Miracle-dz/UniFAR-FTUs huggingface dataset:
Changes in cartilage and subchondral bone in a growing rabbit experimental model of developmental trochlear dysplasia of the knee

ABSTRACT Purpose: Trochlear dysplasia is one of the most frequent lower extremities deformities. Aim of this research was to investigate the changes in cartilage and subchondral bone of trochlea after patellar dislocation in growing rabbits. Materials and Methods: Ninety-six knees from 48 one-month-old rabbits were divided into two groups (experimental, control). Lateral patellar dislocation was established in the experimental group and distal femurs were collected at 4, 8, 12 and 24-week time points, respectively. General examination and histological observations were conducted to research the anatomical structure of the trochlear cartilage and subchondral bone. Structural parameters of trochlear subchondral bone were measured by MicroCT. Subsequently, the expression of TRPV4, collagen II and MMP-13 in cartilage were detected by western blot and RT-PCR analysis, respectively. Results: Subchondral bone loss was found in experimental group from 4 weeks after patellar dislocation, accompanied by increased TRAP-positive osteoclasts in subchondral bone. The trochlear dysplasia model was well established from 8 weeks after patellar dislocation. In addition, degeneration of cartilage was found from 8 weeks, accompanied by decreased expression of mechanically sensitive TRPV4 and collagen II, and increased expression of MMP-13. Conclusions: This study proved that trochlear dysplasia can be caused by patellar dislocation in growing rabbits, accompanied by significant subchondral bone loss. What is more, this study also shows that degenerative cartilage changes occur in the patellar dislocation model and become aggravated with time, accompanied by decreased TRPV4 and collagen II, but increased MMP-13
On-site blood culture incubation shortens the time to knowledge of positivity and microbiological results in septic patients

Introduction To determine whether on-site incubation of blood cultures at the intensive care unit (ICU) improves not only the time to incubation but also time to positivity, time to knowledge of positivity and time to results (identification and antibiotic susceptibility testing). Methods This observational single-centre study in ICU patients with severe sepsis and septic shock investigated the impact of blood culture incubation immediately on-site at the ICU (ICU group) by comparison with traditional processing in a remote laboratory (LAB group) on different time intervals of blood culture diagnostics from obtaining blood to clinician notification of final result. The effect of on-site incubation was evaluated in Kaplan-Meier estimates for the time to positivity, time to knowledge of positivity and time to microbiological results and a linear mixed model was built. Results A total of 3,549 blood culture sets from 657 ICU patients were analysed: 2,381 in the LAB group and 1,168 in the ICU group. Overall, 660 (18.6%) blood culture sets were positive and 2,889 (81.4%) sets remained negative. On-site incubation was associated with reduced time to knowledge of positivity (46.9 h [CI 43.4–50.8 h] vs. 28.0 h [CI 23.6–32.2 h], p < 0.001) and reduced time to result (61.4 h [CI 58.4–64.8 h] vs. 42.1 h [CI 39.1–47.5 h], p < 0.001). In blood cultures processed instantaneously at the ICU compared to incubation in the remote laboratory within 4 h, the time to microbiological result was significantly reduced by 8.5 h (p < 0.001). Pre-existing anti-infective therapy had no significant impact on diagnostic time intervals. Conclusions Instantaneous incubation of blood cultures in the ICU compared to incubation in a remote laboratory significantly improves time to knowledge to positivity and time to result. These effects are even more pronounced during off-hours of the microbiological laboratory. The results underline the importance of 24/7 diagnostics to provide round-the-clock processing of blood culture samples in patients with sepsis and septic shock and an immediate to communication of the results to the clinicians.
Chemotherapy-induced mucositis development in a murine model of colitis-associated colorectal cancer

