Advanced Healthcare Materials, EarlyView.
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Τετάρτη 12 Σεπτεμβρίου 2018
Small‐Sized Cationic miRi‐PCNPs Selectively Target the Kidneys for High‐Efficiency Antifibrosis Treatment
Arbuscular mycorrhizal fungal communities and global change: an uncertain future
Abstract
Arbuscular mycorrhizal (AM) fungi are amongst the most common and functionally important symbionts of terrestrial plants and are highly likely to be affected by global change. The potential consequences of this on plant growth and carbon and nutrient cycling has led to a growing demand for their inclusion in global change models. However, our understanding of their responses to environmental change remains limited. This review provides an overview of recent experiments attempting to predict the effects of atmospheric and climatic change on AM fungal community diversity, composition and functioning. This includes rising atmospheric carbon dioxide and tropospheric ozone levels, altered water availability, warming and nitrogen deposition. Changes detected are often highly variable and context dependent, but trends are emerging such as the similar responses of community composition to enhanced nitrogen deposition and atmospheric CO2, despite the likely contrasting effect of these environmental changes on carbon availability. The review also highlights shortfalls in our current knowledge and suggests priorities for future research, particularly advocating more integrated approaches linking the study of community characteristics and functions and examination of fine level genetic changes, wider geographical contexts and a greater range of AM fungal functions.https://ift.tt/2NCjI5P
Novel lytic bacteriophages of Klebsiella oxytoca ABG-IAUF-1 as the potential agents for mastitis phage therapy
Abstract
Mastitis is an inflammation of the mammary gland that occurs when pathogenic microorganisms enter the udder. Even though tremendous advancements in veterinary diagnosis and therapeutics, mastitis is still the most frequent and costly disease of dairy herds overall the world. The purpose of this research was to isolate and identify the lytic phages as a potential method for biological control of bovine mastitis. In this study Klebsiella oxytoca was isolated from contaminated milk samples of Isfahan dairy herds, Isfahan, Iran and characterized as K. oxytoca ABG-IAUF-1 and its 16s-rDNA sequence was deposited in GenBank under the accession numbers of MF175803.1. Then, the four novel specific lytic bacteriophages of K. oxytoca ABG-IAUF-1 from Isfahan public wastewater were isolated and identified. The results of transmission electron microscopy indicated that theses isolated phages were related to Myoviridae and Podoviridae families of bacteriophages. Also the analysis of the growth curve of K. oxytoca ABG-IAUF-1 before and after treatment with lytic phage showed the 97% success rate of the phages in preventing of bacterial growth. This is the first report indicating the use of bacteriophages as the potential agents for eliminating the pathogenic bacteria responsible for bovine mastitis in Iran. The applications of these lytic phages could be an asset for biocontrolling of pathogenic agents in medical and veterinary biotechnology.https://ift.tt/2NaiMWL
Non-conventional Yeast cell factories for sustainable bioprocesses
Abstract
The non-conventional yeasts Kluyveromyces lactis, Yarrowia lipolytica, Ogataea polymorpha and Pichia pastoris have been developed as eukaryotic expression hosts because of their desirable growth characteristics, including inhibitor and thermo-tolerance, utilization of diverse carbon substrates, and high amount of extracellular protein secretion. These yeasts already have established in the heterologous production of vaccines, therapeutic proteins, food additives, and bio-renewable chemicals, but recent advances in genetic tool box have the potential to greatly expand and diversify their impact on biotechnology. The diversity of these yeasts includes many strains possessing highly useful, and in some cases even uncommon, metabolic capabilities potentially helpful for bioprocess industry. This review outlines the recent updates of non-conventional yeast in sustainable bioprocesses.https://ift.tt/2CQG9A3
Assessment of acute, 14-day, and 13-week repeated oral dose toxicity of Tiglium seed extract in rats
Seed of mature Croton tiglium Linne, also known as Tiglium seed (TS), has been widely used as a natural product due to its several health beneficial properties including anti-tumor and antifungal activities. Desp...
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Cancer in Sexual and Gender Minority Patients: Are We Addressing Their Needs?
Abstract
Purpose of Review
To describe the current literature regarding the cancer care of sexual and gender minority patients and to identify significant knowledge gaps that hinder our understanding of the unique needs of sexual and gender minority patients with cancer.
Recent Findings
Sexual and gender minorities suffer from cancer-related disparities, including lower rates of cancer screening, higher incidence of certain cancers, and higher cancer mortality rates. Sexual side effects, depression, and social isolation are especially common among sexual minority individuals with cancer. While the aforementioned disparities are concerning, the cancer-specific needs of sexual and gender minorities remain understudied. Population-based, prospective studies evaluating cancer-specific risks, mortality, and survivorship issues facing gender and sexual minorities are lacking.
Summary
There is a paucity of literature guiding the cancer care of sexual and gender minority patients. Areas that require further study include epidemiologic evaluations, cancer screening recommendations, and cancer treatment and survivorship.
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Screening of parathyroid gland by high frequency ultrasound and the relationship between recurrent urinary calculi and primary hyperparathyroidism
OBJECTIVE: To understand the value of high frequency ultrasound in the clinical screening of parathyroid gland, and to summarize the intrinsic relationship between primary hyperparathyroidism and recurrent urinary calculi.
PATIENTS AND METHODS: 98 cases of urinary calculi were randomly selected, and the patients were admitted to our hospital from March 2014 to August 2017. A total of 100 healthy subjects were selected as group B in the same period. High frequency color Doppler ultrasonography scan recorded the results.
RESULTS: Among the subjects in group A, 67 (68.37%) showed parathyroid gland, 14 cases (14.29%) had tumor mass in the parathyroid system, 40 cases more than those in group B (40.00%) and 2 cases (2.00%), (p <0.05). There were 10 cases (10.20%) of primary hyperparathyroidism in group A and no cases of primary hyperparathyroidism in group B (p < 0.05). The occurrence of primary hyperparathyroidism was 26.92% (7/26) in the number of cases, with 3 and more cases of urinary calculi, which was higher than that in the first recurrent cases (3/72), (p<0.005).
CONCLUSIONS: One of the key causes of recurrent episodes of urinary calculi is primary hyperparathyroidism, which can be applied to high frequency ultrasonography to develop professional screening of parathyroid gland in cases of urinary calculi.
L'articolo Screening of parathyroid gland by high frequency ultrasound and the relationship between recurrent urinary calculi and primary hyperparathyroidism sembra essere il primo su European Review.
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Treatment satisfaction in women receiving palbociclib combination therapies for advanced/metastatic breast cancer
Future Oncology, Ahead of Print.
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Enzalutamide after chemotherapy in advanced castration-resistant prostate cancer: the Italian Named Patient Program
Future Oncology, Ahead of Print.
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The Italian Mastocytosis Registry: 6-year experience from a hospital-based registry
Future Oncology, Ahead of Print.
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Investigation of surface structure and biocompatibility of chitosan‐coated zirconia and alumina dental abutments
Clinical Implant Dentistry and Related Research, EarlyView.
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Clinical peri‐implant parameters and inflammatory cytokine profile among smokers of cigarette, e‐cigarette, and waterpipe
Clinical Implant Dentistry and Related Research, EarlyView.
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Provider Education and Vaporizer Labeling Lead to Reduced Anesthetic Agent Purchasing With Cost Savings and Reduced Greenhouse Gas Emissions
Anesthetic agents are known greenhouse gases with hundreds to thousands of times the global warming impact compared with carbon dioxide. We sought to mitigate the negative environmental and financial impacts of our practice in the perioperative setting through multidisciplinary staff engagement and provider education on flow rate reduction and volatile agent choice. These efforts led to a 64% per case reduction in carbon dioxide equivalent emissions (163 kg in Fiscal Year 2012, compared with 58 kg in Fiscal Year 2015), as well as a cost savings estimate of $25,000 per month. Accepted for publication August 1, 2018. Funding: K.L.Z. receives nonclinical time for her role as Medical Director of Sustainability for UW Health. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Karin L. Zuegge, MD, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI 53792. Address e-mail to zuegge@wisc.edu. © 2018 International Anesthesia Research Society
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The Perioperative Management of Ascending Aortic Dissection
Acute aortic syndromes are a distinct group of pathologies involving the wall of the aorta that present acutely and can be potentially fatal unless treated in a timely fashion. The syndrome is dominated by aortic dissections, which comprise ≥95% of all such presentations. Those involving the ascending aorta are particularly lethal and require specific and early surgical treatment compared to dissections involving other parts of the aorta. The surgical repair of an ascending aortic dissection presents multiple challenges to the anesthesiologist. Thoughtful management throughout the perioperative period is critical for minimizing the significant morbidity and mortality associated with this condition. In this narrative review, we provide an overview of the perioperative management of patients presenting for the surgical repair of an ascending aortic dissection. Preoperative discussion focuses on assessment, hemodynamic management, and risk stratification. The intraoperative section includes an overview of anesthetic management, transesophageal echocardiographic assessment, and coagulopathy, as well as surgical considerations that may influence anesthetic management. Accepted for publication July 17, 2018. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Madhav Swaminathan, MD, MMCi, FASE, FAHA, Department of Anesthesiology, Duke University Medical Center, Box 3094 DUMC/5691F HAFS, Durham, NC 27710. Address e-mail to madhav.swaminathan@duke.edu. © 2018 International Anesthesia Research Society
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TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer
Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of AR signalling inhibitors (ARSi). Experimental design: Between March 2014 and April 2017, we recruited mCRPC patients (n=168) prior to ARSi in a cohort study encompassing 10 European centres. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA). Targeted CTC RNA-seq allowed the detection of eight AR splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss-of-heterozygosity, mutations and structural rearrangements in ctDNA. Clinical or radiological progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox-regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumour burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value (HR 1.88, 95%CI 1.18-3.00, p = 0.008), and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p < 0.0001), which was validated in an independent mCRPC cohort (n=202) starting first-line ARSi (median, 14.3 vs 6.39 vs 2.23 months, p < 0.0001). Conclusions: In an all-comer cohort, tumour burden estimates and TP53 outperform any AR perturbation to infer prognosis.
