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Babušnica is one of the poorest municipalities in Serbia. Although it is a region with excellent physical geographic features that support the development of recreational and environmentally conscious types of tourism, its natural resources are almost entirely underutilized. The article first discusses Babušnica’s primary development issues before doing a theoretical examination of the ideas of geotourism and sustainable tourism and applying the Modified Geosite Assessment Model. To investigate the potential for their tourism activation, nine geosites were selected and evaluated. The evaluation ratings for most of the sites are very low due to the absence or poor quality of each type of infrastructure. The types of tourism that can be promoted in the region according to its geographical features are identified and recommendations are made to local and higher levels of authority that could form the basis for sustainable growth of the region.

Marián Sedlák,1,2 Adonis Wazir,3 Aikaterini Dima,4 Jakub Gazda,5 Radoslav Morochovič1 1Trauma Surgery Department, Pavol Jozef Safarik University in Kosice, Faculty of Medicine & Louis Pasteur University Hospital, Kosice, Slovakia; 2Zachranna Sluzba Kosice, Kosice, Slovakia; 3Swansea University Medical School, Swansea, UK; 4South London and Maudsley NHS Foundation Trust, London, UK; 5 2nd Department of Internal Medicine, Pavol Jozef Safarik University in Kosice, Faculty of Medicine & Louis Pasteur University Hospital, Kosice, SlovakiaCorrespondence: Marián Sedlák, Pavol Jozef Safarik University in Kosice, Faculty of Medicine & Louis Pasteur University Hospital, Trauma Surgery Department, Kosice, Slovakia, Email marian.sedlak.md@gmail.comBackground: Traumatic brain injury (TBI) is one of the most common trauma-related diagnoses among the elderly population treated in emergency departments (ED). Identification of patients with increased or decreased risk of intracranial bleeding is of clinical importance. The objective of this study was to evaluate the implication of cutaneous impact location (CIL) on the prevalence of intracranial injury after suspected or confirmed TBI irrespective of its severity.Methods: This was a retrospective, single-center, descriptive observational study of geriatric patients aged 65 years and older treated for suspected or confirmed TBI in a trauma surgery ED. The primary outcome of the study was the assessment of a CIL of the injury and its association with the prevalence of intracranial lesions found on a head computed tomography scan.Results: Among 381 patients included in the analysis, the CIL of interest (temporo-parietal and occipital impacts) was present among 178 (46.7%) cases. Thirty-six (9.5%) patients were diagnosed with intracranial bleeding. The prevalence of intracranial bleeding was higher in the CIL of interest group compared with other locations outside (12.9% vs 6.4%; p = 0.030). CIL of interest was a predictor of intracranial bleeding (p = 0.033; OR: 2.17; 95% CI: 1.06 to 4.42).Conclusion: The CIL of head injury is a predictor of intracranial lesions among geriatric patients with traumatic brain injury. Physicians should be aware of this association when assessing elderly patients with head injuries. More studies are needed to develop a clinical management tool incorporating CIL to guide the diagnosis of TBI in this population.Keywords: cutaneous impact location, traumatic brain injury, TBI, geriatric TBI

The paper analyzed the agrarian potential at the level of settlements in the municipality of Varvarin. This work aims to identify the most significant factors that affect agrarian potential. The following methods were applied: the method of successive dividers for determining the direction of agricultural land use, the weighting method for obtaining a reference value for calculating the agricultural potential, and the correlation coefficient for the analysis of cause-and-effect relationships between the value of the agricultural potential by settlements and used parameters. The paper provides an overview of the key problems in agriculture at the local, regional, national, continental, and global levels, including programs implemented by certain developed countries to revitalize agriculture.

This paper analyzed the spatial distribution of drought at meteorological stations on the Lim valley (Plav, Andrijevica, Berane and Bijelo Polje) and on the upper course of the river Ibar (Rožaje). The goal of this research is to point out the modern climatic characteristics in relation to the current state of aridization, which is a limiting factor for economy of the population in many areas throughout the world. The method used for such purposes is the De Marton drought index. Results of the research indicated a decrease in the annual drought index through the Lim valley, with the highest values for Plav (IDM=61,9), and the lowest for the lowest downstream station Bijelo Polje (IDM=41,3). The values of this climate index indicate the conditions of very humid (Berane, Bijelo Polje and Rožaje) and extremely humid climates (Plav and Andrijevica), with huge drainage and forest vegetation. By applying the De Marton index on a seasonal and monthly level, the highest values of this indicator were established in the winter season.