Abstract Objectives: Ulcerative colitis is an incurable inflammatory bowel disease that increases the risk of colorectal cancer (CRC). 5-Fluorouracil (5-FU) is the predominant chemotherapy for CRC patients; however, undesirable side-effects, including mucositis, are common. This study utilised 5-FU-treatment in a model of colitis-associated CRC to develop a pre-clinical setting of intestinal mucositis coincident with manifestation of CRC. Materials/methods: On day 0, female C57BL/6 mice (n = 10/group); (1) saline control, (2) AOM/DSS control, or (3) AOM/DSS + 5-FU were injected with saline or AOM (i.p; 7.4 mg/kg). Groups 2 and 3 underwent cycles of seven days 2%w/v DSS followed by 14 days plain water. After three cycles, 5-FU was administered weekly (i.p; 75 mg/kg) to group 3 for five weeks. Clinical indicators were measured daily and colonoscopy performed at four time-points. Mice were euthanized at 13 weeks (day 91). Intestinal sections were collected for histological and biochemical analyses. p < . 05 was considered significant. Results: AOM/DSS resulted in bodyweight loss, increased disease activity index, colitis-severity and tumour number compared to saline controls (p < .05). 5-FU-treatment in AOM/DSS mice decreased bodyweight and disease activity index at selected time-points compared to AOM/DSS controls (p < .05). 5-FU did not impact colitis-severity or overall tumour burden; although, resulted in fewer small tumours compared to AOM/DSS controls (<2mm; p < .05). AOM/DSS increased histological severity scores in intestinal sections (p < .05), however, 5-FU-treatment did not further increase histologically-assessed disease severity (p > .05). Conclusion: Weekly 5-FU administration at a dose of 75 mg/kg was insufficient to reduce overall tumour burden or induce intestinal mucositis in the AOM/DSS mouse model.
Aortic Stiffness and Age With Cognitive Performance Decline in the ELSA‐Brasil Cohort

Background Increased aortic stiffness has been associated with cognitive decline and dementia, but the results are inconsistent. This study investigated the longitudinal association of aortic stiffness and age with decreased cognitive performance in 3 cognitive tests. Methods and Results This study included 6927 participants, with a mean age of 58.8 years at baseline (2008–2010), who participated in the second wave (2012–2014) of the ELSA‐Brasil (Brazilian Longitudinal Study of Adult Health) (interval between visits ranging from 2–6 years). Cognitive performance was evaluated by Memory, Phonemic, and Semantic Verbal Fluency and Trail B Tests, applied at both cohort visits. Associations with the carotid‐femoral pulse wave velocity and age at baseline were investigated using linear models with mixed effects after adjusting for confounders. After all the adjustments, including for systolic blood pressure, the interaction term carotid‐femoral pulse wave velocity×time proved to be statistically significant for Memory and Verbal Fluency Tests, indicating that the higher carotid‐femoral pulse wave velocity at baseline was associated with a faster decline in cognitive performance in these tests between waves. The interaction term age×time was statistically significant for all cognitive tests, suggesting that increasing age at baseline was also associated with a faster decline in cognitive performance between waves. Conclusions In this relatively young cohort, and after a relatively short interval, an increased aortic stiffness at baseline was associated with a sharper decline in cognitive performances in memory and verbal fluency, regardless of systolic blood pressure levels. This study also showed that the decline in cognitive performance was faster among older individuals than among younger ones at baseline.
Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

BACKGROUND In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).
Effect of TDF-containing regimens on creatinine clearance in HIV patients in Namibia with a baseline CrCl <60ml/min; findings and implications

ABSTRACT Background and aims: The advent of antiretroviral therapy (ART) and early diagnosis of the human immunodeficiency virus (HIV) has resulted in an appreciable reduction in morbidity and mortality among people infected with HIV. However, tenofovir disoproxil fumarate (TDF)–containing ART regimens are associated with a reduction in creatinine clearance (CrCl). No evaluation has been conducted in Namibia to date on the relationship between TDF-containing ART and CrCl among patients with moderate to severe reductions in CrCl to guide future practice. We aimed to address this. Methodology: Retrospective longitudinal study between January 2008 to December 2016 evaluating CrCl in patients with a baseline CrCl <60ml/min who were receiving TDF-containing ART in a leading hospital in Namibia. We identified patients who had experienced an improvement in CrCl and compared their characteristics with those whose CrCl did not improve. We assessed factors for an association with improvement in CrCl using binary logistic regression. Results: 389 patients were included, the majority were female (n = 294). Female vs. male assessments showed no difference in age (p = 0.340), weight (p = 0.920), number who experienced an improvement (105 vs 39, p = 0.349), or absence of improvement (189 vs. 56, p = 0.349). The improvement group (male and female) had a lower baseline CrCl (45.9 vs. 55.0, p < 0.001). The follow-up CrCl for the improvement and no improvement groups were 72.6 and 55.9 respectively. Multivariate analysis showed that the odds of improvement were: 0.905 (0.871–0.940, p < 0.001) for each unit rise in the baseline CrCl, and 0.904(0.880–0.923) for each year of follow-up. Conclusion: More improvement than decline in CrCl was observed. Improvement occurred more in patients with lower baseline CrCl, and occurred in the early period of ART with reduced odds of experiencing this with time. Our findings indicate that TDF may be used in patients with a low baseline CrCl.
Comparison of plasma fatty acid binding protein 4 concentration in venous and capillary blood

