Repeat hepatectomy is independently associated with favorable long-term outcome in patients with colorectal liver metastases

Abstract

Up to three-quarters of patients undergoing liver resection for colorectal liver metastases (CRLM) develop intrahepatic recurrence. Repeat hepatic resection appears to provide the optimal chance of cure for these patients. The aim of this study was to analyze short- and long-term outcomes following index and repeat hepatectomy for CRLM. Clinicopathological data were obtained from a prospectively maintained database. Perioperative variables and outcomes were compared using the Chi-squared test. Variables associated with long-term survival following index and second hepatectomy were identified by Cox regression analyses. Over the study period, 488 patients underwent hepatic resection for CRLM, with 71 patients undergoing repeat hepatectomy. There was no significant difference in rates of morbidity (P = 0.135), major morbidity (P = 0.638), or mortality (P = 0.623) when index and second hepatectomy were compared. Performance of repeat hepatectomy was independently associated with increased overall and cancer-specific survival following index hepatectomy. Short disease-free interval between index and second hepatectomy, number of liver metastases >1, and resection of extrahepatic disease were independently associated with shortened survival following repeat resection. Repeat hepatectomy for recurrent CRLM offers short-term outcomes equivalent to those of patients undergoing index hepatectomy, while being independently associated with improved long-term patient survival.

Hepatic resection offers the only hope of cure to patients with colorectal liver metastases (CRLM), with repeat hepatic resection emerging as a viable therapy for patients with recurrent CRLM following initial resection. This study analyzes the survival of a cohort of 488 patients who had undergone hepatic resection for CRLM, finding the performance of repeat hepatectomy to be independently associated with prolonged overall and cancer-specific survival following hepatectomy.

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Increasing incidence of invasive and in situ cervical adenocarcinoma in the Netherlands during 2004–2013

Abstract

In the developed world, the incidence of cervical squamous cell carcinoma has decreased, however, the incidence of adenocarcinoma in situ (AIS) and invasive adenocarcinoma increased, predominantly in young females. The goal of this study was to evaluate the most recent incidence rates of AIS, adenocarcinoma, and squamous cell carcinoma of the uterine cervix in the Netherlands in 2004–2013. By using Dutch national pathology and cancer registries, we calculated European standardized incidence rates (ESR) and estimated annual percentage changes (EAPC) for AIS during 2004–2013 and for invasive cervical carcinomas during 1989–2013. For AIS, presence or absence of concomitant cervical intraepithelial neoplasia (CIN) was explored. The estimated annual percentage change (EAPC) of squamous cell carcinoma decreased significantly in 1989–2013, predominantly in 1989–2003. The EAPC of invasive adenocarcinoma decreased in 1989–2003, but remained stable in 2004–2013. The EAPC of AIS increased significantly, predominantly in women of 25–39 years old. Of these AIS cases, 58.9% had concomitant CIN and AIS with concomitant CIN showed a significantly higher EAPC compared to AIS without CIN. Our conclusion is that despite a nationwide screening program for cancer of the uterine cervix, the incidence of adenocarcinoma in the Netherlands remained stable during 2004–2013 and the incidence of adenocarcinoma in situ increased. This was most predominant in cases with concomitant CIN and in younger females. The incidence of squamous cell carcinoma decreased in the same timeframe.

Aim of the study was to evaluate the most recent incidence rates of adenocarcinoma in situ (AIS), adenocarcinoma (ACA), and squamous cell carcinoma of the uterine cervix in the Netherlands. The results of our study show that despite a nationwide screening program for cervical cancer, the incidence of AIS increased in the Netherlands in 2004–2013, while the incidence of invasive adenocarcinoma remained stable. This increase was most predominant in young females and cases with concomitant cervical intraepithelial neoplasia (CIN).

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Tumor Evolution: Linear, Branching, Neutral or Punctuated?

