Miracle-dz/UniFAR-FTUs huggingface dataset:
The role of lateral erosion in the evolution of nondendritic drainage networks to dendricity and the persistence of dynamic networks

Significance Most of Earth’s landscapes are dissected by rivers, which are important for providing water, food, and energy resources. From remote imaging, we see that rivers organize themselves into dendritic (tree-like) networks. The shape and organization of river networks determine how and where water and sediment are routed on Earth. To date, models of river network formation, named landscape evolution models, are unable to explain how nondendritic networks evolve into strongly branching systems. Here, we capture this evolution utilizing a model that incorporates how rivers erode in the lateral direction. Dendritic, i.e., tree-like, river networks are ubiquitous features on Earth’s landscapes; however, how and why river networks organize themselves into this form are incompletely understood. A branching pattern has been argued to be an optimal state. Therefore, we should expect models of river evolution to drastically reorganize (suboptimal) purely nondendritic networks into (more optimal) dendritic networks. To date, current physically based models of river basin evolution are incapable of achieving this result without substantial allogenic forcing. Here, we present a model that does indeed accomplish massive drainage reorganization. The key feature in our model is basin-wide lateral incision of bedrock channels. The addition of this submodel allows for channels to laterally migrate, which generates river capture events and drainage migration. An important factor in the model that dictates the rate and frequency of drainage network reorganization is the ratio of two parameters, the lateral and vertical rock erodibility constants. In addition, our model is unique from others because its simulations approach a dynamic steady state. At a dynamic steady state, drainage networks persistently reorganize instead of approaching a stable configuration. Our model results suggest that lateral bedrock incision processes can drive major drainage reorganization and explain apparent long-lived transience in landscapes on Earth.
Optical properties of PECVD deposited DLC films prepared with air addition

Diamond-like carbon (DLC) films with addition of atmospheric air to benzene were prepared by DC discharge plasma enhanced chemical vapor deposition (PECVD). These films were compared with films made from benzene/argon mixture. Some properties of the films including their optical transmission, hydrogen content and Raman spectra were investigated. It was found that such films fabricated with air addition (even at low vacuum) exhibit properties suitable for optical applications.
Stigma towards schizophrenia in Cyprus: Does studying a mental health related programme make a difference?

Background and aims: Students from mental health related programmes may display stigmatising attitudes towards people of schizophrenia, however there are no data available on this population in Cyprus. The purpose of the present study was (a) to examine the levels of contact and stigma towards schizophrenia in Cypriot students of programmes related to mental health and students of other programmes and (b) to examine whether the successful recognition of a person with schizophrenia through a vignette and the estimation of severity levels was related to stigmatising attitudes. Methods: The participants were undergraduate students purposively selected across Cypriot universities (N = 152). A vignette depicting a person with schizophrenia, followed by the OMI to examine stigma and the BAE to examine contact with mental illness were used to collect the data. Results: The results showed that studying a mental health related programme and being a man was associated with more positive views related to social integration. No further stigma dimensions were predicted by the included variables. Similarly, level of contact and being able to identify the mental condition and estimate its severity was not related to stigma. Conclusion: The results emphasise the need to develop educational interventions to tackle stigma across students independently of their study programme and enhance mental health related programmes with opportunities for structured contact with patients with mental illness.
Optimization and Characterization of Brimonidine Tartrate Nanoparticles-loaded In Situ Gel for the Treatment of Glaucoma

ABSTRACT Purposes: The present study aimed to develop brimonidine tartrate loaded poly(lactic-co-glycolic acid) acid vitamin E-tocopheryl polyethylene glycol 1000 succinate (BRT-PLGA-TPGS) nanoparticles in thermosensitivein situ gel to improve mucoadhensive properties and drug holding capacity for the better management of glaucoma. Methods: Nanoparticles was optimized by means of Box-Behnken Design (BBD). The formulations were prepared using various concentration of PLGA (0.1–0.4% w/v) and TPGS (0.3–0.5% w/v). The analytical data of fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) depicted the drug excipients compatibility and confirmed the nanoparticles. Nanoparticles incorporated gel was evaluated for transcorneal permeability, gelation time, gelling temperature, and rheological studies. In addition, in vitro, transcorneal permeation drug release studies and intraocular pressure (IOP) for optimized gel was also performed. Biocompatibility of formulations was investigated in rabbit model. Results: The drug loaded nanoparticles exhibited 115.72 ± 4.18 nm, 0.190 ± 0.02, −11.80 ± 2.24 mV and 74.85 ± 6.54% of mean size, polydispersity index (PDI), zeta potential and entrapment efficiency (% EE), respectively. As compared to marketed eye drop, the sustained and continuous release BRT release from Poloxamer-based in situ gel was 85.31 ± 3.51% till 24 h. The transcorneal steady-state flux (136.32 μg cm−2 h−1) of optimized in situ gel was approximately 3.5 times higher than marketed formulation (38.60 μg cm−2 h−1) flux at 4 h. The optimized formulation produces 3 fold greater influences on percentage reduction of IOP (34.46 ± 4.21%) than the marketed formulation (12.24 ± 2.90%) till 8 h. Conclusion: The incorporation of optimized BRT-PLGA-TPGS nanoparticles into a thermosensitivein situ gel matrix to improve precorneal residence time without causing eye irritation and also serve the sustained release of BRT through cornea for effective management of glaucoma.
Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants

Introduction: This study aimed to investigate whether early treatment with paracetamol reduces the number of infants requiring intervention for patent ductus arteriosus (PDA) and assess the safety profile of paracetamol during the early postnatal period. Methods: This was a double-blind, parallel, randomized, placebo-controlled trial. Preterm infants born at <29-week gestation with a ductus arteriosus >0.9 mm at 6 h of life were randomized to either (1) intravenous paracetamol (15 mg/kg initially and then 7.5 mg/kg every 6 h) or (2) intravenous dextrose for 5 days. The primary outcome was the need for any intervention for PDA up to 5 days. Secondary outcomes included ductal closure at 5 days, ductal size at 48 h, ductal reopening, mortality, and significant morbidities. Results: Of 58 infants randomized, 29 were allocated to the intervention and 29 to the control group. The trial was stopped for benefit at 50% recruitment after reaching the prespecified stopping criteria. Less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs. 17 [59%] infants [p = 0.003]; relative risk reduction 0.35 [95% CI 0.16–0.77; NNT 2.6]). The intervention group had a higher rate of ductal closure (20 [69%] vs. 8 [28%] infants [p = 0.002]) and smaller ductal size (1.0 mm [±0.8] vs. 1.4 mm [±0.9]; p = 0.04). Three deaths occurred (2 in the intervention group), which were not attributed to the intervention. No other adverse events were reported. Discussion/Conclusion: Early paracetamol treatment reduced the number of infants requiring intervention for PDA. Short-term safety data were reassuring, acknowledging the small number of infants involved in the study.
Use of thiopurines in inflammatory bowel disease: an update

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.
Factors Affecting Dilation Interval in Patients With Granulomatosis With Polyangiitis-Associated Subglottic and Glottic Stenosis

Objective Subglottic stenosis (SGS) is a known complication of granulomatosis with polyangiitis (GPA). We investigated the impact of medical and surgical interventions on the surgical dilation interval and characterized patients with glottic involvement. Study Design A retrospective chart review of patients with GPA-associated SGS was performed from 2010 to 2019. Setting Tertiary academic medical center. Methods The impact of medical and surgical interventions on dilation interval was assessed. The prevalence of glottic involvement was assessed, and clinical characteristics and outcomes were compared with patients without glottic involvement. Results A total of 39 patients with GPA-associated SGS were analyzed. Dilation intervals in patients receiving leflunomide (n = 4; median, 484 days; 95% CI, 405-1099) were greater than in those not receiving leflunomide (median, 155 days; 95% CI, 48-305; P = .033). The surgical technique used did not affect dilation interval. Patients with glottic involvement (n = 13) had a greater incidence of dysphonia (13/13 vs 15/26 [58%], P = .007) and a shorter dilation interval with involvement (median, 91 days; interquartile range, 70-277) versus without involvement (median, 377 days; interquartile range, 175-1148; hazard ratio, 3.38; 95% CI, 2.26-5.05; P < .001). Of 13 patients, 8 (62%) did not have glottic involvement on first presentation. Conclusion Although GPA is classically thought to affect the subglottis, it also involves the glottis in a subset of patients. These patients have greater complaints of dysphonia and require more frequent surgery. Systemic therapy may increase dilation intervals. In this preliminary study, patients taking leflunomide demonstrated an improvement, highlighting the need for further study of immunosuppression regimens in the treatment of GPA-associated SGS.
Multidimensional Characterization of Single-Molecule Dynamics in a Plasmonic Nanocavity.

The nanoscale manipulation and characterization of individual molecules is necessary for understanding the intricacies of molecular structure which ultimately governs phenomena such as reaction mechanisms, catalysis, local effective temperatures, surface interactions, and charge transport phenomenon. Here we demonstrate a platform that utilizes Raman enhancement between two nanostructured electrodes in combination with direct charge transport measurements to allow for simultaneous characterization of the electrical, optical, and mechanical properties of a single molecule. This multi-dimensional information yields repeatable, self-consistent, verification of single-molecule resolution, and allows for detailed analysis of structural and configurational changes of the molecule in situ. These experimental results are supported by a machine-learning based statistical analysis of the spectral information and theoretical calculations to provide insight into the correlation between structural changes in a single-molecule and its charge transport properties.
Laterality in Parkinson’s disease: A neuropsychological review

Abstract Laterality of motor symptom onset in Parkinson’s disease is both well-known and under-appreciated. Treatment of disorders that have asymmetric pathological features, such as stroke and epilepsy, demonstrate the importance of incorporating hemispheric lateralization and specialization into therapy and care planning. These practices could theoretically extend to Parkinson’s disease, providing increased diagnostic accuracy and improved treatment outcomes. Additionally, while motor symptoms have generally received the majority of attention, non-motor features (e.g., autonomic dysfunction) also decrease quality of life and are influenced by asymmetrical neurodegeneration. Due to the laterality of cognitive and behavioral processes in the two brain hemispheres, analysis of hemibody side of onset can potentially give insight into expected symptom profile of the patient and allow for increased predictive accuracy of disease progression and outcome, thus opening the door to personalized and improved therapy in treating Parkinson’s disease patients. This review discusses motor and non-motor symptoms (namely autonomic, sensory, emotional, and cognitive dysfunction) of Parkinson’s disease in respect to hemispheric lateralization from a theoretical perspective in hopes of providing a framework for future research and personalized treatment.
Moral foundations in chronotypes: morningness predicts conservative morality

ABSTRACT Recent studies suggest that chronopsychological variables may play an important role in moral behavior. In the present study, we aimed to test whether a person’s chronotype is associated with moral foundations profiles, distinguished in accordance with Haidt’s conceptualization. Morning-oriented people generally tended to rank the importance of the five basic moral foundations – Harm/Care, Fairness/Reciprocity, Ingroup/Loyalty, Authority/Respect, and Purity/Sanctity, highest. Moreover, morningness predicted the affiliation to the “conservative” cluster, as opposed to the “liberal” moral foundations profile. However, after conscientiousness was added to the model, the effect of chronotype was no longer significant. Thus, it seems that the more conservative morality of morning people stems mainly from their elevated conscientiousness. In addition to broadening the current knowledge about the morningness-eveningness’ nomological network, the present results may have some practical implications, e.g., for political marketing strategies.
Radiological and histopathological features of short rib‑polydactyly syndrome type III and identification of two novel DYNC2H1 variants.

Short rib‑polydactyly syndrome type III (SRPS3) is a lethal perinatal skeletal disorder consisting of polydactyly and multi‑system organ abnormalities. To further assess the pathogenicity of two pairs of compound heterozygotes and to search for novel molecular etiology, X‑rays and hematoxylin and eosin staining were conducted in three cases: Two retrospective samples and a newly identified patient with SRPS3. In addition, next‑generation sequencing was used to evaluate a fetus with SRPS3. Typical radiological features of the three cases included a long, narrow thorax with short ribs, shortened long bones, spurs at the metaphysis of the long bones and congenital bowing of the femurs. The present study also observed atypical histopathological changes, together with the absence of proliferation and abundance of retaining cartilage in the primary spongiosum. In addition, two novel compound heterozygous variants were identified in the dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) gene of the fetus: NM_001080463. 1, c. 6591_6593delTGG (chr11:103055738‑103055740); NM_001080463. 1, c.7883T>C (chr11:103070000). The findings of the present study provided further confirmation of the pathogenicity of two compound heterozygous variants in two retrospective samples and identified novel compound heterozygous variants. These findings may improve our knowledge of the histopathological and radiological changes in patients with SRPS3 and the relative effects of DYNC2H1 variants. The findings of the present study may facilitate the clinical and molecular diagnosis of SRPS3.
Venetoclax with azacitidine or decitabine in blast‐phase myeloproliferative neoplasm: A multicenter series of 32 consecutive cases

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast‐phase myeloproliferative neoplasm (MPN‐BP). Pre‐leukemic phenotype included essential thrombocythemia (ET)/post‐ET myelofibrosis (34%), polycythemia vera (PV)/post‐PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty‐nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre‐leukemic PV/post‐PV myelofibrosis phenotype (p < .01), complex karyotype (p < .01) or K/NRAS (p = .03) mutations; seven of eight patients (88%) without vs four of 21 (19%) with complex karyotype or K/NRAS mutation achieved CR/CRi (p < .01); all 11 informative patients with pre‐leukemic PV/post‐PV myelofibrosis phenotype displayed complex karyotype (p < .01). In contrast, neither TP53 (p = .45) nor IDH1/2 (p = .63) mutations affected response. Compared to historical controls treated with HMA alone (n = 26), the CR/CRi rate (44% vs 4%) and median survival (8 vs 5.5 months) were more favorable with Ven + HMA, but without significant difference in overall survival. Importantly, six patients with CR/CRi subsequently received allogeneic hematopoietic stem cell transplant (AHSCT). Note, Ven + HMA produces robust CR/CRi rates in MPN‐BP, especially in the absence of RAS mutations and complex karyotype, thus enabling AHSCT, in some patients.
Plasma Concentrations of Magnesium and Risk of Dementia: A General Population Study of 102 648 Individuals.

BACKGROUND Low and high concentrations of plasma magnesium are associated with increased risk of future all-cause dementia; however, the underlying reasons remain elusive. The magnesium ion is an important electrolyte serving as a cofactor in many enzymatic processes in the human organism. Magnesium affects both neuronal and vascular functions. We investigated the associations of plasma concentrations of magnesium associate with common subtypes of dementia as Alzheimer dementia and non-Alzheimer dementia, and potential pathways by which magnesium may affect risk of dementia. METHODS Plasma concentrations of magnesium were measured in 102 648 individuals from the Copenhagen General Population Study. Cox regression and natural effects mediation analyses evaluated associations with either Alzheimer dementia or non-Alzheimer dementia. RESULTS Multifactorially adjusted hazard ratios for non-Alzheimer dementia were 1.50(95% confidence interval (CI):1.21-1.87) for the lowest and 1.34(1.07-1.69) for the highest vs the fourth quintile (reference) of plasma magnesium concentrations. Diabetes, cumulated smoking, stroke, and systolic blood pressure mediated 10.4%(3.1-22.8%), 6.8%(1.2-14.0%), 1.3%(0.1-3.6%), and 1.0%(0.2-2.6%), respectively, in the lowest quintile, whereas stroke mediated 3.2%(0.4-11.9%) in the highest quintile. No associations were observed for Alzheimer dementia. CONCLUSIONS Low and high plasma magnesium concentrations were associated with high risk of vascular-related non-Alzheimer dementia, with the lowest risk observed at a concentration of 2.07 mg/dL (0.85 mmol/L). No association was observed for Alzheimer dementia. Mediation analysis suggested that diabetes may be in the causal pathway between low plasma magnesium concentrations and high risk of non-Alzheimer dementia, while cumulated smoking, stroke, and systolic blood pressure played minor mediating roles.
Myelofibrosis: challenges for preclinical models and emerging therapeutic targets

ABSTRACT Introduction: Myelofibrosis (MF) is characterized by anemia, splenomegaly, constitutional symptoms and bone marrow fibrosis. MF has no curative treatment to date, except for a small subset of patients that are eligible for allogeneic hematopoietic stem cell transplant. The discovery in recent years of the MF mutational landscape and the role of bone marrow microenvironment in disease pathogenesis has led to further insights into disease biology and consequentially rationally derived therapies. Areas covered: We searched PubMed/Medline/American Society of Hematology (ASH) abstracts until November 2020 using the following terms: myelofibrosis, mouse models, pre-clinical studies and clinical trials. The development of targeted therapies is aimed to modify the history of the disease. Although JAK inhibitors showed encouraging results in terms of spleen and symptoms response, long term remissions and disease modifying ability is lacking. Beyond JAK inhibitors, a range of agents targeting proliferative, metabolic, apoptotic pathways, the microenvironment, epigenetic modification and immunomodulation are in various stages of investigations. We review pre-clinical data, preliminary clinical results of these agents, and finally offer insights on the management of MF patients. Expert opinion: MF patients refractory or with suboptimal response to JAK inhibitors, may be managed by addition of agents with differing mechanisms, such as bromodomain (BET), lysine demethylase 1 (LSD1), MDM2, or Bcl-Xl inhibitors which could prevent emergence of resistance. Immunotherapies as long-acting interferons, and calreticulin directed antibodies or peptide vaccination are eagerly awaited. Historically, therapeutic challenges in MF have arisen due to the fact that rationally derived therapies that are based on murine models have limited impact on fibrosis and underlying disease biology in human studies, the latter illustrates the complex multi-faceted disease pathogenesis of MF. Together, we not only suggest individualized therapy in MF that is guided by genomic signature but also its early implementation potentially in prefibrotic MF.