Miracle-dz/UniFAR-FTUs huggingface dataset:
Temperature Extremes: Estimation of Non-Stationary Return Levels and Associated Uncertainties

Estimating temperature extremes (TEs) and associated uncertainties under the non-stationary (NS) assumption is a key research question in several domains, including the nuclear safety field. Methods for estimating TEs and associated confidence intervals (CIs) have often been used in the literature but in a stationary context, separately and without detailed comparison. The extreme value theory is often used to assess risks in a context of climate change. It provides an accurate indication of distributions describing the frequency of occurrence of TEs. However, in an NS context, the notion of the return period is not easily interpretable. For instance, to predict a high return level (RL) in a future year, time-varying distributions must be used and compared. This study examines the performance of a new concept to predict RLs in an NS context and compares three methods for constructing the associated CIs (delta, profile likelihood, and parametric bootstrap). The present work takes up the concept of integrated return periods that define the T-year RL as the level for which the expected number of events in a T-year period is one and proposes a new method based on conditional predictions that is useful for predicting high RLs of extreme events in the near future (the 100-year RL in the year 2030, for instance). The daily maximum temperature (DMT) observed at the Orange Station in France was used as a case study. Several trend models were compared and a new likelihood-based method to detect breaks in TEs is proposed. The analyses were conducted assuming the time-varying Generalized Extreme Value (GEV) distribution. The concepts have been implemented in a software package (Non-Stationary Generalized Extreme Value (NSGEV)). The application demonstrates that the RL estimates for NS situations can be quite different from those corresponding to stationary conditions. Overall, the results suggest that the NS analysis can be helpful in making a more appropriate assessment of the risk for periodic safety reviews during the life of a nuclear power plant (NPP).
Laboratory Testing in Disseminated Intravascular Coagulation

The diagnosis of disseminated intravascular coagulation (DIC) relies on clinical signs and symptoms, identiﬁcation of the underlying disease, the results of laboratory testing, and differentiation from other pathologies. The clinical features mainly depend on the underlying cause of the DIC. The laboratory diagnosis of DIC uses a combination of tests because no single test result alone can ﬁrmly establish or rule out the diagnosis. Global tests of hemostasis may initially provide evidence of coagulation activation and later in the process provide evidence of consumption of coagulation factors, but their individual diagnostic efﬁciency is limited. Fibrinolytic markers, in particular D-dimer, are reﬂective of activation of both coagulation and ﬁbrinolysis, so that a normal ﬁnding can be useful for ruling-out DIC. Decreased levels of the natural anticoagulants (in particular, antithrombin and protein C) are frequently observed in patients with DIC, but their measurement is not normally incorporated into standard diagnostic algorithms. New tests are being explored for utility in DIC, and some additional tests may be useful on a case-by-case basis, depending on the proposed cause of the DIC or their local availability. For example, clot waveform analysis is useful but currently limited to a single instrument. Also, procalcitonin is an inﬂammatory biomarker that may be useful within the context of septic DIC, and activated factor X clotting time is an emerging test of procoagulant phospholipids that also seems to hold promise in DIC.
Overview of Heparin-Induced Thrombocytopenia. Diagnosis and Treatment in Europe with an Emphasis on France

Although the prevalence of heparin-induced thrombocytopenia (HIT) has decreased these last years in France with the widespread use of low molecular weight heparins, HIT remains an important severe prothrombotic disease that needs to be diagnosed and treated adequately. HIT is caused by IgG antibodies that bind to modiﬁed platelet factor 4 and induce platelet and monocyte activation with increased thrombin generation. Venous and arterial thromboses are therefore frequent in HIT, explaining why substituting heparin with a potent alternative anticoagulant such as danaparoid sodium, lepirudin, or argatroban is necessary in every affected patient. However, the management of these drugs is difﬁcult, and the diagnosis of HIT always has to be assessed on both clinical criteria and laboratory tests that detect heparin-dependent antibodies in the patient’s blood (antigen assays and platelet activation tests). When the clinical probability of HIT is high, the ﬁrst requirement is to discontinue heparin, without waiting for the results of laboratory assays. The choice of the alternative anticoagulant is then driven by several criteria. Danaparoid (mainly anti-Xa) is often preferred in cases of isolated thrombocytopenia, and lepirudin (anti-IIa) is preferred when surgery is required due to its shorter half-life. But with these two drugs the risk of overdosage is high in patients with renal failure. Argatroban (anti-IIa) is thus a useful drug in critically ill patients because of its hepatobiliary excretion. Unfortunately, argatroban is not available in many European countries including France.
Seventh Cranial Neuropathy

