IL-2 is required for the generation of viral-specific CD4+ Th1 tissue-resident memory cells and B cells are essential for maintenance in the lung

CD4⁺ tissue resident cells are an important first line of defense against viral infections in the lungs and are critical for promoting the localization of lung resident CD8⁺ T cells. However, relatively little is known about the signaling programs required for the development of viral-specific CD4⁺ tissue resident cells in the lungs. Recently, it was shown that signaling through the high affinity IL-2 receptor is required for the differentiation of lung-resident Th2 memory (Trm) cells in a murine model of airway inflammation. We therefore tested if IL-2 signaling is also required for the development of viral antigen-specific CD4⁺ Th1 cells in the lung after intranasal infection with LCMV. These studies demonstrate that Th1 CD4⁺ T cells also require IL-2 for lung Trm development. Additionally, they show that B cells potently inhibit early Th1 cell lung residency, but are required for the maintenance of a long-lived population of CD4⁺ Th1 Trm.

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Association between subjective risk perception and objective risk estimation in patients with atrial fibrillation: a cross-sectional study

Objective

Oral anticoagulation (OAC) is state-of-the-art therapy for atrial fibrillation (AF), the most common arrhythmia worldwide. However, little is known about the perception of patients with AF and how it correlates with risk scores used by their physicians. Therefore, we correlated patients' estimates of their own stroke and bleeding risk with the objectively predicted individual risk using CHA₂DS₂-VASc and HAS-BLED scores.

Design

Cross-sectional prevalence study using convenience sampling and telephone follow-up.

Settings

Eight hospital departments and one general practitioner in Austria. Patients' perception of stroke and bleeding risk was opposed to commonly used risk scoring.

Participants

Patients with newly diagnosed AF and indication for anticoagulation.

Main outcome measures

Comparison of subjective risk perception with CHA₂DS₂-VASc and HAS-BLED scores showing possible discrepancies between subjective and objective risk estimation. Patients' judgement of their own knowledge on AF and education were also correlated with accuracy of subjective risk appraisal.

Results

Ninety-one patients (age 73±11 years, 45% female) were included in this study. Subjective stroke and bleeding risk estimation did not correlate with risk scores (=0.08 and =0.17). The majority of patients (57%) underestimated the individual stroke risk. Patients feared stroke more than bleeding (67% vs 10%). There was no relationship between accurate perception of stroke and bleeding risks and education level. However, we found a correlation between the patients' judgement of their own knowledge of AF and correct assessment of individual stroke risk (=0.24, p=0.02). During follow-up, patients experienced the following events: death (n=5), stroke (n=2), bleeding (n=1). OAC discontinuation rate despite indication was 3%.

Conclusions

In this cross-sectional analysis of OAC-naive patients with AF, we found major differences between patients' perceptions and physicians' assessments of risks and benefits of OAC. To ensure shared decision-making and informed consent, more attention should be given to evidence-based and useful communication strategies.

Trial registration number

NCT03061123.

http://ift.tt/2y5dRyx

Effects of a workplace prevention programme for problem gambling: study protocol for a cluster randomised controlled trial

Introduction

Despite being considered a public health problem, no prevention programme for problem gambling in workplace settings has been scientifically evaluated. This study aims to fill a critical gap in the field of problem gambling by implementing and evaluating a large-scale prevention programme in organisations.

Methods and analysis

Ten organisations, with a total of n=549 managers and n=8572 employees, will be randomised to either receiving a prevention programme or to a waitlist control condition. Measurements will be collected at the baseline and 3, 12 and 24 months after intervention. The primary outcome of interest is the managers' inclination to act when worried or suspicious about an employee's problem gambling or other harmful use. Additional outcomes of interest include the Problem Gambling Severity Index and gambling habits in both managers and employees. Furthermore, qualitative analyses of the responses from semistructured interviews with managers will be performed.

Ethics and dissemination

This study has been approved by the regional ethics board of Stockholm, Sweden, and it will contribute to the body of knowledge concerning prevention of problem gambling. The findings will be published in peer-reviewed, open-access journals.

Trial registration number

NCT02925286; Pre-results.

http://ift.tt/2y55inc

Qualitative interviews with healthcare staff in four European countries to inform adaptation of an intervention to increase chlamydia testing

Objective

To determine the needs of primary healthcare general practice (GP) staff, stakeholders and trainers to inform the adaptation of a locally successful complex intervention (Chlamydia Intervention Randomised Trial (CIRT)) aimed at increasing chlamydia testing within primary healthcare within South West England to three EU countries (Estonia, France and Sweden) and throughout England.

Design

Qualitative interviews.

Setting

European primary healthcare in England, France, Sweden and Estonia with a range of chlamydia screening provision in 2013.

Participants

45 GP staff, 13 trainers and 18 stakeholders.

Interviews

The iterative interview schedule explored participants' personal attitudes, subjective norms and perceived behavioural controls around provision of chlamydia testing, sexual health services and training in general practice. Researchers used a common thematic analysis.

Results

Findings were similar across all countries. Most participants agreed that chlamydia testing and sexual health services should be offered in general practice. There was no culture of GP staff routinely offering opportunistic chlamydia testing or sexual health advice, and due to other priorities, participants reported this would be challenging. All participants indicated that the CIRT workshop covering chlamydia testing and sexual health would be useful if practice based, included all practice staff and action planning, and was adequately resourced. Participants suggested minor adaptations to CIRT to suit their country's health services.

Conclusions

A common complex intervention can be adapted for use across Europe, despite varied sexual health provision. The intervention (ChlamydiA Testing Training in Europe (CATTE)) should comprise: a staff workshop covering sexual health and chlamydia testing rates and procedures, action planning and patient materials and staff reminders via computer prompts, emails or newsletters, with testing feedback through practice champions. CATTE materials are available at: www.STItraining.eu.

http://ift.tt/2jYSEQw

Prevalence of and factors associated with adopting bone health promoting behaviours among people with osteoporosis in Taiwan: a cross-sectional study

Objectives

To detect osteopenia, osteoporosis, treatments received and bone health promoting behaviours early among postmenopausal women and elderly men, and to explore the associated factors.

Design

A community-based cross-sectional study.

Settings

Two rural townships in Yunlin County, Taiwan.

Participants

A total of 941 adults including 651 postmenopausal women and 290 elderly men aged >65 years.

Outcome measures

Bone mineral density was measured using dual-energy X-ray absorptiometry. Adults with a T-score <–1.0 for bone mineral density were classified as having osteopenia, and those with a T-score <–2.5 as having osteoporosis. The main outcome measures were prevalence of osteopenia, osteoporosis, receiving medication and bone health promoting behaviours. A logistic regression model was used to analyse the factors associated with adopting bone health promoting behaviours.

Results

Across both genders, 63.7% of participants were identified as having osteopenia (46.9%) or osteoporosis (16.8%). A high proportion of participants reported never or seldom performing regular exercise, or having sunlight exposure, a diet containing calcium/vitamin D or taking medications/supplements for bone health. Although 34.8% reported taking supplements, 92.4% were inadequate. The logistic regression model indicated that older age (OR 1.03, 95% CI 1.01 to 1.05, p=0.006) and a high education level (OR 1.07, 95% CI 1.03 to 1.11, p<0.001) were significant factors associated with bone health promoting behaviours.

Conclusion

The prevalence of osteopenia and osteoporosis among postmenopausal women and elderly men is worryingly high and most of them receive inadequate treatment and perform few bone health promoting behaviours. Interventions are therefore urgently required to address the right methods for delaying osteoporosis among postmenopausal women and elderly men in rural areas.

http://ift.tt/2y4IOTB

Barriers and facilitators in the integration of oral health into primary care: a scoping review

Objective

This scoping study has been conducted to map the literature and provide a descriptive synthesis on the barriers and facilitators of the integration of oral health into primary care.

Methods

Grounded in the Rainbow conceptual model and using the Levac et al six-stage framework, we performed a systematic search of electronic databases, organisational websites and grey literature from 1978 to April 2016. All publications with a focus on the integration of oral health into primary care were included except commentaries and editorials. Thematic analyses were performed to synthesise the results.

Results

From a total of 1619 citations, 58 publications were included in the review. Barrier-related themes included: lack of political leadership and healthcare policies; implementation challenges; discipline-oriented education; lack of continuity of care and services and patients' oral healthcare needs. The facilitators of integration were supportive policies and resources allocation, interdisciplinary education, collaborative practices between dental and other healthcare professionals, presence of local strategic leaders and geographical proximity.

Discussion and public health implications

This work has advanced the knowledge on the barriers and facilitators at each integration domain and level, which may be helpful if the healthcare organisations decide to integrate oral health and dental services into primary care. The scoping review findings could be useful for both dental and medical workforce and allied primary healthcare providers. They could also guide the development of healthcare policies that support collaborative practices and patient-centred care in the field of primary care.

http://ift.tt/2y4Z6vB

The Brain Games study: protocol for a randomised controlled trial of computerised cognitive training for preventing mental illness in adolescents with high-risk personality styles

Introduction

A broad range of mental disorders are now understood as aberrations of normal adolescent brain development. In both adolescents and adults, executive dysfunction has been implicated across a range of mental illnesses, and enhancing executive functioning may prove to be a useful prevention strategy for adolescents at risk for a range of psychopathology.

