Miracle-dz/UniFAR-FTUs huggingface dataset:
First-Line EGFR-TKIs Treatment in Stage I Non-Small-Cell Lung Cancer Patients Harboring EGFR Gene Mutations with Postoperative Intrapulmonary Recurrence

Background The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is an effective treatment for advanced lung cancer harboring EGFR gene mutations, and has improved progression-free survival in several clinical trials. Methods We investigated 30 stage I non-small-cell lung cancer patients harboring EGFR gene mutations with postoperative intrapulmonary recurrence. Progression-free survival and response rate were analyzed. Results Partial response was achieved in 23 patients and stable disease was found in 7 patients. The objective response rate was 76.7% and disease control rate was 100%. The median progression-free survival (PFS) time was 24.5 months. The median PFS in patients with only intrapulmonary recurrence was significantly superior to patients with both intrapulmonary recurrence and metastasis (32.0 months vs 14.0 months, P = 0.003). The median PFS observed in patients who underwent icotinib treatment was significantly longer than in patients who underwent gefitinib treatment (30.5 months vs 12.0 months, p = 0.005). There were no statistical differences in median PFS between patients with tumors harboring exon 21 mutation and exon 19 deletion, age <65 and ≥65, male and female, smoker and non-smoker. Conclusion Our result reveals that first-line EGFR-TKIs treatment for stage I non-small-cell lung cancer patients harboring EGFR gene mutations with postoperative intrapulmonary recurrence is effective and could be a useful option in practical setting.
The Complexity of Living with Diabetes and Urinary Incontinence for Older Adults with Multiple Chronic Conditions Receiving Home Care Services: An Interpretive Description Study

Over 40% of older adults with diabetes receiving home-care services experience urinary incontinence. However, experiential knowledge is lacking on how these older adults live with diabetes and incontinence. Interpretive description methodology was used to explore the experiences of 18 older adults with diabetes and urinary incontinence receiving home-care services in Ontario, Canada. Five themes emerged from the findings: (a) enduring urinary incontinence: “patch it in pads”; (b) struggling to manage diabetes, incontinence, and multiple chronic conditions: “a balancing act”; (c) covering the costs of care: “I can’t afford it”; (d) counting on a caregiver: “he does everything”; and (e) home-care services not meeting my needs: “it’s not individual. ” These findings suggest that living with urinary incontinence and diabetes is a complex and challenging experience. This evidence could inform the provision of comprehensive home care to support self-care for this population.
The link between fear about COVID-19 and insomnia: mediated by economic concerns and psychological distress, moderated by mindfulness

Abstract This paper adds to extant research by examining the relationship between employees’ fear of coronavirus disease 2019 and their suffering from insomnia. It specifically proposes mediating roles of employees' economic concerns and psychological distress and a moderating role of mindfulness in this process. The research hypotheses are tested with survey data collected through two studies among Pakistani-based professionals: 316 in study 1 and 421 in study 2. The results pinpoint a salient risk for employees who experience fear during a pandemic crisis, in that the associated economic and psychological hardships make the situation worse by undermining their sleep quality, which eventually could diminish the quality of their lives even further. It also reveals how organizations can mitigate this risk if employees can leverage pertinent personal resources, such as mindfulness.
Delayed Intravitreal Anti-VEGF Therapy for Patients During the COVID-19 Lockdown: An Ethical Endeavor

