Miracle-dz/UniFAR-FTUs huggingface dataset:
Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition

Selective inhibition of γ-secretase complexes targets T-ALL without the dose-limiting side effects of complete γ-secretase inhibition. The right presenilin for the job The NOTCH signaling pathway is frequently mutated in T cell acute lymphoblastic leukemia and therefore presents a potential therapeutic target. Previous researchers tried to inhibit γ-secretase, a protease that cleaves NOTCH and thereby activates it. Unfortunately, nonspecific inhibition of γ-secretase proved to be too toxic for clinical use because of on-target side effects in a variety of healthy tissues. Habets et al. found that presenilin-1, a component of some γ-secretase complexes, is highly expressed in T cell leukemia relative to healthy T cells. The authors then demonstrated that targeting presenilin-1 is effective and safe in mouse models, suggesting this strategy’s potential for translation. Given the high frequency of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe “on-target” gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of Psen1 in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role.
Facoemulsificação versus extração extracapsular no sistema público de saúde: análise de custos para o hospital, para o governo e para a sociedade

PURPOSE: To compare the costs of cataract surgery for a public hospital, the government and the society between the techniques of phacoemulsification (PHACO) and extracapsular cataract extraction (EECP). METHODS: A review based on several clinical studies between 2002 and 2010 at the Ambulatorial Surgical Center of the University of Sao Paulo. RESULTS: The estimated expenses associated with medical supplies used for surgery were R$ 468.92 and R$ 259.96 in the PHACO and EECP groups respectivelly. The hospital expenditures in the postoperative follow-up was approximately R$ 16.40 (42%) lower in the PHACO. Regarding the estimated spending for Social Security, the EECP group cost an average, US$ 44.58 per patient more than the PHACO group.
Body mass index (BMI) predicts percent body fat better than body adiposity index (BAI) in school children.

BACKGROUND/AIMS Child obesity is associated with increased risk of adult obesity, and is considered as one important health risk factor. Appropriate indicators are required to identify potential risks of child adiposity. This study for the first time compares body mass index (BMI) and body adiposity index (BAI) for predicting percent body fat (PBF) in children. METHODS We measured statures, weights, and hip circumferences of 527 children of Han ethnicity and calculated BMI and BAI. PBF was obtained by bioelectrical impedance analysis. We adopted Pearson correlation analysis, linear regression analysis, and receiver operating characteristic (ROC) analysis. RESULTS For each sex, we found that: 1) BMI and BAI were significantly correlated with PBF; 2) the correlation coefficient between BMI and PBF was higher than that between BAI and PBF; 3) BMI better predicted PBF in the linear regression analysis; 4) the discriminatory capacity of the BMI is higher than the one of BAI in ROC analysis. CONCLUSION Taken together, BMI is a more reliable PBF indicator predicting adiposity in children. This finding may aid future obesity monitoring and intervention in children.
Methylisothiazolinone Contact Allergy Prevalence in Western Canada: Increased Detection With 2000 ppm Patch Test Allergen

Background: Contact allergy to methylisothiazolinone (MI) or to the combination of methylchloroisothiazolinone and MI (MCI/MI) is an important and increasing cause of allergic contact dermatitis, with prevalence rates higher than 10% in some centers. Objectives: The objective of this retrospective chart review is to provide a western Canadian perspective on whether the positive patch testing rate to MCI/MI or MI increased during the testing period of 2008 to 2015 and whether the addition of MI at 2000 ppm resulted in increased detection. Methods: We conducted a retrospective chart review of patients who tested positive (n = 104) of 2177 total patients who were patch tested for MCI/MI or MI at a community dermatology clinic in Vancouver, British Columbia, Canada, from January 2008 through April 2015. Results: One hundred and four patients had positive patch testing results for MCI/MI, MI, or both. Positive results increased over the study period, with the highest prevalence in 2015 at 9.41% for MCI/MI, 12.94% for MI, and 15.29% for either. When testing for MI at 2000 ppm was introduced in 2013, the initial positive patch testing prevalence was 6.6%, followed by 10.1% in 2014, and 12.9% in 2015. Conclusions: We demonstrate an increasing prevalence of MCI/MI and MI allergy between 2008 and 2015, with the highest prevalence of 15.29% in 2015 for MCI/MI and/or MI allergy. The addition of MI 2000 ppm greatly increased the positive patch testing yield for MI. Our results support the importance of continued efforts to monitor and regulate these preservatives.
Approach to the Management of Patients With Hidradenitis Suppurativa: A Consensus Document