Circulating fatty acid binding protein 4 (FABP4) is associated with various diseases and simple and less invasive techniques for assessment of FABP4 concentration are required in clinical research setting. The purpose of the present study was to assess the correlation of plasma FABP4 concentration between venous and capillary blood in healthy young adults. Twenty-eight healthy young adults aged from 20 to 26 years (mean age, 22.2 ± 1.4 years, 14 males and 14 females) were included. Paired resting blood samples were taken from the cubital vein (venous) and fingertip (capillary) blood. Plasma FABP4 concentration in both blood was analyzed by enzyme-linked Immunosorbent assay. Plasma FABP4 concentration did not differ significantly between venous and capillary blood (−0.11± 0.75 ng/mL, p = 0.447, 95%CI: -0.402–0.182). Pearson’s correlation coefficient for plasma FABP4 concentration between venous and capillary blood samples suggests strong correlation (r = 0.961, p < 0.001). The Bland & Altman plot showed a non-significant bias (−0.11 ± 0.75 ng/mL, p = 0.684) and the 95% limits of agreement ranged from −1.59 to 1.37 ng/mL. FABP4 concentration in both venous and capillary blood was significantly higher in females than in males (venous blood: p = 0.041; capillary blood: p = 0.049). These results suggest that capillary blood sampling can detect gender difference and is useful for the assessment of FABP4 concentration.
Alterations in mitochondrial functions and morphology in muscle and non‐muscle tissues in type 1 diabetes: implications for metabolic health

What is the topic of this review? Evidence of impaired mitochondrial functions and/or morphology in people with type 1 diabetes across various organ systems. What advances does it highlight? Impairments to mitochondrial functions and morphology may be a primary mechanism underlying the pathophysiology of various complications in people with type 1 diabetes.
High glycemic index and glycemic load diets as risk factors for insomnia: analyses from the Women's Health Initiative.

BACKGROUND Previous studies have shown mixed results on the association between carbohydrate intake and insomnia. However, any influence that refined carbohydrates have on risk of insomnia is likely commensurate with their relative contribution to the overall diet, so studies are needed that measure overall dietary glycemic index (GI), glycemic load, and intakes of specific types of carbohydrates. OBJECTIVE We hypothesized that higher GI and glycemic load would be associated with greater odds of insomnia prevalence and incidence. METHODS This was a prospective cohort study with postmenopausal women who participated in the Women's Health Initiative Observational Study, investigating the relations of GI, glycemic load, other carbohydrate measures (added sugars, starch, total carbohydrate), dietary fiber, and specific carbohydrate-containing foods (whole grains, nonwhole/refined grains, nonjuice fruits, vegetables, dairy products) with odds of insomnia at baseline (between 1994 and 1998; n = 77,860) and after 3 y of follow-up (between 1997 and 2001; n = 53,069). RESULTS In cross-sectional and longitudinal analyses, higher dietary GI was associated with increasing odds of prevalent (fifth compared with first quintile OR: 1.11; CI: 1.05, 1.16; P-trend = 0.0014) and incident (fifth compared with first quintile OR: 1.16; CI: 1.08, 1.25; P-trend < 0.0001) insomnia in fully adjusted models. Higher intakes of dietary added sugars, starch, and nonwhole/refined grains were each associated with higher odds of incident insomnia. By contrast, higher nonjuice fruit and vegetable intakes were significantly associated with lower odds of incident insomnia. Also, higher intakes of dietary fiber, whole grains, nonjuice fruit, and vegetables were significantly associated with lower odds of prevalent insomnia. CONCLUSIONS The results suggest that high-GI diets could be a risk factor for insomnia in postmenopausal women. Substitution of high-GI foods with minimally processed, whole, fiber-rich carbohydrates should be evaluated as potential treatments of, and primary preventive measures for, insomnia in postmenopausal women.
Effects of choice on neuronal activity in anterior cingulate, prelimbic, and infralimbic cortices in the rat: Comparison of serial lever pressing with delayed nonmatching to position

The ability to choose between response alternatives based on their likely consequences depends on distributed neural circuits that involve rodent medial prefrontal cortex (mPFC). To understand the effects of choice on mPFC function, we compared the activity of mPFC neurons in rats performing two tasks: dynamic delayed nonmatching to position (dDNMTP), a task with a prefrontal‐dependent conditional choice, and serial lever pressing (SLP), a task lacking a choice but trained in the same apparatus with sequences of actions and reinforcements matched to dDNMTP. More neurons exhibited event‐related responses during dDNMTP than SLP. Average firing rate during recording sessions was higher during dDNMTP for neurons with event‐related responses, but lower for neurons with activity unrelated to behavioural events. Thus, compared to SLP, dDNMTP appears to enhance the activity of neurons that represent behaviourally relevant information and to suppress the activity of neurons that do not. dDNMTP was associated with responses related to preparation and memory delay that were not observed during SLP as well as enhanced responses related to movement and reinforcement. These results provide evidence that choice in the dDNMTP task is associated with adaptive changes in background firing rates and coding properties of mPFC neurons.
Myrf guides target gene selection of transcription factor Sox10 during oligodendroglial development