The paper analyzed the impact of tourism development on changes in the employed population in the service sectors by individual activities. The aim of this paper is to point out the relationship between changes in the number of tourists and changes in the number of employed population in service activities. The area of research is limited to the territory of the city of Belgrade. It cover an area of 3.223km2 . The basic methodological procedures used for research are mathematical - statistical methods: Pearson's correlation coefficient (r), testing the significance of the correlation coefficient (t test) and causal relationship (R). By applying the mentioned methods, a strong connection has been established between the growth of tourist traffic and the growth of the number of employed population in the service delivery activities on the territory of Belgrade.

The paper analyzed basic physical-geographical characteristics and changes caused by afforestation. The aim of the paper is to point out the transformation of the natural environment initiated by afforestation, to present positive and negative implications of this action, and to emphasize the importance of the consideration of the cause-and-effect relationships during concrete action in the field. By applying analytical-synthesis and comparative methods, a presentation of the natural features of the Deliblato sand and changes that were made as a result of afforestation, is given. The results of the research present positive changes which are reflected in the stabilization of unbound sand, development of the pedogenetic process and improvement in the microclimate conditions in the forested sectors. Negative changes in afforestation are reflected in the reduction of the area's steppe vegetation and the consequent intensity of forest fires.

Objective: The objective of this study was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug treatment in patients with gout., Methods: We conducted a retrospective analysis of patients with gout using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry from January 2016 through June 2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug treatment, we identified three exposure groups: (1) immunomodulatory drug initiators (patients initiating an immunomodulatory prescription ±60 days from the index date), (2) prevalent immunomodulatory drug recipients (patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of the index date), and (3) immunomodulatory nonrecipients (patients receiving pegloticase without concomitant immunomodulatory drugs). We calculated the proportion of patients who achieved serum urate levels ≤6 mg/dL and who had laboratory abnormalities (white blood cell count <3.4 x 10 9 /L, platelet count <135,000, hematocrit level <30%, alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit normal value) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation, controlling for potential confounders., Results: We identified 700 pegloticase recipients (91 immunomodulatory drug initiators, 33 prevalent immunomodulatory drug recipients, and 576 nonrecipients), with a median follow-up of 14 months. Immunomodulatory drug recipients were less likely to discontinue pegloticase. The adjusted hazard ratios of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation and prevalent treatment were 0.52 (95% confidence interval [CI] 0.37-0.75) and 0.69 (95% CI 0.42-1.16), respectively. Laboratory abnormalities were uncommon (<5%) and were not higher in concomitant immunomodulatory drug treatment., Conclusion: Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug treatment improves pegloticase persistence., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The transient worsening of oral health sometimes accompanies orthodontic treatment (OT), and the extent of this effect might depend on whether the patients are treated with traditional brackets or clear aligners. Saliva is an important tool for monitoring oral health and influences the functional properties of various oral cells. This study aimed to compare the effects of saliva from patients undergoing OT with Invisalign aligners and brackets on human gingival fibroblasts and oral epithelial cells in vitro. Unstimulated saliva was collected from 15 patients treated with Invisalign and 16 patients treated with brackets before and 3 and 6 months after therapy began. The saliva was used to stimulate primary human gingival fibroblasts and the oral epithelial Ca9-22 cell line, and the resulting cell response was investigated. Saliva did not exhibit any toxic effect on investigated cells, as shown by the proliferation/viability assay with the MTT method. In human gingival fibroblasts, saliva increased gene expression of various proinflammatory mediators, such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1, assessed by qPCR. In epithelial cells, saliva increased the production of IL-8 measured by ELISA and decreased gene expression of various proteins involved in the barrier function. During the therapy, the saliva-induced production of IL-8 tended to be decreased, and the saliva-induced decrease in the expression of barrier protein was partially improved. No difference between aligners and brackets was observed in either cell type. Saliva affects the functional properties of oral cells, but this effect is not influenced by the type of OT.

