Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Interpretable Deep Learning Model for Glaucoma Diagnosis

Despite the potential to revolutionise disease diagnosis by performing data-driven classification, clinical interpretability of ConvNet remains challenging. In this paper, a novel clinical interpretable ConvNet architecture is proposed not only for accurate glaucoma diagnosis but also for the more transparent interpretation by highlighting the distinct regions recognised by the network. To the best of our knowledge, this is the first work of providing the interpretable diagnosis of glaucoma with the popular deep learning model. We propose a novel scheme for aggregating features from different scales to promote the performance of glaucoma diagnosis, which we refer to as M-LAP. Moreover, by modelling the correspondence from binary diagnosis information to the spatial pixels, the proposed scheme generates glaucoma activations, which bridge the gap between global semantical diagnosis and precise location. In contrast to previous works, it can discover the distinguish local regions in fundus images as evidence for clinical interpretable glaucoma diagnosis. Experimental results, performed on the challenging ORIGA datasets, show that our method on glaucoma diagnosis outperforms state-of-the-art methods with the highest AUC (0.88). Remarkably, the extensive results, optic disc segmentation (dice of 0.9) and local disease focus localization based on the evidence map, demonstrate the effectiveness of our methods on clinical interpretability.
Is renal beta-adrenergic-WNK4-NCC pathway important in salt hypertension of dahl rats?

In 2011 Fujita and coworkers proposed that beta-adrenergic stimulation causes decreased serine/threonine-protein kinase WNK4 transcription leading to the activation of Na-Cl cotransporter (NCC) which participates in salt sensitivity and salt hypertension development in rodents. The aim of our study was to investigate whether the above hypothesis is also valid for salt hypertension of Dahl rats, which are characterized by high sympathetic tone and abnormal renal sodium handling. Male 8-week-old salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats were fed either low-salt diet (LS, 0.4 % NaCl) or high-salt diet (HS, 4 % NaCl) for 6 weeks. Half of the animals on either diet were chronically treated with non-selective ? -blocker propranolol (100 mg/kg/day). At the end of the experiment diuresis and sodium excretion were measured prior and after hydrochlorothiazide injection (HCTZ, 10 mg/kg i.p.). Furthermore, blood pressure (BP), heart rate (HR), sympathetic (pentolinium 5 mg/kg i.v.) and NO-dependent (L-NAME 30 mg/kg i.v.) BP components were determined. Chronic HS diet feeding increased BP through sympathoexcitation in SS/Jr but not in SR/Jr rats. Concomitant propranolol treatment did not lower BP in either experimental group. Under the conditions of low salt intake HCTZ increased diuresis, natriuresis and fractional sodium excretion in SR/Jr but not in SS/Jr rats. HS diet feeding attenuated renal response to HCT in SR/Jr rats, whereas no HCTZ effect was observed in SS/Jr rats fed HS diet. Propranolol treatment did not modify diuresis or natriuresis in any experimental group. In conclusions, our present data do not support the idea on the essential importance of renal beta-adrenergic-WNK4-NCC pathway in pathogenesis and/or maintenance of salt hypertension in Dahl rats.
Using isotemporal substitution to predict the effects of changing physical behaviour on older adults’ cardio-metabolic profiles

