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Τετάρτη 7 Μαρτίου 2018

Effusion-based lymphoma with morphological regression but with clonal genetic features after aspiration

Effusion-based lymphoma (EBL) is a rare but distinct entity of large B-cell lymphoma in effusion without association with human herpes virus-8 (HHV-8). Spontaneous regression after pleurocentesis has been observed; but to our knowledge, there are no reports on the morphological and molecular features of subsequent aspirations in regressing cases. Here, we report the case of a 92-year-old male with chronic obstructive pulmonary disease, who presented with right pleural effusion. He had no human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection, and CT scans revealed no mass lesion. The first pleural effusion aspiration cytology revealed large lymphoma cells with vesicular nuclei, irregular nuclear contours, and prominent nucleoli, consistent with EBL. The second aspiration cytology showed a few slightly enlarged lymphocytes in a background of small lymphocytes. Immunohistochemical study on cell block of the second aspiration revealed equal amounts of CD3-positive and CD20-positive cells. All these cells on the section tested negative for HHV-8 through immunohistochemistry and Epstein-Barr virus by in situ hybridization. Our initial impression was EBL in regression. However, flow cytometric immunophenotyping showed monotypic light chain expression of the gated B-cells. B-cell receptor gene rearrangement study showed a clonal result. Furthermore, fluorescence in situ hybridization revealed rearrangement of IGH gene. The diagnosis of the second aspiration was EBL with morphological regression but retained clonal genetic features. The patient passed away one month after diagnosis without chemotherapy. This case illustrated the importance of ancillary studies in confirming the clonal nature of a morphologically regressing EBL.



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Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations

Background

Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied.

Methods

To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent.

Results

TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules.

Conclusion

We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.



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Fractures of the femur and blood transfusions

Publication date: Available online 7 March 2018
Source:Injury
Author(s): Adam Wertheimer, Alexander Olaussen, Shanaka Perera, Susan Liew, Biswadev Mitra
BackgroundBlood loss estimation after trauma (i.e. physical injury) and early identification of potential sources of bleeding are important for planning of investigation and management of trauma. Long bone fractures have been reported to be associated with substantial volumes of blood loss requiring blood transfusion. The aim of this study was to assess rates and amounts of blood transfusion in the setting of isolated extra capsular femur fractures and to determine variables associated with the need for transfusion within the first 48 hours of admission.MethodsA retrospective cohort study was conducted of patients in The Alfred Trauma Registry with isolated extra capsular femur fractures over a 7-year period. We compared patients with a femoral shaft fracture (FSF) to patients with either distal femur or proximal femur fractures (i.e. extremity fracture). We collected data potentially associated with blood transfusion within 48 hours as well as operation details and patient outcomesResultsThere were 293 patients included, of which 121 had FSF and 172 extremity fracture. 105 (36%) patients received a blood transfusion during their admission. Admission haemoglobin (AOR 0.92; 95%CI 0.89–0.94, p < 0.01) was the only independently associated variable with blood transfusion within the first 48 hours of hospital admission.ConclusionVolume of blood transfused to patients with extra-capsular femoral fractures was low and usually in the post-operative period. Femoral shaft fractures, compared to femoral extremity fractures, were not more likely to receive blood transfusion within the first 48 hours of admission, and do not receive a higher volume of blood overall. In the setting of major trauma with haemorrhagic shock, alternate sources of bleeding should be sought.



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Flexion-Valgus Unicondylar Tibial Plateau Depression Fracture Pattern: Classification and Treatment

Publication date: Available online 7 March 2018
Source:Injury
Author(s): Yu Zhang, Lijun Song, Xiang Li, Jiahu Fang
PurposeThe authors have identified a subset of unicondylar tibial plateau depression fracture patterns caused by a flexion-valgus force. The purpose of this study was to describe this fracture pattern and suggest a modified lateral approach that may allow for improved reduction and stabilization.MethodsThe preoperative radiographs and CT scans of 102 patients who sustained unicondylar tibial plateau fractures (OTA 41B) were reviewed. Twenty-six fracture patients had posterolateral (PL) tibial plateau depression fractures. By medical record review and telephone follow-up, the injury mechanism of the 22 unicondylar tibial plateau fractures was confirmed as a flexion-valgus force. The radiographic features of those cases were analyzed and measured. To address this specific fracture pattern, a modified approach combined with a novel intra-articular osteotomy was applied.ResultsAccording to the morphological characteristics, this tibial plateau fracture pattern could be divided into two subtypes: type A was a confined, basin-like articular surface depression fracture located in the PL quadrant, and type B was a cancellous fracture involving the PL tibial plateau resulting in a decrease in the posterior slope. One radiographic hallmark of this fracture pattern is an anatomically or a mechanically intact posterior column wall. The novel approach was applied to both types. The postoperative radiographic measurements revealed excellent reduction quality. On axial scans, the distance between the most posterior rafting screw and the tangent line of the tibial plateau rim was 3.0 ± 2.07 mm (from −1.9 to 4.3), and the angulation between them was 8.9 ± 3.02° (from −7.3 to 15.6). These results indicated excellent PL quadrant coverage from the rafting screws.ConclusionFlexion-valgus force-induced unicondylar tibial plateau depression fracture is a unique injury pattern. We suggest a novel surgical approach to address this injury's key features, which may facilitate exposure and enhance fixation strength.



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Virtual simulation of an Osseointegrated Trans-humeral prosthesis: A falling scenario

Publication date: Available online 7 March 2018
Source:Injury
Author(s): A.I. Mirulla, L. Bragonzoni, S. Zaffagnini, M. Bontempi, V. Nigrelli, T. Ingrassia
IntroductionTraditional prosthetic solutions expose the amputee to numerous problems that limit his ability to safely perform the normal activities of daily life. In order to eliminate the problems related to the use of the traditional prosthesis with socket, a new technique was developed for fixing the prosthesis to the amputees based on the principle of osseointegration. The aim of this paper is to study and analyze the stress distribution on the interface between a trans-humeral osseointegrated prosthetic implant and the residual bone, identifying the most stressed areas and thus foreseeing possible failure phenomena of the entire prosthetic system and, after, to compare the stress distribution on three different prosthetic designs that differ from each other for some geometric characteristics.Materials and methodsA healthy individual mimics two fall scenarios of which the trans-humeral amputees can most likely be victims: Static fall and Dynamic fall. A force platform (P-6000, BTS Bioengineering) is required for load data acquisition. The CAD model of the trans-humeral osseointegrated implant was created following the guidelines of the OPRA implant. The bone model was created starting from the CAT scan of a left humerus. The FEM simulation was conducted throught a linear analysis.ResultsBoth during static fall and dynamic fall, similar trends have been observed for the reaction force Fz, the torque moment Tz, the bending moments Mx and My. From the analysis of the von Mises stress distribution it was found that the stress distribution is more homogeneous in the case where the thread of the fixture is made by a triangular profile with height of the thread equal to 0.5 mm. However, it can be seen that, when passing from a thread with height of 0.5 mm to a 1 mm, there is a slight decrease in the stress on the whole contact zone between the fixture and the humerus. The same improvement can also be seen in the case of trapezoidal threading.ConclusionBy modifying the height and/or by varying the thread profile, are obtained slightly better results with respect to the case with a 0.5 mm height triangular thread.



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Watching Others Makes People Overconfident in their Own Abilities

Watching YouTube videos, Instagram demos, and Facebook tutorials may make us feel as though we're acquiring all sorts of new skills but it probably won't make us experts, according to research published in Psychological Science, a journal of the Association for Psychological Science.

"The more that people watched others, the more they felt they could perform the same skill, too–even when their abilities hadn't actually changed for the better," says study author Michael Kardas of The University of Chicago Booth School of Business. "Our findings suggest that merely watching others could cause people to attempt skills that they might not be ready or able to perform themselves."

Social media platforms have made it easy to record, share, and access instructional videos. But does watching videos without practicing the demonstrated skills actually improve our ability to perform them? Kardas and coauthor Ed O'Brien conducted a series of six experiments to find out.

In one online experiment, the researchers assigned 1,003 participants to watch a video, read step-by-step instructions, or merely think about performing the "tablecloth trick," which involves pulling a tablecloth off a table without disturbing the place settings on top. People who watched the 5-second video 20 times were much more confident in their ability to pull off the trick than were those who watched the video once. However, people who simply read or thought about the trick for an extended period of time did not show this confidence boost. These results provided initial evidence that repeated viewing may lead people to an inflated sense of competence.

To find out whether this perception is borne out by actual performance, Kardas and O'Brien tested a group of 193 participants on their dart-throwing abilities. Those who watched a demo video 20 times estimated that they would score more points than those who saw the video only once–this high-exposure group also predicted that they would be more likely to hit the bull's-eye and reported that they had learned more technique and improved more after watching the video.