Mesenchymal stem cells (MSCs) are of great interest to scientists due to their application in cell therapy of many diseases, as well as regenerative medicine and tissue engineering. Recently, there has been growing evidence surrounding the research based on extracellular vesicles (EVs), especially small EVs (sEVs)/exosomes derived from MSCs. EVs/exosomes can be secreted by almost all cell types and various types of EVs show multiple functions. In addition, MSCs-derived exosomes have similar characteristics and biological activities to MSCs and their therapeutic applications are considered as a safe strategy in cell-free therapy. The aim of this study was the characterization of MSCs isolated from the chorion (CHo-MSCs) of human full-term placenta, as well as the isolation and analysis of small EVs obtained from these cells. Accordingly, in this study, the ability of small EVs' uptake is indicated by synovial fibroblasts, osteoblasts and periosteum-derived MSCs. Improvement in the understanding of the structure, characteristics, mechanism of action and potential application of MSCs-derived small EVs can provide new insight into improved therapeutic strategies.

Introduction: Thyroid eye disease (TED) is an autoimmune condition producing ocular pain, dysmotility, and ocular structure and function changes. As disease activity changes, redness, swelling, and pain can improve, but eye comfort, appearance, and motility alterations often persist. There are limited data on chronic TED patient-reported outcomes. This study examined chronic US TED patient-reported symptoms and quality of life (QOL)., Methods: Existing data from an online survey regarding chronic TED signs/symptoms and patient QOL were retrospectively examined. The Graves' Ophthalmopathy QOL instrument (GO-QOL; 0-100, 100 = highest QOL) evaluated overall, appearance, and vision-related QOL. Influencing factors were examined by stratifying patients into low (overall QOL ≤ 50), moderate (> 50 and < 75), and high (≥ 75) QOL categories., Results: One hundred patients (47 women, 81 Caucasian, 45.2 ± 7.6 years) were included. The duration of inactive TED was 3.0 ± 4.6 years and total duration of TED was 5.8 ± 5.9 years. Patients reported an average of 20 doctor visits/year and high prevalence of anxiety (34%) and depression (28%). Prior TED treatments for the polled population included systemic corticosteroids during active TED (25%), orbital radiation (5%), and surgery (25%). The overall GO-QOL score was 60.5 ± 21.8 (vision-related: 58.6 ± 24.0, appearance-related: 62.3 ± 25.1). Patients with low QOL more frequently reported hypothyroidism, anxiety, and a larger number of chronic TED signs/symptoms (average: 4.2). Compared to high QOL patients, low QOL patients had more pain (39% vs. 13%), blurry vision (30% vs. 17%), and diplopia (27% vs. 3%, all p ≤ 0.025). Additionally, the low QOL group more often had TED-specific surgical history (45% vs. 10%, p = 0.002), more often reported disability/unemployment (21% vs. 3%, p = 0.055), and had a higher number of doctor visits (40 vs. 5 visits/person/year, p < 0.001)., Conclusion: TED severely impacts patient QOL, despite becoming stable and chronic. Patients reported vision and appearance impairment and psychosocial impact long after acute TED had subsided., (© 2021. The Author(s).)

Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.

Introduction: Gout is a common, progressive, systemic inflammatory arthritis caused by hyperuricemia. Current guidelines recommend that serum uric acid (sUA) levels be maintained below 6.0 mg/dl to minimize acute gout attacks, tophi development, and long-term joint and organ damage. This study examined the influence of uncontrolled gout on post-diagnosis comorbidities and medication use., Methods: The Humana Research Database (2007-2016, commercial insurance and Medicare) was searched (PearlDiver tool) for patients who had a gout diagnosis code, claims data for at least 6 months before and after diagnosis, and at least 90 days of continuous urate-lowering therapy within 1 year of diagnosis. Patients with controlled (all sUA measurements < 6.0 mg/dl) and uncontrolled (all sUA measurements ≥ 8.0 mg/dl) gout were further examined and compared to better understand the influence of uncontrolled gout on post-diagnosis comorbidities, medication use, and reasons for seeking medical care., Results: A total of 5473 and 1358 patients met inclusion and classification criteria for the controlled and uncontrolled groups, respectively. Identified comorbidities in both groups included hypertension, hyperlipidemia, diabetes, cardiovascular disease, and chronic kidney disease (CKD). However, the uncontrolled group was more likely to have diabetes, CKD, and cardiovascular disease (including heart failure and atrial fibrillation). Additionally, CKD tended to be more advanced in the uncontrolled gout population (Stage 4-5: 34.6 vs. 22.2%). Overall opioid use was higher in uncontrolled patients., Conclusions: The current study identified differences between controlled and uncontrolled gout patients, including usage of medication, severity of CKD, and prevalence of CKD, diabetes, and heart disease.

