Miracle-dz/UniFAR-FTUs huggingface dataset:
Reliable Decision Support using Counterfactual Models

Answering "What if? " questions is important in many domains. For example, would a patient's disease progression slow down if I were to give them a dose of drug A? Ideally, we answer our question using an experiment, but this is not always possible (e.g., it may be unethical). As an alternative, we can use non-experimental data to learn models that make counterfactual predictions of what we would observe had we run an experiment. In this paper, we propose the counterfactual GP, a counterfactual model of continuous-time trajectories (time series) under sequences of actions taken in continuous-time. We develop our model within the potential outcomes framework of Neyman and Rubin. The counterfactual GP is trained using a joint maximum likelihood objective that adjusts for dependencies between observed actions and outcomes in the training data. We report two sets of experimental results using the counterfactual GP. The first shows that it can be used to learn the natural progression (i.e. untreated progression) of biomarker trajectories from observational data. In the second, we show how the CGP can be used for medical decision support by learning counterfactual models of renal health under different types of dialysis.
Inhibition of the Alpha/Beta Interferon Response by Mouse Hepatitis Virus at Multiple Levels

ABSTRACT Mouse hepatitis virus (MHV) was used as a model to study the interaction of coronaviruses with the alpha/beta interferon (IFN-α/β) response. While MHV strain A59 appeared to induce IFN-β gene transcription and low levels of nuclear translocation of the IFN-β transcription factor interferon regulatory factor 3 (IRF-3), MHV did not induce IFN-β protein production during the course of infection in L2 mouse fibroblast cells. In addition, MHV was able to significantly decrease the level of IFN-β protein induced by both Newcastle disease virus (NDV) and Sendai virus infections, without targeting it for proteasomal degradation and without altering the nuclear translocation of IRF-3 or IFN-β mRNA production or stability. These results indicate that MHV infection causes an inhibition of IFN-β production at a posttranscriptional level, without altering RNA or protein stability. In contrast, MHV induced IFN-β mRNA and protein production in the brains of infected animals, suggesting that the inhibitory mechanisms observed in vitro are not enough to prevent IFN-α/β production in vivo. Furthermore, MHV replication is highly resistant to IFN-α/β action, as indicated by unimpaired MHV replication in L2 cells pretreated with IFN-β. However, when L2 cells were coinfected with MHV and NDV in the presence of IFN-β, NDV, but not MHV, replication was inhibited. Thus, rather than disarming the antiviral activity induced by IFN-β pretreatment completely, MHV may be inherently resistant to some aspects of the antiviral state induced by IFN-β. These findings show that MHV employs unique strategies to circumvent the IFN-α/β response at multiple steps.
Exposure‐dependent increases in IL‐1β, substance P, CTGF, and tendinosis in flexor digitorum tendons with upper extremity repetitive strain injury

Upper extremity tendinopathies are associated with performance of forceful repetitive tasks. We used our rat model of repetitive strain injury to study changes induced in forelimb flexor digitorum tendons. Rats were trained to perform a high repetition high force (HRHF) handle‐pulling task (12 reaches/min at 60 ± 5% maximum pulling force [MPF]), or a low repetition negligible force (LRNF) reaching and food retrieval task (three reaches/min at 5 ± 5% MPF), for 2 h/day in 30 min sessions, 3 days/week for 3–12 weeks. Forelimb grip strength was tested. Flexor digitorum tendons were examined at midtendon at the level of the carpal tunnel for interleukin (IL)‐1β, neutrophil, and macrophage influx, Substance P, connective tissue growth factor (CTGF), and periostin‐like factor (PLF) immunoexpression, and histopathological changes. In HRHF rats, grip strength progressively decreased, while IL‐1β levels progressively increased in the flexor digitorum peritendon (para‐ and epitendon combined) and endotendon with task performance. Macrophage invasion was evident in week 6 and 12 HRHF peritendon but not endotendon. Also in HRHF rats, Substance P immunoexpression increased in week 12 peritendon as did CTGF‐ and PLF‐immunopositive fibroblasts, the increased fibroblasts contributing greatly to peritendon thickening. Endotendon collagen disorganization was evident in week 12 HRHF tendons. LRNF tendons did not differ from controls, even at 12 weeks. Thus, we observed exposure‐dependent changes in flexor digitorum tendons within the carpal tunnel, including increased inflammation, nociceptor‐related neuropeptide immunoexpression, and fibrotic histopathology, changes associated with grip strength decline. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:298–307, 2010
Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure.