But these perceptions did not line up with reality: People who watched the video many times scored no better than those who saw it once.

Kardas and O'Brien found evidence for this phenomenon in other domains, including doing the moonwalk, playing a digital computer game, and juggling. The more that participants watched others perform these skills, the more they overestimated their own abilities.

Why does repeatedly watching a video breed such overconfidence? Participants who watched a variation of the tablecloth trick video that did not show the performer's hands evidenced no exposure-related overconfidence, suggesting that people may feel confident only when they can track the specific steps and actions in performing a skill.

Thinking about detailed steps or learning technical information about the objects involved did not lead participants to form more accurate perceptions. In an experiment focused on juggling, only participants who were able to hold the pins after watching a juggling video revised their estimates, reporting that they had learned less and were less capable than they originally thought after watching.

"We see this as a potentially widespread phenomenon given that people have daily access to outlets for watching others perform," says Kardas. "Anyone who goes online to look up tips before attempting a skill — from cooking techniques to DIY home repairs to X Games tricks — would benefit from knowing that they might be overconfident in their own abilities after watching, and should exercise caution before attempting similar skills themselves."

The researchers are interested in testing other strategies—such as playing virtual-reality games—that might mitigate the overconfidence effect, helping people to better appreciate the limitations inherent in merely watching others.

This research was funded by the Willard Graham Faculty Research Award.

All data and materials have been made publicly available via the Open Science Framework (OSF). The design and analysis plans for Experiments 1, 3, 4, and 6 were preregistered at OSF. The complete Open Practices Disclosure for this article is available online. This article has received badges for Open Data, Open Materials, and Preregistration.



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Issue Information



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Prize winners



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SARS abstracts



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BBA abstracts



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Meta-analysis of whole-brain radiotherapy plus temozolomide compared with whole-brain radiotherapy for the treatment of brain metastases from non-small-cell lung cancer

Abstract

The aim of this meta-analysis was to compare the efficiency of whole-brain radiotherapy (WBRT) plus temozolomide (TMZ) with WBRT for the treatment of brain metastases from non-small-cell lung cancer (NSCLC). For dichotomous variables, outcomes were reported as relative risk ratio (RR) and 95% confidence interval (CI) was used to investigate the following outcome measures: overall response rate, headache, gastrointestinal adverse reactions, and hematological adverse reactions. Twelve randomized controlled trials involving 925 participants (480 received WBRT plus TMZ; 445 received WBRT) were included in the meta-analysis. There was a significant difference between the overall response rate (RR = 1.40, 95% CI 1.24–1.57; Z = 5.51; P < 0.00001), gastrointestinal adverse reactions (RR = 1.46, 95% CI 1.05–2.04; Z = 2.27; P = 0.02), and hematological adverse reactions (RR = 1.45, 95% CI 1.04–2.02; Z = 2.21; P = 0.03) of patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. There was no significant difference between headaches (RR = 1.11, 95% CI 0.93–1.02; Z = 1.13; P = 0.26) in patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. In conclusion, the currently available evidence shows that WBRT plus TMZ increases the overall response rate in patients with brain metastases of NSCLC compared with WBRT alone.

Thumbnail image of graphical abstract

The currently available evidence shows that whole-brain radiotherapy (WBRT) plus temozolomide increases the overall response rate in patients with brain metastases of non-small-cell lung cancer compared with WBRT alone.



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Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation

Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation

Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation, Published online: 07 March 2018; doi:10.1038/s41419-018-0414-3

Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation

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Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study

Summary

Background

Eradication of hepatitis C virus (HCV) infection via interferon-based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon-free treatment.

Aims

The objective of this retrospective cohort study was to examine the association of direct-acting antiviral (DAA) exposure with risk of incident liver cancer in real-world data.

Methods

From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods.

Results

Relative to untreated HCV patients, DAA-treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73-0.96), and relative to interferon-based treatment in the pre-DAA era (HR = 0.69, 95% CI: 0.59-0.81).

Conclusions

In this large, population-based study, DAA-based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon-based treatment in the pre-DAA era. As additional follow-up time of DAA-treated patients accrues, we anticipate that the long-term benefits of DAA treatment will become more apparent.



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Commentary on Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery

No abstract available

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The Hospital Readmission Reduction Program for Surgical Conditions: Impactful or Harmful?

No abstract available

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Preoperative Prediction of Postprandial Glycemia After Roux-en-Y Gastric Bypass

imageNo abstract available

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Characterization and Optimal Management of High-risk Pancreatic Anastomoses During Pancreatoduodenectomy

imageObjective: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy. Background: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored. Methods: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching. Results: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P

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Reply to: “Assessing Surgeons’ Technical Performance and Effect on Outcomes Still Early Days”

No abstract available

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Higher Patient Numbers-Stronger Evidence?

No abstract available

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American Exceptionalism and the American Surgical Association: The Rise of Surgery in the United States

imageObjective: To explore use of the notion of American exceptionalism by fellows of the American Surgical Association (ASA) (1880 through World War I) and how this proved instrumental in the rise of surgery in the United States. Background: American exceptionalism is the belief that the United States is innately different from other nations because of its economic, geographic, political, religious, and social foundations. Although, currently, the concept of American exceptionalism implies superiority, in its original 19th century connotation, the idea referred to the distinctive character of America as a free nation. Methods: An analysis of published literature along with unpublished documents to provide new knowledge and unique insight into the use of American exceptionalism by members of the ASA as they promoted their specialty. Results: Beginning with Samuel Gross's desire that the organization he founded represent "the genius of our republican institutions," to Frederick Dennis's declaration that "American surgery eclipses all other nations because of the wonderful adaptability of the American mind," plus Lewis Pilcher's explanation of how the "stimulating climate, prevailing religious tone, regard for learning, and pride of citizenship are the fruit of the American mind when turned to surgical problems," and ending with Edmond Souchon's 106 page article in the Transactions on surgical firsts, the ASA was the avenue that helped the nation's surgeons define and defend themselves. Conclusions: Use of the concept of American exceptionalism by fellows of the ASA was a key factor in the development of surgery in the United States.

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Wanted: Effective Followers in Surgery

imageBrief description: This SURGICAL PERSPECTIVE paper brings to our readers the general topic of "followership." Leadership has received a lot of attention in the administrative education domain; however, there is a history of academic research on the role and importance of the effective follower. We review some of the critical articles in this field, and present a possible approach for incorporating the notion of effective followership in a surgical context.

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Reply to: Oncogenesis in Patients With Pancreatic Intraductal Papillary Mucinous Neoplasms Taking the Thread From the Beginning

No abstract available

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A Proposal to Mitigate the Consequences of Type 2 Error in Surgical Science

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Impact of Different Surgical Techniques on Outcomes in Laparoscopic Sleeve Gastrectomies: Role of a Registry-based Observational Study

No abstract available

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Plasma Micro-RNA Alterations Appear Late in Pancreatic Cancer

imageObjectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at

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So What's the Chance of This Mesh Causing Me a Problem in the Long Run?

No abstract available

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Laparoscopy-assisted versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: Results From a Randomized Phase II Multicenter Clinical Trial (COACT 1001)

imageObjective: This randomized, phase II, multicenter clinical trial was conducted to evaluate the feasibility of laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection compared with open distal gastrectomy (ODG) for the treatment of advanced gastric cancer (AGC). Summary of Background Data: D2 lymph node dissection has been accepted as standard treatment for AGC. Although LADG is widely performed in early gastric cancer (EGC), the feasibility of LADG in AGC has not been proven yet. Methods: Patients with cT2-T4a and cN0-2 (AJCC 7th staging system) distal gastric cancer were randomly but not blindingly assigned to LADG or ODG groups using fixed block sizes with a 1:1 allocation ratio. The primary endpoint was the noncompliance rate of the lymph node dissection, which was used to evaluate feasibility. Secondary endpoints included 3-year disease-free survival (DFS), 5-year overall survival, complications, and surgical stress response. Results: Between June 2010 and October 2011, 204 patients enrolled and underwent either LADG (n = 105) or ODG (n = 99). Of these, 196 patients (100 in LADG and 96 in ODG) were included in the intention-to-treat analysis. There were no significant differences in the overall noncompliance rate of lymph node dissection between LADG and ODG groups (47.0% and 43.2%, respectively; P = 0.648). In the subgroup analysis, the noncompliance rate in the LADG group was significantly higher than the ODG group for clinical stage III disease (52.0% vs 25.0%, P = 0.043). No difference was found in the 3-year DFS rate between the groups (LADG, 80.1%; ODG, 81.9%; P = 0.448). Differences in postoperative complication rates and surgical stress response were found to be insignificant between the 2 arms. Conclusions: LADG was feasible for AGC treatment based on the noncompliance rate of D2 lymph node dissection. Subgroups analysis data suggest that further studies are needed for stage III gastric cancer.

