Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties

This study shows the importance of the chosen method for assessing the glass-forming ability (GFA) and glass stability (GS) of a drug compound. Traditionally, GFA and GS are established using in situ melt-quenching in a differential scanning calorimeter. In this study, we included 26 structurally diverse glass-forming drugs (i) to compare the GFA class when the model drugs were produced by spray-drying with that when melt-quenching was used, (ii) to investigate the long-term physical stability of the resulting amorphous solids, and (iii) to investigate the relationship between physicochemical properties and the GFA of spray-dried solids and their long-term physical stability. The spray-dried solids were exposed to dry (<5% RH) and humid (75% RH) conditions for six months at 25 °C. The crystallization of the spray-dried solids under these conditions was monitored using a combination of solid-state characterization techniques including differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. The GFA/GS class assignment for 85% of the model compounds was method-dependent, with significant differences between spray-drying and melt-quenching methods. The long-term physical stability under dry condition of the compounds was predictable from GFA/GS classification and glass transition and crystallization temperatures. However, the stability upon storage at 75% RH could not be predicted from the same data. There was no strong correlation between the physicochemical properties explored and the GFA class or long-term physical stability. However, there was a slight tendency for compounds with a relatively larger molecular weight, higher glass transition temperature, higher crystallization temperature, higher melting point and higher reduced glass transition temperature to have better GFA and better physical stability. In contrast, a high heat of fusion and entropy of fusion seemed to have a negative impact on the GFA and physical stability of our dataset.
Recombinant protein CCN5/WISP2 promotes islet cell proliferation and survival in vitro

Abstract Pancreatic ß cell proliferation, survival and function are key elements that need to be considered in developing novel antidiabetic therapies. We recently identified CCN5/WISP2 to have potential growth promoting properties when overexpressed in ß cells; however, further investigations are needed to validate those properties. In this study, we demonstrated that exogenous treatment of insulinoma cells and primary islets with recombinant CCN5 (rh-CCN5) protein enhanced the proliferative capacity which was correlated with activation of cell-cycle regulators CDK4 and cyclin D1. Furthermore, pre-incubation of these cells with rh-CCN5 enhanced their survival rate after being exposed to harsh treatments such as streptozotocin and high concentrations of glucose and free fatty acids. CCN5 as well caused an upregulation in the expression of key genes associated with ß cell identity and function such as GLUT-2 and GCK. Finally, CCN5 activated FAK and downstream ERK kinases which are known to stimulate cell proliferation and survival. Hence, our results validate the growth promoting activities of rh-CCN5 in ß cells and open the door for further investigations in vivo.
Vitamin D sufficiency in young Brazilian children: associated factors and relationship with vitamin A corrected for inflammatory status

Abstract Objective: To assess sociodemographic, nutritional and health conditions associated with vitamin D sufficiency among young Brazilian children living at different latitudes. Design: Cross-sectional analysis with a four-level model of inflammation to correct micronutrient concentrations. Prevalence ratios (PR; 95 % CI) were estimated for factors associated with vitamin D sufficiency (≥50 nmol/l), adjusting for child’s sex, age, skin colour, stunting and vitamin A+D supplementation. Setting: Primary health-care units in four Brazilian cities located at lower (7°59′26·9016″S and 9°58′31·3864″S) and higher latitudes (16°41′12·7752″S and 30°2′4·7292″S). Participants: In total 468 children aged 11–15 months were included in the analysis. Results: Only 31·8 % of children were vitamin D sufficient (concentration <30 nmol/l and <50 nmol/l among 32·9 and 68·2 %, respectively). Living at higher latitudes was associated with reduced prevalence of vitamin D sufficiency compared with lower latitudes (PR = 0·65; 95 % CI 0·49, 0·85). Maternal education ≥9 years positively influenced a sufficient vitamin D status in children. After correction for inflammatory status, each increase of 1 µmol/l in vitamin A concentration was associated with a 1·38-fold higher prevalence of vitamin D sufficiency (95 % CI 1·18, 1·61). Progressive decline in the prevalence of vitamin D sufficiency was associated with marginal and deficient status of vitamin A (Ptrend = 0·001). Conclusions: Lower latitude, higher maternal education and vitamin A concentration were positively associated with vitamin D sufficiency in young Brazilian children. These findings are relevant for planning public health strategies for improving vitamin D status starting in early infancy.
Imaging challenges of immunotherapy and targeted therapy in patients with brain metastases: Response, Progression, and Pseudoprogression.