BACKGROUND Cardiovascular disease is a major cause of mortality amongst patients with chronic renal failure (CRF). L-arginine has been used to improve endothelial function by increasing nitric oxide (NO) bioavailability and in animal models this in turn has attenuated the progression of atherosclerosis. We examined whether dietary L-arginine supplementation improved endothelial function in children with CRF. METHODS A randomized, double-blind, placebo-controlled, crossover trial of L-arginine was conducted in 21 normotensive children aged 11.5 +/- 3 (7 to 17) years with CRF (GFR 27.4 +/- 13.2 mL/min/1.73 m(2)) in whom endothelial dysfunction had previously been demonstrated. We examined the effect of L-arginineon the endothelial response to shear stress (NO-dependent) using a non-invasive technique of high-resolution ultrasound. Each subject was studied before and after 4 weeks of L-arginine (2.5 g/m(2) or 5 g/m(2) x 3/day) or placebo, separated by a rest period of 4 weeks. Brachial artery diameter was measured at rest, during increased flow (endothelial-dependent dilation) and after 25 microg of glyceryl trinitrate (endothelial-independent dilation) at each visit. RESULTS After oral L-arginine, plasma L-arginine levels rose from 82 +/- 20 to 179 +/- 110 micromol/L (P < 0.001). No significant change in endothelial-dependent dilation during L-arginine (7.96 +/- 2.35 to 7.71 +/- 3.22%; P> 0.05) or placebo (8.2 +/- 2.89 to 8.3 +/- 3.14%; P> 0.05) was noted. There was no change in endothelial-independent dilation. CONCLUSION Endothelial function was not improved with L-arginine, suggesting that dietary supplementation is not a useful clinical approach in children with CRF.
Androgen and Estrogen Receptor Imaging in Metastatic Breast Cancer Patients as a Surrogate for Tissue Biopsies

In addition to the well-known estrogen receptor (ER) and human epidermal growth factor receptor 2, the androgen receptor (AR) is also a potential drug target in breast cancer treatment. Whole-body imaging can provide information across lesions within a patient. ER expression in tumor lesions can be visualized by 18F-fluoroestradiol (18F-FES) PET, and AR expression has been visualized in prostate cancer patients with 18F-fluorodihydrotestosterone (18F-FDHT) PET. Our aim was to assess the concordance between 18F-FDHT and 18F-FES PET and tumor AR and ER expression measured immunohistochemically in patients with metastatic breast cancer. Methods: Patients with ER-positive metastatic breast cancer were eligible for the study, irrespective of tumor AR status. The concordance of 18F-FDHT and 18F-FES uptake on PET with immunohistochemical expression of AR and ER in biopsies of corresponding metastases was analyzed. Patients underwent 18F-FDHT PET and 18F-FES PET. A metastasis was biopsied within 8 wk of the PET procedures. Tumor samples with more than 10% and 1% nuclear tumor cell staining were considered, respectively, AR- and ER-positive. Correlations between PET uptake and semiquantitative immunohistochemical scoring (percentage positive cells × intensity) were calculated. The optimum threshold of SUV to discriminate positive and negative lesions for both AR and ER was determined by receiver-operating-characteristic analysis. Results: In the 13 evaluable patients, correlation (R2) between semiquantitative AR expression and 18F-FDHT uptake was 0.47 (P = 0.01) and between semiquantitative ER expression and 18F-FES uptake 0.78 (P = 0.01). The optimal cutoff for AR-positive lesions was an SUVmax of 1.94 for 18F-FDHT PET, yielding a sensitivity of 91% and a specificity of 100%; the optimal cutoff was an SUVmax of 1.54 for 18F-FES PET, resulting in a sensitivity and specificity of 100% for ER. Conclusion: 18F-FDHT and 18F-FES uptake correlate well with AR and ER expression levels in representative biopsies. These results show the potential use of whole-body imaging for receptor status assessment, particularly in view of biopsy-associated sampling errors and heterogeneous receptor expression in breast cancer metastases.
Binding sites for blood coagulation factor Xa and protein S involving residues 493–506 in factor Va

Inactivation due to cleavage of Factor Va (FVa) at Arg 506 by activated protein C (APC) helps to downregulate blood coagulation. To identify potential functional roles of amino acids near Arg 506, synthetic overlapping pentadecapeptides comprising FVa heavy chain residues 481–525 were tested for their ability to inhibit prothrombin activation by prothrombinase complexes [Factor Xa (FXa):FVa:phospholipids:Ca2+]. The most potent inhibition was observed for peptide VP493 (residues 493–506), with 50% inhibition at 2.5 μM. VP493 also inhibited FXa in plasma in FXa‐1‐stage clotting assays by 50% at 3 μM. When the C‐terminal carboxamide group of VP493 was replaced by a carboxyl group, most prothrombinase inhibitory activity was lost. VP493 preincubated with FXa inhibited prothrombinase with a pattern of mixed inhibition. Homologous peptides from Factor VIII sequences did not inhibit prothrombinase. Affinity‐purified antibodies to VP493 inhibited prothrombinase activity and prolonged FXa‐1‐stage clotting times. VP493 also blocked the ability of protein S to inhibit prothrombinase independently of APC. Immobilized VP493 bound specifically with similar affinity to both FXa and protein S (Kd ∼ 40 nM), but did not measurably bind prothrombin or APC. These studies suggest that FVa residues 493–506 contribute to binding sites for both FXa and protein S, providing a rationale for the ability of protein S to negate the protective effect of FXa toward APC cleavage of FVa. Possible loss of this FVa binding site for FXa due to cleavage at Arg 506 by APC may help explain why this cleavage causes 40% decrease in FVa activity and facilitates inactivation of FVa.
Workplace exposure to secondhand smoke and its association with respiratory symptoms—a cross-sectional study among workers in Shanghai

Objective To describe workplace exposure to secondhand smoke (SHS) among different working populations in Shanghai; to identify any association between respiratory symptoms and SHS exposure in these workplaces. Design Cross-sectional survey with a standardised questionnaire. Setting 150 worksites (including restaurants, shopping malls, hotels, hospitals, schools, kindergartens). Subjects 3530 workers. Outcome measures Prevalence of workers with workplace exposure to SHS; average time of exposure to SHS per day; proportion of workers reporting any respiratory and sensory symptoms. Results 13.3% of employees were covered by complete smoke-free policies. Restaurant employees had the highest level of exposure to SHS (67% exposed with 2.95±3.10 h of exposure on average per day) while kindergarten employees had the lowest level (0.5% exposed with 0.01±0.01 h of exposure per day). Compared with employees from kindergartens, non-smoking workers from restaurants and shopping malls reported a higher proportion of respiratory and sensory symptoms and were more likely to suffer from all eight respiratory and sensory symptoms (OR 1.8–8.9). The length of exposure to SHS each day was positively associated with all eight symptoms except runny nose. Conclusions Workplace exposure to SHS is extensive in Shanghai and the implementation of the current municipal regulation does not provide adequate worker protection. There is an urgent need to establish 100% smoke-free legislation covering all workplaces and public places in Shanghai.
Pulmonary tuberculosis: relationship between sputum bacilloscopy and radiological lesions.