Facial neuropathy, or seventh cranial neuropathy, is the most common cranial neuropathy. The anatomy of the facial nerve is rather complex for a cranial nerve, with a long intracranial course, in which the nerve takes three bends (or genu). Electrodiagnosis can be helpful in prognosis, but not before several days. Imaging is rarely indicated in Bell’s palsy, but is often abnormal nonetheless, and can be very useful in other causes of facial neuropathy. The clinical presentation is of unilateral facial weakness of upper and lower face, hyperacusis, dysgeusia, and disordered lacrimation and salivation. Many different disease processes can result in facial neuropathy, but 70% of cases are idiopathic, or as it is best known, Bell’s palsy. Ramsay Hunt syndrome, deﬁned as facial neuropathy with herpes zoster oticus, is another common cause. Steroids given acutely are beneﬁcial in improving outcome in Bell’s palsy, and antiviral therapy seems helpful in more severe cases. Antiviral therapy is deﬁnitely helpful in Ramsay Hunt disease when given within 3 days of onset. Antibiotics are helpful in Lyme facial neuropathy, which has a very good prognosis.
Liver Transplantation in HIV-Infected Recipients

Although human immunodeﬁciency virus (HIV)-infected patients are living longer and dying less often from complications related to acquired immunodeﬁciency syndrome (AIDS), they are experiencing signiﬁcant morbidity and mortality related to end-stage liver disease. Advances in the management of HIV disease have made it difﬁcult to continue denying transplantation to this population based upon futility arguments alone. Patient and graft survival rates in HIV-infected study subjects appear similar to those in large transplant databases. There are no reports suggesting signiﬁcant HIV disease progression. There are substantial interactions between immunosuppressants and antiretroviral drugs that require careful monitoring and dose adjustment. The evaluation and management of HIV-infected transplant candidates and recipients require excellent communication among a multidisciplinary team and the primary HIV care provider. It is critical that HIV clinicians and hepatologists are aware that liver transplantation is an option for HIV-infected patients at many transplant centers as delays in referral result in unnecessary mortality during the pretransplantation evaluation process.
Polycystic Ovarian Syndrome and the Risk of Cardiovascular Disease and Thrombosis

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with multiple comorbidities such as diabetes, dyslipidemia, hypertension, and metabolic syndrome, all of which predispose women with PCOS to early atherosclerosis. Women with PCOS also have a higher prevalence of subclinical atherosclerosis, as reﬂected in dysregulation of endothelial function, increased carotid intimal-medial thickness, and presence of coronary artery calciﬁcation. Preliminary data indicate that serum biomarkers of cardiovascular disease such as high-sensitivity C-reactive protein, homocysteine, and adiponectin are abnormal in women with PCOS. There is limited data on abnormalities in the coagulation and ﬁbrinolytic systems, however. The risk of venous thrombosis is unclear in the PCOS population, and further studies are urgently required to address whether ﬁrst-line treatment for PCOS with oral contraceptive pills is advisable.
α1-Antitrypsin Deficiency in Childhood

a 1 -Antitrypsin deﬁciency is a common genetic disease in which individuals homozygous for the mutant Z allele are at risk for the development of liver disease and emphysema. The mutant Z protein product is synthesized in hepatocytes but then accumulates intracellularly rather then being appropriately secreted. The effects of the intracellular accumulation of the mutant Z protein in the liver include the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation, which progress in a cascade causing hepatocellular injury. Liver disease can occur at any age, although the majority of children are free of signiﬁcant liver dysfunction. The variable clinical presentations suggest an important contribution of genetic and environmental disease modiﬁers. The heterozygous carrier state for the mutant Z gene, present in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modiﬁer gene for other liver diseases.
Pathogenesis and Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Once thought to be a mere nuisance, exacerbations are now recognized as a major contributor to the morbidity and mortality associated with chronic obstructive pulmonary disease. This recognition has led to research using new investigative tools that has substantially enhanced our understanding of the pathogenesis of exacerbations. Several overlapping etiologies can precipitate the symptom complex of an exacerbation. Treatment of exacerbations requires the use of several therapeutic modalities with the goal of restoring the patient to baseline. Results of recent clinical trials and observational studies have allowed a reﬁnement of the approach to treatment of exacerbations. These include a rational, stratiﬁed approach to the use of antibiotics and several trials substantiating the use of systemic corticosteroids. Relapse or failure rates of 20 to 33% have been described in the treatment of acute exacerbation, with these treatment failures contributing substantially to the costs associated with exacerbations. Improved treatment based on enhanced understanding and good clinical evidence should lead to better outcomes in this common clinical entity.
Diagnosis and Management of Chronic Daily Headache