The advent of immunotherapy using immune checkpoint inhibitors (ICI) and targeted therapy (TT) has dramatically improved the prognosis of various cancer types. Following ICI therapy or TT, either alone (especially ICI) or in combination with radiotherapy, however, imaging findings on anatomical contrast-enhanced MRI can be unpredictable, highly variable, and are often difficult to interpret regarding treatment response and outcome. This review aims at summarizing the imaging challenges related to TT and ICI monotherapy as well as combined with radiotherapy in patients with brain metastases, and to give an overview on advanced imaging techniques which potentially overcome some of these imaging challenges. Currently, major evidence suggests that imaging parameters especially derived from amino acid PET, perfusion-/diffusion-weighted MRI, or MR spectroscopy may provide valuable additional information for the differentiation of treatment-induced changes from brain metastases recurrence and the evaluation of treatment response.
Caring for People With Young Onset Dementia: An Interpretative Phenomenological Analysis of Family Caregivers' Experiences.

People with young onset dementia (YOD) experience many unique challenges. Similarly, family caregivers experience changing personal, familial, and societal roles. However, YOD is under recognized and under resourced with a lack of dedicated models of care. The current study explored family members' experience of caregiving for persons with YOD to identify barriers and opportunities to accessing support. Qualitative interviews were conducted with six family caregivers, using interpretative phenomenological analysis. Findings show that caregivers experience significant uncertainty within their role, difficulty accessing timely diagnosis, and face unclear care pathways and age-related restrictions to accessing support. These findings also reflect elements of ambiguous loss and anticipatory grief: caregivers experienced sudden changes to relationships and family structure, along with the anticipation of a changed future. Optimum models of care should target timely diagnosis and clear post-diagnosis pathways and services that are flexible, relevant, and accessible. Services should offer psychosocial support for family members as they adjust to their new role as caregivers. [Journal of Psychosocial Nursing and Mental Health Services, xx(x), xx-xx. ].
Genotype and dietary lysine deficiency affect carcass and muscle amino acid composition of pigs growing from 10 to 25 kg body weight.

Amino acid (AA) composition of body protein is considered constant although there are evidences that AA pattern in pigs may be altered by different factors. Pigs with different body composition and protein deposition rates-like fatty and lean pigs-may differ in AA composition, with possible consequences on their AA requirements. This work investigates effects of genotype and dietary lysine deficiency on AA composition of carcass and muscles of Iberian and Landrace × Large White pigs. Twenty-eight barrows (10 kg body weight [BW]), 14 from each breed, were used. They were randomly assigned to two experimental diets according to a factorial arrangement (two breeds × two diets). Diets were isonitrogenous and isoenergetic (200 ± 1 g CP/kg dry matter (DM); 14.7 ± 0.1 MJ ME/kg DM) and with identical chemical composition except for lysine concentration (10.9 and 5.20 g lysine/kg DM, for lysine-adequate (AL) diet and lysine-deficient (DL) diet respectively). Pigs were individually housed, and daily feed allowance was adjusted on a weekly basis according to BW. Pigs were slaughtered at 25 kg BW. Isoleucine, valine and phenylalanine concentration were higher in carcass protein of Iberian pigs (p < .01). In longissimus muscle, higher concentration of arginine, isoleucine, phenylalanine, lysine and valine (p < .001-p < .05), and lower of methionine (p < .001) were detected in Iberian pigs, whereas phenylalanine, leucine, lysine, threonine and methionine concentration decreased and arginine increased (p < .001-p < .05) when pigs were fed DL diet. Genotype and lysine deficiency effects were moderate in the AA composition of protein of biceps femoris muscle. The results show that AA proportions in protein of carcass and longissimus muscle can be influenced by pig genotype and conditions of lysine shortage. The biceps femoris muscle, with different functional and metabolic properties, shows more constant AA composition than longissimus, which seem to prevail independent from genotype or nutritional challenges.
Seroprevalence of spotted fever group rickettsiae in canines along the United States–Mexico border