OBJECTIVES To determine the frequency of radiological manifestations of chest tuberculosis among the tuberculosis outpatients at the Santa Casa de Misericórdia de São Paulo Hospital, and to correlate these radiological findings with the sputum bacilloscopy. SAMPLE AND METHODS A review was made of the medical record cards and chest X-rays of all patients attended between January 1996 and December 1998. Patients with a diagnosis of tuberculosis who presented intrathoracic manifestations of the disease and negative anti-HIV serology were selected. RESULTS The selection included 153 patients, with an average age of 37.5 years, who were predominantly male (60.8%) and white (56.9%). Pulmonary lesions were present in 121 (79.9%) and extrapulmonary lesions in 32 (20.1%). Parenchymal-infiltrate lesions appeared in 56 patients (36.6%), cavity lesions in 55 (36.0%), pleural effusion in 28 (18.3%), isolated nodules in 6 (3.9%), mediastinal enlargement in 4 (2.6%) and miliary pattern in 4 (2.6%). Cavities were present in 45.5% of the patients with pulmonary lesions, generally in association with the parenchymal-infiltrate lesions. Parenchymal infiltrate was present in 86.8% of the patients with pulmonary lesions. There was significant presence of alcohol-acid resistant bacillus in the sputum of patients with cavities (76.4%), in comparison with those without cavities (50%) (p = 0.003). CONCLUSIONS Parenchymal-infiltrate lesions are the most frequent radiological manifestation of pulmonary tuberculosis, and they are generally associated with cavities. There is a relationship between the presence of acid fast bacilli in sputum and pulmonary cavity lesions.
Generalization of back education principles by elementary school children: evaluation with a practical test and a candid camera observation

The efficacy of back education in elementary school children was shown using a practical test. Similar results in a candid camera evaluation were questioned. The purposes of this study were (i) to explore the relationship between the results of a practical test and the results of a candid camera procedure when evaluating back education principles, and (ii) to investigate whether in a candid camera procedure scores are still better in pupils who followed a back education programme than in controls. A candid camera evaluation followed by a practical test was performed in 71 pupils who had participated in a back education programme and 60 controls. Correlations between the two evaluation methods were significant but weak for 5 of the 9 test items in the intervention group (Rs 0.26–0.46) and for 7 test items in the control group (Rs 0.38–0.58). The difference in sum scores between the evaluation methods was significantly higher in the intervention group than in the control group (p < 0.001). The intervention group scored higher than the control group for 8 practical test items and 7 candid evaluation items.
Feline extranodal lymphoma: response to chemotherapy and survival in 110 cats.

OBJECTIVE To determine response to treatment, survival and prognostic factors for feline extranodal lymphoma in the UK. METHODS Records of cats diagnosed with lymphoma of extranodal sites at seven referral centres were reviewed and information on signalment, tumour location, prior treatment and chemotherapy protocol recorded. Factors influencing response to treatment and survival were assessed. RESULTS One hundred and forty-nine cases met inclusion criteria. Sixty-nine cats had nasal lymphoma, 35 renal, 15 central nervous system, 11 laryngeal and 19 miscellaneous locations. Sixty-six cats received cyclophosphamide, vincristine, prednisolone, 25 Wisconsin-Madison doxorubicin-containing multi-agent protocol, 10 prednisolone alone and nine other combinations. The response rate for the 110 treated cats was 85.5 per cent. Of cyclophosphamide, vincristine, prednisolone treated cats 72.7 per cent achieved complete remission, median survival 239 days. Sixty-four per cent of Wisconsin-Madison treated cats achieved complete remission, median survival 563 days. Cats with nasal lymphoma achieving complete remission had the longest survival (749 days) and cats with central nervous system lymphoma the shortest (70 days). If complete remission was achieved, prior treatment with corticosteroids significantly reduced survival time. CLINICAL SIGNIFICANCE Cats with extranodal lymphoma respond to chemotherapy and achieve survival times comparable to other locations. Corticosteroid pretreatment reduced survival time in cats achieving complete remission.
Alcohol Withdrawal

