FDA Adds Boxed Warning for Increased Risk of Death with Gout Medicine Uloric (febuxostat)

Audience: Consumer, Health Professional, Pharmacy This is an update to the FDA Drug Safety Communication: FDA to evaluate increased risk of heart-related death and death from all causes with the gout medicine febuxostat (Uloric) issued on November...

https://ift.tt/2tDzOAl

Cancers, Vol. 11, Pages 261: Loss of Stromal Galectin-1 Enhances Multiple Myeloma Development: Emphasis on a Role in Osteoclasts

Cancers, Vol. 11, Pages 261: Loss of Stromal Galectin-1 Enhances Multiple Myeloma Development: Emphasis on a Role in Osteoclasts

Cancers doi: 10.3390/cancers11020261

Authors: Joséphine Muller Elodie Duray Margaux Lejeune Sophie Dubois Erwan Plougonven Angélique Léonard Paola Storti Nicola Giuliani Martine Cohen-Solal Ute Hempel Victor L. Thijssen Yves Beguin Roy Heusschen Jo Caers

Multiple myeloma osteolytic disease is caused by an uncoupled bone-remodelling process with an increased osteoclast activity. Disease development relies on interactions between myeloma cells and bone marrow stromal cells. Recent findings suggest a role for glycan-binding proteins in myeloma microenvironment. Here, we investigated lectins involved in osteoclastogenesis and their role in myeloma bone disease. Microarray data analysis showed a lower expression of galectin-1 (gal-1) in mature osteoclasts compared to monocytic progenitor cells, confirmed at the RNA and protein levels in osteoclast cultures. Confocal microscopy showed that gal-1 localised predominantly in the sealing zone of mature osteoclasts. Although equal differentiated-osteoclast numbers, gal-1−/− osteoclasts showed a higher resorption activity compared to wild-type controls. Micro-computed tomography showed an aberrant bone phenotype with decreased bone densities in gal-1−/− mice. In vivo, tumour progression was faster in gal-1−/− mice and associated with a marked bone loss. Additionally, myeloma cells were found to decrease gal-1 expression in osteoclasts. Our results demonstrate that galectin-1 regulates osteoclast activity with an increased resorption by gal-1−/− osteoclasts and decreased bone densities in gal-1−/− mice. We observed an enhanced tumour development in gal-1−/− mice compared to wild-type mice, suggesting that galectin-1 has a functional role in stromal cells in myeloma microenvironment.

https://ift.tt/2Ep6nIt

FDA Adds Boxed Warning for Increased Risk of Death with Gout Medicine Uloric (febuxostat)

Audience: Consumer, Health Professional, Pharmacy This is an update to the FDA Drug Safety Communication: FDA to evaluate increased risk of heart-related death and death from all causes with the gout medicine febuxostat (Uloric) issued on November...

https://ift.tt/2tDzOAl

Healthcare professionals, students, patients and donors perceptions of stem cell research and therapy: a systematic review protocol

Introduction

Stem cell research (SCR) and the biomedical potential of developing therapies are crucial topics in biomedicine. Like other biotechnologies, stem cells are context specific entities understood through local conceptualisations of culture, politics, nationhood, as well as their perceived therapeutic efficacy. There is a need to recognise how these developments are understood within the healthcare community and by those who may use them. This protocol describes a systematic literature review that aims to explore healthcare professionals', healthcare students', patients', and donors' perceptions of SCR and therapy (SCR/T) and the factors that influence their perceptions.

Methods and analysis

Following Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines a systematic review will be undertaken. Web of Science, Scopus, Medline+Journals @Ovid and Ariti Library will be systematically searched for studies on healthcare professionals', healthcare students', patients' and donors' perceptions of SCR and developing therapies. All articles will be screened by a researcher for inclusion and evaluation based on 12 criteria for evaluating qualitative research. At least 20% of articles will also be reviewed by a second researcher and any disagreement will be solved via consensus. Data extracted from the articles will be analysed using thematic synthesis enabling the identification of concepts across studies and the development of new theory.

Ethics and dissemination

As part of a larger research project, ethical approval has been provided by the Institutional Research Board (IRB) at Chang Gung Memorial Hospital. This review will be able to determine the impact that certain perceptions of SCR/T will have on the development of future medical knowledge and practice. The results of the study will be published in a peer-reviewed journal and disseminated at relevant conferences.

PROSPERO registration number

CRD42018103627.

https://ift.tt/2GGHzOu

Challenges to achieving universal health coverage through community-based health planning and services delivery approach: a qualitative study in Ghana

Objective

Community-based initiatives have enormous potential to facilitate the attainment of universal health coverage (UHC) and health system development. Yet key gaps exist and threaten its sustainability in many low-income and middle-income countries. This study is first of its kind (following the launch of the Sustainable Developments Goal [SDG]) and aimed to holistically explore the challenges to achieving UHC through the community-based health planning and service (CHPS) initiative in Ghana.

Design

A qualitative study design was adopted to explore the phenomenon. Face-to-face indepth interviews were conducted from April 2017 until February 2018 through purposive and snowball sampling techniques. Data were analysed using inductive and deductive thematic analysis approach.

Setting

Data were gathered at the national level, in addition to the regional, district and subdistrict/local levels of four regions of Ghana. Sampled regions were Central Region, Greater Accra Region, Upper East Region and Volta Region.

Participants

In total, 67 participants were interviewed: national level (5), regional levels (11), district levels (9) and local levels (42). Interviewees were mainly stakeholders—people whose actions or inactions actively or passively influence the decision-making, management and implementation of CHPS, including policy makers, managers of CHPS compound and health centres, politicians, academics, health professionals, technocrats, and community health management committee members.

Results

Based on our findings, inadequate understanding of CHPS concept, major contextual changes with stalled policy change to meet growing health demands, and changes in political landscape and leadership with changed priorities threaten CHPS sustainability.

Conclusion

UHC is a political choice which can only be achieved through sustainable and coherent efforts. Along countries' pathways to reach UHC, coordinated involvement of all stakeholders, from community members to international partners, is essential. To achieve UHC within the time frame of SDGs, Ghana has no choice but to improve its national health governance to strengthen the capacity of existing CHPS.

https://ift.tt/2Np2LJn

Ethnic differences in body mass index trajectories from 18 years to postpartum in a population-based cohort of pregnant women in Norway

Objectives

To explore ethnic differences in changes in body mass index (BMI) from the age of 18 years to 3 months postpartum.

Design

A population-based cohort study.

Setting

Child Health Clinics in Oslo, Norway.

Participants

Participants were 811 pregnant women (mean age 30 years). Ethnicity was categorised into six groups.

Primary outcome measures

The outcome variable was BMI (kg/m²) measured at the age of 18 and 25 years, at prepregnancy and at 3 months postpartum. Body weight at 18 years, 25 years and prepregnancy were self-reported in early pregnancy, while body height and weight at 3 months postpartum were measured. The main statistical method was generalised estimating equations, adjusted for age. The analyses were stratified by parity due to ethnicityxtimexparity interaction (p<0.001).

Results

Primiparous South Asian women had a 1.45 (95% CI 0.39 to 2.52) kg/m² higher and Middle Eastern women had 1.43 (0.16 to 2.70) kg/m² higher mean BMI increase from 18 years to postpartum than Western European women. Among multiparous women, the mean BMI increased 1.99 (1.02 to 2.95) kg/m² more in South Asian women, 1.48 (0.31 to 2.64) kg/m² more in Middle Eastern women and 2.49 (0.55 to 4.42) kg/m² more in African women than in Western European women from 18 years to prepregnancy. From 18 years to postpartum, the mean increase was 4.40 (2.38 to 6.42) kg/m² higher in African women and 1.94 to 2.78 kg/m² higher in the other groups than in Western European women.

Conclusions

Multiparous women of ethnic minority origin seem substantially more prone to long-term weight gain than multiparous Western European women in Norway.

https://ift.tt/2GENYd5

Risk of adverse pregnancy outcomes associated with short and long birth intervals in Bangladesh: evidence from six Bangladesh Demographic and Health Surveys, 1996-2014

Objective

To examine the effect of short (<36 months) and long (≥60 months) birth intervals on adverse pregnancy outcomes in Bangladesh.

Design, setting and participants

We analysed data from six Bangladesh Demographic and Health Surveys (1996–1997, 1999–2000, 2004, 2007, 2011 and 2014). We included all singleton non-first live births, most recently born to mothers within 5 years preceding each survey (n=21 382). We defined birth interval according to previous research which suggests that a birth interval between 36 and 59 months is the most ideal interval. Bivariate and multivariable analyses were conducted to obtain the crude and adjusted ORs (aOR) respectively to assess the odds of first-day neonatal death, early neonatal death and small birth size for both short (<36 months) and long (≥60 months) spacing between births.

Main outcome measures

First-day neonatal death, early neonatal death and small birth size.

Results

In the multivariable analysis, compared with births spaced 36–59 months, infants with a birth interval of <36 months had increased odds of first-day neonatal death (aOR: 2.11, 95% CI: 1.17 to 3.78) and early neonatal death (aOR: 1.58, 95% CI: 1.13 to 2.22). Compared with births spaced 36–59 months, infants with a birth interval of ≥60 months had increased odds of first-day neonatal death (aOR: 2.02, 95% CI: 1.10 to 3.73) and small birth size (aOR: 1.17, 95% CI: 1.02 to 1.34). When there was a history of any previous pregnancy loss, there was an increase in the odds of first-day and early neonatal death for both short and long birth intervals, although it was not significant.

Conclusions

Birth intervals shorter than 36 months and longer than 59 months are associated with increased odds of adverse pregnancy outcomes. Care-providers, programme managers and policymakers could focus on promoting an optimal birth interval between 36 and 59 months in postpartum family planning.

https://ift.tt/2Nlwu66

Experiential knowledge of risk and support factors for physician performance in Canada: a qualitative study

Objective

To identify, understand and explain potential risk and protective factors that may influence individual and physician group performance, by accessing the experiential knowledge of physician-assessors at three medical regulatory authorities (MRAs) in Canada.

Design

Qualitative analysis of physician-assessors' interview transcripts. Telephone or in-person interviews were audio-recorded on consent, and transcribed verbatim. Interview questions related to four topics: Definition/discussion of what makes a 'high-quality physician;' factors for individual physician performance; factors for group physician performance; and recommendations on how to support high-quality medical practice. A grounded-theory approach was used to analyse the data.

Setting

Three provinces (Alberta, Manitoba, Ontario) in Canada.

Participants

Twenty-three (11 female, 12 male) physician-assessors from three MRAs in Canada (the College of Physicians & Surgeons of Alberta, the College of Physicians and Surgeons of Manitoba and the College of Physicians and Surgeons of Ontario).

Results

Participants outlined various protective factors for individual physician performance, including: being engaged in continuous quality improvement; having a support network of colleagues; working in a defined scope of practice; maintaining engagement in medicine; receiving regular feedback; and maintaining work-life balance. Individual risk factors included being money-oriented; having a high-volume practice; and practising in isolation. Group protective factors incorporated having regular communication among the group; effective collaboration; a shared philosophy of care; a diversity of physician perspectives; and appropriate practice management procedures. Group risk factors included: a lack of or ineffective communication/collaboration among the group; a group that doesn't empower change; or having one disruptive or 'risky' physician in the group.

Conclusions

This is the first qualitative inquiry to explore the experiential knowledge of physician-assessors related to physician performance. By understanding the risk and support factors for both individual physicians and groups, MRAs will be better-equipped to tailor physician assessments and limited resources to support competence and enhance physician performance.

https://ift.tt/2GFSCrk

Protocol for a prospective, longitudinal mixed-methods case study: supporting a Model of Care for Healthier Adolescents (The MoCHA study)

Introduction

Improving mental healthcare for adolescents is a global policy priority. Despite demands for community-based services, many adolescents require more intensive interventions, such as an inpatient admission. This is typically at a point of crisis, often accompanied by intense emotional dysregulation, impairment of coping function and impulsivity. However, limited evidence exists on how best to support this group while they are in inpatient care, aside from pharmacological treatments which have a limited role in adolescents. Little is known about the models of care (MoC) offered in inpatient units, whether adolescents perceive these as helpful and the perspectives of caregivers and clinicians. Here, we describe a protocol which aims to explore and evaluate an inpatient MoC.

Methods and analysis

We designed a longitudinal, mixed-methods, case study. The population consists of adolescents, caregivers and clinicians at a single inpatient unit in Melbourne, Australia. Standardised outcome measures, including semi- structured interviews, will be administered to adolescents at three time-points, T1 (admission), T2 (discharge) and T3 (6 months post discharge). Caregivers will also be interviewed at T1, T2 and T3. Clinicians will be interviewed once. The measures include: Life Problems Inventory, Quick Inventory of Depressive Symptomatology, Kessler Psychological Distress Scale and the Youth Self-Report. Health of the Nation Outcome Scales for Children and Adolescents will be collected at T1 and T2. Quantitative analysis will include descriptive statistics and paired t-tests summarising adolescents admitted to the unit, clinical characteristics and longitudinal data on symptomatology. Qualitative data will be analysed using both thematic and trajectory analysis. Data collection began in May 2017 and will cease with T3 interviews by October 2018.