Background: Hidradenitis suppurativa (HS) is a painful, debilitating, and poorly understood condition, which is suboptimally diagnosed, managed, and treated. Evidence supporting various treatment modalities is sparse. Objectives: To incorporate scientific evidence and expert opinions to develop useful guidance for the evaluation and management of patients with HS. Methods: An expert panel of Canadian dermatologists and surgeons developed statements and recommendations based on available evidence and clinical experience. The statements and recommendations were subjected to analysis and refinement by the panel, and voting was conducted using a modified Delphi technique with a prespecified cutoff agreement of 75%. Results: Ten specific statements and recommendations were accepted by the expert panel. These were grouped into 4 domains: diagnosis and assessment, treatment and management, comorbidities and a multidisciplinary approach, and education. Conclusions: These statements and recommendations will serve to increase awareness of HS and provide a framework for decisions involving diagnosis and management. Evidence suggests that antibacterial and anti–tumour necrosis factor therapies are effective in the treatment of HS. This is supported by the clinical experience of the authors. Further clinical research and the establishment of multidisciplinary management teams will continue to advance management of HS in Canada.
Genetic Factors Associated with Elevated Carbapenem Resistance in KPC-Producing Klebsiella pneumoniae

ABSTRACT In the United States, the most prevalent mechanism of carbapenem resistance among Enterobacteriaceae is the production of a Klebsiella pneumoniae carbapenemase (KPC). KPC-producing isolates often exhibit a range of carbapenem MICs. To better understand the factors that contribute to overall carbapenem resistance, we analyzed 27 KPC-producing K. pneumoniae isolates with different levels of carbapenem resistance, 11 with low-level (i.e., meropenem or imipenem MIC ≤ 4 μg/ml), 2 with intermediate-level (i.e., meropenem and imipenem MIC = 8 μg/ml), and 14 with high-level (i.e., imipenem or meropenem MIC ≥ 16 μg/ml) carbapenem resistance, that were received from throughout the United States. Among 14 isolates that exhibited high-level carbapenem resistance, Western blot analysis indicated that 10 produced an elevated amount of KPC. These isolates either contained an increased blaKPC gene copy number (n = 3) or had deletions directly upstream of the blaKPC gene (n = 7). Four additional isolates lacked elevated KPC production but had high-level carbapenem resistance. Porin sequencing analysis identified 22 isolates potentially lacking a functional OmpK35 and three isolates potentially lacking a functional OmpK36. The highest carbapenem MICs were found in two isolates that lacked both functioning porins and produced elevated amounts of KPC. The 11 isolates with low-level carbapenem resistance contained neither an upstream deletion nor increased blaKPC copy number. These results suggest that both blaKPC copy number and deletions in the upstream genetic environment affect the level of KPC production and may contribute to high-level carbapenem resistance in KPC-producing K. pneumoniae, particularly when coupled with OmpK36 porin loss.
Level of willingness to report to work during a pandemic among the emergency department health care professionals

Objectives: To quantify the knowledge and attitudes of Health care providers (HCP) towards their willingness to work during an influenza pandemic. Methods: A Questionnaire based cross sectional study among the 350 emergency departments’ staff in seven different tertiary hospitals in Riyadh, Saudi Arabia was conducted in Jan 2010. A structured questionnaire with items to quantify the knowledge and attitudes of health care providers based on hypothetical scenario about the occurrence of H1N1 pandemic was developed. The questionnaire was validated before it was distributed among the study subjects. Data was analyzed using SPSS Pc+ 21.0 statistical software. Results: Out of the 254 responders, 190 (74.8%) stated that they will report to work during a pandemic, 29 (11.4%) won’t, and 35 (13.7%) don’t know. From those who won’t report or don’t know; 29 (45.31%) won’t change their minds for salary increase, and 40 (62.5%) won’t change their mind even if it meant they were to be dismissed. About 93 (36.4%) of study subjects were of the opinion that, HCP without children should primarily look after the patients. Among the HCPs, higher number of consultants and nurses were more willing to work than other HCPs. The consultants were having positive attitudes towards working during pandemics. Conclusion: Our results suggested that most participants were having positive attitudes towards willingness to work during an influenza pandemic. Their concerns should be considered, so that during a real situation faced, plans could be translated to reality smoothly.
High-Speed Ice Friction Experiments under Lab Conditions: On the Influence of Speed and Normal Force

