The impact of delayed maternity on foetal growth in Spain: An assessment by population attributable fraction

Publication date: Available online 18 September 2017
Source:Women and Birth
Author(s): Carlos Varea, José Manuel Terán, Cristina Bernis, Barry Bogin
BackgroundDelayed childbearing is considered a risk factor for maternal–foetal health. As in other higher-income countries, in Spain age at maternity has steadily increased during the last two decades.AimTo quantify the impact of the delay in the age at maternity on small for gestational age (SGA) categories of <3rd, 3rd–5th and 5th–10th percentiles.Methods2,672,350 singleton live births born to Spanish mothers in 2007–2015 were analysed. Adjusted relative risk was calculated to estimate the adjusted partial population attributable fractions (PAFp) for mothers aged 35–39 and ≥40 years for each category of SGA considering the interaction between age at maternity and parity.FindingsPrimipara 35–39 years old mothers have the highest PAFp in the three categories of SGA, with the maximum value for SGA <3rd percentile (2.57%, 95% CI 2.25, 2.88). PAFp for both primipara and multipara ≥40 years old mothers were less than 1%. PAFp for primipara older mothers increased significantly in 2007–2015 for the three categories of SGA, more clearly among those aged 35–39 years. The contribution of multipara mothers of both age groups did not increase significantly during the period.ConclusionDelayed maternity is a significant adjusted risk factor for SGA, contributing to the increase of its prevalence. However, results also suggest a limited clinical impact of delayed maternity on foetal growth. Positive changes in maternal profile associated with the shift in maternal age might contribute to explain the limited impact of mothers aged 35 years and older on negative birth outcome in Spain.



http://ift.tt/2wrSp6r

Advances in delivery of ambulatory autologous stem cell transplantation for multiple myeloma.

Purpose of review: Autologous stem cell transplantation (ASCT) is generally performed in the inpatient setting in its entirety. Several centers have demonstrated the feasibility of performing ASCT for myeloma in the ambulatory setting. We review the safety, cost-effectiveness, complications and outcomes of outpatient ASCT for myeloma. Recent findings: Published studies are heterogeneous but suggest that outpatient ASCT for myeloma is cost-effective and associated with a shorter or no initial hospitalization, albeit there is a high rate of readmission for complications. The transplant-related mortality rate is less than 1%. Stringent patient selection criteria that include emphasis on functional status, caregiving support and psychosocial aspects for each patient are critical for identifying patients most appropriate for ASCT in the ambulatory setting. There exists considerable variability in outpatient transplant models and supportive care guidelines and data do not support preference for one delivery model over another. Survival and other transplant-related outcomes have not been reported widely and whether patients fare better with outpatient transplantation remains to be explored. Summary: Outpatient ASCT for multiple myeloma is feasible and well tolerated in selected patients. Several care models for outpatient ASCT exist and can be implemented based on transplant resources and preference. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2xtDPul

The role of vitamin D in cancer cachexia.

Purpose of review: The possibility to use vitamin D supplementation to improve muscle wasting, with particular focus on cancer cachexia, is discussed. Recent findings: Vitamin D exerts biological actions on myogenic precursor proliferation and differentiation, impinging on muscle regeneration. However, the effects of VitD supplementation in diseases associated with muscle atrophy, such as cancer cachexia, are poorly investigated. Data obtained in experimental models of cancer cachexia show that the administration of vitamin D to tumor-bearing animals is not able to prevent or delay both muscle wasting and adipose tissue depletion, despite increased expression of muscle vitamin D receptor. Not just vitamin D supplementation impairs muscle damage-induced regeneration, suggesting that upregulation of vitamin D receptor signaling could contribute to muscle wasting. Summary: Vitamin D supplementation is likely beneficial to reduce or delay aging-related sarcopenia and osteoporosis, although the available data still put in evidence significant discrepancies. By contrast, VitD supplementation to tumor-bearing animals or to rats with arthritis was shown to be totally ineffective. In this regard, the adoption of VitD treatment in patients with cancer cachexia or other chronic diseases should be carefully evaluated, in particular whenever a regenerative process might be involved. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2ffaYDu

Population-based models of planning for palliative care in older people.

Purpose of review: Health service planning requires demographic, clinical, and health systems data and is unique to each health system. Planning for palliative care in older people must include patients and their carers. This review explores literature from the last 24 months. Recent findings: The proportion of people living in skilled nursing facilities is increasing and many residents require quality palliative care. Simultaneously, the complexity of care for older people is also increasing. Systematic approaches to improving palliative care in these facilities have shown benefits that are cost-effective. Although advance care planning is widely promoted, a randomized controlled trial failed to show the benefits seen in nonrandomized trials. This requires a reconceptualization of current programs that seek to increase uptake. Caregivers take on complex decision-making which can be stressful. By contrast, patients are often very confident that the people who are close to them will make good decisions on their behalf. Specific subgroups considered in this review include carers (and the challenges they face), the 'oldest old' and people with dementia. Summary: Excellent research is being done to improve the care of older people with palliative care needs. Ultimately, how can key findings be incorporated into clinical care? Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2xuiqBz

Health professionals' quality of life in relation to end of life care.

Purpose of review: Palliative care professionals are frequently exposed to stressful and demanding situations in the assistance of patients and their families, therefore research related to their quality of life is a relevant topic to provide evidence on interventions oriented to professional self-care. Recent findings: Research about professionals' quality of life is having a profuse development with core concepts being under review. Summary: Currently, burnout syndrome and compassion fatigue are considered relevant determinants of professionals' quality of life. Self-awareness-based interventions could bring positive influence on the context of a multidimensional approach to professionals' self-care. Self-care topics should be considered to be included in professional training programmes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2xtDO9L

Spiritual needs of patients with cancer in palliative care: an integrative review.

Purpose of review: The experience of a life crisis, such as the experience of end-of-life terminality whenever facing cancer can make the spiritual needs of patients clear. The goal of this revision was to synthesize the existing evidence regarding the spiritual needs of patients with cancer in palliative care. Recent findings: An integrated revision of the literature was conducted regarding the database sources from PubMed, CINAHL, EMBASE, LILACS and Scopus, without publishing year restrictions. There were 16 primary studies included. A total of 1469 patients have been evaluated, whereas eight groups of spiritual needs have been identified: finding the meaning and purpose of life; finding the meaning in experiencing the disease; being connected to other people, God and nature; having access to religious/spiritual practices; physical, psychological, social and spiritual wellbeing; talking about death and the experience of dying; making the best out of their time; being independent and being treated like a normal person. Summary: It is essential to pay attention to patients' spiritual dimensions regarding palliative care. Therefore, patients' spiritual needs must be identified and remedied or mitigated. It is necessary to develop studies that find specific strategies and interventions for the treatment of these needs. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2ffaUne

Trends in active surveillance for very low-risk prostate cancer: do guidelines influence modern practice?

Abstract

As recommended by current NCCN guidelines, patients with very low-risk prostate cancer may be treated with active surveillance (AS), but this may be underutilized. Using the National Cancer Database (NCDB), we identified men (2010–2013) with biopsy-proven, very low-risk prostate cancer that met AS criteria as suggested by Epstein (stage ≤ T1c; Gleason score (GS) ≤ 6; PSA < 10; and ≤2 [or <33%] positive biopsy cores) and aged ≤76, and low comorbidity index (Charlson-Deyo score = 0). For those patients meeting this criteria, we performed generalized estimation equation (GEE) method with incorporation of correlation in patients clustered within facility to determine the likelihood of undergoing AS. Among the 448 773 patients in the NCDB with low-risk prostate cancer, 40 839 patients met the inclusion criteria. AS was utilized in 5798 patients (14.2%), while within the very low-risk patients receiving treatment, up to 52.2% received radical prostatectomy. In univariate analyses, AS utilization was associated with older age, uninsured status (compared to private insurance), farther distance from facility, academic/research institutions and particularly in the New England region (all P < 0.01). After adjustments of other predictors in multivariate analysis, patients preferentially received AS if they were older (all OR's > 1 compared to younger groups), uninsured (vs. any insurance type, OR's > 1); or treated at academic/research center (OR > 1). The overall use of AS increased from 11.6% (2010) to 27.3% (2013). We found a low, but rising rate of AS in a nationally representative group of very low-risk prostate cancer patients. Disparities in the use of AS may be targeted to improve adherence to national guidelines.

This article demonstrates one of the largest series examining the role of active surveillance in patients with very low-risk prostate cancer. Our results in disparities and trends in recommendations for active surveillance reveal an important aspect of cancer care in the management of this disease entity.

http://ift.tt/2hegSlh

Impact of perioperative nutritional status on the outcome of abdominal surgery in a sub-Saharan Africa setting

Malnutrition is a clinical condition of multifactorial etiologies and it is associated with several adverse outcomes. In high-income countries, malnutrition has been described as a determinant of delayed wound...

http://ift.tt/2yltaQD

Intestinal parasitic infections and risk factors: a cross-sectional survey of some school children in a suburb in Accra, Ghana

This study aimed to determine the prevalence and establish some risk factors associated with the acquisition of gastrointestinal parasitic infections in school children in Accra, Ghana.

http://ift.tt/2wtguKk

“I think it is right”: a qualitative exploration of the acceptability and desired future use of oral swab and finger-prick HIV self-tests by lay users in KwaZulu-Natal, South Africa

The uptake of HIV testing has increased in sub-Saharan Africa over the past three decades. However, the proportion of people aware of their HIV status remains lower than required to change the pandemic. HIV se...

http://ift.tt/2ylxhMu

Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report

Dubin–Johnson syndrome and intrahepatic cholestasis of pregnancy are rare chronic liver disorders. Dubin–Johnson syndrome may manifest as conjugated hyperbilirubinemia, darkly pigmented liver, presence of abno...

http://ift.tt/2wrwmg9

Exercise for patients with major depression: a systematic review with meta-analysis and trial sequential analysis

Objectives

To assess the benefits and harms of exercise in patients with depression.