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Chest Wall Resection for Recurrent Breast Cancer in the Modern Era: A Systematic Review and Meta-analysis

imageObjective: To review the literature on chest wall resection for recurrent breast cancer and evaluate overall survival (OS) and quality-of-life (QOL) outcomes. Background: Full-thickness chest wall resection for recurrent breast cancer is controversial, as historically these recurrences have been thought of as a harbinger of systemic disease. Methods: A systematic search in MEDLINE, EMBASE, and Cochrane CENTRAL identified 48 eligible studies, all retrospective, accounting for 1305 patients. The review is reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Primary end points were patient-centered QOL outcomes and OS; secondary outcomes included disease-free survival (DFS) and 30-day morbidity. Risk of bias was assessed using the Methodological Index for Non-Randomized Studies instrument and the Oxford Centre for Evidence-Based Medicine's levels of evidence tool. Random-effects meta-analysis was used to create pooled estimates. Meta-regressions and sensitivity analyses were used to explore study heterogeneity by age, year of publication, risk of bias, and surgical intent (curative vs palliative). Results: Studies consistently reported excellent OS and DFS in properly selected patients. Pooled estimates for 5-year OS in all studies and those from the past 15 years were 40.8% [95% confidence interval (CI) 35.2–46.7) and 43.1% (95% CI 35.8–50.7), whereas pooled 5-year DFS was 27.1% (95% CI 16.6–41.0). Eight studies reported excellent outcomes related to QOL. Mortality was consistently low (

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Reply to: “Laparoscopic Lavage for Perforated Diverticulitis”

imageNo abstract available

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How Do We Value Postoperative Recovery?: A Systematic Review of the Measurement Properties of Patient-reported Outcomes After Abdominal Surgery

imageObjective: To appraise the level of evidence supporting the measurement properties of patient-reported outcome measures (PROMs) in the context of postoperative recovery after abdominal surgery. Background: There is growing interest in using PROMs to support value-based care in abdominal surgery; however, to draw valid conclusions regarding patient-reported outcomes data, PROMs with robust measurement properties are required. Methods: Eight databases (MEDLINE, EMBASE, Biosis, PsycINFO, The Cochrane Library, CINAHL, Scopus, Web of Science) were searched for studies focused on the measurement properties of PROMs in the context of recovery after abdominal surgery. The methodological quality of individual studies was evaluated using the consensus-based COSMIN checklist. Evidence supporting the measurement properties of each PROM was synthetized according to standardized criteria and compared against the International Society of Quality of Life Research minimum standards for the selection of PROMs for outcomes research. Results: We identified 35 studies evaluating 22 PROMs [12 focused on nonspecific surgical populations (55%), 4 focused on abdominal surgery (18%), and 6 generic PROMs (27%)]. The great majority of the studies (74%) received only poor or fair quality ratings. Measurement properties of PROMs were predominantly supported by limited or unknown evidence. None of the PROMs fulfilled International Society of Quality of Life Research's minimum standards, hindering specific recommendations. Conclusions: There is very limited evidence supporting the measurement properties of existing PROMs used in the context of recovery after abdominal surgery. This precludes the use of these PROMs to support value-based surgical care. Further research is required to bridge this major knowledge gap. Review Registration: International Prospective Register of Systematic Reviews (PROSPERO): CRD42014014349.

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Monoclonal Antibodies for Emerging Infectious Diseases — Borrowing from History

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Although antibodies play pivotal roles in the immune response to infection, they have seen limited use as therapeutic agents for infectious diseases. Yet there is a long history of plasma-derived treatments for several pathogens. Emil Adolf von Behring, for example, won the Nobel Prize in…

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Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

Prior studies have suggested that human IFIT1, unlike its mouse ortholog, might not recognize viral RNA molecules lacking 2′-O methylation on their cap structures. Johnson et al. report a crystal structure between cap 0 (m7GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain (CTD) of human IFIT3. The CTD of IFIT3 bound to IFIT1 and allosterically regulated the IFIT1 RNA-binding channel and promoted selective recognition of cap 0 RNA. Functional studies demonstrated that IFIT3 interaction with IFIT1 was important for stabilizing IFIT1 expression and was required for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures

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PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity

Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb).Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow-cytometry analysis were used to delineate mechanisms underpinning the observed synergy. Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN-, TNF-α, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for anti-tumor immunity. Finally, we show that a clinically-relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice. Conclusions: Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches co-operate for CD8+ T-cell activation.



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Identification and Validation of Stromal Immunotype Predict Survival and Benefit from Adjuvant Chemotherapy in Patients with Muscle Invasive Bladder Cancer

Purpose: This study aims to construct the stromal immunotype which could improve prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC). Patients and Methods: A total of 118 MIBC patients from Shanghai Cancer Center, 140 MIBC patients from Zhongshan hospital and 287 MIBC patients from TCGA cohort were included in the study. Immune cell infiltration was evaluated by immunohistochemical staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotype based on LASSO Cox regression model. Result: Using the LASSO model, we classified MIBC patients into stromal immunotype A subgroup (CTL high NK high Treg low Macrophage low MC low) and stromal immunotype B subgroup (CTL low NK low Treg high Macrophage high MC high). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (76.0% vs. 44.0%; P<0.001) and 5-year disease-free survival (62.8% vs. 48.3%; P<0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either overall survival or disease-free survival was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients. But further analysis revealed that overall survival and disease-free was significantly improved by ACT in pT3+pT4 patients. (P=0.016 and P=0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, CTLA-4) expression. Conclusion: The stromal immunotypes could predict survival and recurrence of MIBC effectively. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT.



http://ift.tt/2Fkpe9R

The Magnitude of Androgen Receptor Positivity in Breast Cancer is Critical for Reliable Prediction of Disease Outcome

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically-validated primary breast cancer cohorts (training cohort n=219; validation cohort n=418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively). The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22/46 (48%) of previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1 nor 10% cut-points were robustly prognostic. ROC analysis revealed a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR 0.41, P=0.015) and validation (HR 0.50, P=0.014) cohorts. Ten-fold cross validation confirmed the robustness of this AR cut-point. Patients with ERα positive tumors and AR positivity >78% had the best survival in both cohorts (P<0.0001). Among the combined ERα positive cases, those with comparable or higher levels of AR (AR:ERα positivity ratio >0.87) had the best outcomes (P<0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.



http://ift.tt/2D8VSFE

Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model

Purpose: Currently, <50% of high-risk pediatric solid tumors like neuroblastoma (NB), can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature. Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles (NPs). Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance NP retention. We treated NBs with SN38-TOA NPs and compared the efficacy to the parent prodrug CPT-11 using a mouse xenograft model. Results. NP treatment induced prolonged event-free survival (EFS) in most mice, compared to CPT-11. This was shown for both SH-SY5Y and IMR-32 NB xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared to conventional CPT-11 delivery. Interestingly, when recurrent CPT-11-treated tumors were retreated with SN38-TOA NPs, the tumors transformed from undifferentiated NBs to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology. Conclusion. NP delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in NPs during circulation should decrease toxicity. We propose that NP-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors.



http://ift.tt/2FiSLRa

COX-2/PGE2 Axis Regulates HIF-2{alpha} Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

Purpose: Hypoxia-inducible factor (HIF)-2α is regarded as a preferential target for individualized HCC treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF-2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF-2α activity and of sorafenib resistance in hypoxic HCC cells. Experimental Design: The cell viability, migration and invasion abilities were measured to analyze the effects of HIF-2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF-2α level and activity, which then reduce the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF-2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF-2α activity by promoting HIF-2α nuclear translocation via MAPK pathway. The activation of HIF-2α then led to the enhanced activation of VEGF, cyclin D1, and TGF-α/EGFR pathway to mediate HCC progression and reduce the sensitivity of sorafenib. More importantly, COX-2 specific inhibitors synergistically enhanced the antitumour activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF-2α expression and activity to promote HCC progression and attenuate sorafenib sensitivity by constitutively activating the TGF-α/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment.



http://ift.tt/2FpSGai

Genome-wide discovery and identification of a novel miRNA signature for recurrence prediction in stage II and III colorectal cancer