Methods and analysis

This study will consist of a double-blind, randomised controlled trial with a 12-month follow-up period. Participants will consist of 200 people aged 16–24 years who are at risk for a range of mental disorders based on personality risk factors, but have not experienced a lifetime mental illness as determined by a structured diagnostic interview. Participants will be randomly allocated to either an intervention group who complete an online cognitive training programme specifically targeting executive functioning ability or a control group who complete an online cognitive training programme that has limited executive functioning training potential. Superiority of the executive functioning training programme compared with the control training programme will be assessed at baseline, post-training and at 3-month, 6-month and 12-month follow-up. All assessments will be conducted online. The primary outcome of the study will be general psychopathology as measured by the Strengths and Difficulties Questionnaire. Secondary outcomes will include executive functioning ability, day-to-day functioning and alcohol consumption. All analyses will be undertaken using mixed-model repeated measures analysis of variance with planned contrasts.

Ethics and dissemination

Ethics approval has been obtained from the University of New South Wales Human Research Ethics Committee (HC15094). Results of the trial immediately post-treatment and at 12 months follow-up will be submitted for publication in peer-reviewed journals.

Trial registration number

ACTRN12616000127404; Pre-results.

http://ift.tt/2jZ0Gc5

Is one-stop surgery for carpal tunnel syndrome safe? A retrospective long-term follow-up study in a neurosurgical unit in Copenhagen

Objectives

The aim of this study was to evaluate one-stop surgery (OSS) for carpal tunnel syndrome (CTS) regarding symptom relief and patient satisfaction. OSS in our setting means only one visit to the hospital for surgery and no hospital appointments for preassessment or follow-up. We hypothesised that relief of symptoms with OSS is comparable with that in non-OSS patients reported in the literature.

Design

This is a long-term retrospective follow-up study (56.5 months) of 1003 patients referred for CTS and discharged with or without surgery from an OSS clinic. Of the original cohort, 671 patients completed the long-term follow-up telephone interview.

Results

Two-thirds of the patients were free of even minor symptoms following surgery. The symptom relief and patient satisfaction in this study were comparable with results in non-OSS patients reported in the literature.

Conclusion

The implementation of a clinical pathway and OSS for the management of CTS was safe with good long-term symptom relief and high patient satisfaction.

http://ift.tt/2y4VjOR

Cost-effectiveness of milk powder fortified with potassium to decrease blood pressure and prevent cardiovascular events among the adult population in China: a Markov model

Objective

To model the long-term cost-effectiveness of consuming milk powder fortified with potassium to decrease systolic blood pressure (SBP) and prevent cardiovascular events.

Design

A best case scenario analysis using a Markov model was conducted.

Participants

8.67% of 50–79 year olds who regularly consume milk in China, including individuals with and without a prior diagnosis of hypertension.

Intervention

The model simulated the potential impact of a daily intake of two servings of milk powder fortified with potassium (+700 mg/day) vs the consumption of a milk powder without potassium fortification, assuming a market price equal to 0.99 international dollars (intl$; the consumption of a milk powder without potassium fortification, assuming a market price equal to intl$0.99 for the latter and to intl$1.12 for the first (+13.13%). Both deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the results.

Main outcome measures

Estimates of the incidence of cardiovascular events and subsequent mortality in China were derived from the literature as well as the effect of increasing potassium intake on blood pressure. The incremental cost-effectiveness ratio (ICER) was used to determine the cost-effectiveness of a milk powder fortified with potassium taking into consideration the direct medical costs associated with the cardiovascular events, loss of working days and health utilities impact.

Results

With an ICER equal to int$4711.56 per QALY (quality-adjusted life year) in the best case scenario and assuming 100% compliance, the daily consumption of a milk powder fortified with potassium shown to be a cost-effective approach to decrease SBP and reduce cardiovascular events in China. Healthcare savings due to prevention would amount to intl$8.41 billion. Sensitivity analyses showed the robustness of the results.

Conclusion

Together with other preventive interventions, the consumption of a milk powder fortified with potassium could represent a cost-effective strategy to attenuate the rapid rise in cardiovascular burden among the 50–79 year olds who regularly consume milk in China.

http://ift.tt/2k0lfF0

Association between mothers screening uptake and daughters HPV vaccination: a quasi-experimental study on the effect of an active invitation campaign

Objectives

In Emilia-Romagna, the Human Papillomavirus (HPV) vaccination campaign started in 2008 offering free vaccines for 1996 and 1997 cohorts. Systematic active invitation was implemented for the 1997 cohort. Our study aimed at measuring the impact of the active invitation campaign on HPV vaccine coverage and on coverage inequalities in 11-year-old girls. Second, we evaluated the effect of the HPV vaccination campaign on participation in cervical cancer screening by mothers of target girls.

Methods

We collected information on vaccination status for girls residing in Reggio Emilia in 2008 and mothers' screening history, before and after the 2008 vaccination campaign. Log-binomial regression models were performed to estimate Relative Risk (RR) and 95% confidence intervals (CIs) of being vaccinated as regarded citizenship, siblings, mothers' education, marital status and screening history, stratified by birth cohort. We also calculated RR of receiving a Pap test after the vaccination campaign as regarded education, daughter's cohort and mothers' decision to have their daughter vaccinated. Interaction between education and cohort in mothers overdue for Pap testing was calculated.

Results

Vaccination coverage was 46.3% for the uninvited cohort (1046/2260) and 77.9% for the invited cohort (1798/2307). In the uninvited cohort, daughters' vaccination showed association with mothers' education (8 to 11 years of education vs. graduated mothers, RR 1.61 95% CI 1.14–2.28), citizenship (foreigners vs. Italians, RR 0.45 95% CI 0.37–0.56) and screening history (regular vs. non-participant; RR 1.72 95% CI 1.26–2.36). In the invited cohort, only a slight association with screening history persisted (regular vs. non-participant; RR 1.20 95% CI 1.04–1.40). Highly educated under-screened mothers of the invited cohort showed a higher probability of receiving a Pap test after the vaccination campaign period (RR 1.27 95% CI 1.04–1.56) compared with those not invited,

Conclusion

Active invitation could increase overall HPV immunisation coverage and reduce socio-demographic inequalities and the association with mothers' screening participation.

http://ift.tt/2y6fqMw

Effects of a new parallel primary healthcare centre and on-campus training programme on history taking, physical examination skills and medical students' preparedness: a prospective comparative study in Taiwan

Objectives

The primary healthcarecentre (PHCC) is the first place that medical students experience patient contact. Usually, medical students are frustrated by a lack of proper skills training for on-campus history taking (HT), physical examination (PE) and self-directed learning (SDL) to prepare for their PHCC and inhospital patient contact. For pre-clerks, this study aims to compare the effectiveness of PHCC training and PHCC training in combination with on-campus HT and PE training modules (PHCC+on-campus) on their clerkship preparedness.

Design

This comparative study utilised prospective, consecutive, end of pre-clerkship group objective structured clinical examination (GOSCE), beginning of clerkship OSCE and self-administered Preparation for Hospital Practice Questionnaire (PHPQ).

Setting/participants

128 pre-clinical clerk volunteers (64 each year) receiving PHCC training (7 week PHCCtraining in addition to 7 week assignment based group learning, academic year 2014, controls) and PHCC training in combination with on-campus module training (academic year 2015, 7 week PHCCtraining in addition to 7 week on-campus sessions) were sequentially assessed before the module (week 1), at the end of the module (week 14) and at the beginning of clerkship (week 25).

Results

For overall HT and PE skills, both PHCC and PHCC+on-campus module trained pre-clerks performed better on OSCE than GOSCE. Additionally, the improvement was accompanied by higher self-reported PHPQ scores in 'confidence/coping' and 'SDL' domains. At the end of the pre-clerkship and the beginning of the clerkship stages, the degree of improvement in preparedness in 'confidence/coping' and 'SDL' domains was higher for those in the PHCC+on-campus group than for those in the PHCC group. Among the PHCC+on-campus module participants, a positive association was observed between high mean PHPQ-SDL scores and high OSCE scores.

Conclusions

Our study suggests that the PHCC+on-campus module, which is paired faculty led and pre-trained dyad student assisted, is effective in developing a preclinical clerk's HT and PE skills and intensifying SDL/patient management abilities to prepare for hospital practice in clerkship.

http://ift.tt/2y4hiWa

Vitamin D status in tuberculosis patients with diabetes, prediabetes and normal blood glucose in China: a cross-sectional study

Objective

The association between tuberculosis (TB), diabetes mellitus (DM) and vitamin D status is poorly characterised. We therefore: (1) determined vitamin D status in patients with TB in relation to whether they had normal fasting blood glucose (FBG), pre-DM or DM and (2) assessed whether baseline characteristics in patients with TB, including their DM status, were associated with vitamin D deficiency.

Methods

In patients with TB consecutively attending six clinics or hospitals in China, we measured 25-hydroxycholecalciferol (25-(OH)D₃) at the time of registration using electrochemiluminescence in a COBASE 601 Roche analyser by chemiluminescence immunoassay. Data analysis was performed using the ² test, ORs and multivariate logistic regression.

Results

There were 306 eligible patients with TB, including 96 with smear positive pulmonary TB, 187 with smear negative pulmonary TB and 23 with extrapulmonary TB. Of these, 95 (31%) had normal blood glucose, 83 (27%) had pre-DM and 128 (42%) had DM. Median serum vitamin D levels were 16.1 ng/mL in patients with TB with normal FBG, 12.6 ng/mL in patients with TB with pre-DM and 12.1 ng/mL in patients with TB with DM (p<0.001). The study highlighted certain baseline characteristics associated with vitamin D deficiency (25-(OH)D₃<20 ng/mL). After adjusting for confounders, serum vitamin D deficiency was significantly more common in patients being registered in the cold season (November to April) (p=0.006) and in those with DM (p=0.003).