Publication date: Available online 19 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Alexander Davis, Ruli Gao, Nicholas Navin
Intratumor heterogeneity has been widely reported in human cancers, but our knowledge of how this genetic diversity emerges over time remains limited. A central challenge in studying tumor evolution is the difficulty in collecting longitudinal samples from cancer patients. Consequently, most studies have inferred tumor evolution from single time-point samples, providing very indirect information. These data have led to several competing models of tumor evolution: linear, branching, neutral and punctuated. Each model makes different assumptions regarding the timing of mutations and selection of clones, and therefore has different implications for the diagnosis and therapeutic treatment of cancer patients. Furthermore, emerging evidence suggests that models may change during tumor progression or operate concurrently for different classes of mutations. Finally, we discuss data that supports the theory that most human tumors evolve from a single cell in the normal tissue. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.



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Cancer cell metabolism and mitochondria: nutrient plasticity for TCA cycle fueling

Publication date: Available online 18 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Cyril Corbet, Olivier Feron
Warburg's hypothesis that cancer cells take up a lot of glucose in the presence of ambient oxygen but convert pyruvate into lactate due to impaired mitochondrial function led to the misconception that cancer cells rely on glycolysis as their major source of energy. Most recent ¹³C–based metabolomic studies, including in cancer patients, indicate that cancer cells may also fully oxidize glucose. In addition to glucose-derived pyruvate, lactate, fatty acids and amino acids supply substrates to the TCA cycle to sustain mitochondrial metabolism. Here, we discuss how the metabolic flexibility afforded by these multiple mitochondrial inputs allows cancer cells to adapt according to the availability of the different fuels and the microenvironmental conditions such as hypoxia and acidosis. In particular, we focused on the role of the TCA cycle in interconnecting numerous metabolic routes in order to highlight metabolic vulnerabilities that represent attractive targets for a new generation of anticancer drugs.



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Immunohistochemical phenotype of breast cancer during 25-year follow-up of the Royal Marsden Tamoxifen Prevention Trial

Background The randomized double-blinded Royal Marsden Tamoxifen Breast Cancer Prevention Trial in healthy high-risk women started in 1986 and is still blinded. 2471 eligible participants were randomly assigned to tamoxifen (20mg/day) or placebo for 8 years. Analysis in 2006 showed a 30% risk reduction of ER-positive invasive breast cancer mostly in the post treatment period. Biomarker analysis in this population may identify any sub-group specific preventive effects tamoxifen. Methods After a median follow-up of 18.4 years, 242 patients had developed invasive cancer, 134 on placebo and 108 on tamoxifen. From these, 180 tissue blocks were available and ER, PgR, Ki67, HER2 and EGFR were immunohistochemically analysed. Results A 32% reduction in ER+ and PgR+ invasive cancers resulted after 8 years of treatment. Quantitative levels of ER and PgR were lower in the tamoxifen-treated group, significantly so for ER (p=0.001). These lower ER levels were restricted to the post-treatment period (p=0.018). Amongst the ER+ group there was a similar proportional decrease in PgR+ and PgR- tumours by tamoxifen. The median levels of Ki67 were similar in both arms. The numbers of HER2 positive and EGFR positive cancers were higher in the tamoxifen arm but not significantly so. Conclusions Tamoxifen's preventive effects result in reduced ER-positive but not ER-negative tumours and reduced ER expression in the ER-positive cases largely confined to the post-treatment period. Overall reductions in PgR expression are explained by lower frequency of ER-positive cases. Impact on Ki67, HER2 and EGFR was modest.