Portions of northern Mexico are experiencing a re‐emergence of Rocky Mountain spotted fever (RMSF), a tickborne disease caused by Rickettsia rickettsii, a member of the spotted fever group of rickettsiae (SFGR). Infection with R. rickettsii can result in serious and life‐threatening illness in people and dogs. Canine seroprevalence has been used as a sentinel for human RMSF in previous studies. This study aims to quantify SFGR seroprevalence in canines in three northern Mexican states and identify risk factors associated with seropositivity. A total of 1,136 serum samples and 942 ticks were obtained from dogs participating in government sterilization campaigns and from animal control facilities in 14 Mexican cities in three states. SFGR antibodies were detected using indirect immunofluorescence antibody assays at titre values ≥1/64. Six per cent (69 dogs) showed antibodies to SFGR, with the highest seroprevalence reported in Baja California (12%), Coahuila (4%) and Sonora (4%). Dogs from Baja California had three times higher odds of having SFGR antibodies compared to dogs from Sonora (OR = 3.38, 95% CI, 1.81–6.37). Roughly one quarter (25%) of surveyed dogs were parasitized by ticks (Rhipicephalus sanguineus sensu lato) at the time of sample collection. A portion of collected ticks were tested for rickettsial DNA using polymerase chain reaction. Positive samples were then sequenced, showing evidence of SFGR including R. massiliae, R. parkeri and R. rickettsii. Dogs that spent the majority of time on the street, such as free‐roaming or community‐owned dogs, showed a greater risk of tick infestation, seropositivity, bearing seropositive ticks, and may play a pivotal role in the spread of SFGR among communities. Estimating the seroprevalence of SFGR in the canine population can help public health campaigns target high‐risk communities for interventions to reduce human RMSF cases.
Knowledge Learning Symbiosis for Developing Risk Prediction Models from Regional EHR Repositories

Secondary use of regional EHR data suffers several problems, including data selection bias and limited data size caused by data incompleteness. Here, we propose knowledge learning symbiosis (KLS) as a framework to incorporate domain knowledge to address the problems and make better secondary use of EHR data. Under the framework, we introduce three main categories of methods: knowledge injection to input features, objective functions, and output labels, where knowledge-enhanced neural network (KENN) was first introduced to inject knowledge into objective functions. A case study was conducted to build a cardiovascular disease risk prediction model on the type 2 diabetes patient cohort using regional EHR repositories. By incorporating a well-established knowledge risk model as domain knowledge under our KLS framework, we increased risk prediction performance both on small and biased data, where KENN showed the best performance among all methods.
Initial uptake, time to treatment, and real-world effectiveness of all-oral direct-acting antivirals for hepatitis C virus infection in the United States: A retrospective cohort analysis

Background Data on initiation and utilization of direct-acting antiviral therapies for hepatitis C virus infection in the United States are limited. This study evaluated treatment initiation, time to treatment, and real-world effectiveness of direct-acting antiviral therapy in individuals with hepatitis C virus infection treated during the first 2 years of availability of all-oral direct-acting antiviral therapies. Methods A retrospective cohort analysis was undertaken using electronic medical records and chart review abstraction of hepatitis C virus-infected individuals aged >18 years diagnosed with chronic hepatitis C virus infection between January 1, 2014, and December 31, 2015 from the Indiana University Health database. Results Eight hundred thirty people initiated direct-acting antiviral therapy during the 2-year observation window. The estimated incidence of treatment initiation was 8.8%±0.34% at the end of year 1 and 15.0%±0.5% at the end of year 2. Median time to initiating therapy was 300 days. Using a Cox regression analysis, positive predictors of treatment initiation included age (hazard ratio, 1.008), prior hepatitis C virus treatment (1.74), cirrhosis (2.64), and history of liver transplant (1.5). History of drug abuse (0.43), high baseline alanine aminotransferase levels (0.79), hepatitis B virus infection (0.41), and self-pay (0.39) were negatively associated with treatment initiation. In the evaluable population (n = 423), 83.9% (95% confidence interval, 80.1–87.3%) of people achieved sustained virologic response. Conclusion In the early years of the direct-acting antiviral era, <10% of people diagnosed with chronic hepatitis C virus infection received direct-acting antiviral treatment; median time to treatment initiation was 300 days. Future analyses should evaluate time to treatment initiation among those with less advanced fibrosis.
Identification of miRNAs involved in fruit ripening by deep sequencing of Olea europaea L. transcriptome