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The TLR7/8/9 antagonist IMO-8503 inhibits cancer-induced cachexia
Muscle wasting is a feature of the cachexia syndrome, which contributes significantly to cancer patient mortality. We have previously demonstrated that miR-21 is secreted through extracellular vesicles (EVs) by lung and pancreatic cancer cells and promotes JNK-dependent cell death through its binding to the TLR7 receptor in murine myoblasts. Here we evaluate the ability of IMO-8503, a TLR7, 8 and 9 antagonist, to inhibit cancer-induced cachexia. Using EVs isolated from lung and pancreatic cancer cells and from patient plasma samples, we demonstrate that IMO-8503 inhibits cell death induced by circulating miRNAs with no significant toxicity. Intraperitoneal administration of the antagonist in a murine model for Lewis Lung Carcinoma (LLC-induced cachexia) strongly impaired several cachexia-related features, such as expression of Pax7 as well as caspase 3 and PARP cleavage in skeletal muscles, and significantly prevented the loss of lean mass in tumor-bearing mice. IMO-8503 also impaired circulating miRNA-induced cell death in human primary myoblasts. Taken together, our findings strongly indicate that IMO-8503 serves as a potential therapy for the treatment of cancer cachexia.
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DEDICATE: proposal for a conceptual framework to develop dementia-friendly integrated eCare support
Evidence shows that the implementation of information and communication technologies (ICT) enabled services supporting integrated dementia care represents an opportunity that faces multi-pronged challenges. Fi...
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“You can tell by the way I use my walk.” Predicting the presence of cognitive load with gait measurements
There is considerable evidence that a person's gait is affected by cognitive load. Research in this field has implications for understanding the relationship between motor control and neurological conditions i...
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Resistance pattern and maternal knowledge, attitude and practices of suspected Diarrheagenic Escherichia coli among children under 5 years of age in Addis Ababa, Ethiopia: cross sectional study
Diarrheal illness remains one of the leading causes of morbidity and mortality among children under 5 years of age worldwide, especially in developing countries. Diarrheagenic Escherichia coli (DEC) is the major ...
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Modifying Risks in Ventral Hernia Patients With Prehabilitation: A Randomized Controlled Trial
Objective: The aim of this study was to determine whether preoperative nutritional counseling and exercise (prehabilitation) in obese patients with ventral hernia repair (VHR) results in more hernia-free and complication-free patients. Background: Obesity and poor fitness are associated with complications following VHR. These issues are prevalent in low socioeconomic status patients. Methods: This was a blinded, randomized controlled trial at a safety-net academic institution. Obese patients (BMI 30 to 40) seeking VHR were randomized to prehabilitation versus standard counseling. VHR was performed once preoperative requirements were met: 7% total body weight loss or 6 months of counseling and no weight gain. Primary outcome was the proportion of hernia-free and complication-free patients. Secondary outcomes were wound complications at 1 month postoperative and weight loss measures. Univariate analysis was performed. Results: Among 118 randomized patients, prehabilitation was associated with a higher percentage of patients who lost weight and achieved weight loss goals; however, prehabilitation was also associated with a higher dropout rate and need for emergent repair. VHR was performed in 44 prehabilitation and 34 standard counseling patients. There was a trend toward less wound complication in prehabilitation patients (6.8% vs 17.6%, P = 0.167). The prehabilitation group was more likely to be hernia-free and complication-free (69.5% vs 47.5%, P = 0.015). Conclusions: It is feasible to implement a prehabilitation program for obese patients at a safety-net hospital. Prehabilitation patients have a higher likelihood of being hernia-free and complication-free postoperatively. Although further trials and long-term outcomes are needed, prehabilitation may benefit obese surgical patients, but there may be increased risks of dropout and emergent repair. Clinical Trial Registration: This trial was registered with clinicaltrials.gov (NCT02365194)https://ift.tt/2CRftzf
Analysis of the Learning Curve and Patient Outcomes of Endovascular Repair of Thoracoabdominal Aortic Aneurysms Using Fenestrated and Branched Stent Grafts: Prospective, Nonrandomized, Single-center Physician-sponsored Investigational Device Exemption Clinical Study
Objective: To evaluate the outcomes and learning curve of fenestrated and branched endovascular repair (F/BEVAR) of thoracoabdominal aneurysms. Summary of Background Data: Endovascular aneurysm repair has reduced morbidity and mortality compared with open surgical repair. However, application to thoracoabdominal aneurysm repair remains limited by procedural complexity and device availability. Methods: Fifty patients treated in a prospective, nonrandomized, single-center Investigational Device Exemption (IDE) study between January 2014 and July 2017 were analyzed. Patients (mean age 75.6 ± 7.5 years; mean aneurysm diameter 67.3 ± 9.8 mm) underwent F/BEVAR of thoracoabdominal aneurysms (58% type IV; 42% type I-III) using custom-manufactured endografts. The experience was divided into 3 cohorts (Early: 1 to 17; Mid: 18 to 34; Late: 35 to 50) to evaluate learning curve effects on key process measures. Results: F/BEVAR included 194 visceral arteries (average 3.9 per patient). Technical success was 99.5% (193/194 targeted arteries). Thirty-day major adverse events (MAEs) included 3 (6%) deaths, 1 (2%) new-onset dialysis, 3 (6%) paraparesis/paraplegia, and 2 (4%) strokes. One-year survival was 79 ± 7%. Comparing the Early and Late groups revealed reductions in procedure time (452 ± 74 vs 362 ± 53 minutes; P = 0.0001), fluoroscopy time (130 ± 40 vs 99 ± 27 minutes; P = 0.016), contrast administration (157 ± 73 vs 108 ± 38 mL; P = 0.028), and estimated blood loss (EBL; 1003 ± 933 vs 481 ± 317 mL; P = 0.042). Intensive care unit (ICU) and total length of stay (LOS) decreased from 4 ± 3 to 2 ± 1 days and from 7 ± 6 to 5 ± 2 days, respectively, but was not statistically significant. Conclusions: Use of F/BEVAR for treatment of thoracoabdominal aneurysms is safe and effective. During this early experience, there was a significant improvement in key process measures reflecting improvements in technique and physician learning over time.https://ift.tt/2CRfDXn
Combined analysis of antigen presentation and T cell recognition reveals restricted immune responses in melanoma [Research Briefs]
The quest for tumor-associated-antigens (TAAs) and neo-antigens is a major focus of cancer immunotherapy. Here we combine a neo-antigen prediction-pipeline and human-leukocyte-antigen (HLA)-peptidomics to identify TAAs and neo-antigens in 16 tumors derived from seven melanoma patients, and characterize their interactions with their TILs. Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neo-antigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell co-signatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neo-antigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neo-antigen-specific T-cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA-peptidomics with neo-antigen predictions allows robust identification of targetable neo-antigens, which could successfully guide personalized cancer-immunotherapies.