Introduction: Thyroid eye disease (TED) is an autoimmune disease that causes retro-orbital inflammation and subsequent proptosis, corneal exposure, strabismus, and variable vision changes. European studies have shown that TED can severely impact quality of life (QOL), but little is known about the QOL of patients with TED in the USA. Given that patient QOL influences TED severity classifications and subsequent treatment, understanding physician-perceived patient QOL is extremely important., Methods: This retrospective chart review (conducted in 2018) examined QOL in US patients with moderate-to-severe TED, as reported by treating physicians who regularly manage patients with TED (≥ 5 patients in prior 12 months). The physicians graded patients' overall QOL (7-point Likert scale; 1 = "not at all impaired", 7 = "extremely impaired"), assessing mental health, vision changes, and ocular structural signs/symptoms. Patient demographics and clinical findings were examined to understand the impact of disease presentation on physician-perceived QOL., Results: Medical record data of 714 US patients with moderate-to-severe TED were provided by 181 physicians (73 endocrinologists, 108 ophthalmologists). Patients had a mean age of 49.4 (standard deviation [SD] 13.6) years, and 102 cases (14%) were severe. Anxiety and/or depression was reported in 36% of patients (an increase from the 18.9% prevalence reported for the USA in 2017 by the US National Institute of Mental Health; P < 0.001). The mean physician-reported QOL impact score was 4.1 (SD 1.5). Furthermore, 62 and 89% of patients with moderate and severe TED, respectively, had a high physician-perceived QOL impact (≥ 4). The higher QOL impact group had significantly higher rates of pain symptoms, visual disturbances (including diplopia), and orbito-facial structural changes. Higher disease activity and severity were associated with lower physician-perceived QOL., Conclusion: Patients' QOL, as evaluated by US physicians, is highly impacted by the activity and severity of TED. Additionally, mental health issues were more frequently reported by patients with TED than in the general US population. Ocular pain, strabismus, and diplopia appear to be main drivers of physician-perceived QOL impairment in this sample of US patients with TED.

Microplastics are an emerging contaminant of high environmental concern due to their widespread distribution and availability to aquatic organisms. Filter-feeding organisms like bivalves have been identified as particularly susceptible to microplastics, and because of this, it has been suggested bivalves could be useful bioindicators of microplastic pollution in ecosystems. We sampled resident mussels and clams from five sites within San Francisco Bay for microplastics and other anthropogenic microparticles. Cages of depurated mussels (denoted transplants) were also deployed at four sites in the Bay for 90 days to investigate temporal uptake of microplastics and microparticles. Because microplastics can sorb PAHs, and thus may act as a source of these chemicals upon ingestion, transplant mussels and resident clams were also analyzed for PAHs. We found anthropogenic microparticles in all samples at all sites, some of which were identified as microplastics. There was no statistical difference between the mean number of microparticles found in resident and transplant species. There were significant site-specific differences among microparticle abundances in the Bay, with the highest abundances observed in the South Bay. No correlation was found between the number of microparticles and the sum concentrations of PAHs, priority PAHs, or any individual PAH, suggesting the chemical concentrations observed reflect broader chemical trends in the Bay rather than direct exposure through microplastic ingestion. The pattern of spatial distribution of microparticles in transplanted mussels matched that of sediment samples from the Bay, suggesting bivalves could be a useful bioindicator of microplastic abundances in sediment, but not surface water., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease, which is associated with low levels of physical activity (PA). However, the factors related to low physical activity levels have rarely been studied. Methods: In this cross-sectional study, 70 seropositive RA patients were included. Physical activity was objectively assessed with an ActiGraph GT3X+ accelerometer. In addition, body mass index, smoking status, work ability, and clinical parameters (functional disabilities, disease activity, disease duration, pain, and inflammation parameters) were measured. Results: RA patients performed a mean of 215.2 (SD: 136.6) min a week of moderate physical activity and 9.1 (SD: 26.3) min of vigorous physical activity. The total amount of moderate and vigorous physical activity (MVPA) was associated with BMI, and functional disabilities. In addition, non-smokers and patients with better work ability did more MVPA. No association could be seen with disease activity, disease duration, pain, and inflammatory markers. After mutual adjusting of all the variables, only BMI showed a significant relationship with MVPA. Conclusions: RA patients perform de facto no physical activity with vigorous intensity. Factors related to low physical activity are BMI, functional disabilities, workability and smoking status, whereas due to the study design no causal and temporal link could be made.