Background The ripening process of olive fruits is associated with chemical and/or enzymatic specific transformations, making them particularly attractive to animals and humans. In olive drupes, including ‘Cassanese’ ones, ripening is usually accompanied by progressive chromatic change, resulting in a final red-brown colourization of both epidermis and mesocarp. This event has an exception in the ‘Leucocarpa’, in which we observed the destabilization in the equilibrium between the chlorophyll metabolism and that of the other pigments, particularly the anthocyanins, whose switch-off during maturation promotes the white colouration of the fruits. Recently, transcription profiling of ‘Leucocarpa’ and ‘Cassanese’ olives along ripening, performed through an Illumina RNA-seq approach, has provided useful insights on genes functions involved in fruit maturation such as those related to the biosynthesis of flavonoids and anthocyanins. Methodology To assess expression alterations of genes involved in flavonoids and anthocyanins biosynthetic pathways during ripening, possibly caused by small nuclear RNA (snRNA) in olive drupes, snRNA libraries from ‘Leucocarpa’ and ‘Cassanese’ were constructed with RNAs extracted at 100 and 130 Days After Flowering (DAF) and sequenced by an Illumina approach. 130 conserved microRNAs (miRNA) in the Viridiplantae belonging to 14 miRNA families were identified. Regarding the 130 conserved miRNAs, approximately the 48% were identified in all libraries, 5 and 18 miRNAs were shared between the “Cassanese” (C100, C130) and “Leucocarpa” (L100, L130) libraries, respectively. Conclusion For the remaining reads not-matching with known miRNAs in the Viridiplantae, we combined secondary structure and minimum free energy to discover novel olive miRNAs. Based on these analyses, 492 sequences were considered as putative novel miRNAs. The putative target genes of identified miRNA were computationally predicted by alignment with the olive drupe transcripts obtained from the same samples. A total of 218 transcripts were predicted as targets of 130 known and 492 putative novel miRNAs. Interestingly, some identified target genes are involved in negative regulation of anthocyanin metabolic process. Quantification of the expression pattern of three miRNA and their target transcripts by qRT-PCR assay confirmed the results of Illumina sequencing.
The Effects of Halofuginone on Wound Healing in the Rat Nasal Mucosa

Background Halofuginone is an alkaloid febrifugine analogue and bioactive molecule that was isolated incidentally from the Dichroa febrifuga plant. The therapeutic efficacy of halofuginone in parasitic infections, scleroderma, inflammation, and fibrosis-related diseases, as well as in some types of cancer, has been previously reported. The effects of halofuginone on nasal mucosal damage are not yet known. Objective The aim of this study was to investigate the potential effect of topically applied halofuginone on wound healing in the mechanically injured nasal mucosa of rats. Methods A unilateral mucosal wound was created in the nasal cavity of 32 rats (aged 4 weeks) using the brushing technique. These rats were randomly divided into 4 groups. Although the control group did not receive an intervention, a dry pad, a saline-impregnated pad, or a pad impregnated with halofuginone were placed in the rats of the other 3 groups and left for 5 minutes. Rats were sacrificed on the 14th day, and a histological examination was performed. The nasal mucosa was assessed via hematoxylin-eosin and Masson’s trichrome staining. Results There were no statistically significant differences in epithelial thickness, inflammation, goblet cell formation, and epithelial disarray values between the halofuginone group and the control group (P > .05). The subepithelial thickness was significantly decreased in the saline-treated group and the halofuginone-treated group (P < .05), but a significantly lower level of subepithelial fibrosis was only observed in the halofuginone group compared to the other groups (P < .05). Conclusions Topical halofuginone administration reduces the development of fibrosis and subepithelial edema after experimentally induced nasal mucosal injury, but it does not exert therapeutic or preventive effects on epithelial damage, inflammation, and goblet cell hyperplasia.
Preliminary Experience With a Minimally Invasive Technique for Hallux Valgus Correction With No Fixation

