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Τετάρτη 7 Ιουνίου 2017

Blinding in Surgical Randomized Clinical Trials in 2015

image Lack of blinding in randomized clinical trials can bias the effect estimates of the observed intervention. In trials assessing nonpharmacological interventions (eg, surgical randomized clinical trials) blinding is usually more difficult. In this mini-review the blinding and reporting of blinding was assessed from surgical randomized clinical trials that were published in leading medical and surgical journals in 2015. Conducting a systematic search on PubMed, a total of 99 studies were deemed as relevant and blinding status assessed. Blinding was explicitly stated for practitioners, patients, and outcome observers in 3%, 37%, and 52%, respectively. The blinding status was not clearly stated in a large proportion of studies or had sometimes a misleading classification. Hence, authors and journals publishing randomized controlled trials should pay attention that status of blinding is unambiguously reported.

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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

imageObjective: To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS). Background: WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method. Methods: From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients' pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol. Results: Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients' pain perception (P = 0.28). Conclusion: RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.

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Is Antibiotic Alternative to Appendectomy?

No abstract available

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Beyond “Measure Twice”: New Performance Standards in Surgery

No abstract available

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Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study

imageObjective: To assess clinical and surgical factors affecting local recurrence and survival in young breast cancer patients in the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Background: Emerging data suggest young age is a predictor of increased local recurrence. Methods: POSH is a prospective cohort of 3024 women of 18 to 40 years with breast cancer. Cohort characteristics were grouped by mastectomy or BCS. Endpoints were local-recurrence interval (LRI), distant disease-free interval (DDFI), and overall survival (OS); described using cumulative-hazard and Kaplan-Meier plots and multivariable analyses by Flexible Parametric and Cox regression models. Results: Mastectomy was performed in 1464 patients and breast-conserving surgery (BCS) in 1395. Patients undergoing mastectomy had larger tumors and higher proportions of positive family history, estrogen receptor+, progesterone receptor+, and/or human epidermal growth factor receptor 2+ tumors. Local events accounted for 15% of recurrences. LRI by surgical type varied over time with LRI similar at 18 months (1.0% vs 1.0%, P = 0.348) but higher for BCS at 5 and 10 years (5.3% vs 2.6%, P

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Dual-graft Adult Living Donor Liver Transplantation: An Innovative Surgical Procedure for Live Liver Donor Pool Expansion

imageObjective: To detail the surgical technique and outcomes of dual-graft (DG) adult living donor liver transplantation (ALDLT). Background: DG ALDLT has a great potential for expanding the living donor pool without increasing donor risk. However, little is known about DG ALDLT because it has been performed by a limited number of institutions due to its technical complexity. Methods: The clinical data of patients who underwent DG ALDLT at a single institute between March 2000 and December 2014 were retrospectively reviewed. Results: In total, 400 DG ALDLTs, which accounted for 11.7% of all ALDLTs (n = 3387), were performed at our institute. The 1, 5, and 10-year patient survival rates of DG ALDLT were 89.2%, 85.5%, and 80.2%, respectively. In a propensity-matched cohort, there were no significant differences in the survival outcomes between DG and single-graft ALDLT (P = 0.163). Donor age, body mass index, and steatosis were significantly higher in the DG group. Additionally, the male predominance in the sex ratio of donors was lower in the DG group. In the DG group, the mean operative time was longer (18.7 vs 13.9 h; P

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Reply: Factors Associated With Recurrence and Survival in N0 Gastric Cancer

No abstract available

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Pushing the Limits of Live Donor Liver Transplantation: Is the Western World Ready for Dual Grafts?

No abstract available

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Intraperitoneal Local Anesthetic for Laparoscopic Appendectomy in Children: A Randomized Controlled Trial

imageObjective: The aim of this study was to investigate the efficacy of intraperitoneal local anesthetic (IPLA) on pain after acute laparoscopic appendectomy in children. Summary of Background: IPLA reduces pain in adult elective surgery. It has not been well studied in acute peritoneal inflammatory conditions. We hypothesized that IPLA would improve recovery in pediatric acute laparoscopic appendectomy. Methods: This randomized controlled trial in acute laparoscopic appendectomy recruited children aged 8 to 14 years to receive 20 mL 0.25% or 0.125% bupivacaine (according to weight) atomized onto the peritoneum of the right iliac fossa and pelvis, or 20 mL 0.9% NaCl control. Unrestricted computer-generated randomization was implemented by surgical nurses. Participants, caregivers, and outcome assessors were blinded. The primary outcome was pain score. Analysis was by a linear mixed-effects model. Results: Of 184 randomized participants (92 to each group), the final analysis included 88 IPLA and 87 control participants. There was no statistically significant difference in overall pain scores (effect estimate 0.004, standard error 0.028, 95% confidence interval −0.052, 0.061), and no difference in right iliac fossa or suprapubic site-specific pain scores, opioid use, recovery parameters, or complications. No child experienced a complication related to the intervention. Conclusion: IPLA imparted no clinical benefit to children undergoing acute laparoscopic appendectomy and cannot be recommended in this setting.