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Molecular Epidemiology of Rotavirus in Children under Five in Africa (2006-2016): A Systematic Review

Group A human rotaviruses (RVA) are the most common causes of severe viral gastroenteritis in infants and young children worldwide. The available vaccines, while effective in Europe and North America have shown a reduced efficacy in Africa. One issue raised is the genetic variability of RVA. The objective of this study was to perform a literature review of molecular epidemiology to determine the prevalence of RVA genotypes circulating in Africa so as to establish a mapping of reliable data on these various genotypes. The search for articles was done from the National Institutes of Health (PUBMED) using three set of keywords. Articles were selected with inclusion criteria such as the date of publication, the age of the children, the sample size and the diagnostic techniques (standardized laboratory techniques). The data were imported into STATA SE version 11 software. Specific prevalence was estimated with Confidence Intervals (CI) of 95%. A total of 326 published studies were initially retrieved, out of which 27 studies were finally selected for the systematic review. The selected studies cover 20 African countries. The most encountered genotypes in Africa during this period were G1 (32.72%), followed by G2 (17.17%), G3 (9.88%), G9 (8.61%) and G12 (7.56%) among the G-types. The most common P-types were P[8] (48.71%) followed by P[6] (22.60%) and P[4] (11.58%) and the G1P[8] combination (22.64%) was the most encountered followed by G2P[4] (8.29%), G9P[8] (6.95%) and G2P[6] (5.00%). North Africa presented the highest prevalence of the P[8] genotype (65.70%). This review provides a comprehensive view of the current circulating rotavirus strains in Africa, which can be important in light of the new rotavirus vaccinations. Indeed, in Africa, the pursuit of national and continental studies for epidemiological surveillance of circulating rotavirus strains is vital for the promotion of future successful vaccines.

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Application of Response Surface Methodology for Optimization of Extracellular Glucoamylase Production by Candida guilliermondii

Objective: Glucoamylase is among the most important enzymes in biotechnology. The present study aims to determine better conditions for growth and glucoamylase production by Candida guilliermondii and to reduce the overall cost of the medium using Box-Behnken design with one central point and response surface methodology. Methodology: Box-Behnken factorial design based on three levels was carried out to obtain optimal medium combination of five independent variables such as initial pH, soluble starch, CH₄N₂O, yeast extract and MgSO₄. Forty one randomized mediums were incubated in flask on a rotary shaker at 105 rpm for 72 h at 30°C. Results: The production of biomass was found to be pH and starch dependent, maximum production when the starch concentration was 8 g L¹ and the initial pH was 6, while maximum glucoamylase production was found at 6.5 of initial pH, 4 g L¹ yeast extract and 6 g L¹ starch, whereas yeast extract and urea were highly significant, but interacted negatively. Box-Behnken factorial design used for the analysis of treatment combinations gave a second-order polynomial regression model with R² = 0.976 for Biomass and R² = 0.981 for glucoamylase. Conclusion: The final biomass and glucoamylase activity obtained was very close to the calculated parameters according to the p-values (p<0.001), the predicted optimal parameters were confirmed and provides a basis for further studies in baking additives and in the valuation of starch waste products.

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Phytochemical Analysis, Identification and Quantification of Antibacterial Active Compounds in Betel Leaves, Piper betle Methanolic Extract

Background and Objective: The problems of bacterial diseases in aquaculture are primarily controlled by antibiotics. Medicinal plants and herbs which are seemed to be candidates of replacements for conventional antibiotics have therefore gained increasing interest. Current study was performed to investigate the presence of phytochemical constituents, antibacterial activities and composition of antibacterial active compounds in methanolic extract of local herb, Piper betle . Methodology: Qualitative phytochemical analysis was firstly carried out to determine the possible active compounds in P. betle leaves methanolic extract. The antibacterial activities of major compounds from this extract against nine fish pathogenic bacteria were then assessed using TLC-bioautography agar overlay assay and their quantity were determined simultaneously by HPLC method. Results: The use of methanol has proved to be successful in extracting numerous bioactive compounds including antibacterial compounds. The TLC-bioautography assay revealed the inhibitory action of two compounds which were identified as hydroxychavicol and eugenol. The $-caryophyllene however was totally inactive against all the tested bacterial species. In this study, the concentration of hydroxychavicol in extract was found to be 374.72±2.79 mg g¹, while eugenol was 49.67±0.16 mg g¹. Conclusion: Based on these findings, it could be concluded that hydroxychavicol and eugenol were the responsible compounds for the promising antibacterial activity of P. betle leaves methanolic extract. This inhibitory action has significantly correlated with the amount of the compounds in extract. Due to its potential, the extract of P. betle leaves or it compounds can be alternative source of potent natural antibacterial agents for aquaculture disease management.

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Effects of Selenium Application on Plant Growth and Some Quality Parameters in Peanut (Arachis hypogaea)

Background and Objective: Selenium (Se) is an essential plant micronutrient and has been repetedly shown to enhance crop growth and crop tolerance to abiotic stresses when applied in trace amounts. However, physiological responses of different plants vary significantly to the Se fertilizer application. The aim of this study was to investigate the effect of Se application on yield and quality parameters of peanut under field conditions. Materials and Methods: A pot experiment was conducted where Se fertilizer was applied (i) To soil at 5 different doses, (ii) As folier fertilizer or (iii) Via seed soaking at 4 different doses. Two years field experiments were conducted under East Mediterranean conditions of Turkey. Results: The yields were significantly increased by all types of Se applications. The highest yield (6130 kg ha¹) was obtained from foliar applications made 40 days after flowering. Increasing doses of Se increased 100 grain weight but oil, protein and nitrogen content of grains were not affected. Conclusion: Two years experiment clearly showed that external Se supply to peanut (all methods tested) increased yield formation in East Mediterranean conditions of Turkey. Here, particularly foliar application (3% sodium selenite) of Se 40 after flowering seems to be most effective way for its application.

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Posterior tail development in the salamander Eurycea cirrigera : exploring cellular dynamics across life stages

Abstract

During embryogenesis, the body axis elongates and specializes. In vertebrate groups such as salamanders and lizards, elongation of the posterior body axis (tail) continues throughout life. This phenomenon of post-embryonic tail elongation via addition of vertebrae has remained largely unexplored, and little is known about the underlying developmental mechanisms that promote vertebral addition. Our research investigated tail elongation across life stages in a non-model salamander species, Eurycea cirrigera (Plethodontidae). Post-embryonic addition of segments suggests that the tail tip retains some aspects of embryonic cell/tissue organization and gene expression throughout the life cycle. We describe cell and tissue differentiation and segmentation of the posterior tail using serial histology and expression of the axial tissue markers, MF-20 and Pax6. Embryonic expression patterns of HoxA13 and C13 are shown with in situ hybridization. Tissue sections reveal that the posterior spinal cord forms via cavitation and precedes development of the underlying cartilaginous rod after embryogenesis. Post-embryonic tail elongation occurs in the absence of somites and mesenchymal cells lateral to the midline express MF-20. Pax6 expression was observed only in the spinal cord and some mesenchymal cells of adult Eurycea tails. Distinct temporal and spatial patterns of posterior Hox13 gene expression were observed throughout embryogenesis. Overall, important insights to cell organization, differentiation, and posterior Hox gene expression may be gained from this work. We suggest that further work on gene expression in the elongating adult tail could shed light on mechanisms that link continual axial elongation with regeneration.

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Inside front cover-EDB

Publication date: February 2017
Source:Biochimie, Volume 133





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The expanding repertoire of G4 DNA structures

