EED and EZH2 constitutive variants: A study to expand the Cohen‐Gibson syndrome phenotype and contrast it with Weaver syndrome

Overgrowth‐intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen‐Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.

https://ift.tt/2T7z3y2

Content variations in compositions and volatile component in jujube fruits during the blacking process

To facilitate the monitoring of ingredients to provide optimal health products, the thermal processing of black jujube was simulated. The results showed changes in the ingredients with the aging of jujube fruits and support the development of this nutrition product.

Abstract

Dried jujube (Ziziphus jujuba) was incubated at high temperature and humidity for 96 hr in blacking process and sampled every 12 hr. Results showed that the saccharose reduced from 195.6 to 3.1 g/kg rapidly in 24 hr. The total acid content was mild with 8.82 g/kg and increased to 23.45 g/kg by 177.21% with thermal processing for 96 hr. The contents of total polyphenols were enhanced during 0–48 hr processing, and the amount of the compound increased with treatment by 50.99%. The total reducing sugar increased 29.79% on 60 hr. cAMP was decreased with aging and ripening by 65.85%. 5‐HMF was keep growing to 3.52 g/kg. The volatile component had great change in black jujube fruits compared to untreated jujubes, especially treated in 12 hr. The results indicated that backing pretreatment can facilitate the generation of functional food materials and support the development of this nutrition product.

https://ift.tt/2VhotSF

A novel microscopic assay reveals heterogeneous regulation of local endothelial barrier function

Blood vessels are covered with endothelial cells on their inner surfaces forming a selective and semipermeable barrier between the blood and the underlying tissue. Many pathological processes such as inflammation or cancer metastasis are accompanied by an increased vascular permeability. Progress in live cell imaging techniques has recently revealed that the structure of endothelial cell contacts is constantly reorganized and that endothelial junctions display high heterogeneities at a subcellular level even within one cell.

https://ift.tt/2BLyUXe

Keeping tabs on the mabs: a hematopathologist’s dilemma

https://ift.tt/2SUAn7Y

Incidence and relative risk for developing cancers in women with gestational diabetes mellitus: a nationwide cohort study in Taiwan

Objectives

To evaluate the risk of developing cancers, particularly site-specific cancers, in women with gestational diabetes mellitus (GDM) in Taiwan.

Setting

The National Health Insurance Research Database (NHIRD) of Taiwan.

Participants

This study was conducted using the nationwide data from 2000 to 2013. In total, 1 466 596 pregnant women with admission for delivery were identified. Subjects with GDM consisted of 47 373 women, while the non-exposed group consisted of 943 199 women without GDM. The participants were followed from the delivery date to the diagnosis of cancer, death, the last medical claim or the end of follow-up (31 December 2013), whichever came first.

Primary outcome measures

Patients with a new diagnosis of cancer (International Classification of Diseases, ninth edition, with clinical modification (ICD-9-CM codes 140–208)) recorded in NHIRD were identified. The risk of 11 major cancer types was assessed, including cancers of head and neck, digestive organs, lung and bronchus, bone and connective tissue, skin, breast, genital organs, urinary system, brain, thyroid gland and haematological system.

Results

The rates of developing cancers were significantly higher in women with GDM compared with the non-GDM group (2.24% vs 1.96%; p<0.001). After adjusting for maternal age at delivery and comorbidities, women with GDM had increased risk of cancers, including cancers of nasopharynx (adjusted HR, 1.739; 95 % CI, 1.400 to 2.161; p<0.0001), kidney (AHR, 2.169; 95 % CI, 1.428 to 3.293; p=0.0003), lung and bronchus (AHR, 1.372; 95 % CI, 1.044 to 1.803; p=0.0231), breast (AHR, 1.234; 95% CI, 1.093 to 1.393; p=0.007) and thyroid gland (AHR, 1.389; 95 % CI, 1.121 to 1.721; p=0.0026).

Conclusion

Women with GDM have a higher risk of developing cancers. Cancer screening is warranted in women with GDM. Future research should be aimed at establishing whether this association is causal.

https://ift.tt/2SjKLB4

Prevalence and risk factors for pterygium: a cross-sectional study in Han and Manchu ethnic populations in Hebei, China

Aims

To investigate the prevalence, ethnic differences and associated risk factors for pterygium in Han and Manchu populations aged 40–79 years in Hebei province, China.

Design

Cross-sectional study, as a part of the China National Health Survey.

Setting

Hebei province, China.

Participants

A multistage cluster sampling method with urbanisation level-based stratification was used to select participants for this study. A total of 4591 individuals over 40 years were recruited for this study. Inclusive criteria: (1) residents who had been living in Hebei for more than 1 year; (2) Han individuals with both parents being Han, or Manchu individuals with both parents being Manchu; (3) underwent ophthalmic examinations and (4) information in the questionnaire was complete.

Main outcome measures

Multiple logistic regression analysis was used to evaluate the association between pterygium prevalence and factors of interest.

Results

A total of 3790 individuals (2351 Hans and 1439 Manchus) met the study criteria, of which 248 were diagnosed with pterygium (6.5%). There was no significant difference between the prevalence rates in Hans (6.2%) and Manchus (7.2%) (p=0.232). Multivariate analysis revealed that the risk factors for grade 2 or higher pterygium were increasing age (p<0.001) and rural residence (OR 1.83; 95% CI 1.11 to 3.02; p=0.018), while the protective factors include gender (female) (OR 0.58; 95% CI 0.37 to 0.88; p=0.011), cigarette smoking (OR 0.53; 95% CI 0.34 to 0.83; p=0.005) and myopia (OR 0.50; 95% CI 0.33 to 0.77; p=0.002). Premature menopause (OR 2.66; 95% CI 1.05 to 6.72; p=0.038) increased the risk of grade 2 or higher pterygium in females, while higher high-density lipoprotein (HDL) (OR 1.94; 95% CI 1.08 to 3.47; p=0.027) was a risk factor of grade 2 or higher pterygium in males.

Conclusion

The overall prevalence of pterygium in Han and Manchu population in Hebei, China was approximately 6.1%. There were no differences in the prevalence of pterygium between Hans and Manchus, and the race was not a risk factor. This is the first study to report on the positive association between premature menopause and pterygium in females and between higher HDL levels and pterygium in males.

https://ift.tt/2SiKfDk

Identifying the risk factors for catheter-associated urinary tract infections: a large cross-sectional study of six hospitals

Motivation

Catheter-associated urinary tract infections (CAUTI) are a common and serious healthcare-associated infection. Despite many efforts to reduce the occurrence of CAUTI, there remains a gap in the literature about CAUTI risk factors, especially pertaining to the effect of catheter dwell-time on CAUTI development and patient comorbidities.

Objective

To examine how the risk for CAUTI changes over time. Additionally, to assess whether time from catheter insertion to CAUTI event varied according to risk factors such as age, sex, patient type (surgical vs medical) and comorbidities.

Design

Retrospective cohort study of all patients who were catheterised from 2012 to 2016, including those who did and did not develop CAUTIs. Both paediatric and adult patients were included. Indwelling urinary catheterisation is the exposure variable. The variable is interval, as all participants were exposed but for different lengths of time.

Setting

Urban academic health system of over 2500 beds. The system encompasses two large academic medical centres, two community hospitals and a paediatric hospital.

Results

The study population was 47 926 patients who had 61 047 catheterisations, of which 861 (1.41%) resulted in a CAUTI. CAUTI rates were found to increase non-linearly for each additional day of catheterisation; CAUTI-free survival was 97.3% (CI: 97.1 to 97.6) at 10 days, 88.2% (CI: 86.9 to 89.5) at 30 days and 71.8% (CI: 66.3 to 77.8) at 60 days. This translated to an instantaneous HR of. 49%–1.65% in the 10–60 day time range. Paraplegia, cerebrovascular disease and female sex were found to statistically increase the chances of a CAUTI.