Conclusion

Vitamin D levels are lower in patients with TB with pre-DM and DM and are also affected by certain baseline characteristics that include being registered in the cold season and having DM. TB programmes need to pay more attention to vitamin D status in their patients, especially if there is coexisting pre-DM or DM.

http://ift.tt/2jZnCZ1

Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: protocol for a systematic review and meta-analysis

Introduction

Attention-deficit hyperactivity disorder (ADHD) has been related to increased rates of unintentional injuries. However, the magnitude of the effect and to which extent variables such as sex, age or comorbidity can influence this relationship is unknown. Additionally, and importantly, it is unclear if, and to which degree, ADHD medications can decrease the number of unintentional injuries. Due to the amount of economic and social resources invested in the treatment of injuries, filling these gaps in the literature is highly relevant from a public health standpoint. Here, we present a protocol for a systematic review and meta-analysis to estimate the relationship between ADHD and unintentional injuries and assess the impact of pharmacological treatment for ADHD

Methods and analysis

We will combine results from 114 bibliographic databases for studies relating ADHD and risk of injuries. Bibliographic searches and data extraction will be carried out independently by two researchers. The studies' risk of bias will be assessed using the Newcastle-Ottawa Scale. Articles reporting ORs or HRs of suffering an injury in ADHD compared with controls (or enough data to calculate them) will be combined using Robust Variance Estimation, a method that permits to include multiple non-independent outcomes in the analysis. All analyses will be carried out in Stata. Age, sex and comorbid conduct disorders will be considered as potential causes of variance and their effect analysed through meta-regression and subgroup analysis. Sensitivity analyses will exclude articles with longer follow-ups, non-stringent definitions of ADHD or controls and statistically uncontrolled/controlled outcomes. Studies implementing a self-controlled case series methodology to investigate if ADHD drugs reduce the risk of injuries will be combined with a generalised linear mixed model using the Poisson distribution and a log link function.

Registration details

PROSPERO—Prospective Register of Systematic Reviews (CRD42017064967)

http://ift.tt/2jZ7hU9

Perforated appendicitis in patients with schizophrenia: a retrospective cohort study

Objective

Altered pain sensitivity may affect the outcome of appendicitis in patients with schizophrenia. We aimed to compare the prevalence of perforation in appendicitis between patients with and without schizophrenia.

Design

Retrospective cohort study with random matching.

Setting

A single tertiary medical centre in Japan.

Participants

From 1985 to 2013, 1821 cases of appendicitis requiring appendectomy were collected. Patients with schizophrenia and a cohort of randomly selected control subjects without schizophrenia who underwent appendectomy were identified.

Primary and secondary outcome measures

The primary outcome was the rate of perforated appendicitis in patients with and without schizophrenia. Secondary outcome was the odds of perforated appendicitis by different clinical factors.

Results

62 patients with schizophrenia and randomly sampled 200 non-schizophrenic patients were compared. The prevalence of perforation was 53% in patients with schizophrenia versus 17% in controls (p<0.0001). The adjusted OR for perforation were 4.87 (95% CI: 2.33 to 10.2) for schizophrenia, 3.35 (95% CI 1.51 to 7.45) for age >55 years and 2.18 (95% CI: 1.12 to 4.27) for delayed presentation.

Conclusion

Appendiceal perforation was more frequent in patients with schizophrenia than controls, which may be partly attributable to delayed presentation and altered responses to pain.

http://ift.tt/2y4hpB4

Evolving landscape of stroke prevention in atrial fibrillation within the UK between 2012 and 2016: a cross-sectional analysis study using CPRD

Objective

To describe the changes in prescribing of oral anticoagulant (AC) and antiplatelet (AP) agents in patients with non-valvular atrial fibrillation (NVAF) in the UK and to identify the characteristics associated with deviation from guideline-based recommendations.

Design

Five cross-sectional analyses in a large retrospective population-based cohort study.

Setting

General practices contributing data to the UK Clinical Practice Research Datalink.

Participants

The study included patients with a diagnosis of NVAF and eligible for anticoagulation (CHA₂DS₂-VASc score ≥2) on 1 April of 2012, 2013, 2014, 2015 and 1st January 2016.

Results

The proportion of patients being treated with AC increased at each index date, showing an absolute rise of 16.7% over the study period. At the same time, the proportion of patients treated with an AP alone was reduced by half, showing an absolute decrease of 16.8%. The proportion of patients not receiving any antithrombotic (AT) treatment remained the same across the study period. A number of predictors were identified for AP alone or no treatment compared with AC treatment.

Conclusion

Major improvements in the AT management of patients with NVAF for stroke prevention in the UK were observed between April 2012 and January 2016. Despite this, nearly 20% of at-risk patients still received AP alone and over 15% were on no AT agents in January 2016.

http://ift.tt/2k1nmsy

Prevalence and risk factors of epiretinal membranes: a systematic review and meta-analysis of population-based studies

Objective

This study was to aggregate the prevalence and risks of epiretinal membranes (ERMs) and determine the possible causes of the varied estimates.

Design

Systematic review and meta-analysis.

Data sources

The search strategy was designed prospectively. We searched PubMed, Embase and Web of Science databases from inception to July 2016. Reference lists of the included literatures were reviewed as well.

Study selection

Surveys published in English language from any population were included if they had a population-based design and reported the prevalence of ERM from retinal photography with or without optical coherence tomography. Eligibility and quality evaluation was conducted independently by two investigators.

Data extraction

The literature search generated 2144 records, and 13 population-based studies comprising 49 697 subjects were finally included. The prevalence of ERM and the ORs of potential risk factors (age, sex, myopia, hypertension and so on) were extracted.

Results

The pooled age-standardised prevalence estimates of earlier ERM (cellophane macular reflex (CMR)), advanced ERM (preretinal macular fibrosis (PMF)) and any ERM were 6.5% (95% CI 4.2% to 8.9%), 2.6% (95% CI 1.8% to 3.4%) and 9.1% (95% CI 6.0% to 12.2%), respectively. In the subgroup analysis, race and photography modality contributed to the variation in the prevalence estimates of PMF, while the WHO regions and image reading methods were associated with the varied prevalence of CMR and any ERM. Meta-analysis showed that only greater age and female significantly conferred a higher risk of ERMs.

Conclusions

Our findings suggest that ERMs are relatively common among aged population. Race, image taking and reading methodology may play important roles in influencing the large variability of ERM prevalence estimates.

http://ift.tt/2y4hm8m

Suitability of a three-dimensional model to measure empathy and its relationship with social and normative adjustment in Spanish adolescents: a cross-sectional study

Objectives

(1) To examine the psychometric properties of the Basic Empathy Scale (BES) with Spanish adolescents, comparing a two and a three-dimensional structure;(2) To analyse the relationship between the three-dimensional empathy and social and normative adjustment in school.

Design

Transversal and ex post facto retrospective study. Confirmatory factorial analysis, multifactorial invariance analysis and structural equations models were used.

Participants

747 students (51.3% girls) from Cordoba, Spain, aged 12–17 years (M=13.8; SD=1.21).

Results

The original two-dimensional structure was confirmed (cognitive empathy, affective empathy), but a three-dimensional structure showed better psychometric properties, highlighting the good fit found in confirmatory factorial analysis and adequate internal consistent valued, measured with Cronbach's alpha and McDonald's omega. Composite reliability and average variance extracted showed better indices for a three-factor model. The research also showed evidence of measurement invariance across gender. All the factors of the final three-dimensional BES model were direct and significantly associated with social and normative adjustment, being most strongly related to cognitive empathy.

Conclusions

This research supports the advances in neuroscience, developmental psychology and psychopathology through a three-dimensional version of the BES, which represents an improvement in the original two-factorial model. The organisation of empathy in three factors benefits the understanding of social and normative adjustment in adolescents, in which emotional disengagement favours adjusted peer relationships. Psychoeducational interventions aimed at improving the quality of social life in schools should target these components of empathy.

http://ift.tt/2k0xfGD

Aqueous root extract of Asparagus cochinchinensis (Lour.) Merr. Has antioxidant activity in D-galactose-induced aging mice

Extracts of plants have been considered as sources of natural antioxidant agents. In this study, we aimed to explore the antioxidant capacity of the aqueous root extract of Asparagus cochinchinensis (Lour.) Merr.

http://ift.tt/2xwTnM3

Extract from mango mistletoes Dendrophthoe pentandra ameliorates TNBS-induced colitis by regulating CD4+ T cells in mesenteric lymph nodes

Mango mistletoes Dendrophthoe pentandra (MMDP) extract has attracted interest due to its pharmacological properties, including gastro protective effects. The aim of this study was to investigate whether MMDP extr...

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Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials

Abstract

The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

http://ift.tt/2y59Km5

Protein Tyrosine Phosphatase PTPN22 regulates IL-1β dependent Th17 responses by modulating dectin-1 signaling in mice

A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno-receptors. Fungal β-glucan receptor dectin-1 signals via Syk, and dectin-1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin-1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and Ptpn22^−/− mutant mice, were pulsed with OVA_323-339 and the dectin-1 agonist curdlan and co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice, and T-cell responses were determined by immunoassay. Dectin-1 activated Ptpn22^−/− BMDCs enhanced T-cell secretion of IL-17 in vitro and in vivo in an IL-1β dependent manner. Immunoblotting revealed that compared to WT, dectin-1 activated Ptpn22^−/− BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing Ptpn22^R619W (the mouse orthologue of human PTPN22^R620W) also resulted in increased IL-1β secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22^R619W operates as a loss-of-function variant. These findings highlight PTPN22 as a novel regulator of dectin-1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease.