Background It has been advocated that older adults should concomitantly spend less time in sedentary behaviour (SB), and engage in sufficient physical activity (PA), to reduce their risk of cardio-metabolic diseases. However, it is not clear what intensity of PA must be done to offset SB engagement. Aim Model how cardio-metabolic profiles could change if older adults replaced an hour per day (hr·day-1) of a physical behaviour intensity with 1 hr·day-1 of another physical behaviour of a different intensity. Methods Older adults (n = 93, 60–89 years old, 55% female) wore a thigh-mounted triaxial accelerometer for seven consecutive free-living days to estimate mean daily hourly engagement in SB, Standing, Light Intensity PA (LIPA), sporadic moderate to vigorous physical activity (sMVPA, bouts <10 continuous minutes), and 10-minute MVPA (10MVPA, bouts ≥10 continuous minutes. Fasting whole blood concentration of plasma glucose, triglyceride, total cholesterol, and glycated haemoglobin (%), along with serum concentration of lipoprotein lipase (LPL), interleukin-6 (IL-6), and procollagen III N-terminal propeptide (PIIINP) were measured. Results Isotemporal Substitution, with covariate adjustment, suggested that: total cholesterol concentration could theoretically decrease when 1 hr·day-1 of SB is replaced with Standing, when 1 hr.day-1 of LIPA is replaced with Standing, and when 1 hr·day-1 of sMVPA is replaced with Standing. Triglyceride concentration theoretically decreased when 1 hr·day-1 of SB, Standing, LIPA, or sMVPA is replaced with 10MVPA. Triglyceride concentration theoretically increases when 1 hr·day-1 of 10MVPA is replaced with SB, Standing, or LIPA. No associations with time reallocation appears to exist for LPL, HbA1c, IL-6, and PIIINP. Conclusion The type of physical behaviour being replaced could be crucial for total cholesterol maintenance. Engagement in 10MVPA could be necessary to improve triglyceride concentration.
Evaluation of Candidate Items for Severe PTSD Screening for Patients With Chronic Pain: Pilot Data Analysis With the IRT Approach

Post‐traumatic stress disorder (PTSD) commonly co‐occurs with chronic pain. Although PTSD symptoms are associated with negative health outcomes in patients with chronic pain, PTSD is typically under‐detected and under‐treated in outpatient pain settings. There is a need for rapid, brief screening tools to identify those at greatest risk for severe PTSD symptoms. To achieve that goal, our aim was to use item response theory (IRT) to identify the most informative PTSD symptoms characterizing severe PTSD in patients with chronic pain.
Inactivation of folylpolyglutamate synthetase Met7 results in genome instability driven by an increased dUTP/dTTP ratio

Abstract The accumulation of mutations is frequently associated with alterations in gene function leading to the onset of diseases, including cancer. Aiming to find novel genes that contribute to the stability of the genome, we screened the Saccharomyces cerevisiae deletion collection for increased mutator phenotypes. Among the identified genes, we discovered MET7, which encodes folylpolyglutamate synthetase (FPGS), an enzyme that facilitates several folate-dependent reactions including the synthesis of purines, thymidylate (dTMP) and DNA methylation. Here, we found that Met7-deficient strains show elevated mutation rates, but also increased levels of endogenous DNA damage resulting in gross chromosomal rearrangements (GCRs). Quantification of deoxyribonucleotide (dNTP) pools in cell extracts from met7Δ mutant revealed reductions in dTTP and dGTP that cause a constitutively active DNA damage checkpoint. In addition, we found that the absence of Met7 leads to dUTP accumulation, at levels that allowed its detection in yeast extracts for the first time. Consequently, a high dUTP/dTTP ratio promotes uracil incorporation into DNA, followed by futile repair cycles that compromise both mitochondrial and nuclear DNA integrity. In summary, this work highlights the importance of folate polyglutamylation in the maintenance of nucleotide homeostasis and genome stability.
Pomegranate juice improves the cardiometabolic risk factors, biomarkers of oxidative stress and inflammation in hemodialysis patients: A randomized crossover trial.