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Global Surgery: Effective Involvement of US Academic SurgeryReport of the American Surgical Association Working Group on Global Surgery
There is an unacceptably high burden of death and disability from conditions that are treatable by surgery, worldwide and especially in low- and middle-income countries (LMICs). The major actions to improve this situation need to be taken by the surgical communities, institutions, and governments of the LMICs. The US surgical community, including the US academic surgical community, has, however, important roles to play in addressing this problem. The American Surgical Association convened a Working Group to address how US academic surgery can most effectively decrease the burden from surgically treatable conditions in LMICs. The Working Group believes that the task will be most successful (1) if the epidemiologic pattern in a given country is taken into account by focusing on those surgically treatable conditions with the highest burdens; (2) if emphasis is placed on those surgical services that are most cost-effective and most feasible to scale up; and (3) if efforts are harmonized with local priorities and with existing global initiatives, such as the World Health Assembly with its 2015 resolution on essential surgery. This consensus statement gives recommendations on how to achieve those goals through the tools of academic surgery: clinical care, training and capacity building, research, and advocacy. Through all of these, the ethical principles of maximally and transparently engaging with and deferring to the interests and needs of local surgeons and their patients are of paramount importance. Notable benefits accrue to US surgeons, trainees, and institutions that engage in global surgical activities.https://ift.tt/2QorJtw
Long-term Quality of Life and Gastrointestinal Functional Outcomes After Pancreaticoduodenectomy
Objective: To perform a comprehensive assessment of long-term quality of life (QOL) and gastrointestinal (GI) function in patients following pancreaticoduodenectomy (PD). Summary of Background Data: Survival after PD has greatly improved and thus has resulted in a larger population of survivors, yet long-term QOL and GI function after PD is largely unknown. Methods: Patients were identified from a global online support group. QOL was measured using the Short Form-36, while GI function was assessed using the Gastrointestinal Symptom Rating Scale. QOL and GI function were analyzed across subgroups based on time after PD. QOL was compared with preoperative measurements and with established values of a general healthy population (GHP). Multivariate linear regression was used to identify predictors of QOL. Results: Of the 7605 members of the online support group, 1102 responded to the questionnaire with 927 responders meeting inclusion criteria. Seven hundred seventeen (77.3%) of these responders underwent PD for malignancy. Mean age was 57 ± 12 years and 327 (35%) were male. At the time of survey, patients were 2.0 (0.7, 4.3) years out from surgery, with a maximum 30.7-year response following PD. Emotional and physical domains of QOL improved with time and surpassed preoperative levels between 6 months and 1 year after PD (both P 5 years) included total GSRS score [β = −1.70 (−1.91, −1.50)], female sex [β = 3.58 (0.67, 6.46)], and being a cancer survivor [β = 3.93 (0.60, 7.25)]. Conclusions: Long-term QOL following PD improves over time, however never approaches that of a GHP. GI dysfunction persists in long-term survivors and is an independent predictor of poor QOL. Long-term physical, psychosocial, and GI functional support after PD is encouraged.https://ift.tt/2CRfxPv
Is it Time to Abandon the Milan Criteria?: Results of a Bicoastal US Collaboration to Redefine Hepatocellular Carcinoma Liver Transplantation Selection Policies
Objectives: European liver transplant (LT) centers have moved away from using the Milan Criteria (MC) for hepatocellular carcinoma (HCC) patient selection, turning to models including tumor biological indices, namely alpha-fetoprotein (AFP). We present the first US model to incorporate an AFP response (AFP-R), with comparisons to MC and French-AFP models (F-AFP). Methods: AFP-R was measured as differences between maximum and final pre-LT AFP in HCC patients undergoing LT at 3 US centers (2001 to 2013). Cox and competing risk-regression analyses identified predictors of recurrence-free survival (RFS). Results: Of 1450 patients, 235 (16.2%) were outside MC. Tumor size, number, and AFP-R were independent predictors of RFS and were assigned weighted points based on Cox-regression analysis. An AFP-R consistentlyhttps://ift.tt/2x6DYSQ
The Clinical Significance of Breast-only and Node-only Pathologic Complete Response (pCR) After Neoadjuvant Chemotherapy (NACT): A Review of 20,000 Breast Cancer Patients in the National Cancer Data Base (NCDB)
Objective: To determine whether the association between overall survival (OS) and response to neoadjuvant chemotherapy (NACT) in breast cancer patients varies with tumor subtype and anatomic extent of pathologic complete response (pCR). Background: pCR after NACT predicts improved OS in breast cancer, but it is unclear whether pCR limited to the breast or axilla is also associated with OS. Methods: Women with cT1-3/cN0-1 breast cancer diagnosed in 2010 to 2014 who underwent surgery following NACT were identified in the NCDB and divided into 4 subtypes based on reported hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Kaplan-Meier curves and Cox proportional hazards models were used to estimate OS. Multivariate logistic regression was used to identify factors associated with post-NACT response, defined as upstage (yp stage>clinical stage); no change (clinical stage = yp stage); overall (breast+axilla, ypT0N0), breast-only (ypT0N1/N1mic), or node-only (ypT1-3N0) pCR. Results: Of 33,162 identified patients, 20,265 experienced overall pCR (n = 6370, 19.2%), breast-only pCR (n = 494, 1.5%), node-only pCR (n = 1133, 3.4%), no stage change (n = 9641, 29.1%), or upstage (n = 2627, 7.9%). Compared with no stage change, breast-only pCR was associated with improved OS in triple-negative disease [hazard ratio = 0.58, 95% confidence interval (95% CI) = 0.37–0.89], and node-only pCR was associated with improved OS in both triple-negative (hazard ratio = 0.55,95% CI = 0.39–0.76) and HR+/HER2− disease (hazard ratio = 0.54, 95% CI = 0.33–0.89). For patients achieving overall (breast+axilla) pCR, unadjusted 5-year OS was 0.94 (95% CI = 0.93–0.95), with no difference between patients who were cN0 (hazard ratio = 0.95, 95% CI = 0.93–0.96) or cN1 (hazard ratio = 0.94, 95% CI = 0.92–0.96) at diagnosis. Conclusions: In node-positive patients, pCR limited to either the breast or axilla predicts survival for select receptor subtypes. In patients achieving pCR in both the breast and axilla, survival is driven by response to NACT rather than presenting cN stage.https://ift.tt/2Qr6BTM
Impact of a Novel Preoperative Patient-centered Surgical Wellness Program
Objective: The objective of this study was to evaluate if a preoperative wellness bundle significantly decreases the risk of hospital acquired infections (HAI). Background: HAI threaten patient outcomes and are a significant burden to the healthcare system. Preoperative wellness efforts may significantly decrease the risk of infections. Methods: A group of 12,396 surgical patients received a wellness bundle in a roller bag during preoperative screening at an urban academic medical center. The wellness bundle consisted of a chlorhexidine bath solution, immuno-nutrition supplements, incentive spirometer, topical mupirocin for the nostrils, and smoking cessation information. Study staff performed structured patient interviews, observations, and standardized surveys at key intervals throughout the perioperative period. Statistics compare HAI outcomes of patients in the wellness program to a nonintervention group using the Fisher's exact test, logistic regression, and Poisson regression. Results: Patients in the nonintervention and intervention groups were similar in demographics, comorbidity, and type of operations. Compliance with each element was high (80% mupirocin, 72% immuno-nutrition, 71% chlorhexidine bath, 67% spirometer). The intervention group had statistically significant reductions in surgical site infections, Clostridium difficile, catheter associated urinary tract infections, and patient safety indicator 90. Conclusions: A novel, preoperative, patient-centered wellness program dramatically reduced HAI in surgical patients at an urban academic medical center.https://ift.tt/2QqdgNW
Pure Laparoscopic Donor Hepatectomies: Ready for Widespread Adoption?
Objective: In order to minimize the impact of donation, fully laparoscopic donor hepatectomy (LDH) is being investigated at a few centers throughout the world. We report here our experience with 51 living donor pure laparoscopic hepatectomies. Background: Adoption of minimal access techniques to living donor liver transplantation (LDLT) has been slowed by concerns about donor safety and the quality of the grafts. Methods: Of 344 donor hepatectomies (DHs) for living donor liver transplantation (LDLT) since 1998, 51 pure LDH have been performed since 2009. We report here our experience with 51 living donor pure laparoscopic hepatectomy (LH), based on prospectively collected data. There were 31 left lateral sectionectomy and 20 full lobectomies LH. We matched full lobe LH to open DH prior to introduction of LH. Results: LH increased from 21% of all DH in first 5 years of performing LH to 45% of DH in the most recent 3 years. Laparoscopic donors were more likely female, had lower body mass index, smaller total livers, and smaller allografts but longer operating room times. In the total LD experience, total 5 donors were converted to open surgery (10%), 2 donors required transfusion (4%), and there was 2 donor bile leaks (4%). Recipient patient and graft 1-year survival was 98% and 94%. Conclusions: Our experience indicates that LDH for LDLT can be safely used with appropriate attention to learning curve and progression from left lateral sectionectomy to right hepatectomy.https://ift.tt/2CRfNhr
Declining Resident Experience in Open Vascular Operations Threatens the Status of Vascular Surgery as an Essential Content Area of General Surgery Training
Objective: The objective of this study was to document trends in the performance of open arterial vascular surgery procedures (OAVP) by general surgery residents (GSR). Background: The ACGME Review Committee for Surgery considers vascular surgery (VS) to be an "essential content area." However, the operative experience in VS for GSRs is threatened by 1) increasing numbers of GSRs, 2) increasing numbers of VS trainees, and 3) the proliferation of endovascular surgery. Methods: The last 16 years of ACGME national reports of case logs for completing GSRs were reviewed. Total vascular operations and OAVPs performed as "surgeon" were recorded and analyzed. The number of individuals completing ACGME programs in general and vascular surgery annually over that period were also recorded and analyzed. To better understand long-term and more recent trends, trends were analyzed for the 15-year period spanned by the 16 years of data as well as the most recent 10- and 5-year periods. Results: The number of individuals completing both general and vascular surgery programs increased significantly. Over 15 years, the total vascular operations performed by GSRs significantly declined as did the total OAVPs and the OAVPs in 7 of 9 categories. In just the last 5 years, significant declines occurred in 5 OAVP categories. Conclusions: Operative experience in OAVPs for GSRs has significantly declined. Because fundamental VS skills are necessary for operative general surgery, VS should remain an essential content area. However, programs cannot solely depend on operative experience to teach fundamental VS skills.https://ift.tt/2Qr6iIC
A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma
Objectives: One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery. Methods: In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery. Results: The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC. Conclusions: We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.https://ift.tt/2Qr6wPY
Insurance Status Biases Trauma-system Utilization and Appropriate Interfacility Transfer: National and Longitudinal Results of Adult, Pediatric, and Older Adult Patients
Objective: To identify the association between insurance status and the probability of emergency department admission versus transfer for patients with major injuries (Injury Severity Score >15) and other complex trauma likely to require higher-level trauma center (TC) care across the spectrum of TC care. Background: Trauma systems were developed to facilitate direct transport and transfer of patients with major/complex traumatic injuries to designated TCs. Emerging literature suggests that uninsured patients are more likely to be transferred. Methods: Nationally weighted Nationwide Emergency Department Sample (2010–2014) and longitudinal California State Inpatient Databases/State Emergency Department Databases (2009–2011) data identified adult (18–64 yr), pediatric (≤17 yr), and older adult (≥65 yr) trauma patients. Risk-adjusted multilevel (mixed-effects) logistic regression determined differences in the relative odds of direct admission versus transfer and outcome measures based on initial level of TC presentation. Results: In all 3 age groups, insured patients were more likely to be admitted [eg, nontrauma center (NTC) private vs uninsured odds ratio (95% confidence interval): adult 1.54 (1.40–1.70), pediatric 1.95(1.45–2.61)]. The trend persisted within levels III and II TCs (eg, level II private vs uninsured adult 1.83 (1.30–2.57)] and among other forms of trauma likely to require transfer. At the state level, among transferred NTC patients, 28.5% (adult), 34.1% (pediatric), and 39.5% (older adult) of patients with major injuries were not transferred to level I/II TCs. An additional 44.3% (adult), 50.9% (pediatric), and 57.6% (older adult) of all NTC patients were never transferred. Directly admitted patients experienced higher morbidity [adult: 19.6% vs 8.2%, odds ratio (95% confidence interval):2.74 (2.17–3.46)] and mortality [3.3% vs 1.8%, 1.85 (1.13–3.04)]. Conclusions: Insured patients with significant injuries initially evaluated at NTCs and level III/II TCs were less likely to be transferred. Such a finding appears to result in less optimal trauma care for better-insured patients and questions the success of transfer-guideline implementation.https://ift.tt/2Qqd7tS
Stem Cell Mobilization Is Lifesaving in a Large Animal Preclinical Model of Acute Liver Failure
Introduction: Acute liver failure (ALF) affects 2000 Americans each year with no treatment options other than liver transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rodents. The objective of this study was to assess whether stem cell mobilizing drugs are lifesaving in a large animal preclinical model of ALF, to assess readiness for a clinical trial. Methods: Male Yorkshire pigs (14–18 kg) were divided into 2 groups, control (n = 6) and treatment (n = 6). All pigs received an intravenous bolus of the hepatotoxin D-galactosamine (0.5 g/kg) via central line and were followed up until death or day 28. Treated animals received simultaneous intramuscular injection of plerixafor (1 mg/kg) and G-CSF (2 μg/kg) at baseline, 24 and 48 hours after toxin infusion to mobilize endogenous stem cells, as previously described. Control animals received saline. Results: All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by clinical, biochemical, and histopathological evidence of ALF. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by a mean of 4× in the treated group at the peak of mobilization (P = 0.0004). Conclusions: Stem cell mobilizing drugs were lifesaving in a preclinical large animal model of ALF. Since no therapeutic options other than liver transplantation are currently available for critically ill patients with ALF, a multicenter clinical trial is warranted.https://ift.tt/2CQ8XIP
Depression Characterization and Race among Stroke Survivors Receiving Inpatient Rehabilitation
Race and ethnicity play a significant role in post-stroke outcomes. This brief report describes the presence of depression among stroke survivors who received inpatient rehabilitation and whether depression differs by race. Data from eRehabData® and electronic medical records were analyzed for patients who received rehabilitation after an acute ischemic or hemorrhagic stroke. Of 1501 stroke patients, 61.3% were White, 33.9% were African American (AA) and 4.8% were of other race/ethnic backgrounds. By retrospective clinical review, depression was documented for 29.7% of stroke patients. Pre-morbid versus new onset of post-stroke depression was documented for 13.4% and 21.6% of Whites, 7.5% and 11.5% of AA, and 0% and 16.7% of patients of other race/ethnic groups. Compared with Whites, AA and people of other races had a lower odds of post-stroke depression (AA adjusted odds ratio [OR]=0.52, 95% confidence interval [CI]=0.41-0.68; other races OR=0.37, 95% CI=0.19-0.71), after adjusting for all other significant risk factors identified in the bivariate analysis (sex, hyperlipidemia, cognitive deficit, neglect). Depression was documented for one in three stroke survivors who received inpatient rehabilitation, and highest among Whites especially for pre-stroke depression. Addressing depression in rehabilitation care needs to consider individual patient characteristics and pre-stroke health status. Corresponding author: Janet Prvu Bettger, ScD, FAHA; DUMC 2919, 40 Medicine Circle, Durham, NC, 27710; Office: 919-613-0379; Email: janet.bettger@duke.edu Funding Disclosure: This work was supported in part by NIH NR25GM102739, NIH/NINR P30NR014139, and institutional grants from Duke University School of Nursing and Cannon Research Center Carolinas Medical Center Author Disclosures or Conflicts of Interest: Nothing disclose from any author Previous Dissemination: Preliminary findings for this study were presented by Gabrielle M Harris at the International Stroke Conference on February 12, 2015 in Nashville, Tennessee. The presentation was entitled: "Depression differs by race among stroke survivors receiving inpatient rehabilitation" and the abstract was published as Harris GM, Thomas JG, Nguyen V, Hirsch MA, Guerrier T, Hamm D, Pereira C, Bettger JP. Depression differs by race among stroke survivors receiving inpatient rehabilitation. Stroke 2015;46(Suppl 1):ATP129-ATP129. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2xd0QQq
https://ift.tt/2xd0QQq
Physiatry as a Leader for Post Acute Care in Integrated Healthcare Systems
As health care is being moved to a higher level of accountability, there has been a focus on improving outcomes through improving post acute care. The issues of cost and readmissions to acute care settings are very important, but the focus on patient function has not been foremost. Due to the fact that most post acute care needs are based on functional limitations, and that physiatrists are well versed in transitions of care, rehabilitation of patients back to community settings, team building, and leadership, it is appropriate for rehabilitation medicine to take a leadership role in the planning and development of post acute care services in the new integrated healthcare systems that are becoming prevalent in healthcare. This review discusses some of the issues in post acute care, the growth of the integrated health system model, and how there are opportunities and challenges for physiatric leadership to help develop these new models of care. Funding source: No external Funding Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2x8Ch7n
https://ift.tt/2x8Ch7n
Fingolimod Cuts Multiple Sclerosis Relapses in Pediatric Patients
WEDNESDAY, Sept. 12, 2018 -- Among pediatric patients with relapsing multiple sclerosis, fingolimod is associated with a lower rate of relapse but a higher rate of serious adverse events than interferon beta-1a, according to a study published in the...
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Highest Opioid-Related Mortality Seen in Construction Jobs
WEDNESDAY, Sept. 12, 2018 -- Proportional mortality ratios (PMRs) for heroin-related overdose deaths and methadone-related overdose deaths from 2007 to 2012 were highest among construction workers, according to research published in the Aug. 24...
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FDA Gets Tough on Juul, Other Electronic Cigarette Makers
WEDNESDAY, Sept. 12, 2018 -- Calling the use of electronic cigarettes a burgeoning epidemic among teens, the U.S Food and Drug Administration today announced a crackdown on the sale of Juuls and other flavored e-cigarette devices to minors. More...
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At Least 15 Men Near Ground Zero Have Breast Cancer
WEDNESDAY, Sept. 12, 2018 -- At least 15 men who worked near Ground Zero after the 9/11 attacks have been diagnosed with breast cancer, a New York City law firm claims. According to CBS News, one of the firm's clients worked for a data storage...
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RUSSCO-RSP comparative study of immunohistochemistry diagnostic assays for PD-L1 expression in urothelial bladder cancer
Abstract
In this collaborative study by the Russian Society of Clinical Oncology and the Russian Society of Pathology, we assessed the concordance among three validated, commercially available PD-L1 immunohistochemistry assays for patients with urothelial cancer. Tumors from 100 urothelial cancer patients were stained with the antibody clones 22C3 (Agilent), SP142 (Ventana Medical Systems), and SP263 (Ventana Medical Systems), which are used in clinical trials of second-line therapy with checkpoint inhibitors. Four trained pathologists independently evaluated the percentages of tumor cells (TC) and tumor-infiltrating immune cells (IC) that were stained at any intensity by each of the antibodies. The test-specific cutoffs for the proportions of stained cells in a positive sample were pre-specified as TC + IC ≥ 10% or TC ≥ 10% for 22C3, IC ≥ 5% for SP142, and TC ≥ 25% or IC ≥ 25% for SP263. Three hundred immunohistochemistry slides were scored. The percentages of PD-L1 staining in the three assays without using any cutoff were higher in the IC than in the TC (55% versus 24% for 22C3, 45% versus 8% for SP142, and 72% versus 27% for SP263, respectively). The Pearson correlation coefficients for anti-PD-L1 staining in the IC were 0.5, 0.69, and 0.85 with 22C3/SP142, 22C3/SP263, and SP142/SP263, respectively. The Pearson correlation coefficients for PD-L1 staining in the TC were 0.93, 0.99, and 0.91 for the same pairs. Among the patients who were negative for PD-L1 staining by one test, 91–100% were also negative by the other tests. Among the patients who were positive by one test, 43–100% were also positive by the other tests. Our data indicate that repeated testing can be avoided as a patient with urothelial cancer who is classified as negative for PD-L1 expression by one of the three single tests using the corresponding cutoff rule is highly likely (91–100%) to be classified as negative by either of the other tests.
https://ift.tt/2Ql6hpk
Surprising image of an enterovesical fistula resulting from a perforated Meckel's diverticulitis
ANZ Journal of Surgery, EarlyView.
https://ift.tt/2N8INpn
Malignant phyllodes: excellent response to neoadjuvant radiotherapy
ANZ Journal of Surgery, EarlyView.
https://ift.tt/2x9YS3D
Migrating faecolith: an unusual case of small bowel obstruction
ANZ Journal of Surgery, EarlyView.