Design

Systematic review

Data sources

Bibliographical databases were searched until 20 June 2017.

Eligibility criteria and outcomes

Eligible trials were randomised clinical trials assessing the effect of exercise in participants diagnosed with depression. Primary outcomes were depression severity, lack of remission and serious adverse events (eg, suicide) assessed at the end of the intervention. Secondary outcomes were quality of life and adverse events such as injuries, as well as assessment of depression severity and lack of remission during follow-up after the intervention.

Results

Thirty-five trials enrolling 2498 participants were included. The effect of exercise versus control on depression severity was –0.66 standardised mean difference (SMD) (95% CI –0.86 to –0.46; p<0.001; grading of recommendations assessment, development and evaluation (GRADE): very low quality). Restricting this analysis to the four trials that seemed less affected of bias, the effect vanished into –0.11 SMD (–0.41 to 0.18; p=0.45; GRADE: low quality). Exercise decreased the relative risk of no remission to 0.78 (0.68 to 0.90; p<0.001; GRADE: very low quality). Restricting this analysis to the two trials that seemed less affected of bias, the effect vanished into 0.95 (0.74 to 1.23; p=0.78). Trial sequential analysis excluded random error when all trials were analysed, but not if focusing on trials less affected of bias. Subgroup analyses found that trial size and intervention duration were inversely associated with effect size for both depression severity and lack of remission. There was no significant effect of exercise on secondary outcomes.

Conclusions

Trials with less risk of bias suggested no antidepressant effects of exercise and there were no significant effects of exercise on quality of life, depression severity or lack of remission during follow-up. Data for serious adverse events and adverse events were scarce not allowing conclusions for these outcomes.

Systematic review registration

The protocol was published in the journal Systematic Reviews: 2015; 4:40.

http://ift.tt/2fwvfBs

How novice, skilled and advanced clinical researchers include variables in a case report form for clinical research: a qualitative study

Objectives

Despite varying degrees in research training, most academic clinicians are expected to conduct clinical research. The objective of this research was to understand how clinical researchers of different skill levels include variables in a case report form for their clinical research.

Setting

The setting for this research was a major academic institution in Beijing, China.

Participants

The target population was clinical researchers with three levels of experience, namely, limited clinical research experience, clinicians with rich clinical research experience and clinical research experts.

Methods

Using a qualitative approach, we conducted 13 individual interviews (face to face) and one group interview (n=4) with clinical researchers from June to September 2016. Based on maximum variation sampling to identify researchers with three levels of research experience: eight clinicians with limited clinical research experience, five clinicians with rich clinical research experience and four clinical research experts. These 17 researchers had diverse hospital-based medical specialties and or specialisation in clinical research.

Results

Our analysis yields a typology of three processes developing a case report form that varies according to research experience level. Novice clinician researchers often have an incomplete protocol or none at all, and conduct data collection and publication based on a general framework. Experienced clinician researchers include variables in the case report form based on previous experience with attention to including domains or items at risk for omission and by eliminating unnecessary variables. Expert researchers consider comprehensively in advance data collection and implementation needs and plan accordingly.

Conclusion

These results illustrate increasing levels of sophistication in research planning that increase sophistication in selection for variables in the case report form. These findings suggest that novice and intermediate-level researchers could benefit by emulating the comprehensive planning procedures such as those used by expert clinical researchers.

http://ift.tt/2xaQoLz

Integrated management of atrial fibrillation including tailoring of anticoagulation in primary care: study design of the ALL-IN cluster randomised trial

Introduction

In our ageing society, we are at the merge of an expected epidemic of atrial fibrillation (AF). AF management requires an integrated approach, including rate or rhythm control, stroke prevention with anticoagulation and treatment of comorbidities such as heart failure or type 2 diabetes. As such, primary care seems to be the logical healthcare setting for the chronic management of patients with AF. However, primary care has not yet played a dominant role in AF management, which has been in fact more fragmented between different healthcare providers. This fragmentation might have contributed to high healthcare costs. To demonstrate the feasibility of managing AF in primary care, studies are needed that evaluate the safety and (cost-)effectiveness of integrated AF management in primary care.

Methods and analysis

The ALL-IN trial is a multicentre, pragmatic, cluster randomised, non-inferiority trial performed in primary care practices in a suburban region in the Netherlands. We aim to include a minimum of 1000 patients with AF aged 65 years or more from around 18 to 30 practices. Duration of the study is 2 years. Practices will be randomised to either the intervention arm (providing integrated AF management, involving a trained practice nurse and collaboration with secondary care) or the control arm (care as usual). The primary endpoint is all-cause mortality. Secondary endpoints are cardiovascular mortality, (non)-cardiovascular hospitalisation, major adverse cardiac events, stroke, major bleeding, clinically relevant non-major bleeding, quality of life and cost-effectiveness.

Ethics and dissemination

The protocol was approved by the Medical Ethical Committee of the Isala Hospital Zwolle, the Netherlands. Patients in the intervention arm will be asked informed consent for participating in the intervention. Results are expected in 2019 and will be disseminated through both national and international journals and conferences.

Trial registration number

This trial is registered at the Netherlands Trial Register (NTR5532).

http://ift.tt/2fvCYPZ

Controlling Nutritional Status (CONUT) score as a predictor of all-cause mortality in elderly hypertensive patients: a prospective follow-up study

Objectives

The aim of this study was to elucidate the impact of nutritional status on survival per Controlling Nutritional Status (CONUT) score and Geriatric Nutritional Risk Index (GNRI) in patients with hypertension over 80 years of age.

Design

Prospective follow-up study.

Participants

A total of 336 hypertensive patients over 80 years old were included in this study.

Outcome measures

All-cause deaths were recorded as Kaplan-Meier curves to evaluate the association between CONUT and all-cause mortality at follow-up. Cox regression models were used to investigate the prognostic value of CONUT and GNRI for all-cause mortality in the 90-day period after admission.

Results

Hypertensive patients with higher CONUT scores exhibited higher mortality within 90 days after admission (1.49%, 6.74%, 15.38%, respectively, ²=30.92, p=0.000). Surviving patients had higher body mass index (24.25±3.05 vs 24.25±3.05, p=0.012), haemoglobin (123.78±17.05 vs 115.07±20.42, p=0.040) and albumin levels, as well as lower fasting blood glucose (6.90±2.48 vs 8.24±3.51, p=0.010). Higher GRNI score (99.42±6.55 vs 95.69±7.77, p=0.002) and lower CONUT (3.13±1.98 vs 5.14±2.32) both indicated better nutritional status. Kaplan-Meier curves indicated that survival rates were significantly worse in the high-CONUT group compared with the low-CONUT group (¹ =13.372, p=0.001). Cox regression indicated an increase in HR with increasing CONUT risk (from normal to moderate to severe). HRs (95% CI) for 3-month mortality was 1.458 (95% CI 1.102 to 1.911). In both respiratory tract infection and 'other reason' groups, only CONUT was a sufficiently predictor for all-cause mortality (HR=1.284, 95% CI 1.013 to 1.740, p=0.020 and HR=1.841, 95% CI 1.117 to 4.518, p=0.011). Receiver operating characteristic showed that CONUT higher than 3.0 was found to predict all-cause mortality with a sensitivity of 77.8% and a specificity of 64.7% (area under the curve=0.778, p<0.001).

Conclusion

Nutritional status assessed via CONUT is an accurate predictor of all-cause mortality 90 days postadmission. Evaluation of nutritional status may provide additional prognostic information in hypertensive patients.

http://ift.tt/2x9MxOH

Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) versus alteplase (rt-PA) as fibrinolytic therapy for acute ST-segment elevation myocardial infarction (China TNK STEMI): protocol for a randomised, controlled, non-inferiority trial

Aim

To evaluate the efficacy and safety of recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) in lowering major adverse cardiovascular and cerebrovascular events (MACCEs) in Chinese acute ST-segment elevation myocardial infarction (STEMI) patients.

Methods and analysis

The study is designed as a multicentre, randomised, controlled non-inferiority phase IV trial with balanced randomisation (1:1) in patients with STEMI. The planned sample size is 6200 participants (or 3100 per arm). Participants with STEMI will be randomised to receive either rhTNK-tPA or alteplase (rt-PA), with stratification by research centre, age and the time from symptom onset to randomisation. All patients will receive concomitant antiplatelet and anticoagulant therapy before fibrinolytic therapy. The participants assigned to the intervention group will receive an intravenous bolus of 16 mg rhTNK-tPA, while those assigned to the control group will receive an intravenous bolus of 8 mg rt-PA followed by 42 mg infusion over 90 mins. Other medications can also be administered at the discretion of the cardiologists in charge. All participants will be followed up for the primary study endpoint, the occurrence of MACCEs within 30 days after fibrinolytic therapy, which is defined as all-cause mortality, non-fatal re-infarction, non-fatal stroke, percutaneous coronary intervention (PCI) due to thrombolysis failure, and PCI due to reocclusion. Both intention-to-treat and per-protocol analyses will be done for the primary analyses.

Ethics and dissemination

The study procedures and informed consent form were approved by all participating hospitals. The results will be disseminated in peer review journals and academic conferences. This multicentre randomised controlled trial will provide high-quality data about the efficacy and safety of rhTNK-tPA and, once approved, its easier use should help improve the application of reperfusion therapy and hence the treatment outcomes of STEMI patients.

Trial registration number

NCT02835534.

http://ift.tt/2fwxCUY

Adherence and dosing interval of subcutaneous antitumour necrosis factor biologics among patients with inflammatory arthritis: analysis from a Canadian administrative database

Objectives

Subcutaneous tumour necrosis factor alpha TNFαinhibitors (SC-TNFis) such as golimumab (GLM), adalimumab (ADA), etanercept (ETA) and certolizumab pegol (CZP) have been used for many years for the treatment of inflammatory arthritis. Non-adherence to therapy is an important modifiable factor that may compromise patient outcomes. The aim of this analysis was to compare adherence and dosing interval of SC-TNFis in the treatment of people with inflammatory arthritis.