Purpose The current TNM (Tumor Node Metastasis) staging system is inadequate at identifying high-risk colorectal cancer (CRC) patients. Using a systematic and comprehensive-biomarker discovery and validation approach, we aimed to identify a miRNA-recurrence classifier (MRC) that can improve upon the current TNM-staging as well as superior to currently offered molecular assays. Experimental Design Three independent genome-wide miRNA-expression profiling datasets were used for biomarker discovery (N=158) and in-silico validation (N=109 and N=40) to identify a miRNA signature for predicting tumor recurrence in CRC patients. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh frozen (N=127, cohort 1) and FFPE (N=165, cohort 2 and N=139, cohort 3) specimens. Results We identified an 8-miRNA signature that significantly predicted recurrence free interval (RFI) in the discovery (p=0.002) and two independent publicly available datasets (p=0.00006 and p=0.002). The RT-PCR based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in stage II and III CRC patients [cohort 1: HR: 3.44 (1.56-7.45), P=0.001, cohort 2: HR: 6.15 (3.33-11.35), P=0.001 and cohort 3: HR: 4.23 (2.26-7.92), P=0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence, and achieved superior predictive accuracy than the currently available molecular assays. Conclusions This novel miRNA-recurrence classifier works superior to currently used clinicopathological features, as well as NCCN criteria, and works independent of adjuvant chemotherapy status in identifying high-risk stage II and III CRC patients. This can be deployed in clinical practice with FFPE specimens.



http://ift.tt/2FjQVzE

The transcriptional co-activator TAZ is a potent mediator of alveolar rhabdomyosarcoma tumorigenesis

Purpose: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. 5-year survival for aRMS is <50%, with no improvement in over four decades. Although the transcriptional co-activator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis. Experimental Design: After determining from public datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss-of-function on aRMS oncogenic phenotypes in vitro and tumorigenesis in vivo. Last, we performed pharmacological studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity. Results: TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression. In vitro, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G2/M. In vivo, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine. Conclusions: TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS.



http://ift.tt/2FpSFTM

Osteoblast-secreted factors mediate dormancy of metastatic prostate cancer in the bone via activation of the TGF{beta}RIII-p38MAPK-pS249/T252RB pathway

Bone metastasis from prostate cancer (PCa) can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTC are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 PCa cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single cell level revealed that conditioned medium from differentiated, but not undifferentiated osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to PCa cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating PCa tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates RB at the novel N-terminal S249/T252 sites to block PCa cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 PCa cell lines abolished tumor cell dormancy both in vitro and in vivo. Lower TGFβRIII expression in PCa patients correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTC are induced into a dormant state through TGFβRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent PCa recurrence in the bone.

http://ift.tt/2Fltwhk

Kinesin 6 Regulation in Drosophila Female Meiosis by the Non-conserved N- and C- Terminal Domains

Bipolar spindle assembly occurs in the absence of centrosomes in the oocytes of most organisms. In the absence of centrosomes in Drosophila oocytes, we have proposed that the kinesin 6 Subito, a MKLP-2 homolog, is required for establishing spindle bipolarity and chromosome biorientation by assembling a robust central spindle during prometaphase I. Although the functions of the conserved motor domains of kinesins is well studied, less is known about the contribution of the poorly conserved N- and C- terminal domains to motor function. In this study, we have investigated the contribution of these domains to kinesin 6 functions in meiosis and early embryonic development. We found that the N-terminal domain has antagonistic elements that regulate localization of the motor to microtubules. Other parts of the N- and C- terminal domains are not required for microtubule localization but are required for motor function. Some of these elements of Subito are more important for either mitosis or meiosis, as revealed by separation-of-function mutants. One of the functions for both the N- and C-terminals domains is to restrict the CPC to the central spindle in a ring around the chromosomes. We also provide evidence that CDK1 phosphorylation of Subito regulates its activity associated with homolog bi-orientation. These results suggest the N- and C-terminal domains of Subito, while not required for localization to the central spindle microtubules, have important roles regulating Subito, by interacting with other spindle proteins and promoting activities such as bipolar spindle formation and homologous chromosome bi-orientation during meiosis. Supplemental Material available at Figshare: http://ift.tt/2oWC82X



http://ift.tt/2I9KAVi

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy, Published online: 08 March 2018; doi:10.1038/s41416-018-0016-y

Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

http://ift.tt/2HfBGo1

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

AKR1C enzymes sustain therapy resistance in paediatric T-ALL, Published online: 08 March 2018; doi:10.1038/s41416-018-0014-0

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

http://ift.tt/2FymDbx

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer, Published online: 08 March 2018; doi:10.1038/s41416-018-0004-2

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

http://ift.tt/2FAAgqT

Carboplatin (every 21 days) and divided-dose paclitaxel (days 1, 11): rationale and tolerance in chemotherapy naïve women with high-grade epithelial cancers of Mullerian origin

Abstract

Purpose

We report here on the tolerance of a carboplatin–'divided dose' paclitaxel (given on days 1 and 11) regimen in chemotherapy-naïve patients with resected and staged endometrial epithelial neoplasms deemed at high-risk of recurrence or early stage epithelial high-grade serous tubo-ovarian adenocarcinomas after risk-reducing surgery. More recently, we applied this regimen as neoadjuvant chemotherapy for advanced ovarian cancer presentations.

Methods

A retrospective chart review of patients receiving this day 1, 11 paclitaxel regimens in combination with carboplatin at AUC 6 every 3 weeks since 2004 was carried out by the second author with subsequent updates by the first and third authors. Tolerance over the first three cycles was analyzed.

Results

A total of 27 women were treated with at least three cycles of this paclitaxel 'divided dose' schedule combined with carboplatin: 6 had endometrial adenocarcinoma, 9 had early stage ovarian cancer, and 12 received it as part of neoadjuvant therapy prior to undergoing cytoreductive surgery. Only 14 of 27 patients required dose reductions to complete the first three cycles of treatment.

Conclusions

A median of three cycles of divided dose paclitaxel (D1, D11) concurrent with carboplatin dosed every 3 weeks was found to be safe and feasible as adjuvant to surgery in early endometrial and ovarian cancers or as neoadjuvant treatment in chemotherapy-naive women with ovarian cancer.



http://ift.tt/2trDqrZ

P2X receptor-ion channels in the inflammatory response in adipose tissue and pancreas—potential triggers in onset of type 2 diabetes?

Ivana Novak | Anna Solini

http://ift.tt/2FodgYI

Radiotherapy for anal squamous cell carcinoma: must the upper pelvic nodes and the inguinal nodes be treated?

Background

Loco-regional failure is the predominant cause of death in anal squamous cell carcinoma. We assessed patterns of loco-regional recurrence to determine the impact of radiotherapy (RT) volumes on patient outcome.

Methods

Retrospective clinical study, including patients treated curatively with RT or chemo-radiotherapy between 1994 and 2007. RT fields/volumes were reviewed and compared with patterns of failure. Patients were classified as having whole pelvic radiotherapy (WPRT) if RT extended to L5/S1 or lower pelvic radiotherapy (LPRT) if it extended to the lower sacroiliac joints or below. Patients with negative inguinal nodes either underwent prophylactic inguinal radiotherapy (PIRT) or had inguinal observation (IO). Patterns of failure were compared.

Results

Twenty-seven patients (53%) had WPRT and 24 (47%) had LPRT. Forty-two patients had negative inguinal nodes: 29 (69%) had PIRT and 13 (31%) had IO. Median follow-up was 5.8 years. Twelve regional failures occurred in eight patients: three pelvic, one inguinal and four pelvic and inguinal. All patients with regional failure died of disease. Pelvic nodal failure was 7.7% in N0 and 33% in N1–3 patients (P = 0.012). There was no difference in pelvic regional failure between WPRT and LPRT (11% versus 16%, P = 0.64). There was only one possible regional failure above LPRT in this group (4%). Inguinal failure was 0% in the PIRT group compared with 23% in IO group (P = 0.009).

Conclusion

There was no difference in pelvic regional failure between WPRT and LPRT. LPRT is likely to be safe in N0 patients. Inguinal nodes should be treated in all patients.



http://ift.tt/2I7tIhX

Working memory alpha-beta band oscillatory signatures in adolescents and young adults

Abstract

The timing of neural activity is an intriguing way of exposing behaviourally-relevant neural activity, as neural populations exploit transient windows of synchronized activations to exchange dynamic communications in the service of various cognitive operations. The link between neural synchrony and working memory (WM) has been supported at the theoretical and empirical level. However, findings have also shown that WM encoding is also related to significant alpha-beta desynchronization. These findings have been primarily recorded during subsequent memory effect paradigms that compare correct with incorrect encoding trials. The dissociable contribution imparted by various processes to WM performance suggests that incorrect performance may not be directly translatable to unsuccessful encoding. Here, we address the relationship between alpha-beta desynchronization and encoding through the use of an alternative paradigm design by contrasting frontal and parietal human scalp EEG activity during the encoding interval of a delayed-matching to sample task with that recorded during a control task. The additional use of nonverbal/semantic visual stimulation and recruitment of typically developing adolescent subjects, has led us to the conclusion that encoding-relevant alpha-beta decrements can be replicated via a nonverbal/semantic delayed matching to sample task and these are also evident in typically developing adolescents, in addition to adults, as has been previously demonstrated. The identification of encoding-related alpha-beta decrements in adolescent subjects performing such WM tasks may open new avenues to explore whether such a rhythmic signature may explain WM and electrophysiological deficits that emerge in various adolescent neuropsychiatric disorders such as ADHD.