BACKGROUND Pomegranate has antioxidant, cardioprotective, and anti-inflammatory properties. We designed a crossover study, aimed to determine if consumption of pomegranate juice (PJ) improves lipid profile and oxidative and inflammatory biomarkers of hemodialysis patients. Forty-one hemodialysis patients were randomly assigned to one of the two groups: PJ-treated group receiving 100 ml natural PJ immediately after their dialysis session three times a week and the control group receiving the usual care. After 8 weeks, a 4-week washout period was established and then the role of the groups was exchanged. Lipid profile, blood pressure, and oxidative and inflammatory biomarkers were measured before and after each sequence. RESULTS Based on the results of intention-to-treat analysis, triglycerides were decreased in PJ condition and increased in the controls. Conversely, high-density lipoprotein (HDL)-cholesterol was increased in PJ and decreased in the control group. Total and low-density lipoprotein (LDL)-cholesterol did not significantly change in either condition. Systolic and diastolic blood pressure significantly decreased in PJ condition. Total antioxidant capacity increased in PJ condition (P<0.001) and decreased in the controls (P<0.001). Conversely, malondialdehyde and interleukin-6 decreased in PJ (P<0.001) and increased in the control group (P≤0.001). The changes of these biomarkers were significantly different between the two conditions. CONCLUSION Eight-week PJ consumption showed beneficial effects on blood pressure, serum triglycerides, HDL cholesterol, oxidative stress, and inflammation in hemodialysis patients. This article is protected by copyright. All rights reserved.
The effects of oral arginine on its metabolic pathways in Sprague–Dawley rats

Abstract Oral arginine supplements are popular mainly for their presumed vasodilatory benefit. Arginine is a substrate for at least four enzymes including nitric oxide synthase (NOS) and arginase, but the impact of oral supplements on its different metabolic pathways is not clear. Deficiencies of arginine-metabolising enzymes are associated with conditions such as hyperammonaemia, endothelial dysfunction, central nervous system and muscle dysfunction, which complicate the use of oral arginine supplements. We examined the effect of l-arginine (l-Arg) and d-arginine (d-Arg), each at 500 mg/kg per d in drinking water administered for 4 weeks to separate groups of 9-week-old male Sprague–Dawley rats. We quantified the expression of enzymes and plasma, urine and organ levels of various metabolites of arginine. l-Arg significantly decreased cationic transporter-1 expression in the liver and the ileum and increased endothelial NOS expression in the aorta and the kidney and plasma nitrite levels, but did not affect the mean arterial pressure. l-Arg also decreased the expression of arginase II in the ileum, arginine:glycine amidinotransferase in the liver and the kidney and glyoxalase I in the liver, ileum and brain, but increased the expression of arginine decarboxylase and polyamines levels in the liver. d-Arg, the supposedly inert isomer, also unexpectedly affected the expression of some enzymes and metabolites. In conclusion, both l- and d-Arg significantly affected enzymes and metabolites in several pathways that use arginine as a substrate and further studies with different doses and treatment durations are planned to establish their safety or adverse effects to guide their use as oral supplements.
Respiratory Syncytial Virus Disease Severity is Associated with Distinct CD8+ T Cell Profiles.

RATIONALE Respiratory syncytial virus (RSV) presents causes significant morbidity and mortality in infants worldwide. Although T helper type 2 (Th2) pathology is implicated in severe disease, the mechanisms underlying the development of immunopathology are incompletely understood. OBJECTIVES We aimed to identify local immune responses associated with severe respiratory syncytial virus disease in infants. Our hypothesis was that disease severity would correlate with enhanced Th2 cellular responses. METHODS Nasal aspirates were collected from infants hospitalized with severe (admitted to the pediatric intensive care unit) or moderate (maintained in the general ward) RSV disease at 7 days after enrollment. The immune response was investigated by evaluating T lymphocyte cellularity, cytokine concentration, and viral load. MEASUREMENTS AND MAIN RESULTS Severe patients had increased proportions of CD8+ T cells expressing IL-4 (Tc2) and reduced proportions of CD8+ T cells expressing IFNγ (Tc1). Nasal aspirates from severe patients had reduced concentrations of IL-17. Patients with greater frequencies of Tc1, CD8+ T cells expressing IL-17 (Tc17), and CD4+ T cells expressing IL-17 (Th17) had shorter durations of hospitalization. CONCLUSIONS Severe RSV disease was associated with distinct T cell profiles. Tc1, Tc17, and Th17 may play protective roles in RSV infection, while Tc2 cells may play a previously underappreciated role in pathology.
Nitrogen isotopic fractionation associated with growth on dinitrogen gas and nitrate by cyanobacteria

This study investigated the bulk nitrogen isotopic composition and fractionation of marine and freshwater cyanobacteria growing at the expense of atmospheric dinitrogen gas (N2) or nitrate (NO3−). In agreement with previous studies, cyanobacteria using N2 had Δ15N values ranging from ‐2‰ to ‐1‰ and fractionated by 2‐3‰ against atmospheric N2. When grown on NO3−, the analyzed cyanobacteria had a remarkably large range in Δ15N, from ‐14‰ to 1‰, and fractionated by 4‐19‰ relative to the supplied NO3−. Interestingly, several of the NO3−‐utilizing cyanobacteria expressed a nitrogen isotopic signal similar to the one expected for diazotrophic species. Extrapolation to the natural environment indicates that Δ15N signals considered to be associated with dinitrogen fixation could also be generated by NO3− utilization, depending on the isotopic composition of the nitrogen source, the degree of fractionation, and the type of cyanobacterium involved.
Inhibition of cancer cell growth by Tangeretin flavone in drug-resistant MDA-MB-231 human breast carcinoma cells is facilitated via targeting cell apoptosis, cell cycle phase distribution, cell invasion and activation of numerous Caspases.

PURPOSE In this study, the anticancer effects of a natural flavonoid-Tangeretin, were examined against the drug-resistant MDA-MB-231 breast cancer (BC) cell line and the normal breast cell line Hs 841.T. METHODS The MTT assay was employed for cell viability determination. Apoptosis was demonstrated by DAPI and Annexin V/propidium iodide (PI) staining. Flow cytometric analyses were performed to gain insights about cell cycle distribution. Western blot assay was used for protein expression determination. RESULTS Tangeretin inhibited the growth of the drug-resistant MDA-MB-231 cells concentration-dependently and its IC50 was 9 µM, whereas the IC50 was >100 µM against the normal cells. The anti-proliferative effects were due to induction of apoptotic cell death. The apoptotic cell percentage was increased from 5.7% to around 69% as the concentration of Tangeretin was increased. Tangeretin also caused an increase in the Bax/Bcl-2 ratio and activation of the Caspase 3, 8 and 9. In addition, Tangeretin led to arrest of the cells at G2/M phase which was accompanied by depletion of cyclin B1 and D. Transwell assay showed that Tangeretin also reduced the invasion of the MDA-MB-231 cells. CONCLUSION The findings of this study suggest that Tangeretin exerts potent anticancer effects on the MDA-MB-231 cells and may therefore prove a beneficial lead molecule in BC research.
A Retrospective Study to Compare the Recurrence Rate After Treatment of Pterygium by Conjunctival Autograft, Primary Closure, and Amniotic Membrane Transplantation

Background This study aimed to investigate the effectiveness of conjunctival autograft compared with primary closure and amniotic membrane transplantation for primary pterygium excision. Material/Methods Data were retrospectively studied from all primary pterygium excisions from January 2002 to December 2017 from the electronic database at the University Eye Hospital, Tübingen. Results From 521 primary pterygium excisions, 284 (54.5%) were primary closures, 203 (39.0%) were conjunctival autografts, and 34 (6.5%) were amniotic membrane transplants. The mean number of primary pterygium excisions was 33 per year (range, 14–56 per year). The mean patient age was 58±15 years. Younger age was associated with a significantly increased recurrence rate (P=0.002). The mean pterygium recurrence rate in the three study groups at 12 months after surgery was 11.3% (range, 6.4–14.7%). Recurrence occurred 13 patients (6.4%) in the conjunctival autograft group, 41 patients (14.4%) in the primary closure group, and five patients (14.7%) in the amniotic membrane transplantation group. Conjunctival autograft was associated with a significantly lower recurrence rate (P=0.005). Conclusions A retrospective study at a single center to compare conjunctival autograft with primary closure and amniotic membrane transplantation for primary pterygium excision showed a significantly lower recurrence rate after surgery using a conjunctival autograft.
A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.
Assessing the multidisciplinary team approaches to placenta accreta spectrum across five institutions within the University of California fetal Consortium (UCfC)