Design

We used the IMS Brogan database combining both Canadian private and public drug plan databases of Ontario and Quebec. Target drugs included SC-TNFis for inflammatory arthritis. The index period was from 1 January 2010 to 30 June 2012 and patients were followed for 24 months through 30 June 2014. Inclusion criteria were adult patients newly prescribed a SC-TNFis with at least three prescriptions and retained on therapy at 24 months.

Dosing regimens as per the product monographs were used to compare actual versus expected drug utilisation. The mean possession ratio was used as a marker for adherence. Patients who scored >80% were considered adherent. The average days between units was estimated by taking the total days on therapy and divided by the number of units the patient received.

Results

4035 patients were included: 683 (16.9%), 1400 (34.7%), 1765 (43.7%) and 187 (4.6%) were treated with GLM, ADA, ETA and CZP, respectively. The proportion of adherent patients in the GLM cohort (n=595/683, 87%, p<0.0001) was greater compared with ADA (n=1044/1400, 75%), ETA (n=1285/1765, 73%) and CZP-treated patients (132/187, 71%). In addition, the number of patients receiving biological drug at a shorter dosing interval was similar between cohorts, and was 5%, 6%, 12% and 4% in GLM (≤26 days), ADA (≤12 days), ETA (≤6 days) and CZP-treated patients (≤12 days), respectively.

Conclusions

In this real-life administrative database, GLM had better adherence compared with other SC-TNFis.

http://ift.tt/2wsfrdk

Interdisciplinary model of care (RADICALS) for early detection and management of chronic obstructive pulmonary disease (COPD) in Australian primary care: study protocol for a cluster randomised controlled trial

Introduction

Up to half of all smokers develop clinically significant chronic obstructive pulmonary disease (COPD). Gaps exist in the implementation and uptake of evidence-based guidelines for managing COPD in primary care. We describe the methodology of a cluster randomised controlled trial (cRCT) evaluating the efficacy and cost-effectiveness of an interdisciplinary model of care aimed at reducing the burden of smoking and COPD in Australian primary care settings.

Methods and analysis

A cRCT is being undertaken to evaluate an interdisciplinary model of care (RADICALS — Review of Airway Dysfunction and Interdisciplinary Community-based care of Adult Long-term Smokers). General practice clinics across Melbourne, Australia, are identified and randomised to the intervention group (RADICALS) or usual care. Patients who are current or ex-smokers, of at least 10 pack years, including those with an existing diagnosis of COPD, are being recruited to identify 280 participants with a spirometry-confirmed diagnosis of COPD. Handheld lung function devices are being used to facilitate case-finding. RADICALS includes individualised smoking cessation support, home-based pulmonary rehabilitation and home medicines review. Patients at control group sites receive usual care and Quitline referral, as appropriate. Follow-ups occur at 6 and 12 months from baseline to assess changes in quality of life, abstinence rates, health resource utilisation, symptom severity and lung function. The primary outcome is change in St George's Respiratory Questionnaire score of patients with COPD at 6 months from baseline.

Ethics and dissemination

This project has been approved by the Monash University Human Research Ethics Committee and La Trobe University Human Ethics Committee (CF14/1018 – 2014000433). Results of the study will be disseminated in peer-reviewed journals and research conferences. If the intervention is successful, the RADICALS programme could potentially be integrated into general practices across Australia and sustained over time.

Trial registration number

ACTRN12614001155684; Pre-results.

http://ift.tt/2wCRzio

Diagnostic validity of early-onset obsessive-compulsive disorder in the Danish Psychiatric Central Register: findings from a cohort sample

Objectives

Employing national registers for research purposes depends on a high diagnostic validity. The aim of the present study was to examine the diagnostic validity of recorded diagnoses of early-onset obsessive-compulsive disorder (OCD) in the Danish Psychiatric Central Register (DPCR).

Design

Review of patient journals selected randomly through the DPCR.

Method

One hundred cases of OCD were randomly selected from DPCR. Using a predefined coding scheme based on the Children's Yale Brown Obsessive Compulsive Scale (CYBOCS), experienced research nurse or child and adolescent psychiatrists assessed each journal to determine the presence/absence of OCD diagnostic criteria. The detailed assessments were reviewed by two senior child and adolescent psychiatrists to determine if diagnostic criteria were met.

Primary outcome measurements

Positive predictive value (PPV) was used as the primary outcome measurement.

Results

A total of 3462 children/adolescents received an OCD diagnosis as the main diagnosis between 1 January 1995 and 31 December 2015. The average age at diagnosis was 13.21±2.89 years. The most frequent registered OCD subcode was the combined diagnosis DF42.2. Of the 100 cases we examined, 35 had at least one registered comorbidity. For OCD, the PPV was good (PPV 0.85). Excluding journals with insufficient information, the PPV was 0.96. For the subcode F42.2 the PPV was 0.77. The inter-rater reliability was 0.94. The presence of the CYBOCS in the journal significantly increased the PPV for the OCD diagnosis altogether and for the subcode DF42.2.

Conclusion

The validity and reliability of International Classification of Disease 10th revision codes for OCD in the DPCR is generally high. The subcodes for predominant obsessions/predominant compulsions are less certain and should be used with caution. The results apply for both children and adolescents and for both older and more recent cases. Altogether, the study suggests that there is a high validity of the OCD diagnosis in the Danish National Registers.

http://ift.tt/2wD5pkU

Comparative effectiveness of injectable penicillin versus a combination of penicillin and gentamicin in children with pneumonia characterised by indrawing in Kenya: protocol for an observational study

Introduction

WHO treatment guidelines are widely recommended for guiding treatment for millions of children with pneumonia every year across multiple low-income and middle-income countries. Guidelines are based on synthesis of available evidence that provides moderate certainty in evidence of effects for forms of pneumonia that can result in hospitalisation. However, trials have included fewer children from Africa than other settings, and it is suggested that African children with pneumonia have higher mortality. Thus, despite improving access to recommended treatments and deployment with high coverage of childhood vaccines, pneumonia remains one of the top causes of mortality for children in Kenya. Establishing whether there are benefits of alternative treatment regimens to help reduce mortality would require pragmatic clinical trials. However, these remain relatively expensive and time consuming. This protocol describes an approach to using secondary analysis of a new, large observational dataset as a potentially cheaper and quicker way to examine the comparative effectiveness of penicillin versus penicillin plus gentamicin in treatment of indrawing pneumonia. Addressing this question is important, as although it is now recommended that this form of pneumonia is treated with oral medication as an outpatient, it remains associated with non-trivial mortality that may be higher outside trial populations.

Methods and analysis

We will use a large observational dataset that captures data on all admissions to 13 Kenyan county hospitals. These data represent the findings of clinicians in practice and, because the system was developed for large observational research, pose challenges of non-random treatment allocation and missing data. To overcome these challenges, this analysis will use a rigorous approach to study design, propensity score methods and multiple imputation to minimise bias.

Ethics and dissemination

The primary data are held by hospitals participating in the Kenyan Clinical Information Network project with de-identifed data shared with the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme for agreed analyses. The use of data for the analysis described received ethical clearance from the KEMRI scientific and ethical review committee. The findings of this analysis will be published.

http://ift.tt/2wCRjQB

A cross-sectional study in a tertiary care hospital in China: noise or silence in the operating room

Objectives

This study aims to provide a comprehensive description of noise levels in operating rooms (ORs) in a tertiary care hospital in China. Additionally, the study aims to examine the deviation in noise levels from international and internal standards as well as the differences in noise levels by category of surgery and day of the week.

Methods

We monitored noise levels in 23 ORs in a tertiary care hospital in China between August 2015 and March 2016. Dosimeters were used to determine noise levels. The noise data collected in the dosimeter were downloaded to an IBM computer for subsequent analysis. One-way analysis of variance and Student's t-test were used to examine the differences in noise levels.

Results

The noise level in the ORs ranged between 59.2 and 72.3 dB(A), with 100% of the measurements exceeding the recommended hospital noise standards. There was substantial similarity in noise levels from Monday to Friday (F=1.404, p=0.234), with a range between 63.7 and 64.5 dB(A). The difference in noise levels by category of surgery was significant (F=3.381, p<0.001). The results of the post hoc analysis suggested that ophthalmic surgery had significantly higher noise levels than otolaryngological surgery or general surgery.

Conclusions

Ophthalmic surgery had significantly higher noise levels than otolaryngological or general surgeries. High noise levels were identified in all evaluated ORs during weekdays, and these levels consistently exceeded the currently accepted standards. These findings warrant further investigation to determine the harmful effects of noise on both patients and staff in ORs.

http://ift.tt/2wrlrDb

Development of core outcome sets for effectiveness trials of interventions to prevent and/or treat delirium (Del-COrS): study protocol

Introduction

Delirium is a common, serious and potentially preventable condition with devastating impact on the quality of life prompting a proliferation of interventional trials. Core outcome sets aim to standardise outcome reporting by identifying outcomes perceived fundamental for measurement in trials of a specific interest area. Our aim is to develop international consensus on two core outcome sets for trials of interventions to prevent and/or treat delirium, irrespective of study population. We aim to identify additional core outcomes specific to the critically ill, acutely hospitalised patients, palliative care and older adults.

Methods and analysis

We will conduct a systematic review of published and ongoing delirium trials (1980 onwards) and one-on-one interviews of patients who have experienced delirium and family members. These data will inform Delphi round 1 of a two-stage consensus process. In round 2, we will provide participants their own response, summarised group responses and those of patient/family participants for rescoring. We will randomise participants to receive feedback as proportion scoring the outcome as critical or as group mean responses. We will hold a consensus meeting using nominal group technique to finalise outcomes for inclusion. We will repeat the Delphi process and consensus meeting to select measures for each core outcome. We will recruit 240 Delphi participants giving us 80% power to detect a 1.0–1.5 point (9-point scale) difference by feedback method between rounds. We will analyse differences for subsequent scores, magnitude of opinion change, items retained and level of agreement.