https://ift.tt/2N9QCv1
Treatment of Punctate Inner Choroidopathy with Choroidal Neovascularization Using Corticosteroid and Intravitreal Ranibizumab
Background. To evaluate the treatment outcomes of patients with punctate inner choroidopathy (PIC) and secondary choroidal neovascularization (CNV). Methods. This is a retrospective study of 24 eyes in 22 patients suffering from PIC with CNV. Patients were treated with intravitreal ranibizumab monotherapy (14 eyes) or combined oral corticosteroid and intravitreal ranibizumab therapy (corticosteroid-ranibizumab group, 10 eyes). Mean follow-up duration was 24.0 months. We evaluated best-corrected visual acuity (BCVA), fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and optical coherence tomography, before and after treatment. The following variables were compared between groups: number of intravitreal ranibizumab injections, BCVA, recurrence of CNV, and change in PIC lesions. Results. The ranibizumab monotherapy group received an average of 3 intravitreal ranibizumab injections; mean logMAR visual acuity improvement was 0.34, and 8 eyes developed recurrent CNV during follow-up. The corticosteroid-ranibizumab group received an average of 1.9 intravitreal ranibizumab injections; mean logMAR visual acuity improvement was 0.61, and there was no recurrence of CNV. Combined corticosteroid-ranibizumab therapy also resulted in better resolution of PIC lesions and fewer new PIC lesions. Conclusion. Both corticosteroid-ranibizumab treatment and ranibizumab monotherapy could significantly improve the vision of PIC patients with CNV. Combined corticosteroid and intravitreal ranibizumab treatment appeared to reduce CNV recurrence and development of new PIC lesions compared with ranibizumab monotherapy.
https://ift.tt/2x3INNu
Global Trends in Application of Stereology as a Quantitative Tool in Biomedical Research
Stereology is a quantitative and comparative method that utilizes planes, lines, and points for the estimation of three-dimensional parameters in morphological studies. It primarily focuses on geometrical features of objects such as number, density, length, area, and volume. A scientometric study was conducted to analyze global research trends in application of stereology in biomedical research. Stereology has gained wide application resulting into design-based stereological methods. Data for this study were retrieved from the SCOPUS database. At least 5,732 publications employing stereology as analytical tool were produced in a period of 50 years between 1966 and 2016. Half (2,858; 49.87%) of these publications were produced in the last 12 years from 2005 to 2016. The relative growth rate (RGR) of publications decreased from 1967 (0.69) to 2016 (0.03) whereas the doubling time (DT) increased from 1.00 to 20.56 in the same period. A great majority (5,332; 93.02%) of the publications retrieved from SCOPUS were journal articles in various biomedical fields. The Journal of Microscopy tops the list of journals with at least 205 articles. The most productive country was USA with at least 1663 (23.10%) publications and Aarhus Universitet tops the list of institutions with at least 306 publications. J.R. Nyengaard was the most prolific author who contributed at least 125 publications. The highly cited article had a total of 2,054 citations with an average of over 82 citations per year. Given the growing importance of stereology in biomedical research, it is necessary to promote its application among scholars.
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Social Cognition through the Lens of Cognitive and Clinical Neuroscience
Social cognition refers to a set of processes, ranging from perception to decision-making, underlying the ability to decode others' intentions and behaviors to plan actions fitting with social and moral, besides individual and economic considerations. Its centrality in everyday life reflects the neural complexity of social processing and the ubiquity of social cognitive deficits in different pathological conditions. Social cognitive processes can be clustered in three domains associated with (a) perceptual processing of social information such as faces and emotional expressions (social perception), (b) grasping others' cognitive or affective states (social understanding), and (c) planning behaviors taking into consideration others', in addition to one's own, goals (social decision-making). We review these domains from the lens of cognitive neuroscience, i.e., in terms of the brain areas mediating the role of such processes in the ability to make sense of others' behavior and plan socially appropriate actions. The increasing evidence on the "social brain" obtained from healthy young individuals nowadays constitutes the baseline for detecting changes in social cognitive skills associated with physiological aging or pathological conditions. In the latter case, impairments in one or more of the abovementioned domains represent a prominent concern, or even a core facet, of neurological (e.g., acquired brain injury or neurodegenerative diseases), psychiatric (e.g., schizophrenia), and developmental (e.g., autism) disorders. To pave the way for the other papers of this issue, addressing the social cognitive deficits associated with severe acquired brain injury, we will briefly discuss the available evidence on the status of social cognition in normal aging and its breakdown in neurodegenerative disorders. Although the assessment and treatment of such impairments is a relatively novel sector in neurorehabilitation, the evidence summarized here strongly suggests that the development of remediation procedures for social cognitive skills will represent a future field of translational research in clinical neuroscience.
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Mummification in Korea and China: Mawangdui, Song, Ming and Joseon Dynasty Mummies
Over the decades, mummy studies have expanded to reconstruct a multifaceted knowledge about the ancient populations' living conditions, pathologies, and possible cause of death in different spatiotemporal contexts. Mainly due to linguistic barriers, however, the international knowledge of East Asian mummies has remained sketchy until recently. We thus analyse and summarize the outcomes of the studies so far performed in Korea and China in order to provide mummy experts with little-known data on East Asian mummies. In this report, similarities and differences in the mummification processes and funerary rituals in Korea and China are highlighted. Although the historical periods, the region of excavation, and the structures of the graves differ, the cultural aspects, the mechanisms of mummification, and biological evidence appear to be essentially similar to each other. Independently from the way they are called locally, the Korean and Chinese mummies belong to the same group with a shared cultural background.
https://ift.tt/2CNYmhN
Two Cases of Sinonasal Non-Intestinal-Type Adenocarcinoma with Squamoid Morules Expressing Nuclear β-Catenin and CDX2: A Curious Morphologic Finding Supported by Molecular Analysis
Sinonasal non-intestinal-type adenocarcinoma (non-ITAC) is a rare, morphologically diverse neoplasm of the head and neck. Squamoid morular metaplasia has recently been reported as an occasional finding in non-ITAC. Interestingly, these squamoid morules often show aberrant expression of CDX2 as well as nuclear expression of β-catenin, similar to other tumors that show this type of metaplasia, but the underlying mechanism responsible for this finding is not completely understood. We present two cases of low-grade non-ITAC with squamoid morules coexpressing CDX2 and nuclear β-catenin by immunohistochemistry, both of which were found to harbor a mutation in CTNNB1, the gene encoding β-catenin. This finding provides support that an alteration in the β-catenin pathway, including mutations in the β-catenin gene itself, is responsible for this recently described morphologic phenomenon in non-ITAC.
https://ift.tt/2Og8m4m
Circulating Extracellular Vesicles in Human Disease
It is well known that cells release fluid-filled sacs (vesicles) to the extracellular environment during cell death, or apoptosis, but it has been increasingly recognized that healthy cells may also release vesicles in the process of normal functions. Vesicles that are released by healthy cells…
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The motor unit number index (MUNIX) profile of patients with adult Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a genetically determined lower motor neuron (LMN) disease caused by loss of function of the SMN1 gene on chromosome 5 (Finkel et al. 2015) (Lefebvre et al. 1995). The disease typically manifests with proximal and symmetrical muscle weakness and atrophy, and exhibits considerable clinical heterogeneity depending on SMN2 copy numbers (Mercuri et al. 2018). SMA type III and IV are considered slowly progressive forms of the disease, extending well into adulthood and characterized by acquisition of walking ability (Wang et al.
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The Use of Donation After Cardiac Death Organs for Simultaneous Liver-Kidney Transplant: To DCD or Not to DCD?