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Commentary on: “Ensuring Excellence in Centers of Excellence Programs”

No abstract available

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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

imageObjective: To analyze long-term outcome of a randomized clinical trial comparing laparoscopic Nissen fundoplication (LNF) and conventional Nissen fundoplication (CNF) for the treatment of gastroesophageal reflux disease (GERD). Background: LNF has replaced CNF, based on positive short and mid-term outcome. Studies with a follow-up of over 15 years are scarce, but are desperately needed for patient counselling. Methods: Between 1997 and 1999, 177 patients with proton pump inhibitor (PPI)-refractory GERD were randomized to CNF or LNF. Data regarding the presence of reflux symptoms, dysphagia, general health, PPI use, and need for surgical reintervention at 17 years are reported. Results: A total of 111 patients (60 LNF, 51 CNF) were included. Seventeen years after LNF and CNF, 90% and 95% of the patients reported symptom relief, with no differences in GERD symptoms or dysphagia. Forty-three and 49% of the patients used PPIs (NS). Both groups demonstrated significant improvement in general health (77% vs 71%; NS) and quality of life (75.3 vs 74.7; NS). Surgical reinterventions were more frequent after CNF (18% vs 45%; P = 0.002), mainly due to incisional hernia corrections (3% vs 14%; P = 0.047). Conclusions: The effects of LNF and CNF on symptomatic outcome and general state of health remain for up to 17 years after surgery, with no differences between the 2 procedures. CNF carries a higher risk of surgical reintervention, mainly due to incisional hernia corrections. Patients should be informed that 17 years after Nissen fundoplication, 60% of the patients are off PPIs, and 16% require reoperation for recurrent GERD and/or dysphagia.

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Synbiotic Therapy With Surgery for Chronic Pancreatitis

No abstract available

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Predicting Heterotopic Ossification Early After Burn Injuries: A Risk Scoring System

imageObjective: The purpose of this study is to develop a scoring system that stratifies burn patients at the time of hospital admission according to risk of developing heterotopic ossification (HO). Summary of Background Data: HO in burns is an uncommon but severely debilitating problem with a poorly understood mechanism and no fully effective prophylactic measures. Methods: Data were obtained from the Burn Model System National Database from 1994 to 2010 (n = 3693). The primary outcome is diagnosis of HO at hospital discharge. Logistic regression analysis was used to determine significant demographic and medical predictors of HO. A risk scoring system was created in which point values were assigned to predictive factors and final risk score is correlated with the percent risk of developing HO. The model was internally and externally validated. Results: The mean age of the subjects is 42.5 ± 16.0 years, the mean total body surface area (TBSA) burned is 18.5 ± 16.4%, and the population is 74.9% male. TBSA and the need for grafting of the arm, head/neck, and trunk were significant predictors of HO development (P

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Oncologic Procedures Amenable to Fluorescence-guided Surgery

imageObjective: Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type. Background: For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye. Methods: We performed a systematic review of clinicatrials.gov using search terms "fluorescence," "image-guided surgery," and "near-infrared imaging" to identify trials utilizing FGS for those received on or before May 2016. Inclusion criteria: fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases. Exclusion criteria: fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence. Results: Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision. Conclusions: The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.

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Critical View of the Myopectineal Orifice

No abstract available

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Transplantation of Bioprinted Tissues and Organs: Technical and Clinical Challenges and Future Perspectives

image Three-dimensional (3D) bioprinting is a revolutionary technology in building living tissues and organs with precise anatomic control and cellular composition. Despite the great progress in bioprinting research, there has yet to be any clinical translation due to current limitations in building human-scale constructs, which are vascularized and readily implantable. In this article, we review the current limitations and challenges in 3D bioprinting, including in situ techniques, which are one of several clinical translational models to facilitate the application of this technology from bench to bedside. A detailed discussion is made on the technical barriers in the fabrication of scalable constructs that are vascularized, autologous, functional, implantable, cost-effective, and ethically feasible. Clinical considerations for implantable bioprinted tissues are further expounded toward the correction of end-stage organ dysfunction and composite tissue deficits.

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Is an RCT the Best Way to Investigate the Effectiveness of Nonoperative Management of Pediatric Appendicitis?

No abstract available

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Variation and Impact of Multiple Complications on Failure to Rescue After Inpatient Surgery

imageObjective: To examine the extent to which multiple, sequential complications impacts variation in institutional postoperative mortality rates. Background: Failure to rescue (FTR) has been proposed as an underlying factor in hospital variation in surgical mortality. However, little is currently known about hospital variation in FTR after multiple complications or the contribution of sequential complications to variation. Methods: Retrospective cohort study of 266,101 patients within the Veterans Affairs Surgical Quality Improvement Program (2000–2014) who underwent a subset of high-mortality inpatient general, vascular, or thoracic procedures. The association between number of postoperative complications (0, 1, 2, or ≥3) and 30-day mortality across quintiles of hospital risk-adjusted mortality was evaluated with multivariable, multilevel mixed-effects models. Results: Among patients who had a complication, over half (60.9%) had 1, but those with more than 1 accounted for the majority of the deaths (63.1%). Across hospital quintiles, there were no differences in complications (23.5% very low mortality vs 23.6% very high mortality; trend test P = 0.15). FTR increased significantly (12.0% vs 18.1%; trend test P

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Reply to Letter: “Hey, I Just Did a Better Operation! Toward an IDEAL Innovation Model”

No abstract available

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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

imageObjectives: Following calls from the National Institutes of Health and American College of Surgeons for "urgently needed" research, the objectives of the present study were to (1) ascertain whether differences in 30/90/180-day mortality, major morbidity, and unplanned readmissions exist among adult (18–64 yr) and older adult (≥65 yr) emergency general surgery (EGS) patients; (2) vary by diagnostic category; and (3) are explained by variations in insurance, income, teaching status, hospital EGS volume, and a hospital's proportion of minority patients. Background: Racial/ethnic disparities have been described in in-hospital and 30-day settings. How longer-term outcomes compare—a critical consideration for the lived experience of patients—has, however, only been limitedly considered. Methods: Survival analysis of 2007 to 2011 California State Inpatient Database using Cox proportional hazards models. Results: A total of 737,092 adults and 552,845 older adults were included. In both cohorts, significant differences in 30/90/180-day mortality, major morbidity, and unplanned readmissions were found, pointing to persistently worse outcomes between non-Hispanic Black and White patients [180-d readmission hazard ratio (95% confidence interval):1.04 (1.03–1.06)] and paradoxically better outcomes among Hispanic adults [0.85 (0.84–0.86)] that were not encountered among Hispanic older adults [1.06 (1.04–1.07)]. Stratified results demonstrated robust morbidity and readmission trends between non-Hispanic Black and White patients for the majority of diagnostic categories, whereas variations in insurance/income/teaching status/EGS volume/proportion of minority patients all significantly altered the effect—combined accounting for up to 80% of risk-adjusted differences between racial/ethnic groups. Conclusions: Racial/ethnic disparities exist in longer-term outcomes of EGS patients and are, in part, determined by differences in factors associated with emergency care. Efforts such as these are needed to understand the interplay of influences—both in-hospital and during the equally critical, postacute phase—that underlie disparities' occurrence among surgical patients.

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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.

Thumbnail image of graphical abstract

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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Editorial Board



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Contents



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Contrasting results of tests of peripheral vestibular function in patients with bilateral large vestibular aqueduct syndrome



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Analysis of ictal magnetoencephalography using gradient magnetic-field topography (GMFT) in patients with neocortical epilepsy



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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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ERCP and Laparoscopic cholecystectomy in a patient with situs inversus totalis



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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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Delayed Onset Biallelic Mismatch Repair Deficiency Syndrome



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Increased risk of in-hospital mortality and non-ICU death in patients with cirrhosis after cardiac arrest



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More Benefits from Interrupted Time Series in Evaluating Recent Market Release of DAAs and State Medicaid Reimbursement Programs



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Primary splenic flexure schwanomma- pre-operatively diagnosed with EUS guided fine needle biopsy



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Should Nibolmab-Induced Colitis be Treated by Infliximab?



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Gastrointestinal safety profiles differ among non-vitamin K antagonist anticoagulants?



