Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanisms of hysteresis in human brain networks during transitions of consciousness and unconsciousness: Theoretical principles and empirical evidence

Hysteresis, the discrepancy in forward and reverse pathways of state transitions, is observed during changing levels of consciousness. Identifying the underlying mechanism of hysteresis phenomena in the brain will enhance the ability to understand, monitor, and control state transitions related to consciousness. We hypothesized that hysteresis in brain networks shares the same underlying mechanism of hysteresis as other biological and non-biological networks. In particular, we hypothesized that the principle of explosive synchronization, which can mediate abrupt state transitions, would be critical to explaining hysteresis in the brain during conscious state transitions. We analyzed high-density electroencephalogram (EEG) that was acquired in healthy human volunteers during conscious state transitions induced by the general anesthetics sevoflurane or ketamine. We developed a novel method to monitor the temporal evolution of EEG networks in a parameter space, which consists of the strength and topography of EEG-based networks. Furthermore, we studied conditions of explosive synchronization in anatomically informed human brain network models. We identified hysteresis in the trajectory of functional brain networks during state transitions. The model study and empirical data analysis explained various hysteresis phenomena during the loss and recovery of consciousness in a principled way: (1) more potent anesthetics induce a larger hysteresis; (2) a larger range of EEG frequencies facilitates transitions into unconsciousness and impedes the return of consciousness; (3) hysteresis of connectivity is larger than that of EEG power; and (4) the structure and strength of functional brain networks reconfigure differently during the loss vs. recovery of consciousness. We conclude that the hysteresis phenomena observed during the loss and recovery of consciousness are generic network features. Furthermore, the state transitions are grounded in the same principle as state transitions in complex non-biological networks, especially during perturbation. These findings suggest the possibility of predicting and modulating hysteresis of conscious state transitions in large-scale brain networks.
Genomic alterations at the basis of treatment resistance in metastatic breast cancer: clinical applications

The standard of care for breast cancer has gradually evolved from empirical treatments based on clinical-pathological characteristics to the use of targeted approaches based on the molecular profile of the tumor. Consequently, an increasing number of molecularly targeted drugs have been developed. These drugs target specific alterations, called driver mutations, which confer a survival advantage to cancer cells. To date, the main challenge remains the identification of predictive biomarkers for the selection of the optimal treatment. On this basis, we evaluated a panel of 25 genes involved in the mechanisms of targeted treatment resistance, in 16 primary breast cancers and their matched recurrences, developed during treatment. Overall, we found a detection rate of mutations higher than that described in the literature. In particular, the most frequently mutated genes were ERBB2 and those involved in the PI3K/AKT/mTOR and the MAPK signaling pathways. The study revealed substantial discordances between primary tumors and metastases, stressing the need for analysis of metastatic tissues at recurrence. We observed that 85.7% of patients with an early-stage or locally advanced primary tumor showed at least one mutation in the primary tumor. This finding could explain the subsequent relapse and might therefore justify more targeted adjuvant treatments. Finally, the mutations detected in 50% of relapsed tissues could have guided subsequent treatment choices in a different way. This study demonstrates that mutation events may be present at diagnosis or arise during cancer treatment. As a result, profiling primary and metastatic tumor tissues may be a major step in defining optimal treatments.
A stable meta‐carborane enables the generation of boron‐rich peptide agonists targeting the ghrelin receptor

Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron‐containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein‐coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor‐directed boron uptake. In this study, we present the generation of short, boron‐rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super‐agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta‐carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron‐loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin.
Increased expression of phosphoenolpyruvate carboxykinase cytoplasmic isoform by hepatitis B virus X protein affects hepatitis B virus replication

Hepatitis B virus X protein (HBx) can stimulate the transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate‐determining enzyme in gluconeogenic pathway. Two isoforms of PEPCK exist, a cytoplasmic form (PCK1) and a mitochondrial isoform (PCK2). The current study investigated the direct effect of HBx‐stimulated PEPCK on hepatitis B virus (HBV) replication. We showed that PCK1 rather than PCK2 was upregulated by HBx. We also demonstrated that overexpression of PCK1 decreased HBV replication, whereas inhibition of PCK1‐enhanced HBV replication. Furthermore, we found overexpression of PCK1 led to reduced expression of peroxisome proliferator‐activated receptor‐coactivator 1α (PGC‐1α) and peroxisome proliferator‐activated receptor γ (PPAR‐γ), whereas knocking down PCK1 resulted in an increased expression of PGC‐1α and PPAR‐γ. When PPAR‐γ was inhibited, knocking down PCK1 could not induce the apparent enhanced HBV replication. Our data suggested that PCK1 induced by HBx led to decreased HBV replication through the downregulation of PGC‐1α and PPAR‐γ. Thus, our study demonstrates a negative‐feedback loop involving PCK1 and HBV may provide a balanced cell environment for HBV persistent infection.
Pilot Study to Evaluate the Association Between the Length of the Luteal Phase and Estrous Activity Detected by Automated Activity Monitoring in Dairy Cows

The ability of automated activity monitoring (AAM) systems to detect estrus is influenced by multiple variables. The luteal phase (LP) preceding estrus has been shown to be important for hormones release, and behavior during estrus in ruminants, but its impact on activity as measured by AAM systems has not been studied. The objective of this study was to investigate the impact of the length of the preceding LP on the intensity and duration of estrus as measured by AAM, and on the expression of estrogen receptor alpha (ERα) in the endometrium. A total of 60 cows between 46 and 53 days in milk were assigned to either a normal or a short length LP. Length of the LP was insured by the use of hormonal synchronization programs. Cows in both treatments were matched on parity, milk production, body condition score (BCS), and lameness score (assessed at enrolment). Expression of ERα receptors in the endometrium were evaluated by nuclear staining by immunohistochemistry of biopsies. Estrus was defined as the day on which the AAM system detected estrus. Cows that were not synchronized by the protocol or that were not detected in estrus by the AAM systems were excluded, which left 21 and 11 cows for analyses in the normal and short length LP, respectively. Peak activity index of estrus, duration of estrus, and expression of ERα were outcomes for multivariable linear regression models. Cows with short length LP tended to have lower peak activity at estrus, but there was no significant effect of treatment when BCS was accounted for. Cows with BCS ≤ 2.5 had less intense and shorter estrus than cows with BCS ≥ 2.75. There was no association between the length of the LP and the expression of ERα in the endometrium.
XANAP: A real‐world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation in Asia

ROCKET AF and its East Asian subanalysis demonstrated that rivaroxaban was non‐inferior to warfarin for stroke/systemic embolism (SE) prevention in patients with non‐valvular atrial fibrillation (NVAF), with a favorable benefit–risk profile. XANAP investigated the safety and effectiveness of rivaroxaban in routine care in Asia‐Pacific.
PhenoSpD: an integrated toolkit for phenotypic correlation estimation and multiple testing correction using GWAS summary statistics

Background Identifying phenotypic correlations between complex traits and diseases can provide useful etiological insights. Restricted access to individual-level phenotype data makes it difficult to estimate large-scale phenotypic correlation across the human phenome. State-of-the-art methods, metaCCA and LD score regression, provide an alternative approach to estimate phenotypic correlation using genome-wide association study (GWAS) summary statistics. Results Here, we present an integrated R toolkit, PhenoSpD, to 1) apply metaCCA (or LD score regression) to estimate phenotypic correlations using GWAS summary statistics; and 2) to utilize the estimated phenotypic correlations to inform correction of multiple testing for complex human traits using the spectral decomposition of matrices (SpD). The simulations suggest it is possible to estimate phenotypic correlation using samples with only a partial overlap, but as overlap decreases correlations will attenuate towards zero and multiple testing correction will be more stringent than in perfectly overlapping samples. In a case study, PhenoSpD using GWAS results suggested 324.4 independent tests among 452 metabolites, which is close to the 296 independent tests estimated using true phenotypic correlation. We further applied PhenoSpD to estimated 7,503 pair-wise phenotypic correlations among 123 metabolites using GWAS summary statistics from Kettunen et al. and PhenoSpD suggested 44.9 number of independent tests for theses metabolites. Conclusion PhenoSpD integrates existing methods and provides a simple and conservative way to reduce dimensionality for complex human traits using GWAS summary statistics, which is particularly valuable for post-GWAS analysis of complex molecular traits. Availability R code and documentation for PhenoSpD V1.0. 0 is available online (https://github.com/MRCIEU/PhenoSpD).
Global prevalence and incidence of surgical site infections after appendectomy: a systematic review and meta-analysis protocol