Ethics and dissemination

https://ift.tt/2NmooKC

Cohort profile: Children in Need Census (CIN) records of children referred for social care support in England

Purpose

The Children in Need Census (CIN) is a case-based administrative dataset on children referred to social care services in England. CIN includes information on the 'needs' of children, and whether they received social care support. Local and national government bodies in England currently use CIN for evaluation purposes. Data are accessible to researchers under certain conditions, allowing researchers to investigate the health implications of adverse childhood experiences. However, CIN suffers from lack of metadata, meaning it can be challenging for researchers to process and interpret data, particularly if researchers are unfamiliar with the English children's social care system. To address this issue, we provide the background to CIN and describe the available data from 2008 to 2016.

Participants

CIN is derived from case records held by English local authorities on all children referred to children's social care for a 'needs assessment', regardless of whether they are eventually assessed as 'in need of social care support'. Local authorities submit these case records to the UK Department for Education for collation. CIN holds information on an estimated 2.76 million children from October 2008 to March 2016. Since 2013/2014, just under 900 000 children have been recorded in the CIN annually, equivalent to around 8% of children in England (annual prevalence). Approximately, 650 000 children enter or renter the dataset each year, equivalent to 5% of children in England (annual incidence).

Data summary

Of the estimated 2.76 million children in the data, 50% are male and 47% female. 45% are referred to children's social care services due to abuse or neglect. 10.7% of children in CIN went onto a child protection plan, meaning they were judged to be (at risk of) suffering significant harm.

Future plans

CIN data collection is annual and ongoing. Data from the most recent census period typically become available for researchers in the following Spring.

https://ift.tt/2GFSxE2

Premarket evaluation of medical devices: a cross-sectional analysis of clinical studies submitted to a German ethics committee

Objective

To assess the methodological quality of pre-market clinical studies performed on medical devices (MDs), including in-vitro diagnostic (IVD) MDs, in Europe.

Design

Observational cross-sectional study.

Setting

A large German ethics committee.

Materials

From the consecutive sample of study applications between March 2010 and December 2013, we selected MD study applications requiring approval by an ethics committee and the competent federal authority. These included pre-market studies on devices that had not yet received a CE (Conformité Européenne) mark or had previously been CE marked for a different indication. Also included were post-CE studies requiring federal authority approval because the study entailed additional invasive or otherwise burdensome components.

Primary and secondary outcome measures

Besides the design of the studies, we assessed the planned sample size, study duration and other aspects.

Results

122 study applications were analysed: 98 (80%) concerned therapeutic rather than diagnostic devices and 84 (69%) were pre-market studies. The proportion of studies on class I, IIa, IIb and III devices was 10%, 15%, 28% and 39%, respectively. 10 studies (8%) investigated IVD MDs. A randomised controlled trial (RCT) was planned in 70 (57%) of the 122 applications; studies with non-randomised control groups (n=23; 19%) or without controls (n=29; 24%) were less common. In the sub-group of pre-market studies on therapeutic devices, the proportion of RCTs was 66% (43/65). The median sample size was 120 participants or samples (IQR 53–229). The median study duration was 24 (14–38) months. 87 studies (71%) considered at least one patient-relevant outcome. 12 (17%) and 37 (53%) of the 70 RCTs applied a fully or partially blinded design, respectively.

Conclusion

A large proportion of MD studies in Germany apply a randomised controlled design, thus contradicting the industry argument that RCTs on MDs are commonly infeasible.

https://ift.tt/2NqNfNu

Author misrepresentation of institutional affiliations: protocol for an exploratory case study

Introduction

University ranking systems and the publish-or-perish dictum, among other factors, are driving universities and researchers around the world to increase their research productivity. Authors frequently report multiple affiliations in published articles. It is not known if the reported institutional affiliations are real affiliations, which is when the universities have contributed substantially to the research conducted and to the published manuscript. This study aims to establish whether there is an empirical basis for author affiliation misrepresentation in authors with multiple institutional affiliations.

Methods and analysis

This individual secondary data exploratory analysis on Scopus-indexed articles for 2016 will search all authors who report multiple institutional affiliations in which at least one of the affiliations is to a Chilean university. We will consider that misrepresentation of an affiliation is more likely when it is not possible to verify objectively a link between the author and the mentioned institution through institutional websites. If we cannot corroborate the author affiliation, we will consider this a finding of potential misrepresentation of the affiliation. We will summarise results with descriptive statistics.

Ethics and dissemination

The study protocol was approved by the institutional ethics committee of Universidad de Santiago de Chile, Resolution No. 261, and dated January 15, 2018. Results will be submitted to the World Conference on Research Integrity, among other meetings on publication ethics and research integrity, and will be published in scientific, peer-reviewed journals.

https://ift.tt/2GFSrMG

Health professionals in a changing climate: protocol for a scoping review

Introduction

Climate change will impose significant health impacts. Although we know health professionals should play a critical role in protecting human health from climate change, their preparedness to engage with these issues worldwide is unclear. This study aims to map the range and nature of existing evidence regarding health professionals' knowledge, attitudes, perceptions and practices regarding climate change and health impacts and the challenges they face, and identify knowledge gaps to guide future development of research, policy and practices.

Methods and analysis

We will perform a scoping review based on the six-stage framework proposed by Arksey and O'Malley. Our study includes peer-reviewed literature focusing on any aspect of health professionals' work regarding climate change and health since 2002 and indexed in MEDLINE/Pubmed, Web of Science, Scopus or Embase. Identified papers will be described and assessed. Thematic analysis will be applied to evaluate and categorise the study findings.

Implications and dissemination

This is the first scoping review of health professionals' activities to anticipate and prepare for health impacts attributable to climate change. It will provide evidence regarding the current situations worldwide and gaps in preparedness. The findings can be used to highlight accomplishments to date, identify gaps and further develop good practices for health professionals' engagement. The results will be published in the peer-reviewed literature and shared at health professional society meetings.

https://ift.tt/2NqNfwY

Shortening patient-reported outcome measures through optimal test assembly: application to the Social Appearance Anxiety Scale in the Scleroderma Patient-centered Intervention Network Cohort

Objectives

The Social Appearance Anxiety Scale (SAAS) is a 16-item measure that assesses social anxiety in situations where appearance is evaluated. The objective was to use optimal test assembly (OTA) methods to develop and validate a short-form SAAS based on objective and reproducible criteria.

Design

This study was a cross-sectional analysis of baseline data from adults enrolled in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort.

Setting

Adults in the SPIN Cohort in the present study were enrolled at 28 centres in Canada, the USA and the UK.

Participants

The SAAS was administered to 926 adults with scleroderma.

Primary and secondary measures

The SAAS, Brief Fear of Negative Evaluation II (BFNE II), Brief Satisfaction with Appearance Scale (Brief-SWAP), Patient Health Questionnaire-8 (PHQ8) and Social Interaction Anxiety Scale-6 (SIAS-6) were collected, as well as demographic characteristics.

Results

OTA methods identified a maximally informative shortened version for each possible form length between 1 and 15 items. The final shortened version was selected based on prespecified criteria for reliability, concurrent validity and statistically equivalent convergent validity with the BFNE II scale. A five-item short version was selected (SAAS-5). The SAAS-5 had a Cronbach's α of 0.95 and had high concurrent validity with the full-length form (r=0.97). The correlation of the SAAS-5 with the BFNE II was 0.66, which was statistically equivalent to that of the full-length form. Furthermore, the correlation of the SAAS-5 with the two subscales of the Brief-SWAP, and the SIAS-6, were statistically equivalent to that of the full-length form.

Conclusions

OTA was an efficient method for shortening the full-length SAAS to create the SAAS-5.

https://ift.tt/2GFSpo2

Aussiedler Mortality (AMOR): cohort studies on ethnic German migrants from the Former Soviet Union

Purpose

The Aussiedler Mortality cohorts represent the unique migrant group of ethnic Germans (resettlers) from the former Soviet Union who migrated to Germany mainly after the fall of the iron curtain in 1989. Resettlers are the second largest migrant group in Germany and their health status was largely unknown before the cohorts were set up.

Participants

Four retrospective register-based cohorts were set up in different federal states of Germany, each focussing on different health aspects. In total, the cohorts include 92 362 resettlers (men: 51.5%, women: 48.5%) who immigrated between 1990 and 2005 with a mean age at immigration of 36.6 years (range 0–105 years). Resettlers are of German ancestry and they are immediately granted the German citizenship with all rights and duties.

Findings to date

Vital status and causes of death (International Classification of Diseases codes based on death certificates or record linkage) were collected for three cohorts as well as cancer incidence and incidence of acute myocardial infarction in three of the cohorts. Currently, an observation period of 20 years (1990–2009) is covered. Overall mortality among resettlers was surprisingly lower in comparison to the German population with standardised mortality ratios of 0.87 (95% confidence limits 0.84–0.91) for women and 0.96 (0.92–0.99) for men, and even stronger for cardiovascular diseases (women: 0.84 (0.79–0.89); men: 0.80 (0.75–0.86). However, observed differences can neither be explained by the 'healthy migrant effect' nor by common behavioural risk factors and may be related to factors which have not yet been studied.

Future plans

The existing cohorts will be continued and prospective studies on resettlers are underway: one cohort will be followed-up prospectively and two other large prospective cohort studies in Germany will be used for a detailed assessment of lifestyle, environmental and genetic/epigenetic factors on the mortality and morbidity pattern of resettlers.

https://ift.tt/2Nop16j

Systematic scoping review of frameworks used to develop rehabilitation interventions for older adults

Objectives

Rehabilitation interventions for older adults are complex as they involve a number of interacting components, have multiple outcomes of interest and are influenced by a number of contextual factors. The importance of rigorous intervention development prior to formal evaluation has been acknowledged and a number of frameworks have been developed. This review explored which frameworks have been used to guide the development of rehabilitation interventions for older adults.

Design

Systematic scoping review.

Setting

Studies were not limited for inclusion based on setting.

Participants

Studies were included that featured older adults (>65 years of age).

Interventions

Studies were included that reported the development of a rehabilitation intervention.

Primary and secondary outcome measures

Data were extracted on study population, setting, type of intervention developed and frameworks used. The primary outcome of interest was the type of intervention development framework.

Results

Thirty-five studies were included. There was a range of underlying medical conditions including mild cognitive impairment and dementia (n=5), cardiac (n=4), stroke (n=3), falls (n=3), hip fracture (n=2), diabetes (n=2), breast cancer (n=1), Parkinson's disease (n=1), depression (n=1), chronic health problems (n=1), osteoarthritis (n=1), leg ulcer (n=1), neck pain (n=1) and foot problems (n=1). The intervention types being developed included multicomponent, support based, cognitive, physical activities, nursing led, falls prevention and occupational therapy led. Twelve studies (34%) did not report using a framework. Five frameworks were reported with the Medical Research Council (MRC) framework for developing and evaluating complex interventions being the most frequently cited (77%, n=17).

Conclusion

At present, the MRC framework is the most popular for developing rehabilitation interventions for older adults. Many studies do not report using a framework. Further, specific guidance to assist this complex field of rehabilitation research is required.

https://ift.tt/2GFSlEO

Effects of high-fidelity simulation based on life-threatening clinical condition scenarios on learning outcomes of undergraduate and postgraduate nursing students: a systematic review and meta-analysis

Objective

The purpose was to analyse the effectiveness of high-fidelity patient simulation (HFPS) based on life-threatening clinical condition scenarios on undergraduate and postgraduate nursing students' learning outcomes.

Design

A systematic review and meta-analysis were conducted based on the Cochrane Handbook for Systematic Reviews of Interventions and its reporting was checked against the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.

Data sources

PubMed, Scopus, CINAHL with Full Text, Wiley Online Library and Web of Science were searched until July 2017. Author contact, reference and citation lists were checked to obtain additional references.

Study selection

To be included, available full-texts had to be published in English, French, Spanish or Italian and (a) involved undergraduate or postgraduate nursing students performing HFPS based on life-threatening clinical condition scenarios, (b) contained control groups not tested on the HFPS before the intervention, (c) contained data measuring learning outcomes such as performance, knowledge, self-confidence, self-efficacy or satisfaction measured just after the simulation session and (d) reported data for meta-analytic synthesis.

Review method

Three independent raters screened the retrieved studies using a coding protocol to extract data in accordance with inclusion criteria.

Synthesis method

For each study, outcome data were synthesised using meta-analytic procedures based on random-effect model and computing effect sizes by Cohen's d with a 95% CI.

Results

Thirty-three studies were included. HFPS sessions showed significantly larger effects sizes for knowledge (d=0.49, 95% CI [0.17 to 0.81]) and performance (d=0.50, 95% CI [0.19 to 0.81]) when compared with any other teaching method. Significant heterogeneity among studies was detected.

Conclusions

Compared with other teaching methods, HFPS revealed higher effects sizes on nursing students' knowledge and performance. Further studies are required to explore its effectiveness in improving nursing students' competence and patient outcomes.

https://ift.tt/2Nngz7x

Trends in comparative efficacy and safety of malaria control interventions for maternal and child health outcomes in Africa: a study protocol for a Bayesian network meta-regression exploring the effect of HIV and malaria endemicity spectrum

Introduction

Unprecedented global efforts to prevent malaria morbidity and mortality in sub-Saharan Africa have saved hundreds of thousands of lives across the continent in the last two decades. This study aims to determine how the comparative efficacy and safety of available malaria control interventions intended to improve maternal and child health outcomes have changed over time considering the varied epidemiological contexts on the continent.