Background Due to challenges with organ scarcity, many centers performing simultaneous liver-kidney transplant are opting to accept donation after cardiac death (DCD) organs as a means of facilitating earlier transplant and reducing death rates on the waitlist. It has been suggested however, that DCD organs may have inferior graft and patient survival posttransplant compared with donation after neurologic death (DND) organs. Methods We created a Markov model to compare the overall outcomes of accepting a DCD SLKT now versus waiting for a DND SLKT in patients waitlisted for SLKT, stratified by base MELD score (≤ 20, 21-30, >30). Results Waiting for DND SLKT was the preferred treatment strategy for patients with a MELD score of ≤ 30 (incremental value of 0.54 and 0.36 QALYs for MELD ≤ 20 and MELD 21-30 with DND versus DCD SLKT, respectively). The option to accept a DCD SLKT became the preferred choice for those with a MELD score > 30 (incremental value of 0.31 QALYs for DCD versus DND SLKT). This finding was confirmed in a probabilistic sensitivity analysis and persisted when analyzing total life years obtained for accept DCD versus do not accept DCD. Conclusions There is a benefit to accepting DCD SLKT for patients with MELD > 30. Although not accepting DCD SLKT and waiting for DND SLKT is the preferred option for patients with MELD ≤ 30, the incremental value is small. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Corresponding Author: Amanda J Vinson, MD, 5082 Dickson Building, QEII Health Sciences Centre-VG site, 5820 University Avenue, Halifax, Nova Scotia, B3H 1V9, 902-473-2675, 902-473-2749. Email: Amanda.vinson@nshealth.ca Authorship Page Authorship: All authors participated in research design. AV and BK did the initial data analysis and KT and BK provided feedback and suggestions to make the analysis more robust. AV wrote the initial manuscript and BK, BGL and KT provided feedback and helped with constructing the figures. Disclosures: The authors declare no conflicts of interest. Funding: There was no funding for this study. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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https://ift.tt/2NCMRhj
Blood Pressure in De novo Heart Transplant Recipients Treated with Everolimus Compared with a Cyclosporine-Based Regimen: Results from the Randomized SCHEDULE Trial
Background Systemic hypertension is prevalent in heart transplant recipients, and has been partially attributed to treatment with calcineurin inhibitors (CNIs). The SCHEDULE trial was the first randomized trial to study early withdrawal of CNIs in de novo heart transplant recipients, comparing an everolimus-based immunosuppressive regimen with conventional CNI-based treatment. As a prespecified secondary endpoint, blood pressure was repeatedly compared across treatment arms. Methods SCHEDULE was a prospective, multicenter, randomized, controlled, parallel-group, open-label trial in de novo adult heart transplant recipients, undertaken at transplant centers in Scandinavia. Blood pressure was assessed with 24-hour ambulatory blood pressure monitoring up to 3 years after HTx in 83 patients. Results Overall, systolic blood pressure fell with time, from 138 ± 15 mmHg 2 weeks after HTx to 134 ± 11 mmHg after 12 months and 132 ± 14 mmHg after 36 months (p = 0.003). Diastolic blood pressure did not change over time. After 12 months, there was a numerically larger fall in systolic blood pressure in the everolimus arm (between-group difference 8 mmHg; p = 0.053), and after 36 months, there was a significant between group difference of 13 mmHg (p = 0.02) in favor of everolimus. Conclusions In this first, randomized trial with early CNI avoidance in de novo HTx recipients, we observed a modest fall in systolic blood pressure over the first 1 – 3 years after transplantation. The fall in systolic blood pressure was more pronounced in patients allocated to everolimus. Clinical trial registration: ClinicalTrials.gov (NCT01266148) at https://ift.tt/KkipBP Address for correspondence: Arne K. Andreassen, Department of Cardiology, Oslo University Hospital Rikshospitalet, PO Box 4950 Nydalen, 0424 Oslo, Norway. Phone +47230700. aandreas@ous-hf.no Authorship statement AK Andreassen participated in research design, performance of the research, writing of the manuscript, and critical revision of the manuscript for important intellectual content K Broch participated in writing of the manuscript, performance of the research, data analysis, and critical revision of the manuscript for important intellectual content H Eiskjær participated in research design, performance of the research, and critical revision of the manuscript for important intellectual content K Karason participated in research design, performance of the research, and critical revision of the manuscript for important intellectual content E Gude participated in research design, performance of the research, and critical revision of the manuscript for important intellectual content D Mølbak participated in performance of the research, and critical revision of the manuscript for important intellectual content W Stueflotten participated in performance of the research, and critical revision of the manuscript for important intellectual content L Gullestad participated in research design, performance of the research, and critical revision of the manuscript for important intellectual content Disclosure: The authors declare no conflicts of interest. Funding: The SCHEDULE trial was funded by Novartis Scandinavia. The funding source had no role in the design of the study, in the analyses of the results, or in the decision to publish. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2x9LCMp
https://ift.tt/2x9LCMp
IL-17A is critical for CD8+ T effector response in airway epithelial injury after transplantation
Background Airway epithelium is the primary target of trachea and lung transplant rejection, the degree of epithelial injury is closely correlated with obliterative bronchiolitis development. In this study, we investigated the cellular and molecular mechanisms of IL-17A-mediated airway epithelial injury after transplantation. Methods Murine orthotopic allogeneic trachea or lung transplants were implemented in wild type or RORγt-/- mice. Recipients received anti-IL-17A or anti-IFNγ for cytokine neutralization, anti-CD8 for CD8+ T cell depletion, or STAT3-inhibitor to suppress Th17/Tc17 development. Airway injury and graft inflammatory cell infiltration were examined by histopathology and immunohistochemistry. Gene expression of IL-17A, IFNγ, perforin, granzyme B and chemokines in grafts was quantitated by real-time RT-PCR. Results IL-17A and IFNγ were rapidly expressed and associated with epithelial injury and CD8+ T cell accumulation after allotransplantation. Depletion of CD8+ T cells prevented airway epithelial injury. Neutralization of IL-17A or devoid of IL-17A production by RORγt deficiency improved airway epithelial integrity of the trachea allografts. Anti-IL-17A reduced the expression of CXCL9, CXCL10, CXCL11 and CCL20, and abolished CD8+ T cell accumulation in the trachea allografts. Inhibition of STAT3 activation significantly reduced IL-17A expression in both trachea and lung allografts; however it increased IFNγ expression and cytotoxic activities, which resulted in the failure of airway protection. Conclusions Our data reveal the critical role of IL-17A in mediating CD8+ T effector response that causes airway epithelial injury and lung allograft rejection, and indicate that inhibition of STAT3 signals could drive CD8+ T cells from Tc17 toward Tc1 development. Correspondence: Jiangnan Xu, MD, Department of Immunology, Capital Medical University, No.10 Xi Tou Tiao, You An Men Wai, Beijing 100069, China. Phone: +8610-83911826; Fax: +8610-83911439; E-mail addresses: xujn@ccmu.edu.cn. Authorship Y.D. and J.X. participated in the research design. R.Z. performed the experiments, analyzed the data and prepared the figures. H.F. and R.C. helped with some experiments and data analysis. R.Z. and Y.D. wrote the manuscript. J.C.O. and J.X. provided critical revision of the article. All authors approved the final version of article. Disclosures The authors declare no conflicts of interest. Funding This work was supported by the National Natural Science Foundation of China (grants 81370188 and 81770092). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2xbmRzk
https://ift.tt/2xbmRzk
Kidney Transplant in the Era of Modern Therapy for Multiple Myeloma
Chronic kidney disease is common in patients with multiple myeloma. Historically individuals with end stage renal disease and multiple myeloma did poorly with renal transplantation due to higher mortality rates from the malignancy itself or associated comorbidities. However, over the past 2 decades there have been significant advances in the treatment of multiple myeloma with the advent of new therapeutic agents resulting in an improvement of long term survival. As a result, more individuals with multiple myeloma are being referred for kidney transplantation, especially those with good functional capacity and minimal comorbidities. Recent literature has suggested that certain patients with multiple myeloma can successfully undergo renal transplantation after stem transplantation with consideration for maintenance therapy, although caution should be used with immunomodulating drugs due to the anecdotally reported risk of acute rejection. Therefore, having a multi-disciplinary approach with the transplant team and hematology both before and after transplant is crucial in maximizing the chance of success for these individuals. This review summarizes the literature on renal transplantation in patients with multiple myeloma as well as the therapeutic advancements that have occurred which may allow certain patients to undergo successful transplantation. Corresponding Author: Raymond L. Heilman, MD, 5777 East Mayo Boulevard, Phoenix, Arizona 85054, Heilman.Raymond@mayo.edu Authorship Page Janna L. Huskey – Participated in the writing of this paper Raymond L. Heilman - Participated in the writing of this paper Hasan Khamash - Participated in the writing of this paper Rafael Fonseca - Participated in the writing of this paper Rafael Fonseca Consulting: Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Merck, Juno, Kite, Aduro, AbbVie. Scientific Advisory Board Adaptive Biotechnologies. Mayo Clinic and Rafael Fonseca hold a patent for the prognostication of myeloma using FISH. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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https://ift.tt/2NIwsrs
Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation
Background When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. Methods The CIT-01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an APTT of 150±10 and 50±5 seconds respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. Results LMW-DS was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75±5 days after the first transplant) between the 2 arms (1.33±1.10 versus 1.56±1.36 ng/mL, p=0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life and safety were similar between the 2 treatments groups. Conclusions Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Corresponding author: Bengt von Zur-Mühlen, Department of Transplantation surgery, University hospital in Uppsala, S-751 85 Uppsala, Sweden, Phone: + 476 18 611 31 70; E-mail: bengt.muhlen@medsci.uu.se ClinicalTrials.gov ID: NCT00789308 Authorship page Authorship: B.Z-M. and T.L. contributed equally B.Z-M. contributed to the design of the study, analysed the data, performed pre and posttransplant care of the patients and wrote the article T.L. designed the study, analysed the data, performed pre and posttransplant care of the patients and wrote the article L.B. executed analysis plan, coordinated DCC protocol, managed data and statistical analysis, assisted writing final study report and edited the article C.B. designed the study and edited the article N.D.B. designed the study, provided safety oversight as the NIAID Medical Monitor and edited the article W.C. designed the study, managed data and statistical analysis T.E. designed the study and coordinated the study with the Clinical Islet Transplantation Consortium, NIDDK and the DSMB A.F. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the article J.G. designed the study and cleared regulatory pathways T.J. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the article C.J. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the article Y.M. contributed to the design of the study, coordinated study and funding M.R. contributed to the design of the study and edited the article T.S. executed analysis plan, coordinated DCC protocol, managed data and statistical analysis, assisted writing final study report and edited the article G.T. contributed to the design of the study, performed pre and posttransplant care of the patients and edited the study B.N. designed the study, performed experiments, analysed the data and wrote the article O.K. conceived, designed and directed the study, performed islet isolation, analysed the data and wrote the article Conflicts of interest: The authors have no financial disclosures to report. Funding: The study was funded by grants from: The National Institute of Allergy and Infectious Disease of the National Institutes of Health (2U01AI065192-06) The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as the funding agency for the DCC at University of Iowa (U01DK070431) Swedish Medical Research Council (K2015-54X-12219-19-4 and K2013-64X-08268-26-3) Swedish national strategic research initiative EXODIAB (Excellence Of Diabetes Research in Sweden) Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Liraglutide, a Glucagon-Like Peptide-1 Receptor Agonist, Attenuates Development of Cardiac Allograft Vasculopathy in a Murine Heart Transplant Model
