Miracle-dz/UniFAR-FTUs huggingface dataset:
The Mitochondria-Targeted Metabolic Tubular Injury in Diabetic Kidney Disease.

BACKGROUND/AIMS Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide, and the importance of tubular injury has been highlighted in recent years. However, the underlying mechanisms and effective therapeutic targets are still unclear. In this study, we investigated mtDNA, mitochondrial dynamics, function and metabolic pathways to determine if mitochondrial damage plays a critical role in the development of tubular injury in DKD patients. METHODS A cross-sectional study was carried out among healthy controls (HCs, n = 65), diabetes patients without kidney disease (DCs, n = 48) and DKD patients (n = 60). Serum, peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens were obtained from participants. Metabolomics was employed to investigate cellular metabolism. RESULTS DKD patients had decreased mtDNA copy numbers and increased mtDNA damage compared to DCs. Mitochondrial fragmentation was specifically presented in tubules, but not in podocytes of DKD patients. The accumulation of damaged mtDNA and fragmented mitochondria resulted in increased reactive oxygen species (ROS) generation, activation of apoptosis and loss of mitochondrial membrane potential (ΔΨm) in tubules and PBMCs. Furthermore, glycolysis and tricarboxylic acid (TCA) cycle was perturbed, and increased dihydroxyacetone phosphate (DHAP) and decreased succinyl-CoA synthetase (SCS) respectively in these two metabolic pathways were identified as potential biomarkers for tubular injury in DKD. CONCLUSION Our study indicates that mitochondrial damage could be the hallmark of tubular injury in DKD patients, and this would provide a novel and attractive therapeutic target to improve this disease.
Culture-Negative and Culture-Positive Sepsis: A Comparison of Characteristics and Outcomes.

BACKGROUND The primary objective of this study was to compare the characteristics of culture-positive and culture-negative status in septic patients. We also determined whether culture status is associated with mortality and whether unique variables are associated with mortality in culture-positive and culture-negative patients separately. METHODS Utilizing patient records from intensive care units, emergency department, and general care wards in a large academic medical center, we identified adult patients with suspected infection and ≥2 systemic inflammatory response syndrome criteria between January 1, 2007, and May 31, 2014. We compared the characteristics between culture-positive and culture-negative patients and used binary logistic regression to identify variables independently associated with culture status and mortality. We also did sensitivity analyses using patients with Sequential Organ Failure Assessment and quick Sequential Organ Failure Assessment criteria for sepsis. RESULTS The study population included 9288 culture-negative patients (89%) and 1105 culture-positive patients (11%). Culture-negative patients received more antibiotics during the 48 hours preceding diagnosis but otherwise demonstrated similar characteristics as culture-positive patients. After adjusting for illness severity, a positive culture was not independently associated with mortality (odds ratio = 1.01 [95% CI, 0.81-1.26]; P = .945). The models predicting mortality separately in culture-negative and culture-positive patients demonstrated very good and excellent discrimination (C-statistic ± SD, 0.87 ± 0.01 and 0.92 ± 0.01), respectively. In the sensitivity analyses using patients with sepsis by Sequential Organ Failure Assessment and quick Sequential Organ Failure Assessment criteria, after adjustments for illness severity, positive cultures were still not associated with mortality (odds ratio = 1.13 [95% CI, 0.86-1.43]; P = .303; and odds ratio = 1.05 [95% CI, 0.83-1.33]; P = .665), respectively. In all models, physiological derangements were associated with mortality. CONCLUSIONS While culture status is important for tailoring antibiotics, culture-negative and culture-positive patients with sepsis demonstrate similar characteristics and, after adjusting for severity of illness, similar mortality. The most important factor associated with negative cultures is receipt of antibiotics during the preceding 48 hours. The risk of death in patients suspected of having an infection is most associated with severity of illness. This is aligned with the Sepsis-3 definition using Sequential Organ Failure Assessment score to better identify those suspected of infection at highest risk of a poor outcome.
Three-unit posterior zirconia-ceramic fixed dental prostheses (FDPs) veneered with layered and milled (CAD-on) veneering ceramics: 1-year follow-up of a randomized controlled clinical trial.

OBJECTIVE The aim of this multicenter randomized controlled clinical trial was to test posterior zirconia-ceramic fixed dental prostheses (FDPs) veneered with a computer-aided design/computer- assisted manufacture (CAD/CAM) lithium disilicate veneering ceramic (CAD-on) and manually layered zirconia veneering ceramic with respect to survival of the FDPs, and technical and biologic outcomes. METHOD AND MATERIALS Sixty patients in need of one posterior three-unit FDP were included. The zirconia frameworks were produced with a CAD/CAM system (Cerec inLab 3D/Cerec inEOS inLab). Thirty FDPs were veneered with a CAD/CAM lithium disilicate veneering ceramic (Cad-on) (test) and 30 were veneered with a layered zirconia veneering ceramic (control). For the clinical evaluation at baseline, 6, and 12 months, the United States Public Health Service (USPHS) criteria were used. The biologic outcome was judged by comparing the plaque control record (PCR), bleeding on probing (BOP), and probing pocket depth (PPD). Data were statistically analyzed. RESULTS Fifty-six patients were examined at a mean follow-up of 13.9 months. At the 1-year follow-up the survival rate was 100% in the test and in the control group. No significant differences of the technical outcomes occurred. Major chipping occurred in the control group (n = 3) and predominantly minor chipping in the test group (minor n = 2, major n = 1). No biologic problems or differences were found. CONCLUSIONS Both types of zirconia-ceramic FDPs exhibited very good clinical outcomes without differences between groups. Chipping occurred in both types of FDPs at small amounts, yet the extension of the chippings differed. The test FDPs predominantly exhibited minor chipping, the control FDPs major chipping.
Modelling of growth kinetics of isolated Pseudomonas sp. and optimisation of parameters for enhancement of xanthine oxidoreductase production by statistical design of experiments

Abstract This report presents the substrate inhibitory effect of xanthine (XN) on microbial growth and optimisation of effective parameters to achieve high enzyme activity of xanthine oxidoreductase (XOR) through statistical design. Three efficient isolated strains (Pseudomonas aeruginosa CEBP1 and CEBP2, Pseudomonas sp. CEB1G) were screened for growth kinetic studies. Substrate inhibitory models (eg. Aiba, Edward) could explain the growth kinetics of CEBP1, CEBP2 and CEB1G very well with various initial [XN] (S0), e.g., 0.1–35 g L−1. Highest XOR activity was obtained at stationary phase when biomass yield was high. Highest catalytic efficiency (kcat/KM) of XOR was obtained by CEBP1 at optimum specific growth rate of 0.082 h−1 and biomass yield of 0.196 g g−1 at S0 = 5 g L−1. The effects of S0, pH and temperature were studied by Box-Behnken experimental design to evaluate the interactive effects of the significant variables influencing XOR production by CEBP1. ANOVA with high correlation coefficient (R2 > 0.99) and lower ‘Prob > F’value (< 0.05) validated the second order polynomial model for the enzyme production. The highest XOR activity of 31.2 KU min−1 mg−1 was achieved by CEBP1 under optimised conditions (35 °C; S0=5 g L−1; pH = 7.0) as compared to any report in literature. A sevenfold substrate affinity of the enzyme was observed after purification.
Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis

See Wekerle (doi:10.1093/brain/awz068) for a scientific commentary on this article. The peripheral immunological changes associated with conversion of multiple sclerosis to the secondary progressive phase are largely unknown. Kadowaki et al. demonstrate that CCR9+CD4+ T cells – whose frequencies vary with age and with gut microbiota status – are reduced in number and show altered regulatory function in secondary progressive disease.
A hard-core predicate for all one-way functions

