Miracle-dz/UniFAR-FTUs huggingface dataset:
‘Hy's law,’ the ‘Rezulin Rule,’ and other predictors of severe drug‐induced hepatotoxicity: putting risk‐benefit into perspective

Hyman J. Zimmerman, MD (known affectionately as ‘Hy’ to his countless friends) is widely credited for defining a prognostic rule of drug-induced hepatotoxicity that predicted a case-fatality rate of 10% or higher for drugs causing severe acute hepatocellular jaundice in the pre-transplant era. First enunciated with publications defining the hepatotoxicity of iproniazid, phenytoin, isoniazid, dantrolene, nitrofurantoin, aspirin and acetaminophen, halothane, andother agents as far backas the late 1950s, Dr Zimmerman codified this observation in the first edition of his textbook in 1978 and reiterated it in the second version published in 1999. Referring to the outcome of drug-induced hepatocellular necrosis, he states: ‘This is a serious entity. The mortality rates range from 10% to 50%. Ten to 15% of patients with jaundice induced by iproniazid or isoniazid and even a greater proportion of those with phenytoin jaundice have died. The estimated case fatality rate in halothane-related jaundice has ranged from 14 to 70% with an average figure approaching 50%. The series of cases of cinchophen-related jaundice of yesteryear were also estimated to have a 50% fatality rate. ’ (10 [p.433]). The actual wording of his oft-quoted aphorism relating to themortality of hepatocellular jaundicewas, therefore, drawn fromhis own clinical experiencewith, and from descriptions of a relatively select number of well-described older hepatotoxins where detailed case series were available for analysis. Several agents of more recent vintage for which there exist a sufficient number of cases for review, also appear to adhere to this mortality rate. For example, phenylbutazone, ketoconazole, ticrynafen, valproic acid, enflurane, pemoline, labetolol, diclofenac, and even sulindac have case-fatality rates of approximately 10% in patients who develop severe acute hepatocellular jaundice leading to liver failure. It should be noted, however, that the published case series for all of these agents defined the natural history of acute druginduced hepatocellular necrosis prior to the advent of routine liver enzyme testing or other means to detect and prevent irreversible injury that are in routine use today. Dozens ofmarketed drugs have been associatedwith fulminant hepatic failure leading to case fatalities, and several others have been withdrawn or were never approved due to hepatotoxicity (Table 1). However, it was not until the highly publicized withdrawals of troglitazone and bromfenac in 2000 [see the accompanying article by Goldkind and Laine,] and the restrictions placed on trovafloxacin after its approval, all due to instances of irreversible liver failure, that Hy’s Law was increasingly invoked
DESIGN OF A SOFT-CORE PROCESSOR BASED ON OPENCORES WITH ENHANCED PROCESSING FOR EMBEDDED APPLICATIONS

Soft-core processors are being increasingly used in various embedded applications due to their flexibility, cost effectiveness and platform independence. It enables designers to modify the core designs with ease to achieve specific application goals. In this paper, the design of an enhanced soft-core processor based on OpenCores that is suited for telecommunication, multimedia and a variety of embedded applications is presented. The OR1200 platform, which is a 32-bit DSP, with RISC Harvard micro architecture including a 5-stage integer execution pipeline, is used. We enhance the processor design to include a Global Memory Stall Controller which manages the Data Path Unit of the processor and distributes stall signals whenever the memory latency cannot be hidden. Also, we suggest improvements in the data path of the processor to enhance it for better multimedia applications. Finally, we propose to add a Hazard Controller to the execution pipeline to handle data and branch hazard.
A Divide-and-Conquer Approach for Solving Interval Algebra Networks

Deciding consistency of constraint networks is a fundamental problem in qualitative spatial and temporal reasoning. In this paper we introduce a divide-and-conquer method that recursively partitions a given problem into smaller sub-problems in deciding consistency. We identify a key theoretical property of a qualitative calculus that ensures the soundness and completeness of this method, and show that it is satisfied by the Interval Algebra (IA) and the Point Algebra (PA). We develop a new encoding scheme for IA networks based on a combination of our divide-and-conquer method with an existing encoding of IA networks into SAT. We empirically show that our new encoding scheme scales to much larger problems and exhibits a consistent and significant improvement in efficiency over state-of-the-art solvers on the most difficult instances.
Development of a Living Library of Digital Health Technologies for Alzheimers Disease and Related Dementias: Initial Results from a Landscape Analysis and Community Collaborative Effort

