Miracle-dz/UniFAR-FTUs huggingface dataset:
Interleukin-1β-Induced Senescence Promotes Osteoblastic Transition of Vascular Smooth Muscle Cells

Introduction: Interleukin (IL)-1β, as a key biomarker and mediator of vascular calcification in patients with end-stage renal disease (ESRD), may be involved in the process of premature senescence of vascular smooth muscle cells (VSMCs). This work sought to investigate whether IL-1β-induced premature senescence contributes to the process of osteoblastic transition and vascular calcification in VSMCs. Methods: Eighty-eight patients with ESRD (aged 25–81 years), 11 healthy individuals, and 15 cases of lesion-free distal radial arteries from dialysis ESRD patients with angiostomy were collected in this study. Immunohistochemical analysis was performed to detect expression of IL-1β, p21, and bone morphogenetic protein-2 (BMP2) in the distal radial arteries. Primary human VSMCs from healthy neonatal umbilical cords were incubated with test agents for 1–3 days. Intracellular levels of reactive oxygen species (ROS) and senescence-associated-β-galactosidase (SA-β-gal) staining were used to detect senescent cells. Alizarin red staining and the calcium content of the cell layer were used to detect mineral deposition in VSMCs. Results: Coincident with positive staining of IL-1β, p21, and BMP2 in the lesion-free distal radial arteries, 66.67% patients showed mineral deposition. Serum IL-1β was 0.24 ± 0.57, 1.20 ± 2.95, and 9.41 ± 40.52 pg/mL in 11 healthy individuals, 20 patients without calcification, and 53 patients with calcification, respectively. Analysis of the cross-table chi-square test showed cardiovascular calcification is not correlated with levels of serum IL-1β in patients with ESRD (p = 0.533). In response to IL-1β, VSMCs showed a senescence-like phenotype, such as flat and enlarged morphology, increased expression of p21, an increased activity of SA-β-gal, and increased levels of ROS. IL-1β-induced senescence of VSMCs was required for the activation of IL-1β/NF-κB/p53/p21 signaling pathway. IL-1β-induced senescent VSMCs underwent calcification due to osteoblastic transition mainly depending upon the upregulation of BMP2. Resveratrol, an activator of sirtuin-1, postponed the IL-1β-induced senescence through blocking the NF-κB/p53/p21 pathway and attenuated the osteoblastic transition and calcification in VSMCs. Conclusions: High levels of IL-1β in medial smooth muscles of arteries may play roles in inducing senescence-associated calcification. IL-1β-induced senescence depending on the activation of the NF-κB/p53/p21 signaling pathway and contributing to osteoblastic transition of VSMCs.
Assessment on the Stepwise Laboratory Improvement Process Towards Accreditation (SLIPTA) Implementation in Selected Public Hospital Laboratories in Ethiopia.

Background; Strengthening Laboratory Improvement Process Towards Accreditation recognizes laboratories where they are in the process of quality improvement; through audits and direct on technical assistance. Objective: The aim of this study was to assess the implementation status of SLIPTA in selected public hospital laboratories in Ethiopia. Methods: Hospital based cross sectional study design was used to assess the implementation status of SLIPTA in four public hospital laboratories in Ethiopia. The facilities were selected using purposive technique. Their implementation status was assessed using SLIPTA standard checklist, and a semi-structured questioner to identify factors during the implementation phases. The current and the last audit scores of the facilities had compared against the SILPTA score level. Interview based exploratory discussion for the key informants were used. This study was conducted from April to October 2015. Results: This finding indicated that two laboratories (lab.3 and lab.4) were improved from zero stars [82(31.78%) and 102(39.5%) points] in pervious audit result to two stars [175(67.8%) and 182(70.5%) points] in current audit result respectively. The other two laboratories (Lab.1 and Lab. 2) had no changes that score zero stars with pervious audit result [94 (36.4%) and 82 (32.56%)] to current audit result [95 (36.8%) and 104 (40.31%)] respectively. All (16/16) key informants responded that they had no written plan, follow up, report of the SLIPTA program; and with staff attrition rate, no written duties and responsibilities. Conclusion: Improvements were seen with Lab.3 and Lab.4 which reaching two stars from zero stars at the WHO SLIPTA audit result within one year. These laboratories had better partnership support that initiate or drive the laboratories and better management style when it is compare to the other two laboratories. The factors that affect the SLIPTA program were mainly in human resources and development part that corresponding to lack of concern, commitment, dedication, managerial skill; and resistance to new approach, staff attrition rate, no written duties and responsibilities and demotivation.
An Improved Boosting to Amplify Signal with Isobaric Labeling (iBASIL) Strategy for Precise Quantitative Single-cell Proteomics*

