Miracle-dz/UniFAR-FTUs huggingface dataset:
Health and Wellbeing Benefits from Nature Experiences in Tropical Settings Depend on Strength of Connection to Nature

A growing number of policies and programmes in cities aim to increase the time people spend in nature for the health and wellbeing benefits delivered by such interactions. Yet, there is little research investigating the extent to which, and for whom, nature experiences deliver such benefits outside Europe, North America, and Australia. Here, we assessed the relationships between nature dose (frequency, duration, and intensity) and three mental wellbeing (depression, stress, and anxiety) and two physical health (high blood pressure, diabetes) outcomes in Singapore, an intensely urbanised tropical city. Our analyses accounted for individual factors, including socio-economic status, nature connection (nature relatedness), and whether people with poor health are prevented by their condition from visiting green spaces. Our results show that the association between nature dose (specifically duration) and mental wellbeing is moderated by a nature connection. Specifically, people with a stronger nature connection were less likely to be depressed, stressed, and anxious, regardless of the duration of their nature dose. For those with a weaker connection to nature, spending longer in nature was associated with being more depressed, stressed, and anxious. We did not find a relationship between nature dose and high blood pressure or diabetes. Our results highlight that the relationship between nature dose and wellbeing might vary substantially among cities.
Molecular Mechanism of the Anti-Inflammatory Action of Heparin

Our objective is to reveal the molecular mechanism of the anti-inflammatory action of low-molecular-weight heparin (LMWH) based on its influence on the activity of two key cytokines, IFNγ and IL-6. The mechanism of heparin binding to IFNγ and IL-6 and the resulting inhibition of their activity were studied by means of extensive molecular-dynamics simulations. The effect of LMWH on IFNγ signalling inside stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. We found that LMWH binds with high affinity to IFNγ and is able to fully inhibit the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα, thus preventing the formation of the IL-6/IL-6Rα/gp130 signalling complex. These findings shed light on the molecular mechanism of the anti-inflammatory action of LMWH and underpin its ability to influence favourably conditions characterised by overexpression of these two cytokines. Such conditions are not only associated with autoimmune diseases, but also with inflammatory processes, in particular with COVID-19. Our results put forward heparin as a promising means for the prevention and suppression of severe CRS and encourage further investigations on its applicability as an anti-inflammatory agent.
Management of Adverse Events and Supportive Therapy in Relapsed/Refractory Multiple Myeloma

Simple Summary Multiple myeloma (MM) patients with relapsing and/or refractory (RR) disease are exposed for a prolonged time to multiple drugs, which increase the risk of toxicity. In addition to tumor response, preserving the quality of life represents an important goal for this patient population. Therefore, supportive therapy plays a pivotal role in their treatment by limiting disease- and drug-related complications. The aim of this review is to outline current standards and future strategies to prevent and treat renal insufficiency, anemia, bone disease, and infection, including COVID-19, in RRMM patients. In addition, the incidence and treatment of side effects of novel anti-MM agents will be discussed. Abstract Relapsed/refractory (RR) multiple myeloma (MM) patients are a fragile population because of prolonged drug exposure and advanced age. Preserving a good quality of life is of high priority for these patients and the treatment of disease- and treatment-related complications plays a key role in their management. By preventing and limiting MM-induced complications, supportive care improves patients’ outcome. Erythropoietin-stimulating agents and bisphosphonates are well-established supportive strategies, yet novel agents are under investigation, such as anabolic bone agents and activin receptor-like kinase (ALK) inhibitors. The recent dramatic changes in the treatment landscape of MM pose an additional challenge for the routine care of RRMM patients. Multidrug combinations in first and later lines increase the risk for long-lasting toxicities, including adverse cardiovascular and neurological events. Moreover, recently approved first-in-class drugs have unique side-effect profiles, such as ocular toxicity of belantamab mafodotin or gastrointestinal toxicity of selinexor. This review discusses current standards in supportive treatment of RRMM patients, including recommendations in light of the recent SARS-CoV-19 pandemic, and critically looks at the incidence and management of side effects of standard as well as next generation anti-MM agents.
Benefits of a Disease Management Program for Sickle Cell Disease in Germany 2011–2019: The Increased Use of Hydroxyurea Correlates with a Reduced Frequency of Acute Chest Syndrome