Publication date: Available online 19 January 2017
Source:Biochimie
Author(s): Anna Varizhuk, Dmitry Ischenko, Vladimir Tsvetkov, Roman Novikov, Nikolay Kulemin, Dmitry Kaluzhny, Maria Vlasenok, Vladimir Naumov, Igor Smirnov, Galina Pozmogova
The definition of DNA and RNA G-quadruplexes (G4s) has recently been broadened to include structures with certain defects: bulges, G-vacancies or mismatches. Despite the striking progress in computational methods for assessing G4 folding propensity, predicting G4s with defects remains problematic, reflecting the enhanced sequential diversity of these motifs. “Imperfect” G4 motifs, i.e., those containing interrupted or truncated G-runs, are typically omitted from genomic analyses. We report here studies of G4s with defects and compare these structures with classical (“perfect”) quadruplexes. Thermal stabilities and ligand interactions are also discussed. We exploited a simple in-house computational tool for mining putative G4s with defects in the human genome. The obtained profiles of the genomic distribution of imperfect G4 motifs were analyzed. Collectively, our findings suggest that, similar to classical G4s, imperfect G4s could be considered as potential regulatory elements, pathology biomarkers and therapeutic targets.



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UCP1 in adipose tissues: two steps to full browning

Publication date: Available online 18 January 2017
Source:Biochimie
Author(s): Anastasia V. Kalinovich, Jasper M.A. de Jong, Barbara Cannon, Jan Nedergaard
The possibility that brown adipose tissue thermogenesis can be recruited in order to combat the development of obesity has led to a high interest in the identification of “browning agents”, i.e. agents that increase the amount and activity of UCP1 in brown and brite/beige adipose tissues. However, functional analysis of the browning process yields confusingly different results when the analysis is performed in one of two alternative steps.Thus, in one of the steps, using cold acclimation as a potent model browning agent, we find that if the browning process is followed in mice initially housed at 21 °C (the most common procedure), there is only weak molecular evidence for increases in UCP1 gene expression or UCP1 protein abundance in classical brown adipose tissue; however, in brite/beige adipose depots, there are large increases, apparently associating functional browning with events only in the brite/beige tissues.Contrastingly, in another step, if the process is followed starting with mice initially housed at 30 °C (thermoneutrality for mice, thus similar to normal human conditions), large increases in UCP1 gene expression and UCP1 protein abundance are observed in the classical brown adipose tissue depots; there is then practically no observable UCP1 gene expression in brite/beige tissues.This apparent conundrum can be resolved when it is realized that the classical brown adipose tissue at 21 °C is already essentially fully differentiated and thus expands extensively through proliferation upon further browning induction, rather than by further enhancing cellular differentiation. When the limiting factor for thermogenesis, i.e. the total amount of UCP1 protein per depot, is analyzed, classical brown adipose tissue is by far the predominant site for the browning process, irrespective of which of the two steps is being analyzed.There are to date no published data demonstrating that alternative browning agents would selectively promote brite/beige tissues versus classical brown tissue to a higher degree than does cold acclimation. Thus, to restrict studies to processes in adipose tissue depots where only a limited part of the adaptation process occurs (i.e. the brite/beige tissues) and to use initial conditions different from the thermoneutrality normally experienced by adult humans may seriously hamper the identification of therapeutically valid browning agents. The data presented here have therefore important implications for the analysis of the potential of browning agents and the nature of human brown adipose tissue.



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HILLSBOROUGH: Ciattarelli to continue gubernatorial race, despite ongoing cancer battle - Packet Online

Packet Online

HILLSBOROUGH: Ciattarelli to continue gubernatorial race, despite ongoing cancer battle Packet Online Mr. Ciattarelli, 55, said that last fall, he had noticed a lump in his neck, later diagnosed as oropharyngeal cancer affecting the back of the throat and tonsils. He has been getting radiation treatment five times a week since the middle of December ... Ciattarelli Kicks off Gubernatorial Campaign at Somerville Elks Jan. 19TAPinto.net all 5 news articles »

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Masthead

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1





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Table of Contents

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1





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Editorial Board

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1





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American Brachytherapy Task Group Report: A pooled analysis of clinical outcomes for high-dose-rate brachytherapy for cervical cancer

