Involvement of the Cytokine MIF in the Snail Host Immune Response to the Parasite Schistosoma mansoni

We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Furthermore, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia and led to a significant increase in the parasite burden of the snails. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

A Wedding Gone Wrong The Rather Worldly Woes of a Rather Wealthy Qādirī Sufi Shaykh. Two 18th Century Documents from the Ottoman Court Records of Ḥamā and Aleppo

A rather intricate legal case took place first in Ḥamā’s and then in Aleppo’s Ottoman Islamic courts around the middle of the 18th century. The setting, the social standing of the individuals involved, and the alleged circumstances of the case all contribute to make clear that this was not just another routine court case. Altogether, the two documents are a good example of the scope and quality of the information preserved in the archives of local courts and they both demonstrate the extent and modes of implementation of Islamic law in a specific Ottoman milieu. The long inventory of personal property in the Aleppo document gives us a good idea of the social status and affluence enjoyed by the plaintiff – a member of the Jīlānī/Qādirī family - and an interesting insight into material culture and what constituted wealth and affluence at the time.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Development of a Supervisory Skills Course for Hospital Pharmacy Workplaces

ABSTRACTBackground and Objective: Many Canadian hospital pharmacies are experiencing difficulties recruiting supervisory personnel. It was expected that, through a "learning-by-doing" course, pharmacy staff would learn to apply basic skills in the day-to-day supervision of pharmacy operations and human resources and to apply the principles of supervisory documentation.Methods: A supervisory skills course targeted to pharmacy staff members was developed and implemented by the pharmacy department of a large urban health region. The course was initially offered to practising pharmacy technicians. The course design emphasized a constructivist framework incorporating authentic learning and reflective practice during seminars, with experiential and self-directed learning in the workplace. Preceptors assisted learners to achieve the course goals. Learners and preceptors provided feedback about hours spent (as the course progressed) and about their satisfaction with the course itself (at the end of the course). Learners and preceptors completed a post - program evaluation 2 months after completing the course to help in the assessment of the transfer of learning (lasting impact) associated with the course. Overall performance in the course was assessed on a pass/fail basis.Results: Eighteen pharmacy technicians were admitted to the program, but one withdrew because of a job change. All learners successfully completed the course. Two months after the course, learners and preceptors described enhanced organization, time management, leadership, communication, and conflict-resolution skills on the part of learners, as well as their increased confidence, maturity, and ability to supervise staff. Learners' evaluations revealed a broadened perspective of pharmacy. The preceptors valued the enhancement of learners' skills and their increased enthusiasm. At the time of writing, 6 of the participants had secured supervisory positions.Conclusion: Creating formal instruction that engages pharmacy staff to pursue management positions is challenging. Instructional design grounded in constructivist theory and incorporating authentic learning experiences and reflection resulted in high learner satisfaction with learning outcomes.R&Eacute;SUM&Eacute;Contexte et objectif : De nombreuses pharmacies hospitali&egrave;res au Canada ont des difficult&eacute;s &agrave; recruter du personnel cadre. On escomptait que, par le truchement d'un cours &laquo; pratique &raquo;, les employ&eacute;s de la pharmacie puissent acqu&eacute;rir les comp&eacute;tences de base pour la supervision au quotidien des activit&eacute;s de la pharmacie et des ressources humaines et qu'ils pourraient appliquer les principes de la consignation exig&eacute;e par la supervision.M&eacute;thodes : Un cours sur les techniques d'encadrement destin&eacute; au personnel de la pharmacie a &eacute;t&eacute; &eacute;labor&eacute; et mis en oeuvre par le service de pharmacie d'une grande r&eacute;gie de la sant&eacute; urbaine. Le cours a d'abord &eacute;t&eacute; offert aux techniciens en pharmacie en fonction. La formule de cours mettait l'accent sur un cadre p&eacute;dagogique constructiviste incorporant un apprentissage authentique et une pratique r&eacute;flexive dans le cadre de s&eacute;minaires, ainsi qu'un apprentissage exp&eacute;rientiel et autodirig&eacute; en milieu de travail. Des pr&eacute;cepteurs ont aid&eacute; les apprenants &agrave; atteindre les objectifs du cours. Les apprenants et les pr&eacute;cepteurs ont fait part de leurs commentaries sur les heures consacr&eacute;es &agrave; l'apprentissage (au fur et &agrave; mesure du cours) et sur la satisfaction relativement au cours (&agrave; la fin du cours). Les apprenants et les pr&eacute;cepteurs ont rempli une &eacute;valuation deux mois apr&egrave;s la fin du cours pour &eacute;valuer le transfert des comp&eacute;tences (effet durable) issues du cours. La r&eacute;ussite du cours a &eacute;t&eacute; &eacute;valu&eacute;e globalement par une note de passage ou d'&eacute;chec.R&eacute;sultats : Dix-huit techniciens en pharmacie ont &eacute;t&eacute; admis au cours et un a abandonn&eacute; &agrave; cause d'un changement d'emploi. Tous les apprenants ont r&eacute;ussi le cours. Deux mois apr&egrave;s le cours, les apprenants et les pr&eacute;cepteurs ont d&eacute;crit une am&eacute;lioration des comp&eacute;tences relatives &agrave; l'organisation, &agrave; la gestion du temps, au leadership, &agrave; la communication &nbsp;et &agrave; la r&eacute;solution de conflits de la part des apprenants, de m&ecirc;me qu'une plus grande confiance, maturit&eacute; et capacit&eacute; &agrave; superviser le personnel. Les &eacute;valuations des apprenants ont r&eacute;v&eacute;l&eacute; une perspective &eacute;largie de la pharmacie. Les pr&eacute;cepteurs ont appr&eacute;ci&eacute; l'am&eacute;lioration des competences des apprenants et leur plus grand enthousiasme. Au moment d'&eacute;crire cet article, six des participants &agrave; ce cours avaient obtenu un poste de superviseur.Conclusion : La conception d'un enseignement syst&eacute;matique qui &eacute;veille l'int&eacute;r&ecirc;t du personnel de la pharmacie &agrave; occuper un poste de cadre constitue un d&eacute;fi. Une formule d'enseignement ancr&eacute;e dans la th&eacute;orie constructiviste et incorporant des exp&eacute;riences d'apprentissage authentique et la r&eacute;flexion ont donn&eacute; aux apprenants une grande satisfaction quant &agrave; leurs r&eacute;sultats p&eacute;dagogiques