Through evaluating and optimizing boosting ratio and MS acquisition conditions (automatic gain control and ion injection time), the improved Boosting to Amplify Signal with Isobaric Labeling (iBASIL) strategy allows for precise and robust quantitative single-cell proteomics. A total of 2,622 proteins were identified and 1,452 proteins (58%) were quantified in more than 70% of the sample channels in the analysis of 104 FACS-isolated AML single cells, which recapitulates the key biological differences amongst three AML cell lines. Graphical Abstract Highlights Higher AGC significantly improves quantitation quality in single-cell analysis. The boosting-to-sample ratio should be carefully evaluated and optimized. iBASIL allows for precise quantitation of 1,500 proteins from 104 AML single cells. iBASIL recapitulates major biological differences in different AML single cells. Mass spectrometry (MS)-based proteomics has great potential for overcoming the limitations of antibody-based immunoassays for antibody-independent, comprehensive, and quantitative proteomic analysis of single cells. Indeed, recent advances in nanoscale sample preparation have enabled effective processing of single cells. In particular, the concept of using boosting/carrier channels in isobaric labeling to increase the sensitivity in MS detection has also been increasingly used for quantitative proteomic analysis of small-sized samples including single cells. However, the full potential of such boosting/carrier approaches has not been significantly explored, nor has the resulting quantitation quality been carefully evaluated. Herein, we have further evaluated and optimized our recent boosting to amplify signal with isobaric labeling (BASIL) approach, originally developed for quantifying phosphorylation in small number of cells, for highly effective analysis of proteins in single cells. This improved BASIL (iBASIL) approach enables reliable quantitative single-cell proteomics analysis with greater proteome coverage by carefully controlling the boosting-to-sample ratio (e.g. in general <100×) and optimizing MS automatic gain control (AGC) and ion injection time settings in MS/MS analysis (e.g. 5E5 and 300 ms, respectively, which is significantly higher than that used in typical bulk analysis). By coupling with a nanodroplet-based single cell preparation (nanoPOTS) platform, iBASIL enabled identification of ∼2500 proteins and precise quantification of ∼1500 proteins in the analysis of 104 FACS-isolated single cells, with the resulting protein profiles robustly clustering the cells from three different acute myeloid leukemia cell lines. This study highlights the importance of carefully evaluating and optimizing the boosting ratios and MS data acquisition conditions for achieving robust, comprehensive proteomic analysis of single cells.
Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes

Chondrocytes in growth plates are responsible for longitudinal growth in long bones during endochondral ossification. Discoidin domain receptor 1 (Ddr1) is expressed in chondrocytes, but the molecular mechanisms by which DDR1 regulates chondrocyte behaviors during the endochondral ossification process remain undefined. To elucidate Ddr1‐mediate chondrocyte functions, we generated chondrocyte‐specific Ddr1 knockout (CKOΔDdr1) mice in this study. The CKOΔDdr1 mice showed delayed development of the secondary ossification center and increased growth plate length in the hind limbs. In the tibial growth plate in CKOΔDdr1 mice, chondrocyte proliferation was reduced in the proliferation zone, and remarkable downregulation of Ihh, MMP13, and Col‐X expression in chondrocytes resulted in decreased terminal differentiation in the hypertrophic zone. Furthermore, apoptotic chondrocytes were reduced in the growth plates of CKOΔDdr1 mice. We concluded that chondrocytes with Ddr1 knockout exhibit decreased proliferation, terminal differentiation, and apoptosis in growth plates, which delays endochondral ossification and results in short stature. We also demonstrated that Ddr1 regulates the Ihh/Gli1/Gli2/Col‐X pathway to regulate chondrocyte terminal differentiation. These results indicate that Ddr1 is required for chondrocytes to regulate endochondral ossification in skeletal development.
Comparing the Impact of Primary Care Practice Design in Two Inner City UK Homelessness Services