Methods

We will review all randomised controlled trials that investigated malaria control interventions in pregnant women in sub-Saharan Africa and were published between January 1980 and December 2018. We will subsequently use network meta-regression to estimate temporal trends in the relative and absolute efficacy and safety of Intermittent Preventive Treatments, Intermittent Screening and Treatments, Insecticide-treated bed nets, and their combinations, and predict their ranking according to their relative and absolute efficacy and safety over time. Our outcomes will include 12 maternal and 7 child mortality and morbidity outcomes, known to be associated with either malaria infection or control. We will use intention-to-treat analysis to derive our estimates and meta-regression to estimate temporal trends and the effect modification by HIV infection, malaria endemicity and Plasmodium falciparum resistance to sulfadoxine–pyrimethamine, while adjusting for multiple potential confounders via propensity score calibration.

PROSPERO registration number

CRD42018095138.

https://ift.tt/2GFShoy

Absolute risk and risk factors for stroke mortality in patients with end-stage kidney disease (ESKD): population-based cohort study using data linkage

Introduction

People with end-stage kidney disease (ESKD) have up to 30-fold higher risk of stroke than the general population.

Objective

To determine risk factors associated with stroke death in the ESKD population.

Methods

We identified all patients with incident ESKD in Australia (1980–2013) and New Zealand (1988–2012) from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) registry. We ascertained underlying cause of death from data linkage with national death registries and risk factors from ANZDATA. Using a competing risks multivariable regression model, we estimated cumulative incidence of stroke and non-stroke deaths, and risk factors for stroke deaths (adjusted sub-HR, SHR).

Results

We included 60 823 people with ESKD. There were 941 stroke deaths and 33 377 non-stroke deaths during 381 874 person-years of follow-up. Overall, the cumulative incidence of stroke death was 0.9% and non-stroke death was 36.8% 5 years after starting ESKD treatment. The risk of stroke death was higher at older ages (SHR 1.92, 95% CI 1.45 to 2.55), in females (SHR 1.41, 95% CI 1.21 to 1.64), in people with cerebrovascular disease (SHR 2.39, 95% CI 1.99 to 2.87), with ESKD caused by hypertensive/renovascular disease (SHR 1.39, 95% CI 1.09 to 1.78) or polycystic kidney disease (SHR 1.38, 95% CI 1.00 to 1.90), with earlier year of ESKD treatment initiation (SHR 1.93, 95% CI 1.56 to 2.39) and receiving dialysis (transplant vs haemodialysis SHR 0.27, 95% CI 0.09 to 0.84).

Conclusion

Patients with ESKD with higher risk of stroke death are older, women, with cerebrovascular disease, with hypertensive/renovascular or polycystic kidney disease cause of ESKD, with earlier year of ESKD treatment and receiving dialysis. These groups may benefit from targeted stroke prevention interventions.

https://ift.tt/2NkfHAv

Do hospitals influence geographic variation in admission for preventable hospitalisation? A data linkage study in New South Wales, Australia

Objective

Preventable hospitalisations are used internationally as a performance indicator for primary care, but the influence of other health system factors remains poorly understood. This study investigated between-hospital variation in rates of preventable hospitalisation.

Setting

Linked health survey and hospital admissions data for a cohort study of 266 826 people aged over 45 years in the state of New South Wales, Australia.

Method

Between-hospital variation in preventable hospitalisation was quantified using cross-classified multiple-membership multilevel Poisson models, adjusted for personal sociodemographic, health and area-level contextual characteristics. Variation was also explored for two conditions unlikely to be influenced by discretionary admission practice: emergency admissions for acute myocardial infarction (AMI) and hip fracture.

Results

We found significant between-hospital variation in adjusted rates of preventable hospitalisation, with hospitals varying on average 26% from the state mean. Patients served more by community and multipurpose facilities (smaller facilities primarily in rural areas) had higher rates of preventable hospitalisation. Community hospitals had the greatest between-hospital variation, and included the facilities with the highest rates of preventable hospitalisation. There was comparatively little between-hospital variation in rates of admission for AMI and hip fracture.

Conclusions

Geographic variation in preventable hospitalisation is determined in part by hospitals, reflecting different roles played by community and multipurpose facilities, compared with major and principal referral hospitals, within the community. Care should be taken when interpreting the indicator simply as a performance measure for primary care.

https://ift.tt/2GFSc4e

Cross-sectional evaluation of the relationship between vitamin D status and supplement use across levels of kidney function in adults

Objectives

The objective of this study was to assess vitamin D status of US non-pregnant adults using a standardised assay across 15 mL/min/1.73 m² increments of kidney function, report the use of dietary supplements containing vitamin D and assess relationships between vitamin D and markers of bone resorption.

Design

This study is a cross-sectional evaluation.

Setting

The study is from the US National Health and Nutrition Evaluation Survey in 2001–2012.

Participants

The participants were non-institutionalised, non-pregnant adults, age ≥20 years.

Primary and secondary outcome measures

The primary outcome measure was serum 25OHD evaluated using liquid chromatography-tandem mass spectroscopy traceable to international reference standards. Secondary outcome measures were use of dietary supplements containing vitamin D and the serum intact parathyroid hormone and bone-specific alkaline phosphatase in a subset of participants.

Results

The median 25OHD concentration in 27 543 US non-pregnant adults was 25.7 ng/mL (range, 2.2–150.0 ng/mL). Vitamin D supplements were used by 38.0%; mean (SE)=757 (43) international units/day. The range of 25OHD concentration across groups, stratified by kidney function, was 23.0–28.1 ng/mL. The lowest concentration of 25OHD observed was in people with higher kidney function (23.0 ng/mL for estimated glomerular filtration rate >105 mL/min/1.73 m²). Only 24% of people not taking a dietary supplement had a 25OHD concentration >30 ng/mL. Serum intact parathyroid hormone inversely correlated with 25OHD within all kidney function groups. Bone-specific alkaline phosphatase was also negatively associated with 25OHD concentration.

Conclusions

These data indicate that 25OHD concentrations and supplement use may be suboptimal in a significant proportion of the population, across all kidney function levels. The response of bone resorption markers further suggests that 25OHD levels could be improved. Together, these data support a re-evaluation of the 25OHD concentration associated with health in adults.

https://ift.tt/2NlcMaN

Biosimilars: what the oncologist should know

Future Oncology, Ahead of Print.


https://ift.tt/2NmgEbq

Rare presentation of granulomatosis with polyangiitis

A 62-year-old man with no pertinent medical history presented with lower extremity weakness and worsening distal fingertips and toe cyanosis/gangrene. In the outpatient setting, he was initially being treated for Raynaud's phenomenon with a calcium channel blocker. On presentation, the patient had elevated inflammatory markers and white blood cell count. Serum vasculitis panel (proteinase-3 antibody) supported the diagnosis of granulomatosis with polyangiitis. His hospital course was complicated by ischaemic stroke and a diagnosis of mononeuritis multiplex in his lower extremities. After initiating therapy with intravenous steroid and rituximab, his symptoms overall improved including cyanotic fingertips/toes. His inflammatory markers and leucocytosis also improved. Outpatient follow-up consisted of further rituximab infusions and unrelated umbilical hernia incarceration which required surgery. He was found incidentally to have subsegmental pulmonary emboli which most likely occurred during the initial presentation prior to his diagnosis. The patient moved out of state and was lost to follow-up.

https://ift.tt/2No6IOz

Post pulmonary embolism syndrome: a common, underdiagnosed complication that is not well recognised

A 56-year-old man developed chronic breathlessness which persisted for years after he suffered acute pulmonary embolism (PE) despite all investigations being subsequently normal. This case illustrates a very common complication which occurs in up to half of all patients after an acute PE which has been labelled 'post pulmonary embolism syndrome', yet it is not well recognised and at present there is not much research into the prevention or even possible treatment options for patients who develop these symptoms.

https://ift.tt/2GDPegJ

Oesophageal atresia with tracheo-oesophageal fistula, ileal atresia and Hirschsprungs disease: outcome of a rare phenotype

Oesophageal atresia with or without tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease are surgical malformations of the gastrointestinal tract typically diagnosed early in the neonatal period and varying in severity and prognosis. This report describes a full-term male newborn presenting simultaneous oesophageal atresia with distal tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease. In addition to the complex types of gastrointestinal malformations involved, the combination of ileal atresia and Hirschsprung's disease, as well as ganglion cells distal to intestinal atresia, resulted in a challenging diagnosis. Despite a successful outcome, the patient presented increased morbidity and prolonged hospitalisation. We highlight some important findings that may aid the early diagnosis of Hirschsprung's disease in this clinical setting. To our knowledge, the association of oesophageal atresia/tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease has not been previously reported.

https://ift.tt/2NnqjhZ

Transient sinus arrest due to sinus node artery thrombus after revascularisation of the left circumflex artery

We present a case of sinus arrest and junctional escape rhythm from sinus node artery (SNA) thrombus in a 55-year-old man after revascularisation of right coronary and proximal circumflex arteries for infero-posterior wall ST-segement elevation myocardial infarction (STEMI). Sinus arrest from occlusion of the SNA is uncommon. The ensuing bradycardia may have haemodynamic consequences requiring temporary pacing but is almost always self-limited.

https://ift.tt/2GFnRTq

Atrial myxoma presenting as abdominal pain: an unusual association

https://ift.tt/2GEKS8X

Bouverets syndrome treated with endoscopic electrohydraulic lithotripsy

Bouveret's syndrome is a rare form of small bowel obstruction caused by a large biliary stone entering the lumen of the duodenum or the stomach through a bilioenteric fistula. Treatment options include various surgical techniques. However, recent advances in endoscopy also allow non-surgical endoscopic treatment options. We report a 68-year-old man, with a disseminated small intestinal neuroendocrine tumour, presenting with Bouveret's syndrome without any previously reported biliary disease. He experienced a number of symptoms 1 month prior to his admittance, which were difficult to differentiate from other infectious diseases and complications due to his neuroendocrine tumour. Abdominal CT showed a biliary stone impacted in the duodenal bulb, small bowel obstruction, pneumobilia and a bilioenteric fistula. The patient was treated with endoscopic electrohydraulic lithotripsy to fragment the large gallstone in smaller retractable pieces. The patient avoided major surgery and was discharged the following day.

https://ift.tt/2Nu8xd7

Tuberculosis of the breast: an uncommon presentation of an old disease

Breast tuberculosis (TB) is considered an uncommon disease with an estimated incidence of 0.1% of all breast lesions reported in developed countries. A 53-year-old Caucasian woman, with a medical history of Crohn's disease, previously treated with infliximab for 3 months suspended due to a presumptive diagnosis of TB for which antitubercular regimen was started. Five months after, a painful lump in the left breast was identified by the patient. Mammary ultrasound confirmed left breast nodules and axillary adenopathies. Histology and microbiology of both lesions confirmed breast TB. Molecular drug susceptibility testing in both samples revealed no resistance to first line anti-TB drugs and the regimen was maintained for 1 year, with clinical and radiological improvement. Mammary gland involvement usually results from lymphatic extension and differential diagnosis frequently includes breast cancer or bacterial abscess.

https://ift.tt/2GFoqg0

Liver haematoma as a presentation of peliosis hepatis

Peliosis hepatis (PH) is an uncommon, benign hepatic vascular condition involving liver lesions consisting of dilated sinusoidal spaces that ultimately lead to numerous blood-filled cavities within the liver parenchyma. We detail the case of a 62-year-old woman who presented with a large hepatic haematoma resulting from intracystic haemorrhage. She was subsequently diagnosed with PH via arteriogram. Her symptoms were successfully treated surgically with open fenestration. Patient's postoperative course was unremarkable, with no recurrence of symptoms to date.

https://ift.tt/2NmYSVv

Stroke in a young man: a late complication of radiation therapy

This 37-year-old man presented with left sided facial warmth and numbness associated with new sudden-onset right hemiparesis. The patient first developed sudden numbness of his left lip and warmth in left ear which travelled to the rest of left face. His past medical history was significant for hypertension, Hodgkin lymphoma treated with radiation therapy at the age of 10, and sleeve gastrectomy for obesity 1 year ago complicated by bilateral ischaemic cerebral infarctions with residual left hemiparesis. No acute infarcts were found on MRI. Transesophageal echocardiography revealed a complex atheroma near the sinotubular junction in ascending aorta.

https://ift.tt/2GFhzTN

Transient iatrogenic Horners syndrome following carotid endarterectomy

We present a case of a 72-year-old man who developed a transient Horner's syndrome in the immediate postoperative period after right carotid endarterectomy which resolved within 3 months. Although Horner's syndrome has been reported with several disorders of the carotid artery, our case documents a rare iatrogenic oculosympathetic paresis after elective carotid endarterectomy.

https://ift.tt/2No6E1h

Peripheral ulcerative keratitis with corneal melt as the primary presentation in a case of human immunodeficiency virus