This article is protected by copyright. All rights reserved

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Filamentation Involves Two Overlapping, but Distinct, Programs of Filamentation in the Pathogenic Fungus Candida albicans

The ability of the human pathogenic fungus Candida albicans to switch between yeast-like and filamentous forms of growth has long been linked to pathogenesis. Numerous environmental conditions, including growth at high temperatures, nutrient limitation, and exposure to serum, can trigger this morphological switch and are frequently used in in vitro models to identify genes with roles in filamentation. Previous work has suggested that differences exist between the various in vitro models both in the genetic requirements for filamentation and transcriptional responses to distinct filamentation-inducing media, but these differences had not been analyzed in detail. We compared 10 in vitro models for filamentation and found broad genetic and transcriptomic differences between model systems. The comparative analysis enabled the discovery of novel media-independent genetic requirements for filamentation as well as a core filamentation transcriptional profile. Our data also suggests that the physical environment drives distinct programs of filamentation in C. albicans, which has significant implications for filamentation in vivo.

http://ift.tt/2xChA59

Development of the pediatric daily ulcerative colitis signs and symptoms scale (DUCS): qualitative research findings

The purpose of this study is to develop patient-reported (PRO) and observer-reported (ObsRO) outcome measures of ulcerative colitis (UC) signs/symptoms in children aged 5–17 with mild/moderate UC. The daily ul...

http://ift.tt/2y5zz5E

Biosignals learning and synthesis using deep neural networks

Modeling physiological signals is a complex task both for understanding and synthesize biomedical signals. We propose a deep neural network model that learns and synthesizes biosignals, validated by the morpho...

http://ift.tt/2xIn27f

Emotional response of undergraduates to cadaver dissection

Abstract

Introduction The most effective way to learn human anatomy is through cadaver dissection. Historically, cadaver dissection has been the provenance of professional schools. Increasingly, cadaver-based courses in human anatomy are shifting to the undergraduate level, which creates both problems and opportunities because of differences between undergraduate and graduate student populations. Anxiety associated with dissecting cadavers can create a barrier to learning, and ultimately, entry into the health and medical sciences for some demographic subpopulations of undergraduates.

Methods We surveyed 76 students in 2007 and 51 students in 2009 at four times in the semester to investigate the timing and sociodemographic predictors of anxiety over cadaver dissection. We followed this with a second survey of 44 students in 2014 to test the effect of humanization of cadaver donors (providing information about donor occupation and cause of death) to reduce student anxiety.

Results Students experienced anxiety upon first exposure to cadaver dissection. Female students experienced greater anxiety than male students upon first exposure to cadavers but this effect was short-lived. Self-identified non-white, non-Christian students experienced sustained anxiety throughout the semester, likely because cadaver stress compounded social and financial stressors unique to international students. Humanization was effective in reducing anxiety in non-white, non-Christian students but had the unexpected effect of increasing anxiety in female students.

Conclusions We recommend that humanizing information be offered to students who seek it out, but not forced upon students for whom the information would only add to their stress. This article is protected by copyright. All rights reserved.

http://ift.tt/2ynLoAc

The transcriptional landscape of radiation-treated human prostate cancer: analysis of a prospective tissue cohort

Variability in response to radiation therapy is a major issue in the treatment of localized prostate cancer, and lacks predictive molecular biomarkers. We performed quantitative transcriptional profiling on matched pre- and post-radiation biopsies from a selected prospective cohort of five patients with intermediate-risk prostate cancer treated with high-dose-rate brachytherapy. We recognised both known radiation-responsive pathways plus other more novel genes with no current association with radiation response, along with a strong network of immune-related alterations.

http://ift.tt/2wQqugB

DIBH-IMRT treatment to the mediastinum for lymphoma patients: Setup uncertainties and margins

Patient setup for treating large target volumes can be challenging. In this study we measure local uncertainties in the treatment of mediastinal lymphoma patients and investigate the need for region-specific planning target volume (PTV) margins.

http://ift.tt/2yDLHb9

Microdosimetric evaluation of current and alternative brachytherapy sources - a Geant4-DNA simulation study

Radioisotopes such as 75Se, 169Yb and 153Gd have photon energy spectra and half-lives that make them excellent candidates as alternatives to 192Ir for high dose rate brachytherapy. The aim of this study was to evaluate the relative biological effectiveness (RBE) of current (192Ir, 125I, 103Pd) and alternative (75Se, 169Yb, 153Gd) brachytherapy radionuclides using Monte Carlo (MC) simulations of lineal energy distributions.

http://ift.tt/2yEx2MS

NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-Lymphocyte Responses in Patients with Myelodysplastic Syndrome

Purpose: Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are front-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that AML patients receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in MDS patients receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific-MDS directed cytotoxic T-cell immune response. Experimental Design: In a phase I study, 9 MDS patients received an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a non-overlapping schedule every four weeks with standard dose decitabine. Results: Analysis of samples serially obtained from the 7 patients who reached the end-of-study demonstrated induction of NY-ESO-1 expression in 7/7 patients and NY-ESO-1 specific CD4+ and CD8+ T-lymphocyte responses in 6/7 and 4/7 of the vaccinated patients respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time-points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T-lymphocytes. Vaccine responses were associated with a detectable population of CD141Hi conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in anti-tumor immune responses. Conclusion: These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively non-immunogenic myeloid cancer and highlight the potential for induced-antigen directed immunotherapy in a group of patients with limited options.

http://ift.tt/2wgOLYU

Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients

Purpose: Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline risk alleles. We studied EGFR T790M mutations in non-small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA. Experimental Design: Patients with EGFR-mutant NSCLC, some with known germline EGFR T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested. Results: In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of EGFR driver mutations. Review of plasma NGS results reveals three groups of variants: a low AF tumor group, a heterozygous group (~50% AF), and a homozygous group (~100% AF). As the EGFR driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with non-squamous NSCLC (p<0.0001). Conclusion: With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing.

http://ift.tt/2fnX6TH

Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer

Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect. Experimental Design: LMW-E was examined in breast cancer specimen from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells. Results: Breast cancer recurrence-free interval was significantly worst in LMW-E positive patients who received AI neoadjuvant therapy. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell cycle inhibition by AIs in a CDK2/Rb-dependent manner and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, while treatment with palbociclib, a CDK4/6 inhibitor, did not. Conclusion: Collectively, these findings suggest that cell cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E.

http://ift.tt/2whSOEy

4-1BB agonist focuses CD8+ tumor-infiltrating T-cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer

Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TIL capable of autologous tumor recognition. Additionally, we explored the phenotype and TCR repertoire of the CD8+ TIL in the tumor microenvironment. Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB co-stimulation and assessed changes in TIL growth, phenotype, repertoire, and anti-tumor function. Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TIL were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL-2 alone. TIL from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets. Conclusions: Co-stimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy.

http://ift.tt/2fnhB31

Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Cefepime in an In Vitro Infection Model [PublishAheadOfPrint]

We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (%T>threshold). Using data from studies of Enterobacteriaceae-producing ESBL, a relationship between tazobactam %T>threshold and reduction in log₁₀ CFU from baseline, for which tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment in vitro infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized and a translational relationship across ESBL-producing Enterobacteriaceae was developed. Four clinical isolates, two Escherichia coli and two Klebsiella pneumoniae, known to produce CTX-M-15 β-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/L in the presence of 4 mg/L tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625-1 times the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam %T>threshold and change in log₁₀ CFU from baseline was the product of 0.125 and the cefepime-tazobactam MIC (R²=0.813). The magnitude of %T>threshold associated with net bacterial stasis and a 1-log₁₀ CFU/mL reduction from baseline at 24 hours was 21.9 and 52.8%, respectively. These data will be useful to support the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies.

http://ift.tt/2xGtcEH

SPR741, an antibiotic adjuvant, potentiates the in vitro and in vivo activity of rifampin against clinically relevant XDR-Acinetobacter baumannii [PublishAheadOfPrint]

Acinetobacter baumannii is responsible for 10% of all nosocomial infections and has >50% mortality rates when causing ventilator-associated pneumonia. In this proof-of-concept study, we evaluated SPR741, an antibiotic adjuvant that permeabilizes the Gram-negative membrane, in combination with rifampin against AB5075, an XDR-A. baumannii strain. In standard in vitro assays and in a murine pulmonary model, we found this drug combination can significantly reduce bacterial burden and promote animal survival despite an aggressive infection.

http://ift.tt/2fujE9d

Emergence of Ceftolozane-Tazobactam Resistant Pseudomonas aeruginosa During Treatment is Mediated by a Single AmpC Structural Mutation [PublishAheadOfPrint]

Ceftolozane-tazobactam is a cephalosporin β-lactamase-inhibitor combination that exhibits potent in vitro activity against Pseudomonas aeruginosa, including strains resistant to other β-lactams. Emergence of ceftolozane-tazobactam resistance has rarely been described among clinical isolates of P. aeruginosa. Here we characterized ceftolozane-tazobactam resistant P. aeruginosa strains that were recovered from a patient treated with this agent for 6 weeks for a recurrent wound infection. The result showed that the resistance is mediated by a single AmpC structural mutation.

http://ift.tt/2xGt6Nl

K13-propeller Alleles, Mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015 [PublishAheadOfPrint]

High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as a delayed parasite clearance time, manifesting as a positive thick-blood smear on Day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparum kelch13 gene (K13-propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of parasite isolates showed D3 positivity, 100% (163/163) of isolates carried wild-type K13-propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double-mutant NFSDD mdr1 haplotype. These data suggest that ART resistance is not currently suspected in Colombia, but that monitoring for lumefantrine resistance and AL failures should continue.

http://ift.tt/2fudUfQ

The Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor [PublishAheadOfPrint]