Ethics and dissemination

We are obtaining research ethics approvals according to local governance. Participation will be voluntary and data deidentified. Support from three international delirium organisations will be instrumental in dissemination and core outcome set uptake. We will disseminate through peer-reviewed open access publications and present at conferences selected to reach a wide range of knowledge users.

http://ift.tt/2wrl5MR

Disability acquisition and mental health: effect modification by demographic and socioeconomic characteristics using data from an Australian longitudinal study

Objectives

There is evidence of a causal relationship between disability acquisition and poor mental health, but the substantial heterogeneity in the magnitude of the effect is poorly understood and may be aetiologically informative. This study aimed to identify demographic and socioeconomic factors that modify the effect of disability acquisition on mental health.

Design and setting

The Household, Income and Labour Dynamics in Australia Survey is a nationally representative longitudinal survey of Australian households that has been conducted annually since 2001. Four waves of data were included in this analysis, from 2011 to 2014.

Participants

Individuals who acquired a disability (n=387) were compared with those who remained disability-free in all four waves (n=7936).

Primary outcome measure

Mental health was measured using the mental health subscale of the Short Form 36 (SF-36) general health questionnaire, which measures symptoms of depression, anxiety and psychological well-being.

Methods

Linear regression models were fitted to estimate the effect of disability acquisition on mental health, testing for effect modification by key demographic and socioeconomic characteristics. To maximise causal inference, we used a propensity score approach with inverse probability of treatment weighting to control for confounding and multiple imputation using chained equations to assess the impact of missing data.

Results

On average, disability acquisition was associated with a 5-point decline in mental health score (estimated mean difference: –5.1, 95% CI –7.2 to –3.0). There was strong evidence that income and relationship status modified the effect, with more detrimental effects in the lowest (–12.5, 95% CI –18.5 to –6.5) compared with highest income quintile (–1.1, 95% CI –4.9 to 2.7) and for people not in a relationship (–8.8, 95% CI –12.9 to –4.8) compared with those who were (–3.7, 95% CI –6.1 to –1.4).

Conclusions

Our results suggest that the detrimental effect of disability acquisition on mental health is substantially greater for socioeconomic disadvantaged individuals.

http://ift.tt/2wCRvPG

Gender differences in longevity in free-living older adults who eat-with-others: a prospective study in Taiwan

Objectives

Social activities such as 'eating-with-others' can positively affect the ageing process. We investigated the gender-specific association between eating arrangements and risk of all-cause mortality among free-living older adults.

Setting

A representative sample from the Elderly Nutrition and Health Survey in Taiwan during 1999–2000.

Participants

Some 1894 participants (955 men and 939 women) who aged ≥65 and completed eating arrangement question as well as confirmed survivorship information.

Primary and secondary outcome measures

Eating arrangements, health condition and 24-hour dietary recall information were collected at baseline. We classified eating arrangements as the daily frequency of eating-with-others (0–3). Survivorship was determined by the National Death Registry until the end of 2008. Cox proportional-hazards regression was used to assess the association between eating-with-others and mortality risk.

Results

Overall, 63.1% of men and 56.4% of women ate with others three times a day. Both men and women who ate with others were more likely to have higher meat and vegetable intakes and greater dietary quality than those who ate alone. The HRs (95% CI) for all-cause mortality when eating-with-others two and three times per day were 0.42 (0.28 to 0.61), 0.67 (0.52 to 0.88) in men and 0.68 (0.42 to 1.11), 0.86 (0.64 to 1.16) in women, compared with those who ate alone. Multivariable HRs (95% CI) adjusted for sociodemographic, nutritional and 'activities of daily living' covariates were 0.43 (0.25 to 0.73), 0.63 (0.41 to 0.98) in men and 0.68 (0.35 to 1.30), 0.69 (0.39 to 1.21) in women. With further adjustment for financial status, HR was reduced by 54% in men who ate with others two times a day. Pathway analysis shows this to be dependent on improved dietary quality by eating-with-others.

Conclusions

Eating-with-others is an independent survival factor in older men. Providing a social environment which encourages eating-with-others may benefit survival of older people, especially for men.

http://ift.tt/2wswT1j

Economic volatility in childhood and subsequent adolescent mental health problems: a longitudinal population-based study of adolescents

Objective

The aim of the current paper was to investigate the association between the patterns of duration, timing and sequencing of exposure to low family income during childhood, and symptoms of mental health problems in adolescence.

Setting

Survey administered to a large population-based sample of Norwegian adolescents.

Participants

Survey data from 9154 participants of 16–19 years age (53% participation rate; 52.7% girls) were linked to registry-based information about childhood family income from tax return data.

Outcome measures

Mental health outcomes were symptoms of emotional, conduct, hyperactivity, peer problems and general mental health problems measured with the Strengths and Difficulties Questionnaire, symptoms of depression measured with Short Mood and Feelings Questionnaire and symptoms of attention-deficit/hyperactivity disorder (ADHD) measured with the Adult ADHD Self-Report Scale.

Results

Latent class analysis and the BCH approach in Mplus were used to examine associations between patterns of poverty exposure and mental health outcomes. Four latent classes of poverty exposure emerged from the analysis. Participants moving into poverty (2.3%), out of poverty (3.5%) or those chronically poor (3.1%) had more symptoms of mental health problems (Cohen's d=16-.50) than those with no poverty exposure (91.1%). This pattern was, however, not found for symptoms of ADHD. The pattern of results was confirmed in robustness checks using observed data.

Conclusions

Exposure to poverty in childhood was found to be associated with most mental health problems in adolescence. There was no strong suggestion of any timing or sequencing effects in the patterns of associations.

http://ift.tt/2wD4XTA

Assessing the extent of drug interactions among patients with multimorbidity in primary and secondary care in the West Midlands (UK): a study protocol for the Mixed Methods Multimorbidity Study (MiMMS)

Introduction

The numbers of patients with three or more chronic conditions (multimorbidity) are increasing, and will rise to 2.9 million by 2018 in the UK alone. Currently in the UK, conditions are mainly managed using over 250 sets of single-condition guidance, which has the potential to generate conflicting recommendations for lifestyle and concurrent medication for individual patients with more than one condition. To address some of these issues, we are developing a new computer-based tool to help manage these patients more effectively. For this tool to be applicable and relevant to current practice, we must first better understand how existing patients with multimorbidity are being managed, particularly relating to concerns over prescribing and potential polypharmacy.

Methods and analysis

Up to four secondary care centres, two community pharmacies and between four and eight primary care centres in the West Midlands will be recruited. Interviewees will be purposively sampled from these sites, up to a maximum of 30. In this mixed methods study, we will perform a dual framework analysis on the qualitative data; the first analysis will use the Theoretical Domains Framework to assess barriers and enablers for healthcare professionals around the management of multimorbid patients; the second analysis will use Normalisation Process Theory to understand how interventions are currently being successfully implemented in both settings. We will also extract quantitative anonymised patient data from primary care to determine the extent of polypharmacy currently present for patients with multimorbidity in the West Midlands.

Discussion

We aim to combine these data so that we can build a useful, fully implementable tool which addresses the barriers most amenable to change within both primary and secondary care contexts.

Ethics and dissemination

Favourable ethical approval has been granted by The University of Birmingham Research Ethics Committee (ERN_16–0074) on 17 May 2016. Our work will be disseminated through peer-reviewed literature, trade journals and conferences. We will also use the dedicated web page hosted by the University to serve as a central point of contact and as a repository of our findings. We aim to produce a minimum of three articles from this work to contribute to the international scientific literature.

Protocol registration number

NIHR Clinical Research Network Portfolio Registration CPMS ID 30613.

http://ift.tt/2wswyM5

Which research questions are important for the bereaved families of palliative care cancer patients? A nationwide survey

Bereaved family members are present from diagnosis to the end of life and can look back and evaluate the experience; additionally, the family itself is also an important subject in the care of the patient. Therefore, while it is essential to determine the priority research issues from the viewpoint of the patients and health care workers, it is also crucial to know the important research themes from the viewpoint of the bereaved family members.

http://ift.tt/2xij0Sj

Determining Palliative Care Penetration Rates in the Acute Care Setting

Intermountain Healthcare, in collaboration with Cerner Corporation, developed a hospital-based electronic palliative care algorithm to improve identification of patients who would benefit from palliative care services.

http://ift.tt/2wCShwh

Environmental design for end-of-life care: An integrative review on improving quality of life and managing symptoms for patients in institutional settings

The environment in which end-of-life care is delivered can support or detract from the physical, psychological, social, and spiritual needs of patients, their families, and their caretakers.

http://ift.tt/2xhEIWw

Acute Leukemia Patients’ Needs: Qualitative Findings and Opportunities for Early Palliative Care

Patients with acute leukemias likely have needs that palliative care can respond to, yet little is known about specific challenges they face, particularly during active treatment. We examined acute myeloid leukemia (AML) patients' expressed challenges and supports following intensive induction chemotherapy. We aimed to understand opportunities for palliative care interventions in this population.

http://ift.tt/2wDyCw8

Cancers, Vol. 9, Pages 126: The Impact of DNA Repair Pathways in Cancer Biology and Therapy

Cancers, Vol. 9, Pages 126: The Impact of DNA Repair Pathways in Cancer Biology and Therapy

Cancers doi: 10.3390/cancers9090126

Authors: Anatoly Nikolaev Eddy Yang

Genomic instability is one of the key hallmarks of cancer progression [1].[...]

http://ift.tt/2fgnz9v

380TF The Emergency Medicine Research Rotation

The Residency Review Committee for Emergency Medicine (EM) requires that all residents a scholarly project prior to graduation. This curriculum is intended to provide EM residents with baseline knowledge and skills to design and conduct a research project and to provide protected time for residents to design the scholarly project that they will complete over the remainder of the tenure in residency.