Peripheral ulcerative keratitis (PUK) is an aggressive, potentially sight-threatening cause for peripheral corneal thinning. It is thought to be the result of immune complex deposition at the limbus, resulting in corneal inflammation and stromal melt. We present a case of a 43-year-old female patient of African origin, presenting with PUK and associated corneal perforation as the primary presentation of HIV infection. An urgent tectonic deep anterior lamellar keratoplasty was performed under general anaesthesia with excellent outcome. The patient was referred to the sexual health clinic and anti-retroviral treatment was initiated. This case is to the best of our knowledge the first report from the UK of PUK with corneal perforation as the primary presentation of HIV infection. As highlighted in this report, infection with HIV may initially be silent; therefore, it is vital to consider HIV infection when dealing with PUK of unknown aetiology.

https://ift.tt/2GFnIPS

Unusual KRAS missense mutation (p.E63K) in patient with juvenile pilocytic astrocytoma of the tectum

https://ift.tt/2No6Bm7

Pulmonary embolism with right ventricular thrombus: a management dilemma

https://ift.tt/2GFmrs8

Cancer immunology, inflammation, and tolerance: an introduction

https://ift.tt/2BK72m3

Hyperspectral Reflectance-Derived Relationship Matrices for Genomic Prediction of Grain Yield in Wheat

Hyperspectral reflectance phenotyping and genomic selection are two emerging technologies that have the potential to increase plant breeding efficiency by improving prediction accuracy for grain yield. Hyperspectral cameras quantify canopy reflectance across a wide range of wavelengths that are associated with numerous biophysical and biochemical processes in plants. Genomic selection models utilize genome-wide marker or pedigree information to predict the genetic values of breeding lines. In this study, we propose a multi-kernel GBLUP approach to genomic selection that uses genomic marker-, pedigree-, and hyperspectral reflectance-derived relationship matrices to model the genetic main effects and genotype x environment (G x E ) interactions across environments within a bread wheat (Triticum aestivum L.) breeding program. We utilized an airplane equipped with a hyperspectral camera to phenotype five differentially managed treatments of the yield trials conducted by the Bread Wheat Improvement Program of the International Maize and Wheat Improvement Center (CIMMYT) at Ciudad Obregón, México over four breeding cycles. We observed that single-kernel models using hyperspectral reflectance-derived relationship matrices performed similarly or superior to marker- and pedigree-based genomic selection models when predicting within and across environments. Multi-kernel models combining marker/pedigree information with hyperspectral reflectance phentoypes had the highest prediction accuracies; however, improvements in accuracy over marker- and pedigree-based models were marginal when correcting for days to heading. Our results demonstrate the potential of using hyperspectral imaging to predict grain yield within a multi-environment context and also support further studies on the integration of hyperspectral reflectance phenotyping into breeding programs.

https://ift.tt/2U62bTy

Therapeutic efficacy evaluation of radioimmunotherapy with 90Y‐labeled anti‐podoplanin antibody NZ‐12 for mesothelioma

Summary

Podoplanin is a type I transmembrane sialomucin‐like glycoprotein that is highly expressed in malignant mesothelioma. The rat‐human chimeric antibody NZ‐12 has high affinity for human podoplanin and antibody‐dependent cellular cytotoxicity, and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ‐12 and the antitumor effect of RIT with ⁹⁰Y‐labeled NZ‐12 in an NCI‐H226 (H226) malignant mesothelioma xenograft mouse model. ¹¹¹In‐labeled NZ‐12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with ⁹⁰Y‐labeled NZ‐12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of ⁹⁰Y‐labeled NZ‐12 in patients compared with the H226 tumor xenografts. Our findings suggest that ⁹⁰Y‐labeled NZ‐12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.

This article is protected by copyright. All rights reserved.

https://ift.tt/2EqDo7g

LINC00261 is an epigenetically-regulated tumor suppressor that is essential for activation of the DNA damage response

Lung cancer is the leading cause of cancer-related death in the United States. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules whose role in lung carcinogenesis is poorly understood. In this study, we profiled lncRNA expression in lung adenocarcinoma (LUAD) cell lines, compared their expression to that of purified alveolar epithelial type II cells (the purported cell of origin for LUAD), cross-referenced these with lncRNAs altered in primary human tumors, and interrogated for lncRNA whose expression correlated with patient survival. We identified LINC00261, a lncRNA with unknown function in LUAD, adjacent to the pioneering transcription factor FOXA2. Loss of LINC00261 was observed in multiple tumor types, including liver, breast, and gastric cancer. Reintroduction of LINC00261 into human LUAD cell lines inhibited cell migration and slowed proliferation by inducing a G2/M cell cycle arrest while upregulating DNA damage pathway genes and inducing phosphorylation-mediated activation of components of the DNA damage pathway. FOXA2 was able to induce LINC00261 expression, and the entire locus underwent hypermethylation in LUAD, leading to loss of expression. We have thus identified an epigenetically deregulated lncRNA, whose loss of expression in LUAD promotes the malignant phenotype and blocks activation of the DNA damage machinery, predisposing lung cells to cancer development.

https://ift.tt/2EqpFNJ

Spatio-Temporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement

The unbalanced production of pro- and anti-angiogenic factors in tumors can lead to aberrant vasculature morphology, angiogenesis, and disease progression. In this study, we report that disease progression in various murine models of solid tumors is associated with increased cleavage of full-length chromogranin A (CgA), a circulating vaso-regulatory neuro-secretory protein. Cleavage of CgA led to the exposure of the highly conserved PGPQLR site, which corresponds to residues 368-373 of human CgA1-373, a fragment that has proangiogenic activity. Antibodies against this site, unable to bind full-length CgA, inhibited angiogenesis and reduced tumor perfusion and growth. The PGPQLR sequence of the fragment, but not of the precursor, bound the VEGF binding-site of neuropilin-1; the C-terminal arginine (R373) of the sequence was crucial for binding. The pro-angiogenic activity of the CgA1-373 was blocked by anti-neuropilin-1 antibodies as well as by nicotinic acetylcholine receptor antagonists, suggesting that these receptors, in addition to neuropilin-1, play a role in the proangiogenic activity of CgA1-373. The R373 residue was enzymatically removed in plasma, causing loss of neuropilin-1 binding and gain of anti-angiogenic activity. These results suggest that cleavage of the R373R374 site of circulating human CgA in tumors and the subsequent removal of R373 in the blood represent an important ""on/off"" switch for the spatio-temporal regulation of tumor angiogenesis and may serve as a novel therapeutic target.

https://ift.tt/2Vhc7tI

Translesion Synthesis by DNA Polymerase {theta} Protects from Skin Cancers [Research Watch]

Error-prone DNA polymerase is required for mutagenic replication through UV-induced DNA lesions.

https://ift.tt/2NlHeBr

ALK+ Lymphomas Harbor a Targetable Dependency on Exogenous Cholesterol [Research Watch]

SQLE loss in ALK⁺ lymphomas results in cholesterol auxotrophy and resistance to oxidative cell death.

https://ift.tt/2GEYzVE

FAK Is a Critical Mediator of GNAQ-Driven Uveal Melanoma [Research Watch]

FAK inhibition confers synthetic lethality in GNAQ-activated uveal melanoma.

https://ift.tt/2NlHe4p

ARv7 Is a Transcriptional Repressor in CRPC [Research Watch]

The AR splice variant ARv7 binds to full-length AR and represses transcription of CRPC-suppressive genes.

https://ift.tt/2GGPV9c

A novel mTORC1/2 inhibitor (MTI-31) inhibits tumor growth, epithelial-mesenchymal transition, metastases and improves cancer immunity in preclinical lung cancer models

Purpose: We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance. Experimental design: Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular and animal studies were performed to determine in vitro and in vivo efficacy in NSCLC models of driver mutations and elucidate roles by mTOR-complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth and immune-escape. Results: MTI-31 potently inhibited cell proliferation (IC₅₀ <1 mmol/L) and in vivo tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met or KRAS (MED <10 mg/kg). In EGFR-mutant and/or EML4-ALK-driven NSCLC, MTI-31 or disruption of mTORC2 reduced cell migration, hematogenous metastasis to the lung, and abrogated morphological and functional traits of EMT. Disruption of mTORC2 inhibited EGFR/T790M-positive tumor growth in mouse brain and prolonged animal survival correlating a diminished tumor angiogenesis and recruitment of IBA1+ microglia/macrophages in tumor microenvironment. MTI-31 also suppressed programmed death ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation. Depletion of mTOR protein or disruption of mTOR-complexes profoundly downregulated PD-L1 and alleviated apoptosis in Jurkat T and primary human T cells in a tumor-T cell co-culture system. Conclusions: Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis and immune-escape in EGFR/ALK-mutant and TKI-resistant NSCLC cells. The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1/mTORC2 inhibitors in lung cancer patients.

https://ift.tt/2BPLqVt

A Phase I study of pegylated arginine deiminase (pegargiminase), cisplatin and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma

Purpose: Patients with recurrent high-grade gliomas (HGGs) are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains very poor. Pre-clinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Experimental Design: We expanded a Phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16 - 06/17) to receive weekly ADI-PEG20 36 mg/m² intramuscularly plus pemetrexed 500 mg/m² and cisplatin 75 mg/m² intravenously once every three weeks for up to six cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pre-treated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being CTCAE v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first four weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% CI 2.5-20.8) and overall survival (OS) was 6.3 months (95% CI 1.8-9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

https://ift.tt/2U4LJmm

A C-X-C chemokine receptor type 2-dominated crosstalk between tumor cells and macrophages drives gastric cancer metastasis

Purpose: C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated crosstalk between gastric cancer (GC) cells and macrophages still remains unclear. Experimental Design: The expression of CXCR2 and its ligands in 155 human GC tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A co-culture system was established, and functional assays, including ELISA, transwell, MTT, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting GC growth and metastasis. A xenograft GC model and a lymph node metastasis model were established to study the function of CXCR2 in vivo. Results: CXCR2 expression is associated with prognosis of GC patients (P=0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of GC cells. Macrophages are the major sources of CXCL1 and CXCL5 in the GC microenvironment, and promote migration of GC cells through activating a CXCR2/STAT3 feed-forward loop. GC cells secrete TNF-α to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of GC cells can suppress migration and metastasis of GC in vitro and in vivo. Conclusion: Our study suggested a previously uncharacterized mechanism through which GC cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat GC.

https://ift.tt/2BObal7

On-target resistance to the mutant-selective EGFR inhibitor osimertinib can develop in an allele specific manner dependent on the original EGFR activating mutation

Purpose: The third-generation EGFR inhibitor, osimertinib, is the first mutant selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib. Experimental Design: We combine structure-based predictive modeling of G724S in combination with the two most common EGFR activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling. Results: Our simulations suggest that the G724S mutation selectively reduces osimertinib binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, while cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggests G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse. Conclusions: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug - resistance mutation" pair to one focused on the "activating mutation - drug - resistance mutation" trio. This has broad implications across clinical oncology.

https://ift.tt/2U4zu9x

The dual PI3K/mTOR-pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases

Purpose: Previous studies have shown that the PI3K/Akt/mTOR-pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR-inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models. Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA-wildtype breast cancer cell lines and the isogenic pairs of PIK3CA-wildtype and -mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell cycle analysis and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and immunohistochemistry. Results: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA-wildtype cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA-wildtype brain tumors. Conclusions: The results of this study suggest that the brain-penetrant PI3K/mTOR-targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

https://ift.tt/2BMAojQ

Multiplexed Measurement of Signaling Targets and Cytotoxic T cells in Trastuzumab-treated Patients using Imaging Mass Cytometry

Purpose: Imaging Mass Cytometry (IMC) uses metal-conjugated antibodies to provide multidimensional, objective measurement of protein targets. We used this high-throughput platform to perform an 18-plex assessment of HER2 ICD/ECD, cytotoxic T cell infiltration and other structural and signaling proteins in a cohort of patients treated with trastuzumab to discover associations with trastuzumab benefit. Experimental Design: An antibody panel for detection of 18 targets (Pancytokeratin, HER2 ICD, HER2 ECD, CD8, vimentin, cytokeratin 7, beta-catenin, HER3, MET, EGFR, ERK 1-2, MEK 1-2, PTEN, PI3K p110 alpha, Akt, mTOR, Ki67 and Histone H3) was used with a selection of trastuzumab-treated patients from the HeCOG 10/05 trial (n=180), and identified a case:control series. Results: Patients that recurred after adjuvant treatment with trastuzumab trended toward a decreased fraction of HER2 ECD pixels over threshold compared to cases without recurrence (p=0.057). After exclusion of the lowest HER2 expressers, 5-year recurrence events where associated with reduced total ECD/ ICD ratio intensity in tumor (p=0.044). These observations are consistent with our previous work using QIF but represents the proof on identical cell content. We also describe the association of the extracellular domain of HER2 with CD8 T-cell infiltration on the same slide. Conclusions: The proximity of CD8 cells as a function of the expression of the ECD of HER2 provides further evidence for the role of the immune system in the mechanism of action of trastuzumab.

https://ift.tt/2U9DSUZ

Comparison of Biomarker Assays for EGFR: Implications for Precision Medicine in Patients with Glioblastoma

Purpose: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation between fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods. Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations between various methods were determined using Cohen's kappa (k = 0.61 - 0.80 defines substantial agreement) or R² statistics. Results: EGFR mRNA expression levels by RNAseq and RT-PCR were highly correlated with EGFR amplification assessed by FISH (k = 0.702). High concordance was also observed when comparing FISH to WES (k = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. Conclusions: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapy approaches.