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Duodenal diverticular bleeding managed using an Over-the-scope-clip



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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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Next steps in Ewing sarcoma (epi-)genomics

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.


http://ift.tt/2rNPn74

A review of binimetinib for the treatment of mutant cutaneous melanoma

Future Oncology Ahead of Print.


http://ift.tt/2r4fvgX

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...

http://ift.tt/2qYJZwo

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.

http://ift.tt/2s6e9Cp

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.

http://ift.tt/2s69lNp

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



http://ift.tt/2rO0BIR

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.



http://ift.tt/2r7SGUB

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...

http://ift.tt/2sVbIPi

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.



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Heads you gain, tails you lose: Editorial Focus for R-00351-2016

NA



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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…

http://ift.tt/2r7o99o

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…

http://ift.tt/2rD78re

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…

http://ift.tt/2r7g44G

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...

http://ift.tt/2rCZWLS

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...

http://ift.tt/2r7Isn7

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



http://ift.tt/2pFdkOy

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



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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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Announcements



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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.



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Nanospheres: Selective Coloration of Melanin Nanospheres through Resonant Mie Scattering (Adv. Mater. 22/2017)

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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.



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Masthead: (Adv. Mater. 22/2017)



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Conductive Polymers: A Tunable 3D Nanostructured Conductive Gel Framework Electrode for High-Performance Lithium Ion Batteries (Adv. Mater. 22/2017)

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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.



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Contents: (Adv. Mater. 22/2017)



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Organic Photovoltaics: Direct Free Carrier Photogeneration in Single Layer and Stacked Organic Photovoltaic Devices (Adv. Mater. 22/2017)

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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.



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Surface Patterning: Sub-Micrometer Surface-Patterned Ribbon Fibers and Textiles (Adv. Mater. 22/2017)

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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.



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Luminescence: Dynamic Phosphorescent Probe for Facile and Reversible Stress Sensing (Adv. Mater. 22/2017)

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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.



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Photodetectors: A Broadband Fluorographene Photodetector (Adv. Mater. 22/2017)

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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.



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Masthead: (Adv. Healthcare Mater. 11/2017)



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Angiogenesis: Affinity-Immobilization of VEGF on Laminin Porous Sponge Enhances Angiogenesis in the Ischemic Brain (Adv. Healthcare Mater. 11/2017)

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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.



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Tissue Engineering: Engineered 3D Cardiac Fibrotic Tissue to Study Fibrotic Remodeling (Adv. Healthcare Mater. 11/2017)

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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.



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Contents: (Adv. Healthcare Mater. 11/2017)



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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)

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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.



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Rescue and Characterization of Recombinant Virus from a New World Zika Virus Infectious Clone

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This protocol describes the recovery of infectious Zika virus from a two-plasmid infectious cDNA clone.

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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.



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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.



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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.



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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.



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A Method to Test the Efficacy of Handwashing for the Removal of Emerging Infectious Pathogens

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Handwashing is widely recommended to prevent infectious disease transmission. However, there is little evidence on which handwashing methods are most efficacious at removing infectious disease pathogens. We developed a method to assess the efficacy of handwashing methods at removing microorganisms.

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.

Design

Population-based case–control study.

Setting

Olmsted County, Minnesota (USA).

Participants

From 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).

Methods

Information 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.

Results

We 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.

Conclusions

Women 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.



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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

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A Chronic Autoimmune Dry Eye Rat Model with Increase in Effector Memory T Cells in Eyeball Tissue

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This report describes a method to induce chronic experimental autoimmune dry eye in Lewis rats through immunization with an emulsion of rat lacrimal gland extract, ovalbumin, and complete Freund's adjuvant, followed by the injection of lacrimal gland extract and ovalbumin into the forniceal subconjunctiva and lacrimal glands six weeks later.

http://ift.tt/2sDPmT5

Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity

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Macrophages are plastic cells of the hematopoietic system that have a crucial role in protective immunity and homeostasis. In this report, we describe optimized in vitro techniques to phenotypically and functionally characterize graft-infiltrating regulatory macrophages that accumulate in the transplanted organ under tolerogenic conditions.

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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.



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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.

Design

1805 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.

Results

Nine 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).

Conclusion

We 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.



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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...



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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.

Design

Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15CD11b+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.

Results

Circulating CD14+CD15CD11b+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.

Conclusion

Immunosuppressive 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.



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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...



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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...

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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...

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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.



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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.



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