Conclusions

Using a very large data set, we demonstrated the incremental risk of CAUTI associated with each additional day of catheterisation, as well as the risk factors that increase the hazard for CAUTI. Special attention should be given to patients carrying these risk factors, for example, females or those with mobility issues.

https://ift.tt/2XkugbA

Cohort profile: design and methods in the eye and vision consortium of UK Biobank

Purpose

To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank.

Participants

UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc–macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun.

Findings to date

A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process.

Future plans

UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and sample collection will be performed in subsets of 25 000 participants every 2–3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to investigate the eye diseases in later life.

https://ift.tt/2SiSPlu

Global sustainability (health, environment and monetary costs) of three dietary patterns: results from a Spanish cohort (the SUN project)

Objective

To evaluate the sustainability of the dietary patterns, according to their effects on health and environment and their affordability.

Design

Prospective, ongoing cohort study of university graduates.

Settings

The Spanish SUN project (Seguimiento Universidad de Navarra, University of Navarra Follow-up), starting from 1999.

Participants

A total of 18 429 participants.

Methods

Information from participants is collected every 2 years by validated questionnaires. We assessed three dietary patterns (the Mediterranean, the Western and the Provegetarian dietary patterns). The rate advancement period (RAP) was used to assess the healthiness of each pattern (considering the composite endpoint of all-cause mortality, cardiovascular disease, breast cancer or type 2 diabetes). We also assessed environmental footprints and monetary costs of each dietary pattern.

Results

After a median follow-up of 10.1 years, we identified 469 incident cases of the composite endpoint. The Mediterranean dietary pattern exhibited the best RAP (3.10 years gained [95% CI 4.35 to 1.85] for the highest vs the lowest quartile), while the Western pattern was the unhealthiest pattern (1.33 years lost when comparing extreme quartiles). In a scale between 4 and 16 of harmful environmental effects (the lower, the more environmentally friendly), the Provegetarian pattern scored best (8.82 [95% CI 8.75 to 8.88] when comparing extreme quartiles), whereas the Western pattern was the most detrimental pattern (10.80 [95% CI 10.72 to 10.87]). Regarding monetary costs, the Western pattern was the most affordable pattern (5.87/day [95% CI 5.82 to 5.93], for the upper quartile), while the Mediterranean pattern was the most expensive pattern (7.52/day [95% CI 7.47 to 7.56]). The Mediterranean dietary pattern was the most overall sustainable option, closely followed by the Provegetarian pattern. The least overall sustainable pattern was the Western dietary pattern.

Conclusion

Following plant-based diets, like the Mediterranean or Provegetarian dietary patterns, could be a good option in order to achieve an overall sustainable diet.

Trial registration number

NCT02669602; Results.

https://ift.tt/2SlM8iZ

Comparative risk of new-onset diabetes following commencement of antipsychotics in New Zealand: a population-based clustered multiple baseline time series design

Objective

Newer antipsychotics are increasingly prescribed off-label for non-psychotic ailments both in primary and secondary care settings, despite the purported risk of weight gain and development of type 2 diabetes mellitus. This study aims to determine any relationship between the development of clinically significant new-onset type 2 diabetes mellitus and novel antipsychotic use in New Zealand using hypnotic drugs as control.

Design

A population-based clustered multiple baseline time series design.

Setting

Routinely collected data from a complete national pharmaceutical database in New Zealand between 2005 and 2011.

Participants

Patients aged 40–60 years in the year 2006 who were ever dispensed antipsychotics (exposure groups—first-generation antipsychotics, second-generation antipsychotics and antipsychotics with low, medium and high risk for weight gain) or hypnotics (control group) between 2006 and 2011.

Main outcome measure

First ever metformin dispensed to patients in each study group between 2006 and 2011 as proxy for development of clinically significant type 2 diabetes mellitus, no longer amendable by lifestyle modifications.

Results

Patients dispensed a second-generation antipsychotic had 1.49 times increased risk (95% CI 1.10 to 2.03, p=0.011) of subsequently commencing metformin. Patients dispensed an antipsychotic with high risk of weight gain also had a 2.41 times increased risk of commencing on metformin (95% CI 1.42 to 4.09, p=0.001).

Conclusions

Patients dispensed a second-generation antipsychotic and antipsychotics with high risk of weight gain appear to be at increased risk of being secondarily dispensed metformin. Caution should be taken with novel antipsychotic use for patients with increased baseline risk of type 2 diabetes mellitus.

https://ift.tt/2XjmvCL

Screening and receiving information for intimate partner violence in healthcare settings: a cross-sectional study of Arab and Jewish women of childbearing age in Israel

Objectives

We studied the proportion of women who have ever been screened (ES) for intimate partner violence (IPV) in a healthcare setting, received information (RI) about relevant services, or both, and explored disparities in screening and information provision by ethnicity and other characteristics.

Design

In 2014–2015, we undertook a cross-sectional study, conducting interviews using a structured questionnaire among a stratified sample of 1401 Arab and Jewish women in Israel.

Setting

A sample of 63 maternal and child health clinics (MCH) clinics in four geographical districts.

Participants

Women aged 16–48 years, pregnant or up to 6 months after childbirth.

Primary and secondary outcome measures

We used multivariable generalised estimating equation analysis to determine characteristics of women who were ES (Has anyone at the healthcare services (HCS) ever asked you whether you have experienced IPV?); RI (Have you ever received information about what to do if you experience IPV?); and both (ES&RI).

Results

Less than half of participants (48.8%) reported ES; 50.5% RI; and 30% were both ES&RI. Having experienced any IPV was not associated with ES or ES&RI, but was associated with RI in an unexpected direction. Women at higher risk for IPV (Arab minority women, lower education, unmarried) were less likely to report being ES, RI or both. The OR and 95% CI for not ER&RI were: 1.58 (1.00 to 2.49) among Arab compared with Jewish women; 1.95 (1.42 to 2.66) among low education versus academic education women; 1.34 (1.03 to 1.73) among not working versus working. ES, RI and both differ across districts.

Conclusions

While Israel mandates screening and providing information regarding IPV for women visiting the HCS, we found inequalities, suggesting inconsistencies in policy implementation and missed opportunities to detect IPV. To increase IPV screening and information provision, the ministry of health should circulate clarification and provide support to healthcare providers to conduct these activities.

https://ift.tt/2XjWOCr

Registration audit of clinical trials given a favourable opinion by UK research ethics committees

Objective

To determine levels of public registration for a cohort of clinical trials reviewed and given a favourable opinion by research ethics committees in the United Kingdom.

Study design

Audit of records.

Setting

Clinical trials receiving a favourable ethics opinion between 1 January 2016 and 30 June 2016.

Main outcome measures

Correlation between trials on the UK research ethics committee database and any primary registry entry on the WHO International Clinical Trials Registry Platform or clinicaltrials.gov as of 29 August 2017 (14 to 20 months after the favourable ethics committee opinion).

Results

Over the study period 1014 trials received a favourable ethics opinion, with 397 (39%) registered on the European Union Drug Regulating Authorities Clinical Trials database, and 18 with an agreed clinical trial registration deferral. Excluding these trials, the total number subsequently requiring registration was 599, and of these 405 (40% of total) were found to be registered. Follow-up with the 194 investigators or sponsors of trials not found to be registered produced 121 responses with a further 10 (1%) trials having already registered, 55 commitments to register and a variety of other responses. The overall registration rate was therefore 80%.

Conclusions

Despite researchers and sponsors being reminded that registration of clinical trials is a condition of the research ethics committee (REC) favourable opinion, one-fifth of clinical trials either had not been registered, or their registration could not easily be found, 14 to 20 months after receiving the favourable opinion letter. The methodology trialled here proved effective, and although there are positive indications of a culture change towards greater registration, our results show that more still needs to be done to increase trial registration.

https://ift.tt/2SiK9vs

Kanagawa Investigation of the Total Check-up Data from the National database (KITCHEN): protocol for data-driven population-based repeated cross-sectional and 6-year cohort studies

Introduction

The unmitigated incidence of cardiometabolic diseases, such as type 2 diabetes and metabolic syndrome, has gained attention in Japan. 'Big data' can be useful to clarify conflicting observations obtained from studies with small samples and about rare conditions that are often neglected. We epidemiologically address these issues using data from health check-ups conducted in Kanagawa Prefecture, the prefecture with the second largest population in Japan, in the Kanagawa Investigation of the Total Check-up Data from the National Database (KITCHEN).