This article is protected by copyright. All rights reserved.



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Dopaminergic neuromodulation of high-gamma stimulus phase-locking in gerbil primary auditory cortex mediated by D1/D5-receptors

Abstract

Cortical release of the neurotransmitter dopamine has been implied in adapting cortical processing with respect to various functions including coding of stimulus salience, expectancy, error prediction, behavioral relevance, and learning. Dopamine agonists have been shown to modulate recurrent cortico-thalamic feedback, and should therefore also affect synchronization and amplitude of thalamo-cortical oscillations. In this study we have used multitaper spectral and time-frequency analysis of stimulus-evoked and spontaneous current source density patterns in primary auditory cortex of Mongolian gerbils to characterize dopaminergic neuromodulation of the oscillatory structure of current sources and sinks. We systemically applied D1/D5-receptor agonist SKF-38393 followed by competitive D1/D5-receptor antagonist SCH-23390. Our results reveal an increase in stimulus phase-locking in the high gamma-band (88 to 97 Hz) by SKF-38393, specifically in layers III/IV at the best-frequency, which occurred at 20 ms after tone-onset, and was reversed by SCH-23390. However, changes in induced oscillatory power after SKF-38393 treatment occurred stimulus-independently in the background activity in different layers than phase-locking effects, and were not reversed by SCH-23390. These effects might either reflect longer-lasting changes in neural background-noise, non-specific changes due to ketamine anesthesia, or an interaction of both. Without concomitant stimulus-induced power increase, increased stimulus phase-locking in layers III/IV indicates enhanced phase-resetting of neural oscillations by the stimulus after D1/D5-receptor activation. The frequency characteristics, together with the demonstrated stimulus- and layer-specificity suggest that changes in phase-resetting originate from dopaminergic neuromodulation of thalamo-cortical interactions. Enhanced phase-resetting might be a key step in the recruitment of cortical activity modes interpreting sensory input.

This article is protected by copyright. All rights reserved.



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Neuroanatomical characterization of imidazoline I2 receptor agonist-induced antinociception

Abstract

Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I2 receptor (I2R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I2R-associated behaviors are unknown. I2Rs are enriched in the arcuate nucleus, dorsal raphe (DR), interpeduncular nucleus, lateral mammillary body, medial habenula, nucleus accumbens (NAc), and paraventricular nucleus, thus this study investigated the antinociceptive and hypothermic effects of microinjections of the I2R agonist 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI). In rats, intra-DR microinjections produced antinociception in CFA- and CCI-induced pain models. Intra-NAc microinjections produced antinociception and increased noxious stimulus-associated side time in a place escape/avoidance paradigm. Intra-NAc pretreatment with the I2R antagonist idazoxan but not the D1 receptor antagonist SCH23390 or the D2 receptor antagonist raclopride attenuated intra-NAc 2-BFI-induced antinociception. Intra-NAc idazoxan did not attenuate systemically-administered 2-BFI-induced antinociception. Microinjections into the other regions did not produce antinociception, and in none of the regions produced hypothermia. These data suggest that I2R activation in some but not all I2R-enriched brain regions is sufficient to produce antinociception, and supports the theory that different I2R-associated effects are mediated via distinct receptor populations, which may in turn be distributed differentially throughout the CNS.

This article is protected by copyright. All rights reserved.



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Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine

Abstract

The alarming increase in heroin overdoses in the USA is a reminder of the need for efficacious and novel treatments for opiate addiction. This may reflect the relatively poor understanding of the neural basis of heroin, as compared to cocaine, seeking behavior. While cocaine reinforcement depends on the mesolimbic system, well established cocaine seeking is dependent on dorsolateral striatum (aDLS) dopamine-dependent mechanisms which are disrupted by N-acetylcysteine, through normalisation of corticostriatal glutamate homeostasis. However, it is unknown whether a functional recruitment of aDLS dopamine-dependent control over instrumental responding also occurs for heroin seeking, even though heroin reinforcement does not depend on the mesolimbic dopamine system. Lister Hooded rats acquired heroin self-administration and were subsequently trained to seek heroin daily over prolonged periods of time under the control of drug paired cues, as measured under a second order schedule of reinforcement. At different stages of training, i.e., early on, and when heroin seeking behavior was well established, we measured the sensitivity of drug seeking responses to either bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (5, 10 and μg/side) or systemic administration of N-acetylcysteine (30, 60 and 90 mg/kg). The results demonstrate that control over heroin seeking behavior devolves to aDLS-dopamine dependent mechanisms after extended training. Further aDLS-dependent well established cue-controlled heroin seeking was disrupted by N-acetylcysteine. Comparison with previous data on cocaine suggests that the development of drug seeking habits and the alteration of corticostriatal glutamate homeostasis, which is restored by N-acetylcysteine, are quantitatively similar between heroin and cocaine.

This article is protected by copyright. All rights reserved.



http://ift.tt/2IaGcFj

Spontaneous eye blink rate and dopamine synthesis capacity: Preliminary evidence for an absence of positive correlation

Abstract

Dopamine is central to a number of cognitive functions and brain disorders. Given the cost of neurochemical imaging in humans, behavioral proxy measures of dopamine have gained in popularity in the past decade, such as spontaneous eye blink rate (sEBR). Increased sEBR is commonly associated with increased dopamine function based on pharmacological evidence and patient studies. Yet, this hypothesis has not been validated using in vivo measures of dopamine function in humans. In order to fill this gap, we measured sEBR and striatal dopamine synthesis capacity using [18F]DOPA PET in 20 participants (9 healthy individuals and 11 pathological gamblers). Our results, based on frequentist and Bayesian statistics, as well as region-of-interest and voxel-wise analyses, argue against a positive relationship between sEBR and striatal dopamine synthesis capacity. They show that, if anything, the evidence is in favor of a negative relationship. These results, which complement findings from a recent study that failed to observe a relationship between sEBR and dopamine D2 receptor availability, suggest that caution and nuance are warranted when interpreting sEBR in terms of a proxy measure of striatal dopamine.

This article is protected by copyright. All rights reserved.



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Influence of auditory attention on sentence recognition captured by the neural phase

Abstract

The aim of this study was to investigate whether attentional influences on speech recognition are reflected in the neural phase entrained by an external modulator. Sentences were presented in 7 Hz sinusoidally modulated noise while the neural response to that modulation frequency was monitored by electroencephalogram (EEG) recordings in 21 participants. We implemented a selective attention paradigm including three different attention conditions while keeping physical stimulus parameters constant. The participants' task was either to repeat the sentence as accurately as possible (speech recognition task), to count the number of decrements implemented in modulated noise (decrement detection task), or to do both (dual task), while the EEG was recorded. Behavioral analysis revealed reduced performance in the dual task condition for decrement detection, possibly reflecting limited cognitive resources. EEG analysis revealed no significant differences in power for the 7 Hz modulation frequency, but an attention-dependent phase difference between tasks. Further phase analysis revealed a significant difference 500 ms after sentence onset between trials with correct and incorrect responses for speech recognition, indicating that speech recognition performance and the neural phase are linked via selective attention mechanisms, at least shortly after sentence onset. However, the neural phase effects identified were small and await further investigation.

This article is protected by copyright. All rights reserved.



http://ift.tt/2IacVuz

Paracetamol Serum Concentrations in Neonates Treated Enterally for Ductal Closure: A Pilot Study

We determined serum paracetamol concentrations 4 hours after the eighth dose in infants treated enterally for ductal closure. Serum paracetamol concentrations correlated (P = .0026) with ductal response. No patent ductus arteriosus in a baby with paracetamol levels <20 mg/L closed in response to treatment. Paracetamol levels also correlated (P = .046) with postnatal age.

http://ift.tt/2FyrCJn

Infant Weight and Length Growth Trajectories Modeled Using Superimposition by Translation and Rotation Are Differentially Associated with Body Composition Components at 3 and 7 Years of Age

To evaluate how infant weigh and length growth trajectories associate with body composition at 3 and 7 years because previous studies have noted that rapid infant weight gain increases risk for high body mass index (BMI) in children.

http://ift.tt/2HbB4zB

Trends in Teenagers' Nonopiod Substance Exposures Reported to Poison Control Centers, 2010-2015

To describe current trends in nonopioid substance exposures and associated outcomes among teenagers nationwide.

http://ift.tt/2FvNB3L

Factors Influencing Pediatric Resident Exposure to Adolescents in their Continuity Clinic

Adequate training in adolescent primary care is a challenge for pediatric residency programs. We examined residents' pediatric continuity clinic exposure to and comfort with adolescents, and their knowledge about best practices. Comfort was predicted by patient numbers, training level, and completing the adolescent rotation. Knowledge was predicted by completing the adolescent rotation.

http://ift.tt/2HfD1Lg

Poster Abstracts



http://ift.tt/2tlKRRq

Direct acting antivirals for patients without advanced liver disease: all for treatment and treatment for all?



http://ift.tt/2Fw0M4L

A Gain-of-Function Mutation in EPO in Familial Erythrocytosis

New England Journal of Medicine, Volume 378, Issue 10, Page 924-930, March 2018.


http://ift.tt/2FAxC4s

Ambient Temperature and Screening for Nasopharyngeal Cancer

New England Journal of Medicine, Volume 378, Issue 10, Page 962-963, March 2018.


http://ift.tt/2Hh9i4R

Tumors and Transformations

New England Journal of Medicine, Volume 378, Issue 10, Page 887-889, March 2018.


http://ift.tt/2FAxxha

Case 7-2018: A 25-Year-Old Man with New-Onset Seizures

New England Journal of Medicine, Volume 378, Issue 10, Page 941-948, March 2018.


http://ift.tt/2FAxsdm

Balancing Safety and Innovation for Cell-Based Regenerative Medicine

New England Journal of Medicine, Volume 378, Issue 10, Page 954-959, March 2018.


http://ift.tt/2HfhS3V

Letermovir Prophylaxis for Cytomegalovirus

New England Journal of Medicine, Volume 378, Issue 10, Page 963-965, March 2018.


http://ift.tt/2FBMyPQ

Analysis of Plasma Epstein–Barr Virus DNA to Screen for Nasopharyngeal Cancer

New England Journal of Medicine, Volume 378, Issue 10, Page 973-973, March 2018.


http://ift.tt/2HgUoeR

Effects of Sotagliflozin Added to Insulin in Type 1 Diabetes

New England Journal of Medicine, Volume 378, Issue 10, Page 966-968, March 2018.


http://ift.tt/2FBMv6C

A Shift in Thinking to Reduce Mother-to-Infant Transmission of Hepatitis B

New England Journal of Medicine, Volume 378, Issue 10, Page 952-953, March 2018.


http://ift.tt/2FAxfqA

Xanthogranulomatous Pyelonephritis

New England Journal of Medicine, Volume 378, Issue 10, Page 940-940, March 2018.


http://ift.tt/2HgUzqx

Primary Sjögren’s Syndrome

New England Journal of Medicine, Volume 378, Issue 10, Page 931-939, March 2018.


http://ift.tt/2HgUcMF

Acute Angle-Closure Glaucoma

New England Journal of Medicine, Volume 378, Issue 10, March 2018.


http://ift.tt/2Fx1Aq6

Physician-Assisted Death for Psychiatric Patients — Misguided Public Policy

New England Journal of Medicine, Volume 378, Issue 10, Page 883-885, March 2018.


http://ift.tt/2HgU7sl

Management of Acute Hip Fracture

New England Journal of Medicine, Volume 378, Issue 10, Page 971-972, March 2018.


http://ift.tt/2FCGiHk

Physician-Assisted Suicide and Psychiatric Illness

New England Journal of Medicine, Volume 378, Issue 10, Page 885-887, March 2018.


http://ift.tt/2HgTZcl

Self-Management of an Inferior ST-Segment Elevation Myocardial Infarction

New England Journal of Medicine, Volume 378, Issue 10, Page 960-962, March 2018.


http://ift.tt/2FBMlMy

Hypopituitarism after Single-Fraction Pituitary Adenoma Radiosurgery: Dosimetric Analysis based on Patients treated Using Contemporary Techniques

Hypopituitarism is the most frequent complication after pituitary adenoma radiosurgery (SRS). The dosimetric factors associated with pituitary insufficiency remain unclear despite more than 30 years of clinical usage.

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Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy



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Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer



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AKR1C enzymes sustain therapy resistance in paediatric T-ALL



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Trends in Analgesic Consumption in France Over the last 10 Years and Comparison of Patterns Across Europe

Summary

Aims

To describe consumption trends of three groups of analgesics (non-opioids, mild and strong opioids) between 2006 and 2015 in France, and compare this pattern of use with six European countries in 2015.

Methods

Annual drugs sales were extracted from the French national authority's consumption database and from the IMS-MIDAS and national databases for European countries.

Results

The use of mild opioids in France decreased by 53% during the last 10 years due to the declining use of dextropropoxyphene combinations, along with an increase in the use of non-opioids and strong opioids (from 72 to 93 and 2 to 2.8 defined daily doses/1,000 inhabitants/day, respectively). Paracetamol, the most-consumed analgesic, has increased during the last 10 years, particularly for the adult high dosage (+140%). The use of tramadol and codeine combinations has also increased by 62% and 42%, respectively. Morphine remained the most-used strong opioid although there were also high increases in the consumption of oxycodone (+613%) and fentanyl (+263% and +72% for transmucosal and transdermal forms, respectively). A comparison of the patterns of use in Europe in 2015 showed a higher consumption of both mild and strong opioids in the UK. France ranked first and third place respectively for paracetamol and mild opioid consumption, while its strong opioid use was among the lowest.

Conclusions

Paracetamol consumption is clearly highest in France, while its use of strong opioids is amongst the lowest in Europe, although the consumption of oxycodone has increased significantly. Further studies are required specifically to monitor these drugs.



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Prevalence of Exceeding Maximum Daily Dose of Acetaminophen, and Seasonal Variations in Cold-Flu Season

Abstract

Aims

To estimate prevalence of excess intake of acetaminophen, and investigate seasonal variations therein.

Methods

Between 2011 and 2016, 14,481 US adults who used acetaminophen in the preceding 30 days were sampled from national online panels and completed a detailed online daily diary of acetaminophen medication use for 7 days. Respondents were not told the study concerned acetaminophen. Cold/flu season (CFS), identified using Google© Trends data, was contrasted to off-season in symptoms, use of acetaminophen medications, and consumption exceeding 4 grams (the recommended daily maximum).

Results

Overall, 6.3% [95% CI: 6.0%-6.6%] of users exceeded 4 grams on at least one day; 3.7% [3.5%-3.9%] of usage days exceeded 4 grams. Cold/flu symptoms were more likely to be experienced and treated with acetaminophen in CFS than off-season. Acetaminophen users were more likely to exceed 4 grams during CFS (6.5% vs 5.3%; OR= 1.24, 1.04-1.48); days exceeding 4 grams also increased (3.9% vs 2.8%; OR= 1.37, 1.11-1.69). This was not due to differences in characteristics of individuals using acetaminophen in CFS, but primarily to increased use of over-the-counter (OTC) combination medications designed to treat upper respiratory cold/flu symptoms (33.2% of usage days in CFS vs 24.8% in off-season; OR=1.6, 1.5-1.7). When such medications were omitted, there was no statistically significant seasonal variation in exceeding 4 grams.

Conclusions

Acetaminophen use and over-dosing increases in CFS, primarily due to increased use of OTC combinations treating upper respiratory cold/flu symptoms. Pharmacists should warn users to follow labeled dosing directions, especially during CFS.



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Monoclonal Antibodies for Emerging Infectious Diseases — Borrowing from History

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New England Journal of Medicine, Ahead of Print.


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The Enigma of Blood Pressure Measurement in Children with CKD



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Need to Reclassify Etiologies of ESRD on the CMS 2728 Medical Evidence Report



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Intensive Hemodialysis Fails to Reduce Plasma Levels of Uremic Solutes



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Responsive Designed Interventions Are Needed to Support Positive Outcomes of Children and Adolescents with CKD



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Rest Easy with Intravenous Iron for Dialysis Patients?: High Dose IV Iron Safety



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A View of the Bundle from a Home Dialysis Perspective: Present at the Creation



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Serum Sodium and Cognition in Older Community-Dwelling Men

Background and objectives

Mild hyponatremia is a common finding in older adults; however, the association of lower serum sodium with cognition in older adults is currently unknown. We determined whether lower normal serum sodium is associated with cognitive impairment and risk of cognitive decline in community-dwelling older men.

Design, setting, participants, & measurements

Five thousand four hundred thirty-five community-dwelling men aged ≥65 years who participated in Osteoporotic Fractures in Men, a cohort study with a median follow-up for cognitive function of 4.6 years, were included in this analysis. Multivariable logistic regression was used to examine the association between baseline fasting serum sodium levels and the odds of prevalent cognitive impairment (cross-sectional analysis; modified Mini-Mental Status [3MS] score <1.5 SD [<84] below or Trail Making Test Part B time >1.5 SD above the mean [>223 seconds]) and cognitive decline (prospective analysis [n=3611]; decrease in follow-up 3MS score or increase in Trails B time >1.5 SD of the mean score/time change [>9 or >67 seconds]).