Purpose To assess the impact of Jordanian’s Corona Virus Disease (COVID-19) lockdown on visual acuity and macular thickness in patients with macular edema receiving intravitreal injections, and to assess the ethical endeavor of lockdown among serious sight threatening conditions. Patients and Methods This retrospective observational study included patients planned for intravitreal injections who did not complete the planned course before the lockdown (ie, before 20th of March 2020). Data included demographics, indication for the intravitreal injection, corrected distance visual acuity (CDVA), and central macular thickness on Optical Coherence Tomography (OCT) before and after the lockdown. Results One-hundred and sixty-six eyes of 125 patients were studied, 68 (54.4%) patients were males, and the mean (± standard deviation, SD) age was 64.79 (±9.41) years. Mean (±SD) duration of delay in the planned injection was 60.97 (±24.35) days. The change in visual acuity was statistically significant for patients with diabetic macular edema (p= 0.045 improvement), patients with central retinal vein thrombosis (CRVO) (p= 0.05 deterioration), and patients with age-related macular degeneration (AMD) (p= 0.005 deterioration). Of interest, delay of more than 2 months and the previous need for 3 or more injections were significant poor prognostic factors for visual outcome for patients with diabetic macular edema (p=0.027 and 0.045). Conclusion The impact of delay in the scheduled intravitreal injections resulted in variable outcomes depending on the indication. Triaging the urgency of patients should be based on the indication to support the equity principle of bioethics, where those in need are prioritized against others, depending on potential adverse outcome.
X-ray Diffraction of Subfractions of Petroleum Asphaltenes

New data are reported from powder X-ray diffraction (XRD) investigations of fractions obtained from separation of the bulk heptane−asphaltenes into subfractions using toluene−heptane mixtures. The latter indicate that when removing large parts of the heptane−asphaltene fraction by extraction with solvent mixtures having an increased toluene content, the stacking distance (or intensity of the 002 peak) or other parameters derived are not particularly changed. Hence, this infers that no increase in molecular interaction takes place by removal of more soluble species. This is confirmed as the stack diameter is insensitive to subfractionation, as observed from the 100 band. The stacking of asphaltenes has previously been inferred from powder X-ray diffraction of solid asphaltenes. The XRD patterns usually reveal three different broad peaks where the stacking of the asphaltene constituents is determined from the 002 peak that sometimes occurs as a shoulder (rather than as a distinct peak) on a peak related to .
Kerr electro-optic field measurement and charge dynamics in transformer-oil/solid composite insulation systems

We measured the electric field in transformer oil/solid composite insulation system under dc voltage application using a Kerr electro-optic measurement system. When a pressboard was inserted at the center between two parallel-plane electrodes, the electric field at the mid-point between the pressboard and the cathode decreased with time. On the other hand, the electric field at the mid-point between the pressboard and the anode increased initially with time, reached a maximum value and then fell down. We measured also the electric field before and after polarity reversal of the dc voltage. The results revealed that the electric field after polarity reversal reached a magnitude 2.7/spl times/ as much as the average dc applied field. We interpreted the above results on the time transition of the electric field in terms of a charge dynamic model, considering the difference in charge accumulation speed on the pressboard between positive and negative charges. This model was verified to be applicable to the time transition of the electric field in oil/solid composite system and BTA added oil/solid composite system as well.
Single Crystals of V-Amylose Inclusion Complexes

Lamellar single crystals of V-amylose have been prepared from dilute solutions in the presence of various complexing agents (isopropanol, thymol, linalool, terpineol, α-naphthol and quinoline). They were characterized by means of electron microscopy imaging and electron crystallography. Crystals of the V isopropanol -type were more frequently obtained even with complexing molecules with different sizes and chemical structures. α-naphthol and quinoline formed crystals involving 8-fold amylose helices. Flower-like pseudo-spherocrystals of lamellar units were observed when the crystallization was carried out at higher amylose concentration.
Physical modelling of multivalent interactions in the nuclear pore complex

In the nuclear pore complex (NPC), intrinsically disordered proteins (FG Nups) along with their interactions with more globular proteins called nuclear transport receptors (NTRs) are vital to the selectivity of transport into and out of the cell nucleus. While such interactions can be modelled at different levels of coarse graining, in-vitro experimental data have been quantitatively described by minimal models that describe FG Nups as cohesive homogeneous polymers and NTRs as uniformly cohesive spheres, where the heterogeneous effects have been smeared out. By definition, these minimal models do not account for the explicit heterogeneities in FG Nup sequences, essentially a string of cohesive and non-cohesive polymer units, and at the NTR surface. Here, we develop computational and analytical models that do take into account such heterogeneity at a level of minimal complexity, and compare them to experimental data on single-molecule interactions between FG Nups and NTRs. Overall, we find that the heterogeneous nature of FG Nups and NTRs plays a minor role for their equilibrium binding properties, but is of significance when it comes to (un)binding kinetics. Using our models, we predict how binding equilibria and kinetics depend on the distribution of cohesive blocks in the FG Nup sequences and of the binding pockets at the NTR surface, with multivalency playing a key role. Finally, we observe that single-molecule binding kinetics has a rather minor influence on the diffusion of NTRs in polymer melts consisting of FG-Nup-like sequences.
The Promises and Limitations of N-Acetylcysteine as a Potentiator of First-Line and Second-Line Tuberculosis Drugs