Background: Specialist homeless primary health care services in the United Kingdom have arisen from the need for bespoke approaches to providing health care for people experiencing homelessness but descriptions of the design characteristics of homeless health services together with associated long-term condition (LTC) prevalence, health care utilization, and prescribing remain unexplored, thereby limiting our understanding of potential impact of service configuration on outcomes. Aim: Description of specialist homeless general practitioner services in Glasgow and Edinburgh, in terms of practice design (staff, skill mix, practice systems of registration, and follow-up); and exploration of the potential impact of differences on LTC prevalence, health care utilization, and prescribing. Method: Patient data were collected from computerized general practitioner records in Glasgow (2015, n = 133) and Edinburgh (2016, n = 150). Homeless health service configuration and anonymized patient data, including demographics, LTCs service utilization, and prescribing were summarized and compared. Results: Marked differences in infrastructure emerged between 2 practices, including the patient registration process, segmentation versus integration of services, recording systems, and the availability of staff expertise. Patient characteristics differed in terms of LTC diagnoses, health care utilization and prescribing. Higher rates of recorded mental health and addiction problems were found in Edinburgh, as well as higher rates of physical LTCs, for example, cardiovascular and respiratory conditions. There were significantly higher rates of consultations with nurses and other staff in Edinburgh, although more patients had consultations with pharmacists in Glasgow. Medication adherence was low in both cohorts, and attendance at referral appointments was particularly poor in Glasgow. Conclusion: Service design and professional skill mix influence recording of LTCs, service uptake, and identification and management of health conditions. Service configuration, professional skill mix, and resources may profoundly affect diagnoses, utilization of health care, and prescribing. Attention to homeless service design is important when providing care to this disadvantaged patient group.
The developmental trajectory of fronto‐temporoparietal connectivity as a proxy of the default mode network: a longitudinal fNIRS investigation

The default mode network (DMN) is a network of brain regions that is activated while we are not engaged in any particular task. While there is a large volume of research documenting functional connectivity within the DMN in adults, knowledge of the development of this network is still limited. There is some evidence for a gradual increase in the functional connections within the DMN during the first 2 years of life, in contrast to other functional resting‐state networks that support primary sensorimotor functions, which are online from very early in life. Previous studies that investigated the development of the DMN acquired data from sleeping infants using fMRI. However, sleep stages are known to affect functional connectivity. In the current longitudinal study, fNIRS was used to measure spontaneous fluctuations in connectivity within fronto‐temporoparietal areas—as a proxy for the DMN—in awake participants every 6 months from 11 months till 36 months. This study validates a method for recording resting‐state data from awake infants, and presents a data analysis pipeline for the investigation of functional connections with infant fNIRS data, which will be beneficial for researchers in this field. A gradual development of fronto‐temporoparietal connectivity was found, supporting the idea that the DMN develops over the first years of life. Functional connectivity reached its maximum peak at about 24 months, which is consistent with previous findings showing that, by 2 years of age, DMN connectivity is similar to that observed in adults.
Heat‐Shock protein A12A is a novel PCNA‐binding protein and promotes hepatocellular carcinoma growth

