Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison of different three dimensional-printed resorbable materials: In vitro biocompatibility, In vitro degradation rate, and cell differentiation support

Biodegradable materials play a crucial role in both material and medical sciences and are frequently used as a primary commodity for implants generation. Due to their material inherent properties, they are supposed to be entirely resorbed by the patients' body after fulfilling their task as a scaffold. This makes a second intervention (e.g. for implant removal) redundant and significantly enhances a patient’s post-operative life quality. At the moment, materials for resorbable and biodegradable implants (e.g. polylactic acid or poly-caprolactone polymers) are still intensively studied. They are able to provide mandatory demands such as mechanical strength and attributes needed for high-quality implants. Implants, however, not only need to be made of adequate material, but must also to be personalized in order to meet the customers’ needs. Combining three dimensional-printing and high-resolution imaging technologies a new age of implant production comes into sight. Three dimensional images (e.g. magnetic resonance imaging or computed tomography) of tissue defects can be utilized as digital blueprints for personalized implants. Modern additive manufacturing devices are able to use a variety of materials to fabricate custom parts within short periods of time. The combination of high-quality resorbable materials and personalized three dimensional-printing for the custom application will provide the patients with the best suitable and sustainable implants. In this study, we evaluated and compared four resorbable and three dimensional printable materials for their in vitro biocompatibility, in vitro rate of degradation, cell adherence and behavior on these materials as well as support of osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells. The tests were conducted with model constructs of 1 cm2 surface area fabricated with fused deposition modeling three dimensional-printing technology.
Genetic and clinical features of social cognition in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol‐O‐methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior.
Mechanistic modelling of interventions against spread of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) within a Danish farrow-to-finish pig herd

Knowledge on successful interventions against livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) within pig herds is sparse. In situations like this, a mechanistic simulation model can be a valuable tool for assessing the effect of potential intervention strategies, and prioritising which should be tested in the field. We have simulated on-farm interventions in a farrow-to-finish pig herd, with a previously published LA-MRSA spread model, within four different areas: 1) Reduced antimicrobial consumption, 2) Reduced number of pigs within each section, 3) Reduced mixing of pigs, and 4) Improved internal biosecurity. To model a decrease in the selective pressure, the transmission rates were reduced after LA-MRSA had become fully established within a herd, which resulted in a marked decrease in the prevalence within all stable units. However, LA-MRSA rarely disappeared completely from the herd; this was only observed in scenarios where the transmission rates were reduced to ≤ 30% of the original level. While changes in antimicrobial consumption patterns might be a very important step towards reducing the spread of LA-MRSA, the simulation results indicate that it may need to be paired with other preventive or intervention measures. Reducing the number of pigs within each section, reducing mixing of pigs, or improving internal biosecurity after LA-MRSA had become established within the herd only resulted in marginal changes in the median prevalence within the herd. However, these factors might be important in relation to being able to achieve or maintain a low level of antimicrobial consumption, and thus still indirectly influence the LA-MRSA prevalence within the herd. The results of a sensitivity analysis indicated the assumptions regarding the existence of pigs persistently shedding MRSA have a noticeable influence on the model results. The assumptions regarding transmission from sow to offspring at the day of birth also had a considerable influence on the MRSA prevalence within the farrowing unit but did not cause any marked changes in the simulated effect of interventions. Effects might differ between different farm types contaminated in different levels and this simulation study highlights a strong need for more knowledge from on-farm trials.
Allosteric regulation of epidermal growth factor (EGF) receptor ligand binding by tyrosine kinase inhibitors