Abstract Alcohol withdrawal is a common clinical condition that has a variety of complications and morbidities. The manifestations can range from mild agitation to withdrawal seizures and delirium tremens. The treatments for alcohol withdrawal include benzodiazepines, anticonvulsants, beta-blockers and antihypertensives. Although benzodiazepines are presently a first-line therapy, there is controversy regarding the efficacies of these medications compared with others. Treatment protocols often involve one of two contrasting approaches: symptom-triggered versus fixed-schedule dosing of benzodiazepines. We describe these protocols in our review and examine the data supporting symptom-triggered dosing as the preferred method for most patients in withdrawal. The Clinical Institute Withdrawal Assessment for Alcohol scoring system for alcohol withdrawal streamlines care, optimizes patient management, and is the best scale available for withdrawal assessment. Quality improvement implications for inpatient management of alcohol withdrawal include increasing training for signs of withdrawal and symptom recognition, adding new hospital protocols to employee curricula, and ensuring manageable patient-to-physician and patient-to-nurse ratios.
A dynamic energy-based model to analyze sublethal effects of chronic gamma irradiation in the nematode Caenorhabditis elegans

ABSTRACT Understanding how toxic contaminants affect wildlife species at various levels of biological organization (subcellular, histological, physiological, organism, and population levels) is a major research goal in both ecotoxicology and radioecology. A mechanistic understanding of the links between different observed perturbations is necessary to predict the consequences for survival, growth, and reproduction, which are critical for population dynamics. In this context, experimental and modeling studies were conducted using the nematode Caenorhabditis elegans. A chronic exposure to external gamma radiation was conducted under controlled conditions. Results showed that somatic growth and reproduction were reduced with increasing dose rate. Modeling was used to investigate whether radiation effects might be assessed using a mechanistic model based upon the dynamic energy budget (DEB) theory. A DEB theory in toxicology (DEB-tox), specially adapted to the case of gamma radiation, was developed. Modelling results demonstrated the suitability of DEB-tox for the analysis of radiotoxicity and suggested that external gamma radiation predominantly induced a direct reduction in reproductive capacity in C. elegans and produced an increase in costs for growth and maturation, resulting in a delay in growth and spawning observed at the highest tested dose rate.
Capillary hydraulic conductivity is decreased by nitric oxide synthase inhibition.

Nitric oxide (NO) has been reported to modulate microvascular permeability to solutes in whole organs, venules, and cultured endothelial cell monolayers. NO derived from L-arginine via NO synthase activates soluble guanylate cyclase in vascular smooth muscle and endothelial cells. While the effects of NO on capillary water permeability have not been characterized, other activators of guanylate cyclase, such as sodium nitroprusside and atrial natriuretic peptide, increase capillary hydraulic conductivity (Lp). We hypothesized that inhibition of NO synthase with the arginine analogue, NG-monomethyl-L-arginine (L-NMMA), would decrease Lp from control levels. Lp was assessed in situ in single perfused frog mesenteric capillaries, first during control conditions (Lcontrolp) and then during superfusion (Ltestp) with either L-NMMA, NG-monomethyl-D-arginine (D-NMMA), a biologically inert enantiomer, or L-NMMA and L-arginine. Superfusion with 1 microM L-NMMA caused a decrease in Lp (Ltestp/Lcontrolp = 0.6 +/- 0.1, P < 0.001), whereas 1 microM D-NMMA was without effect on Lp (Ltestp/Lcontrolp = 1.0 +/- 0.2). The decrease in Lp by 1 microM L-NMMA was not only prevented by the presence of excess L-arginine (100 microM), but Lp increased from control (Ltestp/Lcontrolp = 1.4 +/- 0.2, P < 0.05). Furthermore, superfusion of L-arginine (100 microM) caused an increase in capillary Lp (Ltestp/Lcontrolp = 2.4 +/- 0.9, P < 0.05), whereas D-arginine had no effect on Lp (Ltestp/Lcontrolp = 1.2 +/- 0.3). The results of this study support our hypothesis that inhibition of NO synthase decreases capillary Lp in the intact circulation. In addition, L-arginine increases capillary Lp in our model. (ABSTRACT TRUNCATED AT 250 WORDS)
Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

PURPOSE Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. PATIENTS AND METHODS A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. RESULTS Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. CONCLUSION The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.