Using a high-speed tribometer, coefficients of friction for bobsled runners were measured over a wide range of loads and speeds. Between 2.8 m/s and 28 m/s (equal to 10 km/h and 100 km/h), the measured coefficients of friction showed a linear decrease with increasing speed. The experiments revealed ultra-low friction coefficients of less than 0.01 after exceeding a sliding speed of about 20 m/s. At maximum speed of 28 m/s, the average coefficient of friction was 0.007. The experiments help to bridge the gap between numerous low-speed friction tests by other groups and tests performed with bobsleds on real tracks. It was shown that the friction data obtained by other groups and our measurements can be approximated by a single master curve. This curve exhibits the largest decrease in friction up to a sliding speed of about 3 m/s. The further increase in speed generates only a small decrease in friction. In addition, friction decreases with increasing load. The decrease stops when ice wear becomes effective. The load point of constant friction depends on the cross-sectional radius of the runner. The larger the radius is, the higher the load is, before the ice shows signs of fracture. It turned out that besides aerodynamic drag (not considered in this work), ice friction is one of the main speed-limiting factors. In terms of runner geometry, a flat contact of runner and ice ensures the lowest friction. The rocker radius of the runner is of greater importance for a low coefficient of friction than the cross-sectional radius.
The Impact of Hospital Libraries on Patient Care and Clinical Decision-Making: A Survey of Teaching Hospitals

This article reports the results of a survey of 150 doctors working in teaching hospitals in Multan, Pakistan. The survey was undertaken to ascertain how often doctors use hospital libraries, their main reasons for using the hospital libraries, and the impact of information they received/gathered from the hospital libraries on patient care and clinical decision-making.
The motherhood choice: Themes arising in the decision-making process for women with multiple sclerosis

Objective This study aimed to determine the main themes and concerns for women with Multiple Sclerosis when considering motherhood. Method Twenty women with multiple sclerosis from various stages in the decision-making process participated in focus-groups where information was gathered regarding their experiences of making this decision. Results The themes emerging most frequently during the decision-making process were: a) concerns about the mother's own health and well-being; b) well-being of the child; c) coping with parenting; d) societal attitudes; e) experiencing parenting and f) timing and pressure of the decision. Conclusion The results indicate that information regarding the effect of MS on pregnancy and child-rearing and the effect of pregnancy on MS and its progression need to be made more accessible to women. Information would be a valuable resource for women going through this decision-making process.
Disease-modifying agents in the Sonya Slifka Longitudinal Multiple Sclerosis Study

Background Although experts recommend that people with multiple sclerosis (MS) should begin treatment with disease-modifying agents (DMAs) as soon as possible after diagnosis and continue indefinitely, many do not use these agents or discontinue them prematurely. Since DMAs reduce relapse rates and slow disease progression, and since even benign relapses and course can lead to axonal damage and permanent neurologic impairment, it is important that all appropriate candidates have access to treatment. We used a population-based sample of people with MS to determine rates, predictors, and reasons for use, non-use, and discontinuation of DMAs. Methods We collected data from 2156 people with MS on their use of and experience with DMAs. We used chi-squared tests to compare current, past, and never users of any DMA and ever users of individual DMAs, and logistic regression to identify predictors of use. Results One-half of the participants were using a DMA at the time of the interview; 12.2% had used previously, but stopped. Reasons for never using and reasons for stopping were at odds with expert recommendations. Characterization of users, and of their experiences by type of DMA, was consistent with current knowledge of these agents. Seeing a neurologist for usual MS care was an important factor in starting and persisting with DMA therapy. Conclusions Dissemination of expert opinion about, and management strategies for, use of DMAs to non-neurologic professionals and patients and their families might help more people who are appropriate candidates for DMA therapy to start and continue treatment.
Sexual dysfunction in newly diagnosed multiple sclerosis women