Abstract Oligodendrocytes generate myelin in the vertebrate central nervous system and thus ensure rapid propagation of neuronal activity. Their development is controlled by a network of transcription factors that function as determinants of cell identity or as temporally restricted stage-specific regulators. The continuously expressed Sox10 and Myrf, a factor induced during late development, are particularly important for terminal differentiation. How these factors function together mechanistically and influence each other, is not well understood. Here we show that Myrf not only cooperates with Sox10 during the induction of genes required for differentiation and myelin formation. Myrf also inhibits the activity of Sox10 on genes that are essential during earlier phases of oligodendroglial development. By characterization of the exact DNA-binding requirements of Myrf, we furthermore show that cooperative activation is a consequence of joint binding of Sox10 and Myrf to the same regulatory regions. In contrast, inhibition of Sox10-dependent gene activation occurs on genes that lack Myrf binding sites and likely involves physical interaction between Myrf and Sox10 followed by sequestration. These two opposite activities allow Myrf to redirect Sox10 from genes that it activates in oligodendrocyte precursor cells to genes that need to be induced during terminal differentiation.
Beneficial effects of Cuscuta chinensis extract on glucocorticoid-induced osteoporosis through modulation of RANKL/OPG signals

Cuscuta chinensis Lam. (Convolvulaceae) is an important herbal medicine widely used to improve sexual function, treat osteoporosis, and prevent aging, and has been reported to exhibit anti-osteoporotic effects in vitro. However, the activity of Cuscuta chinensis Lam. on glucocorticoid-induced osteoporosis still remains unclear. The present study aimed to assess the protective effect and the underlying mechanism of action of Cuscuta chinensis extract (CCE) against glucocorticoid-induced osteoporosis in vivo. Sprague-Dawley rats were randomly divided into four groups as follows: control group, osteoporosis group, and 2 CCE-treated osteoporosis groups (100 mg·kg-1·day-1). Blood samples and femur bones were collected for immunohistochemistry, biochemical, mRNA expression, and western blot analysis. HPLC analysis revealed that chlorogenic acid, quercetin, and hyperin were the major constituents of CCE. The results indicated that CCE increased bone length, bone weight, and bone mineral density and suppressed dexamethasone (DEX)-induced reduction in body weight. In addition, TRAP staining indicated that CCE reduced osteoclasts in DEX-induced osteoporosis rats. Mechanistically, CCE treatment alleviated the increase of bone resorption markers and the decline of osteogenic markers, which might be partially mediated by regulation of RANKL/OPG and RunX2 pathways. These results suggest that CCE showed promising effects in the protection against glucocorticoid-induced osteoporosis through protecting osteoblasts and suppressing osteoclastogenesis.
Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09).

PURPOSE Approximately 10% of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) harbor uncommon mutations. Here, we report the efficacy and safety of osimertinib in patients with NSCLC harboring uncommon EGFR mutations. PATIENT AND METHODS This was a multicenter, single-arm, open-label, phase II study in Korea. Patients with histologically confirmed metastatic or recurrent NSCLC harboring EGFR mutations other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion were eligible for the study. The primary end point of objective response rate was assessed every 6 weeks by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary end points were progression-free survival, overall survival, duration of response, and safety. RESULTS Between March 2016 and October 2017, 37 patients were enrolled. All were evaluable except one patient who withdrew consent after starting treatment. Median age was 60 years, and 22 (61%) were male. Among patients, 61% received osimertinib as first-line therapy. The mutations identified were G719X (n = 19; 53%), followed by L861Q (n = 9; 25%), S768I (n = 8; 22%), and others (n = 4; 11%). Objective response rate was 50% (18 of 36 patients; 95% CI, 33% to 67%). Median progression-free survival was 8.2 months (95% CI, 5.9 to 10.5 months), and median overall survival was not reached. Median duration of response was 11.2 months (95% CI, 7.7 to 14.7 months). Adverse events of any grade were rash (n = 11; 31%), pruritus (n = 9; 25%), decreased appetite (n = 9; 25%), diarrhea (n = 8; 22%), and dyspnea (n = 8; 22%), but all adverse events were manageable. CONCLUSION Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.