http://ift.tt/2wCRaMQ

94 Cost Impact of Hydroxocobalamin as Treatment for Patients With Known or Suspected Cyanide Toxicity Due to Smoke Inhalation Injury

Cyanide toxicity can occur in persons who are exposed to smoke in a closed-space fire. Hydroxocobalamin (HC) is a cyanide antidote indicated for treatment in persons with known or suspected cyanide poisoning including that due to smoke inhalation. The objective of the present analysis was to estimate the cost impact of outcomes with administration of HC compared to historical controls not receiving cyanide antidote.

http://ift.tt/2xhUd0M

95 Safety and Efficacy of Dantrolene Sodium (250 mg/5 mL) in Patients With Exertional Heat Stroke

Exertional heat stroke (EHS) is a rare, life-threatening condition that may affect anyone performing intense physical activity, especially in a hot environment. Morbidity and mortality persist despite aggressive cooling. EHS is a leading cause of death in young athletes and non-combat-related deaths in the military. EHS affects outdoor workers, firefighters, and people performing intense physical activities in hot weather. Severe hyperthermia and CNS dysfunction are hallmark features; rhabdomyolysis, renal failure, liver damage, and coagulation abnormalities are common and as many as 1/3 of survivors have long-term neurologic deficits despite the use of aggressive cooling.

http://ift.tt/2wCIzd4

96 Use of Emergency Medical Services by Law Enforcment

Law enforcement and Emergency Medical Services (EMS) have a close working relationship with frequent requests by police for evaluation, treatment, and transport of patients. Law enforcement agencies also require some level of medical training and allow officers to do certain assessments and interventions on their own. We examined these calls to better identify how EMS was used by law enforcement.

http://ift.tt/2xi4ABA

97 Safety of Out-of-Hospital Midazolam in Behavioral Emergencies

Based on its increasing use in emergency departments, one urban EMS agency in California began using midazolam for sedation (up to 5mg IM standard dose). To date, no studies evaluate midazolam safety in the out-of-hospital setting for sedation of patients in acute behavioral emergencies. This study attempts to quantify the incidence of adverse events associated with out-of-hospital patients receiving midazolam.

http://ift.tt/2wCOgrp

98 EMS Utilization Among Patients on Involuntary Psychiatric Holds in Alameda County, April 2014-2016

Involuntary emergency psychiatric holds are placed on individuals suspected of having mental illness who are deemed to be dangerous to themselves or others. The purpose is to legally detain them for an emergency psychiatric evaluation. Although the situation arises frequently in all communities, the process that follows placement of such a hold varies immensely across the country; even neighboring counties having very different protocols. In many cases, these patients are then taken to a health care facility, usually an emergency department (ED).

http://ift.tt/2xiacM7

221 Do Practitioners Still Recommend Rest for Acute Concussion Management?

Children sustain approximately 1 million closed head injuries annually, almost all of which are classified as concussions. The majority of those injured recover from symptoms within four weeks; however, about one-third take longer to recover. The disability from prolonged concussions includes physical and cognitive dysfunction, sleep disturbances, and behavioral changes that may lead to missed days of school or work. Historically, acute concussions were managed with physical and cognitive rest; however, recent literature has questioned the efficacy of cognitive rest.

http://ift.tt/2wCR5Zy

237 A New Method for Assessing Pain in the Emergency Department

Pain is the most common chief complaint in the emergency department (ED), with up to 78% of patients reporting pain as the primary reason for visiting the ED. The visual analog scale (VAS) and the numeric rating scale (NRS) are the most commonly used tools that assess the severity of pain in the ED, but they do not capture how pain interferes with the patient's daily functions, which is important to guiding pain management. The Brief Pain Inventory, Short Form (BPI-SF) is a validated, self-administered questionnaire designed to assess the severity of pain and the impact of pain on the patient's daily functions.

http://ift.tt/2xi4xFU

391 Same Physician, Different Location: Variation in Press Ganey Scores Between Freestanding and Hospital-Based Emergency Departments

Patient satisfaction scores have become quality benchmarks for hospitals, are publicly reported, and are often tied to financial incentives. As a result, patient satisfaction scores have become an increasing priority for health systems. In spite of this, no published research has compared freestanding emergency departments (FED) to hospital-based emergency departments (HBED) in relation to patient satisfaction scores. Our objective was to determine whether patient satisfaction scores for individual emergency physicians varied according to the clinical setting in which the care was provided, comparing HBEDs versus FEDs.

http://ift.tt/2wCIxBY

229 EMS Can Safely Transport Patients to a Sobering Center as an Alternate Destination

This purpose of this study is to evaluate the ability of the sobering center to operate as a safe alternative destination for paramedics [EMS] by evaluating all secondary transports from the Center to the emergency department (ED). Our aims are to 1) introduce the concept of a sobering center as an alternative destination for EMS, and 2) quantify and analyze all secondary transfers from the sobering center to the ED.

http://ift.tt/2xiaant

383 A Novel Technique for Improving Fluid Resuscitation in Septic Shock

Rapid fluid delivery is commonly required in sepsis and other conditions leading to shock and hypotension. Since gravity flow and infusion pumps are unable to deliver a fluid bolus rapidly, pressure bags are commonly used to increase flow rates. Disadvantages of this technique include progressive decrease in flow rate without continuous re-inflation of the bag, difficulty administering accurate doses, particularly with smaller volumes, and the risk of inadvertent air embolism. LifeFlow is an intuitive single-use device that provides rapid and controlled infusion, enabling a health care provider to administer a measured fluid bolus and quickly assess clinical response.

http://ift.tt/2wD2KHT

233 Effectiveness of Rural Emergency Department-Based Pain Contract on Emergency Department Visits Among Emergency Department Frequent Users

Caring for patients with non-acute pain in the emergency department (ED) can be particularly challenging, both for patients and for physicians. This study seeks to determine, in a rural setting, the effect of an ED-based pain contract on the rate of ED visits among patients with frequent visits for pain or complaints of chronic pain not related to cancer.

http://ift.tt/2xi7XZ6

225 Does Telepsychiatry Help Disposition Psychiatric Patients Faster?

The purpose of our study was to determine whether telepsychiatry decreased length of stay for patients who were medically cleared for discharge as compared to consulting house psychiatry.

http://ift.tt/2wD2Xeb

217 Making the Diagnosis of Concussion in the Emergency Department: Are We Hitting the Mark?

There has been increased interest in concussion among the scientific and lay press in the last 20 years, and the emergency department (ED) is where patients commonly seek medical evaluation after a head injury. The diagnosis of concussion can be easily missed because it is a clinical diagnosis, often made after ruling out more serious injuries. The objective of this study is to determine the prevalence of concussion among children seen at our ED (17k annual visits in 2015) and determine the extent of underdiagnosis.

http://ift.tt/2xi7Wo0

387 Increasing Compliance With Repeat Lactate Measurement Utilizing Automated Repeat Lactate Ordering

The Centers for Medicare and Medicaid (CMS) sepsis management bundle (SEP-1) core measure requires that serum lactate levels be obtained and repeated within 6 hours if > 2.0 mmol/L and evidence supports prognostic value of improvement in serum lactate values. We developed an order in our electronic health record (EHR) that includes a repeat lactate order if the initial lactate level is elevated. We hypothesize that implementation of a lactate order that includes triggers for repeat testing will increase compliance with repeat lactate measurement in patients with severe sepsis and septic shock.

http://ift.tt/2xifzeu

239 Mortality of Motor Vehicle Accidents by Elderly Drivers: A Nationwide Hospital-Based Registry in Japan

Japan is the leading aging country, and motor vehicle accidents (MVAs) by elderly drivers have been exceedingly increasing in recent years. However, there were no clinical studies evaluating the impact of MVAs by elderly drivers in Japan. We aimed to assess the MVA incidence and outcomes by elderly drivers, especially by those aged >=75 years who were transported to emergency department and registered in the Japan Trauma Data Bank.

http://ift.tt/2wD1LY6

235 Whose Pain is it Anyway? Qualitative Research Exploring How the 0-10 Pain Score is Used in Practice Within the Adult Emergency Department

The assessment of pain in the emergency department (ED) is difficult but important for appropriate management of pain. Guidelines for the management of acute pain in the ED worldwide advocate the use of numeric rating scales such as the 0-10 pain score as tools to ensure consistency of documenting patient's pain, and the score is mandated at initial assessment in many EDs. Many pain protocols use the pain score to guide treatment, and pain management performance is often audited or assessed based upon whether pain score-appropriate treatment has been given.

http://ift.tt/2xi12iQ

Personal use of hair dyes and risk of leukemia: a systematic literature review and meta-analysis

Abstract

The objective of this study was to examine the association between personal use of hair dyes and the risk of leukemia. We conducted a systematic literature review of epidemiology studies reporting leukemia-specific cancer risks among hair dye users, and estimated the meta-relative risk (meta-RR) and corresponding 95% confidence interval (95% CI) of leukemia, comparing hair dye users to nonusers. When data from all 20 studies that met the inclusion criteria were combined, ever use of hair dye was associated with a nonstatistically significant increased risk of leukemia, meta-RR = 1.09 (95% CI: 0.97–1.22). When restricted to studies that adjusted for smoking, ever use of hair dye was not associated with leukemia, meta-RR = 0.99 (95% CI: 0.76–1.29). A statistically significant increased risk of leukemia was associated with permanent hair dye use (meta-RR = 1.19 [95% CI: 1.07–1.33]), dark hair dye use (meta-RR = 1.29 [95% CI: 1.11–1.50]), hair dye use among males (meta-RR = 1.42 [95% CI: 1.01–2.00]), hair dye use pre-1980 (meta-RR = 1.49 [95% CI: 1.21–1.83]), and hair dye use for ≥15 years (meta-RR = 1.35 [95% CI: 1.13–1.62]). Overall, findings suggest that ever use of hair dye is not a significant risk factor for leukemia. Certain hair dye use characteristics were associated with a statistically significant increased risk, but further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.