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic hepatitis C virus (HCV) genotype 1 or 4 infection. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR 200, 100, and 50 mg in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, versus healthy matched controls (Protocol MK-5172_p013). Participants with mild, moderate, or severe HI and race-, age-, sex-, and body mass index--matched controls (aged 18-65 years) were enrolled in a 3-part, open-label, sequential-panel, pharmacokinetic study. Participants received multiple oral doses of 200 (2x100-mg tablets), 100 (1x100-mg tablet), or 50 mg (2x25-mg tablets) GZR once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls per hepatic cohort. Participants with HI demonstrated higher GZR exposure compared with healthy matched controls, and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC_0-24 in participants with mild, moderate, or severe HI was 2-, 5-, and 12-fold higher, respectively, than healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated in those with moderate or severe HI (Child-Pugh B or C), as they may have significantly increased GZR exposures that may lead to increased risk of transaminase elevations.

http://ift.tt/2xGt2x5

Genetics of nevirapine metabolic pathways at steady state in HIV-infected Cambodians [PublishAheadOfPrint]

Nevirapine is metabolized by several hepatic cytochrome P450 (CYP) isoforms to generate four primary hydroxylated metabolites: 2-hydroxynevirapine, 3-hydroxynevirapine, 8-hydroxynevirapine and 12-hydroxynevirapine. The present study characterized associations between genetic polymorphisms and metabolite ratios in HIV-infected Cambodians. We demonstrate associations between CYP2B6 polymorphisms and metabolite ratios for both 3-hydroxynevirapine and 8-hydroxynevirapine, suggesting involvement of CYP2B6 in generating these metabolites.

http://ift.tt/2fu80va

Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane and Meropenem: The Pharmacological Basis for a Stand-Alone {beta}-Lactamase Inhibitor [PublishAheadOfPrint]

A major challenge in treating patients is the selection of the "right" antibiotic regimen. Given that the optimal β-lactam-β-lactamase inhibitor pair is dependent upon the spectrum of β-lactamase enzymes produced and the frequency of resistance to the β-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the "right" β-lactam rather than only in a fixed combination. In this communication, we describe a one-compartment in vitro infection model studies conducted to identify the magnitude of the pharmacokinetic-pharmacodynamic (PK-PD) index for a β-lactamase inhibitor, CB-618, that would restore the activity of four β-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with varying dose (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (5), Escherichia coli (2), and Enterobacter cloacae (1), which produced a large variety of β-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each partner β-lactam. The CB-618 ratio of the area under the concentration-time curve from 0 to 24 hours to the minimum inhibitory concentration (AUC:MIC ratio) associated with net bacterial stasis and 1- and 2-log₁₀ CFU/mL reduction from baseline at 24 hours was 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone β-lactamase inhibitor.

http://ift.tt/2xHJcWS

Detection of OXA-58-producing Acinetobacter seifertii recovered from black-necked swan at a Zoo Lake [PublishAheadOfPrint]

Acinetobacter spp. are ubiquitous pathogens broadly encountered in the environmental with some species like A. baumannii, A. pittii and A. nosocomialis more frequently detected in the nosocomial settings (1)....

http://ift.tt/2ftyiNV

Long-term results of temperature-controlled endobiliary radiofrequency ablation in a normal swine model

Endobiliary radiofrequency ablation (EB-RFA) is a new adjunctive method for biliary drainage restoration. However, a concern remains about long-term adverse events of this procedure, such as biliary stricture, perforation and hemorrhage. Therefore, we aimed to assess the long-term effects of in vivo EB-RFA in a swine model.

http://ift.tt/2wicCr8

The impact of advanced endoscopic imaging on Barrett’s esophagus in daily clinical practice

Several advanced imaging techniques have been proposed to improve the visualization of dysplastic regions within Barrett's epithelium, with some evidence for the use of narrow-band imaging and acetic acid chromo-endoscopy.

http://ift.tt/2wicwzM

Alcoholic Cardiomyopathy: Translation Model

We developed a translation model of alcoholic cardiomyopathy in rats. By the end of forced alcoholization (the rats received 10% ethanol solution as the only source of fluid for 24 weeks; mean daily ethanol consumption was 5.0-6.5 g/kg), the rats developed dilated heart failure. Echocardiography and morphometric study of the myocardium revealed a decrease in inotropic function of the heart and dilatation of the right and left ventricles. Fatty degeneration of the myocardium (pathognomonic sign of alcoholic cardiomyopathy) and decrease in electrical stability of cardiomyocytes reliably reproduce the clinical pattern of alcoholic cardiomyopathy.

http://ift.tt/2fnUfKt

Effects of Fluorencarbonic Acid Derivative on the Levels of Monoamines and Their Metabolites in Brain Structures of Rats with Modeled Depression-Like State

The effects of the new structural analogue of benactyzine, a derivative of fluorencarbonic acid, on monoamine levels in brain structures were studied in male Wistar rats with experimental depression. Depressive state in rats was modeled by single injection of reserpine (4 mg/kg). The concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the hypothalamus and striatum were measured by HPLC. It was found that preliminary treatment (30 days) with the derivative of fluorencarbonic acid prevented a decrease in monoamine level in the hypothalamus (NE, 5-HT, and 5-HIAA) and striatum (DA, 5-HT, and 5-HIAA). The neurochemical shifts (correction of 5-HT deficiency and stabilization of DA and NE levels) correlated with the high antidepressant activity of this agent observed in Porsolt forced swimming test.

http://ift.tt/2whdIU8

Matrixins in the Salivary Fluid of Patients with Tumors of the Maxillofacial Region during Orthopedic Rehabilitation with Different Prosthetic Structures

Dental and immunological features of the influence of various prosthetic structures of orthopedic prostheses on tissues and organs of the maxillofacial region were evaluated by the parameters of expression of oral fluid biomarkers. Healthy people without tumor and somatic diseases and patients with neoplasms of maxillofacial area in need of dental rehabilitation were examined before and in 2 weeks and 3 months after treatment. Certain regularities in the reaction of biomarkers to orthopedic prostheses were observed: a decrease in activity of MMP-2 and MMP-8 and their inhibitors or an increase in MMP-9; an increase in activity of biomarkers at early terms and a decrease in delayed terms after prosthetics.

http://ift.tt/2fn2feU

hsa-miR-1973 MicroRNA is Significantly and Differentially Expressed in MDA-MB-231 Cells of Breast Adenocarcinoma and Xenografts Derived from the Tumor

The gene expression profiles of MDA-MB-231 cell line of breast cancer and xenografts derived from this tumor in murine model were analyzed using GeneChip Human Transcriptome array 2.0 platform (Affymetrix). A more than 1000-fold increase in the MIR1973 gene expression was observed in the xenografts compared to the original cell line. Real-time reverse transcription PCR showed that the content of mature hsa-miR-1973 microRNA encoded by this gene was elevated in the xenografts by more than 300 times. According to microarray analysis, none of hsa-miR-1973 target genes available in the databases changed the expression in the cell line and xenografts. A possible role of hsa-miR-1973 is reduction of apoptosis in the tumor.

http://ift.tt/2whCinY

Relationship between the Contents of Cyclins, Cyclin-Dependent Kinases, and Their Inhibitors in Whole Blood Mononuclear Leukocytes during the Postclinical Stage of Community-Acquired Pneumonia under the Influence of 1-GHz Microwaves

The contents of cyclins A1, B1, E1, and D1, cyclin-dependent kinases 2 and 4 (CDK2 and CDK4), cyclin-dependent kinase 2C inhibitor (p18), and cyclin-dependent kinase 1C inhibitor (p57) in whole blood mononuclear cells of practically healthy donors and convalescents from community-acquired pneumonia were measured after cell exposure to low-intensity electromagnetic radiation of 1 GHz. The level of cyclins A1, D1, and B1, p57, and p18 proteins, and CDK2 was reduced in convalescents, while the content of cyclin B1 was elevated in both groups. A strong correlation was found between the content of cyclin B1 and the levels of cyclin A1 and CDK2 in convalescents. Single exposure of whole blood cells to 1-GHz microwaves was accompanied by an increase in the content of the analyzed factors (particularly, cyclins A1 and E1). These data indicate that radiation induced activation of the synthetic phase of the cell cycle.

http://ift.tt/2fn2c2I

Effects of Pegylated Glucagon-Like Peptide-1 Analogue in C57Bl/6 Mice under Optimal Conditions and During Streptozotocin-Induced Diabetes

Biological activity of a new pegylated form of an of glucagon-like peptide-1 (GLP-1) analogue pegGLP-1 was studied in C57Bl/6 mice under normal conditions and during modeling of streptozotocin-induced type I diabetes mellitus. pegGLP-1 differs from GLP-1 (7-37) by polyethylene glycol residue covalently bound to His₇, Lys₂₆, and Lys₃₄ of the GLP-1 molecule. It was shown that single intragastrical administration of pegGLP-1 induced an increase in GLP-1 level in blood serum of healthy mice. The maximum level of this parameter was observed in 4-8 h. pegGLP-1 elimination half-time was 8.5 h and mean retention time was 15 h. Administration of pegGLP-1 to animals with modeled type I diabetes mellitus was followed by an increase in the levels of GLP-1 and insulin in blood serum, produced a hypoglycemic effect, and improved the parameters of glucose-tolerance test. Biological activity of pegGLP-1 was higher than activity of GLP-1.

http://ift.tt/2wicpnQ

Approved Drugs Might Work in More Cancers [News in Brief]

Multiarm trial successfully matches patients with available therapies based on mutation, tissue type.

http://ift.tt/2hs5xSc

Checkpoint Inhibitor Combo Effective for RCC [News in Brief]

Nivolumab plus ipilimumab increases progression-free survival in high- and intermediate-risk patients.

http://ift.tt/2hvhWkR

Modifiable risk factors for typhoid intestinal perforations during a large outbreak of typhoid fever, Kampala Uganda, 2015