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death. Proliferating cell nuclear antigen (PCNA) plays a pivotal role in cancer development and progression. However, the long‐term dismal prognosis of HCC mandates more investigation to identify novel regulators in HCC pathogenesis. Heat‐shock protein A12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that HCC cells showed increased HSPA12A expression, and overexpression of HSPA12A promoted HCC growth and angiogenesis in mice. Gain‐ and loss‐of‐functional studies demonstrated that the proliferation of HCC HepG2 cells, as well as β‐catenin expression and nuclear translocation, was promoted by HSPA12A overexpression, but in turn suppressed by HSPA12A knockdown. HSPA12A did not impact PCNA expression; however, mass spectrometry and co‐immunoprecipitation immunoblotting analysis revealed that HSPA12A directly binds to PCNA and promotes its trimerization, which is an essential functional conformation of PCNA for carcinogenesis. Importantly, PCNA inhibition by PCNA‐I1 reversed the HSPA12A‐mediated HepG2 cell differentiation. These findings indicate that HSPA12A is a novel regulator of HCC cell proliferation and tumor growth through binding to PCNA for its trimerization. HSPA12A inhibition might represent a viable strategy for the management of HCC in humans.
Optimizing investments in Former Yugoslav Republic OF Macedonia’s HIV response

This report summarizes the findings of an Allocative efficiency analysis on the Former Yugoslav Republic (FYR) of Macedonia `s national HIV epidemic and response conducted in 2014-15. The report addresses core questions for resource allocation such ‘How can HIV funding be optimally allocated to the combination of HIV response interventions that will yield the highest impact? ’ or ‘What level of investment is required to achieve national targets, if we allocate resources optimally? ’. The report describes epidemiological and HIV financing trends as well as identifies sub-populations, which are most affected by the epidemic. Based on this information, the optimized mix of interventions for minimizing new HIV infections and deaths is identified using mathematical modeling techniques. Required investments into programs for key populations and antiretroviral treatment are established and translated into policy recommendations. The FYR Macedonia experiences a low level, concentrated HIV epidemic. The small number of people currently living with HIV is attributable, in part, to an effective HIV response to date. There is increasing HIV prevalence among certain key population groups, particularly men who have sex with men (MSM) and male sex workers (MSW). This recent trend warrants early attention. MSM accounted for 64 percent of newly diagnosed people living with HIV in 2014. In that same year, programs specifically targeting MSM accounted for only 2.4 percent of HIV spending.
Use of an Electronic Clinical Decision Support System in Primary Care to Assess Inappropriate Polypharmacy in Young Seniors With Multimorbidity: Observational, Descriptive, Cross-Sectional Study

Background Multimorbidity is a global health problem that is usually associated with polypharmacy, which increases the risk of potentially inappropriate prescribing (PIP). PIP entails higher hospitalization rates and mortality and increased usage of services provided by the health system. Tools exist to improve prescription practices and decrease PIP, including screening tools and explicit criteria that can be applied in an automated manner. Objective This study aimed to describe the prevalence of PIP in primary care consultations among patients aged 65-75 years with multimorbidity and polypharmacy, detected by an electronic clinical decision support system (ECDSS) following the 2015 American Geriatrics Society Beers Criteria, the European Screening Tool of Older Person’s Prescription (STOPP), and the Screening Tool to Alert doctors to Right Treatment (START). Methods This was an observational, descriptive, cross-sectional study. The sample included 593 community-dwelling adults aged 65-75 years (henceforth called young seniors), with multimorbidity (≥3 diseases) and polypharmacy (≥5 medications), who had visited their primary care doctor at least once over the last year at 1 of the 38 health care centers participating in the Multimorbidity and Polypharmacy in Primary Care (Multi-PAP) trial. Sociodemographic data, clinical and pharmacological treatment variables, and PIP, as detected by 1 ECDSS, were recorded. A multivariate logistic regression model with robust estimators was built to assess the factors affecting PIP according to the STOPP criteria. Results PIP was detected in 57.0% (338/593; 95% CI 53-61) and 72.8% (432/593; 95% CI 69.3-76.4) of the patients according to the STOPP criteria and the Beers Criteria, respectively, whereas 42.8% (254/593; 95% CI 38.9-46.8) of the patients partially met the START criteria. The most frequently detected PIPs were benzodiazepines (BZD) intake for more than 4 weeks (217/593, 36.6%) using the STOPP version 2 and the prolonged use of proton pump inhibitors (269/593, 45.4%) using the 2015 Beers Criteria. Being a woman (odds ratio [OR] 1.43, 95% CI 1.01-2.01; P=.04), taking a greater number of medicines (OR 1.25, 95% CI 1.14-1.37; P<.04), working in the primary sector (OR 1.91, 95% CI 1.25-2.93; P=.003), and being prescribed drugs for the central nervous system (OR 3.75, 95% CI 2.45-5.76; P<.001) were related to a higher frequency of PIP. Conclusions There is a high prevalence of PIP in primary care as detected by an ECDSS in community-dwelling young seniors with comorbidity and polypharmacy. The specific PIP criteria defined by this study are consistent with the current literature. This ECDSS can be useful for supervising prescriptions in primary health care consultations.
Prediction of Adverse Outcomes in Pediatric Acute Hematogenous Osteomyelitis.

BACKGROUND Clinicians cannot reliably predict complications of acute hematogenous osteomyelitis (AHO). METHODS Consecutive cases of AHO from two pediatric centers in the United States were analyzed retrospectively to develop clinical tools from data obtained within 96 hours of hospitalization to predict acute and chronic complications of AHO. Two novel composite prediction scores derived from multivariable logistic regression modeling were compared with a previously published Severity of Illness (SOI) score, CRP, and ESR using area under the receiver operating characteristic (ROC) curve analyses. RESULTS The causative organisms were identified in 73% of 261 cases. Bacteremia (45%), abscesses (38%), and associated suppurative arthritis (23%) were relatively common. Acute or chronic complications occurred in 24% and 11% of patients, respectively. Multivariable logistic regression identified bone abscess (OR 2.3, 95% CI 1.0-5.2), fever >48 hours (OR 2.7, 95% CI 1.2-6.0), suppurative arthritis (OR 3.2, 95% CI 1.3-7.5), disseminated disease (OR 4.6, 95% CI 1.5-14.3), and delayed source control (OR 5.1, 95% CI 1.4-19.0) as strong predictors of acute complications. In a separate model, CRP ≥100 mg/L at 2-4 days after antibiotics (OR 2.7, 95% CI 1.0-7.3), disseminated disease (OR 3.3, 95% CI 1.1-10.0), and requirement for bone debridement (OR 6.7, 95% CI 2.1-21.0) strongly predicted chronic morbidity. These variables were combined to create weighted composite prediction scores for acute (A-SCORE) and chronic (C-SCORE) osteomyelitis, which were superior to SOI, CRP and ESR, and had negative predictive values >90%. CONCLUSIONS Two novel composite clinical scores were superior to existing tools to predict complications of pediatric AHO.
Clinical, Microbiological and Inflammatory Evidence of the Efficacy of Combination Therapy Including Serratiopeptidase in the Treatment of Periimplantitis

The present study was aimed to evaluate the effect of introducing administration of the proteolytic enzyme serratiopeptidase in the combined mechanical-antibiotic treatment of periimplantitis (PI). Two randomized groups of 64 adults with a diagnosis of PI were studied over a 6-month period. All patients were treated with a combined mechanical and antibiotic protocol for 15 days. The experimental group (EG) was administered antibiotic and serratiopeptidase, while the control group was administered antibiotic alone. To evaluate the effects of the two treatment protocols, clinical and radiographic indices, the concentration of IL-lβ, IL-6 and TNF-α in the gingival crevicular fluid, the amount of total bacteria] DNA and the presence of specific bacteria were assessed at baseline and at 6 months from treatment. Success rates of combined treatments at 6 months were 96.9% and 78.1% for the EG and CG respectively (P≤0.01). Implants of the EG showed greater enhancement of clinical, microbiological and inflammatory parameters as compared to those of the CG. Microbiological analyses showed that resistance to combined therapy was constantly associated with the isolation of bacterial species that are not common periodontal pathogens (mainly S.aureus and P.aeruginosa). The data demonstrate that the addition of serratiopeptidase to combined mechanical-antibiotic treatment protocols of periimplantitis significantly improves outcomes and suggest that serratiopeptidase acts at different levels during the healing process.