https://ift.tt/2BK0Fz9

Overcoming BET inhibitor resistance in malignant peripheral nerve sheath tumors

Purpose: BET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in pre-clinical studies, including Neurofibromatosis Type 1 (NF1)-associated Malignant Peripheral Nerve Sheath Tumor (MPNST). However, potential mechanisms underlying resistance to these inhibitors in different cancers are not completely understood. In this study, we explore new strategy to overcome BET inhibitor resistance in MPNST. Experimental Design: Through modeling tumor evolution by studying genetic changes underlying the development of MPNST, a lethal sarcoma with no effective medical treatment, we identified a targetable addiction to BET bromodomain family member BRD4 in MPNST. This served as a controlled model system to delineate mechanisms of sensitivity and resistance to BET bromodomain inhibitors in this disease. Results: Here, we show that a malignant progression-associated increase in BRD4 protein levels corresponds to partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 protein levels synergistically sensitized MPNST cells to diverse BET inhibitors in culture and in vivo. Conclusions: Collectively, MPNST sensitivity to combination genetic and pharmacological inhibition of BRD4 revealed the presence of a unique addiction to BRD4 in MPNST. Our discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 protein levels nominates MPNST for the investigation of emerging therapeutic interventions such as proteolysis-targeting chimeras (PROTACs) that simultaneously target bromodomain activity and BET protein abundance.

https://ift.tt/2U4LtDU

Adherence to Enhanced Recovery Protocols in NSQIP and Association With Colectomy Outcomes

Objective: To evaluate the effect of protocol adherence on length of stay (LOS) and recovery-specific outcomes after colectomy. Background: Enhanced recovery protocols (ERPs) may decrease postoperative morbidity and LOS; however, the effect of overall protocol adherence remains unclear. Methods: Using American College of Surgeons' National Surgical Quality Improvement Program colectomy data (July 2014–December 2015) and 13 novel ERP variables, propensity scores were constructed for low (0–5), moderate (6–9), and high adherence (10–13 components). Prolonged LOS (>75th percentile, uncomplicated cases) was modeled with multivariable logistic regression with robust standard errors, adjusted for hospital-level clustering and propensity score. Secondary recovery-specific outcomes were modeled with negative binomial regression. Subgroup analysis was conducted on uncomplicated cases. Results: Among 8139 elective colectomies at 113 hospitals, LOS increased with decreasing adherence (4.3 days [SD 3.3] high adherence vs 7.8 [SD 6.8] low adherence; P

https://ift.tt/2tBX8hS

FDA: Gout Drug Uloric Increases Risk of Death

FRIDAY, Feb. 22, 2019 -- The gout medicine Uloric (febuxostat) carries a higher risk of death than allopurinol, according to the U.S. Food and Drug Administration. The agency said its in-depth review of results from a safety clinical trial found...

https://ift.tt/2E8b5ZS

Higher Triglycerides May Be Protective in the Very Elderly

FRIDAY, Feb. 22, 2019 -- Higher triglycerides (TGs) is associated with a decreased risk of cognitive decline, activities of daily living (ADL) decline, frailty aggravation, and mortality in the oldest old, according to a study recently published in...

https://ift.tt/2SW0uM0

Most Patients Do Not Disclose Complementary Medicine Use

FRIDAY, Feb. 22, 2019 -- Just one-third of users of biologically based complementary medicine (CM) disclose their use to traditional health care providers, according to a review published online Feb. 7 in Scientific Reports. Hope Foley, from the...

https://ift.tt/2E8Jh7R

Since Early 2000s, Overdose Death Rates Are Highest in U.S.

FRIDAY, Feb. 22, 2019 -- Since the early 2000s, the United States has had the highest drug overdose death rates among its peer countries, according to a study published online Feb. 21 in the Population and Development Review. Jessica Y. Ho, Ph.D.,...

https://ift.tt/2SW0ueY.

Impact of pre‐analytic variables on deep learning accuracy in histopathology

Abstract

Aims

Machine Learning (ML) binary classification in diagnostic histopathology is an area of intense investigation. Several assumptions, including training image quality/format and the number of training images required, appear similar in many studies irrespective of the paucity of supporting evidence.

Methods

We empirically compared training image file type, training set size, and two common Convolutional Neural Networks (CNN) using transfer learning (ResNet50, SqueezeNet). Thirty H&E slides with carcinoma or normal tissue from three tissue types (breast, colon, prostate) were photographed generating 3,000 partially overlapping images (1,000 per tissue type). These lossless PNGs were converted to lossy JPGs. Tissue type‐specific binary classification ML models were developed using all PNG or JPG images, and repeated with a subset of 500, 200, 100, 50, 30, and 10 images. Eleven models were generated for each tissue type, at each quantity of training images, for each file type, and for each CNN, resulting in 924 models. Internal accuracies and generalization accuracies were compared.

Results

There was no meaningful significant difference between accuracies in PNG vs JPG models. Models trained with more images did not invariably perform better. ResNet50 typically outperformed SqueezeNet. Models were generalizable within a tissue type but not across tissue types.

Conclusions

Lossy JPG images were not inferior to lossless PNG images in our models. Large numbers of unique H&E slides were not required for training optimal ML models. This reinforces the need for an evidence‐based approach to best practices for histopathologic ML.

This article is protected by copyright. All rights reserved.

https://ift.tt/2TZCFz7

Patient controlled analgesia for children with life-limiting conditions in the community: Results of a prospective observational study

The use of patient controlled analgesia (PCA) for children and young people with life-limiting conditions and life-threatening illnesses is an emerging intervention in paediatric palliative care as an alternative to continuous parental infusion with a separate breakthrough analgesia (1, 2). In paediatric palliative care PCA is characteristically a continuous infusion of opioid administered via a programmable pump which enables patients to control their pain by use of on-demand supplemental bolus analgesia (2, 3).

https://ift.tt/2T3wFbJ

Intensity of Cancer Care Near the End-of-Life at a Tertiary Care Cancer Center in Jordan

Chemotherapy use in the last month of life is an indicator of poor quality of end-of-life care. We assessed the frequency of chemotherapy use at the end-of-life at our comprehensive cancer center in Jordan, and identified the factors associated with chemotherapy use.

https://ift.tt/2IudmnD

The hand-held fan and the Calming Hand for people with chronic breathlessness: a feasibility trial

The battery operated hand-held fan ("fan") and the Calming Hand (CH), a cognitive strategy, are interventions used in clinical practice to relieve chronic breathlessness.

https://ift.tt/2TdW0zB

Yield of Surveillance Colonoscopies 1 Year After Curative Surgical Colorectal Cancer Resections

Endoscopic surveillance after curative colorectal cancer (CRC) resection is routine. However, there is controversy whether the 1-year interval between pre- and postoperative colonoscopy is justified, due to improved colonoscopy standards. We aimed to assess the yield of surveillance colonoscopies 1 year after CRC surgery.

https://ift.tt/2Iwims2

Should Pregnancy After Liver Transplantation Bring Joy or Fear?

https://ift.tt/2TbM49R

Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Trial

Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD.

https://ift.tt/2IxVUyA

A multisource fusion framework driven by user-defined knowledge for egocentric activity recognition

Recently, egocentric activity recognition has attracted considerable attention in the pattern recognition and artificial intelligence communities because of its widespread applicability to human systems, inclu...

https://ift.tt/2STdVMt

A fast STAP method using persymmetry covariance matrix estimation for clutter suppression in airborne MIMO radar

In general, the space-time adaptive processing (STAP) can achieve excellent clutter suppression and moving target detection performance in the airborne multiple-input multiple-output (MIMO) radar for the incre...

https://ift.tt/2E7DL5e

Isolating Malignant and Non-Malignant B Cells from lck:eGFP Zebrafish

Transgenic lck:eGFP zebrafish express GFP highly in T lymphocytes, and have been used to study T cell development and acute lymphoblastic leukemia. This line can be used to study B cells, which express lck at lower levels. This protocol describes purification of malignant and non-malignant B cells from lck:eGFP zebrafish.

https://ift.tt/2VfRj5x

Sample Preparation for Mass-spectrometry-based Proteomics Analysis of Ocular Microvessels

Proteome characterization of ocular microvascular beds is pivotal for in-depth understanding of many ocular pathologies in humans. This study demonstrates an effective, rapid, and robust method for protein extraction and sample preparation from small blood vessels employing the porcine short posterior ciliary arteries as model vessels for mass-spectrometry-based proteomics analyses.

https://ift.tt/2Eq3MhA

Spontaneous and Evoked Measures of Pain in Murine Models of Monoarticular Knee Pain

We have developed an evoked measure of arthritis pain and coupled it with a standardized method for measuring spontaneous pain in different murine models of chemically induced arthritis. These measures are sensitive and reproducible for different types of joint pain.

https://ift.tt/2twGsbT

Evaluation of Host-Pathogen Responses and Vaccine Efficacy in Mice

Here we present an elegant protocol for in vivo evaluation of vaccine effectiveness and host immune responses. This protocol can be adapted for vaccine models that study viral, bacterial, or parasitic pathogens.

https://ift.tt/2GV1rNc

Cholecystectomy in Pregnancy Tied to Worse Outcomes

FRIDAY, Feb. 22, 2019 -- Women who undergo cholecystectomy during the third trimester of pregnancy experience worse outcomes than women who wait until after delivery, according to a study published online Feb. 12 in the Journal of the American...

https://ift.tt/2NpU8i4

Excessively Sleepy OSA Subtype Tied to Increased CVD Risk

FRIDAY, Feb. 22, 2019 -- Obstructive sleep apnea (OSA) patients with excessive daytime sleepiness are at a substantially increased risk for cardiovascular disease (CVD) compared with individuals with other OSA subtypes, according to a study...

https://ift.tt/2NlzZcS

One-Third of PCPs Discuss Breast Cancer Treatments With Patients

FRIDAY, Feb. 22, 2019 -- One-third of primary care providers (PCPs) report participating in breast cancer treatment decisions, according to a study published online Feb. 1 in Cancer. Lauren P. Wallner, Ph.D., M.P.H., from the University of Michigan...

https://ift.tt/2GITGL8

Guideline Covers Extracutaneous Manifestations of Psoriasis

FRIDAY, Feb. 22, 2019 -- The extracutaneous manifestations of psoriasis and guidance on use of biologic treatment for management of psoriasis are discussed in two new guidelines published online Feb. 13 in the Journal of the American Academy of...

https://ift.tt/2Nku5sx

44.4 Million Estimated to Be Diagnosed With Cervical Cancer by 2069

FRIDAY, Feb. 22, 2019 -- In the absence of further intervention, in the next 50 years, an estimated 44.4 million women will be diagnosed with cervical cancer globally, according to a study published online Feb. 19 in The Lancet Oncology. Kate T....

https://ift.tt/2GFnFDA

Operative Treatment Seems Most Effective for Adult Lumbar Scoliosis

FRIDAY, Feb. 22, 2019 -- In as-treated analyses, surgery is superior to nonoperative care at two years among patients with adult symptomatic lumbar scoliosis, according to a study published in the Feb. 20 issue of The Journal of Bone & Joint...

https://ift.tt/2NkJBV8

Higher Salt Intake in DASH Diet Tied to More Lightheadedness

FRIDAY, Feb. 22, 2019 -- Higher sodium intake in the context of the Dietary Approaches to Stop Hypertension (DASH) diet is tied to more frequent and severe lightheadedness, according to a study published recently in the Journal of Clinical...

https://ift.tt/2GCrGJf

Odds of Receiving Tx for CAD Up With Medicare Advantage

FRIDAY, Feb. 22, 2019 -- For patients with coronary artery disease (CAD), those enrolled in Medicare Advantage (MA) are more likely to receive secondary prevention treatments than those enrolled in traditional fee-for-service (FFS) Medicare,...

https://ift.tt/2NjU1Eo

Hospital Program Does Not Cut Mortality for Acute Kidney Injury

FRIDAY, Feb. 22, 2019 -- A multifaceted intervention for acute kidney injury (AKI), which includes AKI e-alerts, an AKI care bundle, and an education program, does not reduce 30-day mortality but reduced AKI episode duration and hospital length of...

https://ift.tt/2GCrxpb

EMS Today 2019 Quick Take: Keeping female emergency services personnel safe

While exposed to the same on-the-job dangers as their male colleagues, female firefighters, EMTs and paramedics have different levels of risks

https://ift.tt/2IwfGdN

A New Portable In Vitro Exposure Cassette for Aerosol Sampling

Here, we present a protocol to perform portable cellular aerosol exposures and measure cellular response. The method uses cells, grown at the air-liquid interface, mimicking in vivo physiology. Cellular response to copper nanoparticle aerosols was observed as oxidative stress through reactive oxygen species generation and cytotoxicity as lactate dehydrogenase release.

https://ift.tt/2NlydbI

Using a Bacterial Pathogen to Probe for Cellular and Organismic-level Host Responses

We describe both in vitro and in vivo infection assays that can be used to analyze the activities of host-encoding factors.

https://ift.tt/2GD5zSR

Messenger RNA therapy for rare genetic metabolic diseases

Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called 'protein replacement therapy' could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.

https://ift.tt/2NkUciL

Response to the letter: Identification of trimethylamine N-oxide (TMAO)-producer phenotype is interesting, but is it helpful?

