Miracle-dz/UniFAR-FTUs huggingface dataset:
Aromatase inhibitors in early breast cancer therapy: a variety of treatment strategies

Until recently, standard endocrine therapy for estrogen receptor-positive early breast cancer in the preoperative neoadjuvant and postoperative adjuvant settings was the selective estrogen receptor modulator tamoxifen. An alternate therapeutic approach is to suppress total-body estrogen synthesis using an aromatase inhibitor. The highly potent and specific third-generation aromatase inhibitors (anastrozole, exemestane and letrozole) have consistently demonstrated improved efficacy over tamoxifen in large randomised neoadjuvant and adjuvant clinical trials. As neoadjuvant therapy, compared with tamoxifen, all three aromatase inhibitors significantly improved breast-conserving surgery rates, but only letrozole achieved a significantly higher overall response rate. These agents have also been evaluated in three adjuvant strategies: instead of tamoxifen for 5 years, sequenced after 2 – 3 years of tamoxifen, or as extended adjuvant therapy following a full 5-year course of tamoxifen. In all cases, the aromatase inhibitor was significantly more effective in reducing the risk of recurrence, compared with tamoxifen in the first two approaches and with placebo or no treatment as extended therapy. Long-term aromatase inhibitor treatment is associated with less endometrial cancer, thromboembolic events and strokes than tamoxifen, but more musculoskeletal disorders and bone loss. Further investigation is focusing on identification of the patient subgroups most likely to benefit from each of these adjuvant therapy options.
Selection Bias in Cancer Risk Estimation from A-Bomb Survivors

Abstract Pierce, D. A. , Vaeth, M. and Shimizu, Y. Selection Bias in Cancer Risk Estimation from A-Bomb Survivors. Radiat. Res. 167, 735–741 (2007). We consider the possible bias in cancer risk estimation from A-bomb survivors due to selection of the cohort by survival. The paper considers both relevant information from the data and basic theoretical issues involved. The most direct information from the data comes from making various restrictions on the dose–distance range, partly to reduce differential selection and partly just to reduce the magnitude of the selection. These analyses suggest that there are no serious biases, but they are not conclusive. Theoretical considerations include laying out more explicitly than usual just how biases could result from the selection. This involves heterogeneities in the ability to survive acute effects, in baseline and radiogenic cancer rates, and most importantly the correlation between survival-related and cancer-related heterogeneities. Following on this, idealized modeling is used to quantify the extent of possible bias in terms of the assumed values of the magnitude of these heterogeneities and their correlation. It is indicated that these values would need to be very large to introduce substantial bias. Based on all these considerations, it seems unlikely that the bias in cancer risk estimation could be large in relation to other uncertainties in generalizing from what is seen among A-bomb survivors; in particular, indications are that the bias in relative risks is unlikely to be as large as 0.05 to 0.07. For solid cancer this would correspond to bias in the excess relative risk at 1 Sv of at most about 15–20%.
Emotion Regulation Skills Mediate the Effects of Shame on Eating Disorder Symptoms in Women

We examined the impact of negative affectivity, chronic shame, and emotion regulation skills on eating disorder symptoms in undergraduate women (N = 154). We hypothesized that self-reported emotion regulation skills would mediate the well-documented relationship between chronic shame and eating disorder symptoms. Results revealed that chronic shame predicted eating disorder symptoms over and above general negative affectivity. Further, difficulties with emotion regulation mediated the relationship between chronic shame and ED symptoms. These findings suggest that chronic shame's role in eating disorder symptoms can be ameliorated by skillful emotion regulation.
The propylthiouracil dilemma

Purpose of reviewTo bring to the attention of healthcare professionals the additional information on propylthiouracil (PTU)-related hepatotoxicity, based on a reanalysis of medical files reported to the Food and Drug Administration (1982–2008) for acute liver failure in PTU-treated hyperthyroid patients, and propose recommendations for the clinical use of PTU. Thirteen files of PTU-related severe liver adverse effects were analyzed for the pediatric population, seventeen for nonpregnant adults and two for pregnant women. Recent findingsThe recent findings showed that the daily PTU dose administered was high in the children, with a mean of 300 mg/day for an average 10-year-old individual. With regard to treatment duration, PTU administration lasted for at least 4 months in 75% of pediatric cases. Similarly, in a majority of adult cases (64%), PTU-induced liver injury occurred after a relatively long treatment period (4 months to >1 year). SummaryPTU should not be used in children, in whom methimazole (MMI) represents the logical alternative. In adults, PTU should be restricted to those rare patients with Graves’ disease for whom no better alternative can be offered and in patients with thyroid storm. For the special circumstance of pregnancy, PTU is the preferred choice during early gestation; switching back to MMI during later gestational stages remains a matter of clinical judgment. It is unknown whether liver function tests monitoring is worthwhile to prevent life-threatening, PTU-related hepatotoxicity.
The effects of co-morbidity on the onset and persistence of generalized anxiety disorder in the ICPE surveys

Background. Although it is well known that generalized anxiety disorder (GAD) is highly co-morbid with other mental disorders, little is known about the extent to which earlier disorders predict the subsequent first onset and persistence of GAD. These associations are examined in the current report using data from four community surveys in the World Health Organization (WHO) International Consortium in Psychiatric Epidemiology (ICPE). Method. The surveys come from Brazil, Canada, the Netherlands and the United States. The Composite International Diagnostic Interview (CIDI) was used to assess DSM-III-R anxiety, mood and substance use disorders in these surveys. Discrete-time survival analysis was used to examine the associations of retrospectively reported earlier disorders with first onset of GAD. Logistic regression analysis was used to examine the associations of the disorders with persistence of GAD. Results. Six disorders predict first onset of GAD in all four surveys: agoraphobia, panic disorder, simple phobia, dysthymia, major depression and mania. With the exception of simple phobia, only respondents with active disorders have elevated risk of GAD. In the case of simple phobia, in comparison, respondents with a history of remitted disorder also have consistently elevated risk of GAD. Simple phobia is also the only disorder that predicts the persistence of GAD. Conclusions. The causal processes linking temporally primary disorders to onset of GAD are likely to be state-dependent. History of simple phobia might be a GAD risk marker. Further research is needed to explore the mechanisms involved in the relationship between simple phobia and subsequent GAD.
The long-term results of speech perception in elderly cochlear implant users

Objectives: To evaluate the speech discrimination performance of elderly post-lingually deafened cochlear implant (CI) users and the stability of performance over time relative to a control group of younger CI users. Methods: The study group consisted of 20 native Dutch speaking, post-lingually deafened CI users, aged 70 or older at the time of implantation. Controls were patients aged 40–60 years at implantation and included according to the same inclusion criteria (except age). Linear mixed models assessed speech recognition scores between groups, the variability of their performance, and stability over time. Results: 20 elderly and 37 controls were included. The mean follow-up was 4.4 and 5.3 years for elderly and controls, respectively. There was no significant difference in average speech discrimination between both groups. The elderly group had a larger intra-subject variability over time. There was no significant effect of follow-up on the speech discrimination, indicating a stable performance over time. Discussion: This study has a longer follow-up than methodologically comparable previous studies. We found no difference in speech discrimination between elderly patients and controls and no deterioration of performance over time. The subjects in the elderly group exhibit a larger variability around their mean performance. Conclusion: Speech recognition in both elderly and younger adult CI users is stable over time and is not significantly related to the age of implantation.
The postantibiotic effect of imipenem: relationship with drug concentration, duration of exposure, and MIC

The postantibiotic effect (PAE) of imipenem against Escherichia coli was measured at a wide variety of drug concentrations and times of exposure. We observed that the area under the concentration-time curve of drug exposure (AUC), the product of time of exposure and concentration of drug, is a much better predictor of the duration of the PAE than either parameter alone. We also measured the PAE of imipenem against strains of gram-positive and gram-negative bacteria for which MICs varied widely. The E50, the AUC required to produce 50% of the maximum PAE, is correlated with the MIC and is independent of species. This may explain why the duration of the PAE differs for bacteria of the same species for which MICs are different.
A 23,000-Year Record of Surface Water pH and PCO2 in the Western Equatorial Pacific Ocean