Methods and analysis

This research consists of a series of population-based cross-sectional studies repeated from 2008–2014 and 6-year cohort studies. Since 2017, we have reviewed the data of people living in Kanagawa Prefecture who underwent a health check-up mainly for general health and the prevention of metabolic syndrome. The sample size ranges from 1.2 million to 1.8 million people in the cross-sectional studies and from 370 000 to 590 000 people in the cohort studies. These are people aged 40–74 years, whose clinical parameters were measured and who responded individually to a questionnaire. We investigate potential associations and causalities of various aetiologies, including diabetes and metabolic syndrome, using clinical data and lifestyle information. With multidisciplinary analysis, including data-driven analysis, we expect to obtain a wide range of novel findings, to confirm indeterminate previous findings, especially in terms of cardiometabolic disease, and to provide new perspectives for human health promotion and disease prevention.

Ethics and dissemination

Ethical approval was received from the Ethics Committee of Kanagawa University of Human Services (10-43). The protocol was approved in December 2016 by the Japanese Ministry of Health, Labour and Welfare (No. 121). The study results will be disseminated through open platforms including journal articles, relevant conferences and seminar presentations.

https://ift.tt/2XhQlYl

The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME)

Purpose

The currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme.

Participants

All consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually.

Finding to date

With a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort.

Future plans

These real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings.

Trial registration number

NCT03275311; Pre-results.

https://ift.tt/2Xj2aNZ

Determinants of BCG vaccination coverage in Ethiopia: a cross-sectional survey

Objective

The objective of this study is to assess the determinants of BCG vaccination in Ethiopia from 2016 Ethiopia Demographic and Health Survey (EDHS).

Setting

Since Ethiopia has nine regional states and two administrative cities, sample was taken from all the divisions. The population-based sample was intended to provide estimates of key indicators for the country.

Participant

The sampling frame used for the 2016 EDHS is the Ethiopia Population and Housing Census. From 15 683 women recorded in EDHS dataset, women with no child (n=10 379) were excluded from the study. Therefore, the total sample size for this study was 5304 women. The outcome variable was BCG immunisation status of children.

Result

Out of the study participants (n=5304), the majority were in between 20 and 34 years of age (73.8%). The median age of the respondents was 28.4 (SD=±6.5) years old. Prevalence of BCG vaccination was 63.6% (n=3373) and BCG vaccination coverage in urban residents was higher (88%) than rural residents (57.3%). Mothers' age between 20 up to 34 (Adjusted odds ratio (AOR)=1.48; 95% CI: 1.13 to 1.93) and between 35 up to 49 (AOR=1.83; 95% CI: 1.35 to 2.46) were more likely to vaccinate their child's than those mothers' age less than 20. Mothers settled in urban areas were two times more likely to vaccinate their child's than those living in rural areas (AOR=1.94; 95% CI: 1.45 to 2.60). Mothers with greater antenatal visits show higher BCG vaccination, Antenatal Care (ANC) 4 and above (AOR=3.48; 95% CI: 2.91 to 4.15). BCG vaccination is higher for mothers delivered at non-governmental organisation health facility than home (AOR=2.9; 95% CI: 1.69 to 4.96). Maternal occupation and wealth index also had a significant association with BCG vaccination.

Conclusion

BCG vaccination coverage, in this study, was lower and determinant factors for BCG vaccination were residence, mother's age, place of delivery, mother's antenatal visit, wealth index and mother's occupation.

https://ift.tt/2Xg5TMq

Impact of drug consumption rooms on risk practices and access to care in people who inject drugs in France: the COSINUS prospective cohort study protocol

Introduction

The high prevalence of hepatitis C and the persistence of HIV and hepatitis C virus (HCV) risk practices in people who inject drugs (PWID) in France underlines the need for innovative prevention interventions. The main objective of this article is to describe the design of the COSINUS cohort study and outline the issues it will explore to evaluate the impact of drug consumption rooms (DCR) on PWID outcomes. Secondary objectives are to assess how DCR (a) influence other drug-related practices, such as the transition from intravenous to less risky modes of use, (b) reduce drug use frequency/quantity, (c) increase access to treatment for addiction and comorbidities (infectious, psychiatric and other), (d) improve social conditions and (e) reduce levels of violence experienced and drug-related offences. COSINUS will also give us the opportunity to investigate the impact of other harm reduction tools in France and their combined effect with DCR on reducing HIV-HCV risk practices. Furthermore, we will be better able to identify PWID needs.

Methods and analysis

Enrollment in this prospective multi-site cohort study started in June 2016. Overall, 680 PWID in four different cities (Bordeaux, Marseilles, Paris and Strasbourg) will be enrolled and followed up for 12 months through face-to-face structured interviews administered by trained staff to all eligible participants at baseline (M0), 3 month (M3), 6 month (M6) and 12 month (M12) follow-up visits. These interviews gather data on socio-demographic characteristics, past and current drug and alcohol consumption, drug-use related practices, access to care and social services, experience of violence (as victims), offences, other psychosocial issues and perception and needs about harm reduction interventions and services. Longitudinal data analysis will use a mixed logistic model to assess the impact of individual and structural factors, including DCR attendance and exposure to other harm reduction services, on the main outcome (HIV-HCV risk practices).

Ethics and dissemination

This study was reviewed and approved by the institutional review board of the French Institute of Medical Research and Health (opinion number: 14–166). The findings of this cohort study will help to assess the impact of DCR on HIV-HCV risk practices and other psycho-social outcomes and trajectories. Moreover, they will enable health authorities to shape health and harm reduction policies according to PWID needs. Finally, they will also help to improve current harm reduction and therapeutic interventions and to create novel ones.

https://ift.tt/2Xj2agX

Evaluation of the implementation of a relationship and sexuality education project in Western Australian schools: protocol of a multiple, embedded case study

Introduction

There is recognition of the importance of comprehensive relationships and sexuality education (RSE) throughout the school years worldwide. Interventions have found some positive outcomes; however, the need for a greater focus on positive sexuality and relevant contemporary issues has been identified by teachers and students. The Curtin RSE Project provides training for teachers and preservice teachers and supports schools through training and advice to implement comprehensive school health promotion (CSHP) focusing on RSE allowing schools to develop programmes relevant to their school community. To examine contemporary phenomenon within a real word context, a case study design will be used to measure implementation. This paper will describe the protocol for a multiple, embedded case study to measure the implementation of CSHP focusing on RSE in a purposive sample of Western Australian schools.

Methods and analysis

This mixed methods study will include a multiple, embedded case study. Schools (n=3–4) will be purposively selected from within Western Australia based on their capacity to commit to implementing RSE as a case study school. Data will be collected from students (Grade 6 for primary school; Grades 7–12 for secondary school); teachers and other key staff and parents. Methods include school climate and school curriculum audits, documentation (collected with key staff at baseline and annually), interviews (parents and teachers at Year 2), focus groups (students at Year 2) and an online student survey (collected with students baseline and annually).

Ethics and dissemination

School principals will provide consent for school participation and staff and parents will provide individual consent. Student assent and parental consent will be obtained for student participants. Results will be disseminated through open-access reports, peer-reviewed journals and conference presentations.

https://ift.tt/2Sj4l0p

Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study

Introduction

Patients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD.

Methods and analysis

We outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population—the IMpact of Phosphate Reduction On Vascular End-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels.

Ethics and dissemination

Ethical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences.