Sickle Cell Disease (SCD) is the most common monogenic disorder globally but qualifies as a rare disease in Germany. In 2012, the German Society for Paediatric Oncology and Haematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. Besides other activities, this consortium issued treatment guidelines for SCD that strongly favour the use of hydroxyurea and propagated these guidelines in physician and patient education events. In order to quantify the effect of these recommendations, we made use of claims data that were collected by the research institute (WIdO) of the major German insurance company, the Allgemeine Ortskrankenkasse (AOK), and of publicly accessible data collected by the Federal Statistical Office (Statistisches Bundesamt, Destatis). While the number of patients with SCD in Germany increased from approximately 2200 in 2011 to approximately 3200 in 2019, important components of the recently issued treatment guidelines have been largely implemented. Specifically, the use of hydroxyurea has more than doubled, resulting in a proportion of approximately 44% of all patients with SCD being treated with hydroxyurea in 2019. In strong negative correlation with the use of hydroxyurea, the frequency of acute chest syndromes decreased. Similarly, the proportion of patients who required analgesics and hospitals admissions declined. In sum, these data demonstrate an association between the dissemination of treatment guidelines and changes in clinical practice. The close temporal relationship between the increased use of hydroxyurea and the reduction in the incidence of acute chest syndrome in a representative population-based analysis implies that these changes in clinical practice contributed to an improvement in key measures of disease activity.
Could Physical Fitness Be Considered as a Protective Social Factor Associated with Bridging the Cognitive Gap Related to School Vulnerability in Adolescents? The Cogni-Action Project

The first aim was to compare differences between school vulnerability groups, fitness levels, and their combination in adolescent cognitive performance. The second aim was to determine the mediation role of fitness in the association between school vulnerability and cognitive performance. A total of 912 Chilean adolescents aged 10–14 years participated in this study. The school vulnerability index (SVI) assigned by the Chilean Government was categorized into high-, mid-, or low-SVI. Adolescents were classified as fit or unfit according to their global fitness z-score computed from their cardiorespiratory (CRF), muscular (MF), and speed/agility fitness (SAF) adjusted for age and sex. A global cognitive score was estimated through eight tasks based on a neurocognitive battery. Covariance and mediation analyses were performed, adjusted for sex, schools, body mass index, and peak high velocity. Independent analyses showed that the higher SVI, the lower the cognitive performance (F(6,905) = 18.5; p < 0.001). Conversely, fit adolescents presented a higher cognitive performance than their unfit peers (F(5,906) = 8.93; p < 0.001). The combined analysis found cognitive differences between fit and unfit adolescents in both the high- and mid-SVI levels (Cohen’s d = 0.32). No differences were found between fit participants belonging to higher SVI groups and unfit participants belonging to lower SVI groups. Mediation percentages of 9.0%, 5.6%, 7.1%, and 2.8% were observed for the global fitness score, CRF, MF, and SAF, respectively. The mediation effect was significant between low- with mid-high-SVI levels but not between mid- and high-SVI levels. These findings suggest that an adequate physical fitness level should be deemed a protective social factor associated with bridging the cognitive gap linked to school vulnerability in adolescents. This favourable influence seems to be most significant in adolescents belonging to a more adverse social background.
Ergonomic Risk Assessment of Dental Students—RULA Applied to Objective Kinematic Data

Musculoskeletal disorder (MSD) is already prevalent in dental students despite their young age and the short duration of dental practice. The current findings state that the causes of MSD are related to posture during dental work. This study aims to investigate the ergonomic risk of dental students. In order to analyze the ergonomic risk of dental students, 3D motion analyses were performed with inertial sensors during the performance of standardized dental activities. For this purpose, 15 dental students and 15 dental assistant trainees (all right-handed) were measured in a team. Data were analyzed using the Rapid Upper Limb Assessment (RULA), which was modified to evaluate objective data. Ergonomic risk was found for the following body parts in descending order: left wrist, right wrist, neck, trunk, left lower arm, right lower arm, right upper arm, left upper arm. All relevant body parts, taken together, exhibited a posture with the highest RULA score that could be achieved (median Final Overall = 7), with body parts in the very highest RULA score of 7 for almost 80% of the treatment time. Dental students work with poor posture over a long period of time, exposing them to high ergonomic risk. Therefore, it seems necessary that more attention should be paid to theoretical and practical ergonomics in dental school.
Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial

Simple Summary Cancer-related fatigue (CRF) is one of the most frequently reported symptoms with prevalence rates of 25 to 60 percent in (non-)Hodgkin lymphoma survivors. Several (pilot) studies showed promising effects of light therapy to reduce CRF. The aim of the current study is to evaluate the short- and long-term efficacy of light therapy on CRF and associated symptoms in chronically fatigued (non-)Hodgkin lymphoma survivors. Eighty-three survivors were exposed to bright white light (intervention) and another 83 survivors were exposed to dim white light (comparison). Results showed that all participants, irrespective of light condition, reported reduced levels of fatigue after the completion of light therapy. Similar results were found for depression, sleep quality, and some aspects of quality of life. No effect was found on circadian rhythms or objectively assessed sleep. Therefore, it is important to further investigate which aspects of intervention are associated with the improvements observed after light therapy. Abstract Purpose: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. Methods: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. Results: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = −0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. Conclusions: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.
Carfilzomib Enhances the Suppressive Effect of Ruxolitinib in Myelofibrosis

Simple Summary Myelofibrosis (MF) is a progressive myeloproliferative neoplasm with tendency towards leukemic transformation and has the poorest prognosis amongst the Philadelphia-negative classical myeloproliferative neoplasms (MPN). Ruxolitinib, the first FDA-approved JAK1/2 tyrosine kinase inhibitor, is efficient in reducing spleen size and improving patient symptoms, but it has not been shown to eradicate the MF clone. In this study, using functional genomics techniques, we identified the proteasome family as an additional therapeutic target and demonstrated that inhibition of the proteasome family by carfilzomib in combination with ruxolitinib enhanced suppression of primary MF cells in vitro. Abstract As the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive action of ruxolitinib may be due to intrinsic or extrinsic mechanisms leading to activity of additional pro-survival genes or signalling pathways that function independently of JAK2/STAT5. To identify alternative therapeutic targets, we applied a pooled-shRNA library targeting ~5000 genes to a JAK2V617F-positive cell line under a variety of conditions, including absence or presence of ruxolitinib and in the presence of a bone marrow microenvironment-like culture medium. We identified several proteasomal gene family members as essential to HEL cell survival. The importance of these genes was validated in MF cells using the proteasomal inhibitor carfilzomib, which also enhanced lethality in combination with ruxolitinib. We also showed that proteasome gene expression is reduced by ruxolitinib in MF CD34+ cells and that additional targeting of proteasomal activity by carfilzomib enhances the inhibitory action of ruxolitinib in vitro. Hence, this study suggests a potential role for proteasome inhibitors in combination with ruxolitinib for management of MF patients.
Inhibition of tumor progression and M2 microglial polarization by extracellular vesicle-mediated microRNA-124 in a 3D microfluidic glioblastoma microenvironment

Background: Glioblastoma (GBM) is one of the most aggressive types of brain cancer. GBM progression is closely associated with microglia activation; therefore, understanding the regulation of the crosstalk between human GBM and microglia may help develop effective therapeutic strategies. Elucidation of efficient delivery of microRNA (miRNA) via extracellular vesicles (EVs) and their intracellular communications is required for therapeutic applications in GBM treatment. Methods: We used human GBM cells (U373MG) and human microglia. MiRNA-124 was loaded into HEK293T-derived EVs (miR-124 EVs). Various anti-tumor effects (proliferation, metastasis, chemosensitivity, M1/M2 microglial polarization, and cytokine profile) were investigated in U373MG and microglia. Anti-tumor effect of miR-124 EVs was also investigated in five different patient-derived GBM cell lines (SNU-201, SNU-466, SNU-489, SNU-626, and SNU-1105). A three-dimensional (3D) microfluidic device was used to investigate the interactive microenvironment of the tumor and microglia. Results: MiR-124 EVs showed highly efficient anti-tumor effects both in GBM cells and microglia. The mRNA expression levels of tumor progression and M2 microglial polarization markers were decreased in response to miR-124 EVs. The events were closely related to signal transducer and activator of transcription (STAT) 3 signaling in both GBM and microglia. In 3D microfluidic experiments, both U373MG and microglia migrated to a lesser extent and showed less-elongated morphology in the presence of miR-124 EVs compared to the control. Analyses of changes in cytokine levels in the microfluidic GBM-microglia environment showed that the treatment with miR-124 EVs led to tumor suppression and anti-cancer immunity, thereby recruiting natural killer (NK) cells into the tumor. Conclusions: In this study, we demonstrated that EV-mediated miR-124 delivery exerted synergistic anti-tumor effects by suppressing the growth of human GBM cells and inhibiting M2 microglial polarization. These findings provide new insights toward a better understanding of the GBM microenvironment and provide substantial evidence for the development of potential therapeutic strategies using miRNA-loaded EVs.
The Role of Complement Component C3 Activation in the Clinical Presentation and Prognosis of IgA Nephropathy—A National Study in Children