Background: The causal relationship between gout and renal transplant outcomes is difficult to assess due to multiple interacting covariates. This study sought to estimate the independent effect of new-onset gout on renal transplant outcomes using a methodology that accounted for these interactions., Methods: This study analyzed data on patients in the US Renal Data System (USRDS) who received a primary kidney transplant between 2008 and 2015. The exposure was new-onset gout, and the primary endpoint was returning to dialysis >12 months postindex date (transplant date). A marginal structural model (MSM) was fitted to determine the relative risk of new-onset gout on return to dialysis., Results: 18 525 kidney transplant recipients in the USRDS met study eligibility. One thousand three hundred ninety-nine (7.6%) patients developed new-onset gout, and 1420 (7.7%) returned to dialysis >12 months postindex. Adjusting for baseline and time-varying confounders via the MSM showed new-onset gout was associated with a 51% increased risk of return to (RR, 1.51; 95% CI, 1.03-2.20)., Conclusions: This finding suggests that new onset gout after kidney transplantation could be a harbinger for poor renal outcomes, and to our knowledge is the first study of kidney transplant outcomes using a technique that accounted for the dynamic relationship between renal dysfunction and gout., (Copyright © 2020 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Introduction: Limited data exist on US referral/management patterns for moderate-to-severe thyroid eye disease (TED), a disabling condition., Methods: US ophthalmologists and endocrinologists experienced in treating TED provided medical record data of moderate-to-severe TED patients and information on referral/treatment practices. Data on signs/symptoms, medical/surgical treatments, treatment response, and referral history were collected. Moderate and severe cases were stratified to interrogate treatment/practice differences., Results: A total of 181 physicians provided data on 714 patients (49.4 ± 13.6 years old, 65% women, 14% severe disease). Reporting physicians diagnosed 55% of patients themselves and solely managed 37% of cases, with similar referral/comanagement patterns between moderate and severe cases. Topical therapies included lubricating (79%) and glucocorticoid (39%) eye drops. Systemic therapies included oral glucocorticoids (36%), IV glucocorticoids (15%), and rituximab and/or tocilizumab (12%). Few patients underwent orbital radiation (4%) or surgical intervention (4%). IV glucocorticoids (33% vs. 12%), biologics (26% vs. 10%), orbital radiation (11% vs. 3%), and ocular surgery (12% vs. 3%) were used more often in severe versus moderate cases (all P  < 0.001). However, severe disease was less responsive to therapy (very responsive to therapy: 28% vs. 49%, P  < 0.001)., Conclusions: Participating physicians were primarily responsible for just over one-half of TED diagnoses, but solely treated <40% of patients. Severe TED was treated more often with surgery and systemic immunologic therapies than moderate disease, but was less likely to respond to treatment. These results reinforce that moderate-to-severe TED is difficult to treat with an unmet medical need in the United States., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

