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Τετάρτη 7 Ιουνίου 2017
Blinding in Surgical Randomized Clinical Trials in 2015
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Radioactive Seed Localization or Wire-guided Localization of Nonpalpable Invasive and In Situ Breast Cancer: A Randomized, Multicenter, Open-label Trial
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Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study
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Dual-graft Adult Living Donor Liver Transplantation: An Innovative Surgical Procedure for Live Liver Donor Pool Expansion
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Intraperitoneal Local Anesthetic for Laparoscopic Appendectomy in Children: A Randomized Controlled Trial
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Seventeen-year Outcome of a Randomized Clinical Trial Comparing Laparoscopic and Conventional Nissen Fundoplication: A Plea for Patient Counseling and Clarification
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Predicting Heterotopic Ossification Early After Burn Injuries: A Risk Scoring System
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Oncologic Procedures Amenable to Fluorescence-guided Surgery
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Transplantation of Bioprinted Tissues and Organs: Technical and Clinical Challenges and Future Perspectives
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Variation and Impact of Multiple Complications on Failure to Rescue After Inpatient Surgery
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The Need to Consider Longer-term Outcomes of Care: Racial/Ethnic Disparities Among Adult and Older Adult Emergency General Surgery Patients at 30, 90, and 180 Days
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Delocalized Spin States in 2D Atomic Layers Realizing Enhanced Electrocatalytic Oxygen Evolution
The electrocatalytic activity of transition-metal-based compounds is strongly related to the spin states of metal atoms. However, the ways for regulation of spin states of catalysts are still limited, and the underlying relationship between the spin states and catalytic activities remains unclear. Herein, for the first time, by taking NiII-based compounds without high or low spin states for example, it is shown that their spin states can be delocalized after introducing structural distortion to the atomic layers. The delocalized spin states for Ni atoms can provide not only high electrical conductivity but also low adsorption energy between the active sites and reaction intermediates for the system. As expected, the ultrathin nanosheets of nickel-chalcogenides with structural distortions show dramatically enhanced activity in electrocatalytic oxygen evolution compared to their corresponding bulk samples. This work establishes new way for the design of advanced electrocatalysts in transition-metal-based compounds via regulation of spin states.
Delocalized spin states in transition-metal-based compounds by introducing structural distortion to their confined 2D atomic layers can enhance activity in electrocatalytic oxygen evolution. This work establishes new way for the design of advanced electrocatalysts in transition-metal-based compounds via regulation of spin states.
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Behavioral ‘Nudges’ Offer a Cost-Effective Policy Tool
Governments around the world have increasingly turned to behavioral science to help address various policy problems – new research shows that some of the best-known strategies derived from behavioral science, commonly referred to as 'nudges,' may be extremely cost effective. The new study, which examined the cost-effectiveness of nudges and typical intervention strategies like financial incentives side-by-side, found that nudges often yield particularly high returns at a low cost when it comes to boosting retirement savings, college enrollment, energy conservation, and vaccination rates.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"The changes in behavior produced by nudges tend be quite cost effective relative to those produced by traditional policy tools – so there is a big opportunity to use nudging more widely in government in conjunction with traditional policy tools," says Professor Katherine L. Milkman of The Wharton School at the University of Pennsylvania, one of the authors of the new study.
"Our findings show that it's important to calculate and report the cost effectiveness of available policy tools, and not simply the impact of an intervention without an adjustment for cost," adds study co-author Professor John Beshears of Harvard Business School. "This will facilitate wiser decisions by governments and other organizations regarding which policy tools to use under various circumstances."
Nudges – which are now being tested and implemented by government agencies in the United Kingdom, Australia, Germany, the Netherlands, Singapore, and the United States – diverge from traditional policy tools in that they encourage certain behaviors without restricting an individual's options or exacting financial penalties.
When organizations automatically enroll employees in their company's retirement savings program but allow them to opt out, for example, they are using a nudge that takes advantage of the fact that people tend to accept the default while still protecting employees' freedom to choose whether to participate in the program.
Although many nudges have been proven to increase individuals' access to various services and programs, they may not produce large shifts in overall behavior. As such, they may be overlooked as useful policy tools despite their relatively low cost.
With this in mind, a research team including academics and practitioners inside and outside of government examined existing studies to evaluate the relative cost effectiveness of nudges and other policy interventions.
Looking at the 2015 reports from the SBST and the UK Behavioural Insights Team, the researchers developed a list of relevant policy areas and identified one behavior as the outcome of interest within each area. They then searched leading academic journals in science, economics, psychology, and medicine for original research published from 2000 to mid-2015 that directly examined interventions targeting these outcomes.
The team compared the effectiveness of nudge-type strategies with more standard policy interventions, calculating the ratio between an intervention's causal effect and its implementation cost.
The results showed a pattern: In each of the domains that the researchers examined, nudges were highly cost effective, often more so than the traditional policy interventions.
In the case of retirement savings, for example, a nudge that prompted new employees to indicate their preferred contribution rate to a workplace retirement-savings plan yielded a $100 increase in employee contributions per $1 spent on implementing the program; the next most cost-effective strategy, offering monetary incentives for employees who attended a benefits fair, yielded only a $14.58 increase in employee contributions per $1 spent on the program.
Similarly, a nudge-based mailing that prompted employees to write down when and how they planned on getting their flu shot led to about 13 additional people getting vaccinated per $100 spent on the mailing; by contrast, an education campaign on the benefits of the flu vaccine led to only about 9 additional employees at a health care facility getting vaccinated per every $100 spent on the campaign.
"We had a hunch that nudging, and especially digital nudging, would be very cost effective, but I was truly surprised to see that the cost effectiveness of nudging is often 100, and even 1,000, times greater than more traditional interventions," says co-author Shlomo Benartzi, a professor at the Anderson School of Management at the University of California, Los Angeles. "This has huge implications for governments and businesses alike."
The researchers acknowledge that their analyses do not offer an exhaustive review of the comparative effectiveness of nudges and traditional policy tools. And there are many cases in which traditional tools – such as prohibitions and mandates – are essential for achieving specific policy objectives, and nudges might not be of value.
But the new findings clearly show that nudge-type strategies based in behavioral science do offer a useful, low-cost approach to promoting behaviors tied to a variety of important outcomes. Unlike traditional interventions that are designed to influence the cost-benefit calculations that people make, nudges harness decision-making processes that operate automatically. Thus, nudges may be especially useful in guiding behavior when people are making decisions in less than ideal circumstances, such as when they are busy, tired, or otherwise not able to fully engage with the choices available to them.
The findings also underscore how critical sharing data and knowledge about the effectiveness of various interventions will be to coordinated policy efforts among researchers, practitioners, and policymakers
"Tracking failures is as important for knowledge creation as tracking successes," the researchers conclude.
Additional co-authors on the paper include Cass R. Sunstein of Harvard Law School, Richard H. Thaler of the University of Chicago Booth School of Business, Maya Shankar of the White House Office of Science and Technology Policy, Will Tucker-Ray and William J. Congdon of ideas42, and Steven Galing of the United States Department of Defense.
J. Beshears received financial support from the Pershing Square Fund for Research on the Foundations of Human Behavior. M. Shankar received financial support from the Alfred P. Sloan Foundation. W. Tucker-Ray and W. J. Congdon received financial support from the Laura and John Arnold Foundation.
All materials have been made publicly available via the Open Science Framework and the complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Materials.
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Impact of atrial fibrillation on long-term survival following oesophagectomy: a 21-year observational study
Background
Post-operative atrial fibrillation (AF) is a common complication of oesophagectomy and thought to signal a complicated post-operative course. AF is associated with prolonged admissions, increased healthcare costs and inpatient mortality. However, the impact of post-operative AF on long-term outcomes remains uncertain.
Methods
Patients undergoing open Ivor-Lewis oesophagectomy from 1994 to 2014 at Palmerston North Hospital, New Zealand, were retrospectively evaluated. Demographic, perioperative and tumour variables were collected. Regression models were used to identify independent predictors of AF and assess post-discharge survival following oesophagectomy.
Results
In total, 89 patients were included. New-onset AF developed post-operatively in 27 patients (30%). Median follow-up was 6.3 years. Logistic regression identified volume of intravenous fluid in the first 24 h post-operatively as a predictor of AF. Post-discharge survival was predicted by AF occurrence (hazard ratio (HR): 2.99, 95% confidence interval (CI): 1.37–6.53, P = 0.006), preoperative chemoradiotherapy (HR: 0.43, 95% CI: 0.20–0.91, P = 0.03), 1–4 positive lymph nodes (HR: 2.29, 95% CI: 1.06–4.96, P = 0.04), ≥5 positive nodes (HR: 2.95, 95% CI: 1.25–6.94, P = 0.01) and year of operation from 2008 to 2014 (HR: 0.30, 95% CI: 0.12–0.75, P = 0.01).
Conclusion
Post-operative AF was associated with poorer long-term survival following oesophagectomy in this cohort. Further research should evaluate the influence of AF on cardiovascular and oncological outcomes following oesophagectomy.
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It's worth the wait: optimizing questioning methods for effective intraoperative teaching
Background
The use of questioning to engage learners is critical to furthering resident education intraoperatively. Previous studies have demonstrated that higher level questioning and optimal wait times (>3 s) result in learner responses reflective of higher cognition and retention. Given the importance of intraoperative learning, we investigated question delivery in the operating room.
Methods
A total of 12 laparoscopic cholecystectomies were observed and recorded. All questions were transcribed and classified using Bloom's Taxonomy, a framework associated with hierarchical levels of learning outcomes. Wait time between question end and response was recorded.
Results
Six faculty attendings and seven house officers at our institution were observed. A total of 133 questions were recorded with an average number of questions per case of 11.2. The majority of questions 112 out of 133 (84%) were classified as Bloom's levels 1–3, with only 6% of questions of the highest level. The wait time before the resident answered the question averaged 1.75 s, with attendings interceding after 2.50 s. Question complexity and wait time did not vary based on resident postgraduate year level suggesting limited tailoring of question to learner.
Conclusions
Intraoperative questioning is not aligned with higher level thinking. The majority of questions were Bloom's level 3 or below, limiting the complexity of answer formulation. Most responses were given within 2 s, hindering opportunity to pursue higher-order thinking. This suggests including higher level questions and tailoring questions to learner level may improve retention and maximize gains. In addition, with attendings answering 20% of their own questions, increasing their wait time offers another area for teaching development.
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Age 80 years and over is not associated with increased morbidity and mortality following pancreaticoduodenectomy
Background
Pancreaticoduodenectomy (PD) is associated with high morbidity, which is perceived to be increased in the elderly. To our knowledge there have been no Australian series that have compared outcomes of patients over the age of 80 undergoing PD to those who are younger.
Methods
Patients who underwent PD between January 2008 and November 2015 were identified from a prospectively maintained database.
Results
A total of 165 patients underwent PD of whom 17 (10.3%) were aged 80 or over. The pre-operative health status, according to American Society of Anesthesiologists class was similar between the groups (P = 0.420). The 90-day mortality rates (5.9% in the elderly and 2% in the younger group; P = 0.355) and the post-operative complication rates (64.7% in the elderly versus 62.8% in the younger group; P = 0.88) were similar. Overall median length of hospital stay was also similar between the groups, but older patients were far more likely to be discharged to a rehabilitation facility than younger patients (47.1 versus 12.8%; P < 0.0001). Older patients with pancreatic adenocarcinoma (n = 10) had significantly lower median survival than the younger group (n = 69) (16.6 versus 22.5 months; P = 0.048).
Conclusion
No significant differences were seen in the rate of complications following PD in patients aged 80 or over compared to younger patients, although there appears to be a shorter survival in the elderly patients treated for pancreatic cancer. Careful selection of elderly patients and optimal peri-operative care, rather than age should be used to determine whether surgical intervention is indicated in this patient group.
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Economic burden of diverticular disease: an observational analysis based on real world data from an italian region
Diverticular disease (DD), a herniation of the colonic mucosa through the muscle layer, covers a wide variety of conditions associated with the presence of diverticula in the colon. The most serious form is an acute episode of diverticulitis, which can lead to hospitalization and surgery with various types of consequences. The main aim of this study is to evaluate the economic burden of hospitalizations arising from acute episodes of diverticulitis using data from the administrative databases used in the Marche region in Italy and, as a secondary objective of this real-world data analysis, to study patient outcome variables following initial hospitalization for diverticulitis.
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Derivation and validation of the prediabetes self-assessment screening score after acute pancreatitis (PERSEUS)
Approximately 40% of patients develop abnormal glucose metabolism after a single episode of acute pancreatitis. This study aimed to develop and validate a prediabetes self-assessment screening score for patients after acute pancreatitis.
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New Developments in Hepatorenal Syndrome
Hepatorenal Syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain due to the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal function. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to more accurately estimate true GFR.
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An update on genomic-guided therapies for pediatric solid tumors
Future Oncology Ahead of Print.
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Cancer care in lesbian, gay, bisexual, transgender and queer populations
Future Oncology Ahead of Print.
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Potential prognostic value of clinical characteristics, hormone status and major depressive disorder in breast cancer
Future Oncology Ahead of Print.
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Opportunities to significantly reduce expenditure associated with cancer drugs
Future Oncology Ahead of Print.
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Prognostic value of Ki-67 expression in patients with extensive-stage small cell lung cancer
Future Oncology Ahead of Print.
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Report from European Association for the Study of the Liver: HCC Summit, Geneva, Switzerland, 2–5 February 2017
Future Oncology Ahead of Print.
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The emerging role of professional social media use in oncology
Future Oncology Ahead of Print.
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Imatinib mesylate in desmoplastic small round cell tumors
Future Oncology Ahead of Print.
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Leukemic transformation in patients with myeloproliferative neoplasms: a population-based retrospective study
Future Oncology Ahead of Print.
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Targeting ALK-rearranged non-small-cell lung cancer: an update
Future Oncology Ahead of Print.
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Variation in genital human papillomavirus infection prevalence and vaccination coverage among men and women in the USA
Future Oncology Ahead of Print.
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A review of binimetinib for the treatment of mutant cutaneous melanoma
Future Oncology Ahead of Print.
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Single-fiber electromyography in the orbicularis oculi muscle in patients with ocular myasthenia gravis symptoms: does abnormal jitter predict response to treatment?
Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of...
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Cost-effectiveness Analysis of Vascular Access Referral Policies in CKD
The optimal timing of vascular access referral for patients with chronic kidney disease who may need hemodialysis (HD) is a pressing question in nephrology. Current referral policies have not been rigorously compared with respect to costs and benefits and do not consider patient-specific factors such as age.
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Reply
We appreciate the inquiry by Marinschek et al1 regarding the omission of their work from our systematic review and meta-analysis. Their letter raises a number of points for consideration. First, the study in question evaluated a new treatment approach—Netcoaching described as involving a home-based model of care delivered over the Internet based on the Graz model of tube weaning. Although there is a clear need to investigate new and innovative approaches for delivering feeding intervention, given the prevalence of feeding disorders in pediatric populations, the purpose of our review was to summarize and evaluate multidisciplinary intervention occurring as part of a day treatment or inpatient hospital admission.
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Rethinking the Use of Body Mass Index z-Score in Children and Adolescents with Severe Obesity: Time to Kick It to the Curb?
As the prevalence of pediatric severe obesity continues to increase,1 it has become apparent that some of the "tried and true" body mass index (BMI) metrics many researchers and clinicians have become accustomed to using, such as BMI z-score, are proving less reliable in certain circumstances and in many cases can be misleading.2 Two reports from Freedman et al, the most recent published in the current volume of The Journal,3 raise important concerns about the use of BMI z-score in studies that include children with severe obesity.
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Dual Checkpoint Blockade Takes Aim at Relapsed Mesothelioma [News in Brief]
The addition of ipilimumab to nivolumab nudged up response rates and survival outcomes for patients—but with increased toxicity.
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Dacomitinib Beats Gefitinib for EGFR+ NSCLC [News in Brief]
The second-generation EGFR inhibitor extended progression-free survival, but proved more toxic.
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Initial anticoagulation in patients with pulmonary embolism: thrombolysis, unfractionated heparin, LMWH, fondaparinux, or DOACs?
Abstract
The initial treatment of hemodynamically stable patients with pulmonary embolism (PE) has dramatically changed since the introduction of low molecular weight heparins (LMWHs). With the recent discovery of the direct oral anticoagulant drugs (DOACs), initial treatment of PE will be simplified even further. In several large clinical trials it has been demonstrated that DOACs are non-inferior to standard therapy for the initial treatment of PE, and because of their practicability they are becoming the agents of first choice. However, many relative contraindications to DOACs were exclusion criteria in the clinical trials. Therefore, LMWHs will continue to play an important role in initial PE treatment and in some cases there still is a role for unfractionated heparin (UFH). In this review we will give an overview of the biophysical, pharmacokinetic and pharmacodynamic properties of anticoagulants currently available for the initial management of PE. In addition, we will provide a comprehensive overview of the indications for the use of UFH, LMWHs and DOACs in the initial management of PE from a pharmacokinetic/-dynamic point of view
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Whole Genome Resequencing Identifies the Molecular Genetic Cause for the Absence of a Gy5 Glycinin Protein in Soybean PI 603408
During ongoing proteomic analysis of the soybean (Glycine max (L.) Merr) germplasm collection, PI 603408 was identified as a landrace whose seeds lack accumulation of one of the major seed storage glycinin protein subunits. Whole genomic resequencing was used to identify a two-base deletion affecting glycinin 5. The newly discovered deletion was confirmed causative through immunological, genetic and proteomic analysis, and no significant differences in total seed protein content were found to be due to the glycinin 5 loss-of-function mutation per se. In addition to focused studies on this one specific glycinin subunit-encoding gene, a total of 1,858,185 nucleotide variants were identified, of which 39,344 were predicted to affect protein coding regions. In order to semi-automate analysis of a large number of soybean gene variants, a new SIFT 4G database was designed to predict the impact of non-synonymous single nucleotide soybean gene variants, potentially enabling more rapid analysis of soybean resequencing data in the future.
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Comparative Mapping of Seed Dormancy Loci Between Tropical and Temperate Ecotypes of Weedy Rice (Oryza sativa L.)
Genotypic variation at multiple loci for seed dormancy (SD) contributes to plant adaptation to diverse ecosystems. Weedy rice (Oryza sativa) was used as a model to address the similarity of SD genes between distinct ecotypes. A total of 12 quantitative trait loci for SD were identified in a primary and two advanced backcross populations derived from a temperate ecotype of weedy rice (34.3°N Lat.). Nine (75%) of the 12 loci were mapped to the same positions as those identified from a tropical ecotype of weedy rice (7.1°N Lat.). The high similarity suggested that a majority of SD genes were conserved during the ecotype differentiation. These common loci are largely those collocated/linked with the awn, hull color, pericarp color or plant height loci. Phenotypic correlations observed in the populations support that indirect selections for the wild-type morphological characters, together with direct selections for germination time, were major factors influencing allelic distributions of SD genes across ecotypes. Indirect selections for crop-mimic traits (e.g. plant height and flowering time) could also alter allelic frequencies for some SD genes in agroecosystems. In addition, three of the 12 loci were collocated with segregation distortion loci, indicating that some gametophyte development genes could also influence genetic equilibria of SD loci in hybrid populations. The SD genes with a major effect on germination across ecotypes could be used as silencing targets to develop transgene mitigation strategies to reduce the risk of gene flow from genetically modified crops into weed/wild relatives.
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Duplication and Loss of Function of Genes Encoding RNA Polymerase III Subunit C4 Causes Hybrid Incompatibility in Rice
Reproductive barriers are commonly observed in both animals and plants, in which they maintain species integrity and contribute to speciation. This report shows that a combination of loss-of-function alleles at two duplicated loci, DUPLICATED GAMETOPHYTIC STERILITY 1 (DGS1) on chromosome 4 and DGS2 on chromosome 7, causes pollen sterility in hybrid progeny derived from an interspecific cross between cultivated rice, Oryza sativa, and an Asian annual wild rice, Oryza nivara. Male gametes carrying the DGS1 allele from O. nivara (DGS1-nivaras) and the DGS2 allele from O. sativa (DGS2-T65s) were sterile, but female gametes carrying the same genotype were fertile. We isolated the causal gene, which encodes a protein homologous to DNA-dependent RNA polymerase III subunit C4 (RPC4). RPC4 facilitates the transcription of 5S rRNAs and tRNAs. The loss-of-function alleles at DGS1-nivaras and DGS2-T65s were caused by weak or non-expression of RPC4 and absence of RPC4, respectively. Phylogenetic analysis demonstrated that gene duplication of RPC4 at DGS1 and DGS2 was a recent event that occurred after divergence of the ancestral population of Oryza from other Poaceae or during diversification of AA-genome species.
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Genetic Dissection of Morphometric Traits Reveals that Phytochrome B Affects Nucleus Size and Heterochromatin Organization in Arabidopsis thaliana
Microscopically visible chromatin is partitioned into two major components in Arabidopsis thaliana nuclei. Chromocenters on one hand are conspicuous foci of highly condensed 'heterochromatic' domains that contain mostly repeated sequences. On the other hand, less condensed and gene-rich 'euchromatin' emanates from these chromocenters. This differentiation, together with the dynamic nature of chromatin compaction in response to developmental and environmental stimuli, makes Arabidopsis a powerful system for studying chromatin organization and dynamics. Heterochromatin dynamics can be monitored by measuring the Heterochromatin Index, i.e. the proportion of nuclei displaying well-defined chromocenters, or the DNA fraction of chromocenters (Relative Heterochromatin Fraction). Both measures are composite traits, thus their values represent the sum of effects of various underlying morphometric properties. We exploited genetic variation between natural occurring accessions to determine the genetic basis of individual nucleus and chromocenter morphometric parameters; Area, Perimeter, Density, Roundness and Heterogeneity, that together determine chromatin compaction. Our novel reductionistic genetic approach revealed Quantitative Trait Loci (QTLs) for all measured traits. Genomic co-localization among QTLs was limited, which suggests a complex genetic regulation of chromatin compaction. Yet, genomic intervals of QTLs for nucleus size (Area and Perimeter) both overlap with a known QTL for heterochromatin compaction that is explained by natural polymorphism in the red/far-red light and temperature receptor Phytochrome B. Mutant analyses and genetic complementation assays show that Phytochrome B is a negative regulator of nucleus size, unveiling that perception of climatic conditions by a phytochrome-mediated hub is a major determinant for coordinating nucleus size and heterochromatin compaction.
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Apigenin Attenuates Adriamycin-Induced Cardiomyocyte Apoptosis via the PI3K/AKT/mTOR Pathway
Treatment with Adriamycin (ADR) is one of the major causes of chemotherapy-induced cardiotoxicity and therefore is the principal limiting factor in the effectiveness of chemotherapy for cancer patients. Apigenin (API) has been shown to play a cardioprotective role. The present study examined the effect of API on ADR-induced cardiotoxicity in mice. Sixty male Kunming mice were randomly divided into 4 groups: a control group, ADR model group, low-dose API treatment group (125 mg·kg−1), and high-dose API treatment group (250 mg·kg−1). Blood samples were taken to evaluate a spectrum of myocardial enzymes. Cardiomyocyte apoptosis was measured using a TUNEL assay, and cardiomyocyte autophagy was observed using electron microscopy. Moreover, apoptosis-related proteins, such as Bax and Bcl-2, autophagy-related proteins, including Beclin1 and LC3B, and PI3K/AKT/mTOR pathway-related proteins were examined with western blot. Our results demonstrate that ADR caused an increase in the serum levels of cardiac injury markers and enhanced cardiomyocyte apoptosis and autophagy. API administration prevented the effects associated with ADR-induced cardiotoxicity in mice and inhibited ADR-induced apoptosis and autophagy. API also promoted PI3K/AKT/mTOR pathway activity in ADR-treated mice. In conclusion, API may have a protective effect against ADR-induced cardiotoxicity by inhibiting apoptosis and autophagy via activation of the PI3K/AKT/mTOR pathway.
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Immunological effect of local ablation combined with immunotherapy on solid malignancies
Recent comprehensive investigations clarified that immune microenvironment surrounding tumor cells are deeply involved in tumor progression, metastasis, and response to treatment. Furthermore, several immunoth...
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The effects of 10 days of separate heat and hypoxic exposure on heat acclimation and temperate exercise performance
Adaptations to heat and hypoxia are typically studied in isolation, but are often encountered in combination. Whether the adaptive response to multiple stressors affords the same response as when examined in isolation is unclear. We examined: i) the influence of overnight moderate normobaric hypoxia on the time course and magnitude of adaption to daily heat exposure; ii) whether heat acclimation (HA) was ergogenic and if this was influenced by an additional hypoxic-stimulus. Eight males (VO2max=58.5[8.3] mL·kg-1·min-1) undertook two 11-day HA programmes (balanced-crossover design), once with overnight normobaric hypoxia (8[1] h per night; 10 nights; FIO2=0.156; SpO2=91[2]% [HAHyp]) and once without (HACon). Days 1, 6, 11 were exercise-heat stress tests (HST [40°C, 50% RH]); days 2-5 and 7-10 were isothermal-strain (target rectal temperature [Tre] ~38.5°C), exercise-heat sessions. A graded exercise test and 30-minute cycle trial were undertaken pre, post and 14-days after HA in temperate-normoxia (22°C, 55% RH; FIO2=0.209). HA was evident on day 6 (e.g. reduced Tre, mean skin temperature [Tsk], heart rate, sweat [Na+], P<0.05) with additional adaptations on day 11 (further reduced Tsk, heart rate). HA increased plasma volume (+5.9[7.3]%) and erythropoietin concentration (+1.8[2.4] mIU/mL); tHbmass was unchanged. Peak power output (+12[20] W), lactate threshold (+15[18] W) and work done (+12[20] kJ) increased following HA. The additional hypoxic-stressor did not affect these adaptations. In conclusion, a separate moderate overnight normobaric hypoxic-stimulus does not affect the time-course or magnitude of HA. Performance may be improved in temperate-normoxia following HA, but this is unaffected by an additional hypoxic stressor.
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Localized and systemic variations in central motor drive at different local skin and muscle temperatures
This study investigated the ability to sustain quadriceps central motor drive while subjected to localized heat and metaboreceptive feedback from the contralateral leg. Eight active males each completed two counter-balanced trials, in which muscle temperature (Tm) of a single-leg (TEMP-LEG) was altered to 29.4 (COOL) or 37.6°C (WARM), while the contralateral leg (CL-LEG) remained thermoneutral; 35.3 and 35.2°C Tm in COOL and WARM respectively. To activate metaboreceptive feedback, participants first performed one 120-s isometric maximal voluntary contraction (MVC) of the knee extensors in the TEMP-LEG, immediately followed by post-exercise muscle ischemia (PEMI) via femoral blood flow occlusion. To assess central motor drive of a remote muscle group immediately following PEMI, another 120-s MVC was subsequently performed in the CL-LEG. Voluntary muscle activation (VA) was assessed using the twitch interpolation method. Perceived mental effort and limb discomfort were also recorded. In a cooled muscle, a significant increase in mean force output and mean VA (force, p<0.001; VA, p<0.05) as well as a significant decrease in limb discomfort (p<0.05) occurred during the sustained MVC in the TEMP-LEG. However, no differences between Tm were observed in mean force output, mean VA or limb discomfort during the sustained MVC in the CL-LEG (Force, p=0.33; VA, p>0.68, limb discomfort, p=0.73). The present findings suggest that elevated local Tsk and Tm can increase limb discomfort and decrease central motor drive, but this does not limit systemic motor activation of a thermoneutral muscle group.
http://ift.tt/2sFiQjB
Targeting Unconscionable Prescription-Drug Prices — Maryland’s Anti–Price-Gouging Law
Why, in the early 21st century, are so many drugs that were cheaply available in the 20th century becoming prohibitively expensive? The past few years have seen a series of dramatic price hikes on essential off-patent medications, from albendazole to albuterol, digoxin to naloxone, Daraprim to…
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Cyberattack on Britain’s National Health Service — A Wake-up Call for Modern Medicine
As you would expect in a pandemic, the headlines were alarmist: we were reportedly locked in a race against time to protect millions of patients from a new virus of unprecedented virulence that had crippled the United Kingdom's National Health Service (NHS) and was spreading rapidly across the…
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Effective Legislative Advocacy — Lessons from Successful Medical Trainee Campaigns
"What is the best way for me to get involved politically?" Since last November's election, I have fielded this question frequently from fellow residents as well as medical students. Many of them have never been politically active, having assumed that the arc of progress would continue…
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Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli
Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective, randomized, open-label comparison of the thera...
http://ift.tt/2r7T6uc
Radiologic findings as a determinant and no effect of macrolide resistance on clinical course of Mycoplasma pneumoniae pneumonia
With the emergence of macrolide resistance, concerns about the efficacy of macrolides for the treatment of Mycoplasma pneumoniae (MP) pneumonia in children have been raised. This study aimed to determine the effe...
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High burden of complicated skin and soft tissue infections in the Indigenous population of Central Australia due to dominant Panton Valentine leucocidin clones ST93-MRSA and CC121-MSSA
Superficial skin and soft tissue infections (SSTIs) are common among the Indigenous population of the desert regions of Central Australia. However, the overall burden of disease and molecular epidemiology of Stap...
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Evaluation of targeted antimicrobial prophylaxis for transrectal ultrasound guided prostate biopsy: a prospective cohort trial
We evaluated the effectiveness of targeted antimicrobial prophylaxis in transrectal ultrasound guided prostate biopsy (TRUSP).
http://ift.tt/2rD9XZn
The influence of climatic factors on the development of hemorrhagic fever with renal syndrome and leptospirosis during the peak season in Korea: an ecologic study
Hemorrhagic fever with renal syndrome (HFRS) and leptospirosis are seasonal rodent-borne infections in the Republic of Korea (Korea). The occurrences of HFRS and leptospirosis are influenced by climatic variab...
http://ift.tt/2r7cFTs
The differential expression of omega-3 and omega-6 fatty acid metabolising enzymes in colorectal cancer and its prognostic significance
The differential expression of omega-3 and omega-6 fatty acid metabolising enzymes in colorectal cancer and its prognostic significance
British Journal of Cancer 116, 1612 (6 June 2017). doi:10.1038/bjc.2017.135
Authors: Abdo Alnabulsi, Rebecca Swan, Beatriz Cash, Ayham Alnabulsi & Graeme I Murray
http://ift.tt/2sbfh4h
Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma
Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma
British Journal of Cancer 116, 1572 (6 June 2017). doi:10.1038/bjc.2017.126
Authors: Zhen Dong, Qian Lei, Rui Yang, Shunqin Zhu, Xiao-Xue Ke, Liqun Yang, Hongjuan Cui & Liang Yi
http://ift.tt/2r7ZwuG
Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies
Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies
British Journal of Cancer 116, 1505 (6 June 2017). doi:10.1038/bjc.2017.92
Authors: Rastislav Bahleda, Juneko E Grilley-Olson, Ramaswamy Govindan, Fabrice Barlesi, Laurent Greillier, Maurice Perol, Isabelle Ray-Coquard, Dirk Strumberg, Beate Schultheis, Grace K Dy, Gérard Zalcman, Glen J Weiss, Annette O Walter, Martin Kornacker, Prabhu Rajagopalan, David Henderson, Hendrik Nogai, Matthias Ocker & Jean-Charles Soria
http://ift.tt/2qwhy9u
Herpes zoster risk after 21 specific cancers: population-based case–control study
Herpes zoster risk after 21 specific cancers: population-based case–control study
British Journal of Cancer 116, 1643 (6 June 2017). doi:10.1038/bjc.2017.124
Authors: Erik Hansson, Harriet J Forbes, Sinéad M Langan, Liam Smeeth & Krishnan Bhaskaran
http://ift.tt/2p3r6Hb
A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) vs mrEMVI-negative cases
A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) vs mrEMVI-negative cases
British Journal of Cancer 116, 1513 (6 June 2017). doi:10.1038/bjc.2017.99
Authors: Muhammed R S Siddiqui, Constantinos Simillis, Chris Hunter, Manish Chand, Jemma Bhoday, Aurelie Garant, Te Vuong, Giovanni Artho, Shahnawaz Rasheed, Paris Tekkis, Al-Mutaz Abulafi & Gina Brown
http://ift.tt/2prWzql
Clinical value of R-spondins in triple-negative and metaplastic breast cancers
Clinical value of R-spondins in triple-negative and metaplastic breast cancers
British Journal of Cancer 116, 1595 (6 June 2017). doi:10.1038/bjc.2017.131
Authors: F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni & I Bièche
http://ift.tt/2p33eID
Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study
Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study
British Journal of Cancer 116, 1520 (6 June 2017). doi:10.1038/bjc.2017.103
Authors: Luca Triggiani, Filippo Alongi, Michela Buglione, Beatrice Detti, Riccardo Santoni, Alessio Bruni, Ernesto Maranzano, Frank Lohr, Rolando D'Angelillo, Alessandro Magli, Alberto Bonetta, Rosario Mazzola, Nadia Pasinetti, Giulio Francolini, Gianluca Ingrosso, Fabio Trippa, Sergio Fersino, Paolo Borghetti, Paolo Ghirardelli & Stefano Maria Magrini
http://ift.tt/2prOxxp
Pre-diagnosis diet and survival after a diagnosis of ovarian cancer
Pre-diagnosis diet and survival after a diagnosis of ovarian cancer
British Journal of Cancer 116, 1627 (6 June 2017). doi:10.1038/bjc.2017.120
Authors: Mary C Playdon, Christina M Nagle, Torukiri I Ibiebele, Leah M Ferrucci, Melinda M Protani, Jonathan Carter, Simon E Hyde, Deborah Neesham, James L Nicklin, Susan T Mayne & Penelope M Webb
http://ift.tt/2qw7D3Q
Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab
Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab
British Journal of Cancer 116, 1526 (6 June 2017). doi:10.1038/bjc.2017.122
Authors: A Custodio, A Carmona-Bayonas, P Jiménez-Fonseca, M L Sánchez, A Viudez, R Hernández, J M Cano, I Echavarria, C Pericay, M Mangas, L Visa, E Buxo, T García, A Rodríguez Palomo, F Álvarez Manceñido, A Lacalle, I Macias, A Azkarate, A Ramchandani, A Fernández Montes, C López, F Longo, R Sánchez Bayona, M L Limón, A Díaz-Serrano, A Hurtado, R Madero, C Gómez & J Gallego
http://ift.tt/2qvSEXD
One-carbon metabolism in cancer
One-carbon metabolism in cancer
British Journal of Cancer 116, 1499 (6 June 2017). doi:10.1038/bjc.2017.118
Authors: Alice C Newman & Oliver D K Maddocks
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Comorbid conditions delay diagnosis of colorectal cancer: a cohort study using electronic primary care records
Comorbid conditions delay diagnosis of colorectal cancer: a cohort study using electronic primary care records
British Journal of Cancer 116, 1536 (6 June 2017). doi:10.1038/bjc.2017.127
Authors: Luke T A Mounce, Sarah Price, Jose M Valderas & William Hamilton
http://ift.tt/2r7C5l4
BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses
BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses
British Journal of Cancer 116, 1585 (6 June 2017). doi:10.1038/bjc.2017.130
Authors: E S Papadakis, T Reeves, N H Robson, T Maishman, G Packham & R I Cutress
http://ift.tt/2qpLuqj
Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data
Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data
British Journal of Cancer 116, 1544 (6 June 2017). doi:10.1038/bjc.2017.128
Authors: Chikuma Hamada, Takuji Okusaka, Takaaki Ikari, Hiroyuki Isayama, Junji Furuse, Hiroshi Ishii, Yousuke Nakai, Shogo Imai & Shota Okamura
http://ift.tt/2p2UG4w
Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer
Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer
British Journal of Cancer 116, 1604 (6 June 2017). doi:10.1038/bjc.2017.132
Authors: Steffen Wagner, Claus Wittekindt, Shachi Jenny Sharma, Nora Wuerdemann, Theresa Jüttner, Miriam Reuschenbach, Elena-Sophie Prigge, Magnus von Knebel Doeberitz, Stefan Gattenlöhner, Ernst Burkhardt, Jörn Pons-Kühnemann & Jens Peter Klussmann
http://ift.tt/2pFvP5g
GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project
GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project
British Journal of Cancer 116, 1551 (6 June 2017). doi:10.1038/bjc.2017.129
Authors: Sally C Benton, Piers Butler, Katy Allen, Michelle Chesters, Sally Rickard, Sally Stanley, Richard Roope, Daniel Vulkan & Stephen W Duffy
http://ift.tt/2rkf810
Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma
Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma
British Journal of Cancer 116, 1621 (6 June 2017). doi:10.1038/bjc.2017.147
Authors: Leanne de Kock, Barbara Rivera, Timothée Revil, Paul Thorner, Catherine Goudie, Dorothée Bouron-Dal Soglio, Catherine S Choong, John R Priest, Paul J van Diest, Jantima Tanboon, Anja Wagner, Jiannis Ragoussis, Peter FM Choong & William D Foulkes
http://ift.tt/2pZkL0u
Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases
Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases
British Journal of Cancer 116, 1558 (6 June 2017). doi:10.1038/bjc.2017.142
Authors: Sagun Parakh, John J Park, Shehara Mendis, Rajat Rai, Wen Xu, Serigne Lo, Martin Drummond, Catherine Rowe, Annie Wong, Grant McArthur, Andrew Haydon, Miles C Andrews, Jonathan Cebon, Alex Guminski, Richard F Kefford, Georgina V Long, Alexander M Menzies, Oliver Klein & Matteo S Carlino
http://ift.tt/2rknRQw
The contribution of body mass index to appraisal delay in colorectal cancer diagnosis: a structural equation modelling study
The contribution of body mass index to appraisal delay in colorectal cancer diagnosis: a structural equation modelling study
British Journal of Cancer 116, 1638 (6 June 2017). doi:10.1038/bjc.2017.123
Authors: Karen E Dyer, Levent Dumenci, Laura A Siminoff, Maria D Thomson & Jennifer Elston Lafata
http://ift.tt/2qvSFe9
Mutation status among patients with sinonasal mucosal melanoma and its impact on survival
Mutation status among patients with sinonasal mucosal melanoma and its impact on survival
British Journal of Cancer 116, 1564 (6 June 2017). doi:10.1038/bjc.2017.125
Authors: Moran Amit, Samantha Tam, Ahmed S Abdelmeguid, Dianna B Roberts, Yoko Takahashi, Shaan M Raza, Shirley Y Su, Michael E Kupferman, Franco DeMonte & Ehab Y Hanna
http://ift.tt/2r7HjgD
Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study
Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study
British Journal of Cancer 116, 1652 (6 June 2017). doi:10.1038/bjc.2017.139
Authors: Ronan T Gray, Maurice B Loughrey, Peter Bankhead, Chris R Cardwell, Stephen McQuaid, Roisin F O'Neill, Kenneth Arthur, Victoria Bingham, Claire McGready, Anna T Gavin, Jacqueline A James, Peter W Hamilton, Manuel Salto-Tellez, Liam J Murray & Helen G Coleman
http://ift.tt/2pZcmuc
3 scenarios to train for diagnosis, treatment of sepsis
Use simulation education to teach EMS providers to recognize and treat sepsis
http://ift.tt/2s5jLwO
Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions
Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.
Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.
Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from –100% to 567% (median, –18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained <20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with <20% tumor burden increase from baseline had longer OS than patients with ≥20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with <20% tumor burden increase during therapy had significantly reduced hazards of death [HR = 0.19; 95% confidence interval (CI), 0.08–0.43; P < 0.0001 univariate; HR = 0.18; 95% CI, 0.08–0.41; P < 0.0001, multivariable]. Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.
Conclusions: Tumor burden increase of <20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention. Clin Cancer Res; 1–9. ©2017 AACR.
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Less Chemotherapy May Be Best Choice for Some Patients with Colon Cancer, Study Shows
A shorter course of chemotherapy following surgery may be preferred to longer treatment for some patients with colon cancer, results of an international collaborative study suggest.
http://ift.tt/2r3mbMe
Nanospheres: Selective Coloration of Melanin Nanospheres through Resonant Mie Scattering (Adv. Mater. 22/2017)
Melanin, a major component in brunette hairs, is commonly black. However, hairs appear brown when they are exposed to direct sunlight. Inspired from the selective coloration of hair, Shin-Hyun Kim and co-workers study the coloration of artificial melanin-like nanospheres in article number 1700256. Special inks are formulated based on the size-dependent coloration property of the nanospheres.
http://ift.tt/2qXyXb1
Conductive Polymers: A Tunable 3D Nanostructured Conductive Gel Framework Electrode for High-Performance Lithium Ion Batteries (Adv. Mater. 22/2017)
In article number 1603922, Amy C. Marschilok, Esther S. Takeuchi, Guihua Yu, and co-workers develop a 3D nanostructured conductive-polymer gel as a novel binder system for lithium-ion batteries. The gel binder greatly enhances the rate capability and cyclic stability of battery electrodes because the molecular framework facilitates both electron and ion transport and the polymer coating formed in situ improves the dispersity of active particles within the entire electrode.
http://ift.tt/2sgpv6A
Organic Photovoltaics: Direct Free Carrier Photogeneration in Single Layer and Stacked Organic Photovoltaic Devices (Adv. Mater. 22/2017)
In article number 1606909, Ming-Fai Lo, Chun-Sing Lee, and co-workers report unusual free-carrier generation in some bipolar organic materials (SubNc and SubPc) upon photoexcitation. Single-layer devices with SubNc or SubPc sandwiched between two electrodes can give power conversion efficiencies 30 times higher than previously reported single-layer devices. Interestingly, these photoactive layers can be stacked onto each other with any sequence to generate a photocurrent in OPV devices.
http://ift.tt/2qXs3Tb
Surface Patterning: Sub-Micrometer Surface-Patterned Ribbon Fibers and Textiles (Adv. Mater. 22/2017)
In article number 1605868, Yoel Fink and co-workers (Fink Lab RLE MIT) develop a novel technique that enables high-spatial-resolution surface patterning of polymer fibers. The thermally drawn fibers, with micrometer/sub-micrometer features patterned on their surface, are woven into a textile with multiple engineered properties, including structural coloration and directional wetting.
http://ift.tt/2qXShVo
Luminescence: Dynamic Phosphorescent Probe for Facile and Reversible Stress Sensing (Adv. Mater. 22/2017)
A dynamic phosphorescent probe incorporated into a polymer main chain can report mechanical stress with outstanding reversibility. In article number 1700563, Georgy Filonenko and Julia Khusnutdinova develop a new class of phosphorescent probe that responds to mechanical force with a rapid and reversible change in emission-lifetime characteristics while preserving its structure. This robust and fully reversible sensor has remarkable potential for assessing stress and dynamic phenomena in soft materials in a simple and accurate way.
http://ift.tt/2qXCyFV
Photodetectors: A Broadband Fluorographene Photodetector (Adv. Mater. 22/2017)
Graphene can be used for wide-broadband photodetectors since its photoresponse spectrum covers from the UV to the terahertz frequencies. A graphene hyperspectral image of West-Lake in Hangzhou, China is shown, indicating the wealth of sufficient information held in the broad spectral domain. The work described in article number 1700463 by Yang Xu, Weida Hu, and co-workers shows potential application in, for example, global climate research, mapping of wetlands, mineral identification, crop analysis, and bathymetry.
http://ift.tt/2qXXRr5
Angiogenesis: Affinity-Immobilization of VEGF on Laminin Porous Sponge Enhances Angiogenesis in the Ischemic Brain (Adv. Healthcare Mater. 11/2017)
Itsuki Ajioka and co-workers report a laminin-sponge (purple) with affinity-immobilized VEGF (yellow), which is an angiogenic growth factor. Neovascularization from existing blood vessels (red) in ischemic brain can potentially prevent the excess death of neurons (cyan) and improve functional recovery. The angiogenic activity of this sponge in vivo in a mouse stroke model is demonstrated in article number 1700183.
http://ift.tt/2rCsuFj
Tissue Engineering: Engineered 3D Cardiac Fibrotic Tissue to Study Fibrotic Remodeling (Adv. Healthcare Mater. 11/2017)
Ali Khademhosseini and co-workers describe an engineered 3D fibrotic heart tissue, which is created by fabricating physiologically relevant cardiac tissues with native-like mechanical properties in article number 1601434. Upon exogenous stimulation with profibrotic transforming growth factor beta-1, these tissues reveal fibrogenic changes, such as collagen production, myofibroblast activation, and electrophysiological disturbances.
http://ift.tt/2rC2VE8
Cancer Therapy: Injectable Supramolecular Hydrogels as Delivery Agents of Bcl-2 Conversion Gene for the Effective Shrinkage of Therapeutic Resistance Tumors (Adv. Healthcare Mater. 11/2017)
In article number 1700159, Zibiao Li, Xian Jun Loh, Yun-Long Wu, and co-workers design injectable MPEG-PCL-PEI/α-CD based supramolecular hydrogels that possess good sustained release ability of Bcl-2 conversion genes in form of polyplex, to effectively inhibit in vivo tumor growth. This long term "enemy to friend" strategy will benefit various applications, including on-demand gene delivery and personalized medicine.
http://ift.tt/2r78Nlv
Rescue and Characterization of Recombinant Virus from a New World Zika Virus Infectious Clone
http://ift.tt/2qX9dLS
Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice
Animals detect odorous chemicals through specialized olfactory sensory neurons (OSNs) that transduce odorants into neural electrical signals. We identified a novel and evolutionarily conserved protein, cilia- and flagella-associated protein 69 (CFAP69), in mice that regulates olfactory transduction kinetics. In the olfactory epithelium, CFAP69 is enriched in OSN cilia, where olfactory transduction occurs. Bioinformatic analysis suggests that a large portion of CFAP69 can form Armadillo-type α-helical repeats, which may mediate protein–protein interactions. OSNs lacking CFAP69, remarkably, displayed faster kinetics in both the on and off phases of electrophysiological responses at both the neuronal ensemble level as observed by electroolfactogram and the single-cell level as observed by single-cell suction pipette recordings. In single-cell analysis, OSNs lacking CFAP69 showed faster response integration and were able to fire APs more faithfully to repeated odor stimuli. Furthermore, both male and female mutant mice that specifically lack CFAP69 in OSNs exhibited attenuated performance in a buried food pellet test when a background of the same odor to the food pellet was present even though they should have better temporal resolution of coding olfactory stimulation at the peripheral. Therefore, the role of CFAP69 in the olfactory system seems to be to allow the olfactory transduction machinery to work at a precisely regulated range of response kinetics for robust olfactory behavior.
SIGNIFICANCE STATEMENT Sensory receptor cells are generally thought to evolve to respond to sensory cues as fast as they can. This idea is consistent with mutational analyses in various sensory systems, where mutations of sensory receptor cells often resulted in reduced response size and slowed response kinetics. Contrary to this idea, we have found that there is a kinetic "damper" present in the olfactory transduction cascade of the mouse that slows down the response kinetics and, by doing so, it reduces the peripheral temporal resolution in coding odor stimuli and allows for robust olfactory behavior. This study should trigger a rethinking of the significance of the intrinsic speed of sensory transduction and the pattern of the peripheral coding of sensory stimuli.
http://ift.tt/2sgww7j
Energy Requirements of Odor Transduction in the Chemosensory Cilia of Olfactory Sensory Neurons Rely on Oxidative Phosphorylation and Glycolytic Processing of Extracellular Glucose
The mechanisms that power the physiological events occurring in cilia, flagella, and microvilli are of fundamental importance for the functions of these important and ubicuous organelles. The olfactory epithelium is mostly populated by ciliated olfactory sensory neurons (OSNs) and surrounding sustentacular cells (SCs) with apical microvilli. The only OSN dendrite extends to the surface forming a knob projecting several chemosensory cilia of ~50 x 0.2 μm, devoid of inner membranes embedded in a mucus layer. Upon odorant binding, odor receptors couple to G-protein activating adenylyl cyclase, producing cAMP. cAMP opens cyclic nucleotide-gated channels allowing a Ca2+ influx that opens Ca2+-activated Cl– channels, generating the receptor potential. Many enzymes are activated in chemotransduction to hydrolyze ATP. The knob contains approximately two mitochondria; assuming that the cilia ATP is 1 mm and diffuses along it at ~10 μm in 500 ms, ATP from the knob mitochondria may not fulfill the demands of transduction over the full length of the cilium, which suggests an additional ATP source. We measured millimolar glucose in rat mucus; we detected glucose transporter GLUT3 in rat and toad (Caudiverbera caudiverbera) OSN cilia, SC microvilli, and glycolytic enzymes in rat cilia. We also found that the cilia and knob can incorporate and accumulate 2-deoxyglucose (glucose analog), but not when blocking GLUT. Glucose removal and the inhibition of glycolysis or oxidative phospholylation impaired the odor response. This evidence strongly suggests that glycolysis in the cilia and knob oxidative phosphorylation together fuel chemotransduction.
SIGNIFICANCE STATEMENT How processes occurring in cilia and flagella are powered is a matter of general interest. Substantial progress has been made in unraveling the sensory transduction mechanisms, commonly occurring in such structures; however, the energy sources powering them have been scarcely explored. Accessibility to the specialized sensory organelles and their small dimensions have been limiting factors. Olfactory sensory neurons chemosensory cilia are elongated, mucus embedded, fully exposed structures particularly amenable for a multidisciplinary study of this problem, as done here. We demonstrate the occurrence and functionality of glucose uptake and glycolysis in the cilia. We support that odor transduction relies on ATP generated by oxidative phosphorylation in the dendrite and glycolytically in the cilia using glucose internalized from the mucus.
http://ift.tt/2qWXYD1
G6pd Deficiency Does Not Affect the Cytosolic Glutathione or Thioredoxin Antioxidant Defense in Mouse Cochlea
Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway; it catalyzes the conversion of glucose-6-phosphate to 6-phosphogluconate and NADP+ to NADPH and is thought to be the principal source of NADPH for the cytosolic glutathione and thioredoxin antioxidant defense systems. We investigated the roles of G6PD in the cytosolic antioxidant defense in the cochlea of G6pd hypomorphic mice that were backcrossed onto normal-hearing CBA/CaJ mice. Young G6pd-deficient mice displayed a significant decrease in cytosolic G6PD protein levels and activities in the inner ears. However, G6pd deficiency did not affect the cytosolic NADPH redox state, or glutathione or thioredoxin antioxidant defense in the inner ears. No histological abnormalities or oxidative damage was observed in the cochlea of G6pd hemizygous males or homozygous females. Furthermore, G6pd deficiency did not affect auditory brainstem response hearing thresholds, wave I amplitudes or wave I latencies in young males or females. In contrast, G6pd deficiency resulted in increased activities and protein levels of cytosolic isocitrate dehydrogenase 1, an enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate and NADP+ to NADPH, in the inner ear. In a mouse inner ear cell line, knockdown of Idh1, but not G6pd, decreased cell growth rates, cytosolic NADPH levels, and thioredoxin reductase activities. Therefore, under normal physiological conditions, G6pd deficiency does not affect the cytosolic glutathione or thioredoxin antioxidant defense in mouse cochlea. Under G6pd deficiency conditions, isocitrate dehydrogenase 1 likely functions as the principal source of NADPH for cytosolic antioxidant defense in the cochlea.
SIGNIFICANCE STATEMENT Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway; it catalyzes the conversion of glucose-6-phosphate to 6-phosphogluconate and NADP+ to NADPH and is thought to be the principal source of NADPH for the cytosolic glutathione and thioredoxin antioxidant defense systems. In the current study, we show that, under normal physiological conditions, G6pd deficiency does not affect the cytosolic glutathione or thioredoxin antioxidant defense in the mouse cochlea. However, under G6pd deficiency conditions, isocitrate dehydrogenase 1 likely functions as the principal source of NADPH for cytosolic antioxidant defense in the cochlea.
http://ift.tt/2sgcppA
Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates Netrin-1 Repulsion
Modulation of microtubule (MT) dynamics is a key event of cytoskeleton remodeling in the growth cone (GC) during axon outgrowth and pathfinding. Our previous studies have shown that the direct interaction of netrin receptor DCC and DSCAM with polymerized TUBB3, a neuron-specific MT subunit in the brain, is required for netrin-1-mediated axon outgrowth, branching, and attraction. Here, we show that uncoupling of polymerized TUBB3 with netrin-1-repulsive receptor UNC5C is involved in netrin-1-mediated axonal repulsion. TUBB3 directly interacted with UNC5C and partially colocalized with UNC5C in the peripheral area of the GC of primary neurons from the cerebellar external granule layer of P2 mouse pups of both sexes. Netrin-1 reduced this interaction as well as the colocalization of UNC5C and TUBB3 in the GC. Results from the in vitro cosedimentation assay indicated that UNC5C interacted with polymerized TUBB3 in MTs and netrin-1 decreased this interaction. Knockdown of either TUBB3 or UNC5C blocked netrin-1-promoted axon repulsion in vitro and caused defects in axon projection of DRG toward the spinal cord in vivo. Furthermore, live-cell imaging of end-binding protein 3 tagged with EGFP (EB3-GFP) in primary external granule layer cells showed that netrin-1 differentially increased MT dynamics in the GC with more MT growth in the distal than the proximal region of the GC during repulsion, and knockdown of either UNC5C or TUBB3 abolished the netrin-1 effect. Together, these data indicate that the disengagement of UNC5C with polymerized TUBB3 plays an essential role in netrin-1/UNC5C-mediated axon repulsion.
SIGNIFICANCE STATEMENT Proper regulation of microtubule (MT) dynamics in the growth cone plays an important role in axon guidance. However, whether guidance cues modulate MT dynamics directly or indirectly is unclear. Here, we report that dissociation of UNC5C and polymerized TUBB3, the highly dynamic β-tubulin isoform in neurons, is essential for netrin-1/UNC5C-promoted axon repulsion. These results not only provide a working model of direct modulation of MTs by guidance cues in growth cone navigation but also help us to understand molecular mechanisms underlying developmental brain disorders associated with TUBB3 mutations.
http://ift.tt/2qWU6lx
A Method to Test the Efficacy of Handwashing for the Removal of Emerging Infectious Pathogens
http://ift.tt/2r6pKwo
Adverse childhood or adult experiences and risk of bilateral oophorectomy: a population-based case-control study
Objectives
Bilateral oophorectomy has commonly been performed in conjunction with hysterectomy even in women without a clear ovarian indication; however, oophorectomy may have long-term deleterious consequences. To better understand this surgical practice from the woman's perspective, we studied the possible association of adverse childhood or adult experiences with the subsequent occurrence of bilateral oophorectomy.
DesignPopulation-based case–control study.
SettingOlmsted County, Minnesota (USA).
ParticipantsFrom an established population-based cohort study, we sampled 128 women who underwent bilateral oophorectomy before age 46 years for a non-cancerous condition in 1988–2007 (cases) and 128 age-matched controls (±1 year).
MethodsInformation about adverse experiences was abstracted from the medical records dating back to age 15 years or earlier archived in the Rochester Epidemiology Project (REP) records-linkage system. Adverse childhood experiences were summarised using the Adverse Childhood Experience (ACE) score.
ResultsWe observed an association of bilateral oophorectomy performed before age 46 years with verbal or emotional abuse, physical abuse, any abuse, substance abuse in the household, and with an ACE score ≥1 experienced before age 19 years (OR=3.23; 95% CI 1.73 to 6.02; p<0.001). In women who underwent the oophorectomy before age 40 years, we also observed a strong association with physical abuse experienced during adulthood (OR=4.33; 95% CI 1.23 to 15.21; p=0.02). Several of the associations were higher in women who underwent oophorectomy at a younger age (<40 years) and in women without an ovarian indication for the surgery. None of the psychosocial or medical variables explored as potential confounders or intervening variables changed the results noticeably.
ConclusionsWomen who suffered adverse childhood experiences or adult abuse are at increased risk of undergoing bilateral oophorectomy before menopause. We suggest that the association may be explained by a series of biological, emotional, and psychodynamic mechanisms.
http://ift.tt/2r6kkBd
EMS students using virtual reality to learn about real-life scenarios
A 360-degree video camera allows faculty to recreate real life locations and situations
http://ift.tt/2qXgPxT
A Chronic Autoimmune Dry Eye Rat Model with Increase in Effector Memory T Cells in Eyeball Tissue
http://ift.tt/2sDPmT5
Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
http://ift.tt/2sEbRHB
The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS
There is an intensifying interest in the interaction between diet and the functional GI symptoms experienced in IBS. Recent studies have used MRI to demonstrate that short-chain fermentable carbohydrates increase small intestinal water volume and colonic gas production that, in those with visceral hypersensitivity, induces functional GI symptoms. Dietary restriction of short-chain fermentable carbohydrates (the low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet) is now increasingly used in the clinical setting. Initial research evaluating the efficacy of the low FODMAP diet was limited by retrospective study design and lack of comparator groups, but more recently well-designed clinical trials have been published. There are currently at least 10 randomised controlled trials or randomised comparative trials showing the low FODMAP diet leads to clinical response in 50%–80% of patients with IBS, in particular with improvements in bloating, flatulence, diarrhoea and global symptoms. However, in conjunction with the beneficial clinical impact, recent studies have also demonstrated that the low FODMAP diet leads to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown. This review aims to present recent advances in the understanding of the mechanisms by which the low FODMAP diet impacts on symptoms in IBS, recent evidence for its efficacy, current findings regarding the consequences of the diet on the microbiome and recommendations for areas for future research.
http://ift.tt/2r2NB4V
Rome Foundation-Asian working team report: Asian functional gastrointestinal disorder symptom clusters
Objective
Functional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID.
Design1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters.
ResultsNine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence).
ConclusionWe found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings.
http://ift.tt/2rLXcKd
FOXAI: a phase II trial evaluating the efficacy and safety of hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin for advanced hepatocellular carcinoma
We read with interest the article of recent advances in clinical practice of hepatocellular carcinoma (HCC) treatment by Bruix et al in Gut.1 In this review, the Barcelona Clinic Liver Cancer (BCLC) Group recommended sorafenib as the standard treatment for BCLC-C stage (advanced stage) HCC. However, application of sorafenib as first treatment for advanced HCC worldwide was low according to a multiregional, large-scale, longitudinal cohort study.2 This may be attributed to some limitations of sorafenib: low response rate, modest survival advantage, complex mechanism underlying acquired resistance and high-level heterogeneity of individual response.3 4 Recently, evidence from an individual patient data meta-analysis of phase III randomised controlled trial showed no improvement in overall survival attributable to sorafenib for HBV-related HCC.5 Therefore, more alternative strategies are highly required.6
Hepatic arterial infusion (HAI) chemotherapy (HAIC) attracted more attentions in recent years due...
http://ift.tt/2r2EEZg
CD14+CD15-HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure
Objective
Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR– myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.
DesignPatients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15–CD11b+HLA-DR– cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.
ResultsCirculating CD14+CD15–CD11b+HLA-DR– M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo.
ConclusionImmunosuppressive CD14+HLA-DR– M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
http://ift.tt/2rMgKy4
High body mass index and the risk of hepatocellular carcinoma
We read with great interest the recent article by Hagström et al,1 in which they used register data from more than 1.2 million Swedish men enlisted for conscription between 1969 and 1996 in order to investigate the relationship between body mass index (BMI) in late adolescence and future liver diseases. During a follow-up of more than 34 million person-years, 251 cases of hepatocellular carcinoma (HCC) were identified from the Swedish Cancer Register (SCR). In this study, the authors used a sample survey from the year 19982 for reference to indicate the high register completeness from the SCR, which has captured around 96% of all diagnosed tumours. However, another study, also from Sweden, which was just recently published on Hepatology, indicates that up to 37%–45% of HCCs in Sweden were never reported to the SCR, and this percentage has increased slightly over time.3 If calculated according to this...
http://ift.tt/2r2pJ1f
Machine learning techniques for diabetic macular edema (DME) classification on SD-OCT images
Spectral domain optical coherence tomography (OCT) (SD-OCT) is most widely imaging equipment used in ophthalmology to detect diabetic macular edema (DME). Indeed, it offers an accurate visualization of the mor...
http://ift.tt/2rVDQEz
Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study
Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mu...
http://ift.tt/2sTDImh
Development of Relative Disparity Sensitivity in Human Visual Cortex
Stereopsis is the primary cue underlying our ability to make fine depth judgments. In adults, depth discriminations are supported largely by relative rather than absolute binocular disparity, and depth is perceived primarily for horizontal rather than vertical disparities. Although human infants begin to exhibit disparity-specific responses between 3 and 5 months of age, it is not known how relative disparity mechanisms develop. Here we show that the specialization for relative disparity is highly immature in 4- to 6-month-old infants but is adult-like in 4- to 7-year-old children. Disparity-tuning functions for horizontal and vertical disparities were measured using the visual evoked potential. Infant relative disparity thresholds, unlike those of adults, were equal for vertical and horizontal disparities. Their horizontal disparity thresholds were a factor of ~10 higher than adults, but their vertical disparity thresholds differed by a factor of only ~4. Horizontal relative disparity thresholds for 4- to 7-year-old children were comparable with those of adults at ~0.5 arcmin. To test whether infant immaturity was due to spatial limitations or insensitivity to interocular correlation, highly suprathreshold horizontal and vertical disparities were presented in alternate regions of the display, and the interocular correlation of the interdigitated regions was varied from 0% to 100%. This manipulation regulated the availability of coarse-scale relative disparity cues. Adult and infant responses both increased with increasing interocular correlation by similar magnitudes, but adult responses increased much more for horizontal disparities, further evidence for qualitatively immature stereopsis based on relative disparity at 4–6 months of age.
SIGNIFICANCE STATEMENT Stereopsis, our ability to sense depth from horizontal image disparity, is among the finest spatial discriminations made by the primate visual system. Fine stereoscopic depth discriminations depend critically on comparisons of disparity relationships in the image that are supported by relative disparity cues rather than the estimation of single, absolute disparities. Very young human and macaque infants are sensitive to absolute disparity, but no previous study has specifically studied the development of relative disparity sensitivity, a hallmark feature of adult stereopsis. Here, using high-density EEG recordings, we show that 4- to 6-month-old infants display both quantitative and qualitative response immaturities for relative disparity information. Relative disparity responses are adult-like no later than 4–7 years of age.
http://ift.tt/2sg5dd3
Multiple Transient Signals in Human Visual Cortex Associated with an Elementary Decision
The cerebral cortex continuously undergoes changes in its state, which are manifested in transient modulations of the cortical power spectrum. Cortical state changes also occur at full wakefulness and during rapid cognitive acts, such as perceptual decisions. Previous studies found a global modulation of beta-band (12–30 Hz) activity in human and monkey visual cortex during an elementary visual decision: reporting the appearance or disappearance of salient visual targets surrounded by a distractor. The previous studies disentangled neither the motor action associated with behavioral report nor other secondary processes, such as arousal, from perceptual decision processing per se. Here, we used magnetoencephalography in humans to pinpoint the factors underlying the beta-band modulation. We found that disappearances of a salient target were associated with beta-band suppression, and target reappearances with beta-band enhancement. This was true for both overt behavioral reports (immediate button presses) and silent counting of the perceptual events. This finding indicates that the beta-band modulation was unrelated to the execution of the motor act associated with a behavioral report of the perceptual decision. Further, changes in pupil-linked arousal, fixational eye movements, or gamma-band responses were not necessary for the beta-band modulation. Together, our results suggest that the beta-band modulation was a top-down signal associated with the process of converting graded perceptual signals into a categorical format underlying flexible behavior. This signal may have been fed back from brain regions involved in decision processing to visual cortex, thus enforcing a "decision-consistent" cortical state.
SIGNIFICANCE STATEMENT Elementary visual decisions are associated with a rapid state change in visual cortex, indexed by a modulation of neural activity in the beta-frequency range. Such decisions are also followed by other events that might affect the state of visual cortex, including the motor command associated with the report of the decision, an increase in pupil-linked arousal, fixational eye movements, and fluctuations in bottom-up sensory processing. Here, we ruled out the necessity of these events for the beta-band modulation of visual cortex. We propose that the modulation reflects a decision-related state change, which is induced by the conversion of graded perceptual signals into a categorical format underlying behavior. The resulting decision signal may be fed back to visual cortex.
http://ift.tt/2sg92is
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