Background Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model. Methods Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II (MHC-II)-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 μg-1kg-112 h-1) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells (HCAECs) challenged with transforming growth factor-beta 1 (TGF-β1). Results GLP-1R was predominantly localized to vascular endothelial cells and was up-regulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and down-regulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in TGF-β1-treated HCAECs. Conclusions Administration of liraglutide from the time of transplantation up-regulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV. Corresponding author: Yan-wen Shu, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan 430022, China. (shuyanwen@yahoo.com). Corresponding author: Jun Yang, PhD, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1095, Wuhan 430030, Hubei Province, China. (jy@tjh.tjmu.edu.cn). Authorship J.Y, Z.-M.W., and Y.-W.S. conceived and designed the experiments. Z.-M.W., X.-F.H, Y.-K.L., D.-X.M., G.-Y.Z., M.-J.W., and Y.-N.X. performed the experiments. J.Y., Z.-M.W. and X.-F.H. analyzed the data. J.Y. and Z.-M.W. wrote the paper. Disclosure The authors declare no conflicts of interest. Funding The study was supported by the National Nature Science Foundation of China (No. 81373169 to JY). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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https://ift.tt/2NIwlMy
A Step Forward in the Treatment of Influenza
For many years, antiviral treatment of influenza has consisted of monotherapy with a neuraminidase inhibitor. The Food and Drug Administration (FDA) approved the neuraminidase inhibitors oseltamivir (oral administration) and zanamivir (oral inhalation) in 1999 and peramivir (intravenous…
https://ift.tt/2p3VyTM
Circulating Extracellular Vesicles in Human Disease
It is well known that cells release fluid-filled sacs (vesicles) to the extracellular environment during cell death, or apoptosis, but it has been increasingly recognized that healthy cells may also release vesicles in the process of normal functions. Vesicles that are released by healthy cells…
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Glandular Tularemia
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Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents
Additional effective antiviral agents are needed for the treatment and prevention of influenza virus infections. Two classes of agents, M2 ion-channel inhibitors and neuraminidase inhibitors, are widely available. However, circulating influenza viruses are now largely resistant to M2 ion-channel…
https://ift.tt/2MoINN3
Circulating Extracellular Vesicles in Human Disease
It is well known that cells release fluid-filled sacs (vesicles) to the extracellular environment during cell death, or apoptosis, but it has been increasingly recognized that healthy cells may also release vesicles in the process of normal functions. Vesicles that are released by healthy cells…
https://ift.tt/2MqiaXL
Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma
Rituximab plus chemotherapy followed by maintenance therapy with rituximab has been shown to be effective in patients with advanced follicular lymphoma for whom treatment is indicated, with median progression-free survival reaching approximately 6 to 10 years and with a 3-year overall survival rate…
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High-Risk Clonal Hematopoiesis as the Origin of AITL and NPM1-Mutated AML
https://ift.tt/2QqmWb1
Just Beneath the Surface
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. A 55-year-old man was evaluated in…
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Black Hairy Tongue
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Just Beneath the Surface
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. A 55-year-old man was evaluated in…
https://ift.tt/2QjWxfb
Glandular Tularemia
https://ift.tt/2CRBgqk
Circulating Extracellular Vesicles in Human Disease
It is well known that cells release fluid-filled sacs (vesicles) to the extracellular environment during cell death, or apoptosis, but it has been increasingly recognized that healthy cells may also release vesicles in the process of normal functions. Vesicles that are released by healthy cells…
https://ift.tt/2MqiaXL
Voluntary Euthanasia — Implications for Organ Donation
In 2015, the Supreme Court of Canada decided to decriminalize medical assistance in dying for patients who are experiencing "grievous and irremediable" suffering. The next year, the Canadian government passed legislation that permits physicians to hasten the death of a patient by means of…
https://ift.tt/2MqtZNP
The Violence of Uncertainty — Undermining Immigrant and Refugee Health
Hawa rushed her husband Ahmed to the emergency department when she found him unconscious. For months, Ahmed had refused to go to the hospital because he knew Immigration and Customs Enforcement (ICE) officers were nearby. Ahmed is a U.S. citizen, but he fears deportation — he knows refugees who…
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Quality of Care in the United Kingdom after Removal of Financial Incentives
Pay-for-performance schemes are increasingly used by health care payers to support improvement in the quality of care and have become widespread in many health systems, including those in the United States, the United Kingdom, Canada, Germany, Israel, Taiwan, Thailand, New Zealand, and Australia.…
https://ift.tt/2Qqlzt6
Voluntary Euthanasia — Implications for Organ Donation
In 2015, the Supreme Court of Canada decided to decriminalize medical assistance in dying for patients who are experiencing "grievous and irremediable" suffering. The next year, the Canadian government passed legislation that permits physicians to hasten the death of a patient by means of…
https://ift.tt/2MqtZNP
Clinical and endoscopic predictors for intraprocedural mucosal injury during per-oral endoscopic myotomy
Mucosal injury (MI) is one of the most common perioperative adverse events of per-oral endoscopic myotomy (POEM). Severe undertreated MI may lead to contamination of the tunnel and even mediastinitis. This study explored the characteristics, predictors and management approaches of intraoperative MI.
https://ift.tt/2MpVtDl
Kidney Tattoos
Dan and Matt have a great deal in common, although they have never met. Both were in their teens when they were diagnosed with immunoglobulin A nephropathy. Both had inexorable decline in their kidney function in their 20s. They both had kidney transplants—Matt from a step-brother, Dan from a sister initially, and then when that transplant failed, via a paired exchange. Both have been patients of mine for over 10 years.
https://ift.tt/2Qqfk8p
Unusual BK polyomavirus‐associated urologic malignancies in renal transplant recipients: Report of two cases and review of the literature.
Diagnostic Cytopathology, EarlyView.
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Does Mechanical Bowel Preparation Reduce the Risk of Developing Infectious Complications in Pediatric Colorectal Surgery? A Systematic Review and Meta-Analysis
To evaluate whether the application of mechanical bowel preparation (MBP) before colorectal surgery reduces the risk of developing infectious complications in children.
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Unveiling the RNA World
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Appendix Cancers Are Genetically Distinct from Other Gastrointestinal Cancers, Study Shows
The largest-ever study of DNA changes in appendix cancer shows that it is distinct from colorectal and other gastrointestinal cancers and suggests that specific mutations in appendix tumors may help predict whether they may be aggressive.
https://ift.tt/2COJvn3
Stereolithographic 3D Printing with Renewable Acrylates
A protocol for additive manufacturing with renewable photopolymer resins on a stereolithography apparatus is presented.
https://ift.tt/2p00Cse
Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes
Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.
https://ift.tt/2ObXXHa
Protocol for Producing Three-Dimensional Infrared Video of Freezing in Plants
Here, we present a protocol to image a strawberry plant freezing in 3 dimensions. Two infrared cameras positioned at slightly different angles are used to produce a red-blue anaglyph video to observe the freezing of the plant in 3 dimensions.
https://ift.tt/2p3OMgZ
Federal pursuit of anti-kickback statute takes millions from local EMS
Expert witness commentary on the recent Paramedics Plus litigation, in which the government alleged violations of the federal Anti-Kickback Statute
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The neural correlates of flow experience explored with transcranial direct current stimulation
Abstract
The experience of flow ensues when humans engage in a demanding task while task demands are balanced with the individual's level of skill or ability. Here, we further tested the hypothesis that the medial prefrontal cortex (MPFC) plays a causal role in mediating flow experience using transcranial direct current stimulation (tDCS) to interfere with MPFC's deactivation evoked by a flow paradigm and measured by magnetic resonance (MR)-based perfusion imaging. In a balanced, within-subjects repeated measure design, three treatments of tDCS (sham, anodal, cathodal) were applied in a sample of 22 healthy male participants. tDCS-modulatory effects on flow-specific regional cerebral blood flow (rCBF) and subjective flow experience significantly depended on participants' baseline level of flow experience during sham tDCS. Those participants with lower-flow experience during sham tDCS (LF) benefitted from tDCS, particularly from the anodal polarity, whereas both active treatments did not substantially affect subjects with relatively higher baseline flow experience (HF). Functionally, in LF subjects, relative deactivation of the right amygdala got more pronounced under anodal and cathodal tDCS, and changed inconsistently in HF subjects. Inter-individual regression analyses of rCBF data suggested that involvement of the subgenual anterior cingulate cortex appears crucial for affecting the response pattern in the right amygdala and can be modulated by tDCS. Present data support the notion that valuable insights into the neural mechanism of flow can be obtained using tDCS. However, a clearer understanding of tDCS' baseline dependency in terms of individual variations in brain connectivity states appears a necessary prerequisite to exploit this technique further.
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In Situ Lithiated Reference Electrode: Four Electrode Design for In-operando Impedance Spectroscopy
The incorporation of reference electrodes in a Li-ion battery provides valuable information to elucidate degradation mechanisms at high voltages. In this article, we present a cell design that accommodates multiple reference electrodes, along with the assembly steps to assure maximum accuracy of the data obtained in electrochemical measurements.
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Visual and Microscopic Evaluation of Streptomyces Developmental Mutants
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SCN VIP Neurons Are Essential for Normal Light-Mediated Resetting of the Circadian System
The suprachiasmatic nucleus (SCN) synchronizes circadian rhythms in behavior and physiology to the external light cycle, but the mechanisms by which this occurs are unclear. As the neuropeptide vasoactive intestinal peptide (VIP) is important for circadian light responses, we tested the hypothesis that rhythmic VIP-producing SCN neurons mediate circadian light responses in male and female mice. Using in vivo fiber photometry over multiple days, we found daily rhythms in spontaneous calcium events of SCN VIP neurons that peaked during the subjective day and were disrupted by constant light. The light-evoked calcium responses peaked around subjective dusk and were greater during the subjective night. Using novel VIP sensor cells, we found that the activity patterns in SCN VIP neurons correlated tightly with spontaneous and NMDA-evoked VIP release. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons exhibit circadian rhythms in spontaneous and light-responsive activity and are essential for the normal resetting of daily rhythms by environmental light.
SIGNIFICANCE STATEMENT Daily rhythms in behavior and physiology, including sleep/wake and hormone release, are synchronized to local time by the master circadian pacemaker, the suprachiasmatic nucleus (SCN). The advent of artificial lighting and, consequently, light exposure at night, is associated with an increased risk of disease due to disrupted circadian rhythms. However, the mechanisms by which the SCN encodes normal and pathological light information are unclear. Here, we find that vasoactive intestinal peptide (VIP)-producing SCN neurons exhibit daily rhythms in neuronal activity and VIP release, and that blocking the activity of these neurons attenuates light-induced phase shifts. We conclude that rhythmic VIP neurons are an essential component of the circadian light transduction pathway.
https://ift.tt/2ObLTp7
Autophosphorylated CaMKII Facilitates Spike Propagation in Rat Optic Nerve
Repeated spike firing can transmit information at synapses and modulate spike timing, shape, and conduction velocity. These latter effects have been found to result from voltage-induced changes in ion currents and could alter the signals carried by axons. Here, we test whether Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates spike propagation in adult rat optic nerve. We find that small-, medium-, and large-diameter axons bind anti-Thr286-phosphorylated CaMKII (pT286) antibodies and that, in isolated optic nerves, electrical stimulation reduces pT286 levels, spike propagation is hastened by CaMKII autophosphorylation and slowed by CaMKII dephosphorylation, single and multiple spikes slow propagation of subsequently activated spikes, and more frequent stimulation produces greater slowing. Likewise, exposing freely moving animals to flickering illumination reduces pT286 levels in optic nerves and electrically eliciting spikes in vivo in either the optic nerve or optic chiasm slows subsequent spike propagation in the optic nerve. By increasing the time that elapses between successive spikes as they propagate, pT286 dephosphorylation and activity-induced spike slowing reduce the frequency of propagated spikes below the frequency at which they were elicited and would thus limit the frequency at which axons synaptically drive target neurons. Consistent with this, the ability of retinal ganglion cells to drive at least some lateral geniculate neurons has been found to increase when presented with light flashes at low and moderate temporal frequencies but less so at high frequencies. Activity-induced decreases in spike frequency may also reduce the energy required to maintain normal intracellular Na+ and Ca2+ levels.
SIGNIFICANCE STATEMENT By propagating along axons at constant velocities, spikes could drive synapses as frequently as they are initiated. However, the onset of spiking has been found to alter the conduction velocity of subsequent ("follower") spikes in various preparations. Here, we find that spikes reduce spike frequency in rat optic nerve by slowing follower spike propagation and that electrically stimulated spiking ex vivo and spike-generating flickering illumination in vivo produce net decreases in axonal Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation. Consistent with these effects, propagation speed increases and decreases, respectively, with CaMKII autophosphorylation and dephosphorylation. Lowering spike frequency by CaMKII dephosphorylation is a novel consequence of axonal spiking and light adaptation that could decrease synaptic gain as stimulus frequency increases and may also reduce energy use.
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Robustness of Spike Deconvolution for Neuronal Calcium Imaging
Calcium imaging is a powerful method to record the activity of neural populations in many species, but inferring spike times from calcium signals is a challenging problem. We compared multiple approaches using multiple datasets with ground truth electrophysiology and found that simple non-negative deconvolution (NND) outperformed all other algorithms on out-of-sample test data. We introduce a novel benchmark applicable to recordings without electrophysiological ground truth, based on the correlation of responses to two stimulus repeats, and used this to show that unconstrained NND also outperformed the other algorithms when run on "zoomed out" datasets of ~10,000 cell recordings from the visual cortex of mice of either sex. Finally, we show that NND-based methods match the performance of a supervised method based on convolutional neural networks while avoiding some of the biases of such methods, and at much faster running times. We therefore recommend that spikes be inferred from calcium traces using simple NND because of its simplicity, efficiency, and accuracy.
SIGNIFICANCE STATEMENT The experimental method that currently allows for recordings of the largest numbers of cells simultaneously is two-photon calcium imaging. However, use of this powerful method requires that neuronal firing times be inferred correctly from the large resulting datasets. Previous studies have claimed that complex supervised learning algorithms outperform simple deconvolution methods at this task. Unfortunately, these studies suffered from several problems and biases. When we repeated the analysis, using the same data and correcting these problems, we found that simpler spike inference methods perform better. Even more importantly, we found that supervised learning methods can introduce artifactual structure into spike trains, which can in turn lead to erroneous scientific conclusions. Of the algorithms we evaluated, we found that an extremely simple method performed best in all circumstances tested, was much faster to run, and was insensitive to parameter choices, making incorrect scientific conclusions much less likely.
https://ift.tt/2x5jfzw
Isolation of Cerebral Capillaries from Fresh Human Brain Tissue
Isolated brain capillaries from human brain tissue can be used as a preclinical model to study barrier function under physiological and pathophysiological conditions. Here, we present an optimized protocol to isolate brain capillaries from fresh human brain tissue.
https://ift.tt/2Of1ioM
An Optimized Evans Blue Protocol to Assess Vascular Leak in the Mouse
In this article, an economical, optimized, and simple protocol is described which uses the Evans blue dye method for assessing plasma extravasation in the organs of FVBN mice that can be adapted for use in other strains, species, and other organs or tissues.
https://ift.tt/2NAXCAC
High-Touch Surfaces at Airports Often Covered in Pathogens
WEDNESDAY, Sept. 12, 2018 -- Many frequently touched surfaces at airports are contaminated with respiratory virus pathogens, according to a study published online Aug. 29 in BMC Infectious Diseases. Niina Ikonen, from the National Institute for...
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Loss of Synaptic Tagging in the Anterior Cingulate Cortex after Tail Amputation in Adult Mice
Anterior cingulate cortex (ACC) is known to play important roles in key brain functions such as pain perception, cognition, and emotion. Different forms of homosynaptic plasticity such as long-term potentiation (LTP) and long-term depression have been studied in ACC synapses. However, heterosynaptic plasticity such as synaptic tagging has not been reported. Here, we demonstrate synaptic tagging in the ACC of adult male mice by using a 64-channel multielectrode array recording system. Weak theta burst stimulation (TBS), normally inducing early-phase LTP or No-LTP in most of the activated channels, produced late phase-LTP (L-LTP) in a majority of channels when a strong TBS was applied earlier to a separate input within a certain time window. Similar to hippocampus, synaptic tagging in the ACC depends on the synthesis of new proteins. Tail amputation-induced peripheral injury caused a loss of this heterosynaptic L-LTP and occluded strong TBS-evoked L-LTP as well. Together, we provide the first report of the synaptic tagging-like phenomenon in the ACC of adult mice, and the loss of synaptic tagging to amputation may contribute to injury-related cognitive changes and phantom limb sensation and pain.
SIGNIFICANCE STATEMENT ACC is an important cortical region involved in many brain functions. Previous studies have dissected the molecular mechanism of multiple types of homosynaptic plasticity of ACC synapses. Here, we report a novel form of heterosynaptic plasticity occurring in the ACC. This newly identified, protein synthesis-dependent neocortical synaptic tagging is sensitive to peripheral tail amputation injury and may provide basic mechanisms for synaptic pathophysiology of phantom pain and related cognitive changes.
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Drosophila Exo70 Is Essential for Neurite Extension and Survival under Thermal Stress
The octomeric exocyst complex governs the final step of exocytosis in both plants and animals. Its roles, however, extend beyond exocytosis and include organelle biogenesis, ciliogenesis, cell migration, and cell growth. Exo70 is a conserved component of the exocyst whose function in Drosophila is unclear. In this study, we characterized two mutant alleles of Drosophila exo70. exo70 mutants exhibit reduced synaptic growth, locomotor activity, glutamate receptor density, and mEPSP amplitude. We found that presynaptic Exo70 is necessary for normal synaptic growth at the neuromuscular junction (NMJ). At the neuromuscular junction, exo70 genetically interacts with the small GTPase ralA to regulate synaptic growth. Loss of Exo70 leads to the blockage of JNK signaling-, activity-, and temperature-induced synaptic outgrowths. We showed that this phenotype is associated with an impairment of integral membrane protein transport to the cell surface at synaptic terminals. In octopaminergic motor neurons, Exo70 is detected in synaptic varicosities, as well as the regions of membrane extensions in response to activity stimulation. Strikingly, mild thermal stress causes severe neurite outgrowth defects and pharate adult lethality in exo70 mutants. exo70 mutants also display defective locomotor activity in response to starvation stress. These results demonstrated that Exo70 is an important regulator of induced synaptic growth and is crucial for an organism's adaptation to environmental changes.
SIGNIFICANCE STATEMENT The exocyst complex is a conserved protein complex directing secretory vesicles to the site of membrane fusion during exocytosis, which is essential for transporting proteins and membranes to the cell surface. Exo70 is a subunit of the exocyst complex whose roles in neurons remain elusive, and its function in Drosophila is unclear. In Drosophila, Exo70 is expressed in both glutamatergic and octopaminergic neurons, and presynaptic Exo70 regulates synaptic outgrowth. Moreover, exo70 mutants have impaired integral membrane transport to the cell surface at synaptic terminals and block several kinds of induced synaptic growth. Remarkably, elevated temperature causes severe arborization defects and lethality in exo70 mutants, thus underpinning the importance of Exo70 functions in development and adaptation to the environment.
https://ift.tt/2x6HJsi
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