N-Acetylcysteine (NAC) is most commonly used for the treatment of acetaminophen overdose and acetaminophen-induced liver injury. In patients infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), NAC is given to treat hepatotoxicity induced by TB drugs. ABSTRACT N-Acetylcysteine (NAC) is most commonly used for the treatment of acetaminophen overdose and acetaminophen-induced liver injury. In patients infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), NAC is given to treat hepatotoxicity induced by TB drugs. We had previously shown that cysteine, a derivative of NAC, potentiated the activity of isoniazid, a first-line TB drug, by preventing the emergence of INH resistance and persistence in M. tuberculosis in vitro. Here, we demonstrate that, in vitro, NAC has the same boosting activity with various combinations of first- and second-line TB drugs against drug-susceptible and multidrug-resistant M. tuberculosis strains. Similar to cysteine, NAC increased M. tuberculosis respiration. However, in M. tuberculosis-infected mice, the addition of NAC did not augment the activity of first- or second-line TB drugs. A comparison of the activity of NAC combined with TB drugs in murine and human macrophage cell lines revealed that studies in mice might not be recapitulated during host infection in vivo.
Effect of Itraconazole-Ezetimibe-Miltefosine Ternary Therapy in Murine Visceral Leishmaniasis

Drug combination therapy is an interesting approach to increase the success of drug repurposing for neglected diseases. Thus, the objective of this work was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe, and miltefosine for the treatment of visceral leishmaniasis. ABSTRACT Drug combination therapy is an interesting approach to increase the success of drug repurposing for neglected diseases. Thus, the objective of this work was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe, and miltefosine for the treatment of visceral leishmaniasis. Intracellular Leishmania infantum amastigotes were incubated with the drugs alone or in combination for 72 h. For in vivo experiments, we tested long-course (21 days, once per day) and short-course (5 days, twice per day) treatments for the binary combination of itraconazole and ezetimibe. For the ternary therapy including miltefosine, we adopted the short-course treatment and varied the vehicle. None of the combinations were toxic to macrophages. The binary combination of itraconazole plus ezetimibe and the ternary combination of itraconazole, ezetimibe, and miltefosine had synergistic effects in intracellular amastigotes, for some of the proportions evaluated. Although the in vivo long-course therapy had been more effective than the short-course protocol, it showed hepatic toxicity signs. Ezetimibe has been proven to be able to reduce the parasite burden alone or in combination. Both suspensions of the ternary combination were active, but when the drugs were suspended in the commercial Ora-Plus formulation instead of purified water, the parasite burden was reduced by 98% in the liver and spleen. Altogether, the results demonstrate for the first time the activity of ezetimibe in a viscerotropic species of Leishmania and indicate that ternary treatment composed of miltefosine, itraconazole, and ezetimibe at low doses is a promising therapeutic alternative for the treatment of visceral leishmaniasis.
Effectiveness of non-pharmaceutical interventions to contain COVID-19: a case study of the 2020 spring pandemic wave in New York City