We present a model to predict the long-term distribution and concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in estuaries comprising multiple intercommunicated sub-embayments. To that end, a mass balance model including rate constants and time-varying water inputs was designed to calculate levels of these compounds in water and sediment for every sub-embayment. Subsequently, outflows and tidal water exchanges were used to interconnect the different regions of the estuary. To calculate plausible risks to population, outputs of the model were used as inputs in a previously designed model to simulate concentrations of PFOA and PFOS in a sport fish species (Cymatogaster aggregata). The performance of the model was evaluated by applying it to the specific case of San Francisco Bay, (California, USA), using 2009 sediment and water sampled concentrations of PFOA and PFOS in North, Central and South regions. Concentrations of these compounds in the Bay displayed exponential decreasing trends, but with different shapes depending on region, compound, and compartment assessed. Nearly stable PFOA concentrations were reached after 50 years, while PFOS needed close to 500 years to stabilize in sediment and fish. Afterwards, concentrations stabilize between 4 and 23 pg/g in sediment, between 0.02 and 44 pg/L in water, and between 7 and 104 pg/g wet weight in fish, depending on compound and region. South Bay had the greatest final concentrations of pollutants, regardless of compartment. Fish consumption is safe for most scenarios, but due to model uncertainty, limitations in monthly intake could be established for North and South Bay catches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of unknown etiology, which lasts for greater than 6 weeks with onset before 16 years of age. JIA is the most common chronic rheumatic disease in children. NSAIDs have been the mainstay of initial management with naproxen (NAP) being commonly used, but they may cause serious side effects such as gastric ulcers which can be reduced by concomitant administration of proton pump inhibitors, such as esomeprazole (ESO)., Methods: Primary objective was to evaluate the safety and tolerability of 3 fixed doses of NAP/ESO in JIA patients aged 12 to 16 years. Forty-six children and adolescents with JIA by International League of Associations for Rheumatology criteria, mean age of 13.6 years, from 18 US sites were prospectively enrolled over 2 years and followed for up to 6 months. Doses of the NAP/ESO fixed combination were based on baseline weight. The exploratory efficacy outcome was assessed with the ACR Pediatric-30, - 50, - 70, - 90 Response and the Childhood Health Assessment Questionnaire (CHAQ) discomfort and functional scores at months 1, 3, and 6 as change from baseline. Occurrence and causality were assessed for treatment emergent AEs (TEAEs) and discontinuations were monitored monthly., Results: Forty-six patients received at least 1 dose of naproxen/esomeprazole and 36 completed the trial. Thirty-seven (80.4%) had at least 1 treatment emergent adverse event (TEAE) and, with the exception of 2 events in one patient, all of the TEAEs were mild or moderate. Frequent TEAEs (≥5% of patients) were upper respiratory tract and gastrointestinal related. Eleven (23.9%) had at least 1 TEAE considered to be related to study drug. Four patients (8.7%) discontinued due to a TEAE with one of these being the only serious AE reported, acute hepatitis. Mean number of active joints at baseline was 3.1. Improvement in JIA signs and symptoms occurred at most assessments and by month 6, the percentage of patients with an ACR Pediatric-30, - 50, - 70, and - 90 Response was 47.1, 38.2, 32.4, and 17.6%, respectively. The percent of patients achieving ACR Pediatric response increased over time. CHAQ discomfort improved at each assessment and functional scores improved at all assessments for 'Arising, Walking, and Activities' with several improved for 'Dressing and Grooming, Eating, Hygiene, and Grip'. There was no indication of a dose-related efficacy effect., Conclusion: NAP/ESO was well tolerated in JIA patients aged 12 to 16 years with high levels of response to ACR criteria. No new safety signals were identified for the well-characterized components of this fixed dosed JIA treatment, which was developed to reduce the risk of gastric ulcers., Trial Registration: Clinicaltrials.gov, NCT01544114 . Registered February 21, 2012.