Objectives The aim of the study was to evaluate female sexuality in a selective population of newly diagnosed multiple sclerosis (MS) women. Materials and methods In this clinic-based study, 63 newly diagnosed consecutive women affected by definite MS were admitted. Disability and depression were evaluated with the expanded disability status scale (EDSS) and Beck depression inventory, respectively. Sexual function was evaluated with the female sexual function index (FSFI). A group of 61 healthy female volunteers with the same baseline characteristics were used as controls. Postmenopausal women and patients with other major concomitant neurological, endocrinological, vascular, gynecological, psychiatric disorders, use of medicines that can cause female sexual dysfunction (FSD) and disease-modifying drugs were excluded from the study. Results All the evaluated patients were ambulant with no major neurological impairment (mean EDSS score 2.5, range 0—3.5). None of the patients were considered clinically depressed, but some of them were sad or worried. According to the sexual history and FSFI scores, sexual dysfunction was diagnosed in 22 (34.9%) out of the 63 patients and in 13 (21.31%) out of the 61 healthy females (P > 0.05). Conclusions In the newly diagnosed MS patients, FSD represent an important issue even though disability and other concomitant disorders affecting sexual function were excluded. Multiple Sclerosis 2008; 14: 561—563. http://msj.sagepub. com
Comorbid Risk Factors of Persistent Pulmonary Hypertension of the Newborn in Infants with Meconium Aspiration Syndrome.

Purpose: Persistent pulmonary hypertension (PPHN) is considered an important prognostic factor in meconium aspiration syndrome (MAS). The aim of this study was to determine the comorbid risk factors for PPHN in infants with MAS. Methods: We retrospectively analyzed 60 infants diagnosed with MAS and .
Utilization of health care by patients with multiple sclerosis is based on professional and patient-defined health needs

Objective This cross-sectional study investigates healthcare utilization, and determines which predisposing, enabling, and health factors are associated with healthcare utilization among 121 patients with multiple sclerosis (MS). Methods Data on patient-related predisposing, enabling, and health factors were collected by means of written questionnaires and a home visit from a well-trained physiotherapist. Results Of the 121 patients with MS (mean age 43 years, mean score on the Expanded Disability Status Scale 3.5, disease duration 6 years), 16% were hospitalized in the previous year; 62% consulted their general practitioner, and 69% consulted their neurologist in the previous 6 months. Other medical specialists were consulted in the 6-month period by 50% of the study population. In a 4-week period preceding the home visit, 41% of the patients were treated by an allied healthcare professional. Multivariate logistic regression analyses showed that consulting the general practitioner, the neurologist, other medical specialists, and allied healthcare professionals, and the use of equipment/aids by MS patients is primarily related to their health, either as perceived by the patients themselves or defined by the professional. Conclusions MS patients in the Netherlands make appropriate use of healthcare facilities, because their utilization can predominantly be explained by health-related factors, and not by predisposing or enabling factors.
The Aminoglycoside Antibiotic Kanamycin Damages DNA Bases in Escherichia coli: Caffeine Potentiates the DNA-Damaging Effects of Kanamycin while Suppressing Cell Killing by Ciprofloxacin in Escherichia coli and Bacillus anthracis

ABSTRACT The distribution of mutants in the Keio collection of Escherichia coli gene knockout mutants that display increased sensitivity to the aminoglycosides kanamycin and neomycin indicates that damaged bases resulting from antibiotic action can lead to cell death. Strains lacking one of a number of glycosylases (e.g., AlkA, YzaB, Ogt, KsgA) or other specific repair proteins (AlkB, PhrB, SmbC) are more sensitive to these antibiotics. Mutants lacking AlkB display the strongest sensitivity among the glycosylase- or direct lesion removal-deficient strains. This perhaps suggests the involvement of ethenoadenine adducts, resulting from reactive oxygen species and lipid peroxidation, since AlkB removes this lesion. Other sensitivities displayed by mutants lacking UvrA, polymerase V (Pol V), or components of double-strand break repair indicate that kanamycin results in damaged base pairs that need to be removed or replicated past in order to avoid double-strand breaks that saturate the cellular repair capacity. Caffeine enhances the sensitivities of these repair-deficient strains to kanamycin and neomycin. The gene knockout mutants that display increased sensitivity to caffeine (dnaQ, holC, holD, and priA knockout mutants) indicate that caffeine blocks DNA replication, ultimately leading to double-strand breaks that require recombinational repair by functions encoded by recA, recB, and recC, among others. Additionally, caffeine partially protects cells of both Escherichia coli and Bacillus anthracis from killing by the widely used fluoroquinolone antibiotic ciprofloxacin.
A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

ABSTRACT A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate β, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate δ, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (β) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation.