Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1β Production, and the Host Immune Response to Infection

Objectives: Monocytes and macrophages produce interleukin-1β by inflammasome activation which involves adenosine triphosphate release, pannexin-1 channels, and P2X7 receptors. However, interleukin-1β can also be produced in an inflammasome-independent fashion. Here we studied if this mechanism also involves adenosine triphosphate signaling and how it contributes to inflammasome activation. Design: In vitro studies with human cells and randomized animal experiments. Setting: Preclinical academic research laboratory. Subjects: Wild-type C57BL/6 and pannexin-1 knockout mice, healthy human subjects for cell isolation. Interventions: Human monocytes and U937 macrophages were treated with different inhibitors to study how purinergic signaling contributes to toll-like receptor-induced cell activation and interleukin-1β production. Wild-type and pannexin-1 knockout mice were subjected to cecal ligation and puncture to study the role of purinergic signaling in interleukin-1β production and host immune defense. Measurements and Main Results: Toll-like receptor agonists triggered mitochondrial adenosine triphosphate production and adenosine triphosphate release within seconds. Inhibition of mitochondria, adenosine triphosphate release, or P2 receptors blocked p38 mitogen-activated protein kinase and caspase-1 activation and interleukin-1β secretion. Mice lacking pannexin-1 failed to activate monocytes, to produce interleukin-1β, and to effectively clear bacteria following cecal ligation and puncture. Conclusions: Purinergic signaling has two separate roles in monocyte/macrophage activation, namely to facilitate the initial detection of danger signals via toll-like receptors and subsequently to regulate nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 inflammasome activation. Further dissection of these mechanisms may reveal novel therapeutic targets for immunomodulation in critical care patients. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by grants from the National Institutes of Health, GM-51477, GM-60475, GM-116162, AI-080582, and T32 GM-103702. Drs. Lee, Zhang, and Junger received support for article research from the National Institutes of Health. Dr. Li received support for article research from National Natural Science Foundation of China No. 81701564. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: wjunger@bidmc.harvard.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2I61qVb

Impact of Mean Arterial Pressure Fluctuation on Mortality in Critically Ill Patients

Objective: The purpose of this study was to investigate the association between mean arterial pressure fluctuations and mortality in critically ill patients admitted to the ICU. Design: Retrospective cohort. Setting: All adult ICUs at a tertiary care hospital. Patients: All adult patients with complete mean arterial pressure records were selected for analysis in the Multiparameter Intelligent Monitoring in Intensive Care II database. Patients in the external cohort were newly recruited adult patients in the Medical Information Mart for Intensive Care III database. Interventions: None. Measurements and Main Results: The records of 8,242 patients were extracted. Mean arterial pressure fluctuation was calculated as follows: (mean nighttime mean arterial pressure – mean daytime mean arterial pressure)/mean arterial pressure. Patients were divided into two groups according to the degree of mean arterial pressure fluctuation: group A (between –5% and 5%) and group B (5%). The endpoints of this study were ICU and hospital mortality. Patients in group A (n = 4,793) had higher ICU and hospital mortality than those in group B (n = 3,449; 11.1% vs 8.1%, p

https://ift.tt/2pAI8PH

Long-Term Mortality and Hospital Resource Use in ICU Patients With Alcohol-Related Liver Disease

Objectives: Data describing long-term outcomes following ICU for patients with alcohol-related liver disease are scarce. We aimed to report long-term mortality and emergency hospital resource use for patients with alcohol-related liver disease and compare this with two comparator cohorts. Design: Retrospective cohort study linking population registry data. Setting: All adult general Scottish ICUs (2005–2010) serving 5 million population. Patients: ICU patients with alcohol-related liver disease were compared with an unmatched cohort with Acute Physiology and Chronic Health Evaluation defined diagnoses of severe cardiovascular, respiratory, or renal comorbidity and a matched general ICU cohort. Interventions: None. Measurements and Main Results: Outcomes were 5-year mortality, emergency hospital resource use, and emergency hospital readmission. Multivariable regression was used to identify risk factors and adjust for confounders. Of 47,779 ICU admissions, 2,463 patients with alcohol-related liver disease and 3,590 patients with severe comorbidities were identified; 2,391(97.1%) were matched to a general ICU cohort. The alcohol-related liver disease cohort had greater 5-year mortality than comorbid (79.2% vs 75.3%; p

https://ift.tt/2I7Ebu3

Beyond Low Tidal Volume Ventilation: Treatment Adjuncts for Severe Respiratory Failure in Acute Respiratory Distress Syndrome

Objectives: Despite decades of research, the acute respiratory distress syndrome remains associated with significant morbidity and mortality. This Concise Definitive Review provides a practical and evidence-based summary of treatments in addition to low tidal volume ventilation and their role in the management of severe respiratory failure in acute respiratory distress syndrome. Data Sources: We searched the PubMed database for clinical trials, observational studies, and review articles describing treatment adjuncts in acute respiratory distress syndrome patients, including high positive end-expiratory pressure strategies, recruitment maneuvers, high-frequency oscillatory ventilation, neuromuscular blockade, prone positioning, inhaled pulmonary vasodilators, extracorporeal membrane oxygenation, glucocorticoids, and renal replacement therapy. Study Selection and Data Extraction: Results were reviewed by the primary author in depth. Disputed findings and conclusions were then reviewed with the other authors until consensus was achieved. Data Synthesis: Severe respiratory failure in acute respiratory distress syndrome may present with refractory hypoxemia, severe respiratory acidosis, or elevated plateau airway pressures despite lung-protective ventilation according to acute respiratory distress syndrome Network protocol. For severe hypoxemia, first-line treatment adjuncts include high positive end-expiratory pressure strategies, recruitment maneuvers, neuromuscular blockade, and prone positioning. For refractory acidosis, we recommend initial modest liberalization of tidal volumes, followed by neuromuscular blockade and prone positioning. For elevated plateau airway pressures, we suggest first decreasing tidal volumes, followed by neuromuscular blockade, modification of positive end-expiratory pressure, and prone positioning. Therapies such as inhaled pulmonary vasodilators, glucocorticoids, and renal replacement therapy have significantly less evidence in favor of their use and should be considered second line. Extracorporeal membrane oxygenation may be life-saving in selected patients with severe acute respiratory distress syndrome but should be used only when other alternatives have been applied. Conclusions: Severe respiratory failure in acute respiratory distress syndrome often necessitates the use of treatment adjuncts. Evidence-based application of these therapies in acute respiratory distress syndrome remains a significant challenge. However, a rational stepwise approach with frequent monitoring for improvement or harm can be achieved. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources had no role in the design or conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; or the decision to submit the article for publication. All authors provided final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by grants HL51856 (to Dr. Matthay) and HL140026 (to Dr. Calfee). All authors disclosed off-label product use of therapies listed in the article, as there are no Food and Drug Administration approved therapies for acute respiratory distress syndrome (ARDS). Dr. Matthay's institution has received funding from Bayer, GlaxoSmithKline, and Amgen. Dr. Matthay has received other support from Roche/Genentech (Chair Data Safety Monitoring Board), Cerus Therapeutics (consultant), CSL Behring (consultant), Boehringer Ingelheim (consultant), and Quark Pharmaceuticals (consultant). Dr. Calfee's institution has received research funding from the National Institutes of Health, GlaxoSmithKline, and Bayer. Dr. Calfee has served on advisory boards or as a consultant for GlaxoSmithKline, Bayer, CSL Behring, Boehringer Ingelheim, Prometic, and Roche/Genentech. Address requests for reprints to: Carolyn S. Calfee, MD, MAS, Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, 505 Parnassus Avenue, Box 0111, San Francisco, CA. E-mail: carolyn.calfee@ucsf.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2pAI6ax

A Comparison of Mortality From Sepsis in Brazil and England: The Impact of Heterogeneity in General and Sepsis-Specific Patient Characteristics

Objectives: To test whether differences in both general and sepsis-specific patient characteristics explain the observed differences in sepsis mortality between countries, using two national critical care (ICU) databases. Design: Cohort study. Setting: We analyzed 62 and 164 ICUs in Brazil and England, respectively. Patients: Twenty-two–thousand four-hundred twenty-six adult ICU admissions from January 2013 to December 2013. Interventions: None. Measurements and Main Results: After harmonizing relevant variables, we merged the first ICU episode of adult medical admissions from Brazil (ORganizational CHaractEeriSTics in cRitical cAre study) and England (Intensive Care National Audit & Research Centre Case Mix Programme). Sepsis-3 definition was used, and the primary outcome was hospital mortality. We used multilevel logistic regression models to evaluate the impact of country (Brazil vs England) on mortality, after adjustment for general (age, sex, comorbidities, functional status, admission source, time to admission) and sepsis-specific (site of infection, organ dysfunction type and number) patient characteristics. Of medical ICU admissions, 13.2% (4,505/34,150) in Brazil and 30.7% (17,921/58,316) in England met the sepsis definition. The Brazil cohort was older, had greater prevalence of severe comorbidities and dependency compared with England. Respiratory was the most common infection site in both countries. The most common organ dysfunction was cardiovascular in Brazil (41.2%) and respiratory in England (85.8%). Crude hospital mortality was similar (Brazil 41.4% vs England 39.3%; odds ratio, 1.12 [0.98–1.30]). After adjusting for general patient characteristics, there was an important change in the point-estimate of the odds ratio (0.88 [0.75–1.02]). However, after adjusting for sepsis-specific patient characteristics, the direction of effect reversed again with Brazil having higher risk-adjusted mortality (odds ratio, 1.22 [1.05–1.43]). Conclusions: Patients with sepsis admitted to ICUs in Brazil and England have important differences in general and sepsis-specific characteristics, from source of admission to organ dysfunctions. We show that comparing crude mortality from sepsis patients admitted to the ICU between countries, as currently performed, is not reliable and that the adjustment for both general and sepsis-specific patient characteristics is essential for valid international comparisons of mortality amongst sepsis patients admitted to critical care units. Drs. Rowan and Soares are senior authors. † In memoriam. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. Drs. Ranzani and Shankar-Hari are equal contributors. Dr. Ranzani did data analyses. Drs. Ranzani and Shankar-Hari wrote the first draft of the article. Drs. Harrison, Rabello, Salluh, Rowan, and Soares led data collection. Dr. Rabello died during the peer-review process of this article. All authors unanimously agreed on her fundamental contribution for this study. All authors conceptualized and designed the study, interpreted data, and critically revised the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). The original ORganizational CHaractEeriSTics in cRitical cAre study was supported by the National Council for Scientific and Technological Development (Grant number 304240/2014-1), Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro and by departmental funds from the D'Or Institute for Research and Education. The Case Mix Programme is a subscription-based, national quality assessment program. The current study was funded internally by Intensive Care National Audit & Research Centre. The funding sources had no role in the design, conduct or analyses of the study. Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (NIHR-CS-2016-16-011). Dr. Soares disclosed that he is founder and equity shareholder at Epimed Solutions. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: otavioranzani@usp.br Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2I5XqUT

Keys to Amyloid City: Computational sampling, refined by solution NMR, captures potential TDP-43 intermediates in ALS neurodegeneration

https://ift.tt/2znaxhA

Possible Role of Glymphatic System of the Brain in the Pathogenesis of High-Altitude Cerebral Edema

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2pr8Jye

Response to Burtscher re: “Increased Cytokines at High Altitude: Lack of Effect of Ibuprofen on Acute Mountain Sickness, Physiological Variables, or Cytokine Levels”

High Altitude Medicine &Biology, Volume 19, Issue 3, Page 304-305, September 2018.


https://ift.tt/2ppWJNI

Migration for obstetric care: the impact of regional Obstetric Care Facility Density disparities in Tanzania

This is an extended analysis of the previously published data to demonstrate the relationship between high Obstetric Care Facility Density (OCFD) and migration for obstetric services in Tanzania.

https://ift.tt/2xx8tm5

Physicians’ utilization of microbiologic reports and determinants of their preference to order culture in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia

The main aim of the study was to assess physicians' utilization of microbiologic reports and determinants of their preference in ordering microbiologic culture among patients with systemic bacterial infection...

https://ift.tt/2MSu50X

Comparison of low calorie high protein and low calorie standard protein diet on waist circumference of adults with visceral obesity and weight cycling

Many individuals with visceral obesity who previously had succeeded in reducing body weight regain and this loss–gain cycle repeats several times which is called as weight cycling. We aimed to evaluate the eff...

https://ift.tt/2xuFIGD

Corrections: Impact of patient characteristics on the Canadian Patient Experiences Survey-Inpatient Care: survey analysis from an academic tertiary care centre

Rubens FD, Rothwell DM, Al Zayadi A, et al. Impact of patient characteristics on the Canadian Patient Experiences Survey–Inpatient Care: survey analysis from an academic tertiary care centre. BMJ Open 30;8:e021575. 10.1136/bmjopen-2018-021575.

This article was previously published with an error in author's name.

Second author name 'Diana M Rothwell' should be spelled 'Deanna M Rothwell'.

https://ift.tt/2QN3aHb

The association between mentoring and training outcomes in junior doctors in medicine: an observational study

Objective

To determine quantitatively if a positive association exists between the mentoring of junior doctors and better training outcomes in postgraduate medical training within the UK.

Design

Observational study.

Participants

117 trainees from the East of England Deanery (non-mentored group) and the recently established Royal College of Physicians (RCP) Mentoring scheme (mentored group) who were core medical trainees (CMTs) between 2015 and 2017 completed an online survey. Trainees who received mentoring at the start of higher specialty training, incomplete responses and trainees who were a part of both the East of England deanery and RCP Mentoring scheme were excluded leaving 85 trainees in the non-mentored arm and 25 trainees in the mentored arm. Responses from a total of 110 trainees were analysed.

Main outcome measures

Pass rates of the various components of the Membership of the Royal College of Physicians (MRCP) (UK) examination (MRCP Part 1, MRCP Part 2 Written and MRCP Part 2 PACES), pass rates at the Annual Review of Competency Progression (ARCP), trainee involvement in significant events, clinical incidents or complaints and trainee feedback on career progression and confidence.

Results

Mentored trainees reported higher pass rates of the MRCP Part 1 exam versus non-mentored trainees (84.0% vs 42.4%, p<0.01). Mentored international medical graduates (IMGs) reported higher pass rates than non-mentored IMGs in the MRCP Part 2 Written exam (71.4% vs 24.0%, p<0.05). ARCP pass rates in mentored trainees were observed to be higher than non-mentored trainees (95.8% vs 69.9%, p<0.05). Rates of involvement in significant events, clinical incidents and complaints in both groups did not show any statistical difference. Mentored trainees reported higher confidence and career progression.

Conclusions

A positive association is observed between the mentoring of CMTs and better training outcomes. Further studies are needed to investigate the causative effects of mentoring in postgraduate medical training within the UK.

https://ift.tt/2QTuVxR

Hepatitis B virus contact disclosure and testing in Lusaka, Zambia: a mixed-methods study

Objectives

The aim of this study was to estimate the frequency of disclosure to and testing of contacts of patients with hepatitis B virus (HBV) in Zambia.

Design

We used a convergent parallel mixed-method research design including a quantitative survey and focus group discussions with patients with HBV.

Setting

A university hospital in Lusaka, Zambia.

Participants

79 hepatitis B surface antigen (HBsAg)-positive, HIV-negative, adults (18+ years) receiving HBV care completed a quantitative survey and 32 also participated in a focus group discussion.

Outcomes and analysis

Contacts of patients with HBV were enumerated and patient-reported disclosure, contact testing and contact HBV test results were used to develop a testing cascade. Using multivariable logistic regression, we identified factors associated with disclosure of HBV status. In focus groups, we explored how index patient knowledge and awareness of their condition shaped perspectives on contact disclosure and testing. Focus groups coding and analysis followed a thematic analysis approach.

Results

Among 79 patients with HBV (median age 35 years; 26.6% women), the majority reported disclosure to ≥1 contact. According to the index patients' knowledge, of 776 contacts enumerated, 326 (42.1%) were disclosed to, 77 (9.9%) were tested, 67 (8.6%) received results and 8 (11.9%) were HBsAg-positive. Increased stigma score was associated with reduced disclosure. In focus groups, HBV awareness, knowledge and stigma emerged as barriers to disclosure and referral of contacts for testing. Association of HBV with HIV-related stigma was also reported as a strong barrier to contact disclosure and testing and to taking antivirals for HBV monoinfection.

Conclusions

HBV contact disclosure and testing were feasible and yielded new diagnoses in Zambia. A better understanding of barriers to seeking HBV testing and treatment is needed to scale-up this important intervention in Africa.

Trials registration number

NCT03158818.

https://ift.tt/2xJB2f6

Integration of academic and health education for the prevention of physical aggression and violence in young people: systematic review, narrative synthesis and intervention components analysis

Objectives

To systematically review evidence on the effectiveness of interventions including integration of academic and health education for reducing physical aggression and violence, and describe the content of these interventions.

Data sources

Between November and December 2015, we searched 19 databases and 32 websites and consulted key experts in the field. We updated our search in February 2018.

Eligibility criteria

We included randomised trials of school-based interventions integrating academic and health education in students aged 4–18 and not targeted at health-related subpopulations (eg, learning or developmental difficulties). We included evaluations reporting a measure of interpersonal violence or aggression.

Data extraction and analysis

Data were extracted independently in duplicate, interventions were analysed to understand similarities and differences and outcomes were narratively synthesised by key stage (KS).

Results

We included 13 evaluations of 10 interventions reported in 20 papers. Interventions included either full or partial integration, incorporated a variety of domains beyond the classroom, and used literature, local development or linking of study skills and health promoting skills. Evidence was concentrated in KS2, with few evaluations in KS3 or KS4, and evaluations had few consistent effects; evaluations in KS3 and KS4 did not suggest effectiveness.

Discussion

Integration of academic and health education may be a promising approach, but more evidence is needed. Future research should consider the 'lifecourse' aspects of these interventions; that is, do they have a longitudinal effect? Evaluations did not shed light on the value of different approaches to integration.

https://ift.tt/2QNrmJk

Perceptions of French general practitioners and patients regarding dextropropoxyphene withdrawal: a qualitative study

Objectives

Dextropropoxyphene (DXP), a step 2 analgesic commonly prescribed in France, was withdrawn from the French market in 2011 following a European decision due to its poor risk-benefit ratio. The purpose of this study was to explore the perceptions of French general practitioners (GPs) and patients regarding DXP withdrawal.

Design

Qualitative study based on 26 individual semi-structured interviews.

Setting

Rhône-Alpes region of France.

Participants

Thirteen patients and 13 GPs.

Methods

Interviews were conducted to collect data concerning the status of DXP, its efficacy and safety, the conditions of DXP's withdrawal and its potential impact. The transcripts were analysed using NVivo software.

Results

DXP was a very popular drug among both patients and GPs. Its withdrawal was a bad experience for patients and many GPs; these misunderstood the reasons for its withdrawal and several contested them. They generally recognised more benefits than risks of DXP and considered alternative drugs unsatisfactory. In the same period, a French court case regarding another drug led to distrust towards the pharmaceutical industry and healthcare institutions, which contributed to the negative feelings reported. However, the experience was positive for the GPs who had been alerted to the poor DXP risk-benefit ratio well before its withdrawal.

Conclusions

Apart from physicians who were previously informed of its poor risk-benefit ratio, DXP withdrawal was not a good experience for patients and GPs. Better anticipation by the health authorities, in terms of pharmacoepidemiological surveillance and communication to healthcare professionals as well as the general public, should provide better acceptance of such a decision in the future.

https://ift.tt/2QRpSxz

Are short-stem prostheses superior to conventional stem prostheses in primary total hip arthroplasty? A systematic review and meta-analysis of randomised controlled trials

Objective

Cementless total hip arthroplasty (THA) is associated with reliable clinical results and high patient satisfaction. Short-stem prostheses (SS) were designed to achieve superior preservation of proximal bone stock and stability compared with those of conventional-stem prostheses (CS). This meta-analysis was conducted to determine the proximal bone remodelling, revision rate, Harris Hip Score, radiolucent line and maximum total point motion values of both SS and CS for primary THA.

Method

Relevant randomised controlled trials (RCTs) involving SS and CS in primary THA were identified from electronic databases, such as EMBASE, PubMed and the Cochrane Library.

Result

Ultimately, 12 RCTs involving 1130 patients (1387 hips) were included. The results showed that compared with CS, SS resulted in less bone mineral density (BMD) changes in Gruen zone 7 at 1 year and 2 years postoperatively (mean difference (MD)=5.11; 95% CI, 1.61, 8.61; P=0.30; and MD=4.90; 95% CI, 1.01, 8.79; P=0.17, respectively). No difference in BMD changes was found for Gruen zone 1 (MD=2.66; 95% CI, –3.31, 8.64; P<0.00001), and no differences were observed for the revision rate (relative risk (RR)=1.52; 95% CI, 0.71, 3.26; P=0.94), Harris Hip Score (MD=–0.38; 95% CI, –1.02, 0.26; P=0.89) or stem migration (MD=0.02; 95% CI, –0.07, 0.11; P=0.04).

Conclusion

Our results suggest that compared with CS, SS may provide superior bone remodelling and similar survival rates and clinical outcomes. However, the short-term follow-up of the included studies was inadequate to determine the long-term performance of SS.

https://ift.tt/2QNIChv

Impact of group practices on patients, physicians and healthcare systems: protocol for a scoping review

Introduction

Group practices have potential benefits for patients, physicians and healthcare systems. Although group practices have been around for many years, research in this area is lacking and generally is centred around the economic benefits that may be realised from group practice. The aim of this scoping review is to identify the impact that group practices have on patients, physicians and healthcare systems to guide further research in this area.

Methods and analysis

A scoping review will be performed based on the methodology proposed by Arksey and O'Malley and refined by Levac and colleagues. MEDLINE, EMBASE, Cochrane Central and Cochrane Economic Database will be searched from inception to present day to identify relevant studies that assess the impact of group practices on patient care, satisfaction and outcomes; physician quality of life, satisfaction and income and healthcare systems. Titles and abstracts will be screened by two members and the abstraction results charted and verified. Qualitative and quantitative analyses will be performed to identify key themes.

Ethics and dissemination

Research ethics board approval is not required for this scoping review. A consultation phase will be used to discuss the results with key stakeholders followed by dissemination at local and national levels. We will also publish the results in a peer-reviewed journal.

https://ift.tt/2xJAKVy

Development of the individualised Comparative Effectiveness of Models Optimizing Patient Safety and Resident Education (iCOMPARE) trial: a protocol summary of a national cluster-randomised trial of resident duty hour policies in internal medicine

Introduction

Medical trainees' duty hours have received attention globally; restrictions in Europe, New Zealand and some Canadian provinces are much lower than the 80 hours per week enforced in USA. In USA, resident duty hours have been implemented without evidence simultaneously reflecting competing concerns about patient safety and physician education. The objective is to prospectively evaluate the implications of alternative resident duty hour rules for patient safety, trainee education and intern sleep and alertness.

Methods and analysis

63 US internal medicine training programmes were randomly assigned 1:1 to the 2011 Accreditation Council for Graduate Medical Education resident duty hour rules or to rules more flexible in intern shift length and number of hours off between shifts for academic year 2015–2016. The primary outcome is calculated for each programme as the difference in 30-day mortality rate among Medicare beneficiaries with any of several prespecified principal diagnoses in the intervention year minus 30-day mortality in the preintervention year among Medicare beneficiaries with any of several prespecified principal diagnoses. Additional safety outcomes include readmission rates, prolonged length of stay and costs. Measures derived from trainees' and faculty responses to surveys and from time-motion studies of interns compare the educational experiences of residents. Measures derived from wrist actigraphy, subjective ratings and psychomotor vigilance testing compare the sleep and alertness of interns. Differences between duty hour groups in outcomes will be assessed by intention-to-treat analyses.

Ethics and dissemination

The University of Pennsylvania Institutional Review Board (IRB) approved the protocol and served as the IRB of record for 40 programmes that agreed to sign an Institutional Affiliation Agreement. Twenty-three programmes opted for a local review process.

Trial registration number

NCT02274818; Pre-results.

https://ift.tt/2QRjw1t

Physical activity-related injuries among university students: a multicentre cross-sectional study in China

Objectives

This study aimed to investigate the epidemiological characteristics and preliminarily explore possible risk factors of physical activity-related injury (PARI) occurrences among Chinese university students via a multicentre mixed survey.

Design

Cross-sectional study.

Participants

A total of 4758 undergraduates graded 1–3 in nine universities in three Chinese cities were enrolled via cluster random sampling and completed the self-administered online questionnaires during March and April 2017.

Main outcome measures

PARI in the past 12 months.

Results

Of the 4758 participants, 1081 sustained PARI in the past 12 months, with an overall PARI incidence rate of 22.7% (27.3% (367/1343) in males and 20.9%(714/3415) in females). Around one-quarter of the injured (26.4%) suffered from PARI over at least three episodes. More than half of the injured subjects experienced physical activity (PA) absenteeism and sought medical attention. All PA indicators were significantly and positively associated with PARI, with a frequency of sports and leisure-time vigorous-intensity PA (VPA) participation being the strongest (adjusted OR: 1.079, 95% CI: 1.018 to 1.144). Moreover, males (OR=1.199), Shantou students (OR=4.239), year 1 students (OR=1.287), university and other sports team members (OR=1.717–2.360) and those with insufficient sleep time (OR=1.262–1.333) were also at a higher risk of PARI.

Conclusions

PARI is prevalent among university students in China. The frequency of sports and leisure-time VPA participation was most strongly associated with PARI among all PA indicators. These data can inform future programmes for injury intervention among university students. Safety issues should also be emphasised when promoting PA among the public to reduce PARI.

https://ift.tt/2QR7hSA

Education, sex and risk of stroke: a prospective cohort study in New South Wales, Australia

Objective

To determine whether the association between highest educational attainment and stroke differed by sex and age; and whether potential mediators of observed associations differ by sex.

Design

Prospective cohort study.

Setting

Population based, New South Wales, Australia.

Participants

253 657 stroke-free participants from the New South Wales 45 and Up Study.

Outcome measures

First-ever stroke events, identified through linkage to hospital and mortality records.

Results

During mean follow-up of 4.7 years, 2031 and 1528 strokes occurred among men and women, respectively. Age-standardised stroke rate was inversely associated with education level, with the absolute risk difference between the lowest and highest education group greater among women than men. In relative terms, stroke risk was slightly more pronounced in women than men when comparing low versus high education (age-adjusted HRs: 1.41, 95% CI 1.16 to 1.71 and 1.25, 95% CI 1.07 to 1.46, respectively), but there was no clear evidence of statistical interaction. This association persisted into older age, but attenuated. Much of the increased stroke risk was explained by modifiable lifestyle factors, in both men and women.

Conclusion

Low education is associated with increased stroke risk in men and women, and may be marginally steeper in women than men. This disadvantage attenuates but persists into older age, particularly for women. Modifiable risk factors account for much of the excess risk from low education level. Public health policy and governmental decision-making should reflect the importance of education, for both men and women, for positive health throughout the life course.

https://ift.tt/2xE0t1L

Strategies to improve the implementation of policies, practices or programmes in sporting organisations targeting poor diet, physical inactivity, obesity, risky alcohol use or tobacco use: a systematic review

Objectives

The primary aim for this review is to determine the effectiveness of strategies to improve the implementation of policies, practices or programmes in sporting organisations. The secondary aims are to describe the cost or cost-effectiveness and adverse effects of such strategies and to examine the effects of those implementation strategies on individual's diet, physical activity, obesity, alcohol use or tobacco use.

Methods

We conducted searches of academic databases (eg, MEDLINE, EMBASE and CENTRAL), trial registers and hand searches of selected journals. Studies were included if they were conducted at a sporting venue; described a strategy to improve implementation of policies, practices or programmes focusing on one or more health risks (diet, physical inactivity, obesity, alcohol or tobacco use), and included a parallel control group. Two authors independently screened citations and extracted data. The results of included studies were synthesised narratively.

Results

Of the 5926 citations screened three studies met the inclusion criteria. Two studies were randomised controlled trials. Two studies sought to improve the implementation of nutrition-related policy and practices and one study sought to improve implementation of alcohol-related policy and practices. Each study reported improvement in at least one measure of policy or practice implementation. Two studies reported individual-level outcomes and found a reduction in excessive alcohol consumption and an increase in purchase of fruits and vegetables at the sports club ground. Two studies assessed club revenue as a potential adverse effect, neither reported significant between-group differences on these measures.

Conclusion

There is a sparse evidence base regarding the effectiveness of strategies to improve the implementation of policies, practices or programmes targeting chronic disease risk factors in sporting clubs. While all studies reported some improvements in implementation, for some multistrategic implementation strategies it is difficult to determine the extent to which such effects are generalisable.

PROSPERO registration number

CRD42016039490.

https://ift.tt/2xFVBsS

Rare case of Propionibacterium acnes-related splenic abscess

A 64-year-old woman with a medical history of morbid obesity, chronic hepatitis C, essential hypertension, multiple episodes of abdominal cellulitis, diabetes mellitus type 2 on insulin, intravenous and subcutaneous drug abuse presented to the emergency department complaining of left lower chest pain for 6 weeks along with multiple episodes of vomiting. Initial laboratory data revealed leucocytosis of 17 200x10³/μL with left shift. She reported multiple episodes of fever spikes. Abdominal and pelvic CT showed a splenic hypodense lesion. Specimens from interventional radiology aspiration and splenectomy grew Propionibacterium acnes. Following splenectomy, patient's symptoms resolved. To the best of our knowledge, this would represent the fifth reported case of P. acnes splenic abscess.

https://ift.tt/2Q1311F

Alpha-2 antiplasmin-associated aortic valve thrombus presenting as a STEMI in a patient with Graves disease

Description  

A 36-year-old Caucasian woman with a medical history of Graves disease presented to the emergency department with typical chest pain, and she was found to have a ST-elevation myocardial infarction (STEMI) via ECG and elevated troponins. Emergent cardiac catheterisation revealed distal blockages in the left anterior descending artery and second obtuse marginal artery (figure 1A,B). After distal balloon angioplasty, the decision was made to further treat the patient medically and discharge home after clinical stability was achieved. She was readmitted 2 days later for new onset of palpitations with up-trending troponins. Laboratory tests were significant for a low thyroid-stimulating hormone of <0.01 µLU/mL (reference range: 0.27–4.2 µLU/mL), and elevated free T4 of 4.02 µLU/mL (reference range: 0.9–1.7 ng/dL), free T3 of 4.8 pg/mL (reference range: 2.5–4.3 pg/mL) and a thyroid stimulating immunoglobulin of 386 (reference range: <140% baseline). She was immediately started on both methimazole 20 mg and potassium iodine oral solution (SSKI). Further workup...

https://ift.tt/2O1edhj

Haemorrhagic cholecystitis: a rare entity not to be forgotten

Haemorrhagic cholecystitis is a rare entity of acute cholecystitis that carries a high morbidity and mortality rate if management is delayed. Its clinical course can mirror that of acute cholecystitis. Characteristic findings on ultrasound or CT scan are useful clues to early diagnosis. Urgent cholecystectomy is required prior to progressing to perforation of gallbladder. Most of the literature are case reports with causes associated with anticoagulation. Herein, we described a morbidly obese patient with poorly controlled diabetes presenting with non-specific right upper quadrant pain and was subsequently diagnosed with haemorrhagic cholecystitis. A review of the literature was also performed to summarise the potential clinical presentations, distinctive imaging findings and management options available for this rare condition.

https://ift.tt/2PWjVy7

Pneumomediastinum: a complication of reinserting a dislodged tracheostomy

Description 

A 54-year-old woman with a background of obesity and hypertension presented following a pulseless electrical activity (PEA) cardiac arrest. Cardiopulmonary resuscitation (CPR) was commenced on arrival of the paramedics and she was intubated and ventilated (figure 1). Return of spontaneous circulation was achieved in the emergency department following a total of 45 min of CPR. No clear cause of her arrest was identified. She was transferred to the intensive care unit (ICU) for post-arrest management.

Figure 1

Initial chest radiograph following return of spontaneous circulation, with endotracheal tube present (included as a baseline for comparison).

Seizure activity off of sedation necessitated further investigation. Her CT head was unremarkable, but her lumbar puncture showed features in keeping with meningitis. She was therefore treated with antibiotics and antiepileptics. Her cerebrospinal fluid viral PCR and blood HIV tests were negative.

Although appropriate seizure control was achieved,...

https://ift.tt/2NWZUub

Naclerios V sign and continuous diaphragm sign after endoscopy

Description 

An otherwise healthy 72-year-old woman presented with dyspnoea and systemic subcutaneous emphysema. She had undergone upper endoscopy, in which duodenal ulcer was found. The community hospital where the endoscopy was conducted transferred her to our tertiary hospital for further diagnosis and management. On arrival, she complained of severe difficulty in breathing; massive subcutaneous emphysema on her chest to the feet was observed on palpation. Chest X-ray image showed Naclerio's V sign (figure 1A, black arrow) and continuous diaphragm sign (figure 1A, white arrows). CT scan confirmed massive subcutaneous and mediastinal emphysema with pneumothorax, pneumopericardium and free air in retroperitoneal space (figure 1B,C). Emergent laparotomy revealed duodenal perforation, 9 mm in diameter at the descending part of duodenum (figure 1D, white arrow), and was surgically repaired. After the surgery, the emphysema gradually disappeared in weeks and had not recurred at 6-month follow-up.

...

https://ift.tt/2PWjUKz

Cancers, Vol. 10, Pages 348: Role of COX-2/PGE2 Mediated Inflammation in Oral Squamous Cell Carcinoma

Cancers, Vol. 10, Pages 348: Role of COX-2/PGE2 Mediated Inflammation in Oral Squamous Cell Carcinoma

Cancers doi: 10.3390/cancers10100348

Authors: Walaa Hamed Shaker Nasry Juan Carlos Rodriguez-Lecompte Chelsea K. Martin

A significant amount of research indicates that the cyclooxygenase/prostaglandin E2 (PGE2) pathway of inflammation contributes to the development and progression of a variety of cancers, including squamous cell carcinoma, or the oral cavity and oropharynx (OSCC). Although there have been promising results from studies examining the utility of anti-inflammatory drugs in the treatment of OSCC, this strategy has been met with only variable success and these drugs are also associated with toxicities that make them inappropriate for some OSCC patients. Improved inflammation-targeting therapies require continued study of the mechanisms linking inflammation and progression of OSCC. In this review, a synopsis of OSCC biology will be provided, and recent insights into inflammation related mechanisms of OSCC pathobiology will be discussed. The roles of prostaglandin E2 and cluster of differentiation factor 147 (CD147) will be presented, and evidence for their interactions in OSCC will be explored. Through continued investigation into the protumourigenic pathways of OSCC, more treatment modalities targeting inflammation-related pathways can be designed with the hope of slowing tumour progression and improving patient prognosis in patients with this aggressive form of cancer.

https://ift.tt/2OFOBDO

Long-term, telephone-based follow-up after stroke and TIA improves risk factors: 36-month results from the randomized controlled NAILED stroke risk factor trial

Strategies are needed to improve adherence to the blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) level recommendations after stroke and transient ischemic attack (TIA). We investigated whe...

https://ift.tt/2I7ylJ9

Dynamic stability and spatiotemporal parameters during turning in healthy young adults

Turning while walking has a frequent occurrence in daily life. Evaluation of its dynamic stability will facilitate fall prevention and rehabilitation scheme. This knowledge is so limited that we set it as the ...

https://ift.tt/2PUV6CJ

In this issue

https://ift.tt/2NyN5H5

The genetic architecture of aniridia and Gillespie syndrome

Abstract

Absence of part or all of the iris, aniridia, is a feature of several genetically distinct conditions. This review focuses on iris development and then the clinical features and molecular genetics of these iris malformations. Classical aniridia, a panocular eye malformation including foveal hypoplasia, is the archetypal phenotype associated with heterozygous PAX6 loss-of-function mutations. Since this was identified in 1991, many genetic mechanisms of PAX6 inactivation have been elucidated, the commonest alleles being intragenic mutations causing premature stop codons, followed by those causing C-terminal extensions. Rarely, aniridia cases are associated with FOXC1, PITX2 and/or their regulatory regions. Aniridia can also occur as a component of many severe global eye malformations. Gillespie syndrome—a triad of partial aniridia, non-progressive cerebellar ataxia and intellectual disability—is phenotypically and genotypically distinct from classical aniridia. The causative gene has recently been identified as ITPR1. The same characteristic Gillespie syndrome-like iris, with aplasia of the pupillary sphincter and a scalloped margin, is seen in ACTA2-related multisystemic smooth muscle dysfunction syndrome. WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies and mental retardation/intellectual disability), is caused by contiguous deletion of PAX6 and WT1 on chromosome 11p. Deletions encompassing BDNF have been causally implicated in the obesity and intellectual disability associated with the condition. Lastly, we outline a genetic investigation strategy for aniridia in light of recent developments, suggesting an approach based principally on chromosomal array and gene panel testing. This strategy aims to test all known aniridia loci—including the rarer, life-limiting causes—whilst remaining simple and practical.

https://ift.tt/2OIqVi9

Association between unhygienic menstrual management practices and prevalence of lower reproductive tract infections: a hospital-based cross-sectional study in Odisha, India

The extent to which reproductive tract infections (RTIs) are associated with poor menstrual hygiene management (MHM) practices has not been extensively studied. We aimed to determine whether poor menstrual hyg...

https://ift.tt/2I3RETy

Seroprevalence of hepatitis B virus infection and associated factors among healthcare workers in northern Tanzania

Hepatitis B virus infection is a global health problem with the highest prevalence in East Asia and Sub-Saharan Africa. The majority of infected people, including healthcare workers are unaware of their status...

https://ift.tt/2prCuiy

Methods for conducting a double-blind randomized controlled clinical trial of three days versus five days of amoxicillin dispersible tablets for chest indrawing childhood pneumonia among children two to 59 months of age in Lilongwe, Malawi: a study protocol

Pneumonia is the leading infectious cause of death in children under 5 years of age around the globe. In addition to preventing pneumonia, there is a critical need to provide greater access to appropriate and ...

https://ift.tt/2QVcTLA

Immunogenicity of the CYD tetravalent dengue vaccine using an accelerated schedule: randomised phase II study in US adults

The live attenuated tetravalent dengue vaccine (CYD-TDV) is licensed using a 0-, 6- and 12-month schedule in dengue-endemic areas. An effective shorter schedule may provide more rapid, optimal protection of ta...

https://ift.tt/2puebAM

Trabectedin plus Olaparib Has Activity in Patients with Soft-Tissue Sarcoma [Research Watch]

Trabectedin had manageable toxicity in combination with olaparib in a phase Ib trial.

https://ift.tt/2OFUn8f

Ground Beef Recalled After E. Coli Outbreak

FRIDAY, Sept. 21, 2018 -- More than 132,000 pounds of ground beef have been recalled by a Colorado company following a suspected outbreak where one person was killed and 17 were sickened by Escherichia coli after eating the meat. Cargill Meat...

https://ift.tt/2MSZlNs

Long-Term Outcomes of Breast Implants Explored

FRIDAY, Sept. 21, 2018 -- The long-term outcomes of breast implants include increased rates of certain conditions for silicone implants, according to a study published online Sept. 14 in the Annals of Surgery. Christopher J. Coroneos, M.D., from the...

https://ift.tt/2xwA0UC

Mortality Rate From Heart Failure Higher in Women Than Men

FRIDAY, Sept. 21, 2018 -- Despite decreases in overall heart failure incidence and mortality in ambulatory patients from 2009 to 2014, mortality rates remain higher in women than in men, according to a study recently published in CMAJ, the journal...

https://ift.tt/2MTzmVO

Prevalence of Alzheimer's, Related Dementia Set to Double

FRIDAY, Sept. 21, 2018 -- The burden of Alzheimer's disease and related dementias (ADRD) is expected to increase to 3.3 percent in the United States by 2060, according to a study published online Sept. 19 in Alzheimer's & Dementia. Kevin A....

https://ift.tt/2xxDh5U

Some Clinicians, Patients Record Clinic Visits for Patient Use

FRIDAY, Sept. 21, 2018 -- A considerable proportion of clinicians and patients report having recorded a clinic visit for the patient's personal use, according to a study published in the September issue of the Journal of Medical Internet...

https://ift.tt/2MMX46l

Camrelizumab Has Activity in Patients with Nasopharyngeal Carcinoma [Research Watch]

The PD-1 antibody camrelizumab was well tolerated in patients with nasopharyngeal carcinoma.

https://ift.tt/2zn4AS0

The Tumor Microenvironment Drives Liver Cancer Lineage Commitment [Research Watch]

The hepatic microenvironment epigenetically directs lineage commitment to promote ICC or HCC liver tumors.

https://ift.tt/2OIrkRE

MLL1-Induced Oncogenic Reprogramming Drives EZH2 Inhibitor Resistance [Research Watch]

Tumor-intrinsic MLL1 drives transcriptional reprogramming in response to EZH2 inhibition.

https://ift.tt/2znyhST

(R)-2HG Inhibits the BCAT Transaminase in IDH-Mutant Glioma [Research Watch]

BCAT inactivation renders IDH-mutant cells dependent on glutaminase for glutamate and glutathione synthesis.

https://ift.tt/2OKMSNh

Cushing response-based warning system for intensive care of brain-injured patients

Sivakumar et al. (Sivakumar et al., 2017) found in their investigation that neurointensivists taking care of patients with acute brain injury tended to employ more neurological and hemodynamic monitoring. Neurocritical patients usually have intracranial pressure (ICP) monitoring and ICP has become a valuable parameter in the daily care of these patients during the past four decades. Neurosurgeons and neurointensivists adjust their treatment and estimate the outcome according to the trend of ICP, among other parameters.

https://ift.tt/2xuCuTv

Little effort with big effect – implementing the new IFCN 2017 recommendations on standard EEGs

One year ago, the International Federation of Clinical Neurophysiology (IFCN) recommended the 25-channel montage for the standard use in clinical EEG recording (Seeck et al., 2017), augmenting the world-widely used 60-year old 10/20-System by 6 additional inferotemporal electrodes to a "triple banana" configuration. Still many EEG centers have not yet implemented this simple but very effective measure. Here we demonstrate the big effect of this simple measure in a demonstrative case.

https://ift.tt/2MTKUsl

Network characteristics in benign epilepsy with centro-temporal spikes patients indicating defective connectivity during spindle sleep: a partial directed coherence study of EEG signals

Benign epilepsy with centro-temporal spikes (BECTS) is the earliest recognised and most frequent form of benign focal epilepsy in childhood, accounting for 10-20% of all childhood epilepsies (Holmes, 1993). It appears in children aged 3-13 years, peaks between the ages of seven and nine years, and invariably goes into remission by the age of 14 years(Bouma et al. 1997; Callenbach et al., 2010). It may have genetic determinants with a complex inheritance pattern, but there are few genetic data available (Xiong and Zhou, 2017).

https://ift.tt/2xxU7la

Correction: Higher HbA1c Measurement Quality Standards are Needed for Follow-Up and Diagnosis: Experience and Analyses from Germany

Horm Metab Res 2018; 50: e5-e5
DOI: 10.1055/a-0746-4288

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2NZKSnm

The present profile of chronic hepatitis B virus infection highlights future challenges: An analysis of the Multicenter Italian MASTER-B cohort

Chronic hepatitis B virus (HBV) infection remains a primary cause of morbidity and mortality worldwide.

https://ift.tt/2zlVyEP

The burden of HBV infection in HCV patients in Italy and the risk of reactivation under DAA therapy

There is increasing awareness of HBV reactivation in HCV-RNA-positive/HBV-coinfected patients with chronic liver disease (CLD) treated with oral direct-acting antivirals (DAAs).

https://ift.tt/2OIyZPG

Very high-risk individuals for colorectal cancer: Local oncologic networks are critically needed!

https://ift.tt/2zngz20

IS SOFOSBUVIR/LEDIPASVIR SAFE FOR THE HEARTS OF CHILDREN WITH HEPATITIS C VIRUS?

Symptomatic bradycardia has been reported in adults treated for chronic hepatitis C using sofosbuvir based regimens.

https://ift.tt/2OIyXaw

The risk of Parkinson’s disease in inflammatory bowel disease: A systematic review and meta-analysis

Several studies have reported an increased prevalence of Parkinson disease (PD) amongst patients with inflammatory bowel disease (IBD) with conflicting results. We aimed to evaluate the risk of PD in the IBD population by conducting a meta-analysis (MA).

https://ift.tt/2znhboi

Impact of oversedation prevention in ventilated critically ill patients: a randomized trial—the AWARE study

Although oversedation has been associated with increased morbidity in ventilated critically ill patients, it is unclear whether prevention of oversedation improves mortality. We aimed to assess 90-day mortali...

https://ift.tt/2Dnk9x4

Cdk4/6-inhibitor as a novel therapeutic approach for advanced Bladder Cancer independently of RB1 status

Purpose: Bladder cancer (BC) is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP). Experimental Design: BC cell lines were tested for in vitro sensitivity to CDK4/6 inhibition. A novel metastatic BC mouse model was developed and used to test its in vivo activity. Results: Cell lines tested were sensitive to CDK4/6 inhibition, independent on RB1 gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation in vitro and in vivo and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exert important oncogenic roles in BC. Conclusions: CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for advanced BC patients previously classified as unfit for current treatment options.

https://ift.tt/2MTXUOv

Immunotherapy targeting HPV 16/18 generates potent immune responses in HPV-Associated Head and Neck Cancer

Purpose: Clinical responses with programmed death (PD-1) receptor directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18 are attractive targets for therapeutic immunization, and offer an immune activation strategy that may be complementary to PD-1 inhibition. Experimental Design: We report Phase Ib/II safety, tolerability and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL-12 encoding plasmids) delivered by electroporation with CELLECTRA^® constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions but no treatment related grade 3-5 adverse events (AEs). Eighteen of 21 evaluable patients showed elevated antigen specific T cell activity by IFNg ELISpot and persistent cellular responses surpassing 100 SFU/10⁶ PBMC were noted out to one year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4/5 post-immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all five patients. One patient developed metastatic disease and was treated with anti-PD-1 therapy with a rapid and durable complete response. Flow cytometric analyses revealed induction of HPV16 specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.

https://ift.tt/2pAaqd7

Multi-modal meta-analysis of 1494 hepatocellular carcinoma samples reveals significant impact of consensus driver genes on phenotypes

Although driver genes in hepatocellular carcinoma (HCC) have been investigated in various previous genetic studies, prevalence of key driver genes among heterogeneous populations is unknown. Moreover, the phenotypic associations of these driver genes are poorly understood. This report aims to reveal the phenotypic impacts of a group of consensus driver genes in HCC. We used MutSigCV and OncodriveFM modules implemented in the IntOGen pipeline to identify consensus driver genes across six HCC cohorts comprising 1,494 samples in total. To access their global impacts, we used TCGA mutations and copy number variations to predict the transcriptomics data, under generalized linear models. We further investigated the associations of the consensus driver genes to patient survival, age, gender, race and risk factors. We identify 10 consensus driver genes across six HCC cohorts in total. Integrative analysis of driver mutations, copy number variations and transcriptomic data reveals that these consensus driver mutations and their copy number variations are associated with majority (62.5%) of the mRNA transcriptome, but only a small fraction (8.9%) of miRNAs. Genes associated with TP53, CTNNB1, and ARID1A mutations contribute to the tripod of most densely connected pathway clusters. These driver genes are significantly associated with patients' overall survival. Some driver genes are significantly linked to HCC gender (CTNNB1, ALB, TP53 and AXIN1), race (TP53 and CDKN2A), and age (RB1) disparities. This study prioritizes a group of consensus drivers in HCC, which collectively show vast impacts on the phenotypes. These driver genes may warrant as valuable therapeutic targets of HCC.

https://ift.tt/2pqEUxM

Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial

To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants.

https://ift.tt/2NvLcL1

Guidance Document for Hepatic Hemangioma (Infantile and Congenital) Evaluation and Monitoring

To define the types of hepatic hemangiomas using the updated International Society for the Study of Vascular Anomalies classification and to create a set of guidelines for their diagnostic evaluation and monitoring.

https://ift.tt/2Dlhbco

Use of Audio Computer-Assisted Self-Interviews to Gather Information on Risk Behaviors in a Population of Pregnant Adolescents

In a prospective study comparing the use of the Audio Computer-Assisted Self-Interview (ACASI) with a traditional clinical interview in 40 pregnant adolescents, there was significantly greater disclosure of violence with the ACASI method. Better identification of high-risk behaviors may help to optimize care and programing for pregnant adolescents.

https://ift.tt/2DtqDu2

Staphylococcus aureus Bacteremia in Children Aged 5-18 Years—Risk Factors in the New Millennium

To assess the association between comorbidities and Staphylococcus aureus bacteremia in children aged 5-18 years, thus, in children with a matured immune system. Further, we aimed to identify presumably healthy children acquiring bacteremia.

https://ift.tt/2DwUYIz

Associations of Neighborhood-Level Social Determinants of Health with Bacterial Infections in Young, Febrile Infants

To examine the sociodemographic characteristics of one population of young, febrile infants and identify associations between neighborhood-level social determinants of health (SDHs) with bacterial infections.

https://ift.tt/2NrwPHP

Major Depressive Disorder Screening Remains Low Even Among Privately Insured Adolescents

To determine if screening for major depressive disorder (MDD) increased in a national sample of privately insured adolescents following the US Preventive Services Task Force 2009 endorsement of universal screening for adolescent MDD.

https://ift.tt/2DwUX7t

Parental Perspectives on Diagnosis and Prognosis of Neonatal Intensive Care Unit Graduates with Cerebral Palsy

To describe how parents of neonatal intensive care unit (NICU) graduates with cerebral palsy (CP) perceive both the accuracy of prognoses provided in the NICU and the timing of their child's diagnosis of CP, and to assess the influence of functional outcome on these perceptions.

https://ift.tt/2NtfVZb

Echocardiographic Measurements of Right Ventricular Mechanics in Infants with Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age

To test the hypothesis that specific echocardiographic measurements of right ventricular (RV) mechanics at 36 weeks postmenstrual age (PMA) are associated with the severity of bronchopulmonary dysplasia (BPD).

https://ift.tt/2NtfWfH

Evaluation of Gentamicin Exposure in the Neonatal Intensive Care Unit and Hearing Function at Discharge

To characterize the association between gentamicin dosing, duration of treatment, and ototoxicity in hospitalized infants.

https://ift.tt/2NrLVgi

Social Adversity and Cognitive, Language, and Motor Development of Very Preterm Children from 2 to 5 Years of Age

To assess the extent to which social and family factors explain variability in cognitive, language, and motor development among very preterm (<30 weeks of gestation) children from 2 to 5 years of age.

https://ift.tt/2DmRvfq

Hepatitis B Virus Infection and the Progress toward its Elimination

Hepatitis B virus (HBV) infection is a major global health problem and may cause acute, fulminant, chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma (HCC).1,2 In May 2016, the World Health Assembly adopted the first Global Health Sector Strategy on Viral Hepatitis, 2016-2021. The strategy has a vision of eliminating viral hepatitis as a public health problem. The global targets are set to reduce new viral hepatitis infections by 90% and reduce deaths attributable to viral hepatitis by 65% by 2030 (https://ift.tt/1bSgm4u).

https://ift.tt/2Nzo2Uo

Using All Longitudinal Data to Define Time to Specified Percentages of Estimated GFR Decline: A Simulation Study

The standard method to calculate time to the event of a specified percentage decline in estimated glomerular filtration rate (eGFR) uses 2 eGFR assessments, 1 at baseline and 1 at the event time. However, event times may be inaccurate due to eGFR variability and restriction of events to study visit times. We propose a novel method for calculating time to a specified percentage decline in eGFR that uses all available longitudinal eGFR assessments.

https://ift.tt/2Dkxfen

Urine Sediment Examination in the Diagnosis and Management of Kidney Disease: Core Curriculum 2019

Automated urine technology and centralized laboratory testing are becoming the standard for providing urinalysis data to clinicians, including nephrologists. This trend has had the unintended consequence of making examination of urine sediment by nephrologists a relatively rare event. In addition, the nephrology community appears to have lost interest in and forgotten the utility of provider-performed urine microscopy. However, it is critical to remember that urine sediment examination remains a time-honored test that provides a wealth of information about the patient's underlying kidney disease.

https://ift.tt/2Nzs2UU

Variations of immunoglobulin A in serum, tracheal, and intestinal tissues in chickens following inoculation of two strains of Newcastle disease vaccines

Abstract

To elucidate secretory immunoglobulin A (IgA) response as a part of mucosal immunity, it is decided to compare the effectiveness of intraocular administration of Hitchner B1 and thermostable I-2 vaccines in broiler chickens challenged with viscerotropic velogenic Newcastle disease virus (vvNDV) (Herts33). For this purpose, 301-day-old chicks were randomly divided in to the four groups. Groups 1 and 2 were inoculated with I-2 and HB1 vaccines twice via intraocular route with 1-week intervals, and groups 3 and 4 were considered positive and negative controls and birds were challenged 2 weeks after the second inoculation. Protection rate in I-2 and HB1 vaccine groups was 100% and 97% respectively with no significant differences (P > 0.05). All vaccinated groups showed elevation in ND HI antibody titer after vaccination. There were no significant differences (P > 0.05) in ND HI antibody between two vaccinated groups. First levels of detectable total IgA in a serum sample were observed 3 dpv1. No significant differences (P > 0.05) were observed between two vaccinated groups in IgA antibody titer in sera. The vaccinated groups were evaluated by IHC for detection IgA in the trachea and intestine. There were some differences between the vaccinated groups but these differences were not significant. Experimental studies have shown that both vaccines induce antibody production in mucosal surface and circulatory system and thermostable I-2 vaccine could be successfully used in the broiler chicken as effective as HB1 vaccine, so I-2 vaccine could be a suitable heat resistance candidate to reduce mortality in the poultry industry faced to vvND.

https://ift.tt/2pqxFWC

Radiometal-labeled anti-VCAM-1 nanobodies as molecular tracers for atherosclerosis – impact of radiochemistry on pharmacokinetics

Journal Name: Biological Chemistry
Issue: Ahead of print


https://ift.tt/2DldzXQ

EMS Agenda 2050 Quick Take: Healthy people are better students, workers and citizens

Making the EMS Agenda 2050 become reality will require strengthening the collaboration between EMS, public health and healthcare

https://ift.tt/2pufiAl

CD38 is methylated in prostate cancer and regulates extracellular NAD +

Abstract

Background

Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD⁺) which is maintained by a balance of NAD⁺ hydrolase activity and NAD⁺ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD⁺-consuming enzyme CD38. CD38 expression is reduced in prostate cancer compared to benign prostate, suggesting that tumor cells may reduce CD38 expression in order to enhance pools of NAD⁺. However, little is known about how CD38 expression is repressed in advanced prostate cancer and whether CD38 plays a role in regulating NAD⁺ levels in prostate epithelial cells.

Methods

CD38 expression, its association with recurrence after prostatectomy for clinically localized prostate cancer, and DNA methylation of the CD38 promoter were evaluated in human prostate tissues representing various stages of disease progression. CD38 was inducibly over-expressed in benign and malignant human prostate cell lines in order to determine the effects on cell proliferation and levels of NAD⁺ and NADH. NAD⁺ and NADH were also measured in urogenital tissues from wild-type and CD38 knockout mice.

Results

CD38 mRNA expression was reduced in metastatic castration-resistant prostate cancer compared to localized prostate cancer. In a large cohort of men undergoing radical prostatectomy, CD38 protein expression was inversely correlated with recurrence. We identified methylation of the CD38 promoter in primary and metastatic prostate cancer. Over-expression of wild-type CD38, but not an NAD⁺ hydrolase-deficient mutant, depleted extracellular NAD⁺ levels in benign and malignant prostate cell lines. However, expression of CD38 did not significantly alter intracellular NAD⁺ levels in human prostate cell lines grown in vitro and in urogenital tissues isolated from wild-type and CD38 knockout mice.

Conclusions

CD38 protein expression in prostate cancer is associated with risk of recurrence. Methylation results suggest that CD38 is epigenetically regulated in localized and metastatic prostate cancer tissues. Our study provides support for CD38 as a regulator of extracellular, but not intracellular, NAD⁺ in epithelial cells. These findings suggest that repression of CD38 by methylation may serve to increase the availability of extracellular NAD⁺ in prostate cancer tissues.

https://ift.tt/2NxdN2E

Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells

Abstract

Background

Pancreatic cancer (PC) is the fourth most common cause of cancer death. Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Consequently, new therapeutic options for this disease are urgently needed. In this study, we explored the effect of two repurposed drug candidates nelfinavir and nitroxoline, approved for non-anticancer human use, in PC cell lines. Nelfinavir and nitroxoline were tested as single agents, or in combinations with or without erlotinib, a targeted drug approved for PC treatment.

Methods

The effects of the drugs on the viability of AsPC-1, Capan-2 and BxPC-3 PC cell lines were assessed by MTT. The impact of the treatments on cell cycle distribution and apoptosis was analyzed by flow cytometry. The effects of treatments on proteins relevant in cell cycle regulation and apoptosis were evaluated by western blot. Self-renewal capacity of PC cell lines after drug treatments was assessed using a clonogenic assay.

Results

When used as single agents, nelfinavir and nitroxoline decreased viability, affected cell cycle and reduced the expression of relevant cell cycle proteins. The effects on apoptosis were variable among PC cell lines. Moreover, these agents drastically impaired clonogenic activity of the three PC cell lines. Combinations of nelfinavir and nitroxoline, with or without erlotinib, resulted in dose- and cell-dependent synergistic effects on cell viability. These effects were paralleled by cell cycle alterations and more consistent apoptosis induction as compared to single agents. Treatments with drug combinations induced drastic impairment of clonogenic activity in the three cell lines.

Conclusions

This study shows that two non-antitumor drugs, nelfinavir and nitroxoline, as single agents or in combination have antitumor effects that appear comparable, or in some case more pronounced than those of erlotinib in three PC cell lines. Our results support repurposing of these approved drugs as single agents or in combination for PC treatment.

https://ift.tt/2xE9Xu0

Autonomic Function Following Concussion in Youth Athletes: An Exploration of Heart Rate Variability Using 24-hour Recording Methodology

We demonstrate a 24 h heart rate recording methodology to evaluate the influence of concussion across the recovery trajectory in youth athletes, within an ecologically valid context.

https://ift.tt/2DkN2K2

https://ift.tt/2OFfNm1

Lifestyle Interventions Cut Excess Gestational Weight Gain

FRIDAY, Sept. 21, 2018 -- Lifestyle interventions focusing on diet and physical activity result in less excess gestational weight gain (GWG) among women with overweight and obesity, according to a study published in the September issue of...

https://ift.tt/2zlx4LG

Low Vitamin D Levels Tied to Interstitial Lung Disease

FRIDAY, Sept. 21, 2018 -- Vitamin D deficiency is independently associated with subclinical interstitial lung disease (ILD) and its progression, according to a study recently published in the Journal of Nutrition. Samuel M. Kim, M.D., from the Johns...

https://ift.tt/2I4y8Xf

Pediatric End-Stage Liver Disease Score Underestimates Mortality

FRIDAY, Sept. 21, 2018 -- The Pediatric End-stage Liver Disease (PELD) score underestimates the actual probability of 90-day pretransplant mortality for children undergoing a primary liver transplant, according to a study published online Sept. 17...

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HbA1c Variability Is a Strong Predictor of Mortality in T2DM

FRIDAY, Sept. 21, 2018 -- Hemoglobin A1c (HbA1c) variability may be a more powerful predictor of all-cause mortality with type 2 diabetes than average HbA1c, according to a study published in the August issue of Diabetes, Obesity and...

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Sensitivity for CRC Detection Up With Decreasing FIT Threshold

FRIDAY, Sept. 21, 2018 -- Programmatic sensitivity for colorectal cancer (CRC) detection increases modestly with decreasing fecal immunochemical test (FIT) positivity thresholds, according to a study published online Sept. 18 in the Annals of...

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Repeat CT Common in Peds Traumatic Epidural Hematoma

FRIDAY, Sept. 21, 2018 -- For children with traumatic epidural hematomas (EDHs), repeated computed tomography (CT) imaging is common, but rarely impacts management, according to a study published in the September issue of Pediatrics. Brian F....

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More Hurt, Killed in Shootings With Semiautomatic Rifles

FRIDAY, Sept. 21, 2018 -- More people are wounded and killed in active shooter incidents in which semiautomatic rifles are used, according to a research letter published in the Sept. 11 issue of the Journal of the American Medical...

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Promising New Way to Identify Breast Cancer Tumors

FRIDAY, Sept. 21, 2018 -- Molecular markers of breast cancer tumors can be identified by focusing on parameters of a cell's nucleus, and aided by machine learning, according to a study published online Sept. 4 in npj Breast Cancer. Rishi R. Rawat,...

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Age, Sex, APOE Genotype Identify Alzheimer's, Dementia Risk

FRIDAY, Sept. 21, 2018 -- Age, sex and apolipoprotein E (APOE) genotype can identify groups at high 10-year risk for Alzheimer's disease and all dementia, according to a study published Sept. 4 in CMAJ, the journal of the Canadian Medical...

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Dozens of Medical Groups Join Forces to Improve Diagnoses

FRIDAY, Sept. 21, 2018 -- Every nine minutes, a patient in a U.S. hospital dies because a diagnosis was wrong or delayed -- resulting in 80,000 deaths a year. That sobering estimate comes from the Society to Improve Diagnosis in Medicine (SIDM). To...

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EMS Agenda 2050 Quick Take: Healthy people are better students, workers and citizens

Making the EMS Agenda 2050 become reality will require strengthening the collaboration between EMS, public health and healthcare

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Heart Problems: Investigating the Cardiac Side Effects of Cancer Treatments

Certain cancer treatments can damage the heart and the cardiovascular system, a problem known as cardiotoxicity. Cardiologists and oncologists met recently to discuss strategies and future research directions for addressing these side effects.

https://ift.tt/2MSOZwJ

Tox and Hound – Fellow Friday – Cyanomythology: The Toxicomythology of Cyanide Poisoning

Binding to Cytochrome Oxidase and the Mysterious Cyanhemoglobin by Steven Curry, M.D. Banner – University Medical Center Phoenix University of Arizona College of Medicine – Phoenix Phoenix, AZ @SteveCurryMD Every toxicology fellow learns about cyanide. But not all of what they learn is necessarily correct. As a resident, I was taught that the CN– ion […]

EMCrit Project by Tox & Hound.

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The supportive care needs of women experiencing gynaecological cancer: a Western Australian cross-sectional study

Abstract

Background

Women diagnosed with gynaecological cancer experience supportive care needs that require care provision to reduce the impact on their lives. International evidence suggests supportive care needs of women with gynaecological cancer are not being met and provision of holistic care is a priority area for action. Knowledge on gynaecological cancer supportive care needs is limited, specifically comparison of needs and cancer gynaecological subtype.

Our aim was to identify supportive care needs of Western Australian women experiencing gynaecological cancer, their satisfaction with help and explore associations between participant's demographic characteristics and identified needs.

Methods

A cross-sectional design incorporating a modified version of the Supportive Care Needs Survey – short form (SCNS-SF34) assessed 37 supportive care needs under five domains in conjunction with demographic data. Three hundred and forty three women with gynaecological cancer attending a tertiary public referral hospital completed the survey over 12 months. Statistical analysis was performed using the R environment for statistical computing. A linear regression model was fitted with factor scores for each domain and demographic characteristics as explanatory variables.

Results

Three hundred and three women (83%) identified at least one moderate or high level supportive care need. The five highest ranked needs were, 'being informed about your test results as soon as feasible' (54.8%), 'fears about cancer spreading' (53.7%), 'being treated like a person not just another case' (51.9%), 'being informed about cancer which is under control or diminishing (that is, remission)' (50.7%), and 'being adequately informed about the benefits and side-effects of treatments before you choose to have them' (49.9%). Eight of the top ten needs were from the 'health system and information' domain. Associations between supportive care items and demographic variables revealed 'cancer type', and 'time since completion of treatment' had no impact on level of perceived need for any domain.

Conclusions

Western Australian women with gynaecological cancer identified a high level of supportive care needs. The implementation of a supportive care screening tool is recommended to ensure needs are identified and care is patient-centred. Early identification and management of needs may help to reduce the burden on health system resources for managing ongoing needs.

https://ift.tt/2OIwg94

Predictive and prognostic value of Matrix metalloproteinase (MMP) - 9 in neoadjuvant chemotherapy for triple-negative breast cancer patients

Abstract

Background

This study aimed to investigate the clinical utility of serum and histological MMP-9 detection during neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC).

Methods

A total of 303 TNBC patients who underwent weekly paclitaxel plus carboplatin treatments followed by surgical resection were included in this study. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum level of Matrix metalloproteinase-9 (sMMP-9) at baseline and prior to surgery. Immunohistochemistry was used to detect histological MMP-9 (hMMP-9) expression in patients with residual tumors after NAC. The value of MMP-9 to predict the response to NAC and patient survival was studied.

Results

Of the 303 patients, 103 (34.0%) patients experienced pathological complete response (pCR) after completion of NAC. Univariate and multivariate analyses revealed that the relative change in sMMP-9, rather than sMMP-9 at baseline or surgery, had a remarkable predictive value for pCR. Each 1 ng/ml decrease in sMMP-9 after NAC was shown to result in a 0.3% increase in pCR rate. Additionally, in survival analyses, hMMP-9 expression in residual tumors was independently correlated with disease-free survival for non-pCR responders (P < 0.001).

Conclusions

Our findings indicate that monitoring serum MMP-9 and detection of histological MMP-9 could help identify TNBC patients who will respond to NAC and will display varying risks of disease relapse. MMP-9 may serve as a predictive and prognostic biomarker for tailoring and modifying the NAC strategy for TNBC.

https://ift.tt/2O2cp7J

Biomarkers: paving stones on the road towards the personalized precision medicine for oral squamous cell carcinoma

Abstract

Traditional therapeutics have encountered a bottleneck caused by diagnosis delay and subjective and unreliable assessment. Biomarkers can overcome this bottleneck and guide us toward personalized precision medicine for oral squamous cell carcinoma. To achieve this, it is important to efficiently and accurately screen out specific biomarkers from among the huge number of molecules. Progress in omics-based high-throughput technology has laid a solid foundation for biomarker discovery. With credible and systemic biomarker models, more precise and personalized diagnosis and assessment would be achieved and patients would be more likely to be cured and have a higher quality of life. However, this is not straightforward owing to the complexity of molecules involved in tumorigenesis. In this context, there is a need to focus on tumor heterogeneity and homogeneity, which are discussed in detail. In this review, we aim to provide an understanding of biomarker discovery and application for precision medicine of oral squamous cell carcinoma, and have a strong belief that biomarker will pave the road toward future precision medicine.

https://ift.tt/2OHwygs

A trend towards a more intense adjuvant treatment of low-grade-gliomas in tertiary centers in Germany after RTOG 9802 – results from a multi-center survey

Abstract

Background

The treatment recommendations for Low-grade Gliomas (LGG) underwent profound changes due to results from RTOG 9802 published in April 2016. This work aims to investigate whether the results from the trial were already incorporated into the treatment recommendations at German oncology centers before an update of the official guidelines.

Methods

An online based questionnaire with questions covering all aspects of adjuvant treatments of LGGs was generated, including three cases with distinct clinical situations. We contacted all members of the neuro-oncologic working group (NOA) of the German Cancer Society (DKG) as well as all German-speaking members of the European Low-Grade Glioma Network via E-mail.

Results

We collected 38 responses. All responders were at least specialists; they predominantly worked at tertiary hospitals with a high volume of LGGs treated annually (75% with more than 10 cases per year). All responders stated to consent treatment recommendation for LGGs within interdisciplinary oncologic boards. The treatment recommendations for LGGs changed profoundly between 2015 and 12/2016. There is a trend towards PCV-based multimodal treatments, especially for oligodendroglial LGGs, as well as a trend away from watchful-waiting-policies for astrocytic LGGs.

Conclusion

Neurooncologists do adapt results from clinical trials quickly. None the less, there is still an immense heterogeneity within the treatment recommendations, predominantly for astrocytic LGGs. Well planned clinical trials and concise treatment recommendations are warranted; additionally, individual counseling of patients is essential.

https://ift.tt/2NWiS47

Prediction of perioperative complications after robotic-assisted radical hysterectomy for cervical cancer using the modified surgical Apgar score

Abstract

Background

Although there has been marked development in surgical techniques, there is no easy and fast method of predicting complications in minimally invasive surgeries. We evaluated whether the modified surgical Apgar score (MSAS) could predict perioperative complications in patients undergoing robotic-assisted radical hysterectomy.

Methods

All patients with cervical cancer undergoing robotic-assisted radical hysterectomy at our institution between January 2011 and May 2017 were included. Their clinical characteristics were retrieved from their medical records. The surgical Apgar score (SAS) was calculated from the estimated blood loss, lowest mean arterial pressure, and lowest heart rate during surgery. We modified the SAS considering the lesser blood loss typical of robotic surgeries. Perioperative complications were defined using a previous study and the Clavien-Dindo classification and subdivided into intraoperative and postoperative complications. We analyzed the association of perioperative complications with low MSAS.

Results

A total of 138 patients were divided into 2 groups: with (n = 53) and without (n = 85) complications. According to the Clavien-Dindo classification, 49 perioperative complications were classified under Grade I (73.1%); 13, under Grade II (19.4%); and 5, under Grade III (7.5%); 0, under both Grade IV and Grade V. Perioperative complications were significantly associated with surgical time (p = 0.026). The MSAS had a correlation with perioperative complications (p = 0.047). The low MSAS (MSAS, ≤6; n = 52) group had significantly more complications [40 (76.9%), p = 0.01]. Intraoperative complications were more correlated with a low MSAS than were postoperative complications [1 (1.2%) vs. 21 (40.4%); p < 0.001, 13 (15.1%) vs. 25 (48.1%); p = 0.29, respectively]. We also analyzed the risk-stratified MSAS in 3 subgroups: low (MSAS, 7–10), moderate (MSAS 5–6), and high risks (MSAS, 0–4). The prevalence of intraoperative complications significantly increased as the MSAS decreased p = 0.01).

Conclusions

This study was consistent the concept that the intuitive and simple MSAS might be more useful in predicting intraoperative complications than in predicting postoperative complications in minimally invasive surgeries, such as robotic-assisted radical hysterectomy for cervical cancer.

https://ift.tt/2ODrtFQ

PEG-L-CHOP treatment is safe and effective in adult extranodal NK/T-cell lymphoma with a low rate of clinical hypersensitivity

Abstract

Background

The combination of chemotherapy and L-asparaginase (L-ASP) treatment significantly increased survival rate in an adult patient with extranodal natural killer (NK)/T-cell lymphoma (NKTCL). However, hypersensitivity reactions of L-ASP in some patients limited its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and longer circulating half-life than unconjugated L-ASP, and has been reported to be effective and well-tolerated in children with acute lymphoblastic leukemia. Cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisolone (CHOP) is the most common chemotherapy for non-Hodgkin lymphoma. In this report, we sought to study the efficacy and safety of PEG-L- CHOP in NKTCL in adult Chinese patients.

Methods

Our study is a prospective, multi-center, open-label clinical trial. Patients with newly diagnosed adult NKTCL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included six cycles of PEG-L-CHOP regimen. Radiotherapy was scheduled after 2–4 cycles of PEG-L-CHOP regimen, depending on the stage and primary anatomic site.

Results

We enrolled a total of 33 eligible patients. All 33 patients completed 170 cycles of chemotherapy combined with radical radiotherapy. The overall response rate was 96.9% (32/33) with 75.8% (25/33) achieving complete responses and 21.2% (7/33) achieving partial responses. The overall survival (OS) at 1, 2, 3-year were 100, 90.61 and 80.54%, respectively. The major adverse effects were bone marrow suppression, reduction of fibrinogen level, liver dysfunction, and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded.

Conclusions

PEG-L-CHOP chemotherapy in combination radiotherapy is safe and durably effective treatment for adult extranodal NK/T-cell lymphoma with fewer allergic reactions.

This study was approved by the Peking University Beijing Cancer Hospital Ethics Review Committee (reference number: 2011101104). The clinical trial registration number ChiCTR1800016940 was registered on July 07, 2018 at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx). The clinical trial was registered retrospectively.

https://ift.tt/2NZmBhe

https://ift.tt/2DiT0LJ

Enantiomer discrimination in β-phenylalanine degradation by a newly isolated Paraburkholderia strain BS115 and type strain PsJN

Despite their key role in numerous natural compounds, β-amino acids have rarely been studied as substrates for microbial degradation. Fermentation of the newly isolated Paraburkholderia strain BS115 and the type ...

https://ift.tt/2Nx5YtI

Enhancing biomass and lipid accumulation in the microalgae Schizochytrium sp. by addition of fulvic acid and EDTA

Enhancing lipid productivity and reducing oxidative damage is essential for lipid overproduction in microalgae. In this study, addition of 20 mg/L fulvic acid (FA) resulted a 34.4% increase of lipid yield in Schi...

https://ift.tt/2DmMbc2

Isolation and Fluorescence Imaging for Single-particle Reconstruction of Chlamydomonas Centrioles

We have developed a strategy to purify and image a large number of centrioles in different orientations amenable for super-resolution microscopy and single-particle averaging.

https://ift.tt/2Nvn2AA

Worth a local treatment? – Analysis of modern radiotherapy concepts for oligometastatic prostate cancer

Abstract

Background

Prostate cancer (PCA) is the most-prevalent non-skin cancer in men worldwide. Nevertheless, the treatment of oligometastatic, especially lymph-node (ln) recurrent, PCA remains elusive. The aim of our study was to provide insights in radiotherapy (RT)-treatment of recurrent PCA exhibiting ln- or osseous (oss)-oligometastases.

Methods

Between April 2012 and April 2017, 27 oligometastatic PCA patients (19 ln and 8 single oss) were treated with RT at our institution.

Results

The metastasis-free survival (MFS) was 24.8 m (22.0–36.0 m) and 25.4 m (23.9–28.1 m) for the ln- and oss-subgroup resulting in 1-year MFS of 75.4 and 100% and 2-year MFS of 58.7 and 83.3% for ln- and oss-metastatic patients, respectively. Of notice, none of the recurrences for ln-patients was in the RT-field, constituting a local control of 100%.

Within the ln-group, pre-RT median-PSA was 2.6 ng/ml, median post-RT PSA was 0.3 ng/ml, which was significant (p = 0.003). Median biochemical-free survival (bfS) was 12.2 m. PCA that was initially confined to the prostate had a better bfS (p < 0.001) and MFS (p = 0.013). The oss-group had a median PSA of 4.9 ng/ml pre-treatment which dropped to a median value of 0.14 ng/ml (p = 0.004).

Toxicities were moderate, with only 1 case of III° toxicity. There were no deaths in the ln-group, thus overall survial was 100% here.

Conclusion

Our study points out the feasibility of RT as a treatment option in recurrent PCA and demonstrates an excellent local control with a low-toxicity profile.

https://ift.tt/2I7nlM4

miR-203 inhibits ovarian tumor metastasis by targeting BIRC5 and attenuating the TGFβ pathway

Abstract

Background

We previously reported that miR-203 functions as a tumor suppressor in ovarian cancer cells by directly targeting transcription factor Snai2 and inhibiting epithelial to mesenchymal transition (EMT), whereas BIRC5/survivin promotes EMT. In this study, we tested our hypothesis that miR-203 inhibits ovarian tumor metastasis by suppressing EMT through targeting BIRC5, using an orthotopic ovarian cancer mouse model.