Digital health technologies offer valuable advantages to dementia researchers and clinicians as screening tools, diagnostic aids, and monitoring instruments. To support the use and advancement of these resources, a comprehensive overview of the current technological landscape is essential. A multi-stakeholder working group, convened by the Digital Medicine Society (DiMe), conducted a landscape review to identify digital health technologies for Alzheimers disease and related dementia populations. We searched studies indexed in PubMed, Embase, and APA PsycInfo to identify manuscripts published between May 2003 to May 2023 reporting analytical validation, clinical validation, or usability/feasibility results for relevant digital health technologies. Additional technologies were identified through community outreach. We collated 172 peer-reviewed manuscripts, poster presentations, or regulatory documents for 106 different technologies for Alzheimers disease and related dementia assessment covering diverse populations such as Lewy Body, vascular dementias, frontotemporal dementias, and all severities of Alzheimers disease. Wearable sensors represent 32% of included technologies, non-wearables 61%, and technologies with components of both account for the remaining 7%. Neurocognition is the most prevalent concept of interest, followed by physical activity and sleep. Clinical validation is reported in 69% of evidence, analytical validation in 34%, and usability/feasibility in 20% (not mutually exclusive). These findings provide a landscape overview for clinicians and researchers to appraise the clinical utility and relative maturity of technologies for assessing Alzheimers disease and related dementias.
Exploitation of the additive component of the polarimetric noise model for speckle filtering

Ratio filters for speckle noise reduction in SAR imagery are recursive filters where the image structure is iteratively recovered from an initial oversmoothed image. We show that the MBPolSAR filter could be interepreted as a ratio filter applied to the off-diagonal terms of the covariance/coherency matix. From this observation, we propose a new polarimetric ratio filter allowing us to recover the image structure from all the terms of the covariance matrix. In addition, we briefly look at how the additive noise component could also be exploited for the image structure extraction. Filtering results on both simulated and real PolSAR images are shown.
Adaptation to Human Populations Is Revealed by Within-Host Polymorphisms in HIV-1 and Hepatitis C Virus

CD8+ cytotoxic T-lymphocytes (CTLs) perform a critical role in the immune control of viral infections, including those caused by human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). As a result, genetic variation at CTL epitopes is strongly influenced by host-specific selection for either escape from the immune response, or reversion due to the replicative costs of escape mutations in the absence of CTL recognition. Under strong CTL-mediated selection, codon positions within epitopes may immediately “toggle” in response to each host, such that genetic variation in the circulating virus population is shaped by rapid adaptation to immune variation in the host population. However, this hypothesis neglects the substantial genetic variation that accumulates in virus populations within hosts. Here, we evaluate this quantity for a large number of HIV-1– (n ≥ 3,000) and HCV-infected patients (n ≥ 2,600) by screening bulk RT-PCR sequences for sequencing “mixtures” (i.e., ambiguous nucleotides), which act as site-specific markers of genetic variation within each host. We find that nonsynonymous mixtures are abundant and significantly associated with codon positions under host-specific CTL selection, which should deplete within-host variation by driving the fixation of the favored variant. Using a simple model, we demonstrate that this apparently contradictory outcome can be explained by the transmission of unfavorable variants to new hosts before they are removed by selection, which occurs more frequently when selection and transmission occur on similar time scales. Consequently, the circulating virus population is shaped by the transmission rate and the disparity in selection intensities for escape or reversion as much as it is shaped by the immune diversity of the host population, with potentially serious implications for vaccine design.
Distribution, Growth and above ground Biomass of Teak (Tectonagrandis L.) Plantation in Mullaitivu District of Sri Lanka

Teak plantation was established in Northern Province of Sri Lanka since 1960’s and it is widely used for the purpose as timber in Sri Lanka. Among the districts of the Northern region, Mullaitivu is a potential district for teak plantation. However, no scientific studies were done regarding teak plantation and its distribution pattern in Northern region. Therefore, a study was carried out to assess the distribution patterns, growth conditions and aboveground biomass in Mullaitivu district during the period of February to May, 2015. Plant height, diameter (dbh), crown height and canopy diameter were measured from selected teak plants in four locations such as Mulliyawalai, Mankulam, Karripatammuripu and Theravil. The measurements were taken with square plot of the size 15m × 15m and findings from the Mulliyawalai and Theravil sites had same aged plantation of 22 years, highest average height and dbh value had observed in Theravil site as 19.80±0.28 m and 20.10±0.24 cm, respectively. The highest aboveground biomass of 410.37t/ha and tree volume of 579.58m/ha was found in Mulliyawalai. Among the four locations, the highest average aboveground biomass (1,301.49t/ha) and tree volume (2,043.77m/ha) were observed in Karripatammuripu plantation. From this study Theravil site was selected as the best site for the plantation of teak.
Using the Future to Sort Out the Present: Rankprop and Multitask Learning for Medical Risk Evaluation