The purpose of this study was to synthesize and examine the evidence on the relative risk of leukemia among hair dye users under various exposure scenarios. Findings suggest that personal hair dye use is not a significant risk factor for leukemia when data from all studies were combined. Upon stratification, permanent hair dye use, dark hair dye use, hair dye use pre-1980, hair dye use among males, and hair dye use for ≥15 years were associated with a statistically significant increased risk of leukemia. Further research is required to determine whether these associations truly reflect a risk of leukemia due to methodological limitations in the underlying studies.

http://ift.tt/2xdRYdj

Relationship of tumor PD-L1 (CD274) expression with lower mortality in lung high-grade neuroendocrine tumor

Abstract

Programmed death-ligand 1 (PD-L1) promotes immunosuppression by binding to PD-1 on T lymphocytes. Although tumor PD-L1 expression is a potential predictive marker of clinical response to anti-PD-1/PD-L1 therapy, little is known about its association with clinicopathological features, including prognosis, in high-grade neuroendocrine tumors (HGNETs), including small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC), of the lung. We immunohistochemically examined the membranous of expression of PD-L1 in 115 consecutive surgical cases of lung HGNET (74 SCLC cases and 41 LCNEC cases). We examined the prognostic association of tumor PD-L1 positivity using the log-rank test as well as Cox proportional hazards regression models to calculate the hazard ratio (HR) for mortality. Programmed death-ligand 1 immunostaining (at least 5% tumor cells) was observed in 25 (21%) of the 115 HGNET cases. In a univariable analysis, PD-L1 positivity was associated with lower lung cancer-specific (univariable HR = 0.23; 95% confidence interval [CI] = 0.056–0.64; P = 0.0028) and overall (univariable HR = 0.28; 95% CI = 0.11–0.60; P = 0.0005) mortality. Additionally, in a multivariable analysis, PD-L1 positivity was independently associated with lower lung cancer-specific (multivariable HR = 0.24; 95% CI = 0.058–0.67; P = 0.0039) and overall (multivariable HR = 0.29; 95% CI = 0.11–0.61; P = 0.0006) mortality. Our study demonstrated the prevalence of PD-L1 positivity in lung HGNET cases, and the independent association of tumor PD-L1 positivity with lower mortality in lung HGNET cases. Further studies are needed to confirm our findings.

High-grade neuroendocrine tumor (HGNET) (small cell lung carcinoma and large cell neuroendocrine carcinoma) is the most aggressive histological subtype of lung cancer, and immunotherapies, including anti-PD-1/Programmed death-ligand 1 (PD-L1) therapy, are emerging and promising. The prevalence of PD-L1 positivity in lung HGNET is shown. PD-L1 positivity is associated with lower mortality in lung HGNET.

http://ift.tt/2yaMpLR

Clinical predictive factors of long-term survival after curative resection of pancreatic cancer: a retrospective study

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to have the poorest prognosis of all gastrointestinal malignancies, even after the tumor has been completely resected. However, only a proportion of patients achieve 5-year survival after resection. The factors predictive of achieving 5-year survival remain unclear. The aim of this study was to investigate the pre- and postoperative clinicopathological characteristics of PDAC patients with a >5-year survival after curative resection. We retrospectively reviewed patients who underwent pancreatectomy for PDAC between January 1995 and December 2011. Logistic regression analysis was performed to determine the predictive factors for 5-year survival. One hundred and fifty-one patients were enrolled, including 38 patients with 5-year survival (actual 5-year survival rate, 25.2%). The independent preoperative factors predictive of achieving 5-year survival included serum albumin levels (odds ratio [OR]: 5.06, 95.0% confidence interval [CI]: 1.49–17.19; P = 0.009) and neoadjuvant chemoradiotherapy (OR: 3.02, 95.0% CI: 1.00–9.08; P = 0.049). Venous infiltration (OR: 2.99, 95.0% CI: 1.09–8.25; P = 0.034), liver recurrence (OR: 0.17, 95.0% CI: 0.04–0.69; P = 0.013), and perioperative portal vein infusion chemotherapy (OR: 3.06, 95.0% CI: 1.09–8.25; P = 0.028) were found to be independent postoperative predictive factors for achieving 5-year survival. Serum albumin levels could be a biomarker for predicting the prognosis of PDAC patients after curative resection. Liver recurrence and perioperative portal vein infusion chemotherapy were independent postoperative factors, suggesting that perioperative portal vein infusion chemotherapy could be promising for improving the survival rate of PDAC patients after curative resection.

Relationship between neoadjuvant chemoradiotherapy (NACRT) and (A) postoperative disease-free survival (DFS) and (B) postoperative overall survival (OS) and relationship between perioperative adjuvant portal vein infusion (PVI) chemotherapy and (C) postoperative DFS and (D) postoperative OS.

http://ift.tt/2jEXe6A

Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor–Based Immunotherapy and Chemotherapy

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2henfZG

Small But Increasingly Mighty: Latest Advances in AAV Vector Research, Design, and Evolution

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2heFYR4

Transposons: Moving Forward from Preclinical Studies to Clinical Trials

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2hb0INi

Minicircle Versus Plasmid DNA Delivery by Receptor-Targeted Polyplexes

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2hdQJTL

The Future Looks Brighter After 25 Years of Retinal Gene Therapy

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2hen1Sk

Advances and Challenges in Cardiovascular Gene Therapy

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2hdWP6x

Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2hemL5O

An eleven-year retrospective hospital-based study of epidemiological data regarding human strongyloidiasis in northeast Thailand

Human strongyloidiasis is a chronic and persistent gastrointestinal disease caused by infection with soil-transmitted helminths of the genus Strongyloides. The aim of this research was to obtain diagnostic preval...

http://ift.tt/2jEFmIR

Sero-epidemiology study of leptospirosis in febrile patients from Terai region of Nepal

Leptospirosis is a re-emerging zoonotic disease caused by pathogenic strains of bacteria belonging to genus Leptospira whose symptoms can range from mild clinical manifestations to a severe life threatening illne...

http://ift.tt/2xMynnF

Caretakers’ understanding of malaria, use of insecticide treated net and care seeking-behavior for febrile illness of their children in Ethiopia

Local understandings of malaria and use of preventive measures-are critical factors in sustained control of malaria. This study assessed caretakers' knowledge on malaria, use of Long Lasting Insecticide Treate...

http://ift.tt/2jEF8Bv

Effects on preventing mother-to-child transmission of syphilis and associated adverse pregnant outcomes: a longitudinal study from 2001 to 2015 in Shanghai, China

Maternal syphilis is a health threat to both the pregnant women and the children. This study aimed to delineate the longitudinal trend of maternal syphilis and burden of associated adverse pregnant outcomes (A...

http://ift.tt/2xNchB8

Functional Validation of Heteromeric Kainate Receptor Models

Kainate receptors require the presence of external ions for gating. Most work thus far has been performed on homomeric GluK2 but, in vivo, kainate receptors are likely heterotetramers. Agonists bind to the ligand-binding domain (LBD) which is arranged as a dimer of dimers as exemplified in homomeric structures, but no high-resolution structure currently exists of heteromeric kainate receptors. In a full-length heterotetramer, the LBDs could potentially be arranged either as a GluK2 homomer alongside a GluK5 homomer or as two GluK2/K5 heterodimers.

http://ift.tt/2yal5NB

Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling

In addition to inducing anesthesia, propofol activates a key component of the pain pathway, the transient receptor potential ankyrin 1 ion channel (TRPA1). Recent mutagenesis studies suggested a potential activation site within the transmembrane domain, near the A-967079 cavity. However, mutagenesis cannot distinguish between protein-based and ligand-based mechanisms, nor can this site explain the complex modulation by propofol. Thus more direct approaches are required to reveal potentially druggable binding sites.

http://ift.tt/2xcsLQg

Functional Validation of Heteromeric Kainate Receptor Models

Kainate receptors require the presence of external ions for gating. Most work thus far has been performed on homomeric GluK2 but, in vivo, kainate receptors are likely heterotetramers. Agonists bind to the ligand-binding domain (LBD) which is arranged as a dimer of dimers as exemplified in homomeric structures, but no high-resolution structure currently exists of heteromeric kainate receptors. In a full-length heterotetramer, the LBDs could potentially be arranged either as a GluK2 homomer alongside a GluK5 homomer or as two GluK2/K5 heterodimers.

http://ift.tt/2yal5NB

Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling

In addition to inducing anesthesia, propofol activates a key component of the pain pathway, the transient receptor potential ankyrin 1 ion channel (TRPA1). Recent mutagenesis studies suggested a potential activation site within the transmembrane domain, near the A-967079 cavity. However, mutagenesis cannot distinguish between protein-based and ligand-based mechanisms, nor can this site explain the complex modulation by propofol. Thus more direct approaches are required to reveal potentially druggable binding sites.

http://ift.tt/2xcsLQg

Localization of Cdc7 Protein Kinase During DNA Replication in Saccharomyces cerevisiae