The epidermal growth factor (EGF) receptor is a classical receptor tyrosine kinase with an extracellular ligand-binding domain and an intracellular kinase domain. Mutations in the EGF receptor have been shown to drive uncontrolled cell growth and are associated with a number of different tumors. Two different types of ATP-competitive EGF receptor tyrosine kinase inhibitors have been identified that bind to either the active (type I) or inactive (type II) conformation of the kinase domain. Despite the fact that both types of inhibitors block tyrosine kinase activity, they exhibit differential efficacies in different tumor types. Here, we show that in addition to inhibiting kinase activity, these inhibitors allosterically modulate ligand binding. Our data suggest that the conformations of the EGF receptor extracellular domain and intracellular kinase domain are coupled and that these conformations exist in equilibrium. Allosteric regulators, such as the small-molecule tyrosine kinase inhibitors, as well as mutations in the EGF receptor itself, shift the conformational equilibrium among the active and inactive species, leading to changes in EGF receptor-binding affinity. Our studies also reveal unexpected positive cooperativity between EGF receptor subunits in dimers formed in the presence of type II inhibitors. These findings indicate that there is strong functional coupling between the intracellular and extracellular domains of this receptor. Such coupling may impact the therapeutic synergy between small-molecule tyrosine kinase inhibitors and monoclonal antibodies in vivo.
Marine Skeletons: Towards Hard Tissue Repair and Regeneration

Musculoskeletal disorders in the elderly have significantly increased due to the increase in an ageing population. The treatment of these diseases necessitates surgical procedures, including total joint replacements such as hip and knee joints. Over the years a number of treatment options have been specifically established which are either permanent or use temporary natural materials such as marine skeletons that possess unique architectural structure and chemical composition for the repair and regeneration of bone tissue. This review paper will give an overview of presently used materials and marine structures for hard tissue repair and regeneration, drugs of marine origin and other marine products which show potential for musculoskeletal treatment.
Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Background In vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na+ transport. Methods and Results To assess nephron NOS3 relevance in vivo, knockout (KO) mice with doxycycline‐inducible nephron‐wide deletion of NOS3 were generated. During 1 week of salt loading, KO mice, as compared with controls, had higher arterial pressure and Na+ retention, a tendency towards reduced plasma renin concentration, and unchanged glomerular filtration rate. Chronic high salt‐treated KO mice had modestly decreased total NCC and total SPAK/OSR1 versus controls, however percent phosphorylation of NCC (at T53) and of SPAK/OSR1 was increased. In contrast, total and phosphorylated NKCC2 (at T96/101) were suppressed by 50% each in KO versus control mice after chronic salt intake. In response to an acute salt load, KO mice had delayed urinary Na+ excretion versus controls; this delay was completely abolished by furosemide, partially reduced by hydrochlorothiazide, but not affected by amiloride. After 4 hours of an acute salt load, phosphorylated and total NCC were elevated in KO versus control mice. Acute salt loading did not alter total NKCC2 or SPAK/OSR1 in KO versus control mice but increased the percent phosphorylation of NKCC2 (at T96/101 and S126) and SPAK/OSR1 in KO versus control mice. Conclusions These findings indicate that nephron NOS3 is involved in blood pressure regulation and urinary Na+ excretion during high salt intake. Nephron NOS3 appears to regulate NKCC2 and NCC primarily during acute salt loading. These effects of NOS3 may involve SPAK/OSR1 as well as other pathways.
Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence

Abstract Purpose: Evidence on the association between depression, antidepressant use and venous thromboembolism (VTE) risk is conflicting. We conducted a systematic review and meta-analysis of published observational studies evaluating the associations of depression and antidepressant use with VTE risk. Design: Eligible studies were identified in a literature search of MEDLINE, Embase, Web of Science and reference list of relevant studies up to April 2018. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were aggregated using random effects models. Results: Eight observational studies with data on 960 113 nonoverlapping participants and 9027 VTE cases were included. The pooled RR (95% CI) for VTE comparing antidepressant use with no antidepressant use was 1.27 (1.06–1.51). Tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants were each associated with an increased VTE risk; 1.16 (1.06–1.27), 1.12 (1.02–1.23), and 1.59 (1.21–2.09), respectively. In pooled analysis of three studies that compared patients with depression versus individuals without depression, the RR for VTE was 1.31 (1.13–1.53). Conclusions: Pooled observational evidence suggests that depression and use of antidepressants are each associated with an increased VTE risk. The effect of antidepressant drugs on VTE may be a class effect. The mechanistic pathways underlying these associations deserve further evaluation. Systematic review registration: PROSPERO 2018: CRD42018095595 Key messages Emerging evidence suggests that depression and antidepressant use may be associated with venous thromboembolism (VTE) risk, but the evidence is conflicting. This first systematic review and meta-analysis of observational studies shows that depression and use of antidepressants are each associated with an increased risk of VTE. There may be a class effect of antidepressant drugs on VTE.
A systematic review and meta-analysis