The oceans play a major role in defining atmospheric carbon dioxide (CO2) levels, and although the geographical distribution of CO2 uptake and release in the modern ocean is understood, little is known about past distributions. Boron isotope studies of planktonic foraminifera from the western equatorial Pacific show that this area was a strong source of CO2 to the atmosphere between approximately 13,800 and 15,600 years ago. This observation is most compatible with increased frequency of La Niña conditions during this interval. Hence, increased upwelling in the eastern equatorial Pacific may have played an important role in the rise in atmospheric CO2 during the last deglaciation.
Cysteine-rich Domain 1 of CD40 Mediates Receptor Self-assembly*

Background: The activation of CD40 is essential for the development of humoral and cellular immune responses. Results: CD40 dimerizes through the extracellular region via the CRD1, and recombinant CRD1 potentiates CD40L activity. Conclusion: CD40-CRD1 participates to dimerization and is required for efficient receptor expression. Significance: CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state. The activation of CD40 on B cells, macrophages, and dendritic cells by its ligand CD154 (CD40L) is essential for the development of humoral and cellular immune responses. CD40L and other TNF superfamily ligands are noncovalent homotrimers, but the form under which CD40 exists in the absence of ligand remains to be elucidated. Here, we show that both cell surface-expressed and soluble CD40 self-assemble, most probably as noncovalent dimers. The cysteine-rich domain 1 (CRD1) of CD40 participated to dimerization and was also required for efficient receptor expression. Modelization of a CD40 dimer allowed the identification of lysine 29 in CRD1, whose mutation decreased CD40 self-interaction without affecting expression or response to ligand. When expressed alone, recombinant CD40-CRD1 bound CD40 with a KD of 0.6 μm. This molecule triggered expression of maturation markers on human dendritic cells and potentiated CD40L activity. These results suggest that CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state.
Limits of the neutral-point balance in back-to-back-connected three-level converters

This paper explores the limits of neutral-point current control in back-to-back connected three-level converters. The theoretical analysis used is based on a mathematical neutral-point current model, which can be extended to apply to converters with higher numbers of levels. The low-frequency ripple, which appears in the neutral-point voltage for some operation conditions, can be removed for an extended operating area when two converters are connected back to back to the same dc bus. As a consequence, a lower voltage is applied to the devices, and the value of the capacitors can also be significantly reduced. Some practical graphics are given to represent the design according to the specifications of the application.
Dynamic IMRT Treatments of Sinus Region Tumors: Comparison of Monte Carlo Calculations with Treatment Planning System Calculations and Ion Chamber Measurements

Results are presented comparing Monte Carlo (MC) calculations for dynamic IMRT treatments of tumors in the sinus region with Eclipse treatment planning system dose calculations, and ion chamber measurements. The EGS4nrc MC code, BEAMnrc, was commissioned to simulate a Varian 21Ex Linac for both open and IMRT fields. The accuracy of the simulation for IMRT plans was evaluated using a head phantom by comparing MC, Eclipse, TLD results, and ion chamber in solid water phantom measurements. The MC code was then used to simulate dose distributions for five patients who were treated using dynamic IMRT for tumors in the sinus region. The results were compared with absolute and relative dose distributions calculated using Eclipse (pencil beam, modified-Batho inhomogeneity correction). Absolute dose differences were also compared with ion chamber results. Comparison of the doses calculated on the head phantom using MC, compared with Eclipse, ion chamber, and TLD measurements showed differences of −3.9%, −1.4%, and −2.0%, respectively (MC is colder). Relative dose distributions for the patient plans calculated using MC agreed well with those calculated using Eclipse with respect to targets and critical organs, indicating the modified-Batho correction is adequate. Average agreement for mean absolute target doses between MC and Eclipse was −3.0 ± 2.3% (1 s.d.). Agreement between ion chamber and Eclipse for these patients was −2.2 ± 1.9%, compared with 0.2 ± 2.0% for all head and neck IMRT patients. When Eclipse doses were corrected based on ion chamber results, agreement between MC and Eclipse was −0.7 ± 2.0%, indicating a small systematic uncertainty in the doses calculated using the treatment planning system for this subset of patients.
HYPOTHYROIDISM ASSOCIATED SYSTEMIC AND PERIPHERAL DISORDERS IN DOGS