Trial registration number

ACTRN12610000650099.

https://ift.tt/2XfGeTU

Expanding disease and undermining the ethos of medicine

Abstract

The expansion of the concept of disease poses problems for epidemiology. Certainly, new diseases are discovered and more people are treated earlier and better. However, the historically unprecedented expansion is criticised for going too far. Overdiagnosis, overtreatment, and medicalization are some of the challenges heatedly debated in medicine, media, and in health policy making. How are we to analyse and handle the vast expansion of disease? Where can we draw the line between warranted and unwarranted expansion? To address this issue, which has wide implications for epidemiology, we need to understand how disease is expanded. This article identifies six ways that our conception of disease is expanded: by increased knowledge (epistemic), making more phenomena count as disease (ontological), doing more (pragmatic), defining more (conceptual), and by encompassing the bad (ethic) and the ugly (aesthetic). Expanding the subject matter of medicine extends its realm and power, but also its responsibility. It makes medicine accountable for ever more of human potential dis-eases. At the same time it blurs the borders and undermines the demarcation of medicine. Six specific advices can guide our action clarifying the subject matter of medicine in general and epidemiology in particular. To avoid unlimited responsibility and to keep medicine on par with its end, we need to direct the expansion of disease to what effectively identifies or reduces human suffering. Otherwise we will deplete medicine and undermine the greatest asset in health care: trust.

https://ift.tt/2BOwAP2

Neurosyphilis presenting as cranial nerve palsy, an entity which is easy to miss

Neurosyphilis is a rare disease that until the 2000s was almost eradicated due to population awareness of HIV and efficient treatment. Since then, the prevalence of the entity is rising due to risk-associated behaviour such as unprotected intercourse. Neurosyphilis is still a difficult entity to diagnose especially when combined with acute HIV infection which can influence the usual clinical course of disease. In rare occasions, both acute HIV and early syphilis infection can present as mono or multiple cranial nerve palsies. This case demonstrates a rare manifestation of misdiagnosed early syphilis infection combined with acute HIV infection in a 34-year-old man with prior history of unprotected sex with men.

https://ift.tt/2Xh32mp

Resistant dermatomyositis in a rural indigenous Maya woman

A 28-year-old indigenous Guatemalan woman presented with 7 months of progressive weakness and numerous dermatological findings. She initially sought care within the free government-run health system and was treated with oral steroids for presumed dermatomyositis. Her symptoms progressed, including severe dysphagia, hypophonia and weakness preventing sitting. She was lost to follow-up in the public system due to financial and cultural barriers. A non-governmental organisation tailored to the needs of Maya patients provided home intravenous pulse dose methylprednisolone in the absence of first-line biologicals. With longitudinal home-based care, she achieved symptom free recovery. The rising burden of chronic non-communicable diseases highlights shortcomings in health systems evident in this case, including lack of provider capacity, limited infrastructure to test for and treat rare diseases and poor continuity of care. We provide potential solutions to help care delivery in low-resource settings adapt to the demans of chronic disease control with particular attention to social determinants of health.

https://ift.tt/2SlrLSI

Giant cell tumour of the scapula treated by partial scapulectomy

Giant cell tumour is a benign, but locally aggressive tumour. It most commonly affects the epiphysial-metaphyseal region of long bones, but rarely in flat bones. We present you a case of 26-year-old man with a large giant cell tumour of the inferior angle of the scapula. The patient was treated with partial scapulectomy with complete resection of tumour. There was excellent retention of shoulder function postoperatively.

https://ift.tt/2XeLdnT

Use of home telemedicine for critical illness rehabilitation: an Indian success story

One-fifth of healthcare beneficiaries in developed nations get discharged from hospitals to physician supervised skilled nursing care facilities. In low-income and middle-income countries like India, postdischarge skilled nursing facilities are at a very nascent stage and largely underequipped in terms of infrastructure, skilled nursing and physician staff to manage complicated patients. Hence the responsibility of management of such patients lies largely with their families. We present a case where a 26-year-old man with Duchenne Muscular Dystrophy who became ventilator dependent following major surgeries was weaned off his ventilator and rehabilitated back to his prehospital state. This was done at his home with visiting nurses and rehabilitation services under telemedicine supervision by a critical care specialist. Use of telemedicine services could be a viable and cost-effective option to ensure adherence to evidence-based medicine and standardisation of care in resource limited countries such as India.

https://ift.tt/2Sj48u9

Brentuximab vedotin in combination with sequential procarbazine, cyclophosphamide and prednisolone for the management of Hodgkins lymphoma-associated vanishing bile duct syndrome (VBDS) with severe obstructive liver failure

We present a novel treatment protocol that was successful in the management of Hodgkin's-associated vanishing bile duct syndrome, a rare but serious complication of Hodgkin's lymphoma. We believe that publication of this treatment protocol and the rationale for its development will be of interest to anyone faced with treating this challenging condition.

https://ift.tt/2Xc3GSd

Iatrogenic adrenal suppression following caudal epidural and facet joint injection

Caudal epidural injections and facet joint injections using steroids and local anaesthetic are widely used methods of pain control in patients suffering from radicular leg pain. In the vast majority of cases this is low risk. We present an interesting case of a patient who suffered from symptomatic adrenal suppression following a caudal epidural injection, and thus wish to draw this rare but significant complication to the attention of orthopaedic practitioners.

https://ift.tt/2SjbD45

Scrotal necrosis and no Fourniers in sight: a rare case of juvenile gangrenous vasculitis

Juvenile gangrenous vasculitis of the scrotum is a rare entity, of which to our knowledge we describe the first documented case in the UK. It follows a typical disease course, demonstrated by an 18-year-old male who presented with three necrotic scrotal lesions; proceeded by 3 days of fever, pharyngitis and lethargy. Previous cases have been managed successfully with systemic steroids. On this occasion, surgical debridement was made of the necrotic areas under antibiotic cover and complete resolution was achieved with excellent wound healing and no evidence of recurrence. This case report discusses the importance of disease recognition and the merits of surgical management. We also add to the debate as to whether this disease is a variation of pyoderma gangrenosum or a distinct entity itself within the pantheon of scrotal gangrene.

https://ift.tt/2XdBuOK

Drug-induced paraspinal myositis mimicking acute bilateral sciatica

Although cocaine induced myopathy and myotoxicity are described in the literature, we report a rare case of cocaine induced paraspinal myositis presenting with acute sciatic symptoms. A 35-year-old man presented with acute left-sided sciatica and was discharged from the emergency department (ED). He subsequently attended ED the following day in severe pain and bilateral sciatic symptoms, but denied symptoms of neurogenic bowel/bladder disturbance. Clinical examination was limited by severe pain: focal midline lumbar tenderness was elicited on palpation, per rectal and limb examinations were within normal limits with no significant neurological deficit. He was admitted for observation and pain management. His blood tests revealed a leucocyte count of 21.5x10⁹/L, C reactive protein of 89 mg/L and deranged renal function with creatinine of 293 μmol/L. An urgent lumbar spine MRI was arranged to rule out a discitis or epidural abscess. Lumbar MRI did not demonstrate any features of discitis but non-specific appearances of paraspinal inflammation raised the suspicion of a paraspinal myositis. Creatinekinase (CK) was found to be 66329 IU/L and a detailed history revealed he was a cocaine user. Paraspinal muscle biopsy confirmed histological features compatible with myositis. Other serological tests were negative, including anti-GBM, ANCA, ANA, Rheumatoid factor, Hep B, Hep C, myositis specific ENA, Treponema pallidum, Borrelia burgdorferi, Rickettsia, Leptospira, EBV and CMV. There was good clinical response to treatment with prednisolone 20 mg OD with an improvement in renal function, CK levels and CRP. He had resumed normal activities and return to work at 6-week follow-up. A detailed social history including substance misuse is important in patients presenting to the ED—especially in cases of severe musculoskeletal pain with no obvious localising features. Drug induced myotoxicity, although rare, can result in symptomatic patients with severe renal failure.

https://ift.tt/2SfXip7

Retained tooth in the nasal cavity: a rare cause of nasal congestion

A 59-year-old man presented with unilateral nasal congestion and discharge. Clinical examination revealed a mass in the floor of the nasal cavity. Sinus CT indicated a retained tooth or a dermoid cyst. It was removed by endoscopic surgery. Histology confirmed the diagnosis of a retained tooth. At follow-up, the patient reported no nasal symptoms. A retained nasal tooth is rare, and the symptoms are variable. It can resemble other diseases such as chronic rhinosinusitis. Surgical removal is recommended to confirm the diagnosis and eliminate symptoms.