As COVID-19 continues to pose significant public health threats, quantifying the effectiveness of different public health interventions is crucial to inform intervention strategies. Using detailed epidemiological and mobility data available for New York City and comprehensive modelling accounting for under-detection, we reconstruct the COVID-19 transmission dynamics therein during the 2020 spring pandemic wave and estimate the effectiveness of two major non-pharmaceutical interventions—lockdown-like measures that reduce contact rates and universal masking. Lockdown-like measures were associated with greater than 50% transmission reduction for all age groups. Universal masking was associated with an approximately 7% transmission reduction overall and up to 20% reduction for 65+ year olds during the first month of implementation. This result suggests that face covering can substantially reduce transmission when lockdown-like measures are lifted but by itself may be insufficient to control SARS-CoV-2 transmission. Overall, findings support the need to implement multiple interventions simultaneously to effectively mitigate COVID-19 spread before the majority of population can be protected through mass-vaccination.
Lipid profiling of mouse intestinal organoids for studying APC mutations

Abstract Inactivating mutations including both germline and somatic mutations in the adenomatous polyposis coli (APC) gene drives most familial and sporadic colorectal cancers. Understanding the metabolic implications of this mutation will aid to establish its wider impact on cellular behaviour and potentially inform clinical decisions. However, to date, alterations in lipid metabolism induced by APC mutations remain unclear. Intestinal organoids have gained widespread popularity in studying colorectal cancer and chemotherapies, because their 3D structure more accurately mimics an in vivo environment. Here, we aimed to investigate intra-cellular lipid disturbances induced by APC gene mutations in intestinal organoids using a reversed-phase ultra-high-performance liquid chromatography mass spectrometry (RP-UHPLC-MS)-based lipid profiling method. Lipids of the organoids grown from either wild-type (WT) or mice with APC mutations (Lgr5–EGFP-IRES-CreERT2 Apcfl/fl) were extracted and analysed using RP-UHPLC-MS. Levels of phospholipids (e.g. PC(16:0/16:0), PC(18:1/20:0), PC(38:0), PC(18:1/22:1)), ceramides (e.g. Cer(d18:0/22:0), Cer(d42:0), Cer(d18:1/24:1)) and hexosylceramides (e.g. HexCer(d18:1/16:0), HexCer(d18:1/22:0)) were higher in Apcfl/fl organoids, whereas levels of sphingomyelins (e.g. SM(d18:1/14:0), SM(d18:1/16:0)) were lower compared with WT. These observations indicate that cellular metabolism of sphingomyelin was up-regulated, resulting in the cellular accumulation of ceramides and production of HexCer due to the absence of Apcfl/fl in the organoids. Our observations demonstrated lipid profiling of organoids and provided an enhanced insight into the effects of the APC mutations on lipid metabolism, making for a valuable addition to screening options of the organoid lipidome.
Letter to the editor in response to the letter from the EPIPARK Study Group regarding the publication ʻProgression of fatigue in Parkinson's disease ‐ a 9‐year follow‐upʼ (Eur J Neurol 2021. doi:10.1111/ene.14520)

Dear Editor, We thank you for the opportunity to comment the letter by the EPIPARK Study Group. The study design and the multidisciplinary approach is very interesting. In the Park West study, we have followed an incident cohort of patients with Parkinson's disease (PD) diagnosed according to the UK Brain Bank criteria. The inclusion process has been thoroughly described. [1] The control group is not subdivided by parameters like general health, and the group was mainly recruited amongst spouses, relatives and friends. Patients and controls were considered comparable regarding demographic variables and comorbidity. We thus find it likely that other somatic comorbidities than PD would evolve similarly in the two groups. Our baseline study shows that fatigue is present in a large proportion of patients (55%) at the time of diagnosis, which is clearly more frequent than in the control population (20%, RR = 2.9). [2] The EPIPARK collaborators have explored the specificity of nonmotor symptoms (NMS) for PD. They found a frequency of fatigue at baseline of about 20% for healthy controls, and 31% for the group with PD and parkinsonism. The authors have analyzed comorbidities previously associated with fatigue, as well as selected medications. They conclude that fatigue is not specific for PD, but may present at similar frequencies in other diseases, and should probably not be an independent premotor marker. We support this conclusion as other NMS have shown more promise. [3] In our 9year study, we have examined fatigue as a continuous rather than a dichotomous parameter for the patient group, using a mixed linear model. Direct comparison with EPIPARK is thus problematic. As the median comorbidity index was 0, it was not subdivided. The medications included in the model for predicting the evolution of fatigue did not yield significant contributions (Table 3, 9year study[4]). The statistically significant factors were the comorbidity index, female gender, followup time, depressive symptoms and dependency in activities of daily living. Our study is a contribution to understanding the evolution of fatigue during the first 9 years and the association to other NMS. This could yield possibilities for further studies exploring future treatments for this symptom, which is closely related to reduced quality of life. AUTHOR CONTRIBUTIONS Solgunn Odinsen Ongre: Writingoriginal draft (lead). Ingvild Dalen: Writingreview & editing (supporting). OleBjorn Tysnes: Writingreview & editing (supporting). Guido Alves: Writingreview & editing (supporting). Karen Herlofson: Writingreview & editing (supporting).
Comparative analysis of extracellular proteomes reveals putative effectors of the boxwood blight pathogens, Calonectria henricotiae and C. pseudonaviculata