Abstract Purpose To describe the multidisciplinary approaches to placenta accreta spectrum (PAS) across five tertiary care centers that comprise the University of California fetal Consortium (UCfC) and to identify potential best practices. Materials and methods Retrospective review of all cases of pathologically confirmed invasive placenta delivered from 2009 to 2014 at UCfC. Differences in intraoperative management and outcomes based on prenatal suspicion were compared. Interventions assessed included ureteral stent use, intravascular balloon use, anesthetic type, gynecologic oncology (Gyn Onc) involvement, and cell saver use. Intervention variation by institution was also assessed. Analyses were adjusted for final pathologic diagnosis. Chi-square, Fisher’s exact, Student’s t-test, and Mann–Whitney’s U-test were used as appropriate. Binary logistic regression and multivariable linear regression were used to adjust for confounders. Results One hundred and fifty-one cases of pathologically confirmed invasive placenta were identified, of which 82% (123) were suspected prenatally. There was no correlation between the degree of invasion on prenatal imaging and use of each intervention. Ureteral stents were placed in 33% (41) of cases and did not reduce GU injury. Intravascular balloons were placed in 29% (36) of cases and were associated with shorter OR time (161 versus 236 min, p < .01) and lower estimated blood loss (EBL) (1800 versus 2500 ml, p < .01). General endotracheal anesthesia (GETA) was used in 70% (86). EBL did not differ between GETA and regional anesthesia. Gyn Onc was involved in 58% (71) of cases and EBL adjusted for final pathology was reduced with their involvement (2200 versus 2250 ml, p = .02) while OR time and intraoperative complications did not differ. Cell saver was used in 20% (24) and was associated with longer OR time (296 versus 200 min, p < .01). Use of cell saver was not associated with a difference in EBL or number of units of packed red cells transfused. All analyses were adjusted for pathologic severity of invasion. Conclusions Intravascular interventions such as uterine artery balloons and the inclusion of Gynecologic Oncologists as part of a multidisciplinary approach to treating PAS reduce EBL. Additionally, the placement of intravascular balloons may reduce OR time. No significant differences were seen in outcomes when comparing the use of ureteral stents, general anesthesia, or institutions. A team of experienced operators with a standard approach may be more significant than specific practices.
Dysfunctional interactions between the default mode network and the dorsal attention network in subtypes of amnestic mild cognitive impairment

An anticorrelated relationship in the spontaneous fluctuations between the default mode network (DMN) and dorsal attention network (DAN) is a robust feature of intrinsic brain organization in healthy individuals. Prior studies have reported a decreased anticorrelation between the DMN and the DAN in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, it is unclear how this anticorrelation changes as MCI progresses to AD. We hypothesized that dysfunctional connectivity between the DMN and DAN may reflect the gradual decline from MCI to AD. To test this hypothesis, we investigated alterations in functional connectivity between the DMN and DAN in subtypes of amnestic MCI (aMCI) by comparing with the same functional pattern in healthy elderly individuals and patients with AD. We retrospectively collected brain imaging and neuropsychological data from 20 AD participants, 22 participants with multiple-domain aMCI (aMCI-m), 29 participants with single-domain aMCI (aMCI-s) and 23 sex-matched normal controls in this study. Resting-state functional connectivity analysis revealed that aMCI-s and aMCI-m groups demonstrated different magnitudes of increased anticorrelation between the DMN and DAN relative to the AD group. Furthermore, in aMCI-s, aMCI-m and AD participants, hypoconnectivity was found in specific regions within the DMN, including the precuneus and angular gyrus, and hyperconnectivity was found in areas outside the typical DMN networks, including the middle occipital gyrus, lingual gyrus and visual cortex, which indicated disease-related adaptations of brain networks. Our findings suggest that DMN-DAN anticorrelation may shed light on the understanding of the adaptations in brain function during the progression from MCI to AD and may serve as a potential biomarker to detect AD in the preclinical stage.