https://ift.tt/2XhuekX

Abdominal mass causing acute kidney injury as a manifestation of acute myeloid leukaemia

https://ift.tt/2SjblKP

'Acute-angled bevel sign to assess donor lenticule orientation in ultra-thin descemet stripping automated endothelial keratoplasty

A 6.5-year-old boy with congenital hereditary endothelial dystrophy underwent clear corneal ultra-thin descemet stripping automated endothelial keratoplasty (DSAEK). After graft insertion, it was difficult to assess graft orientation due to hazy cornea. Intraoperative optical coherence tomography (iOCT) showed a well-attached graft and the bevelled edge of donor lenticule made an acute angle with the overlying stroma. Postoperative anterior segment OCT confirmed the presence of acute-angled bevel sign. A wetlab experiment was performed with experimental corneoscleral tissues to confirm the findings. Donor lenticule was injected in the artificial chamber with stromal-side up as well as stromal side-down. 'Acute-angled bevel sign' was observed on iOCT in the experimental cases with stromal-side up. In inverse graft, the acute-angled bevel was not observed, instead the configuration was obtuse angled. Identifying the 'acute-angled bevel sign' on iOCT confirms correct graft orientation after unfolding and is extremely useful for hazy corneas and ultrathin DSAEK lenticules.

https://ift.tt/2Xh31yR

Fulminant thymomatous AMPAR-antibody limbic encephalitis with hypertonic coma, bruxism, an isoelectric electroencephalogram and temporal cortical atrophy, with recovery

Autoimmune encephalitides are a potentially devastating group of treatable disorders with a wide variety of clinical presentations. The most studied autoimmune encephalitis is caused by antibodies to the N-methyl-D-aspartate glutamate receptor. A rarer cause is due to antibodies against the evolutionarily related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). The full assortment of electroencephalogram (EEG) and clinical descriptions of the latter are yet to be fully described. A 44-year-old woman with impaired consciousness and subsequent coma characterised by an isoelectric EEG was diagnosed with AMPAR-antibody limbic encephalitis. MRI revealed temporal T2 hyperintensities that improved with immunosuppression, although leaving marked cortical atrophy. Gradual clinical improvement saw the development of aggressive bruxism requiring botulinum toxin injection with eventual meaningful clinical recovery. This case expands the clinical spectrum of AMPAR limbic encephalitis to include aggressive bruxism, and highlights that despite poor clinical and EEG findings at the outset, recovery is still possible.

https://ift.tt/2Sj46T3

Ewings sarcoma in maxilla

Ewing sarcoma is a lesion of bone, described in small round cell neoplasm. This tumour resembles primitive neuroectodermal tumour both clinically and histologically. Major difference between these two is that the former arises in the bone and the later in soft tissue. It appears most frequently in males at the age range of of 5–25 years, 80% of which occurs within first two decades of life. Males are more commonly affected than females. Present paper reported with a case report of male patient with 24-year-old showing Ewing's sarcoma of right maxilla.

https://ift.tt/2XhwMzF

Retinal and choroidal circulation determined by optical coherence tomography angiography in patient with amyloidosis

A 43-year-old woman who was diagnosed with the cryopyrine-associated periodic syndrome (CAPS) with severe renal failure and heart failure due to amyloid accumulation was examined by swept source optical cohernce tomography (OCT) (SS-OCT; DRI-OCT, Topcon, Tokyo, Japan) and optical coherence tomography angiography (OCTA) (RTVue XR Avanti, Optovue, Fremont, CA). Her best-corrected visual acuity was 20/40 OD and 20/25 OS. A hyporeflective band of about 100 µm thickness was seen just inferior to the retinal pigment epithelium in the cross-sectional SS-OCT images, but the deeper choroidal structures were clearly visible. In the OCTA images, the density of the retinal capillaries in the superficial and deep capillary plexus slabs were reduced, and no signals of the choroidal capillary slab was detected after removing the projection artefacts. The accumulation of amyloid can cause a reduction of both the retinal and choroidal capillary circulations although the circulation in the larger vessels are preserved.

https://ift.tt/2SlryyU

Melanotan-induced priapism: a hard-earned tan

Melanocortin analogues, such as melanotan, are illegally used for artificial tanning. They have also been suggested as possible therapeutic agents in the treatment of erectile dysfunction. This case study presents a patient attending the accident and emergency department, in a tertiary urology centre, with acute priapism after abdominal subcutaneous injection of melanotan. The priapism was diagnosed as 'low-flow' and managed with cavernosal aspiration, irrigation and subsequent intracavernosal injection of phenylephrine. The patient avoided requiring surgical shunting but had not yet recovered erectile function at 4-week follow-up. Acute priapism is an unreported side effect of melanocortin analogue use and this case report presents a patient managed without surgical intervention. Future therapeutic application of these agents will need to take this potential life altering complication into consideration.

https://ift.tt/2XdBtKG

Clinical Infectious Diseases

The Association of Antibiotic Stewardship With Fluoroquinolone Prescribing in Michigan Hospitals: A Multi-hospital Cohort Study Abstract Background Fluoroquinolones increase the risk of Clostridioides difficile infection and antibiotic resistance. Hospitals often use pre-prescription approval or prospective audit and feedback to target fluoroquinolone prescribing. Whether these strategies impact aggregate fluoroquinolone use is unknown. Methods This study is a 48-hospital, retrospective cohort of general-care, medical patients hospitalized with pneumonia or positive urine culture between December 2015–September 2017. Hospitals were surveyed on their use of pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing during hospitalization (fluoroquinolone stewardship). After controlling for hospital clustering and patient factors, aggregate (inpatient and post-discharge) fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) exposure was compared between hospitals with and without fluoroquinolone stewardship. Results There were 11 748 patients (6820 pneumonia; 4928 positive urine culture) included at 48 hospitals. All hospitals responded to the survey: 29.2% (14/48) reported using pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing. After adjustment, fluoroquinolone stewardship was associated with fewer patients receiving a fluoroquinolone (37.1% vs 48.2%; P = .01) and fewer fluoroquinolone treatment days per 1000 patients (2282 vs 3096 days/1000 patients; P = .01), driven by lower inpatient prescribing. However, most (66.6%) fluoroquinolone treatment days occurred after discharge, and hospitals with fluoroquinolone stewardship had twice as many new fluoroquinolone starts after discharge as hospitals without (15.6% vs 8.4%; P = .003). Conclusions Hospital-based stewardship interventions targeting fluoroquinolone prescribing were associated with less fluoroquinolone prescribing during hospitalization, but not at discharge. To limit aggregate fluoroquinolone exposure, stewardship programs should target both inpatient and discharge prescribing.