Abstract Calonectria henricotiae (Che) and C. pseudonaviculata (Cps) are destructive fungal pathogens causing boxwood blight, a persistent threat to horticultural production, landscape industries, established gardens, and native ecosystems. Although extracellular proteins including effectors produced by fungal pathogens are known to play a fundamental role in pathogenesis, the composition of Che and Cps extracellular proteins has not been examined. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics prediction tools, 630 extracellular proteins and 251 cell membrane proteins of Che and Cps were identified in the classical secretion pathway in the present study. In the non-classical secretion pathway, 79 extracellular proteins were identified. The cohort of proteins belonged to 364 OrthoMCL clusters, with the majority (62%) present in both species, and a subset unique to Che (19%) and Cps (20%). These extracellular proteins were predicted to play important roles in cell structure, regulation, metabolism, and pathogenesis. A total of 124 proteins were identified as putative effectors. Many of them are orthologs of proteins with documented roles in suppressing host defense and facilitating infection processes in other pathosystems, such as SnodProt1-like proteins in the OrthoMCL cluster OG5_152723 and PhiA-like cell wall proteins in the cluster OG5_155754. This exploratory study provides a repository of secreted proteins and putative effectors that can provide insights into the virulence mechanisms of the boxwood blight pathogens.
Longitudinal Symptom Burden Trajectories in a Population-Based Cohort of Women with Metastatic Breast Cancer: A Group-Based Trajectory Modeling Analysis

Understanding the symptom burden trajectory for metastatic breast cancer patients can enable the provision of appropriate supportive care for symptom management. The aim of this study was to describe the longitudinal trajectories of symptom burden for metastatic breast cancer patients at the population-level. A cohort of 995 metastatic breast cancer patients with 16,146 Edmonton Symptom Assessment System (ESAS) assessments was constructed using linked population-level health administrative databases. The patient-reported ESAS total symptom distress score (TSDS) was studied over time using group-based trajectory modeling, and covariate influences on trajectory patterns were examined. Cohort patients experienced symptom burden that could be divided into six distinct trajectories. Patients experiencing a higher baseline TSDS were likely to be classified into trajectory groups with high, uncontrolled TSDS within the study follow-up period (χ2 (1, N = 995) = 136.25, p < 0.001). Compared to patients classified in the group trajectory with the highest relative TSDS (Group 6), patients classified in the lowest relative TSDS trajectory group (Group 1) were more likely to not have comorbidities (97.34% (for Groups 1–3) vs. 91.82% (for Group 6); p < 0.05), more likely to receive chemotherapy (86.52% vs. 80.50%; p < 0.05), and less likely to receive palliative care (52.81% vs. 79.25%; p < 0.0001). Receiving radiotherapy was a significant predictor of how symptom burden was experienced in all identified groups. Overall, metastatic breast cancer patients follow heterogeneous symptom burden trajectories over time, with some experiencing a higher, uncontrolled symptom burden. Understanding trajectories can assist in establishing risk-stratified care pathways for patients.