Between January and June, 2015, a large typhoid fever outbreak occurred in Kampala, Uganda, with 10,230 suspected cases. During the outbreak, area surgeons reported a surge in cases of typhoid intestinal perfo...

http://ift.tt/2wQqxJB

Bordetella bronchiseptica pneumonia in a patient with lung cancer; a case report of a rare infection

Bordetella bronchiseptica (B.bronchiseptica) is a frequent cause of respiratory infections in animals but rarely causes serious infection in humans. We present a rare case of B. bronch...

http://ift.tt/2yCKy3r

Rationale and design of ASPIRE-ICU: a prospective cohort study on the incidence and predictors of Staphylococcus aureus and Pseudomonas aeruginosa pneumonia in the ICU

The epidemiology of ICU pneumonia caused by Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) is not fully described, but is urgently needed to support the development of effective inte...

http://ift.tt/2wQqltR

Long-term outcome in survivors of neonatal tetanus following specialist intensive care in Vietnam

Neonatal tetanus continues to occur in many resource-limited settings but there are few data regarding long-term neurological outcome from the disease, especially in settings with critical care facilities.

http://ift.tt/2yDCkbd

Cervical precancerous changes and selected cervical microbial infections, Kiambu County, Kenya, 2014: a cross sectional study

Cervical cancer is the predominant cancer among women in Kenya and second most common in women in developing regions. Population-based cytological screening and early treatment reduces morbidity and mortality ...

http://ift.tt/2wQqcXl

PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4+ TILs in the presence of PD-L1+ TAMs

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of PD-1-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+ and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-L1 to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TIL. We found that CD4+ TIL were present in equal or greater frequencies than CD8+ TIL in 94% of OTSCC, and that CD4+ FOXP3neg TIL were co-localized with PD-1/PD-L1/CD68 more frequently than CD8+ TIL. However, both CD4+PD1+ and CD8+PD1+ TIL were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TIL as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy.

http://ift.tt/2hveqqB

Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a

Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA (ceRNA) for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting.

http://ift.tt/2hsSgcg

Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment.

http://ift.tt/2hw9txK

Integrated analysis of whole-genome ChIP-Seq and RNA-Seq data of primary head and neck tumor samples associates HPV integration sites with open chromatin marks

Chromatin alterations mediate mutations and gene expression changes in cancer. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has been utilized to study genome-wide chromatin structure in human cancer cell lines, yet numerous technical challenges limit comparable analyses in primary tumors. Here we have developed a new whole-genome analytical pipeline to optimize ChIP-Seq protocols on patient-derived xenografts from human papillomavirus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) samples. We further associated chromatin aberrations with gene expression changes from a larger cohort of the tumor and normal samples with RNA-Seq data. We detect differential histone enrichment associated with tumor-specific gene expression variation, sites of HPV integration in the human genome, and HPV-associated histone enrichment sites upstream of cancer driver genes, which play central roles in cancer associated pathways. These comprehensive analyses enable unprecedented characterization of the complex network of molecular changes resulting from chromatin alterations that drive HPV-related tumorigenesis.

http://ift.tt/2htqXOY

KIT suppresses BRAFV600E-mutant melanoma by attenuating oncogenic RAS/MAPK signaling

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF or NRAS activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation.

http://ift.tt/2hvGeen

Combined CDK4/6 and PI3K{alpha} inhibition is synergistic and immunogenic in triple negative breast cancer

New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy. Combined PI3Kα and CDK4/6 inhibition significantly increased tumor-infiltrating T cell activation and cytotoxicity and decreased the frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined PI3Kα and CDK4/6 inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of PI3Kα and CDK4/6 blockade on cell cycle progression, DNA damage response, and immune-modulation and may provide a novel therapeutic approach for TNBC.

http://ift.tt/2htqSLa

Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric

Metastasis is a significant contributor to morbidity and mortality for many cancer patients and remains a major obstacle for effective treatment. In many tissue types, metastasis is fueled by the epithelial-to-mesenchymal transition (EMT), a dynamic process characterized by phenotypic and morphologic changes concomitant with increased migratory and invasive potential. Recent experimental and theoretical evidence suggests that cells can be stably halted en route to EMT in a hybrid E/M phenotype. Cells in this phenotype tend to move collectively, forming clusters of circulating-tumor-cells that are key tumor-initiating agents. Here we developed an inferential model built on the gene expression of multiple cancer subtypes to devise an EMT metric that characterizes the degree to which a given cell line exhibits hybrid E/M features. Our model identified drivers and fine-tuners of epithelial-mesenchymal plasticity and recapitulates the behavior observed in multiple in vitro experiments across cancer types. We also predicted and experimentally validated the hybrid E/M status of certain cancer cell lines, including DU145 and A549. Lastly, we demonstrated the relevance of predicted EMT scores to patient survival and observed that the role of the hybrid E/M phenotype in characterizing tumor aggressiveness is tissue- and subtype-specific. Our algorithm is a promising tool to quantify the EMT spectrum, to investigate the correlation of EMT score with cancer treatment response and survival, and to provide an important metric for systematic clinical risk stratification and treatment.

http://ift.tt/2hw9v8Q

XRRA1 Targets ATM/CHK1/2-Mediated DNA Repair in Colorectal Cancer

X-ray radiation resistance associated 1 (XRRA1) has been found to regulate the response of human tumor and normal cells to X-radiation (XR). Although XRRA1 overexpression is known to be involved in cancer cell response to XR, there are no reports about whether the expression of XRRA1 in tumors can adjust radioresistance. It is widely known that cell cycle arrest could cause radioresistance. We found that blocked XRRA1 expression could lead to cell cycle G2/M arrest by the regulation of cyclin A, cyclin E, and p21 proteins in colorectal cancer (CRC) and expression of XRRA1 reduced cell cycle arrest and increased cell proliferation in CRC. However, whether regulation of the cell cycle by XRRA1 can influence radioresistance is poorly characterized. Correspondingly, DNA repair can effectively lead to radioresistance. In our study, when cancer cells were exposed to drugs and ionizing radiation, low expression of XRRA1 could increase the phosphorylation of DNA repair pathway factors CHK1, CHK2, and ATM and reduce the expression of γ-H2AX, which is believed to participate in DNA repair in the nucleus. Crucially, our results identify a novel link between XRRA1 and the ATM/CHK1/2 pathway and suggest that XRRA1 is involved in a DNA damage response that drives radio- and chemoresistance by regulating the ATM/CHK1/2 pathway.

http://ift.tt/2y4EVxJ

Vitamin B-6, Independent of Homocysteine, Is a Significant Factor in Relation to Inflammatory Responses for Chronic Kidney Disease and Hemodialysis Patients

The purpose of this study was to investigate whether plasma pyridoxal 5′-phosphate (PLP) and homocysteine were dependent on or independent of each other in order to be associated with inflammatory markers in patients with chronic kidney disease (CKD) or those receiving hemodialysis treatment. This was a cross-sectional study. Sixty-eight stage 2–5 CKD patients and 68 hemodialysis patients had one time fasting blood drawn for measurements of plasma PLP, pyridoxal (PL), homocysteine, and several inflammatory markers. Early CKD stage (stages 2-3) patients showed significantly lower plasma PLP levels and homocysteine concentrations than patients in an advanced CKD stage (stages 4-5) and those undergoing hemodialysis. Plasma PLP significantly correlated with CRP levels (partial = −0.21, ) and plasma PL significantly correlated with IL-10 levels (partial = −0.24, ), while plasma PLP plus PL significantly correlated with both CRP levels (partial = −0.20, ) and interleukin-1β (partial = 0.22, ) levels after adjusting for plasma homocysteine and other potential confounders. Plasma homocysteine displayed no significant correlations with any inflammatory markers. Vitamin B-6 status, rather than homocysteine, appeared to be a significant factor in relation to inflammatory responses for CKD and hemodialysis patients.

http://ift.tt/2jZFpyX

IMP3: a potential diagnostic and therapeutic biomarker for cancers

Immunohistochemical expression levels of insulin-like growth factor II mRNA-binding protein 3 (IMP3) have been reported to be implicated in the migration, invasion, and metastasis of various cancers. However, IMP3 expression signatures and function profiles in human colorectal cancer (CRC) are still largely elusive. Surprisingly, we read with great interest the recently published work by Wei et al. [1], demonstrating that IMP3 is significantly highly regulated in patients with CRC resection specimens.

http://ift.tt/2xxOGkW

The Ethanol Extract of Licorice (Glycyrrhiza uralensis) Protects against Triptolide-Induced Oxidative Stress through Activation of Nrf2

To investigate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2) in licorice ethanol extract (LEE) against triptolide- (TP-) induced hepatotoxicity, HepG2 cells were exposed to LEE (30, 60, and 90 mg·L−1) for 12 h and then treated with TP (50 nM) for 24 h. Besides, an acute liver injury model was established in ICR mice by a single dose of TP (1.0 mg·kg−1, i.p.). Relevant oxidant and antioxidant mediators were analyzed. TP led to an obvious oxidative stress as evidenced by increasing levels of ROS and decreasing GSH contents in HepG2 cells. In vitro results were likely to hold true in in vivo experiments. LEE protected against TP-induced oxidative stress in both in vitro and in vivo conditions. Furthermore, the decreased level of Nrf2 in the TP-treated group was observed. The mRNA levels of downstream genes decreased as well in ICR mice liver, whereas they increased in HepG2 cells. In contrast, LEE pretreatment significantly increased the level of Nrf2 and its downstream genes. LEE protects against TP-induced oxidative stress partly via the activation of Nrf2 pathway.

http://ift.tt/2y4ygDX

32 Consecutive Cases of Whipple’s Operation with Single-Layer End to Side Dunking Pancreatojejunostomy Without Any Pancreatic Fistula: Our Institutional Experience