We thank Arduini et al1 for the feedback. The importance of identifying trimethylanine N-oxide (TMAO)-producer phenotype was challenged in doubt about the significance of TMAO in cardiovascular disease (CVD).1 2 The reason we regard TMAO as a potential harmful rather than a beneficial or bystander molecule for CVD is based on a careful literature review from both affirmative and negative sides.3 4 We appreciated the opportunity to extend our discussions about the role of TMAO in CVD.

The letter mentioned a study conducted by Collins et al5 that TMAO was inversely correlated to atherosclerosis in mice and concluded TMAO as protective for atherosclerosis. In this study, the plasma TMAO only reached 0.2ppm (2.66 µM) for the carnitine group that is far from the estimated pathological TMAO level (>10 µM). Besides, the negative correlation between TMAO and aortic root lesions was modest...

https://ift.tt/2GF7x54

Multimodality imaging of indolent B cell lymphoma from diagnosis to transformation: what every radiologist should know

Abstract

Indolent B cell lymphomas are a group of lymphoid malignancies characterized by their potential to undergo histologic transformation to aggressive lymphomas. While different subtypes of indolent B cell lymphomas demonstrate specific clinical and imaging features, histologic transformation can be suspected on cross-sectional imaging when disproportionate lymph node enlargement or new focal lesions in extranodal organs are seen. On PET/CT, transformed indolent lymphoma may show new or increased nodal FDG avidity or new FDG-avid lesions in different organs. In this article, we will (1) review the imaging features of different subtypes of indolent B cell lymphomas, (2) discuss the imaging features of histologic transformation, and (3) propose a diagnostic algorithm for transformed indolent lymphoma. The purpose of this review is to familiarize radiologists with the spectrum of clinical and imaging features of indolent B cell lymphomas and to define the role of imaging in raising concern for transformation and in guiding biopsy for confirmation.

https://ift.tt/2SRi57V

CT imaging findings of epiploic appendagitis: an unusual cause of abdominal pain

Abstract

Epiploic appendagitis is a rare cause of acute abdominal pain, determined by a benign self-limiting inflammation of the epiploic appendages. It may manifest with heterogeneous clinical presentations, mimicking other more severe entities responsible of acute abdominal pain, such as acute diverticulitis or appendicitis. Given its importance as clinical mimicker, imaging plays a crucial role to avoid inaccurate diagnosis that may lead to unnecessary hospitalization, antibiotic therapy, and surgery. CT represents the gold standard technique for the evaluation of patients with indeterminate acute abdominal pain. Imaging findings include the presence of an oval lesion with fat-attenuation surrounded by a thin hyperdense rim on CT ("hyperattenuating ring sign") abutting anteriorly the large bowel, usually associated with inflammation of the adjacent mesentery. A central high-attenuation focus within the fatty lesion ("central dot sign") can sometimes be observed and is indicative of a central thrombosed vein within the inflamed epiploic appendage. Rarely, epiploic appendagitis may be located within a hernia sac or attached to the vermiform appendix. Chronically infarcted epiploic appendage may detach, appearing as an intraperitoneal loose calcified body in the abdominal cavity. In this review, we aim to provide an overview of the clinical presentation and key imaging features that may help the radiologist to make an accurate diagnosis and guide the clinical management of those patients.

https://ift.tt/2E5Qtl1

BRAF gene mutations in synchronous papillary thyroid carcinoma and Langerhans cell histiocytosis co-existing in the thyroid gland: a case report and literature review

Abstract

Background

Langerhans cell histiocytosis (LCH) is a rare clonal disease, characterized by hyperproliferation of Langerhans cells. It may rarely involve the thyroid gland. Its association with papillary thyroid carcinoma (PTC) is extremely rare; with only few case reports available in the English literature. BRAF mutations are implicated in the development of papillary thyroid carcinoma, and have also been identified in Langerhans cell histiocytosis.

Case presentation

Here we present a rare case of a 36-year-old Indonesian female patient with dysphagia associated with neck mass which was complicated by skin sinus formation. The diagnosis of PTC was rendered on fine needle aspiration (FNA). Debulking thyroidectomy revealed co-existeence of PTC and LCH. On subsequent molecular testing, BRAF V600E and V600K mutations were detected in tissues macrodissected from both lesions, respectively. To the best of our knowledge, this case is the first case to report two different BRAF mutations in tissues of a Langerhans cell histiocytosis and a papillary thyroid carcinoma co-existing in the thyroid gland. The patient received chemotherapy of etoposide combined with prednisone. At the most recent follow-up, the patient is in a stable clinical condition.

Conclusions

The coexistence of a PTC with LCH harboring BRAF mutation may suggest etiologic relation between the two conditions that involves the BRAF gene. Clinically, it may suggest an aggressive, locally advanced thyroid cancer, an impression that may reflect on the selected surgical management, chemotherapy and BRAF mutation-targeting therapy to these patients.

https://ift.tt/2T9l8HB

MUC16 impacts tumor proliferation and migration through cytoplasmic translocation of P120-catenin in epithelial ovarian cancer cells: an original research

Abstract

Background

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic cancers, and its pathogenetic mechanism remains unclear. Here we show that MUC16 promotes the translocation of p120-catenin (p120ctn) to the cytoplasm and consequently activates ras homolog (Rho) GTPases RhoA/Cdc42 activation to modulate the proliferation and migration abilities of EOC cells.

Methods

We collect 94 ovarian cancer (OC) patients' tissue samples to constitute tissue microarray (TMA) and analyze the MUC16 and p120ctn expression levels. Lentivirus transfection is used to overexpress cytoplasmic tail domain (CTD) of MUC16 and CRISPR/Cas9 genome-editing system is firstly used to knock out MUC16 in EOC cells. The proliferation or migration ability of cells is analyzed by MTS or migration assay.

Results

We find that MUC16 and p120ctn are aberrantly overexpressed in 94 clinical OC samples compared with benign ovarian tumors (BOT). MUC16 is a critical inducer of the proliferation and migration of EOC cells and the CTD of MUC16 plays an important role during this process. In addition, we reveal the relationship between MUC16 and p120ctn, which has not previously been studied. We show that MUC16 promotes the translocation of p120ctn to the cytoplasm and consequently activates Rho GTPases to modulate the proliferation and migration abilities of EOC cells. The cell proliferation and migration abilities induced by MUC16 are mediated by p120ctn through RhoA/Cdc42 activation.

Conclusions

The highly expressed MUC16 promotes the translocation of p120ctn to the cytoplasm, where it activates RhoA/Cdc42 to modulate the proliferation and migration abilities of EOC cells. These findings may provide new targets for the treatment of EOC.

https://ift.tt/2IvYW6r

Sequential therapy with ramucirumab and/or checkpoint inhibitors for non-small-cell lung cancer in routine practice

Future Oncology, Ahead of Print.


https://ift.tt/2SjXkwf

Drosophila jumu modulates apoptosis via a JNK-dependent pathway and is required for other processes in wing development

Abstract

Previous studies in several model organisms have revealed that members of the Forkhead (Fkh) transcription factor family have multiple functions. Drosophila Jumeau (Jumu), a member of this family, participates in cardiogenesis, hematopoiesis and immune system homeostasis. Here, we show that loss of jumu function positively regulates or triggers apoptosis via a JNK-dependent pathway in wing development. jumu mutants showed reduced wing size and increased apoptosis. Moreover, we observed a loss of the anterior cross vein (ACV) phenotype that was similar to that observed in wings in which JNK signaling has been ectopically activated. The JNK signaling markers puckered (puc) and p-JNK were also significantly increased in the wing discs of jumu mutants. In addition, apoptosis induced by the loss of jumu was rescued by knocking down JNK, indicating a role for JNK in reducing jumu-induced apoptosis. Jumu could also control wing margin development via the positive regulation of cut expression, and the observed wing margin defect did not result from a loss of jumu-induced apoptosis. Further, jumu deficiency in the pupal wing could induce multiple wing hairs via a Rho1-mediated planar cell polarity pathway, but abnormal Rho1 expression was not why jumu loss induced apoptosis via a JNK-dependent pathway in wing discs.

https://ift.tt/2TYGR2o

Gamification: focus on the strategies being implemented in interventions: a systematic review protocol

Gamification broadly refers to the use of game design elements in non-game contexts with the goal of promoting users' engagement. Gamification strategies appear as an advantageous tool to increase the motivati...

https://ift.tt/2BMuVtA

Draft genome sequence of Enterococcus faecium SP15, a potential probiotic strain isolated from spring water

Enterococci are Gram-positive lactic acid bacteria and common inhabitants of the gastrointestinal tract of mammals, including humans. They are also widely distributed in diverse environments such as soil, wate...

https://ift.tt/2U2DQOx

Assessment of seat belt use and its associated factors among public transport drivers in North Gondar, Ethiopia: a cross-sectional study

Road traffic injuries are the major and neglected public health challenges. It causes 1.2 million deaths and 50 million injuries yearly and the use of seat belt reduces 60% of the cases. However, little is kno...

https://ift.tt/2BPdgkI

The methods and techniques of identifying renal pedicle vessels during retroperitoneal laparoscopic radical and partial nephrectomy

Abstract

Background

Retroperitoneal laparoscopic radical and partial nephrectomy (RLRN and RLPN) have become the preferred modes of management for renal malignancy. One of the most critical steps in the RLRN and RLPN process is to seek and control the renal pedicle. The current study focuses on introducing methods and techniques that can help quickly and accurately identify the renal pedicle vessels during RLRN and RLPN.

Methods

RLRNs and RLPNs were performed for 292 cases in our hospital from November 2014 to January 2017. Different measures were adopted to seek and manage bilateral renal pedicle vessels. All operation procedures were performed by the following three steps: dissection, opening, and clamping. For the left lateral, after the perirenal fat in the dorsal and lateral side was fully dissected, the kidney was pushed toward the ventral side. The renal artery was visible when opening the dense bulging connective tissue, which was located in the middle of the dorsal interior of the kidney. Then, the renal artery was clamped with a Hem-o-lok or the Bulldog clamp. For the right kidney pedicles, the inferior vena cava was first identified and then dissipated upward. When the inferior vena cava was not visible, it was often the location of the right renal artery. The treatment for the artery was the same as for the left renal artery. Relevant clinical characteristics of patients, such as operative time, intraoperative blood loss, and duration of postoperative drainage, were analyzed retrospectively. The three-step method of identifying renal pedicle vessels during retroperitoneal laparoscopic radical and partial nephrectomy was evaluated.

Results

All operations were successfully accomplished with satisfying results, during which the artery could be controlled quickly, and no cases were converted to open surgery due to severe bleeding of renal pedicle vessels. There were no complications involving renal vessels during the entire study. The mean operative times were (81.9 ± 19.71) min and (88.2 ± 21.28) min for RLRN and RLPN, with an average intraoperative blood loss of (91.7 ± 47.10) ml and (62.4 ± 47.45) ml, respectively. The warm ischemia time for RLPN was (19.3 ± 5.6) min. The postoperative drainage-tube was removed within (4.5 ± 1.29) d (RLRN) and (4.6 ± 1.98) d (RLPN); the mean postoperative hospital stay times were (7.0 ± 2.4) d and (5.9 ± 1.98) d, respectively.

Conclusion

The three-step method of identifying renal pedicle vessels during RLRN and RLPN is direct and feasible, and it may help simplify the operating procedure and improve the safety of the surgery. It may be of great practical application value in the clinical field.

https://ift.tt/2E3j3Uj

Optimal diagnostic method using multidetector-row computed tomography for predicting lymph node metastasis in colorectal cancer

Abstract

Background

Prediction of nodal involvement in colorectal cancer is an important aspect of preoperative workup to determine the necessity of preoperative treatment and the adequate extent of lymphadenectomy during surgery. This study aimed to investigate newer multidetector-row computed tomography (MDCT) findings for better predicting lymph node (LN) metastasis in colorectal cancer.

Methods

Seventy patients were enrolled in this study; all underwent MDCT prior to surgery and upfront curative resection for colorectal cancer. LNs with a short-axis diameter (SAD) ≥ 4 mm were identified on MDCT images, and the following measures were recorded by two radiologists independently: two-dimensional (2D) SAD, 2D long-axis diameter (LAD), 2D ratio of SAD to LAD, 2D CT attenuation value, three-dimensional (3D) SAD, 3D LAD, 3D SAD to LAD ratio, 3D CT attenuation value, LN volume, and presence of extranodal neoplastic spread (ENS), as defined by indistinct nodal margin, irregular capsular enhancement, or infiltration into adjacent structures.

Results

Forty-six patients presented 173 LNs with a SAD ≥ 4 mm, while 24 patients exhibited pathologically confirmed LN metastases. Receiver operating characteristic analysis revealed that 2D LAD was the most sensitive measure for LN metastases with an area under the curve of 0.752 (cut-off value, 7.05 mm). When combined with CT findings indicating ENS, 2D LAD (> or ≤ 7 mm) showed enhanced predictive power for LN metastases (area under the curve, 0.846; p < 0.001).

Conclusions

LAD in axial MDCT imaging is the most sensitive measure for predicting colorectal LN metastases, especially when MDCT findings of ENS are observed.

https://ift.tt/2SXFlAX

Aberrant fatty acid profile and FFAR4 signaling confer endocrine resistance in breast cancer

Abstract

Background

Evidence suggests that fatty acid receptor FFAR4 plays a tumor-promoting role in adipose tissue-adjacent malignancies, but its clinical relevance remains unexplored. Here, we investigated the clinical significance and underlying mechanisms of FFAR4 in hormone receptor-positive breast cancer (HRPBC).

