Miracle-dz/UniFAR-FTUs huggingface dataset:
Challenges of treatment adherence with direct oral anticoagulants in pandemic

Purpose of review Direct oral anticoagulants (DOAC) are crucial for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation. Drug adherence by the patient but also adherence to guidelines by the physician are suboptimal. This review highlights aspects of DOAC treatment during the coronavirus disease 2019 (COVID-19) pandemic and selected challenging scenarios. Recent findings For patients with a newly diagnosed indication for oral anticoagulation, a new interim clinical guidance recommends starting DOAC instead of vitamin K antagonists if DOAC are not contraindicated. The goal is to reduce the potential exposure of patients to severe acute respiratory syndrome coronavirus during the routine coagulation monitoring visits. As COVID-19 can lead to kidney failure, we discuss the challenges of DOAC dosing in kidney failures. Finally, we discuss two common challenges – when to start a DOAC after an ischemic stroke linked to atrial fibrillation, and whether cerebral microbleeds, including their count, are per se a contraindication to DOAC. Summary There are still open challenges regarding DOAC treatment on the patient and physician side, both related and unrelated to the pandemic.
Concentration- and pH-Dependent Oligomerization of the Thrombin-Derived C-Terminal Peptide TCP-25

Peptide oligomerization dynamics affects peptide structure, activity, and pharmacodynamic properties. The thrombin C-terminal peptide, TCP-25 (GKYGFYTHVFRLKKWIQKVIDQFGE), is currently in preclinical development for improved wound healing and infection prevention. It exhibits turbidity when formulated at pH 7.4, particularly at concentrations of 0.3 mM or more. We used biochemical and biophysical approaches to explore whether the peptide self-associates and forms oligomers. The peptide showed a dose-dependent increase in turbidity as well as α-helical structure at pH 7.4, a phenomenon not observed at pH 5.0. By analyzing the intrinsic tryptophan fluorescence, we demonstrate that TCP-25 is more stable at high concentrations (0.3 mM) when exposed to high temperatures or a high concentration of denaturant agents, which is compatible with oligomer formation. The denaturation process was reversible above 100 µM of peptide. Dynamic light scattering demonstrated that TCP-25 oligomerization is sensitive to changes in pH, time, and temperature. Computational modeling with an active 18-mer region of TCP-25 showed that the peptide can form pH-dependent higher-order end-to-end oligomers and micelle-like structures, which is in agreement with the experimental data. Thus, TCP-25 exhibits pH- and temperature-dependent dynamic changes involving helical induction and reversible oligomerization, which explains the observed turbidity of the pharmacologically developed formulation.
Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM

Simple Summary The Wnt/β-catenin cell–cell signaling pathway is one of the most basic and highly conserved pathways for intercellular communications regulating key steps during development, differentiation, and cancer. In colorectal cancer (CRC), in particular, aberrant activation of the Wnt/β-catenin pathway is believed to be responsible for perpetuating the disease from the very early stages of cancer development. A large number of downstream target genes of β-catenin-T-cell factor (TCF), including oncogenes, were detected as regulators of CRC development. In this review, we will summarize studies mainly on one such target gene, the L1CAM (L1) cell adhesion receptor, that is selectively induced in invasive and metastatic CRC cells and in regenerating cells of the intestine following injury. We will describe studies on the genes activated when the levels of L1 are increased in CRC cells and their effectiveness in propagating CRC development. These downstream targets of L1-signaling can serve in diagnosis and may provide additional targets for CRC therapy. Abstract Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC.
Distal renal tubular acidosis developments in its diagnosis and pathophysiology

This thesis describes two groups of experiments, both relating to the condition of distal renal tubular acidosis (dRTA). In the first, an alternative diagnostic test of dRTA to the ‘gold standard’ short ammonium chloride (NH4Cl) test was assessed. This was achieved by the simultaneous oral administration of the diuretic furosemide and the mineralocorticoid fludrocortisone to increase distal sodium delivery and a-intercalated cell proton secretion. I evaluated 11 control subjects and 10 patients with known dRTA by giving oral NH4Cl or furosemide/fludrocortisone in random order on separate days. 3 subjects were unable to complete the study due to vomiting after the NH4Cl, however there were no adverse effects with furosemide/fludrocortisone administration. The urine pH decreased to less than 5.3 in the controls with both tests, whereas no patients were able to lower their urine pH below 5.3 with either test. The simultaneous administration of furosemide/fludrocortisone proved to be an easy, effective and well-tolerated alternative to the standard NH4Cl test for the diagnosis of dRTA. The second group were laboratory-based molecular physiology experiments. Anion exchanger 1 (AE1) mediates electroneutral anion exchange across cell membranes. It is the most abundant protein in the red cell membrane, but is also found in the basolateral membrane of renal a-intercalated cells, where it is required for urinary acidification. Point mutations have been described that convert the red cell AE1 into a cation conductance. AE1 mutations can also cause hereditary dRTA. I investigated the properties of four dRTA associated AE1 mutations (R586H, G609R, S613F and G701D) by heterologous expression in Xenopus Laevis oocytes. These mutants proved to be functional anion exchangers, unlike the red cell mutants, but also demonstrated a cation ‘leak’. I found a very large leak property in the G701D mutant, which is prevalent in SE Asia. I hypothesised that this property might confer a survival advantage. I characterised three other AR dRTA-associated AE1 mutants found in SE Asia, S773P, \Delta850 and A858D via similar transport experiments in AE1-expressing Xenopus oocytes. These three SE Asian mutants also had cation leaks of similar magnitude to that seen in G701D, a property that distinguishes them as a discrete group. The clustering of these cation-leaky AE1 mutations to malarious areas of SE Asia suggests that they may confer malaria resistance.
Restoration of an Upper Anterior Tooth in an Adolescent with Autism Spectrum Disorder—A Student Case Report

Background: Patients with autism spectrum disorder (ASD) or other mental or physical limitations experience an imbalance in the frequency of dental treatment as compared with the general patient population, in part, due to inadequate pre-graduate training of future dentists. Case presentation: This case report describes a successful anterior tooth restoration, in awake state, in a 15-year-old boy with early childhood autism. The procedure was carried out independently by students of dentistry within the scope of their integrated clinical training semesters. Desensitization sessions were used as a preparatory measure and elements of behavioral facilitation (tell-show-feel-feel-do) were applied during the treatment. Conclusions: To avoid discrimination of this group of patients in the provision and quality of dental care, a structured approach to the transfer of theoretical and practical knowledge in the field of special care dentistry is indispensable. To this end, treatment strategies for special care patients should be taught to pre-graduate dental students as a fundamental part of their university curriculum.
Chitosan and cottonseed processing method association on carcass traits and meat quality of feedlot lambs

The objective of this study was to evaluate the effects of the association of cottonseed processing method with chitosan on carcass traits and meat quality of lambs finished in feedlot. Eighty lambs with an average body weight of 20.6 kg, with 04 months of age, were distributed in a completely randomized design, in a 2 x 2 factorial arrangement. The factors were represented by two cottonseed processing method (whole or ground) and two levels of chitosan (0 and 136 mg/kg BW). The association of cottonseed processing method with chitosan in the lamb diet did not affect (P>0.05) carcasses traits. The pH, color, cooking losses, shear force, and proximate composition of meat were also not affected (P>0.05) by the processing method of cottonseed or its association with chitosan in the lamb diets. There was an increase in palmitoleic (c9-C16:1; P = 0.01) and conjugated linoleic (P = 0.02) fatty acids when ground cottonseed was associated with chitosan. Ground cottonseed associated with chitosan increases the concentration of unsaturated fatty acids in the meat of feedlot lambs.
Mother–child communication about possible cancer recurrence during childhood cancer survivorship

Providing opportunities to communicate about possible cancer recurrence may be adaptive for youth in remission, yet parents may experience difficulty guiding discussions related to fears of cancer recurrence (FCR). This study aimed to characterize mother–child discussions about potential cancer recurrence during post‐treatment survivorship and to determine predictors of maternal communication.
Family Engagement for Hospitalized COVID-19 Patients: Policy With Unintended Consequences.

D ear Editor: A key factor in the transmissibility of coronavirus disease-2019 (COVID-19) is the high level of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) shedding in the upper respiratory tract. In order to protect vulnerable patients and visitors, it has been necessary for hospitals to curtail family visits. While those policies limiting hospital visitors are ethically justified, families feel helpless and anguished as loved ones suffer alone. For many older adults, the signature of the coronavirus is not the fear of dying but the fear of dying alone and becoming a statistic rather than a human being facing the end-of-life. Loneliness and social isolation are risk factors for all-cause mortality. Loneliness and psychological distress are increasing during the COVID-19 pandemic. COVID-19 patients need family members to advocate, communicate, and make decisions on their behalf. Active participation of patients in their care and decision-making is associated with improved outcomes, and the importance of family engagement in patient outcomes is highly underestimated. Research demonstrates that family visits shorten length of stay, reduce delirium, and reduce medication errors. The lack of family visits is not only dehumanizing for the patient, but also affects family members who confront the realization that their loved one suffers alone. Patients and family both describe that “just being there” is the most important part of a visit. The time is often spent in silence but reinforces family bonds, comforts patients at the end of their lives, and allows families to say goodbye. It also provides the family with a sense of purpose and meaning. Family engagement is also crucial when vulnerable patients are exposed to the hazards of hospitalization. Patient and family engagement is essential for optimal health outcomes and is a key component of providing holistic, patientcentered care. Family engagement is a process driven by the much-needed partnership among physicians, patients, and family that includes active participation of family in decision-making and honoring patient preferences to optimize patient-centered care and the quality of care. To remedy the situation, clinicians have improvised by connecting patients with family by telephone or
Effect of a dual trigger on oocyte maturation in young women with decreased ovarian reserve for the purpose of elective oocyte cryopreservation

Objective The aim of this study was to determine whether co-administration of a gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (hCG) for final oocyte maturation improved mature oocyte cryopreservation outcomes in young women with decreased ovarian reserve (DOR) compared with hCG alone. Methods Between January 2016 and August 2019, controlled ovarian stimulation (COS) cycles in women (aged ≤35 years, anti-Müllerian hormone [AMH] <1.2 ng/mL) who underwent elective oocyte cryopreservation for fertility preservation were retrospectively analyzed. Results A total of 76 COS cycles were triggered with a GnRH agonist and hCG (the dual group) or hCG alone (the hCG group). The mean age and serum AMH levels were comparable between the two groups. The duration of stimulation, total dose of follicle-stimulating hormone used, and total number of oocytes retrieved were similar. However, the number of mature oocytes retrieved and the oocyte maturation rate were significantly higher in the dual group than in the hCG group (p=0.010 and p<0.001). After controlling for confounders, the dual-trigger method remained a significant factor related to the number of mature oocytes retrieved (p=0.016). Conclusion We showed improved mature oocyte collection and maturation rate with the dual triggering of oocyte maturation in young women with DOR. A dual trigger appears to be more beneficial than hCG alone in terms of mature oocyte cryopreservation for young women with DOR.
Mini-Review on Lipofuscin and Aging: Focusing on The Molecular Interface, The Biological Recycling Mechanism, Oxidative Stress, and The Gut-Brain Axis Functionality

Intra-lysosomal accumulation of the autofluorescent “residue” known as lipofuscin, which is found within postmitotic cells, remains controversial. Although it was considered a harmless hallmark of aging, its presence is detrimental as it continually accumulates. The latest evidence highlighted that lipofuscin strongly correlates with the excessive production of reactive oxygen species; however, despite this, lipofuscin cannot be removed by the biological recycling mechanisms. The antagonistic effects exerted at the DNA level culminate in a dysregulation of the cell cycle, by inducing a loss of the entire internal environment and abnormal gene(s) expression. Additionally, it appears that a crucial role in the production of reactive oxygen species can be attributed to gut microbiota, due to their ability to shape our behavior and neurodevelopment through their maintenance of the central nervous system.
Microscopic Deformation Modes and Impact of Network Anisotropy on the Mechanical and Electrical Performance of Five-fold Twinned Silver Nanowire Electrodes

Silver nanowire (AgNW) networks show excellent optical, electrical, and mechanical properties, which make them ideal candidates for transparent electrodes in flexible and stretchable devices. Various coating strategies and testing setups have been developed to further improve their stretchability and to evaluate their performance. Still, a comprehensive microscopic understanding of the relationship between mechanical and electrical failure is missing. In this work, the fundamental deformation modes of five-fold twinned AgNWs in anisotropic networks are studied by large-scale SEM straining tests that are directly correlated with corresponding changes in the resistance. A pronounced effect of the network anisotropy on the electrical performance is observed, which manifests itself in a one order of magnitude lower increase in resistance for networks strained perpendicular to the preferred wire orientation. Using a scale-bridging microscopy approach spanning from NW networks to single NWs to atomic-scale defects, we were able to identify three fundamental deformation modes of NWs, which together can explain this behavior: (i) correlated tensile fracture of NWs, (ii) kink formation due to compression of NWs in transverse direction, and (iii) NW bending caused by the interaction of NWs in the strained network. A key observation is the extreme deformability of AgNWs in compression. Considering HRTEM and MD simulations, this behavior can be attributed to specific defect processes in the five-fold twinned NW structure leading to the formation of NW kinks with grain boundaries combined with V-shaped surface reconstructions, both counteracting NW fracture. The detailed insights from this microscopic study can further improve fabrication and design strategies for transparent NW network electrodes.
A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I

Significance We present a comprehensive structural study, which shows the human GCH1 and GCH1−GFRP complexes in all states (apo, ligand bound, partially and fully inhibited). We observed local rearrangements in the allosteric pocket upon BH4 binding, which result in drastic changes in the quaternary structure of the enzyme leading to a more compact, tense form in the inhibited protein. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by STD-NMR and site-directed mutagenesis. We propose a dissociation rate-controlled mechanism of allosteric, noncompetitive inhibition, which could stimulate further research toward the development of GCH1 inhibitors to treat neuropathic and inflammatory pain disorders. Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP to dihydroneopterin triphosphate (H2NTP), the initiating step in the biosynthesis of tetrahydrobiopterin (BH4). Besides other roles, BH4 functions as cofactor in neurotransmitter biosynthesis. The BH4 biosynthetic pathway and GCH1 have been identified as promising targets to treat pain disorders in patients. The function of mammalian GCH1s is regulated by a metabolic sensing mechanism involving a regulator protein, GCH1 feedback regulatory protein (GFRP). GFRP binds to GCH1 to form inhibited or activated complexes dependent on availability of cofactor ligands, BH4 and phenylalanine, respectively. We determined high-resolution structures of human GCH1−GFRP complexes by cryoelectron microscopy (cryo-EM). Cryo-EM revealed structural flexibility of specific and relevant surface lining loops, which previously was not detected by X-ray crystallography due to crystal packing effects. Further, we studied allosteric regulation of isolated GCH1 by X-ray crystallography. Using the combined structural information, we are able to obtain a comprehensive picture of the mechanism of allosteric regulation. Local rearrangements in the allosteric pocket upon BH4 binding result in drastic changes in the quaternary structure of the enzyme, leading to a more compact, tense form of the inhibited protein, and translocate to the active site, leading to an open, more flexible structure of its surroundings. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by saturation transfer difference NMR (STD-NMR) and site-directed mutagenesis. We propose a dissociation rate controlled mechanism of allosteric, noncompetitive inhibition.
In Vitro Study of Calcium Microsecond Electroporation of Prostate Adenocarcinoma Cells

Electroporation, applied as a non-thermal ablation method has proven to be effective for focal prostate treatment. In this study, we performed pre-clinical research, which aims at exploring the specific impact of this so-called calcium electroporation on prostate cancer. First, in an in-vitro study of DU 145 cell lines, microsecond electroporation (μsEP) parameters were optimized. We determined hence the voltage that provides both high permeability and viability of these prostate cancer cells. Subsequently, we compared the effect of μsEP on cells’ viability with and without calcium administration. For high-voltage pulses, the cell death’s mechanism was evaluated using flow-cytometry and confocal laser microscopy. For lower-voltage pulses, the influence of electroporation on prostate cancer cell mobility was studied using scratch assays. Additionally, we applied calcium-binding fluorescence dye (Fluo-8) to observe the calcium uptake dynamic with the fluorescence microscopy. Moreover, the molecular dynamics simulation visualized the process of calcium ions inflow during μsEP. According to our results calcium electroporation significantly decreases the cells viability by promoting apoptosis. Furthermore, our data shows that the application of pulsed electric fields disassembles the actin cytoskeleton and influences the prostate cancer cells’ mobility.
Leukopenia and Neutropenia at Birth and Sepsis in Preterm Neonates of <32 Weeks' Gestation

Abstract Objective This study aimed to evaluate associations between leukopenia or neutropenia at birth and risk of sepsis in very preterm neonates. Study Design We conducted a retrospective unmatched cohort study of neonates of <32 weeks' gestation. Those with leukopenia (≤5,000/µL) were compared with a unmatched cohort without leukopenia. Comparisons were also made for patients with neutropenia and without neutropenia. The outcomes were early-onset sepsis, late-onset sepsis, and mortality. Results We identified 271 neonates with leukopenia at birth and 271 without. Multivariable analyses identified higher odds of early-onset sepsis (adjusted odds ratio [AOR] = 4.85, 95% confidence interval [CI]: 1.29–18.20) in leukopenic neonates. Of neonates with leukopenia, 183 had both leukopenia and neutropenia and were associated with the highest odds of early-onset sepsis (AOR = 6.94, 95% CI: 1.77–27.15) compared with those with neither or with either alone. Conclusion Leukopenia, neutropenia, and both leukopenia and neutropenia at birth were associated with early-onset sepsis in very preterm neonates. Key Points Leukopenia and neutropenia combined at birth was associated with highest odds of early-onset sepsis. Leukopenia or neutropenia were associated with sepsis in preterm neonates. The risk of infection persist throughout neonatal stay in NICU.