Results

Participants were aged 74±6 years with a fasting mean serum sodium level of 141±3 mmol/L. Fifteen percent (n=274), 12% (n=225), and 13% (n=242) had prevalent cognitive impairment in tertiles 1, 2, and 3, respectively. After adjustment, lower serum sodium was associated with prevalent cognitive impairment (tertile 1 [126–140 mmol/L] versus tertile 2 [141–142 mmol/L], odds ratio [OR], 1.30; 95% confidence interval [95% CI], 1.06 to 1.61). Fourteen percent (n=159), 10% (n=125), and 13% (n=159) had cognitive decline in tertiles 1, 2, and 3, respectively. Lower serum sodium was also associated with cognitive decline (tertile 1 versus tertile 2, OR, 1.37; 95% CI, 1.06 to 1.77). Tertile 3 (143–153 mmol/L) was additionally associated with cognitive decline. Results were similar in sensitivity analyses according to clinical cut-offs and by quartiles.

Conclusions

In community-dwelling older men, serum sodium between 126–140, and 126–140 or 143–153 mmol/L, are independently associated with prevalent cognitive impairment and cognitive decline, respectively.



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Crafting the Prescription for Patients Starting Peritoneal Dialysis



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Person-Centered Integrated Care for Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and objectives

The effectiveness of person-centered integrated care strategies for CKD is uncertain. We conducted a systematic review and meta-analysis of randomized, controlled trials to assess the effect of person-centered integrated care for CKD.

Design, setting, participants, & measurements

We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to April of 2016), and selected randomized, controlled trials of person-centered integrated care interventions with a minimum follow-up of 3 months. Random-effects meta-analysis was used to assess the effect of person-centered integrated care.

Results

We included 14 eligible studies covering 4693 participants with a mean follow-up of 12 months. In moderate quality evidence, person-centered integrated care probably had no effect on all-cause mortality (relative risk [RR], 0.86; 95% confidence interval [95% CI], 0.68 to 1.08) or health-related quality of life (standardized mean difference, 0.02; 95% CI, –0.05 to 0.10). The effects on renal replacement therapy (RRT) (RR, 1.00; 95% CI, 0.65 to 1.55), serum creatinine levels (mean difference, 0.59 mg/dl; 95% CI, –0.38 to 0.36), and eGFR (mean difference, 1.51 ml/min per 1.73 m2; 95% CI, –3.25 to 6.27) were very uncertain. Quantitative analysis suggested that person-centered integrated care interventions may reduce all-cause hospitalization (RR, 0.38; 95% CI, 0.15 to 0.95) and improve BP control (RR, 1.20; 95% CI, 1.00 to 1.44), although the certainty of the evidence was very low.

Conclusions

Person-centered integrated care may have little effect on mortality or quality of life. The effects on serum creatinine, eGFR, and RRT are uncertain, although person-centered integrated care may lead to fewer hospitalizations and improved BP control.



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Neurocognitive and Educational Outcomes in Children and Adolescents with CKD: A Systematic Review and Meta-Analysis

Background and objectives

Poor cognition can affect educational attainment, but the extent of neurocognitive impairment in children with CKD is not well understood. This systematic review assessed global and domain-specific cognition and academic skills in children with CKD and whether these outcomes varied with CKD stage.

Design, setting, participants, & measurements

Electronic databases were searched for observational studies of children with CKD ages 21 years old or younger that assessed neurocognitive or educational outcomes. Risk of bias was assessed using a modified Newcastle–Ottawa scale. We used random effects models and expressed the estimates as mean differences with 95% confidence intervals stratified by CKD stage.

Results

Thirty-four studies (25 cross-sectional, n=2095; nine cohort, n=991) were included. The overall risk of bias was high because of selection and measurement biases. The global cognition (full-scale intelligence quotient) of children with CKD was classified as low average. Compared with the general population, the mean differences (95% confidence intervals) in full-scale intelligence quotient were –10.5 (95% confidence interval, –13.2 to –7.72; all CKD stages, n=758), –9.39 (95% confidence interval, –12.6 to –6.18; mild to moderate stage CKD, n=582), –16.2 (95% confidence interval, –33.2 to 0.86; dialysis, n=23), and –11.2 (95% confidence interval, –17.8 to –4.50; transplant, n=153). Direct comparisons showed that children with mild to moderate stage CKD and kidney transplants scored 11.2 (95% confidence interval, 2.98 to 19.4) and 10.1 (95% confidence interval, –1.81 to 22.0) full-scale intelligence quotient points higher than children on dialysis. Children with CKD also had lower scores than the general population in executive function and memory (verbal and visual) domains. Compared with children without CKD, the mean differences in academic skills (n=518) ranged from –15.7 to –1.22 for mathematics, from –9.04 to –0.17 for reading, and from –14.2 to 2.53 for spelling.

Conclusions

Children with CKD may have low-average cognition compared with the general population, with mild deficits observed across academic skills, executive function, and visual and verbal memory. Limited evidence suggests that children on dialysis may be at greatest risk compared with children with mild to moderate stage CKD and transplant recipients.



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Weekly Standard Kt/Vurea and Clinical Outcomes in Home and In-Center Hemodialysis

Background and objectives

Patients undergoing hemodialysis with a frequency other than thrice weekly are not included in current clinical performance metrics for dialysis adequacy. The weekly standard Kt/Vurea incorporates treatment frequency, but there are limited data on its association with clinical outcomes.

Design, setting, participants, & measurements

We used multivariable regression to examine the association of dialysis standard Kt/Vurea with BP and metabolic control (serum potassium, calcium, bicarbonate, and phosphorus) in patients incidental to dialysis treated with home (n=2373) or in-center hemodialysis (n=109,273). We further used Cox survival models to examine the association of dialysis standard Kt/Vurea with mortality, hospitalization, and among patients on home hemodialysis, transfer to in-center hemodialysis.

Results

After adjustment for potential confounders, patients with dialysis standard Kt/Vurea <2.1 had higher BPs compared with patients with standard Kt/Vurea 2.1 to <2.3 (3.4 mm Hg higher [P<0.001] for home hemodialysis and 0.9 mm Hg higher [P<0.001] for in-center hemodialysis). There were no clinically meaningful associations between dialysis standard Kt/Vurea and markers of metabolic control, irrespective of dialysis modality. There was no association between dialysis standard Kt/Vurea and risk for mortality, hospitalization, or transfer to in-center hemodialysis among patients undergoing home hemodialysis. Among patients on in-center hemodialysis, dialysis standard Kt/Vurea <2.1 was associated with higher risk (adjusted hazard ratio, 1.11; 95% confidence interval, 1.07 to 1.14) and standard Kt/Vurea ≥2.3 was associated with lower risk (adjusted hazard ratio, 0.97; 95% confidence interval, 0.94 to 0.99) for death compared with standard Kt/Vurea 2.1 to <2.3. Additional analyses limited to patients with available data on residual kidney function showed similar relationships of dialysis and total (dialysis plus kidney) standard Kt/Vurea with outcomes.

Conclusions

Current targets for standard Kt/Vurea have limited utility in identifying individuals at increased risk for adverse clinical outcomes for those undergoing home hemodialysis but may enhance risk stratification for in-center hemodialysis.



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Kidney Biomarkers and Decline in eGFR in Patients with Type 2 Diabetes

Background and objectives

Biomarkers may improve identification of individuals at risk of eGFR decline who may benefit from intervention or dialysis planning. However, available biomarkers remain incompletely validated for risk stratification and prediction modeling.

Design, setting, participants, & measurements

We examined serum cystatin C, urinary kidney injury molecule–1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (UNGAL) in 5367 individuals with type 2 diabetes mellitus and recent acute coronary syndromes enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. Baseline concentrations and 6-month changes in biomarkers were also evaluated. Cox proportional regression was used to assess associations with a 50% decrease in eGFR, stage 5 CKD (eGFR<15 ml/min per 1.73 m2), or dialysis.

Results

eGFR decline occurred in 98 patients (1.8%) over a median of 1.5 years. All biomarkers individually were associated with higher risk of eGFR decline (P<0.001). However, when adjusting for baseline eGFR, proteinuria, and clinical factors, only baseline cystatin C (adjusted hazard ratio per 1 SD change, 1.66; 95% confidence interval, 1.41 to 1.96; P<0.001) and 6-month change in urinary neutrophil gelatinase-associated lipocalin (adjusted hazard ratio per 1 SD change, 1.07; 95% confidence interval, 1.02 to 1.12; P=0.004) independently associated with CKD progression. A base model for predicting kidney function decline with nine standard risk factors had strong discriminative ability (C-statistic 0.93). The addition of baseline cystatin C improved discrimination (C-statistic 0.94), but it failed to reclassify risk categories of individuals with and without eGFR decline.