Prevalence, Predictors, and Successful Treatment Outcomes of Xpert MTB/RIF–identified Rifampicin-resistant Tuberculosis in Post-conflict Eastern Democratic Republic of the Congo, 2012–2017: A Retrospective Province-Wide Cohort Study Abstract Background Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program. Methods of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan–Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death. Results Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63–3.59), retreatment of TB (aOR 4.92, 95% CI 2.31–10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01–3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3–60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2–6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88–9.71). Conclusions Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes. The Association of Antibiotic Stewardship With Fluoroquinolone Prescribing in Michigan Hospitals: A Multi-hospital Cohort Study Abstract Background Fluoroquinolones increase the risk of Clostridioides difficile infection and antibiotic resistance. Hospitals often use pre-prescription approval or prospective audit and feedback to target fluoroquinolone prescribing. Whether these strategies impact aggregate fluoroquinolone use is unknown. Methods This study is a 48-hospital, retrospective cohort of general-care, medical patients hospitalized with pneumonia or positive urine culture between December 2015–September 2017. Hospitals were surveyed on their use of pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing during hospitalization (fluoroquinolone stewardship). After controlling for hospital clustering and patient factors, aggregate (inpatient and post-discharge) fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) exposure was compared between hospitals with and without fluoroquinolone stewardship. Results There were 11 748 patients (6820 pneumonia; 4928 positive urine culture) included at 48 hospitals. All hospitals responded to the survey: 29.2% (14/48) reported using pre-prescription approval and/or prospective audit and feedback to target fluoroquinolone prescribing. After adjustment, fluoroquinolone stewardship was associated with fewer patients receiving a fluoroquinolone (37.1% vs 48.2%; P = .01) and fewer fluoroquinolone treatment days per 1000 patients (2282 vs 3096 days/1000 patients; P = .01), driven by lower inpatient prescribing. However, most (66.6%) fluoroquinolone treatment days occurred after discharge, and hospitals with fluoroquinolone stewardship had twice as many new fluoroquinolone starts after discharge as hospitals without (15.6% vs 8.4%; P = .003). Conclusions Hospital-based stewardship interventions targeting fluoroquinolone prescribing were associated with less fluoroquinolone prescribing during hospitalization, but not at discharge. To limit aggregate fluoroquinolone exposure, stewardship programs should target both inpatient and discharge prescribing. Prevalence, Predictors, and Successful Treatment Outcomes of Xpert MTB/RIF–identified Rifampicin-resistant Tuberculosis in Post-conflict Eastern Democratic Republic of the Congo, 2012–2017: A Retrospective Province-Wide Cohort Study Abstract Background Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program. Methods of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan–Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death. Results Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63–3.59), retreatment of TB (aOR 4.92, 95% CI 2.31–10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01–3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3–60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2–6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88–9.71). Conclusions Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes. Glycocalyx Breakdown is Associated with Severe Disease and Fatal Outcome in Plasmodium falciparum Malaria Abstract Background Interactions between the endothelium and infected erythrocytes, microvascular dysfunction and parasite sequestration play major roles in the pathogenesis of severe falciparum malaria. The glycocalyx is a carbohydrate-rich layer lining the endothelium mediating NO production and vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity is not known. Methods We prospectively enrolled Indonesian inpatients (≥18 years old) with severe (SM) or moderately-severe (MSM) falciparum malaria and healthy controls (HCs). Glycocalyx breakdown products were measured in enrolment samples of urine (glycosaminoglycans; dimethylmethylene blue [GAG-DMMB] and liquid chromatography-tandem mass spectrometry [GAG-MS] assays) and plasma (syndecan-1; ELISA), and related to vascular NO bioavailability (reactive hyperemia-peripheral arterial tonometry). Results A total of 129 subjects (SM=43, MSM=57, HC=29) were recruited. Syndecan-1 (µg/ml), GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM [median (range) 332.4 (85-3-1913), 3.16 (0.04-27.9) and 4.73 (2.02-27.13)] compared to MSM [99.1 (19.9-767.6), 1.28 (0.03-9.3) and 4.44 (1.19-13.87)], and HCs [48.9 (32.3-88.3), 0.11 (0.02-1.9) and 2.55 (0.73-10.19)]; P<0.001. In SM, GAG-DMMB and GAG-MS were increased in non-survivors (n=3) [median (IQR): 6.72 (3.80-27.87) and 12.15 (7.88-17.20)] compared to survivors n=39 [(3.10 (0.46-4.5) and 4.64 (2.02-15.20)]; P=0.03. Glycocalyx degradation was associated with parasite biomass in MSM (r=0.31, P=0.03 [syndecan-1]; r=0.48 [GAG-DMMB] and r=0.43 [GAG-MS], P<0.001), and SM patients (r=0.29, P=0.04, r=0.47; P=0.002 and r=0.33, P=0.04), and inversely associated with endothelial NO bioavailability. Conclusions Increased endothelial glycocalyx breakdown is associated with impaired vascular NO, severe disease and fatal outcome in adults with falciparum malaria, likely contributing to pathogenesis. Impact of rotavirus vaccine introduction in children less than 2 years of age presenting for medical care with diarrhea in rural Matlab, Bangladesh Abstract Background Following the conclusion of a Rotarix vaccine (HRV) cluster-randomized controlled trial (CRT) in Matlab, Bangladesh, HRV was included in Matlab's routine immunization program. We describe the population-level impact of programmatic rotavirus vaccination in Bangladesh in children <2 years of age Methods Interrupted time series were used to estimate the impact of HRVintroduction. Diarrheal surveillance collected between 2000 and 2014 within the two service delivery areas (icddr,b service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System administered by icddr,b was used. Age-group specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea of any severity presenting to the hospital. Two models were used to assess impact within each service area: Model 1 used the pre-vaccine time period in all villages (HRV- and control-only) and Model 2 combined the pre-vaccine time period and the CRT time period using outcomes from control-only villages. Results Both models demonstrated a downward trend in RV+ diarrheal incidence in the ISA villages during 3.5 years of routine HRV use, though only Model 2 was statistically significant. Significant impact of HRV on RV+ diarrhea incidence in GSA villages was not observed in either model. Differences in population-level impact between the two delivery areas may be due to varied rotavirus vaccine coverage and presentation rate to the hospital. Conclusions This study provides initial evidence of the population-level impact of rotavirus vaccines in children <2 years of age in Matlab, Bangladesh. Further studies of rotavirus vaccine impact after nationwide introduction in Bangladesh are needed. Transmission-blocking effects of primaquine and methylene blue suggest P. falciparum gametocyte sterilisation rather than effects on sex ratio Abstract Gametocyte density and sex-ratio can predict the proportion of mosquitoes that become infected after feeding on blood of patients receiving non-gametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex-ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects. Principal Controversies in Vaccine Safety in the United States Abstract Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases. We summarize the key evidence on some of the main current vaccine safety controversies in the United States, including: 1) MMR vaccine and autism; 2) thimerosal, a mercury-based vaccine preservative, and the risk of neurodevelopmental disorders; 3) vaccine-induced Guillain-Barré Syndrome (GBS); 4) vaccine-induced autoimmune diseases; 5) safety of HPV vaccine; 6) aluminum adjuvant-induced autoimmune diseases and other disorders; and 7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns. Insertion as resistance mechanism against integrase inhibitors in several retroviruses Birth Cohort Studies Assessing Norovirus Infection and Immunity in Young Children: A Review Abstract Globally, noroviruses are among the foremost causes of acute diarrheal disease, yet there are many unanswered questions on norovirus immunity, particularly following natural infection in young children during the first 2 years of life when the disease burden is highest. We conducted a literature review on birth cohort studies assessing norovirus infections in children from birth to early childhood. Data on infection, immunity, and risk factors are summarized from 10 community-based birth cohort studies conducted in low- and middle-income countries. Up to 90% of children experienced atleast one norovirus infection and up to 70% experienced norovirus-associated diarrhea, most often affecting children 6 months of age and older. Data from these studies help to fill critical knowledge gaps for vaccine development, yet study design and methodological differences limit comparison between studies, particularly for immunity and risk factors for disease. Considerations for conducting future birth cohort studies on norovirus are discussed. In the Literature Saddle Nose Deformity in an Immunosuppressed Patient Cover News Ebola's Curse: 2013–2016 Outbreak in West Africa By OldstoneMichael and OldstoneMadeleine. Elsevier, 2017. 126 pp. $89.95 (hardcover). ISBN: 9780128138885. Cost-effectiveness and Cost-utility of the Adherence Improving Self-management Strategy in Human Immunodeficiency Virus Care: A Trial-based Economic Evaluation Abstract Background Several promising human immunodeficiency virus (HIV) treatment adherence interventions have been identified, but data about their cost-effectiveness are lacking. This study examines the trial-based cost-effectiveness and cost-utility of the proven-effective Adherence Improving Self-Management Strategy (AIMS), from a societal perspective, with a 15-month time horizon. Methods Treatment-naive and treatment-experienced patients at risk for viral rebound were randomized to treatment as usual (TAU) or AIMS in a multicenter randomized controlled trial in the Netherlands. AIMS is a nurse-led, 1-on-1 self-management intervention incorporating feedback from electronic medication monitors, delivered during routine clinical visits. Main outcomes were costs per reduction in log10 viral load, treatment failure (2 consecutive detectable viral loads), and quality-adjusted life-years (QALYs). Results Two hundred twenty-three patients were randomized. From a societal perspective, AIMS was slightly more expensive than TAU but also more effective, resulting in an incremental cost-effectiveness ratio (ICER) of €549 per reduction in log10 viral load and €1659 per percentage decrease in treatment failure. In terms of QALYs, AIMS resulted in higher costs but more QALYs compared to TAU, which resulted in an ICER of €27759 per QALY gained. From a healthcare perspective, AIMS dominated TAU. Additional sensitivity analyses addressing key limitations of the base case analyses also suggested that AIMS dominates TAU. Conclusions Base case analyses suggests that over a period of 15 months, AIMS may be costlier, but also more effective than TAU. All additional analyses suggest that AIMS is cheaper and more effective than TAU. This trial-based economic evaluation confirms and complements a model-based economic evaluation with a lifetime horizon showing that AIMS is cost-effective. Clinical Trials Registration NCT01429142 First Human Case of Metacestode Infection Caused by Versteria sp. in a Kidney Transplant Recipient Abstract Cestodes are emerging agents of severe opportunistic infections among immunocompromised patients. We describe the first case of human infection, with the recently-proposed genus Versteria causing an invasive, tumor-like hepatic infection with regional and distant extension in a 53-year-old female kidney transplant recipient from Atlantic Canada. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus–1 Infection: Week 48 Results of the DRIVE-AHEAD Trial Abstract Background Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment–naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) (-3.83 vs +13.26 mg/dL) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (−1.6 vs +8.7 mg/dL and −3.8 vs +13.3 mg/dL, respectively). Conclusions In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non–HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration NCT02403674 A 44-Year-Old Female With Overwhelming Sepsis sepsisaspleniaRPSA geneHowell-Jolly bodiesStreptococcus pneumonia Concurrent Seroprevalence of Antibodies to Toxoplasma gondii and Toxocara Species in the United States, 2011–2014 To the Editor—We report supplemental findings incorporating Toxoplasma gondii serology results from our study of risk factors for Toxocara seropositivity in the United States [1] using stored serum samples collected from the National Health and Nutrition Examination Survey (NHANES), 2011–2014. Whereas T. gondii is a protozoan parasite and Toxocara is an intestinal nematode, both share ingestion of contaminated soil as means of exposure in humans. Both parasites can contaminate soil when environmentally resistant T. gondii oocysts or Toxocara cati eggs are shed in the feces of infected cats [2, 3].

Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection Abstract Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.

The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast

Abstract

Purpose

According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC).

Methods

Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets.

Results

AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3–20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1–7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not.

Conclusions

AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.

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Strong impact of MammaPrint and BluePrint on treatment decisions in luminal early breast cancer: results of the WSG-PRIMe study

Abstract

Purpose

The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer.

Methods

452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires.

Results

Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in "discordant" groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients' State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients.

Conclusions

MammaPrint and BluePrint test results strongly impacted physicians' therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

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Comparison of protein expression between formalin-fixed core-cut biopsies and surgical excision specimens using a novel multiplex approach

Abstract

Purpose

We evaluated whether multiplex protein quantification using antibody bar-coding with photocleavable oligonucleotides (NanoString) can be applied to evaluate protein expression in breast cancer FFPE specimens. We also assessed whether diagnostic core-cuts fixed immediately at time of procedures and surgical excision sections from routinely fixed breast cancers are affected by the same fixation related differences noted using immunohistochemistry (IHC).

Methods

The expression of 26 proteins was analysed using NanoString technology in 16 pairs of FFPE breast cancer core-cuts and surgical excisions. The measurements yielded were compared with those by IHC on Ki67, PgR and HER2 biomarkers and pAKT and pERK1/2 phosphorylated proteins.

Results

When considered irrespective of sample type, expression measured by the two methods was strongly correlated for all markers (p < 0.001; ρ = 0.69–0.88). When core-cuts and excisions were evaluated separately, the correlations between NanoString and IHC were weaker but significant except for pAKT in excisions. Surgical excisions showed lower levels of 8/12 phosphoproteins and higher levels of 4/13 non-phosphorylated proteins in comparison to core-cuts (p < 0.01). Reduced p4EBP1, pAMPKa, pRPS6 and pRAF1 immunogenicity in excisions was correlated with tumour size and mastectomy specimens showed lower p4EBP1 and pRPS6 expression than lumpectomy (p < 0.05).

Conclusions

Our study supports the validity of the new multiplex approach to protein analysis but indicates that, as with IHC, caution is necessary for the analysis in excisions particularly of phosphoproteins. The specimen type, tumour size and surgery type may lead to biases in the quantitative analysis of many proteins of biologic and clinical interest in excision specimens.

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Survival of adjacent‐dental‐implants in prediabetic and systemically healthy subjects at 5‐years follow‐up

Abstract

Background

Long‐term survival of adjacent dental implants (ADI) in prediabetic patients remained uninvestigated.

Purpose

This 5 years' follow‐up clinical study compared the survival of adjacent implants in prediabetic and nondiabetic subjects.

Materials and Methods

Prediabetic (group‐A) and nondiabetic (group‐B) subjects having undergone dental rehabilitation using ADI were assessed. Data about sex, age treatment and period (in years) since diagnosis of prediabetes, and family history of diabetes was gathered and haemoglobin A1c (HbA1c) levels were recorded. Dental implant related data (dimensions, loading protocol, surface characteristics, restoration type, and duration in function) was recorded. Depth of probing (PD), bleeding‐on‐probing (BOP), and plaque index (PI) were measured and mesial and distal crestal bone loss (CBL) were recorded. P values less than .05 were contemplated as statistically‐significant.

Results

Seventy‐nine male individuals (39 in group‐A and 40 in group‐B) were included. Subjects in groups ‐A and ‐B were 54.3 ± 3.6 and 51.2 ± 2.4 years old, respectively. In group‐A, subjects were diagnosed with prediabetes 5.4 ± 0.2 years ago. Patients in group‐A more often had a family history of diabetes than group‐B. Thirty‐nine and 40 ADI were placed in patients in groups ‐A and ‐B, respectively. Tooth‐brushing once daily was reported by 79.5% and 82.5% individuals in groups ‐A and ‐B, respectively. Peri‐implant PI (P<.001), BOP (P<.001), PD (P<.001), mesial (P<.001), and distal (P<.001) CBL and HbA1c levels (P<.001) were higher in group‐A than group‐B. The implant survival rate in group‐A and group‐B was 100% and 100%, respectively.

Conclusion

Although ADI can survive in prediabetic patients in the long‐term; soft‐tissue inflammation and CBL are worse around adjacent implants in these patients compared with nondiabetic controls.

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Metabolomics‐based identification of metabolic alterations in PARK2

Abstract

Objective

Parkin is the causative gene for autosomal recessive familial Parkinson's disease (PD), although it remains unclear how parkin dysfunction is involved with the general condition. Recently, serum and/or plasma metabolomics revealed alterations in metabolic pathways that might reflect pathomechanisms of idiopathic PD (iPD). Thus, we hypothesized that serum metabolomics of patients with homozygous or compound heterozygous parkin mutations (namely, PARK2) might reflect metabolic alterations due to parkin dysfunction.

Methods

We enrolled 15 PARK2 patients (52 ± 17.6 years) confirmed with homozygous (seven cases) and compound heterozygous (eight cases) parkin mutations, along with 19 healthy age‐matched controls (51 ± 11.5 years). We analyzed 830 metabolites from participants' serum using well‐established metabolomics technologies, including ultra‐high performance liquid chromatography/tandem mass spectroscopy.

Results

Based on metabolic profiles, hierarchical matrix analysis can divide samples between control and PARK2 subjects. Profiles from PARK2 patients showed significantly higher levels of fatty acid (FA) metabolites and oxidized lipids, and significantly lower levels of antioxidant, caffeine, and benzoate‐related metabolites.