A patient visits the doctor; the doctor reviews the patient's history, asks questions, makes basic measurements (blood pressure, .), and prescribes tests or treatment. The prescribed course of action is based on an assessment of patient risk--patients at higher risk are given more and faster attention. It is also sequential--it is too expensive to immediately order all tests which might later be of value. This paper presents two methods that together improve the accuracy of backprop nets on a pneumonia risk assessment problem by 10-50%. Rankprop improves on backpropagation with sum of squares error in ranking patients by risk. Multitask learning takes advantage of future lab tests available in the training set, but not available in practice when predictions must be made. Both methods are broadly applicable.
Hijacking the epigenetic mechanisms of A. baumannii

Epigenetic mechanisms attribute to the resistance and virulence of Acinetobacter baumannii sparking a renewed area of research. Unveiling the targets pertained to the epigenetic modulation in the bacterium would aid in the curbing its complications in various recalcitrant infections. This review thus throws light on the various epigenetic mechanisms exhibited by A. bauamnnii, urging the need to implement epigenetic based novel strategies in precision medicine.
Oncolytic vaccinia virus immunotherapy antagonizes image-guided radiotherapy in mouse mammary tumor models

Ionizing radiation (IR) and oncolytic viruses are both used to treat cancer, and the effectiveness of both agents depends upon stimulating an immune response against the tumor. In this study we tested whether combining image guided ionizing radiation (IG-IR) with an oncolytic vaccinia virus (VACV) could yield a better therapeutic response than either treatment alone. ΔF4LΔJ2R VACV grew well on irradiated human and mouse breast cancer cells, and the virus can be combined with 4 or 8 Gy of IR to kill cells in an additive or weakly synergistic manner. To test efficacy in vivo we used immune competent mice bearing orthotopic TUBO mammary tumors. IG-IR worked well with 10 Gy producing 80% complete responses, but this was halved when the tumors were treated with VACV starting 2 days after IG-IR. VACV monotherapy was ineffective in this model. The antagonism was time dependent as waiting for 21 days after IG-IR eliminated the inhibitory effect but without yielding any further benefits over IR alone. In irradiated tumors, VACV replication was also lower, suggesting that irradiation created an environment that did not support infection as well in vivo as in vitro. A study of how four different treatment regimens affected the immune composition of the tumor microenvironment showed that treating irradiated tumors with VACV altered the immunological profiles in tumors exposed to IR or VACV alone. We detected more PD-1 and PD-L1 expression in tumors exposed to IR+VACV but adding an αPD-1 antibody to the protocol did not change the way VACV interferes with IG-IR therapy. VACV encodes many immunosuppressive gene products that may interfere with the ability of radiotherapy to induce an effective anti-tumor immune response through the release of danger-associated molecular patterns. These data suggest that infecting irradiated tumors with VACV, too soon after exposure, may interfere in the innate and linked adaptive immune responses that are triggered by radiotherapy to achieve a beneficial impact.
Varying the user interaction within multi-agent systems

Agents within an open multi-agent system are located through their advertisements with middle agents. Such advertisements describe the agent's capability, ontology, query or task specification, and details about the data returned once the task has been completed. Agents may have similar capabilities, but exhibit different models of user interaction. A case study of a multi-agent system is described which contains a variety of different agents, some of which have functionally similar capabilities but involve different types of user interaction. We demonstrate how the choice of user interaction can have a significant effect on the performance of the whole agent community. This leads to the proposal that an agent's interactive style should also be included within its capability advertisement.
On the correlation between gratitude and resilience in medical students

Objective: Medical students’ health and resilience have increasingly been the subject of current research in recent years. A variety of interventions are recommended to strengthen resilience or its known or suspected influencing factors, although the literature shows that the evidence on the effectiveness of the interventions is inconsistent. The present study investigated whether gratitude is a direct protective factor for resilience in medical students or whether resilience factors (optimism, self-efficacy, social support) and stress mediate the effects of gratitude on resilience. Methods: 90 medical students at Witten/Herdecke University took part in the study that determined their gratitude, resilience, optimism, self-efficacy, social support and stress levels using validated questionnaires (GQ-6, RS-25, LOT-R, SWE, F-SozU, PSS). Correlations were analyzed using Pearson correlation coefficients. In addition, a multivariate regression analysis and a path analysis were calculated to determine the direct and indirect effects of gratitude on resilience. Results: Multivariate regression analysis showed that only optimism, social support and stress were significantly associated with resilience (B=0.48, 95% CI: 0.31, 0.66; B=0.23, 95% CI: 0.01, 0.44 and B=-0.02, 95% CI: -0.03, -0.001, respectively). The direct effect of gratitude on resilience was minimal and not significant in the path analysis. However, there was an indirect effect of gratitude on resilience (B=0.321; p<0.05). Mediation via the optimism variable was mainly responsible for this effect (indirect effect B=0.197; p<0.05). Conclusion: This study shows that gratitude has only a minimal direct influence on resilience. However, results indicate that optimism as a mediating factor strengthens the resilience of medical students. Against this background, it may be useful to integrate interventions that promote an optimistic attitude into medical studies in order to strengthen the mental health of future doctors in the long term.
Thurston Island (West Antarctica) Between Gondwana Subduction and Continental Separation: A Multistage Evolution Revealed by Apatite Thermochronology