Hypothyroidism is the most common endocrine disorder in dogs. The present paper puts on record various ailments associated with primary hypothyroidism caused by thyroxine (T 4 ) deficiency and peripheral disorders in euthyroid dogs, which mimic hypothyroidism. The study undertaken on 10,172 dogs presented at the clinics with skin and coat incongruity, revealed clinical manifestations suggestive of hypothyroidism in 182 (1.78%) dogs, out of which 47 (25.8%) dogs demonstrated significantly (P0.01) low level of total thyroxine (T 4 ) indicating primary hypothyroidism. The common clinical signs were bilateral alopecia (82.98%), rattail appearance (72.34%), dry and lusture less coat (68.08%), obesity (68.08%), exercise intolerance (78.72%), and lethargy (74.47%). Most of the cases were acquired hypothyroidism (97.87%), the rest (2.13%) were congenital. The disorders in primary hypothyroidism were related to dermatological (80.00%), metabolic (48.93%), ocular (31.91%), neuromuscular (25.53%), renal (17.02%), cardiovascular (14.89%), and musculoskeletal (4.26%) systems. The illnesses detected in euthyroid dogs constituted, demodicosis (31.11%), atopic dermatitis (19.26%), scabies (17.04%), food allergy (14.07%), flea allergy (9.63%), and hyperadrenocorticism (8.89%). Dermatological lesions in primary hypothyroidism revealed complicities of Malassezia pachydermatis (36.6%), Demodex canis (14.89%), and Staphylococci and Escherichia coli bacteria (8.51%). Metabolic disorder displayed exercise intolerance, lethargy, obesity, and dyspnoea at rest. Ocular disorder manifested corneal lipidosis. Neuromuscular disorders constituted seizures, paraplegia, and facial paralysis. Renal disorder constituted poly urea with increased levels of blood sugar, BUN and serum creatinine. The common cardiovascular abnormality was dilated cardiomyopathy. Musculoskeletal disorder reflected lameness due to osteoarthritis. This paper portrays a chronicle of hypothyroidism associated disorders in dogs in India, which were not reported earlier.
Allotransplanted DRG neurons or Schwann cells affect functional recovery in a rodent model of sciatic nerve injury

Abstract Objective: In this study, the functional recoveries of Sprague-Dawley rats following repair of a complete sciatic nerve transection using allotransplanted dorsal root ganglion (DRG) neurons or Schwann cells were examined using a number of outcome measures. Methods: Four groups were compared: (1) repair with a nerve guide conduit seeded with allotransplanted Schwann cells harvested from Wistar rats, (2) repair with a nerve guide conduit seeded with DRG neurons, (3) repair with solely a nerve guide conduit, and (4) sham-surgery animals where the sciatic nerve was left intact. The results corroborated our previous reported histology findings and measures of immunogenicity. Results: The Wistar-DRG-treated group achieved the best recovery, significantly outperforming both the Wistar-Schwann group and the nerve guide conduit group in the Von Frey assay of touch response (P < 0·05). Additionally, Wistar-DRG and Wistar-Schwann seeded repairs showed lower frequency and severity in an autotomy measure of the self-mutilation of the injured leg because of neuralgia. Conclusion: These results suggest that in complete peripheral nerve transections, surgical repair using nerve guide conduits with allotransplanted DRG and Schwann cells may improve recovery, especially DRG neurons, which elicit less of an immune response.
The carnivore remains from the Sima de los Huesos Middle Pleistocene site (Sierra de Atapuerca, Spain).