Interpretation

Metabolomics can identify specific metabolic alterations in PARK2 patients compared with controls. Alterations in FA metabolites suggest a relationship between parkin function and lipid metabolism. The elevation of oxidized lipids in combination with decreasing antioxidants may reflect general hyperoxidative stress. Decreasing benzoate‐related metabolites might be due to the alteration in gut microbiota. Consequently, caffeine and its metabolites may be decreased due to malabsorption. These findings are similar to metabolic alterations in iPD. Thus, serum/plasma metabolomics may reflect the association between parkin dysfunction and parkinsonism.

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Identification of a novel missense mutation in Friedreich's ataxia –FXNW168R

Abstract

Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, we find that frataxin^W168R, a novel disease‐causing missense mutation, is expressed predominantly as the intermediate frataxin^42‐210 form, with very little expression of mature frataxin^81‐210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxin^W168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease‐modifying manner.

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Comparative Analysis of Secretome of Human Umbilical Cord- and Bone Marrow-Derived Multipotent Mesenchymal Stromal Cells

Production of cytokines and growth factors by cultured human umbilical cord tissue- and bone marrow-derived multipotent mesenchymal stromal cells was measured by multiplex analysis. In most cases, the concentrations of bioactive factors in the culture medium conditioned by umbilical cord-derived cells was ten- to hundred-times higher than in the medium conditioned by bone marrow-derived cells. These results suggest that both multipotent mesenchymal stromal cells from the umbilical cord and cell-free products can have more pronounced therapeutic effect in comparison with mesenchymal stromal cells obtained from "adult" sources.

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Massively Parallel Sequencing Analysis of Benign Melanocytic Nevi

Abstract

Aims

Melanocytic nevi are benign lesions of the skin or mucosa, which may constitute non‐obligate precursors of malignant melanoma, particularly when displaying lentiginous and dysplastic features. Here we sought to interrogate the repertoire of somatic genetic alterations in melanocytic nevi.

Methods and Results

DNA extracted from 12 melanocytic nevi and matching normal tissue were separately microdissected and subjected to targeted massively parallel sequencing targeting ≥300 cancer genes. A median of 5.5 (range 1‐12) nonsynonymous somatic mutations was detected, with 10 cases harboring mutually exclusive BRAF V600E (6/12) or NRAS (4/12) clonal hotspot mutations. One of the two cases lacking BRAF and NRAS mutations was a dysplastic nevus harboring a HRAS Q61L hotspot mutation. Analysis of the laser‐capture microdissected components of a nevus synchronously diagnosed with in situ and invasive malignant melanoma revealed a truncal, clonal BRAF V600E mutation, and the acquisition of a CDKN2A homozygous deletion in the invasive component in conjunction with additional clonal mutations affecting NF2, FAT4, and KDR in both in situ and invasive malignant components.

Conclusion

Melanocytic nevi harbor recurrent BRAF V600E or NRAS hotspot mutations with low mutational burdens. Our findings also further validate that progression from nevi to malignant melanoma may be driven by the acquisition of additional genetic alterations, including CDKN2A homozygous deletions.

This article is protected by copyright. All rights reserved.

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Application of Adeno-Associated Virus Vectors for Engineering SCF-Containing Extracellular Vesicles of Mesenchymal Stromal Cells

Mesenchymal stromal cells from rat adipose tissue were transduced with adeno-associated viral (AAV) vector encoding stem cell factor SCF that stimulates proliferation of cardiac c-kit⁺ cells and improved cardiac function and survival of animals after myocardial infarction. Extracellular vesicles isolated from the medium conditioned by mesenchymal stromal cells by ultracentrifugation were characterized by Western blotting, transmission electron microscopy, nanoparticle tracking analysis, immunostaining, and mass spectrometry analysis. Using proteomic analysis, we identified transgenic SCF in extracellular vesicles released by AAV-modified mesenchymal stromal cells and detected some proteins specific of extracellular vesicles secreted by transduced cells. Extracellular vesicles from AAV-transduced mesenchymal stromal cells could be used for delivery of transgenic proteins as they were readily endocytosed by both cardiosphere-derived cells and cardiac-progenitor cells.

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NAEMSP president discusses impact of ET3 model

Our co-hosts sit down with the NAEMSP president to discuss how the new reimbursement model will transform all aspects of the industry

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Phenobarbital‐Induced Liver Injury With Nodal Angiomatosis

Abstract

An 18‐year‐old woman presented with a 2‐week history of spiking fever after 3 weeks of daily use of phenobarbital, amoxicillin, chlorpheniramine, ergotamine, and cinnarizine for sinusitis and migraine. She denied animal contact as well as taking ethanol or supplements. Examination revealed enlarged nontender superficial lymph nodes (LNs) in her neck, a normal white blood cell count, atypical lymphocytes of 8.6%, aspartate aminotransferase of 288 U/L, alanine aminotransferase of 452 U/L, total bilirubin of 4.3 mg/dL, direct bilirubin of 3.6 mg/dL, gamma‐glutamyl transpeptidase of 469 U/L, alkaline phosphatase of 290 U/L, and lactate dehydrogenase of 619 U/L. Viral serology for hepatitis A, B, and C viruses, Epstein‐Barr virus, cytomegalovirus, herpes simplex virus, and human immunodeficiency virus were all negative.

This article is protected by copyright. All rights reserved.

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miR-29a contributes to breast cancer cells epithelial–mesenchymal transition, migration, and invasion via down-regulating histone H4K20 trimethylation through directly targeting SUV420H2

miR-29a contributes to breast cancer cells epithelial–mesenchymal transition, migration, and invasion via down-regulating histone H4K20 trimethylation through directly targeting SUV420H2

miR-29a contributes to breast cancer cells epithelial–mesenchymal transition, migration, and invasion via down-regulating histone H4K20 trimethylation through directly targeting SUV420H2, Published online: 21 February 2019; doi:10.1038/s41419-019-1437-0

miR-29a contributes to breast cancer cells epithelial–mesenchymal transition, migration, and invasion via down-regulating histone H4K20 trimethylation through directly targeting SUV420H2

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Use of Titration as a Therapeutic Individualization Strategy: An Analysis of Food and Drug Administration‐Approved Drugs

Abstract

Selecting a dose regimen that is both safe and effective for patients is one of the most critical elements of a successful drug development program. Titrating the dose regimen of a drug based on patient response may help to identify safe and effective dosages at the individual patient level. Therefore, we quantified and characterized the use of response‐guided titration for drugs recently approved by the U.S. Food and Drug Administration to assess how frequently this dosing strategy is employed and how titration regimens are evaluated during drug development. Most of the 181 drugs approved from 2013‐2017 (78%) had only one approved dosing regimen. Only 30 of 76 (39%) drugs that were considered amenable to response‐guided dosing strategies had information in labeling about such strategies. These findings indicate that while response‐guided titration can be found in labeling, this strategy is used in a minority of drugs for which it may be useful. Careful consideration should be made early in drug development as to whether a new drug is amenable to response‐guided titration as an approach to reducing inter‐patient variability.

This article is protected by copyright. All rights reserved.

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The anti‐resection activity of the X protein encoded by Hepatitis Virus B

Abstract

Chronic infection of hepatitis virus B (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein (HBx) that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits a novel anti‐resection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This anti‐resection activity occurs in primary human hepatocytes (PHHs) undergoing a natural viral infection‐replication cycle, as well as in cells with integrated HBV genomes. Among the seven HBV‐encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A‐DDB1‐RING type of E3 ligase, CRL4^WDR70, via its H‐box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 (uH2B) at double strand breaks, thus reducing the efficiency of long‐range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4^WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrated that lack of H2B monoubiquitylation is manifest in human HBV‐associated HCC (HBVHCC) when compared with HBV‐free HCC, implying corresponding defects of epigenetic regulation and end resection. We conclude that the anti‐resection activity of HBx induces an HR defect and genome instability and contributes to tumorigenesis of host hepatocytes.

This article is protected by copyright. All rights reserved.

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