The aim of the study was to evaluate the influence of the intensity of mesangial C3 deposits in kidney biopsy and the serum C3 level on the clinical course and outcomes of IgAN in children. The study included 148 children from the Polish Pediatric IgAN Registry, diagnosed based on kidney biopsy. Proteinuria, creatinine, IgA, C3 were evaluated twice in the study group, at baseline and the end of follow-up. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The intensity of IgA and C3 deposits were rated from 0 to +4 in immunofluorescence microscopy. The intensity of mesangial C3 > +1 deposits in kidney biopsy has an effect on renal survival with normal GFR in children with IgAN. A reduced serum C3 level has not been a prognostic factor in children but perhaps this finding should be confirmed in a larger group of children.
Systemic Administration of Recombinant Irisin Accelerates Fracture Healing in Mice

To date, pharmacological strategies designed to accelerate bone fracture healing are lacking. We subjected 8-week-old C57BL/6 male mice to closed, transverse, mid-diaphyseal tibial fractures and treated them with intraperitoneal injection of a vehicle or r-irisin (100 µg/kg/weekly) immediately following fracture for 10 days or 28 days. Histological analysis of the cartilaginous callus at 10 days showed a threefold increase in Collagen Type X (p = 0.0012) and a reduced content of proteoglycans (40%; p = 0.0018). Osteoclast count within the callus showed a 2.4-fold increase compared with untreated mice (p = 0.026), indicating a more advanced stage of endochondral ossification of the callus during the early stage of fracture repair. Further evidence that irisin induced the transition of cartilage callus into bony callus was provided by a twofold reduction in the expression of SOX9 (p = 0.0058) and a 2.2-fold increase in RUNX2 (p = 0.0137). Twenty-eight days post-fracture, microCT analyses showed that total callus volume and bone volume were increased by 68% (p = 0.0003) and 67% (p = 0.0093), respectively, and bone mineral content was 74% higher (p = 0.0012) in irisin-treated mice than in controls. Our findings suggest that irisin promotes bone formation in the bony callus and accelerates the fracture repair process, suggesting a possible use as a novel pharmacologic modulator of fracture healing.
Association of Hematuria with Renal Progression and Survival in Patients Who Underwent Living Donor Liver Transplant

Background: This study aimed to determine the association between episodic or persistent hematuria after liver transplantation and long-term renal outcomes. Methods: Patients who underwent living donor liver transplantation between July 2005 and June 2019 were recruited and divided into two groups based on the finding of microscopic or gross hematuria after transplantation. All patients were followed up from the index date until the end date in May 2020. The risks of chronic kidney disease, death, and 30% and 50% declines in estimated glomerular filtration rate (eGFR) were compared between groups. Results: A total of 295 patients underwent urinalysis for various reasons after undergoing transplantation. Hematuria was detected in 100 patients (group A) but was not present in 195 patients (group B). Compared with group B, group A had a higher risk of renal progression, including eGFR decline >50% [aHR = 3.447 (95%CI: 2.24~5.30), p < 0.001] and worse survival. In addition, patients who took non-steroidal anti-inflammatory drugs (NSAIDs) continuously for over seven days within six months before transplant surgery had high risks of rapid renal progression, including a >30% decline in eGFR [aHR = 1.572 (95%CI: 1.12~2.21), p = 0.009)]. Conclusion: Development of hematuria after surgery in patients who underwent living donor liver transplant and were exposed to NSAIDs before surgery were associated with worse long-term renal dysfunction and survival.
Inconel 625/AISI 413 Stainless Steel Functionally Graded Material Produced by Direct Laser Deposition

Functionally graded material (FGM) based on Inconel 625 and AISI 431 stainless steel powders was produced by applying the direct laser deposition (DLD) process. The FGM starts with layers of Inconel 625 and ends with layers of 431 stainless steel having three intermediate zones with the composition (100-X)% Inconel 625-X% 431 stainless steel, X = 25, 50, and 75, in that order. This FGM was deposited on a 42CrMo4 steel substrate, with and without preheating. Microstructures of these FGMs were evaluated, while considering the distribution of chemical composition and grain structure. Microstructures mainly consisted of columnar grains independent of preheating condition; epitaxial growth was observed. The application of a non-preheated substrate caused the formation of planar grains in the vicinity of the substrate. In addition, hardness maps were produced. The hardness distribution across these FGMs confirmed a smooth transition between deposited layers; however, the heat-affected zone was greatly influenced by the preheating condition. This study suggests that an optimum Inconel 625/AISI 431 FGM obtained by DLD should not exceed 50% AISI 431 stainless steel.