The first low‐temperature thermochronological data from Thurston Island, West Antarctica, provide insights into the poorly constrained thermotectonic evolution of the paleo‐Pacific margin of Gondwana since the Late Paleozoic. Here we present the first apatite fission track and apatite (U‐Th‐Sm)/He data from Carboniferous to mid‐Cretaceous (meta‐) igneous rocks from the Thurston Island area. Thermal history modeling of apatite fission track dates of 145–92 Ma and apatite (U‐Th‐Sm)/He dates of 112–71 Ma, in combination with kinematic indicators, geological information, and thermobarometrical measurements, indicate a complex thermal history with at least six episodes of cooling and reheating. Thermal history models are interpreted to reflect Late Paleozoic to Early Mesozoic tectonic uplift of pre‐Jurassic arc sequences, prior to the formation of an extensional Jurassic‐Early Cretaceous back‐arc basin up to 4.5 km deep, which was deepened during intrusion and rapid exhumation of rocks of the Late Jurassic granite suite. Overall Early to mid‐Cretaceous exhumation and basin inversion coincided with an episode of intensive magmatism and crustal thickening and was followed by exhumation during formation of the Zealandia‐West Antarctica rift and continental breakup. Final exhumation since the Oligocene was likely triggered by activity of the West Antarctic rift system and by glacial erosion.
Unrest at the Nevados de Chillán volcanic complex: a failed or yet to unfold magmatic eruption?

Resuming erupting activity at volcanoes that have been long quiescent poses a significant challenge to hazard assessment, as it require assessment of whether the change in activity is an isolated event or the beginning of a new eruptive sequence. Such inception is often poorly characterised as quiescent volcanoes tend to be poorly equipped and not extensively monitored, especially with respect to gas geochemistry. Here, we report gas composition and flux measurements from a newly opened vent at the very onset of eruptive activity at the Nevados de Chillan volcanic complex (Chile) in January-February 2016. The molar proportions of H2O, CO2, SO2, H2S and H2 gases are found to be 98.4, 0.97, 0.11, 0.01 and 0.5 mol% respectively. The mean SO2 flux recorded in early February 2016 during periods of eruptive discharge amounts to 0.4-0.6 kg s-1. Our results indicate that the new vent opening was propelled by magmatic gases, triggering repeated eruptions. Ash particles ejected by the first blast of 8 January are dominated by lithic fragments of dacitic composition. By contrast the ash ejected in a subsequent eruption contains both lithic fragments of dense dacite, and a fresher, sparsely vesicular material of basaltic andesite composition. By October 2017 the ejected ash is back to being dominated by the dense dacitic lithic material. Together with the seismic and deformation record, these observations point to the explosive activity resulting from a small intrusion of basaltic to andesitic magma at shallow level. The fate of this magma, whether stalling or eventually triggering a magmatic eruption, remains to be seen, but current observations suggest the former is most likely.
Candoia: A Platform for Building and Sharing Mining Software Repositories Tools as Apps

We propose Candoia, a novel platform and ecosystemfor building and sharing Mining Software Repositories(MSR) tools. Using Candoia, MSR tools are built as apps, and Candoia ecosystem, acting as an appstore, allows effective sharing. Candoia platform provides, data extraction tools for curating custom datasets for user projects, and data abstractions for enabling uniform access to MSR artifacts from disparate sources, which makes apps portable and adoptable across diverse software project settings of MSR researchers and practitioners. The structured design of a Candoia app and the languages selected for building various components of a Candoia app promotes easy customization. To evaluate Candoia we have built over two dozen MSR apps for analyzing bugs, software evolution, project management aspects, and source code and programming practices showing the applicability of the platform for buildinga variety of MSR apps. For testing portability of apps acrossdiverse project settings, we tested the apps using ten popularproject repositories, such as Apache Tomcat, JUnit, Node.js, etc, and found that apps required no changes to be portable. We performed a user study to test customizability and we found that five of eight Candoia users found it very easy to customize an existing app. Candoia is available for download.