Background: Percutaneous operative techniques for hallux valgus (HV) correction are less damaging to soft tissues and the first metatarsophalangeal joint, and they carry a lower risk of wound complications. We report our preliminary results using a percutaneous technique that allowed correction of the deformity without internal fixation. Methods: One hundred ninety-five consecutive patients with isolated symptomatic HV were surgically treated using a percutaneous technique without any form of internal fixation, with a mean follow-up of 34.6 months. The American Orthopaedic Foot & Ankle Society (AOFAS) hallux-metatarsophalangeal-interphalangeal scale score was used for clinical assessment. Radiographic evaluation included pre- and postoperative assessment of the hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle (DMAA), and sesamoid position in weightbearing radiographs. Results: According to the AOFAS score, the patients improved from a preoperative median of 54.7 to 89.6 at 2 years’ follow-up (P = .002). Patients were satisfied or very satisfied in 94% of cases at the latest follow-up. A mean radiographic correction of the HVA of 15.5 degrees, of the IMA of 5.4 degrees, and of the DMAA of 5.4 degrees was achieved. The AOFAS global score and every individual parameter improved significantly between pretreatment and latest follow-up (P > .01). A total of 19 (9.7%) complications were reported. Conclusion: This percutaneous technique, which did not use any form of internal fixation described, produced durable results for the correction of HV, reliably correcting the deformity and resulting in significant improvement in function and decrease of pain. Level of Evidence: Level IV, retrospective case series.
Resource, data and application management for cloud federations and multi-clouds

Distributed Real-Time Media Processing refers to classes of highly distributed, delay no-tolerant applications that account for the majority of the data traffic generated in the world today. Real-Time audio/video conferencing and live content streaming are of particular research interests as technology forecasts predict video traffic surpassing every other type of data traffic in the world in the near future. These applications are very sensitive to both communication properties such as latency, jitter, packet loss, bit rate as well as backend stream processing load profiles. In this work we provide a novel and generalized large-scale Multi-Cloud architectural blueprint for ISP and Carrier providers, that permits smart geo-distributed service placement in order to optimize latency/locality of stream processing applications. We provide as a well self-managed Intra-Cloud federation algorithm based on gradient topologies in order to optimize routes in a live media streaming backend. Additionally we introduce a novel distributed Network Bandwidth Manager that optimizes system stability by arbitrating network bandwidth between multiple Cloud services sharing the same network infrastructure. At last, an empirical study is provided connecting media quality parameters and Cloud backend load profiles, including an algorithm for stream allocation on Cloud Selective Forwarding units. El procesamiento de medios en tiempo real distribuido se refiere a clases de aplicaciones altamente distribuidas, no tolerantes al retardo, que representan la mayoría del tráfico de datos generado en el mundo actual. Las conferencias de audio y video en tiempo real y la transmisión de contenido en vivo tienen especial interés en investigación, ya que la prospectiva tecnológica estima que el tráfico de video supere a cualquier otro tipo de tráfico de datos en el futuro cercano. La transmisión en vivo se refiere a aplicaciones en las que flujos de audio/vídeo de una fuente se han de entregar a un conjunto de destinos en lugares geográficos diferentes mientras se mantiene baja la latencia de entrega del flujo (como por ejemplo la cobertura de eventos en vivo). Las plataformas de conferencia en tiempo real son plataformas de aplicación que implementan comunicaciones de audio/video en tiempo real entre muchos participantes. Ambas categorías presentan una alta sensibilidad tanto al estado de la red (latencia, jitter, pérdida de paquetes, velocidad de bits) como a los perfiles de carga de la infraestructura de procesamiento de flujo (latencia y jitter introducidos durante el procesamiento en la nube de paquetes de datos multimedia). Esta tesis trata de mejorar el procesamiento de datos multimedia en tiempo real tanto en los parámetros de nivel de red como en las optimizaciones en la nube.