Methods

FFAR4 expression was assessed by immunohistochemistry in an exploration cohort of 307 breast cancer cases collected from two independent institutes. Two public breast cancer microarray datasets served as validation cohorts. Gas chromatography-mass spectrometry was employed to identify FFAR4 ligands in normal and cancerous breast tissues. Survival analyses were performed in all cohorts and designated molecular subgroups. Mechanistic studies were performed in vitro in hormone receptor-positive breast cancer cell lines MCF-7 and T-47D.

Results

Aberrant FFAR4 expression and endogenous FFAR4 ligands were identified in breast cancer tissues, five FFAR4 ligands showed significantly elevated proportions in cancerous versus normal tissues. In the exploration cohort, FFAR4 was demonstrated as an independent prognostic factor for recurrences (HR: 2.183, 95% CI: 1.360–3.504, P = 0.001) and breast cancer-specific deaths (HR: 2.102, 95% CI: 1.173–3.766, P = 0.013) in HRPBC cases. In contrast, FFAR4 expression was not associated with prognosis in hormone receptor-negative cases. In the validation cohorts, FFAR4 mRNA levels were also observed to be associated with disease recurrence in estrogen receptor-positive cases, but not so in estrogen receptor-negative cases. FFAR4 activation by endogenous ligands and a synthetic ligand TUG891 significantly dampened tamoxifen's efficacy on HRPBC cells, whereas FFAR4 knockdown or antagonist AH7614 abrogated this effect. Furthermore, FFAR4-induced tamoxifen resistance was dependent on ERK and AKT pathways in HRPBC.

Conclusions

Our results establish a novel role of FFAR4 and its ligands in the complicated interactions between tissue lipid profile and cancer biology. FFAR4 signaling confers tamoxifen resistance in HRPBC cell line and FFAR4 expression can serve as a prognostic biomarker for tamoxifen-treated HRPBC patients. FFAR4 may serve as a potential target for anti-breast cancer therapies, especially in endocrine resistant cases.

https://ift.tt/2E4BJD7

Keratocystoma of the parotid gland is rare and requires an integrated multidisciplinary approach: Report of a case and a literature review

https://ift.tt/2STawxf

Parkinsonism Caused by Viral Encephalitis Affecting the Bilateral Substantia Nigra

https://ift.tt/2BRlGYV

Dangerous non-food products : Products with serious risks Click to enlarge 1 of 1 photo Share on Alert number: A12/0321/19 Category: Gadgets Product: Waterproof phone case Brand: Unknown Name: Waterproof Case Type / number of model: B74031 Batch number / Barcode: Unknown Risk type: Environment The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 0.32%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. The product does not comply with the Regulation on persistent organic pollutants (POP Regulation). Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor Click to enlarge 1 of 1 photo Share on Alert number: A12/0318/19 Category: Hand tools Produc

Products with serious risks 

1 of 1 photo Share on             Alert number: A12/0321/19        Category:  Gadgets   Product:  Waterproof phone case   Brand: Unknown   Name: Waterproof Case   Type / number of model:  B74031   Batch number / Barcode: Unknown   Risk type:  Environment   The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 0.32%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0318/19        Category:  Hand tools   Product:  Garden hose   Brand: Green>it   Name: Green hose set   Type / number of model:  9025811   Batch number / Barcode:  5708614912768   Risk type:  Environment   The hose contains short-chain chlorinated paraffins (SCCPs) (measured value up to 4.66%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment.  The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0300/19        Category:  Hobby/sports equipment   Product:  Fitness mat   Brand: Deuser   Name: Fitness-Matte   Type / number of model:  121041R   Batch number / Barcode:  4007480015704   Risk type:  Chemical, Environment   The plastic in the mat contains short-chain chlorinated paraffins (SCCPs) (measured value: 2.2%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. SCCPs are suspected human carcinogens. Prolonged exposure to them through the skin may cause cancer.  The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures ordered by public authorities (to: Other): Withdrawal of the product from the market

1 of 1 photo Share on             Alert number: A12/0330/19        Category:  Hobby/sports equipment   Product:  Bicycle saddle cover   Brand: Unknown   Name: Unknown   Type / number of model:  248   Batch number / Barcode: Unknown   Risk type:  Environment   The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 1.12%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the persecutor

1 of 1 photo Share on             Alert number: A12/0334/19        Category:  Hobby/sports equipment   Product:  Football   Brand: Unknown   Name: Unknown   Type / number of model:  9048306   Batch number / Barcode:  5706245581810   Risk type:  Chemical   The plastic ball contains di-2-ethylhexyl phthalate (DEHP) (measured value up to 0.13% by weight). This phthalate may harm the health of children, causing possible damage to their reproductive system.  The product does not comply with the REACH Regulation.   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 2 photos PreviousNext Share on             Alert number: A12/0332/19        Category:  Jewellery   Product:  Necklace   Brand: Jewelry Fashion   Name: Unknown   Type / number of model:  54314   Batch number / Barcode:  6 438278 543143   Risk type:  Chemical   The smaller round medallion contains cadmium (measured value: 94 % by weight). Cadmium is harmful to human health because it accumulates in the body, can damage organs and may cause cancer. The product does not comply with the REACH Regulation.   Measures ordered by public authorities (to: Importer): Import rejected at border

1 of 1 photo Share on             Alert number: A12/0319/19        Category:  Lighting equipment   Product:  LED helmet light   Brand: STEEDS   Name: Unknown   Type / number of model:  940150   Batch number / Barcode:  4052083104386   Risk type:  Environment   The solder in the product contains lead above limit values (measured value up to 46% by weight). Lead poses a risk to the environment.  The product does not comply with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0325/19        Category:  Lighting equipment   Product:  Foldable desk lamp   Brand: Unknown   Name: Unknown   Type / number of model:  93302   Batch number / Barcode:  PO702084   Risk type:  Environment   The solder contains lead (measured value up to 71% by weight) in concentrations above limit values. Lead poses a risk to the environment.  The product does not comply with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0329/19        Category:  Lighting equipment   Product:  Torch   Brand: Unknown   Name: Unknown   Type / number of model:  P513.822   Batch number / Barcode: Unknown   Risk type:  Environment   The solders contain cadmium (measured value up to 0.39% by weight) and lead (measured value up to 48% by weight) in concentrations above limit values. Cadmium and lead pose a risk to the environment.  The product does not comply with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0331/19        Category:  Lighting equipment   Product:  Torch   Brand: Unknown   Name: Unknown   Type / number of model:  341377VN   Batch number / Barcode: Unknown   Risk type:  Environment   The solder contains lead (measured value up to 50% by weight) in concentrations above limit values. Lead poses a risk to the environment.  The product does not comply with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 3 photos PreviousNext Share on             Alert number: A12/0337/19        Category:  Lighting equipment   Product:  Table lamp   Brand: ArtHome   Name: Lume   Type / number of model:  SM1451   Batch number / Barcode:  8034048202029 (on the product); 8034048202128 (on the packaging)   Risk type:  Burns, Electric shock   The insulation is inadequate. Moreover, the power cord can easily detach or become damaged, giving access to live parts. The user can touch live or hot parts and receive an electric shock or suffer burns. The product does not comply with the requirements of the Low Voltage Directive and the relevant European standard EN 60598-1.   Measures ordered by public authorities (to: Distributor): Recall of the product from end users, Withdrawal of the product from the market

Share on             Alert number: A12/0309/19        Category:  Motor vehicles   Product:  Passenger car   Brand: Porsche   Name: Cayenne - conventional and hybrid(PHEV), Macan   Type / number of model:  Cayenne: Type-approval numbers: e13*2007/46*1085* (92A M1G) e13*2007/46*1106* (92A N1G) e13*2007/46*1107* (92AH N1G) e13*2007/46*1108* (92AH M1G) Types: 92A, 92AN, 92AH, 92AHN, Macan: Type-approval numbers: e13*2007/46*1165 (M1) e13*2007/46*1164 (N1) Types: 95B, 95BN   Batch number / Barcode:  The vehicles in question were manufactured between January 2017 and February 2018.   Risk type:  Injuries   The retaining straps on the vehicle's ski bag may be defective. The ski bag may not stay in position when subjected to a high load.   Measures taken by economic operators: Recall of the product from end users (By: Manufacturer)

1 of 2 photos PreviousNext Share on             Alert number: A12/0315/19        Category:  Protective equipment   Product:  Inflatable armbands   Brand: Numerous Star   Name: Arm circle   Type / number of model:  8" X 6"   Batch number / Barcode:  50112393   Risk type:  Chemical   The valve of the inflatable armband contains di(2-etylhexyl) phthalate-DEHP (measured value 21 % by weight) and di-'isononyl' phthalate (DINP) (measured value: 0.3 % by weight). These phthalates may harm the health of children, causing possible damage to the reproductive system and the liver. The product does not comply with the REACH Regulation and the Personal Protective Equipment regulation.   Measures ordered by public authorities (to: Retailer): Withdrawal of the product from the market

1 of 1 photo Share on             Alert number: A12/0322/19        Category:  Protective equipment   Product:  Safety reflector   Brand: Unknown   Name: Unknown   Type / number of model:  731211-z   Batch number / Barcode: Unknown   Risk type:  Environment   The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 0.38%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0328/19        Category:  Protective equipment   Product:  Safety reflector   Brand: Unknown   Name: Unknown   Type / number of model:  288   Batch number / Barcode: Unknown   Risk type:  Environment   The solders contain lead (measured value up to 81%) above limit values and the plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 0.931%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. Lead poses a risk to the environment.  The product does not comply with the Regulation on persistent organic pollutants (POP Regulation) and with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 7 photos PreviousNext Share on             Alert number: A12/0312/19        Category:  Childcare articles and children's equipment   Product:  Baby carrier   Brand: Kekk   Name: Backpack Plus Black   Type / number of model:  Backpack Plus / Baby Pack Plus 015-014-004   Batch number / Barcode:  8 718531 445109   Risk type:  Injuries   The frame of the product is not strong enough and has no locking mechanism. It could break or spontaneously fold while still carrying a baby, causing the baby to fall. The product does not comply with the relevant European Standard EN 13209-1.   Measures taken by economic operators: Recall of the product from end users (By: Manufacturer)

1 of 3 photos PreviousNext Share on             Alert number: A12/0298/19        Category:  Toys   Product:  Inflatable swim-ring   Brand: Sainteve   Name: Swim Ring   Type / number of model:  ITEM N0: SY-A1098   Batch number / Barcode: Unknown   Risk type:  Chemical   The plastic of the swim-ring and the valve contain bis (2-ethylhexyl) phthalate (DEHP) (measured value: 5% and 0.9% by weight, respectively). This phthalate may harm the health of children, causing possible damage to their reproductive system. The product does not comply with the REACH Regulation.   Measures ordered by public authorities (to: Retailer): Withdrawal of the product from the market

1 of 3 photos PreviousNext Share on             Alert number: A12/0299/19        Category:  Toys   Product:  Toy Microphone   Brand: Johntoy   Name: Microphone - Mit light - Avec lumiére - Con luz   Type / number of model:  Item Number: 29389   Batch number / Barcode:  8 711866 293896   Risk type:  Chemical, Environment, Injuries   The microphone can easily break, causing the button batteries to become accessible. A child may put them in the mouth, causing damage to the gastrointestinal tract. Additionally, the solder in three different places inside the toy contains too much lead (measured value up to: 70% by weight). Lead poses a risk to the environment.  The product does not comply with the requirements of the Toy Directive, the relevant European standard EN 62115 and the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures ordered by public authorities (to: Importer): Recall of the product from end users

1 of 3 photos PreviousNext Share on             Alert number: A12/0303/19        Category:  Toys   Product:  Glow stick   Brand: Unknown   Name: Unknown   Type / number of model:  2151-7/1.75   Batch number / Barcode:  8591044542172   Risk type:  Chemical, Choking   The battery compartment can easily be opened without the use of any tools, leaving button cell batteries accessible. A child may put these in the mouth, which could cause damage to the child's gastrointestinal tract. They may also cause choking if swallowed by a small child. The product does not comply with the requirements of the Toy Safety Directive and with the relevant European standard EN 71-1 and EN 62115.   Measures ordered by public authorities (to: Retailer): Withdrawal of the product from the market

1 of 4 photos PreviousNext Share on             Alert number: A12/0304/19        Category:  Toys   Product:  Toy pushchair with doll   Brand: Unknown   Name: Baby Small Cart   Type / number of model:  No. S876   Batch number / Barcode:  6998880080035   Risk type:  Chemical, Injuries   The pushchair is not sufficiently resistant to load and can easily collapse, causing injuries. In addition, the doll contains di-(2-ethylhexyl) phthalate (DEHP) (measured value up to 4.8% by weight). This phthalate may harm the health of children, causing possible damage to their reproductive system.   Measures ordered by public authorities (to: Distributor): Recall of the product from end users, Withdrawal of the product from the market