Conclusions

The addition of cystatin C or biomarkers of tubular injury did not meaningfully improve the prediction of eGFR decline beyond common clinical factors and routine laboratory data in a large cohort of patients with type 2 diabetes and recent acute coronary syndrome.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_01_16_CJASNPodcast_18_3_G.mp3



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Striving to Achieve an Integrated Home Dialysis System: A Report from the Ontario Renal Network Home Dialysis Attrition Task Force



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Mycophenolate Mofetil in Combination with Steroids for Treatment of C3 Glomerulopathy: A Case Series

Background and objectives

C3 glomerulopathy is a form of complement-mediated GN. Immunosuppressive therapy may be beneficial in the treatment of C3 glomerulopathy. Mycophenolate mofetil is an attractive treatment option given its role in the treatment of other complement-mediated diseases and the results of the Spanish Group for the Study of Glomerular Diseases C3 Study. Here, we study the outcomes of patients with C3 glomerulopathy treated with steroids and mycophenolate mofetil.

Design, setting, participants, & measurements

We conducted a retrospective chart review of patients in the C3 glomerulopathy registry at Columbia University and identified patients treated with mycophenolate mofetil for at least 3 months and follow-up for at least 1 year. We studied clinical, histologic, and genetic data for the whole group and compared data for those who achieved complete or partial remission (responders) with those who did not achieve remission (nonresponders). We compared remission with mycophenolate mofetil with remission with other immunosuppressive regimens.

Results

We identified 30 patients who met inclusion criteria. Median age was 25 years old (interquartile range, 18–36), median creatinine was 1.07 mg/dl (interquartile range, 0.79–1.69), and median proteinuria was 3200 mg/g creatinine (interquartile range, 1720–6759). The median follow-up time was 32 months (interquartile range, 21–68). Twenty (67%) patients were classified as responders. There were no significant differences in baseline characteristics between responders and nonresponders, although initial proteinuria was lower (median 2468 mg/g creatinine) in responders compared with nonresponders (median 5000 mg/g creatinine) and soluble membrane attack complex levels were higher in responders compared with nonresponders. For those tapered off mycophenolate mofetil, relapse rate was 50%. Genome-wide analysis on complement genes was done, and in 12 patients, we found 18 variants predicted to be damaging. None of these variants were previously reported to be pathogenic. Mycophenolate mofetil with steroids outperformed other immunosuppressive regimens.

Conclusions

Among patients who tolerated mycophenolate mofetil, combination therapy with steroids induced remission in 67% of this cohort. Heavier proteinuria at the start of therapy and lower soluble membrane attack complex levels were associated with treatment resistance.



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The Dialysis Facility Compare Five-Star Rating System at 2 Years



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An Outcomes-Based Definition of Proteinuria Remission in Focal Segmental Glomerulosclerosis

Background and objectives

Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival.

Design, setting, participants, & measurements

Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan–Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score–adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy.

Results

In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score–adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P=0.01; month 8: hazard ratio, 0.30; P=0.002).

Conclusions

Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_02_20_CJASNPodcast_18_3_T.mp3



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The Affordable Care Act, Medicaid Expansion, and Disparities in Kidney Disease



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Rapid Nanoprobe Signal Enhancement by In Situ Gold Nanoparticle Synthesis

In this work, a protocol for signal enhancement of nanoprobe-based biosensing is presented. The protocol is based on the reduction of chloroauric acid onto the surface of existing nanoprobes that consist of gold, silver, silica or iron-oxide nanoparticles.

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Detection of Detergent-sensitive Interactions Between Membrane Proteins

We describe a protocol for detection of detergent-sensitive interactions between membrane proteins using binding of the sorting receptor, sortilin, to the first luminal loop of the glucose transporter protein, GLUT4, as an example.

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Ultrasonic Fatigue Testing in the Tension-Compression Mode

A protocol for ultrasonic fatigue testing in the high and ultra-high cycle region in axial tension-compression loading mode.

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Need for normalization: the non-standard reference standard for microvascular invasion diagnosis in hepatocellular carcinoma

Abstract

Background

Preoperative microvascular invasion (MVI) assessment in hepatocellular carcinoma (HCC) is one of the current research focuses, with studies reporting controversial results regarding MVI-associated risk factors. As a possible source of bias, reported MVI rate (percentage of MVI-positive patients) varies a lot among studies. Pathological examination should have been the golden criteria of MVI diagnosis, but no standard and generally adopted pathological examination protocol exists.

Methods and results

It is highly possible that underestimated pathological diagnosis of MVI exists. We present two likely examples to stress the problem and indicate the root of the problem partially being an unreliable pathological examination. Results of studies basing on unreliable reference standard can be less convincing and even misleading, which is the most basic and fundamental problem in this research field.

Conclusion

There is an urgent need to settle the disputes regarding pathological sampling, microscopy, and reporting, in order to promote future academic exchange and consensus development on MVI assessment. Several concerns about pathological MVI assessment should be focused on in the future research as we put up in the review.



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Clinical significance and prognostic value of receptor conversion in hormone receptor positive breast cancers after neoadjuvant chemotherapy

Abstract

Background

Neoadjuvant chemotherapy (NAC) is widely used in advanced breast cancer patients. However, there is little known about conversion frequency of estrogen receptor (ER) and/or progesterone receptor (PR) status for hormone receptor positive-breast cancer patients after NAC and their correlation with prognosis.

Methods

In this study, 231 breast cancer patients with residual disease after NAC were enrolled and divided into receptor stable group (having no conversion in both ER and PR status pre- and post-NAC) and any receptor conversion group (having any conversion in either ER or PR status). Univariate and multivariate survival analyses were used to compare survival differences between the two groups.

Results

Fifty-five patients (23.8%) had ER and/or PR conversion after NAC. Younger patients (≤ 50 years) were more likely to have receptor conversion (P = 0.014). For 213 patients (92.2%) who received adjuvant endocrinotherapy after surgery, the 5-year disease free survival (DFS) estimates for patients in the any receptor conversion group (55.2%) was worse than patients in the receptor stable group (73.7%, Log-rank test, P = 0.015). While the 5-year overall survival estimates for patients with or without receptor conversion were not statistically different (86.0 vs. 82.4%, Log-rank test, P = 0.587). In multivariate Cox proportional hazard analyses, patients with any receptor conversion had worse DFS (hazard ratio, 1.995; 95% confidence interval, 1.130–3.521, P = 0.031).

Conclusions

It is necessary to recommend patients to test biomarkers in residual disease and pay more attention to patients who have any receptor conversion. These patients may need more individual therapy after surgery.



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Processing of Bulk Nanocrystalline Metals at the US Army Research Laboratory

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This paper provides a brief overview of the ongoing efforts at the Army Research Laboratory on the processing of bulk nanocrystalline metals with an emphasis on the methodologies used for the production of the novel metal powders.

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Sleep Deprivation Distinctly Alters Glutamate Transporter 1 Apposition and Excitatory Transmission to Orexin and MCH Neurons

Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep–wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep–wake neurons in the male rat following 6 h sleep deprivation (SD) or following 6 h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin neurons in the lateral hypothalamus compared with Rest. Reduced GLT1 apposition was associated with tonic presynaptic inhibition of excitatory transmission to these neurons due to the activation of Group III metabotropic glutamate receptors, an effect mimicked by a GLT1 inhibitor in the Rest condition. In contrast, SD resulted in increased GLT1 apposition with sleep-promoting melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus. Functionally, this decreased the postsynaptic response of MCH neurons to high-frequency synaptic activation without changing presynaptic glutamate release. The changes in GLT1 apposition with orexin and MCH neurons were reversed after 3 h of sleep opportunity following 6 h SD. These SD effects were specific to orexin and MCH neurons, as no change in GLT1 apposition was seen in basal forebrain cholinergic or parvalbumin-positive GABA neurons. Thus, within a single hypothalamic area, GLT1 differentially regulates excitatory transmission to wake- and sleep-promoting neurons depending on sleep history. These processes may constitute novel astrocyte-mediated homeostatic mechanisms controlling sleep–wake behavior.

SIGNIFICANCE STATEMENT Sleep–wake cycles are regulated by the alternate activation of sleep- and wake-promoting neurons. Whether and how astrocytes can regulate this reciprocal neuronal activity are unclear. Here we report that, within the lateral hypothalamus, where functionally opposite wake-promoting orexin neurons and sleep-promoting melanin-concentrating hormone neurons codistribute, the glutamate transporter GLT1, mainly present on astrocytes, distinctly modulates excitatory transmission in a cell-type-specific manner and according to sleep history. Specifically, GLT1 is reduced around the somata of orexin neurons while increased around melanin-concentrating hormone neurons following sleep deprivation, resulting in different forms of synaptic plasticity. Thus, astrocytes can fine-tune the excitability of functionally discrete neurons via glutamate transport, which may represent novel regulatory mechanisms for sleep.



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