Abstract

The aim of this paper is to study the outcome of single-layer end to side dunking pancreatojejunostomy technique in 32 patients of malignant pancreatic disease undergoing Whipple's surgery in a tertiary care oncology centre in India. From January 2013 to January 2016, 32 consecutive patients who underwent pancreatoduodenectomy for malignant diseases were analysed retrospectively. All the patients underwent standard Whipple's operation. Pancreatojejunostomy was established in a single-layer end to side dunking manner with PDS 4-0. Various patient data, i.e. preoperative symptoms and demography, intra-operative time, blood loss and need of blood transfusion, postoperative hospital stay and complications, were noted. Mean operative time was 3.5 h approximately. Mean blood loss was 328 ml approx (range 150–600 ml). Postoperative delayed gastric emptying was observed in 8 (25%) patients. Three (9.4%) patients developed superficial surgical site infection. Mean hospital stay was 16.5 days (range 13–20 days). There were no pancreatic leak or fistula and no perioperative mortality. It is a feasible technique. It achieved zero leak rates, zero mortality and minimal morbidity without compromising any oncologic principles.

http://ift.tt/2htO9N8

Bridge Occlusion Balloon Catheter Model 590-001 by Spectranetics: Class I Recall - Clinical Issue

Audience: Risk Manager, Emergency Medicine, Cardiology [Posted 09/25/2017] ISSUE: Spectranetics is recalling its Bridge Occlusion Balloon Catheter due to the possibility of a blocked guidewire lumen in some device units. If a device with a blocked...

http://ift.tt/2htP3ch

Development of a questionnaire to evaluate patients awareness of cardiovascular disease risk in Englands National Health Service Health Check preventive cardiovascular programme

Background

The National Health Service (NHS) Health Check is a cardiovascular disease (CVD) risk assessment and management programme in England aiming to increase CVD risk awareness among people at increased risk of CVD. There is no tool to assess the effectiveness of the programme in communicating CVD risk to patients.

Aims

The aim of this paper was to develop a questionnaire examining patients' CVD risk awareness for use in health service research evaluations of the NHS Health Check programme.

Methods

We developed an 85-item questionnaire to determine patients' views of their risk of CVD. The questionnaire was based on a review of the relevant literature. After review by an expert panel and focus group discussion, 22 items were dropped and 2 new items were added. The resulting 65-item questionnaire with satisfactory content validity (content validity indices≥0.80) and face validity was tested on 110 NHS Health Check attendees in primary care in a cross-sectional study between 21 May 2014 and 28 July 2014.

Results

Following analyses of data, we reduced the questionnaire from 65 to 26 items. The 26-item questionnaire constitutes four scales: Knowledge of CVD Risk and Prevention, Perceived Risk of Heart Attack/Stroke, Perceived Benefits and Intention to Change Behaviour and Healthy Eating Intentions. Perceived Risk (Cronbach's α=0.85) and Perceived Benefits and Intention to Change Behaviour (Cronbach's α=0.82) have satisfactory reliability (Cronbach's α≥0.70). Healthy Eating Intentions (Cronbach's α=0.56) is below minimum threshold for reliability but acceptable for a three-item scale.

Conclusions

The resulting questionnaire, with satisfactory reliability and validity, may be used in assessing patients' awareness of CVD risk among NHS Health Check attendees.

http://ift.tt/2wPYERG

Reimplantation of an extruded osteoarticular segment of the femur: case series and in vitro study in a rat model

Publication date: Available online 25 September 2017
Source:Injury
Author(s): Tao Li, Ze Z. Yang, Ming Z. Peng, Xiao J. Zhou, Zhi Y. Liu, Bi Y. Rui, Qi Li, Shang C. Guo, Ming Xiao, Jin W. Wang
BackgroundThe treatment of open femur fractures with reimplantation of large extruded segments remains one of the most difficult clinical management scenarios. The situation is even complicated when the extruded segments contains a large osteoarticular segment and no consensus exist about the efficient sterilization. We successfully managed five cases of open femur fracture by reimplantation of a large osteoarticular segment. While the outcomes were favourable, we performed an in vitro investigation in a rat model to determine whether the bone segment preparation strategy was optimal.Materials and methodsAfter meticulous debridement and sterilization with povidone-iodine scrub/orthopaedic antibiotic solution, osteoarticular segments of the femur were reimplanted successfully in five patients with Gustilo-Anderson IIIa-IIIb fractures. Furthermore, in vitro study performed to assess the relative efficacy of various methods of sterilization employed osteoarticular segments of rat femurs. After contamination, osteoarticular segments were treated via one of the following protocols: (1) saline rinse; (2) povidone-iodine scrub and saline rinse; (3) povidone-iodine scrub and autoclaving; (4) povidone-iodine scrub and immersion in antibiotic solution; (5) povidone-iodine scrub and immersion in povidone-iodine solution; or (6) povidone-iodine scrub and gamma-irradiation. The osteoarticular segments were then cultured and finally evaluated for infection and morphological changes.ResultsAt the mean 40 month follow-up, there were no infection in the patients and the fractures achieved completed union. For the basic research, only approaches involving povidone-iodine scrub with autoclaving or antibiotic solution immersion were 100% effective in eliminating bacterial growth. Furthermore, povidone-iodine scrub with antibiotic solution immersion preserved the articular surface morphology.ConclusionOur study suggests that reimplantation of extruded osteoarticular segments of long bone may represent a feasible alternative to amputation. This is the first description of such a technique and its long-term outcomes in the clinical setting, which were corroborated with the outcomes of in vitro investigation in a rat model, concluding that contaminated extruded osteoarticular segments can be adequately sterilized for reimplantation by cleaning with povidone-iodine scrub followed by brief soaking in antibiotic solution. However, it remains unclear whether the antibacterial efficacy of different sterilizations noted in vitro is reflected in vivo, warranting further research.



http://ift.tt/2yDoeqj

Bridge Occlusion Balloon Catheter Model 590-001 by Spectranetics: Class I Recall - Clinical Issue

Audience: Risk Manager, Emergency Medicine, Cardiology [Posted 09/25/2017] ISSUE: Spectranetics is recalling its Bridge Occlusion Balloon Catheter due to the possibility of a blocked guidewire lumen in some device units. If a device with a blocked...

http://ift.tt/2htP3ch

U.S. Immigration Policy and American Medical Research: The Scientific Contributions of Foreign Medical Graduates

Although considerable discussion is under way regarding how proposed policies restricting the immigration of foreign medical graduates might negatively affect patient care in the United States, not much analysis has been done on how such restrictions might affect the U.S. biomedical research enterprise. The authors used a national physician database to provide estimates of the effect of such policies.

http://ift.tt/2htLeUw

Yellow Fever Vaccine Shortages in the United States and Abroad: A Critical Issue

Yellow fever is associated with substantial illness and mortality, and no specific therapy exists. Although a safe and effective vaccine is available, it is currently in very short supply. The author discusses the global implications of this shortage and outlines scientific and programmatic initiatives needed to ensure a future robust vaccine supply.

http://ift.tt/2hweFSa

Age Differences in Hospital Mortality for Acute Myocardial Infarction: Implications for Hospital Profiling

Background:

Publicly reported hospital risk-standardized mortality rates (RSMRs) for acute myocardial infarction (AMI) are calculated for Medicare beneficiaries. Outcomes for older patients with AMI may not reflect general outcomes.

Objective:

To examine the relationship between hospital 30-day RSMRs for older patients (aged ≥65 years) and those for younger patients (aged 18 to 64 years) and all patients (aged ≥18 years) with AMI.

Design:

Retrospective cohort study.

Setting:

986 hospitals in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry—Get With the Guidelines.

Participants:

Adults hospitalized for AMI from 1 October 2010 to 30 September 2014.

Measurements:

Hospital 30-day RSMRs were calculated for older, younger, and all patients using an electronic health record measure of AMI mortality endorsed by the National Quality Forum. Hospitals were ranked by their 30-day RSMRs for these 3 age groups, and agreement in rankings was plotted. The correlation in hospital AMI achievement scores for each age group was also calculated using the Hospital Value-Based Purchasing (HVBP) Program method computed with the electronic health record measure.

Results:

267 763 and 276 031 AMI hospitalizations among older and younger patients, respectively, were identified. Median hospital 30-day RSMRs were 9.4%, 3.0%, and 6.2% for older, younger, and all patients, respectively. Most top- and bottom-performing hospitals for older patients were neither top nor bottom performers for younger patients. In contrast, most top and bottom performers for older patients were also top and bottom performers for all patients. Similarly, HVBP achievement scores for older patients correlated weakly with those for younger patients (R = 0.30) and strongly with those for all patients (R = 0.92).

Limitation:

Minority of U.S. hospitals.

Conclusion:

Hospital mortality rankings for older patients with AMI inconsistently reflect rankings for younger patients. Incorporation of younger patients into assessment of hospital outcomes would permit further examination of the presence and effect of age-related quality differences.