1 of 3 photos PreviousNext Share on             Alert number: A12/0305/19        Category:  Toys   Product:  Toy slime   Brand: Unknown   Name: Crystal Mud   Type / number of model:  CX-1731   Batch number / Barcode:  6 951325 166800   Risk type:  Chemical   The migration of boron from the toy slime is too high (measured value: 879 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 4 photos PreviousNext Share on             Alert number: A12/0307/19        Category:  Toys   Product:  Toy slime   Brand: Unknown   Name: Pu Noise Putty   Type / number of model:  LCP-001   Batch number / Barcode:  Lot No. 0019/12 8 435124 170858   Risk type:  Chemical   The migration of boron from the toy slime is too high (measured value: 981 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 1 photo Share on             Alert number: A12/0308/19        Category:  Toys   Product:  Children's fancy-dress costume   Brand: Star Wars   Name: Executioner Trooper   Type / number of model:  Item No 640110   Batch number / Barcode:  Code: 8 83028 23993, Lot No 7045   Risk type:  Burns   The fancy-dress costume is easily flammable and the flame propagation is too high. If it catches fire, the child could suffer burns. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-2.   Measures taken by economic operators: Withdrawal of the product from the market (By: Retailer)

1 of 7 photos PreviousNext Share on             Alert number: A12/0310/19        Category:  Toys   Product:  Toy slime   Brand: Unknown   Name: Slyme clay   Type / number of model:  55-2   Batch number / Barcode:  6 958455 624569, 6 987542 687507   Risk type:  Chemical   The migration of boron from the toy slime is too high (measured value: up to 546 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 3 photos PreviousNext Share on             Alert number: A12/0313/19        Category:  Toys   Product:  Plastic doll   Brand: ABABABY, SMILE   Name: Annie Baby   Type / number of model:  Item Nr.: KJ883, HKJ368D, YKJ368B   Batch number / Barcode:  6920778206622   Risk type:  Chemical   The plastic material of the doll's head contains 2-ethylhexyl phthalate (DEHP) (measured value: 31 % by weight). This phthalate may harm the health of children, causing possible damage to the reproductive system. The product does not comply with the REACH Regulation.   Measures ordered by public authorities (to: Distributor): Recall of the product from end users, Withdrawal of the product from the market

1 of 2 photos PreviousNext Share on             Alert number: A12/0314/19        Category:  Toys   Product:  Soft toy   Brand: Baby Gong Wei Gang   Name: Unknown   Type / number of model:  V51-3   Batch number / Barcode: Unknown   Risk type:  Choking   The eyes and nose of the toy can easily detach. In addition, the fibrous stuffing material of the toy is easily accessible due to the weakness of the plastic zipper. A small child may put the small parts in the mouth and choke. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-1.   Measures ordered by public authorities (to: Distributor): Recall of the product from end users, Withdrawal of the product from the market

1 of 1 photo Share on             Alert number: A12/0333/19        Category:  Toys   Product:  Wooden toy rattle   Brand: Classic World   Name: Unknown   Type / number of model:  3053   Batch number / Barcode:  6927049001185   Risk type:  Choking   The product contains a small wooden ball that can easily fall out between the bars of the rattle. A small child could put it in the mouth and choke on it. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-1.   Measures taken by economic operators: Recall of the product from end users (By: Distributor)

1 of 3 photos PreviousNext Share on             Alert number: A12/0338/19        Category:  Toys   Product:  Toy slime   Brand: Unknown   Name: Unknown   Type / number of model:  Unknown   Batch number / Barcode:  6 958455 624569   Risk type:  Chemical   The migration of boron from the toy slime is too high (measured value: 533 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 4 photos PreviousNext Share on             Alert number: A12/0339/19        Category:  Toys   Product:  Toy Slime   Brand: Unknown   Name: Unicorn Crystal Mud   Type / number of model:  Unknown   Batch number / Barcode:  6 958455 624569   Risk type:  Chemical   The migration of boron from the toy slime is too high (measured value: 506 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system.  The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 6 photos PreviousNext Share on             Alert number: A12/0341/19        Category:  Toys   Product:  Toy slime   Brand: Unknown   Name: CRYSTAL SOIL - HELLO SUMMER   Type / number of model:  PL00605   Batch number / Barcode:  2 900000 225268   Risk type:  Chemical   The migration of boron from the toy slimes is too high (measured value: up to 874 mg/kg for red). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system.  The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 6 photos PreviousNext Share on             Alert number: A12/0342/19        Category:  Toys   Product:  Toy slime   Brand: Unknown   Name: CRYSTAL MUD   Type / number of model:  PL00604   Batch number / Barcode:  2 900000 225251   Risk type:  Chemical   Due to the container's characteristic form, appearance and size, this product may be mistaken for a foodstuff. This may lead consumers, and specially children, to put them in the mouth and ingest its content. The migration of boron from the toy slime is too high (measured value: up to 1461 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system.  The product does not comply with the requirements of the Food Imitating Products Directive, the Toy Safety Directive and the relevant European standard EN 71-3.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 3 photos PreviousNext Share on             Alert number: A12/0345/19        Category:  Toys   Product:  Play tent   Brand: Eureka Kids   Name: My Little Explorer   Type / number of model:  Ref. 94570874   Batch number / Barcode:  8435404813369   Risk type:  Choking   Some pieces of velcro on the tent can become detached, generating a small part. A small child may put them in the mouth and choke. The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-1.   Measures ordered by public authorities (to: Importer): Import rejected at border

1 of 6 photos PreviousNext Share on             Alert number: A12/0346/19        Category:  Toys   Product:  Toy slime   Brand: HTI   Name: Teamsterz Slime   Type / number of model:  1374304   Batch number / Barcode:  Batch: 05BB1 5 050837 430414   Risk type:  Chemical   The migration of boron from the toy slime is too high (measured value up to 2165 mg/kg). Ingestion or contact with an excessive quantity of boron may harm the health of children by damaging their reproductive system.  The product does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-3.   Measures taken by economic operators: Voluntary withdrawal (By: Manufacturer)

1 of 2 photos PreviousNext Share on             Alert number: A12/0301/19        Category:  Clothing, textiles and fashion items   Product:  Children's dress   Brand: Cutey Pie   Name: Unknown   Type / number of model:  50JTC1005   Batch number / Barcode:  3 664795 008992   Risk type:  Chemical   The dress contains azo-dyes releasing the aromatic amine 4-methyl-m-phenylenediamine (2,4-toluenediamine) (measured concentration: 342 mg/kg). When in direct and prolonged contact with the skin, the aromatic amines may be absorbed by the skin. Aromatic amines can cause cancer, cell mutations and affect reproduction. The product does not comply with the REACH Regulation.   Measures ordered by public authorities (to: Other): Withdrawal of the product from the market

1 of 3 photos PreviousNext Share on             Alert number: A12/0335/19        Category:  Clothing, textiles and fashion items   Product:  Children's sweatshirt   Brand: Hello baby   Name: Unknown   Type / number of model:  XH-9119   Batch number / Barcode:  2100005300094, 5272017091196   Risk type:  Strangulation   The drawstrings may become trapped during various activities of the child, leading to strangulation. The product does not comply with European standard EN 14682.   Measures ordered by public authorities (to: Distributor): Withdrawal of the product from the market

1 of 1 photo Share on             Alert number: A12/0320/19        Category:  Communication and media equipment   Product:  iPad holder   Brand: Unknown   Name: Unknown   Type / number of model:  R.320.601   Batch number / Barcode: Unknown   Risk type:  Environment   The holder contains short-chain chlorinated paraffins (SCCPs) (measured value up to 2.75%). The placing on the market and use of articles containing SCCPs is banned. SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment.  The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market, Withdrawal of the product from the market (By: Distributor, Importer) Measures ordered by public authorities (to: Distributor): Recall of the product from end users

1 of 1 photo Share on             Alert number: A12/0323/19        Category:  Communication and media equipment   Product:  Earbuds   Brand: Unknown   Name: Unknown   Type / number of model:  P326.231   Batch number / Barcode:  8714612097212   Risk type:  Environment   The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 1.89%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0324/19        Category:  Communication and media equipment   Product:  Earbuds   Brand: Unknown   Name: Unknown   Type / number of model:  1899   Batch number / Barcode: Unknown   Risk type:  Environment   The solder contains lead (measured value up to 83% by weight) in concentrations above limit values. Lead poses a risk to the environment.  The product does not comply with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0326/19        Category:  Communication and media equipment   Product:  Headphones   Brand: Unknown   Name: Unknown   Type / number of model:  86004-14   Batch number / Barcode:  7393107720340   Risk type:  Environment   The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 0.32%). SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment. The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 1 photo Share on             Alert number: A12/0327/19        Category:  Communication and media equipment   Product:  Headphones   Brand: Unknown   Name: Unknown   Type / number of model:  91268   Batch number / Barcode:  PO6022829   Risk type:  Environment   The solder contains lead (measured value up to 54% by weight) in concentrations above limit values. Lead poses a risk to the environment.  The product does not comply with the requirements of the Commission Directive on the restriction of the use of certain hazardous substances in electrical and electronic equipment (RoHS 2 Directive).   Measures taken by economic operators: Withdrawal of the product from the market (By: Importer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 2 photos PreviousNext Share on             Alert number: A12/0302/19        Category:  Cosmetics   Product:  Body lotion   Brand: Judith Leiber   Name: Night   Type / number of model:  150 ml reference 17X610203   Batch number / Barcode:  barcode 899219002819   Risk type:  Chemical   The body lotion contains isobutylparaben which has a potential endocrine disrupting activity. At the same time, the product contains limonene, linalool, coumarin, citronellol, alpha-isomethyl ionone (measured values: more than 0.001% by weight). These substances can induce allergic reactions and sensitisation. Consumers are not aware of their presence because they are not indicated in the list of ingredients. The product does not comply with the Cosmetic Products Regulation.   Measures taken by economic operators: Recall of the product from end users (By: Retailer)

1 of 1 photo Share on             Alert number: A12/0317/19        Category:  Electrical appliances and equipment   Product:  Power supply   Brand: Unknown   Name: Powerbank   Type / number of model:  PB0041   Batch number / Barcode: Unknown   Risk type:  Environment   The plastic contains short-chain chlorinated paraffins (SCCPs) (measured value up to 1.65 % by weight). The placing on the market and use of articles containing SCCPs is banned. SCCPs persist in the environment, are toxic to aquatic organisms at low concentrations and bioaccumulate in wildlife and humans, posing a risk to human health and the environment.  The product does not comply with the Regulation on persistent organic pollutants (POP Regulation).   Measures taken by economic operators: Withdrawal of the product from the market (By: Manufacturer) Measures ordered by public authorities (to: Other): The company is reported to the prosecutor

1 of 3 photos PreviousNext Share on             Alert number: A12/0336/19        Category:  Electrical appliances and equipment   Product:  Power Inverter   Brand: Clear view   Name: Unknown   Type / number of model:  H130609520 and H130609476   Batch number / Barcode:  5 999885 948178   Risk type:  Electric shock   Single-pole or partial insertion of a plug into the product's socket is possible. When using the inverter, live pins of the inserted plug could remain accessible, which could result in the user receiving an electric shock. The product does not comply with the requirements of the Low Voltage Directive and the relevant standards EN 60950 and IEC 60884.   Measures ordered by public authorities (to: Distributor): Recall of the product from end users, Withdrawal of the product from the market

1 of 3 photos PreviousNext Share on             Alert number: A12/0340/19        Category:  Electrical appliances and equipment   Product:  Electric shaver   Brand: Surker   Name: RECHARGEABLE SHAVER   Type / number of model:  RSCW-2015 REF: 10105   Batch number / Barcode:  6 955519 320153 (on the packaging); 5 995858 101052 (on a label)   Risk type:  Electric shock   The dimensions of the socket outlet on the mains lead of the shaver are not suitable. The user could consequently touch live parts while connecting the mains lead to the shaver, leading to electric shock. The insulation between live parts and the accessible metal housing is insufficient. Consequently accessible parts could become live, this could cause the user to receive an electric shock when holding the shaver. The product does not comply with the requirements of the Low Voltage Directive and the relevant European standard EN 60335.   Measures ordered by public authorities (to: Distributor): Recall of the product from end users, Withdrawal of the product from the market

1 of 2 photos PreviousNext Share on             Alert number: A12/0344/19        Category:  Electrical appliances and equipment   Product:  Electrical plug cover   Brand: Eastern   Name: 13A Socket Cover Safety Plug   Type / number of model:  SW201   Batch number / Barcode:  3 579901 283883   Risk type:  Electric shock   The product does not have shutters on live parts, nor a fuse. A user could touch live parts of the socket and receive an electric shock. The product does not comply with the relevant National standards BS 1363-3 and BS 8546.   Measures ordered by public authorities (to: Importer): Withdrawal of the product from the market

Products with other risk levels 

1 of 1 photo Share on             Alert number: A11/0009/19        Category:  Toys   Product:  Soft toy animal   Brand: Greenlife   Name: Hibou brun (brown owl)   Type / number of model:  ref 11053413   Batch number / Barcode: Unknown   Risk type:  Choking   The stuffing material is easily accessible. Young children may put it in the mouth, ingest it and choke on it.  The toy does not comply with the requirements of the Toy Safety Directive and the relevant European standard EN 71-1.    Measures taken by economic operators: This product listing was removed by Amazon., Withdrawal of the product from the market (By: Other)