Methods

We overexpressed miR-203 in ovarian cancer SKOV3 and OVCAR3 cells using a lentiviral vector and examined cell migration and invasion using transwell plates. The small molecule inhibitor, YM155, was used to inhibit survivin expression. miR-203-expressing and control SKOV3 cells were intrabursally injected into immunocompromised NSG female mice. Primary tumors in ovaries and metastatic tumors were collected to determine the expression of survivin and EMT markers using Western blot and immunostaining.

Results

Overexpression of miR-203 inhibits EMT by targeting BIRC5 in ovarian cancer SKOV3 and OVCAR3 cells. miR-203 expression enhances the ability of the survivin inhibitor YM155 to reduce tumor cell migration and invasion in vitro. We further showed that miR-203 expression attenuated the TGFβ pathway in both SKOV3 and OVCAR3 cells. miR-203 expression also inhibited primary tumor growth in ovaries and metastatic tumors in multiple peritoneal organs including liver and spleen.

Conclusion

miR-203 inhibits ovarian tumor metastasis by targeting BIRC5/survivin and attenuating the TGFβ pathway.

https://ift.tt/2NXMsWZ

The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model

Abstract

Background

The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential amino acids across the plasma membrane. While LAT1 is overexpressed in a variety of human neoplasms, its expression and its role in thyroid cancer is currently unknown. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy for which no effective therapy exists. The purpose of this study was to explore whether the inhibition of LAT1 in ATC would affect tumor growth both in vitro and in vivo.

Methods

LAT1 was pharmacologically blocked by JPH203 in human ATC and papillary thyroid cancer (PTC) cell lines. The effects on proliferation and mTORC1 activity were addressed in vitro. A genetically engineered mouse model of ATC was used to address the effect of blocking LAT1 on tumor growth in vivo. SLC7A5 transcription was measured in patient-derived ATC samples to address the clinical relevance of the findings.

Results

LAT1 block by JPH203 reduced proliferation and mTORC1 signaling in human thyroid cancer cell lines. SLC7A5 transcription was upregulated in ATC tissues derived from a genetically engineered mouse model and in ATC samples recovered from patients. JPH203 treatment induced thyroid tumor growth arrest in vivo in a fully immunocompetent mouse model of thyroid cancer. Additionally, analysis of publicly available datasets of thyroid carcinomas revealed that high LAT1 expression is associated with potentially untreatable PTC presenting reduced NIS/SLC5A5 transcription and with ATC.

Conclusions

These preclinical results show that LAT1 inhibition is a novel therapeutic approach in the context of thyroid cancers, and more interestingly in untreatable thyroid cancers.

https://ift.tt/2OHV0ON

Welcome to ENT4me

Here is some content to add

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A road map for transforming stroke recovery

As neurologists, we have always been told (by those in other fields) that we work in a speciality that has no treatments and is obsessed by clinical diagnosis and little else. The advent of biological therapeutic targets in neurological disease is of course changing all that. The popular view of neurorehabilitation on the other hand is that it is falling behind because there are no 'recovery' drugs, only physical, behavioural or adaptive therapies that are not particularly effective. As illustration, many years ago a recently appointed consultant neurologist was asked why he had an interest in neurorehabilitation when it amounted to nothing more than the provision of a walking stick or a wheelchair. That behavioural interventions are generally overlooked in neurology is curious for a speciality that deals with the brain, whose very structure and therefore function can be changed through experience. The naive reader of Broken Movement might be surprised to find that when it comes to recovery from hemiplegic stroke there are a wide range of treatments, from behavioural to pharmacological. What Krakauer and Carmichael show us is that with a little clear thinking and honest critical appraisal, we will be on the threshold of some remarkable breakthroughs in a field that has proven stubborn to crack. However, the crisis in confidence in neurorehabilitation that currently grips us is not because existing therapies have been inadequately tested in randomized controlled trials, but because these therapies are ill-conceived from a neurobiological perspective in the first place. The message is clear—develop therapeutic approaches from a mechanistic perspective.

https://ift.tt/2prjwZh

A widely used sampling device in colorectal cancer screening programmes allows for large-scale microbiome studies

We read with interest the article by Passamonti et al,1 reporting the performance of two different faecal immunochemical tests (FITs) highlighting the importance of standardisation and validation of screening methodologies. Conventionally, laboratory-based FIT is the preferred approach in testing for occult blood in faeces, which includes colorectal cancer screening programmes.2–4 The potential of preserving stable faecal samples in a widely used FIT buffer for microbiome research would enable prospective microbiome studies in generally healthy subjects undergoing colorectal cancer screening.

For this purpose, we evaluated faecal sample stability in the commonly used OC-Sensor (Eiken Chemical, Tokyo, Japan) under various storage conditions. Faecal samples from five healthy adult individuals were used for the analysis and exposed to 16 different conditions: immediately frozen at –86°C (with FIT (wFIT)/without FIT (woFIT)); immediately frozen at –20°C (wFIT/woFIT); wFIT stored at 4°C for 1, 2, 7, 14 days; stored at...

https://ift.tt/2MSD81N

Microbiome profiling in extremely acidic soils affected by hydrothermal fluids: the case of Solfatara Crater (Campi Flegrei, southern Italy)

Abstract

An integrated geochemical and microbiological investigation of soils from the Solfatara Crater (Campi Flegrei, southern Italy) demonstrated that interstitial soil gases dominated by CO₂ and other typical hydrothermal gaseous species (e.g. H₂S, CH₄, ethane, benzene, alkenes and S-bearing organic compounds) influenced the composition of microbial communities. The relatively high concentrations of hydrothermal fluids permeating the soil produced acidic conditions and whitish deposits that characterize the Solfatara Crater floor. Archaea and Bacteria showed almost equal cell abundance (up to 3.2 x 10⁷ and 4.2 x 10⁷ cell/g, respectively) with relatively low levels of biodiversity and equitability in sites characterized by elevated temperatures (up to 70°C), very low pH values (up to 2.2) and reducing conditions. In these sites, high-throughput sequencing showed the marked selection of microorganisms, mainly affiliated with the genera Thermoplasma, Ferroplasma and Acidithiobacillus. A relatively high biodiversity and concomitant distinctive structure of the microbial community were observed in soils poorly affected by fumarolic emissions that were oxic and rich in organic matter.

https://ift.tt/2QQck5M

CAMKK2 promotes prostate cancer independently of AMPK via increased lipogenesis

New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here we show that Camkk2 deletion or pharmacological inhibition protects against prostate cancer development in a pre-clinical mouse model that lacks expression of prostate-specific phosphatase and tensin homologue (Pten). In contrast, deletion of AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a post-transcriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signalling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer.

https://ift.tt/2xDlpGf

Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer

The standard treatment for metastatic prostate cancer (PCa), androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP PCa xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide-resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was Dipeptidyl Peptidase 4 (DPP4), which encodes a membrane-anchored protein that cleaves dipeptides from multiple growth factors, resulting in their increased degradation. DPP4 mRNA and protein were also decreased in clinical CRPC cases, and inhibition of DPP4 with sitagliptin enhanced the growth of PCa xenografts following castration. Significantly, DPP4 inhibitors are frequently used to treat type 2 diabetes as they increase insulin secretion. Together these results implicate DPP4 as an AR-regulated tumor suppressor gene whose loss enhances growth factor activity and suggest that treatment with DPP4 inhibitors may accelerate emergence of resistance to ADT.

https://ift.tt/2NW5qx9

Dr. Chanita Hughes-Halbert to Deliver NCI CURE Distinguished Scholars Seminar

On October 17, 2018, Dr. Chanita Hughes-Halbert will deliver the next CURE Distinguished Scholars Seminar. Dr. Hughes-Halbert will present on Translational Issues in Cancer Health Disparities.

https://ift.tt/2pqvUsC

National recognition of first responders and humanizing industry personnel

Our co-hosts discuss two current events that both put a spotlight on the career field and call attention to the individuality of its professionals

https://ift.tt/2OJwDQC

Development of the other‐race effect in Malaysian‐Chinese infants

Developmental Psychobiology, EarlyView.


https://ift.tt/2NxyETF

Postoperative Stroke after Anterior Cervical Discectomy and Fusion in Patients with Carotid Artery Stenosis: A Statewide Database Analysis

Publication date: Available online 21 September 2018

Source: The Spine Journal

Author(s): Morad Chughtai, Assem A. Sultan, Jorge Padilla, George A. Beyer, Jared M. Newman, Iyooh U. Davidson, Haariss Ilyas, Inyang Udo-Inyang, Ryan J. Berger, Linsen T. Samuel, Ganesh M. Shankar, Carl B. Paulino, Dominic Pelle, Jason W. Savage, Michael P. Steinmetz, Thomas E. Mroz

Abstract

Background

Carotid artery injury and stroke secondary to prolonged retraction remains an extremely rare complication in anterior cervical discectomy and fusion (ACDF). However, multiple studies have demonstrated that carotid artery retraction during the surgical approach may alter the normal blood flow, leading to a significant reduction in the cross-sectional area of the vessel. Others have suggested that dislodgment of atherosclerotic plaques following manipulation of the carotid artery can be a potential risk for intracranial embolus and stroke.

Purpose

We aimed to evaluate: 1) the incidence of postoperative stroke following ACDF and 2) incidence of other postoperative complications in a cohort of patients who had a diagnosis of carotid artery stenosis (CAS) versus those who did not.

Patient Sample

This study utilized the Statewide Planning and Research Cooperative System (SPARCS) database from January 1, 2009 to December 31, 2013. All patients who underwent (ACDF) and had a pre-operative diagnosis of CAS were identified using the International Classification of Disease, 9th revision (ICD-9) codes. Those who had a previous history of stroke were excluded. Patients who had CAS were propensity score matched to patients without history of CAS for demographics and Charlson/Deyo comorbidity scores.

Outcome Measures

Incidence of postoperative stroke and other complications were compared between the cohorts. The threshold for statistical significance was set at a p<0.05. This study received no funding. The authors report no conflict of interests relevant to this study.

Results

There were 34,975 patients who underwent an ACDF in the study time period. After excluding those under the age of 18 and with history of previous stroke, there were 61 patients who had CAS that were compared to a propensity-matched cohort. The CAS cohort had a significantly higher incidence of postoperative stroke during their hospitalization (6.6% vs 0%, P<0.042). The CAS cohort also had higher rates of acute renal failure (27.9% vs 4.9%, p=0.01) and sepsis (18% vs 4.9%, p=0.023). There were no stroke related deaths.

Conclusion

Patients with CAS who underwent ACDF had a statistically significant greater incidence of developing a postoperative stroke. To the best of our knowledge, no previous study has evaluated the development of postoperative stroke in patients with CAS undergoing ACDF. Larger, multi-center studies are needed to estimate the true incidence of stroke in this specific patient population. However, our results may illustrate the importance of pre-operative optimization, approach-selection, and postoperative stroke surveillance in patients with a history of CAS who undergo ACDF.

https://ift.tt/2xAMny6