DDK, a conserved serine-threonine protein kinase composed of a regulatory subunit, Dbf4, and a catalytic subunit, Cdc7, is essential for DNA replication initiation during S phase of the cell cycle through MCM2-7 helicase phosphorylation. The biological significance of DDK is well characterized, but the full mechanism of how DDK associates with substrates remains unclear. Cdc7 is bound to chromatin in the Saccharomyces cerevisiae genome throughout the cell cycle, but there is little empirical evidence as to specific Cdc7 binding locations. Using biochemical and genetic techniques, this study investigated the specific localization of Cdc7 on chromatin. The Calling Cards method, using Ty5 retrotransposons as a marker for DNA-protein binding, suggests Cdc7 kinase is preferentially bound to genomic DNA known to replicate early in S phase, including centromeres and origins of replication. We also discovered Cdc7 binding throughout the genome, which may be necessary to initiate other cellular processes, including meiotic recombination and translesion synthesis. A kinase-dead Cdc7 point mutation increases the Ty5 retrotransposon integration efficiency and a 55 amino acid C-terminal truncation of Cdc7, unable to bind Dbf4, reduces Cdc7 binding suggesting a requirement for Dbf4 to stabilize Cdc7 on chromatin during S phase. Chromatin immunoprecipitation demonstrates that Cdc7 binding near specific origins changes during S phase. Our results suggest a model where Cdc7 is loosely bound to chromatin during G₁. At the G₁/S transition, Cdc7 binding to chromatin is increased and stabilized, preferentially at sites that may become origins, in order to carry out a variety of cellular processes.

http://ift.tt/2yld8Gx

Exploiting drug addiction mechanisms to select against MAPKi-resistant melanoma [Research Articles]

Melanoma resistant to MAPK inhibitor(s) (MAPKi) displays loss-of-fitness upon experimental MAPKi withdrawal and, clinically, may be re-sensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi-addiction in MAPKi-resistant MUTBRAF or MUTNRAS melanoma. MAPKi-addiction phenotypes evident upon drug-withdrawal spanned transient cell-cycle slow-down to cell-death responses, the latter of which required a robust p-ERK rebound. Generally, drug withdrawal-induced p-ERK rebound up-regulated p38-FRA1-JUNB-CDKN1A and down-regulated proliferation, but only a robust p-ERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi-addiction across-the-board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant MUTNRAS or atypical MUTBRAF melanoma, treatment with a type I RAF inhibitor intensified p-ERK rebound elicited by MEKi-withdrawal, thereby promoting a cell-death predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi-addiction.

http://ift.tt/2xMfilg

How Ribosomes Translate Cancer [Reviews]

A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis—from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on "onco-ribosomes" as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention.

Significance: The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies. Cancer Discov; 7(10); 1–19. ©2017 AACR.

http://ift.tt/2jHy2wi

A transposon screen identifies loss of primary cilia as a mechanism of resistance to Smo inhibitors [Research Articles]

Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway-dependent cancers, the scope of mechanisms enabling resistance to Smo-inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to Smo-inhibitors and maintains a "persister" state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal novel patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

http://ift.tt/2xLEwjN

In silico modeling of immunotherapy and stroma-targeting therapies in human colorectal cancer

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n=20) including tumor cells, lymphocytes, stroma and necrosis to generate a multi-agent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n=37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n=261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, p=0.0219) as compared with high stroma and low lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in pre-established tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions which target the colorectal cancer microenvironment.

http://ift.tt/2jFACmp

MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and non-invasive magnetic resonance spectroscopy

Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle-related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by co-administration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. 

http://ift.tt/2xM6onN

Upregulation of Cystathionine-{beta}-synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

The transsulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-kappaB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immune compromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/-) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis.

http://ift.tt/2jFnVrv

MetaLnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway

Long non-coding RNAs participate in carcinogenesis and tumor progression in lung cancer. Here we report the identification of a lncRNA signature associated with metastasis of non-small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a co-activator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC.

http://ift.tt/2xM6kEz

Mitosis-mediated intravasation in a tissue-engineered tumor-microvessel platform

Intravasation involves the migration of tumor cells across the local endothelium and escape into vessel flow. While tumor cell invasiveness has been correlated to increased intravasation, the details of transendothelial migration and detachment into circulation are still unclear. Here we analyzed the intravasation of invasive human breast cancer cells within a tissue-engineered microvessel model of the tumor microenvironment. Using live-cell fluorescence microscopy, we captured 2,330 hours of tumor cell interactions with functional microvessels and provide evidence for a mitosis-mediated mechanism where tumor cells located along the vessel periphery are able to disrupt the vessel endothelium through cell division and detach into circulation. This model provides a framework for understanding the physical and biological parameters of the tumor microenvironment that mediate intravasation of tumor cells across an intact endothelium.

http://ift.tt/2jFnTzT

Anti-CD137 suppresses tumor growth by blocking reverse signaling by CD137 ligand

CD137 (4-1BB) is a T cell co-stimulatory molecule and agonstic CD137 antibodies are currently being evaluated in clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL-12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFN-γ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL-12 and IFN-γ which promoted intratumoral differentiation of IFN-γ-producing Tc1, IL-12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance.

http://ift.tt/2xM6ifV

Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer

The PPARG gene encoding the nuclear receptor PPAR-gamma is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene which encodes the heterodimeric partner of PPAR-gamma. Here we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer.

http://ift.tt/2jFnQUJ

Caveolae-Mediated Endocytosis is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy

Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for trans-endothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above which respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells where Cav-1 was attenuated exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs.

http://ift.tt/2jE3DPh

Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies

FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared to either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition.

http://ift.tt/2xMzpzL

TET-mediated sequestration of miR-26 drives EZH2 expression and gastric carcinogenesis

DNA demethylases of the TET family function as tumor suppressors in various human cancers but their pathogenic contributions and mechanisms of action in gastric carcinogenesis and progression remain unclear. Here we report that TET is transcriptionally upregulated in gastric cancer (GC) where it correlates with poor prognosis. Mechanistic investigations revealed that TET facilitated gastric carcinogenesis through a non-coding function of the 3'UTR which interacted with miR-26. This interaction resulted in sequestration of miR-26 from its target EZH2, which released the suppression on EZH2, and thereby leaded to EZH2 overexpression in gastric cancer. Our findings uncover a novel non-coding function for TET family proteins in facilitating gastric carcinogenesis.

http://ift.tt/2jFnGwB

Safety of intravenously applied mistletoe extract – results from a phase I dose escalation study in patients with advanced cancer

Mistletoe extracts have anti-tumor properties and are approved for subcutaneous use in cancer patients. Data on Intravenous application are limited.

http://ift.tt/2xcRALQ

A pilot single centre, double blind, placebo controlled, randomized, parallel study of Calmagen® dermaceutical cream and lotion for the topical treatment of tinea and onychomycosis

Most of the current anti-fungal treatments are chemical-based, fungistatic, have low efficacy in the treatment of tinea and toxicity concerns, while onychomycosis remains recalcitrant to most antifungal therap...

http://ift.tt/2yaeLpt

Immune regulation by histamine and histamine-secreting bacteria

Weronika Barcik | Marcin Wawrzyniak | Cezmi A Akdis | Liam O'Mahony

http://ift.tt/2jF347Q

Interplay among resistance profiles, high-risk clones and virulence in the Caenorhabditis elegans Pseudomonas aeruginosa infection model [PublishAheadOfPrint]

The increasing prevalence of nosocomial infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa is frequently linked to widespread international strains designated as high-risk clones. In this work we attempted to decipher the interplay between resistance profiles, high-risk clones and virulence, testing a large (n=140) collection of well characterized P. aeruginosa isolates from different sources (bloodstream infections, nosocomial outbreaks, cystic fibrosis and environment) in a Caenorhabditis elegans infection model. Consistently with previous data, we documented a clear inverse correlation between antimicrobial resistance and virulence in the C. elegans model. Indeed, lowest virulence was linked to XDR profiles, which were typically linked to defined high-risk clones. However, virulence varied broadly depending on the involved high-risk clone; it was high for ST111 and ST235 but very low for ST175. The highest virulence of ST235 could be attributed to its ExoU+ Type III secretion system (TTSS) genotype, found to be linked with higher virulence in our C. elegans model. Other markers, such as motility or pigment production were not essential for virulence in the C. elegans model, but seemed to be related with the higher values of the statistical normalized data. Opposite to ST235, the ST175 high-risk clone, widespread in Spain and France, seems to be associated with a particularly low virulence in the C. elegans model. Moreover, the previously described G154R AmpR mutation, prevalent in ST175, was found to contribute to the reduced virulence, although it was not the only factor involved. Altogether, our results provide a major step forward for understanding the interplay between P. aeruginosa resistance profiles, high-risk clones and virulence.

http://ift.tt/2fhVhLL

Co-location of the multiresistance gene cfr and the fosfomycin resistance gene fosD on a novel plasmid in Staphylococcus arlettae from chicken farm [PublishAheadOfPrint]

A novel 63,558-bp plasmid pSA-01 harbouring nine antibiotic resistance genes, including cfr, erm(C), tet(L), erm(T), aadD, fosD, fexB, aacA-aphD and erm(B), was characterized in Staphylococcus arlettae strain SA-01 isolated from chicken farm in China. The co-location of cfr and fosD genes was detected for the first time in S. arlettae plasmid. The detection of two IS431-mediated circular forms containing resistance genes in SA-01 suggested that IS431 may facilitate dissemination of antibiotic resistance genes.

http://ift.tt/2xtESug

Vancomycin and clarithromycin show synergy against Mycobacterium abscessus in vitro [PublishAheadOfPrint]

Lung disease caused by Mycobacterium abscessus is increasing and current clarithromycin-based treatment regimens are only moderately effective. Here, we determined the effect of clarithromycin-vancomycin combination against M. abscessus complex isolates in vitro. Synergy was found with an FICI ≤ 0.5 and a 4 to 10-fold decrease of minimum inhibitory concentrations.

http://ift.tt/2xtJxwf

An in vitro comparison of ceftolozane/tazobactam compared to traditional beta-lactams as an alternative to combination antimicrobial therapy for Pseudomonas aeruginosa [PublishAheadOfPrint]

Background: Guidelines for sepsis, febrile neutropenia, and hospital-acquired pneumonia include empiric regimens incorporating two antibiotics from different classes with activity against Pseudomonas aeruginosa for select at-risk patients to increase the likelihood of susceptibility to at least one agent.