Chronic daily headache (CDH) is a descriptive term that encompasses multiple headache diagnoses and affects (cid:1) 4% of the general adult population. Chronic daily headache results in signiﬁcant pain and suffering with substantial impact on quality of life, and enormous economic costs to society. Although most patients with primary CDH suffer from chronic migraine or chronic tension-type headache, other primary and secondary headache disorders can also manifest as a CDH syndrome. For CDH management to succeed, secondary headaches need to be ruled out with proper investigations when judged necessary. If the diagnosis of primary CDH is established, diagnosis of the speciﬁc CDH subtype is imperative to institute appropriate treatment. The diagnosis and management of distinct CDH entities, chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua, are the primary forms of CDH and the emphasis of this review. Although, strictly speaking, medication overuse headache is a secondary form of CDH, it is also highlighted in this review given its frequent association with primary CDH.
Prevention of Deep Vein Thrombosis in Cancer Patients

Venous thromboembolism (VTE) in patients with cancer follows an aggressive course, and it is often resistant to traditional regimens of pharmacological prophylaxis and treatment. Anticoagulant-related bleeding is also common and can complicate VTE treatment as well as cancer therapy. Consequently, the most effective approach to reducing the burden of VTE and its associated morbidity and mortality is to provide appropriate prophylaxis. Few clinical trials have focused on the prevention of VTE in this high-risk patient population, and they consistently demonstrate the efﬁcacy and safety of anticoagulant prophylaxis in reducing thrombotic complications. Currently, low-molecular-weight heparins and oral vitamin K antagonists are the most commonly used anticoagulants for primary prevention in patients with cancer, but compliance with consensus guidelines is poor. Novel anticoagulants with a convenient and favorable risk/ beneﬁt proﬁle may help to improve prophylaxis utilization and treatment. This review will provide a summary of the evidence on the primary prevention of VTE in patients with cancer.
PROTECTIVE EFFECTS OF TRITERPENOID BETULIN ON TYPE 2 DIABETES MELLITUS IN RATS

Type 2 diabetes mellitus (T2DM) is a complex chronic metabolic disease characterized by long-term hyperglycemia, which is, in turn, resulted from the impaired insulin signaling caused by a combination of insulin resistance or inadequate insulin production. Prevalence and incidence of T2DM are increasing dramatically across the world, and it is accompanied with severe complications and premature mortality of patients with diabetes. Given the fact that synthetic drugs have disadvantages in view of the side effects, the implementation of naturally occurring compounds for diabetes treatment may be a promising alternative. Betulin is a naturally occurring triterpenoid which has been shown to possess the ability of altering body lipids and exert hypoglycemic and hepatoprotective effects. It is suggested that the application of betulin in T2DM may have a favorable effect to ease the severity of diabetic complications. Thus, the aim of the present study was to assess biological effects of betulin in T2DM conditions. Diabetes-induced rats were administered with two different doses of betulin for 28 consecutive days. It was shown that long-term administration of betulin at the doses of 50 and 100 mg/kg/day to the rats prevented diabetes-associated changes in a body weight of the animals, significantly reversed insulin resistance and abolished the impairment of glucose metabolism. It was accompanied with the dose-dependent normalization of serum lipid contents. Histopathological changes and structural abnormalities in the liver of diabetics were restored by the administration of betulin. Also, betulin was able to restrain systemic inflammation detected in diabetic animals according to the altered levels of serum TNFα. Thus, the results obtained in the current study were found to be in agreement with earlier findings on beneficial effects of betulin in conditions pathogenetically close to T2DM. We hypothesized that the ability of betulin to restrain systemic inflammation and to normalize the lipid metabolism can explain improved insulin resistance and glycemic control and it can provide a possible mechanism for the beneficial antidiabetic effects of betulin.
Experience-dependent plasticity of a highly specific olfactory circuit in Drosophila melanogaster

Drosophila melanogaster encounters a variety of odor cues signaling potentially harmful threats through-out its life, which are detected by highly specialized olfactory circuits enabling the animal to avoid them. We studied whether such crucial neuronal pathways are hard-wired or can be modulated by experience. Using long-term exposure to high concentrations of geosmin, an indicator of potentially lethal microorganisms, we demonstrate at the single-cell level that the underlying neuronal circuitry undergoes structural changes in the antennal lobe, while higher brain centers remain unaffected. In particular, second-order neurons show neurite extensions and synaptic remodeling after the exposure period, whereas olfactory sensory neurons and glia cells remain unaffected. Flies that were exposed to geosmin tolerate this innately aversive odorant in general choice and oviposition assays. We show that even a highly specific olfactory circuit is plastic and adaptable to environmental changes. HIGHLIGHTS The highly specific geosmin circuit is modulated by experience-dependent plasticity PN dendritic extensions cause a volumetric increase of the geosmin-detecting glomerulus LNs are remodeled while OSNs and glia cells remain unaffected by long-term exposure Flies adapt their behavior to an odorant signaling a potential lethal threat
Revealing a hidden conducting state by manipulating the intracellular domains in KV10.1 exposes the coupling between two gating mechanisms

The KCNH family of potassium channels serves relevant physiological functions in both excitable and non-excitable cells, reflected in the massive consequences of mutations or pharmacological manipulation of their function. This group of channels shares structural homology with other voltage-gated K+ channels. Still, the mechanisms of gating in this family show significant differences with respect to the canonical electromechanical coupling in these molecules. In particular, the large intracellular domains of KCNH channels play a crucial role in gating that is still only partly understood. Using KCNH1(KV10.1) as a model, we have characterized the behavior of a series of modified channels that the current models could not explain. With electrophysiological and biochemical methods combined with mathematical modeling, we show that the behavior of the mutants can be explained by the uncovering of an open state that is not detectable in the wild type, is accessed from deep closed states, and reflects an intermediate step along the chain of events leading to channel opening. This allowed us to study gating steps prior to opening, which, for example, explain the mechanism of gating inhibition by Ca2+-Calmodulin, and generate a gating model that describes the characteristic features of KCNH channels gating.
Pupil Size Sensitivity to Listening Demand Depends on Motivational State

Abstract Motivation plays a role when a listener needs to understand speech under acoustically demanding conditions. Previous work has demonstrated pupil-linked arousal being sensitive to both listening demands and motivational state during listening. It is less clear how motivational state affects the temporal evolution of the pupil size and its relation to subsequent behavior. We used an auditory gap detection task (N = 33) to study the joint impact of listening demand and motivational state on the pupil size response and examine its temporal evolution. Task difficulty and a listener’s motivational state were orthogonally manipulated through changes in gap duration and monetary reward prospect. We show that participants’ performance decreased with task difficulty, but that reward prospect enhanced performance under hard listening conditions. Pupil size increased with both increased task difficulty and higher reward prospect, and this reward prospect effect was largest under difficult listening conditions. Moreover, pupil size time courses differed between detected and missed gaps, suggesting that the pupil response indicates upcoming behavior. Larger pre-gap pupil size was further associated with faster response times on a trial-by-trial within-participant level. Our results reiterate the utility of pupil size as an objective and temporally sensitive measure in audiology. However, such assessments of cognitive resource recruitment need to consider the individual’s motivational state.
Imaging of the Hamstrings

The hamstring muscles, located in the posterior thigh, include the biceps femoris, the semimembranosus, and the semitendinosus. The proximal portions of the hamstring muscles are subject to a variety of injuries and pathology. Many of these entities affect the origin of the hamstrings, including the tendinous enthesis, the underlying ischial tuberosity, and the surrounding tissues. Tendinosis and small partial tears at the origin are the result of chronic attrition. They may be accompanied by bursitis or hamstring syndrome. Apophysitis occurs in teenagers prior to complete fusion of the ischial apophysis and results from repeated traction injuries on the apophysis without discrete displacement. Abrupt injury at the origin from forced ﬂexion of the hip results in osseous avulsions of the apophysis in teenagers and proximal tendon ruptures in adults. Other entities affect the muscles distal to the tendon origins. These injuries include strains and partial tears of the musculotendinous junction from acute indirect trauma, delayed onset muscle soreness from overuse of the muscle group without discrete remembered injury, and contusions and myositis ossiﬁcans from direct blunt impact. The imaging features of these injuries and pathology are fairly speciﬁc and diagnostic, with the exception of some cases of myositis ossiﬁcans and chronic ischial avulsions.
Thrombin Generation and the Pathogenesis of Cancer

Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through ﬁbrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain–deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on speciﬁc features of the local tumor microenvironment.
The Influence of Hydrosalpinx on Markers of Endometrial Receptivity

Hydrosalpinx is a common condition among women of reproductive age. It is related to low pregnancy rates in the settings of in vitro fertilization–embryo transfer programs. Such low rates are not yet well understood, and may be due to poor endometrial receptivity and abnormal expression of key molecules in the endometrium that are important for implantation. The available data on the inﬂammatory response, endometrial blood ﬂow, integrins, leukemia inhibitory factor, matrix metalloproteinases, and homeobox gene A10 expression in the presence of hydrosalpinx are reviewed. In addition, the evidence for treatment options to improve pregnancy rates is also discussed.