 0.05) and in hyperglycemic RRMECs (P < 0.05). Moreover, RRMEC PECAM-1 significantly decreased when treated with plasma collected from diabetic rats. Several MMP-2 cleavage sites on PECAM-1 were identified using in silico analysis. Moreover, PECAM-1/MMP-2 interactions were confirmed using coimmunoprecipitation. PECAM-1 was significantly decreased in RRMECs treated with MMP-2 (P < 0.05), but became comparable to controls with the MMP inhibitor GM6001 in both the diabetic retina and hyperglycemic RRMECs. Conclusions These results indicate a possible role of MMP-2 in hyperglycemia-induced PECAM-1 loss in retinal endothelial cells.
Tuberculosis: treatment failure, or failure to treat? Lessons from India and South Africa

Tuberculosis (TB) remains an enormous public health concern globally. India and South Africa rank among the top 10 high TB burden countries with the highest absolute burden of TB, and the second highest rate of TB incidence, respectively. Although the primary drivers of TB transmission vary considerably between these two countries, they do indeed share common themes. In 2017, only 64% of the global estimated incident cases of TB were reported, the remaining 36% of ‘missing’ cases were either undiagnosed, untreated or unreported. These ‘missing TB cases’ have generated much hype for the challenges they present in achieving the End TB Strategy. Although India and South Africa have indeed made significant strides in TB control, analysis of the patient cascade of care clearly suggests that these ‘missed’ patients are not really missing—most are actively engaging the health system—the system, however, is failing to appropriately manage them. In short, quality of TB care is suboptimal and must urgently be addressed, merely focusing on coverage of TB services is no longer sufficient. While the world awaits revolutionary vaccines, drugs and diagnostics, programmatic data indicate that much can be done to accelerate the decline of TB. In this perspective, we compare and contrast these two national epidemics, and explore barriers, with a particular focus on the role of health systems in finding the missing millions.