Remains of carnivores from the Sima de los Huesos site representing at least 158 adult individuals of a primitive (i.e., not very speleoid) form of Ursus deningeri Von Reichenau 1906, have been recovered through the 1995 field season. These new finds extend our knowledge of this group in the Sierra de Atapuerca Middle Pleistocene. Material previously classified as Cuoninae indet, is now assigned to Canis lupus and a third metatarsal assigned in 1987 to Panthera of gombaszoegensis, is in our opinion only attributable to Panthera sp. The family Mustelidae is added to the faunal list and includes Martes sp. and a smaller species. The presence of Panthera leo cf. fossilis, Lynx pardina spelaea and Felis silvestris, is confirmed. The presence of a not very speloid Ursus deningeri, together with the rest of the carnivore assemblage, points to a not very late Middle Pleistocene age, i.e., oxygen isotope stage 7 or older. Relative frequencies of skeletal elements for the bear and fox samples are without major biases. The age structure of the bear sample, based on dental wear stages, does not follow the typical hibernation mortality profile and resembles a catastrophic profile. The site was not a natal or refuge den. The hypothesis that the site was a natural trap is the most plausible. If the Sima de los Huesos functioned as a natural trap (without an egress out), the human accumulation cannot be attributed to carnivore: activities and must be explained differently.
An Elementary Proof of Private Random Number Generation from Bell Inequalities

The field of device-independent quantum cryptography has seen enormous success in the past several years, including security proofs for key distribution and random number generation that account for arbitrary imperfections in the devices used. Full security proofs in the field so far are long and technically deep. In this paper we show that the concept of the mirror adversary can be used to simplify device-independent proofs. We give a short proof that any bipartite Bell violation can be used to generate private random numbers. The proof is based on elementary techniques and is self-contained.
Frequency and DNA content of micronuclei in rat parenchymal liver cells during experimental hepatocarcinogenesis.

Liver carcinogenesis is considered to be a good experimental model to study the sequential changes leading to cancer and was applied here for the analysis of chromosome/genome mutations. Since the micronucleus test was shown to be an adequate method to detect and analyse chromosome changes in dividing cells, the frequency of micronuclei (MN) together with their relative DNA content (DNA content of the MN divided by the DNA content of the corresponding nucleus) were analysed in hepatocytes isolated from rats at different stages of experimentally induced hepatocarcinogenesis. The protocol used for the induction of liver cancer was based on the triphasic 'Gerlans protocol', a Solt-Farber procedure supplemented with a phenobarbital (PB) promotion step. Male Wistar rats were initiated by a single i.p. dose of diethylnitrosamine (DENA), followed by selection of the resistant hepatocytes by 2-acetylaminofluorene (2-AAF). Subsequent promotion was accomplished by chronic exposure to phenobarbital. For each group of rats a mitotic stimulator (CCl4) is necessary at the end of their treatment period to express the clastogenic and/or aneugenic lesions which may lead to micronuclei. The results of these experiments do confirm that genetic alterations are occurring at the chromosome level (MN expression) during the different steps of experimental rat liver carcinogenesis. DNA measurements seem to be a good genetic parameter to detect eventual differences between the chromosomal content (whole chromosome or chromosome fragments) of MN populations appearing in different stages of the carcinogenic process. Moreover, a comparison between the mono- and bi-nucleated cell population showed that the frequency of micronuclei is higher in mononuclear parenchymal liver cells.
The Relationship Between Compensation, Motivation, And Earnings Management

Regulators and investors remain concerned with earnings management and its effect on the reliability of accounting information. Agency literature suggests that a lack of compensation incentives (i.e., bonus payments) can decrease—but not completely eliminate--earnings management behavior, while theory from psychology suggests that individuals may be motivated to manage earnings, regardless of compensation. Consequently, we examine how compensation incentives and motivation (intrinsic versus extrinsic) affect earnings management behavior. We hypothesize and find that when compensation is linked to firm performance, managers make income increasing (decreasing) decisions when current earnings are below (above) analysts’ forecasts. We find that in the absence of compensation incentives, managers make earnings increasing decisions when current earnings are below analysts’ forecasts, but they do not make earnings decreasing decisions when current earnings are above analysts’ forecasts. Finally and most importantly we show that managers who possess strong extrinsic motivation are more likely to manage earnings upwards to reach targets – in the absence of compensation – possibly because it helps satisfy their competitive spirit and need for recognition. However when current earnings are above the target (analysts’ forecasts), managers are not compelled to manage earnings as this drive has already been satisfied.