A central tool in constructing pseudorandom generators, secure encryption functions, and in other areas are “hard-core” predicates <italic>b</italic> of functions (permutations) ƒ, discovered in [Blum Micali 82]. Such <italic>b</italic>(<italic>x</italic>) cannot be efficiently guessed (substantially better than 50-50) given only ƒ(<italic>x</italic>). Both <italic>b</italic>, ƒ are computable in polynomial time. [Yao 82] transforms any one-way function ƒ into a more complicated one, ƒ<supscrpt>*</supscrpt>, which has a hard-core predicate. The construction applies the original ƒ to many small pieces of the input to ƒ<supscrpt>*</supscrpt> just to get one “hard-core” bit. The security of this bit may be smaller than any constant positive power of the security of ƒ. In fact, for inputs (to ƒ<supscrpt>*</supscrpt>) of practical size, the pieces effected by ƒ are so small that ƒ can be inverted (and the “hard-core” bit computed) by exhaustive search. In this paper we show that every one-way function, padded to the form ƒ(<italic>p</italic>, <italic>x</italic>) = (<italic>p</italic>, <italic>g</italic>(<italic>x</italic>)), ‖‖<italic>p</italic>‖‖ = ‖<italic>x</italic>‖, has by itself a hard-core predicate of the same (within a polynomial) security. Namely, we prove a conjecture of [Levin 87, sec. 5.6. 2] that the scalar product of Boolean vectors <italic>p</italic>, <italic>x</italic> is a hard-core of every one-way function ƒ(<italic>p</italic>, <italic>x</italic>) = (<italic>p</italic>, <italic>g</italic>(<italic>x</italic>)). The result extends to multiple (up to the logarithm of security) such bits and to any distribution on the <italic>x</italic>'s for which ƒ is hard to invert.
Cost-Effectiveness of Angiographic Imaging in Isolated Perimesencephalic Subarachnoid Hemorrhage

Background and Purpose— The purpose of this study is to perform a comprehensive cost-effectiveness analysis of all possible permutations of computed tomographic angiography (CTA) and digital subtraction angiography imaging strategies for both initial diagnosis and follow-up imaging in patients with perimesencephalic subarachnoid hemorrhage on noncontrast CT. Methods— Each possible imaging strategy was evaluated in a decision tree created with TreeAge Pro Suite 2014, with parameters derived from a meta-analysis of 40 studies and literature values. Base case and sensitivity analyses were performed to assess the cost-effectiveness of each strategy. A Monte Carlo simulation was conducted with distributional variables to evaluate the robustness of the optimal strategy. Results— The base case scenario showed performing initial CTA with no follow-up angiographic studies in patients with perimesencephalic subarachnoid hemorrhage to be the most cost-effective strategy ($5422/quality adjusted life year). Using a willingness-to-pay threshold of $50 000/quality adjusted life year, the most cost-effective strategy based on net monetary benefit is CTA with no follow-up when the sensitivity of initial CTA is >97.9%, and CTA with CTA follow-up otherwise. The Monte Carlo simulation reported CTA with no follow-up to be the optimal strategy at willingness-to-pay of $50 000 in 99.99% of the iterations. Digital subtraction angiography, whether at initial diagnosis or as part of follow-up imaging, is never the optimal strategy in our model. Conclusions— CTA without follow-up imaging is the optimal strategy for evaluation of patients with perimesencephalic subarachnoid hemorrhage when modern CT scanners and a strict definition of perimesencephalic subarachnoid hemorrhage are used. Digital subtraction angiography and follow-up imaging are not optimal as they carry complications and associated costs.
Enhanced Recruitment During Executive Control Processing in Cognitively Preserved Patients With Pediatric-Onset MS

Abstract Objectives: Youth and young adults with pediatric-onset multiple sclerosis (MS) are vulnerable to executive dysfunction; however, some patients do not demonstrate functional deficits despite showing abnormalities on structural magnetic resonance imaging (MRI). Cognitively intact adults with MS have shown enhanced activation patterns relative to healthy controls on working memory tasks. We aim to evaluate whether cognitively preserved pediatric-onset MS patients engage compensatory recruitment strategies to facilitate age-normative performance on a task of working memory. Methods: Twenty cognitively preserved patients (mean age=18.7±2.7 years; 15 female) and 20 age- and sex-matched controls (mean age=18.5±2.9 years; 15 female) underwent neuropsychological testing and 3.0 Tesla MRI, including structural and functional acquisitions. Patterns of activation during the Alphaspan task, a working memory paradigm with two levels of executive control demand, were examined via whole-brain and region of interest (ROI) analyses. Results: Across all participants, lower accuracy and greater activation of regions implicated in working memory were observed during the high demand condition. MS patients demonstrated 0.21 s longer response time than controls. ROI analyses revealed enhanced activation for pediatric-onset MS patients relative to controls in the right middle frontal, left paracingulate, right supramarginal, and left superior parietal gyri during the low executive demand condition, over and above differences in response time. MS patients also demonstrated heightened activation in the right supramarginal gyrus in the high executive demand condition. Conclusions: Our findings suggest that pediatric-onset MS patients may engage compensatory recruitment strategies during working memory processing. (JINS, 2019, 25, 432–442)
Steroidal fraction of Carissa carandas L. inhibits microbial hyaluronidase activity by mixed inhibition mechanism

Abstract Hyaluronidase (hyase) is a hyaluronic acid (HA) depolymerizing enzyme produced by many pathogenic bacteria as a virulence factor to establish and spread infections. Present studies established that a steroidal fraction (SF) isolated from leaves of Carissa carandas act as a strong hyase inhibitor. The kinetic parameters involved in the inhibition of hyase by purified SF were studied and compared with standard hyase inhibitor quercetin. The purified SF showed the highest inhibition with an IC50 of 5.19 mM in comparison with a standard inhibitor, quercetin (IC50 8.63 mM). The inhibition constant (Ki) of purified SF determined by Dixon plot was 8.32 mM, which was significantly lower than that of quercetin standard. The kinetic behavior of enzyme hyase revealed to be more complex than classical competitive and uncompetitive inhibition where inhibitor affects both Km and Vmax. The inhibitor (I) favored the binding to the enzyme–substrate (ES) complex where Km value appeared to decrease (Kmapp < Km). The inhibitor also leads to decrease in the apparent maximum velocity of the enzyme–substrate reaction (Vmaxapp < Vmax). These results signpost toward mixed nature of inhibition of enzyme hyase by purified SF. Anti-hyaluronidase activity by a bioactive metabolite from C. carandas has not been reported so far and has high therapeutic potential against spread of pathogen and its toxins in the host. Graphical Abstract
OnabotulinumtoxinA for Simultaneous Treatment of Upper Facial Lines: Subject-Reported Satisfaction and Impact From a Phase 3 Study.

BACKGROUND Patient-reported outcomes are increasingly recognized as important measures of treatment benefit. OBJECTIVE To evaluate subject-reported satisfaction and impact outcomes with onabotulinumtoxinA treatment in neurotoxin-naive adults with forehead lines (FHL), glabellar lines (GL), and crow's feet lines (CFL). METHODS This Phase 3 study randomized 787 subjects to onabotulinumtoxinA 64 U (FHL 20 U, GL 20 U, and CFL 24 U), 40 U (FHL 20 U, GL 20 U, and CFL placebo), or placebo in double-blind Period 1. Subjects could receive up to 2 additional 64 U treatments in open-label Period 2. Patient-reported outcomes were assessed using the validated Facial Line Satisfaction Questionnaire (FLSQ) and 11-item Facial Line Outcomes (FLO-11) Questionnaire. RESULTS The proportion of subjects mostly or very satisfied was significantly greater with onabotulinumtoxinA 64 U and 40 U versus placebo (87.9% and 81.4% vs 3.2%; p < .0001). Responder rates on FLSQ Impact Domain, FLO-11 Items 1, 4, 5, and total score were significantly greater with onabotulinumtoxinA versus placebo on Day 30 (p < .0001). Responder rates favoring onabotulinumtoxinA in Period 1 were maintained with repeated onabotulinumtoxinA 64 U treatment in Period 2. CONCLUSION OnabotulinumtoxinA treatment was associated with high subject satisfaction and significant improvements in appearance-related psychological and emotional impacts.
A risk score model for predicting cardiac rupture after acute myocardial infarction

Background: Cardiac rupture (CR) is a major lethal complication of acute myocardial infarction (AMI). However, no valid risk score model was found to predict CR after AMI in previous researches. This study aimed to establish a simple model to assess risk of CR after AMI, which could be easily used in a clinical environment. Methods: This was a retrospective case-control study that included 53 consecutive patients with CR after AMI during a period from January 1, 2010 to December 31, 2017. The controls included 524 patients who were selected randomly from 7932 AMI patients without CR at a 1:10 ratio. Risk factors for CR were identified using univariate analysis and multivariate logistic regression. Risk score model was developed based on multiple regression coefficients. Performance of risk model was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis. Results: Among all 7985 AMI patients, 53 (0.67%) had CR (free wall rupture, n = 39; ventricular septal rupture, n = 14). Hospital mortalities were 92.5% and 4.01% in patients with and without CR (P < 0.001). Independent variables associated with CR included: older age, female gender, higher heart rate at admission, body mass index (BMI) <25 kg/m2, lower left ventricular ejection fraction (LVEF) and no primary percutaneous coronary intervention (pPCI) treatment. In ROC analysis, our CR risk assess model demonstrated a very good discriminate power (area under the curve [AUC] = 0.895, 95% confidence interval: 0.845–0.944, optimism-corrected AUC = 0.821, P < 0.001). Conclusion: This study developed a novel risk score model to help predict CR after AMI, which had high accuracy and was very simple to use.
PCSK9 Inhibition to Lower LDL-Cholesterol and Reduce Cardiovascular Risk: Great Expectations.

New clinical trials with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab show that these drugs not only lower lowdensity lipoprotein cholesterol (LDL-C) profoundly, but also seem to reduce cardiovascular events, although the number of events and duration of follow-up are limited. Larger trials are underway to confirm these findings and to document safety. First identified as a causal gene for autosomal dominant hypercholesterolemia, 1 PCSK9 promotes the degradation of LDL-C receptors, resulting in higher blood levels LDL-C. Monoclonal antibodies to PCSK9, evolocumab, alirocumab, and bococizumab, all reduce LDL-C profoundly, and phase 3 clinical trials of these agents are hurtling toward completion. Two recent reports of the effects of evolocumab and alirocumab have raised great expectations. 2,3 In the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) study, 2 4465 patients who had completed one of several short-term studies were randomly assigned in a 2:1 ratio to receive either evolocumab 140 mg every 2 weeks or 420 mg monthly plus standard therapy or standard therapy alone. Median follow-up was 11.1 months. Evolocumab reduced LDL-C by 61% compared with standard therapy alone, from a median of 120 to 48 mg/dL, with the reduction remaining stable throughout follow-up. Cardiovascular events at 1 year were 2.18% in the standard therapy group and 0.95% in the evolocumab group (hazard ratio 0.47; 95% confidence interval 0.28–0.78; P=0.003). In the Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) study, 3 2341 patients with heterozygous familial hypercholesterolemia or established coronary heart disease or a coronary heart disease risk equivalent, receiving maximally tolerated doses of statins, with an LDL-C ≥70 mg/dL, were randomly assigned in a 2:1 ratio to receive an alirocumab 150 mg or placebo subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point, the percentage change in calculated LDL-C level from baseline to week 24, was reduced by 62% to a mean LDL-C of 48 mg/dL. In a post hoc analysis, the rate of major CV events was lower with alirocumab than with placebo (1.7% versus 3.3%; hazard ratio 0.52; 95% confidence interval 0.31–0.90; P =0.02).
Thermal and Mechanical Pain Thresholds of Women With Provoked Localized Vulvodynia: A Pilot Study

Abstract Context Vulvodynia is a chronic pain condition defined as vulvar pain lasting at least 3 months in the absence of gross anatomic or neurologic findings. Provoked, localized vulvodynia (PLV), a subtype of vulvodynia, is characterized by vestibular pain in response to light touch. The cause of PLV remains largely unknown, and triggering events have yet to be determined. Objective To evaluate vestibular and peripheral experimental pain thresholds in patients with PLV to further define the somatosensory profile of these patients. Methods After informed consent was provided, eligible participants completed a questionnaire and underwent quantitative sensory testing at the forearm and posterior vestibule. Detection and pain thresholds to thermal (cold and heat) and mechanical (pressure) stimuli were measured. Results Seventeen participants with PLV and 16 control participants were included. Participants in the PLV group scored lower on the patient health questionnaire 9 (PHQ-9) compared with those in the control group (P<.05) and had higher ratings of self-reported genital pain with sex (P<.001) and daily activity (P<.05). Forearm pain thresholds to cold (P<.01) and heat (P<.01) stimuli were also lower in the PLV group compared with those in the control group. Vestibular pain thresholds to cold (P<.05) and pressure (P<.01) stimuli were also lower in the PLV group. Conclusion Lower scores on the PHQ-9 and higher self-reported genital pain ratings of patients with PLV highlight the significant impact of this poorly understood condition on quality of life. Quantitative sensory testing results demonstrated that vestibular cold allodynia may be a somatosensory feature of PLV. Reduced forearm pain thresholds in these patients suggest altered sensory processing at extrapelvic sites, although it is unclear whether these measurements are related to central sensitization.