Primary Funding Source:

American College of Cardiology.

http://ift.tt/2htDT7n

Age-Related Differences in Hospital Quality of Care for Acute Myocardial Infarction: Getting to the Heart of the Matter

Dharmarajan and colleagues found differences in hospital 30-day risk-standardized mortality rates for acute myocardial infarction for patients aged 65 years or older compared with those for younger patients. The editorialist discusses why hospital quality might vary by age and why a single metric calculated by a complex formula that weights performance in different domains is not what patients need to guide decisions.

http://ift.tt/2hufVVY

Using Wearable Devices and Smartphones to Track Physical Activity: Initial Activation, Sustained Use, and Step Counts Across Sociodemographic Characteristics in a National Sample

http://ift.tt/2htLaEg

Curing Hepatitis C Virus Infection: Best Practices From the U.S. Department of Veterans Affairs

The U.S. Department of Veterans Affairs (VA) is the nation's largest care provider for hepatitis C virus (HCV)–infected patients and is uniquely suited to inform national efforts to eliminate HCV. An extensive array of delivery of services, policy guidance, outreach efforts, and funding has broadened the reach and capacity of the VA to deliver direct-acting antiviral (DAA) HCV therapy, supported by an infrastructure to effectively implement change and informed by extensive population health data analysis. The VA has treated more than 92 000 HCV-infected veterans since all-oral DAAs became available in January 2014, with cure rates exceeding 90%; only 51 000 veterans in VA care are known to remain potentially eligible for treatment. Key actions advancing the VA's aggressive treatment of HCV infection that are germane to non-VA settings include expansion of treatment capacity through the use of nonphysician providers, video telehealth, and electronic technologies; expansion of integrated care to address psychiatric and substance use comorbidities; and electronic data tools for patient tracking and outreach. A critical component of effective implementation has been building infrastructure through the creation of regional multidisciplinary HCV Innovation Teams, whose system redesign efforts have produced innovative HCV practice models addressing gaps in care while providing more efficient and effective HCV management for the populations they serve. Financing for HCV treatment and infrastructure resources coupled with reduced drug prices has been paramount to the VA's success in curing HCV infection. The VA is poised to share and extend best practices to other health care organizations and providers delivering HCV care, contributing to a concerted effort to reduce the overall burden of HCV infection.

http://ift.tt/2hv7KsJ

FDA Conducts Major Global Operation to Protect Consumers From Potentially Dangerous Prescription Drugs Sold Online

September 25, 2017 -- The U.S. Food and Drug Administration, in partnership with international regulatory and law enforcement agencies, recently took action against more than 500 websites that illegally sell potentially dangerous, unapproved...

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Criminal and Civil Actions Filed Against Aegerion Pharmaceuticals Inc.

September 22, 2017 -- Today, Aegerion Pharmaceuticals Inc. agreed to plead guilty in the United States District Court for the District of Massachusetts to two misdemeanor counts of violating the Federal Food, Drug, and Cosmetic Act (FD&C Act)...

http://ift.tt/2jYoMUB.

Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment

This protocol describes how to stimulate cells with mitochondrial-derived peptides and assess the signaling cascade and localization of phospho-proteins.

http://ift.tt/2fuaLfW

Whole Transcriptome Profiling: An RNA-Seq Primer and Implications for Pharmacogenomics Research

Abstract

Pharmacogenomics has revealed compelling genetic signals associated with variability in drug response. Gene expression studies represent an additional approach to identify candidate genes accounting for drug response variability. This review focuses on insights that might be gained through analysis of the transcriptome to reveal the influence of gene expression on variable drug response. We provide a basic overview of RNA-Sequencing (RNA-Seq) and its applications, and outline advances in pharmacogenomics achievable with RNA-Seq data.

This article is protected by copyright. All rights reserved

http://ift.tt/2wh6jnZ

Implementing the single institutional review board model in the undiagnosed diseases network

http://ift.tt/2yCsgiV

Myriad Applications of Circulating Cell-Free DNA in Precision Organ Transplant Monitoring

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S237-S241, September 2017.


http://ift.tt/2hrSobQ

Epithelial Barrier Regulation by Hypoxia-Inducible Factor

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S233-S236, September 2017.


http://ift.tt/2hunDQ2

Assessment of Lungs for Transplant Recovered from Uncontrolled Donation after Circulatory Determination of Death Donors

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S251-S251, September 2017.


http://ift.tt/2hsjfVt

Mechanisms of Graft Rejection and Immune Regulation after Lung Transplant

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S216-S219, September 2017.


http://ift.tt/2hvulVV

Immune Tolerance, Xenografts, and Large-Animal Studies in Transplantation

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S220-S225, September 2017.


http://ift.tt/2hsjb8b

Bioactive Lipid Mediators Regulate Lung Epithelial and Mesenchymal Cell Reparative Processes In Vitro

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S252-S253, September 2017.


http://ift.tt/2hufWJG

Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S210-S215, September 2017.


http://ift.tt/2huDnm2

Introduction to the 59th Annual Thomas L. Petty Aspen Lung Conference. Lung Transplantation: Opportunities for Repair and Regeneration

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S209-S209, September 2017.


http://ift.tt/2hslMPi

Opportunities for Lung Repair and Regeneration: An Overview

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S247-S250, September 2017.


http://ift.tt/2hqAHJL

List of Abstracts and Posters Presented at the 59th Thomas L. Petty Aspen Lung Conference

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S254-S261, September 2017.


http://ift.tt/2hrsghp

Cell-Free Hemoglobin-mediated Increases in Vascular Permeability. A Novel Mechanism of Primary Graft Dysfunction and a New Therapeutic Target

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S251-S252, September 2017.


http://ift.tt/2y3Jvwr

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S252-S252, September 2017.


http://ift.tt/2yC29IS

Host–Pathogen Interactions and Chronic Lung Allograft Dysfunction

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S242-S246, September 2017.


http://ift.tt/2yC2nQb

Lymphatic Vessels: The Next Frontier in Lung Transplant

Annals of the American Thoracic Society, Volume 14, Issue Supplement_3, Page S226-S232, September 2017.


http://ift.tt/2yCL9C9

Focal Macropatch Recordings of Synaptic Currents from the Drosophila Larval Neuromuscular Junction

Synaptic currents can be recorded focally from visualized synaptic boutons at the Drosophila third instar larvae neuromuscular junction. This technique enables monitoring the activity of a single synaptic bouton.

http://ift.tt/2xBJhex

Evaluation of 18 F-FDG PET/CT Parameters for Detection of Lymph Node Metastasis in Cutaneous Melanoma

Abstract

Purpose

The purpose of this study was to investigate the value of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters in the detection of regional lymph node (LN) metastasis in patients with cutaneous melanoma.

Methods

We evaluated patients with cutaneous melanoma who underwent FDG PET/CT for initial staging or recurrence evaluation. A total of 103 patients were enrolled, and 165 LNs were evaluated. LNs that were confirmed pathologically or by follow-up imaging were included in this study. PET parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis and tumour-to-liver ratio, were used to determine the presence of metastases, and the results were compared with CT-determined LN metastasis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the FDG PET parameters.

Results

A total of 93 LNs were malignant, and 84 LNs were smaller than 10 mm. In all 165 LNs, an SUVmax of >2.51 showed a sensitivity of 73.1%, a specificity of 88.9%, and an accuracy of 80.0% in detecting metastatic LNs. CT showed a higher specificity (87.3%) and lower accuracy (65.5%). For non-enlarged regional LNs (<10 mm), an SUVmax cut-off value of 1.4 showed the highest negative predictive value (81.3%). For enlarged LNs (≥10 mm), an SUVmax cut-off value of 2.4 showed the highest sensitivity (90.7%) and accuracy (88.9%) in detecting metastatic LNs.

Conclusions

In patients with cutaneous melanoma, an SUVmax of >2.4 showed a high sensitivity (91%) and accuracy (89%) in detecting metastasis in LNs ≥1 cm, and LNs <1 cm with an SUVmax <1.4 were likely to be benign.

http://ift.tt/2fL7w0f

Are You a Slave to Your E-mail?

Do you find yourself constantly checking it throughout the day? Does it keep you from getting other more important tasks done? If so, you may want to read Paul Argenti's Harvard Business Review's article titled Stop Letting Email Control Your Work Day. Professor Argenti first suggests taking a look at all your work tasks and dividing them up into four categories.

Tweet

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A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s

α-hydroxylation of carcinogenic nitrosamines by cytochrome P450s is the accepted metabolic pathway that produces DNA-damaging intermediates, which cause mutations. However, new data indicates further oxidation to nitrosamides can occur. We describe a general method for detecting nitrosamides produced from in vitro cytochrome P450-catalyzed metabolism of nitrosamines.

http://ift.tt/2wS1NM3

Technique of Minimally Invasive Transverse Aortic Constriction in Mice for Induction of Left Ventricular Hypertrophy

The aim of this protocol is to describe step-by-step the technique of minimally invasive transverse aortic constriction (TAC) in mice. By elimination of intubation and ventilation which are mandatory for the commonly used standard procedure, minimally invasive TAC simplifies the operative procedure and reduces the strain put on the animal.

http://ift.tt/2xB93j1

Macromolecular Antiviral Agents against Zika, Ebola, SARS, and Other Pathogenic Viruses

Abstract

Viral pathogens continue to constitute a heavy burden on healthcare and socioeconomic systems. Efforts to create antiviral drugs repeatedly lag behind the advent of pathogens and growing understanding is that broad-spectrum antiviral agents will make strongest impact in future antiviral efforts. This work performs selection of synthetic polymers as novel broadly active agents and demonstrates activity of these polymers against Zika, Ebola, Lassa, Lyssa, Rabies, Marburg, Ebola, influenza, herpes simplex, and human immunodeficiency viruses. Results presented herein offer structure–activity relationships for these pathogens in terms of their susceptibility to inhibition by polymers, and for polymers in terms of their anionic charge and hydrophobicity that make up broad-spectrum antiviral agents. The identified leads cannot be predicted based on prior data on polymer-based antivirals and represent promising candidates for further development as preventive microbicides.

Broad spectrum antiviral agents are designed through systematic variation of the polymer composition, specifically the nature of the anionic charge of the polymer and hydrophobicity of the backbone. Structure–function relationship reveals unexpected lead candidates with inhibitory antiviral activity against all tested enveloped viruses.

http://ift.tt/2wRuJ6Y