Introduction Acute appendicitis is a surgical emergency and the most frequent aetiology of acute surgical abdominal pain in developed countries. Universally, its widely approved treatment is appendectomy. Like all surgical procedures, appendectomy can be associated with many complications among which are surgical site infections (SSIs). Despite the increasing number of appendectomies done around the world and the associated morbidities related to SSI after appendectomy, there is still scarcity of data concerning the global epidemiology of SSI after appendectomy. The current review aims at providing a summary of the published data on epidemiology of SSI after appendectomy. Methods and design We will include randomised controlled trials, cohort studies, case–control and cross-sectional studies. Electronic databases including Embase, MEDLINE and ISI Web of Science (Science Citation Index) will be searched for relevant abstracts of studies published between 1 January 2000 and 30 December 2017, without language restriction. The review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. After screening of abstracts, study selection, data extraction and assessment of risk of bias, we shall assess the studies individually for clinical and statistical heterogeneity. Appropriate meta-analytic techniques will then be used to pool studies judged to be clinically homogenous. Visual inspection of funnel plots and Egger’s test will be used to detect publication bias. Results will be presented by country and continent. Ethics and dissemination Since primary data are not collected in this study, ethical approval is not required. This review is expected to provide relevant data to help in quantifying the global burden of SSI after appendectomy. The final report will be published in a peer-reviewed journal. Trial registration number CRD42017075257.
Pre-post effects of a tetanus care protocol implementation in a sub-Saharan African intensive care unit

Background Tetanus is a vaccine-preventable, neglected disease that is life threatening if acquired and occurs most frequently in regions where vaccination coverage is incomplete. Challenges in vaccination coverage contribute to the occurrence of non-neonatal tetanus in sub-Saharan countries, with high case fatality rates. The current WHO recommendations for the management of tetanus include close patient monitoring, administration of immune globulin, sedation, analgesia, wound hygiene and airway support [1]. In response to these recommendations, our tertiary referral hospital in Tanzania implemented a standardized clinical protocol for care of patients with tetanus in 2006 and a subsequent modification in 2012. In this study we aimed to assess the impact of the protocol on clinical care of tetanus patients and their outcomes. Methods and findings We examined provision of care and outcomes among all patients admitted with non-neonatal tetanus to the ICU at Bugando Medical Centre between 2001 and 2016 in this retrospective cohort study. We compared three groups: the pre-protocol group (2001–2005), the Early protocol group (2006–2011), and the Late protocol group (2012–2016) and determined associations with mortality by univariable logistic regression. We observed a significant increase in provision of care as per protocol between the Early and Late groups. Patients in the Late group had a significantly higher utilization of mechanical ventilation (69.9% vs 22.0%, p< 0.0001), provision of surgical wound care (39.8% vs 20.3%, p = 0.011), and performance of tracheostomies (36.8% vs 6.7%, <0.0001) than patients in the Early group. Despite the increased provision of care, we found no significant decrease in overall mortality in the Early versus the Late groups (55.4% versus 40.3%, p = 0.069), or between the pre-protocol and post-protocol groups (60.7% versus 50.0%, p = 0.28). There was also no difference in 7-day ICU mortality (30.1% versus 27.8%, p = 0.70). Analysis of the causes of death revealed a decrease in deaths related to airway compromise (30.0% to 1.8%, p<0.001) but an increase in deaths due to presumed sepsis (15.0% to 44.6%, p = 0.018). Conclusion The overall mortality in patients suffering non-neonatal tetanus is high (>40%). Institution of a standardized tetanus management protocol, in accordance with WHO recommendations, decreased immediate mortality related to primary causes of death after tetanus. However, this was offset by an increase in death due to later ICU complications such as sepsis. Our results illustrate the complexity in achieving mortality reduction even in illnesses thought to require few critical care interventions. Improving basic ICU care and strengthening vaccination programs to prevent tetanus altogether are essential components of efforts to decrease the mortality caused by this lethal, neglected disease.
Impact of patient characteristics on the Canadian Patient Experiences Survey–Inpatient Care: survey analysis from an academic tertiary care centre

Objective To determine the role of patient demographics, care domains and self-perceived health status in the analysis and interpretation of results from the Canadian Patient Experience Survey–Inpatient Care. Design Cross-sectional survey. Setting Single large Canadian two campus tertiary care academic centre. Participants Random sampling of hospital patients postdischarge. Intervention and main outcome measures Logistic regression models were developed to analyse topbox scoring on four questions of global care (rate experience, recommend hospital, rate hospital, overall helped). Means of each composite domain were correlated to the four overall scores at the patient level to determine Spearman’s rank correlation coefficients which were plotted against the overall (hospital) domain score for the key driver analysis. Results Topbox scoring was decreased with worse degrees of perceived physical and mental health in all four global questions (p<0.05). Female gender and higher levels of education were associated with worse scoring on rate experience, recommend hospital and rate hospital (p<0.001). Whereas there was a significant difference between hospital departments in unadjusted measures, these differences were no longer evident after adjustment with patient covariates. Key driver analysis identified person-centred care, care transition and the domain related to emergency admission as areas of highest potential for improvement. Conclusions Global measures of overall care are influenced by patient-perceived physical and mental health. Caution should be exercised in using patient-satisfaction surveys to compare performance between different healthcare provision entities, as apparent differences could be explained by variation in patient mix rather than variation in performance.
How much "surgical eff ort" should be added to HIPEC?

Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a main comprehensive treatment of malignancies on the peritoneal surface and thus, it has been considered a promising treatment option for a peritoneal-borne disease such as ovarian cancer. The rationale for using HIPEC is based on the direct cytotoxicity of hyperthermia for malignant cells, the enhancement of this cytotoxicity by anticancer drugs, and the pharmacokinetic advantages of the i.p. route for chemotherapy. It could also reduce the mechanisms of cellular chemo-resistance and induce an effi cient anticancer immune response. This technique is delivered intraoperatively, avoiding the need for implantation of peritoneal access devices and thereby reducing catheter-related morbidity and tolerance issues. Despite these potential advantages of HIPEC, there was no clear evidence from randomized controlled trials to advocate this approach as a standard therapy for patients suff ering from advanced ovarian cancer.
Comparison of quantitative multiple-breath specific ventilation imaging using colocalized 2D oxygen-enhanced MRI and hyperpolarized 3He MRI.

Two magnetic resonance specific ventilation imaging (SVI) techniques, namely, oxygen-enhanced proton (OE-1H) and hyperpolarized 3He (HP-3He), were compared in eight healthy supine subjects [age 32 (6) yr]. An in-house radio frequency coil array for 1H configured with the 3He transmit-receive coil in situ enabled acquisition of SVI data from two nuclei from the same slice without repositioning the subjects. After 3 × 3 voxel downsampling to account for spatial registration errors between the two SV images, the voxel-by-voxel correlation coefficient of two SV maps ranged from 0.11 to 0.63 [0.46 mean (0.17 SD); P < 0.05]. Several indexes were analyzed and compared from the tidal volume-matched SV maps: the mean of SV log-normal distribution (SVmean), the standard deviation of the distribution as a measure of SV heterogeneity (SVwidth), and the gravitational gradient (SVslope). There were no significant differences in SVmean [OE-1H: 0.28 (0.08) and HP-3He: 0.32 (0.14)], SVwidths [OE-1H: 0.28 (0.08) and HP-3He: 0.27 (0.10)], and SVslopes [OE-1H: -0.016 (0.006) cm-1 and HP-3He: -0.013 (0.007) cm-1]. Despite the statistical similarities of the population averages, Bland-Altman analysis demonstrated large individual intertechnique variability. SDs of differences in these indexes were 42% (SVmean), 46% (SVwidths), and 62% (SVslopes) of their corresponding overall mean values. The present study showed that two independent, spatially coregistered, SVI techniques presented a moderate positive voxel-by-voxel correlation. Population averages of SVmean, SVwidth, and SVslope were in close agreement. However, the lack of agreement when the data sets were analyzed individually might indicate some fundamental mechanistic differences between the techniques. NEW & NOTEWORTHY To the best of our knowledge, this is the first cross-comparison of two different specific ventilation (SV) MRI techniques in the human lung (i.e., oxygen-enhanced proton and hyperpolarized 3He). The present study showed that two types of spatially coregistered SV images presented a modest positive correlation. The two techniques also yielded similar population averages of SV indexes such as log-normal mean, SV heterogeneity, and the gravitational slope, albeit with some intersubject variability.
Direct Output Connection for a High-Rank Language Model

This paper proposes a state-of-the-art recurrent neural network (RNN) language model that combines probability distributions computed not only from a final RNN layer but also middle layers. This method raises the expressive power of a language model based on the matrix factorization interpretation of language modeling introduced by Yang et al. (2018). Our proposed method improves the current state-of-the-art language model and achieves the best score on the Penn Treebank and WikiText-2, which are the standard benchmark datasets. Moreover, we indicate our proposed method contributes to application tasks: machine translation and headline generation.
Incidence of Acute Kidney Injury Among Critically Ill Patients With Brief Empiric Use of Antipseudomonal β-Lactams With Vancomycin.

BACKGROUND Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations. METHODS The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups. RESULTS The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09). CONCLUSION Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.