Inhibition of granulomatous inflammation and prophylactic treatment of schistosomiasis with a combination of edelfosine and Praziquantel

This is an open access article distributed under the terms of the Creative Commons Attribution License.[Background]: Schistosomiasis is the third most devastating tropical disease worldwide caused by blood flukes of the genus Schistosoma. This parasitic disease is due to immunologic reactions to Schistosoma eggs trapped in tissues. Egg-released antigens stimulate tissue-destructive inflammatory and granulomatous reactions, involving different immune cell populations, including T cells and granulocytes. Granulomas lead to collagen fibers deposition and fibrosis, resulting in organ damage. Praziquantel (PZQ) is the drug of choice for treating all species of schistosomes. However, PZQ kills only adult Schistosoma worms, not immature stages. The inability of PZQ to abort early infection or prevent re-infection, and the lack of prophylactic effect prompt the need for novel drugs and strategies for the prevention of schistosomiasis. [Methodology/Principal Findings]: Using in vitro and in vivo approaches, we have found that the alkylphospholipid analog edelfosine kills schistosomula, and displays anti-inflammatory activity. The combined treatment of PZQ and edelfosine during a few days before and after cercariae infection in a schistosomiasis mouse model, simulating a prophylactic treatment, led to seven major effects: a) killing of Schistosoma parasites at early and late development stages; b) reduction of hepatomegaly; c) granuloma size reduction; d) down-regulation of Th1, Th2 and Th17 responses at late post-infection times, thus inhibiting granuloma formation; e) upregulation of IL-10 at early post-infection times, thus potentiating anti-inflammatory actions; f) down-regulation of IL-10 at late post-infection times, thus favoring resistance to re-infection; g) reduction in the number of blood granulocytes in late post-infection times as compared to infected untreated animals. [Conclusions/Significance]: Taken together, these data suggest that the combined treatment of PZQ and edelfosine promotes a high decrease in granuloma formation, as well as in the cellular immune response that underlies granuloma development, with changes in the cytokine patterns, and may provide a promising and effective strategy for a prophylactic treatment of schistosomiasis.This work was supported by grants from the Junta de Castilla y León (SA342U13, CSI052A11-2, and CSI221A12-2), Real Federación Española de Fútbol-Sociedad Española de Medicina Tropical y Salud Internacional (RFEF-SEMTSI 2013), Spanish Ministerio de Economía y Competitividad (SAF2011-30518, SAF2014-59716-R, and RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), and European Community’s Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS).Peer Reviewe

Evidence to decision frameworks enabled structured and explicit development of healthcare recommendations

Altres ajuts: Universidad Santo Tomás, Bogotá, Colombia (FODEIN project code: 2115005).Objective: The aim of this study is to identify and describe the processes suggested for the formulation of healthcare recommendations in healthcare guidelines available in guidance documents. Methods: We searched international databases in May 2020 to retrieve guidance documents published by organizations dedicated to guideline development. Pairs of researchers independently selected and extracted data about the characteristics of the guidance document, including explicit or implicit recommendation-related criteria and processes considered, as well as the use of evidence to decision (EtD) frameworks. Results: We included 68 guidance documents. Most organizations reported a system for grading the strength of recommendations (88%), half of them being the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Two out of three guidance documents (66%) proposed the use of a framework to guide the EtD process. The GRADE-EtD framework was the most often reported framework (19 organizations, 42%), whereas 20 organizations (44%) proposed their own multicriteria frameworks. Using any EtD framework was related with a more comprehensive set of recommendation-related criteria compared to no framework, especially for criteria like values, equity, and acceptability. Conclusion: Although limited, the use of EtD frameworks was associated with the inclusion of relevant recommendation criteria. Among the EtD structured frameworks, the GRADE-EtD framework offers the most comprehensive perspective for evidence-informed decision-making processes

Statistics of extreme objects in the Juropa Hubble Volume simulation

We present the first results from the JUropa huBbLE volumE (Jubilee) project, based a large N-body, dark matter-only cosmological simulation with a volume of $V=(6 h^{-1}\mathrm{Gpc})^3$, containing 6000$^3$ particles, performed within the concordance $\Lambda$CDM cosmological model. The simulation volume is sufficient to probe extremely large length scales in the universe, whilst at the same time the particle count is high enough so that dark matter haloes down to $1.5\times10^{12} h^{-1}\mathrm{M}_\odot$ can be resolved. At $z = 0$ we identify over 400 million haloes. The cluster mass function is derived using three different halofinders and compared to fitting functions in the literature. The distribution of clusters of maximal mass across redshifts agrees well with predicted masses of extreme objects, and we explicitly confirm that the Poisson distribution is very good at describing the distribution of rare clusters. The Poisson distribution also matches well the level to which cosmic variance can be expected to affect number counts of high mass clusters. We find that objects like the Bullet cluster exist in the far-tail of the distribution of mergers in terms of relative collisional speed. We also derive the number counts of voids in the simulation box for $z = 0$, $0.5$ and $1$.Comment: Version 2. 12 pages, 9 figures. Accepted by MNRA

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Breast implant–associated anaplastic large cell lymphoma: Brief overview of current data and imaging findings

In 2016, the World Health Organization added Breast Implant-Associated Anaplastic Large Cell lymphoma as a provisionally recognized lymphoma to the family of existing Anaplastic Large Cell lymphomas. Current estimates of the lifetime risk of the disease in women with textured breast implants range from 1:1,000 to 1:30,000. The mean interval from implant placement to diagnosis is 10.7 ± 4.6 years and the most common clinical symptom at presentation is breast swelling. A high level of clinical suspicion is recommended in patients presenting with breast symptoms and/or peri-implant fluid collection occurring more than 1 year after breast implant placement. Ultrasound is the imaging modality of choice, with a high sensitivity for peri-implant fluid and a high specificity for peri-implant mass. When ultrasound is inconclusive, breast MRI is indicated. As of today, all confirmed cases have tested positive for CD30 immunohistochemistry and the disease has shown to have an excellent prognosis when it is diagnosed earlier (localized disease), and when complete surgery, consisting of explantation, capsulectomy, and removal of any associated capsule mass, is performed. This overview summarizes the available epidemiological and clinical data of Breast Implant-Associated Anaplastic Large Cell lymphoma, with an emphasis on imaging features

Utility of supplemental screening with breast ultrasound in asymptomatic women with dense breast tissue who are not at high risk for breast cancer

Objective: To assess the results of an initial round of supplemental screening with hand-held bilateral breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue who are not at high risk for breast cancer. Materials and Methods: A retrospective, Health Insurance Portability and Accountability Act compliant, Institutional Research Board approved study was performed at a single academic tertiary breast center. Informed consent was waived. A systematic review of the breast imaging center database was conducted to identify and retrieve data for all asymptomatic women, who were found to have heterogeneously dense or extremely dense breast tissue on screening bilateral mammograms performed from July 1, 2010 through June 30, 2012 and who received a mammographic final assessment American College of Radiology's (ACR) Breast Imaging Reporting and Data System (BI-RADS) category 1 or BI-RADS category 2. Hand-held screening ultrasound was performed initially by a technologist followed by a radiologist. Chi-square and t-test were used and statistical significance was considered at P< 0.05. Results: A total of 1210 women were identified. Of these, 394 underwent the offered supplemental screening ultrasound. BI-RADS category 1 or 2 was assigned to 323 women (81.9%). BI-RADS category 3 was assigned to 50 women (12.9%). A total of 26 biopsies/aspirations were recommended and performed in 26 women (6.6%). The most common finding for which biopsy was recommended was a solid mass (88.5%) with an average size of 0.9 cm (0.5–1.7 cm). Most frequent pathology result was fibroadenoma (60.8%). No carcinoma was found. Conclusion: Our data support the reported occurrence of a relatively high number of false positives at supplemental screening with breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue, who are not at a high risk of developing breast cancer, and suggests that caution is necessary in establishing wide implementation of this type of supplemental screening for all women with dense breast tissue without considering other risk factors for breast cancer

Primary neuroendocrine carcinoma of the breast: report of 2 cases and literature review

Neuroendocrine tumors of the breast are very rare accounting for less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumors. Focal neuroendocrine differentiation can be found in different histologic types of breast carcinoma including in situ and invasive ductal or invasive lobular. However, primary neuroendocrine carcinoma of the breast requires the expression of neuroendocrine markers in more than 50% of the cell population, the presence of ductal carcinoma in situ, and the absence of clinical evidence of concurrent primary neuroendocrine carcinoma of any other organ. Reports discussing the imaging characteristics of this rare carcinoma in different breast imaging modalities are scarce. We present 2 cases of primary neuroendocrine carcinoma of the breast for which mammography, ultrasound, and magnetic resonance imaging findings and pathology findings are described. A review of the medical literature on this particular topic was performed, and the results are presented

The Challenge of Digital Breast Tomosynthesis–Detected Architectural Distortion of the Breast: Inter-reader Variability and Imaging Characteristics That May Improve Positive Predictive Value

Abstract Objective To compare readers’ performances when detecting architectural distortion (AD) on digital breast tomosynthesis (DBT). To determine the risk of malignancy of DBT with synthetic mammogram (SM)–detected AD and evaluate imaging features that are associated with malignancy risk. Methods This IRB-approved retrospective review included all cases of DBT-detected AD that were recommended for biopsy from October 2013 to July 2019. Cases were reviewed by three breast radiologists and the overall agreement between radiologists was calculated. Medical records were reviewed for pathological outcomes and imaging findings. Statistical analyses used were Cohen’s kappa and its 95% confidence interval, and one-way analysis of variance. Results A total of 172 lesions were included. The overall agreement for the presence of AD in our study was fair (0.253). The majority (20/36, 55.5%) of the malignant ADs were associated with asymmetries (13/36, 36.1%), calcifications (4/36, 11.1%), or both (3/36, 8.3%), compared to nonmalignant ADs (40/136, 31.0%; P = 0.038). The positive predictive value (PPV) of DBT with SM-detected AD for malignancy was 21.8% (36/165), 18.8% (18/96) for DBT-detected AD, and 26.0% (18/69) for SM-detected AD, although the difference was not statistically significant (P = 0.258). A breast MRI correlate was identified for all malignant AD lesions (17/17, 100.0%; P = 0.004). Conclusion The detection of AD remains a challenging task for radiologists, with moderate-to-fair interobserver agreement. With a PPV for malignancy of 21.8%, percutaneous biopsy and subsequent pathology-imaging correlation are necessary for AD to exclude the possibility of malignancy

Primary neuroendocrine carcinoma of the breast: report of 2 cases and literature review

Neuroendocrine tumors of the breast are very rare accounting for less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumors. Focal neuroendocrine differentiation can be found in different histologic types of breast carcinoma including in situ and invasive ductal or invasive lobular. However, primary neuroendocrine carcinoma of the breast requires the expression of neuroendocrine markers in more than 50% of the cell population, the presence of ductal carcinoma in situ, and the absence of clinical evidence of concurrent primary neuroendocrine carcinoma of any other organ. Reports discussing the imaging characteristics of this rare carcinoma in different breast imaging modalities are scarce. We present 2 cases of primary neuroendocrine carcinoma of the breast for which mammography, ultrasound, and magnetic resonance imaging findings and pathology findings are described. A review of the medical literature on this particular topic was performed, and the results are presented