Introduction: Rheumatoid arthritis (RA) produces debilitating morning stiffness. Exogenous glucocorticoids can help with these symptoms when timed appropriately. Bedtime dosing of delayed-release prednisone (DR-prednisone) matches the rise of inflammatory cytokines before awakening and can improve stiffness and other RA symptoms. A prospective open-label study was conducted in patients currently on stable doses of immediate-release prednisone (IR-prednisone) who were switched to DR-prednisone to analyze the incremental benefit of better timed and lower dose glucocorticoid therapy., Methods: Twelve US sites enrolled patients with moderate-severe RA into a 12-week prospective study. Patients were switched from IR- to DR-prednisone while maintaining other existing background therapies. Change from baseline in morning stiffness severity, morning stiffness duration, swollen and tender joint counts (S-TJC), 28 joint disease activity score (DAS28), and patient/physician global assessment (PGA/PhGA), among others, were measured. Post-hoc analyses were performed on those completing 10 weeks of treatment and those with >60 min of morning stiffness at baseline., Results: Fifty-six patients had at least one follow-up visit and were similar in demographics to previous controlled trials with DR-prednisone with regard to baseline age and DAS28-CRP but had lower morning stiffness and RA duration. DR-prednisone produced a trend toward lower morning stiffness severity and duration with a reduction in daily prednisone dose of almost 1 mg. Patients treated with DR-prednisone for ≥10 weeks demonstrated significant reductions in morning stiffness duration, SJC, TJC, DAS28-CRP, and PhGA (all p ≤ 0.04). Patients treated for ≥10 weeks with >60 min of baseline morning stiffness produced similar results in these measures as well as a 21% reduction in morning stiffness severity (p = 0.02)., Conclusion: Patients switched to DR-prednisone from IR-prednisone in this practice-based study maintained or improved their outcomes across a variety of domains, and results were comparable to previous controlled trials in which patients completed at least 10 weeks of treatment., Funding: Horizon Pharma USA, Inc., Trial Registration: ClinicalTrials.gov identifier, NCT02287610.

Background: A challenge currently facing the cellulosic biofuel industry is the efficient fermentation of both C5 and C6 sugars in the presence of inhibitors. To overcome this challenge, microorganisms that are capable of mixed-sugar fermentation need to be further developed for increased inhibitor tolerance. However, this requires an understanding of the physiological impact of inhibitors on the microorganism. This paper investigates the effect of salts on Saccharomyces cerevisiae 424A(LNH-ST), a yeast strain capable of effectively co-fermenting glucose and xylose., Results: In this study, we show that salts can be significant inhibitors of S. cerevisiae. All 6 pairs of anions (chloride and sulfate) and cations (sodium, potassium, and ammonium) tested resulted in reduced cell growth rate, glucose consumption rate, and ethanol production rate. In addition, the data showed that the xylose consumption is more strongly affected by salts than glucose consumption at all concentrations. At a NaCl concentration of 0.5M, the xylose consumption rate was reduced by 64.5% compared to the control. A metabolomics study found a shift in metabolism to increased glycerol production during xylose fermentation when salt was present, which was confirmed by an increase in extracellular glycerol titers by 4 fold. There were significant differences between the different cations. The salts with potassium cations were the least inhibitory. Surprisingly, although salts of sulfate produced twice the concentration of cations as compared to salts of chloride, the degree of inhibition was the same with one exception. Potassium salts of sulfate were less inhibitory than potassium paired with chloride, suggesting that chloride is more inhibitory than sulfate., Conclusions: When developing microorganisms and processes for cellulosic ethanol production, it is important to consider salt concentrations as it has a significant negative impact on yeast performance, especially with regards to xylose fermentation.

Objecives: The clinical and histological diagnosis (gold standard) of diabetic nephropathy (dNP) and vascular nephropathy (vNP) were compared in type 2 diabetic patients with end-stage renal disease (ESRD)., Aim: The aim of the study was to investigate indication for renal biopsy in type 2 diabetic patients with renal disease., Design: Retrospective study in diabetic patients with clinical and histological diagnosis of renal disease., Patients and Methods: Eighty-four patients with type 2 diabetes and ESRD were investigated. Histological findings of the kidneys were available in all patients, 14 had undergone a renal biopsy before their first dialysis while a post-mortem kidney investigation was performed in 70 subjects. According to the histological findings, 66 patients had dNP and 18 subjects had vNP. The histological diagnosis was compared with the clinical diagnosis, and the sensitivity as well as the specificity of the clinical diagnosis of dNP and vNP were calculated., Results: The clinical diagnosis was not identical with the histological diagnosis in 10 cases. In the dNP group the diagnosis was 4 false positive and 3 false negative as in the vNP group 1 false positive and 2 false negative. The sensitivity of clinical diagnosis was 95% for dNP and 89% for vNP. Specificity was 78% for dNP and 97% for vNP., Conclusion: The sensitivity of the clinical diagnosis is very high for dNP as well as vNP. A renal biopsy is not required in the majority of type 2 diabetic patients with ESRD, especially in patients who exhibit all criteria for clinical diagnosis.