Objectives: The activity and cross-resistance rates of ceftolozane/tazobactam were compared to β-lactam comparators cefepime, ceftazidime, piperacillin/tazobactam, and meropenem alone and cumulatively with ciprofloxacin or tobramycin against P. aeruginosa.

Methods: Nonurine P. aeruginosa isolates were collected from adult inpatients at 44 geographically diverse U.S. hospitals. MICs were determined using reference broth microdilution methods.

Results: Of the 1257 isolates collected, 29% were from the ICU, and 39% were from respiratory sites. Overall susceptibility to ceftolozane/tazobactam was high at 97%, compared to 72-76% for cefepime, ceftazidime, piperacillin/tazobactam, and meropenem. Non-susceptibility to all four comparator β-lactams was 11%; of these, 80% remained susceptible to ceftolozane/tazobactam. Among the isolates non-susceptible to the tested β-lactam comparator, fewer than half were susceptible to ciprofloxacin. By comparison, approximately 80% of the β-lactam non-susceptible isolates were susceptible to tobramycin, for overall cumulative susceptibilities of 94-95%, nearly 10% higher than that of the ciprofloxacin/β-lactam combinations and approaching that of ceftolozane/tazobactam as a single agent.

Conclusions: Ceftolozane/tazobactam susceptibilities were consistently high, with little observable cross-resistance. Ceftolozane/tazobactam monotherapy performed at or above the level of commonly utilized combination therapies based on in vitro susceptibilities. Ceftolozane/tazobactam should be considered for patients at high risk for resistant P. aeruginosa infection and as an alternative to empiric combination therapy, especially for patients unable to tolerate aminoglycosides.

http://ift.tt/2xtJtN1

Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity and outcome in Liver Transplant Patients; an Observational Study [PublishAheadOfPrint]

The aim of this study was to investigate the variability of voriconazole plasma level and its relationship with clinical outcomes and adverse events, among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included and voriconazole trough levels were quantified by the validated high-performance liquid chromatography method. Cytochrome P450 genotypes of CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable and possible invasive fungal infections were reported in (8/104, 7.7%), (42/104, 40.4%), and (54/104, 51.9%) patients, respectively. ROC curve analysis indicated that trough concentration ≥1.3 μg/ml minimized the incidence of treatment failure (95% CI 0.68–0.91; P < 0.001), and < 5.3 μg/ml minimized the incidence of any adverse events (95% CI 0.83–0.97; P < 0.001). Voriconazole trough levels were significantly higher in heterozygous extensive metabolizers, poor metabolizers and co-administration with proton pump inhibitors. In ultra-rapid metabolizers, oral administration of voriconazole and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patients' age, weight, gender, co-administration of tacrolimus and cyclosporine with voriconazole trough level. In conclusion, the results of our analysis indicated large inter and intra-individual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations between ≥1.3 μg/ml and < 5.3 μg/ml are optimal for treatment and minimize adverse events. Optimizing drug efficacy and safety need rational doses for voriconazole therapy.

http://ift.tt/2ffTPth

The Impact of Vancomycin Area Under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity: a Quasi-Experiment [PublishAheadOfPrint]

Background: Evidence suggests maintaining vancomycin trough concentrations between 15 and 20 mg/L, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC_24h) target of ≥ 400 mg*h/L. Many patients with trough concentrations in this range have AUC_24h in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. Based on this, the Detroit Medical Center switched from trough concentration to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity.

Methods: Single center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by AUC_24h versus trough concentration. Multivariable logistic and Cox-proportional hazard regression examined the independent association between monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies.

Results: Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity in both logistic regression (OR, 0.52; 95% CI, 0.34-0.80; P=0.003) and Cox-proportional hazards regression (HR, 0.53; 95% CI, 0.35-0.78; P=0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations.

Conclusion: Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity which appears to be a result of reduced vancomycin exposure.

http://ift.tt/2xtyvHz

Pharmacological Inhibition of the Pseudomonas aeruginosa MvfR Quorum Sensing System Interferes with Biofilm Formation and Potentiates Antibiotic-Mediated Biofilm Disruption [PublishAheadOfPrint]

Pseudomonas aeruginosa biofilms contribute to its survival on biotic and abiotic surfaces and represent a major clinical threat due to their high tolerance to antibiotics. Therefore, the discovery of anti-biofilm agents may hold great promise. We show that pharmacological inhibition of the P. aeruginosa quorum sensing regulator MvfR (PqsR) using a benzamide-benzimidazole compound interferes with biofilm formation and potentiates biofilm sensitivity to antibiotics. Such a strategy could have a great potential against P. aeruginosa persistence in diverse environments.

http://ift.tt/2ffTMO7

AGAR-BASED SCREENING FOR AZOLE RESISTANCE IN ASPERGILLUS FUMIGATUS USING VIPcheck™: A SINGLE CENTRE EVALUATION [PublishAheadOfPrint]

Introduction Antifungal susceptibility testing is an essential tool for guiding therapy, although EUCAST and CLSI reference methods are often only available in specialized centres. We studied the performance of an agar-based screening method for the detection of azole resistance in Aspergillus fumigatus cultures.

Methods The VIPcheck™ consists of four wells containing voriconazole, itraconazole, posaconazole or a growth control. Ninety-six A. fumigatus isolates were used. Thirty-three isolates harboured a known resistance mechanism: TR₃₄/L98H (11 isolates); TR₄₆/Y121F/T289A (6 isolates); TR₅₃ (2 isolates) and fourteen isolates with other cyp51A-gene point mutations. Eighteen resistant isolates had no cyp51A-mediated azole resistance. 45 isolates had a wild type (WT) azole phenotype. Four technicians and two inexperienced interns, blinded to the geno/phenotype, read the plates visually after 24h and 48h and documented minimal growth, uninhibited growth and no growth. The performance was compared to the EUCAST method.

Results After 24h incubation the mean sensitivity and specificity were 0.54 and 1.00 with uninhibited growth as threshold. After 48h incubation the performance mean sensitivity/specificity were 0.98 and 0.93 with minimal growth. The performance was not affected by experience in mycology. The interclass correlation coefficient was 0.87 after 24h and 0.85 after 48h.

Conclusion VIPcheck™ enabled selection of azole-resistant A. fumigatus colonies with a mean sensitivity and specificity of 0.98 and 0.93. Uninhibited growth on any azole-containing well after 24h and minimal growth after 48h were indicative of resistance. These results indicate that the VIPcheck™ is an easy-to-use tool for azole resistance screening and selection of colonies that require MIC-testing.

http://ift.tt/2xtJlNx

Age-related Trends in Adults with Community-onset Bacteremia [PublishAheadOfPrint]

To understand the epidemiological variation in bacteremia characteristics among differently aged populations, adults with community-onset bacteremia during a 6-year period were studied in a retrospective cohort. A total of 2,349 bacteremic patients were stratified into four age categories: young adults (18-44 years old; 196 patients, 8.3%), adults (45-64; 707, 30.1%), the elderly (65-84; 1,098, 46.7%), and the oldest old (≥ 85; 348, 14.8%). Age-related trends in critical illness (a Pitt bacteremia score ≥ 4) at bacteremia onset, antibiotic-resistant pathogens (ESBL-producing Escherichia coli, Klebsiella species, and Proteus mirabilis [EKP]; methicillin-resistant Staphylococcus aureus [MRSA]; and levofloxacin non-susceptible EKP), inappropriate empirical antibiotic therapy (EAT), and 4-week mortality rate were observed. Using a multivariate regression model, critical illness at bacteremia onset (adjusted odds ratio [AOR], 9.03; P < 0.001) and inappropriate EAT (AOR, 2.67; P < 0.001) were the two leading predictors of 4-week mortality. Moreover, ESBL-producing EKP (AOR, 12.94; P<0.001), MRSA (AOR, 8.66; P<0.001), and levofloxacin non-susceptible EKP (AOR, 4.27; P<0.001) were linked to inappropriate EAT. Conclusively, among adults with community-onset bacteremia, significant positive age-related trends were noted in antibiotic-resistant pathogens and bacteremia severity, which were related to the increasing incidence of inappropriate EAT and 4-week mortality with age. Thus, different empirical antimicrobial regimens should be considered for distinct age groups.

http://ift.tt/2fglVoa

An Anti-Persister Strategy for the Treatment of Chronic Pseudomonas aeruginosa Infections [PublishAheadOfPrint]

Bacterial persisters are a quasi-dormant sub-population of cells that are tolerant to antibiotic treatment. The combination of the aminoglycoside tobramycin with fumarate as an antibacterial potentiator utilizes an anti-persister strategy that is aimed at reducing recurrent Pseudomonas aeruginosa infections by enhancing the killing of P. aeruginosa persisters. Stationary phase cultures of P. aeruginosa were used to generate persister cells. A range of tobramycin concentrations was tested with a range of metabolite concentrations to determine the potentiation effect of the metabolite under a variety of conditions, including a range of pH values and in the presence of azithromycin or cystic fibrosis (CF) patient sputum. In addition, 96-well dish biofilm and colony biofilm assays were performed, and the cytotoxicity of the tobramycin-fumarate combination was determined utilizing an LDH assay. Enhanced killing of up to 6 orders of magnitude of P. aeruginosa persisters over a range of CF isolates including mucoid and non-mucoid strains was observed for the tobramycin-fumarate combination compared to tobramycin alone. Furthermore, significant fumarate-mediated potentiation was seen in the presence of azithromycin or CF patient sputum. Fumarate also reduced the cytotoxicity of tobramycin treated P. aeruginosa to human epithelial airway cells. Finally, in mucoid and non-mucoid CF isolates, complete eradication of P. aeruginosa biofilm was observed in the colony biofilm assay due to fumarate potentiation. These data suggest that a combination of tobramycin with fumarate as an antibacterial potentiator may be an attractive therapeutic for eliminating recurrent P. aeruginosa infections in CF patients through the eradication of bacterial persisters.

http://ift.tt/2xtJiRR