Abstract Migraine is increasingly being reported as a risk factor for primary open angle glaucoma (POAG). However, studies aimed to investigate this association yielded conflicting results. To assess the consistency of the data on the topic, we performed a systematic review and meta-analysis. A systematic literature search from Embase, Web of Science, and PubMed was performed to identify relevant studies on the relationship between migraine and POAG. Random effects models were used to estimate the pooled relative risks (RRs) with 95% confidence intervals (95% CIs) in this meta-analysis. A total of 11 studies meeting the inclusion criteria were included in this meta-analysis. Our findings showed an RR of developing POAG of 1.24 (95%CI=1.12–1.37) in migraine patients. No evidence of significant heterogeneity was detected across studies (P= .071; I=41.7%). This association was not modified by the glaucoma type of the included patients. A significant association was observed in case–control design studies, but not in cohort design studies. Little evidence of publication bias was found. The findings of this meta-analysis suggest that migraine can significantly increase the risk of the development of POAG. However, the cohort study design failed to identify this association. Whether migraines can significantly increase the risk of developing POAG is still controversial.
Intimate partner violence during pregnancy in relation to non-psychotic mental health disorders in Rwanda: a cross-sectional population-based study

Objectives To investigate the prevalence of non-psychotic mental health disorders (MHDs) and the association between exposure to all forms of intimate partner violence (IPV) during pregnancy and MHDs. Design Cross-sectional population-based study conducted in the Northern Province of Rwanda and Kigali city. Participants and settings Totally, 921 women who gave birth ≤13 months before being interviewed were included. Simple random sampling was done to select villages, households and participants. Community health workers helped to identify eligible participants and clinical psychologists, nurses or midwives conducted face-to-face interviews. The collected data were analysed using descriptive statistics and bivariable and multivariable logistic regression modelling Results The prevalence rates of generalised anxiety disorder, suicide ideation and post-traumatic stress disorder (PTSD) were 19.7%, 10.8% and 8.0%, respectively. Exposure to the four forms of IPV during pregnancy was highly associated with the likelihood of meeting diagnostic criteria for each of the non-psychotic MHDs investigated. Physical, psychological and sexual violence, showed the strongest association with PTSD, with adjusted ORs (aORs) of 4.5, 6.2 and 6.3, respectively. Controlling behaviour had the strongest association with major depressive episode in earlier periods with an aOR of 9.2. Conclusion IPV and MHDs should be integrated into guidelines for perinatal care. Moreover, community-based services aimed at increasing awareness and early identification of violence and MHDs should be instituted in all villages and health centres in Rwanda. Finally, healthcare providers need to be educated and trained in a consistent manner to manage the most challenging cases quickly, discreetly and efficiently.
Implications of treatment providers' varying conceptions of the disease model of addiction: A response.

Anthony Barnett B. Psychological Studies (Hons), PhD Candidate, Wayne Hall PhD, Director, Centre for Youth Substance Abuse Research and Professor, National Addiction Centre, Craig L. Fry DrPH, Research Program Leader, Ella Dilkes-Frayne PhD, Research Fellow, Adrian Carter PhD , Senior Research Fellow. Correspondence to Mr Anthony Barnett, Brain and Mental Health Laboratory, Q5 School of Psychological Sciences, Monash University, 770 Blackburn Road, Clayton, Vic. 3800, Australia. Tel: +61 (3) 9905 9322. E-mail: anthony.barnett@monash.edu
Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells

Objective: Resveratrol, a safe and multitargeted natural agent, has been linked with inhibition of survival and invasion of tumor cells. Tumor Necrosis Factor-β (TNF-β) (Lymphotoxin α) is known as an inflammatory cytokine, however, the underlying mechanisms for its pro-carcinogenic effects and whether resveratrol can suppress these effects in the tumor microenvironment are poorly understood. Methods: We investigated whether resveratrol modulates the effects of 5-Fluorouracil (5-FU) and TNF-β on the malignant potential of human colorectal cancer (CRC) cells (HCT116) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R) in 3D-alginate tumor microenvironment. Results: CRC cells cultured in alginate were able to migrate from alginate and the numbers of migrated cells were significantly increased in the presence of TNF-β, similar to TNF-α, and dramatically decreased by resveratrol. We found that TNF-β promoted chemoresistance in CRC cells to 5-FU compared to control cultures and resveratrol chemosensitizes TNF-β-induced increased capacity for survival and invasion of HCT116 and HCT116R cells to 5-FU. Furthermore, TNF-β induced a more pronounced cancer stem cell-like (CSC) phenotype (CD133, CD44, ALDH1) and resveratrol suppressed formation of CSC cells in two different CRC cells and this was accompanied with a significant increase in apoptosis (caspase-3). It is noteworthy that resveratrol strongly suppressed TNF-β-induced activation of tumor-promoting factors (NF-κB, MMP-9, CXCR4) and epithelial-to-mesenchymal-transition-factors (increased vimentin and slug, decreased E-cadherin) in CRC cells. Conclusion: Our results clearly demonstrate for the first time that resveratrol modulates the TNF-β signaling pathway, induces apoptosis, suppresses NF-κB activation, epithelial-to-mesenchymal-transition (EMT), CSCs formation and chemosensitizes CRC cells to 5-FU in a tumor microenvironment.
Pharmacogenomics of Vincristine‐Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose‐limiting vincristine‐induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta‐analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10−5; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10−4; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta‐analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10−4; OR = 2.0), a heritable neuropathy‐related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN.
Provider understandings of and attitudes towards integration: Implementing an HIV and sexual and reproductive health service integration model, South Africa

In South Africa, a lack of integration between sexual and reproductive health (SRH) and HIV services has led to lost opportunities in the treatment cascade. In a context of high HIV, tuberculosis (TB) and unplanned pregnancies, a model for integrating SRH and HIV services was implemented in a hospital and six feeder clinics in KwaZulu-Natal, South Africa. Changes in healthcare provider knowledge, attitudes and understandings were explored following model implementation. Baseline data were collected via focus group discussions (FGDs) and a cross-sectional survey, and were used to inform the development of a model for integrating SRH and HIV services. Following the implementation of the model, an endline survey was conducted to explore any changes. Four FGDs were conducted with healthcare providers at study facilities. A total of 46 providers participated in the baseline survey, and 44 in the endline survey. Qualitative data were thematically analysed using NVivo 11, and quantitative data were descriptively analysed using SPSS 24. The understanding of integration improved by endline. Integration of services was considered important for reducing stigma and increasing access to and improving quality of care. Concerns raised were that integration would increase workload and time per client. Physical structure of facilities was not always conducive to referral or integration. Perceived benefits of integration and actual integration of services improved between baseline and endline. Enhanced understanding of integration and increased levels of reported integration over time imply that providers are more aware, suggesting that the model was effective. Provider perspectives and understandings are important for the successful integration of services. This integration model is relevant and useful to inform training and mentoring of providers, as well as to provide recommendations for policy implementation.
Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism

Significance Shift workers, whose schedules are misaligned relative to their suprachiasmatic nuclei (SCN) circadian pacemaker, are at elevated risk of metabolic disorders. In a study of simulated day- versus night-shift work followed by a constant routine, we separated plasma-circulating metabolites according to whether their 24-h rhythms aligned with the central SCN pacemaker or instead reflected externally imposed behavioral schedules. We found that rhythms in many metabolites implicated in food metabolism dissociated from the SCN pacemaker rhythm, with the vast majority aligning with the preceding sleep/wake and feeding/fasting cycles. Our metabolomics study yields insight into the link between prolonged exposure to shift work and the spectrum of associated metabolic disorders by providing a window into peripheral oscillators and the biobehavioral factors that orchestrate them. Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is essential to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock disturbances may offer new insights. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-shift schedule, compared with a simulated day-shift schedule, were analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhythmicity under constant routine following either or both simulated shift schedules. However, while traditional markers of the circadian clock in the SCN—melatonin, cortisol, and PER3 expression—maintained a stable phase alignment after both schedules, only a few metabolites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine following the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavioral time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circadian clock. Characterization of these metabolite rhythms will provide insight into the underlying mechanisms linking shift work and metabolic disorders.