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1
Author(s): Jyoti Mayadev, Akila Viswanathan, Yu Liu, Chin-Shang Li, Kevin Albuquerque, Antonio L. Damato, Sushil Beriwal, Beth Erickson
PurposeAdvanced imaging used in combination with brachytherapy (BT) has revolutionized the treatment of patients with cervical cancer. We present a comprehensive review of the literature for definitive radiation with high-dose-rate (HDR) BT. In addition, we investigate potential outcome improvement with image-based brachytherapy (IBBT) compared to studies using traditional Point A dosing. This review extensively investigates acute and late toxicities.Methods and MaterialsThis study reviews the literature from 2000 to 2015 with an emphasis on modern approaches including concurrent chemotherapy (chemoRT), radiation, and HDR BT and IBBT. Descriptive statistics and pelvic control (PC), disease-free survival (DFS), and overall survival (OS) outcomes were calculated using weighted means to report pooled analysis of outcomes.ResultsLiterature search yielded 16 prospective, 51 retrospective studies that reported survival outcomes, and 13 retrospective studies that focused on acute and late toxicity outcomes regardless of applicator type. There are 57 studies that report Point A dose specification with 33 having chemoRT, and 10 studies that use IBBT, 8 with chemoRT. Patients receiving radiation and chemoRT with HDR BT in the prospective studies, with >24 months followup, rates of PC were: for RT: 73%, SD: 11; CRT: 82%, SD: 8; DFS—RT: 55%, SD: 10; CRT: 65%, SD: 7; OS—RT: 66%, SD: 7; CRT: 70%, SD: 11. In the retrospective studies, the PC rates (weighted means) for the radiation and chemoradiation outcomes are 75% vs. 80%, and for DFS, the values were 55% vs. 63%, respectively. Comparing patients receiving chemoRT and IBBT to traditional Point A dose specification, there is a significant improvement in PC (p < 0.01) and DFS (p < 0.01) with IBBT. The range of genitourinary late toxicity reported for radiation was Grade 3: 1–6% and for chemoRT 2–20%. The range of late gastrointestinal toxicity for radiation was Grade 3: 4–11% and for chemoRT, 1–11%. For the late gynecologic toxicity, only 1 of the 16 prospective trials report a Grade 1–2 of 17% for radiation and 9% for chemoRT effects.ConclusionsWe present concise outcomes of PC, DFS, OS, and toxicity for cervical cancer patients treated with chemoradiation and HDR BT. Our data suggest an improvement in outcomes with the use of IBBT compared with traditional Point A dose prescriptions. In conclusion, HDR BT is a safe, effective modality when combined with IBBT.



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The American College of Radiology and the American Brachytherapy Society practice parameter for transperineal permanent brachytherapy of prostate cancer

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1
Author(s): Nathan H.J. Bittner, Peter F. Orio, Gregory S. Merrick, Bradley R. Prestidge, Alan Charles Hartford, Seth A. Rosenthal
Transperineal permanent brachytherapy is a safe and effective treatment option for patients with organ-confined prostate cancer. Careful adherence to established brachytherapy standards has been shown to improve the likelihood of procedural success and reduce the incidence of treatment-related morbidity. A collaborative effort of the American College of Radiology (ACR) and the American Brachytherapy Society (ABS) has produced practice parameters for LDR prostate brachytherapy. These practice parameters define the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, physicist and dosimetrist. Factors with respect to patient selection and appropriate use of supplemental treatment modalities such as external beam radiation and androgen suppression therapy are discussed. Logistics with respect to the brachytherapy implant procedure, the importance of dosimetric guidelines, and attention to radiation safety procedures and documentation are presented. Adherence to these parameters can be part of ensuring quality and safety in a successful prostate brachytherapy program.



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The American College of Radiology and the American Brachytherapy Society practice parameter for the performance of low-dose-rate brachytherapy

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1
Author(s): Akila N. Viswanathan, Beth A. Erickson, Geoffrey S. Ibbott, William Small, Patricia J. Eifel
Brachytherapy is the use of radionuclides to treat malignancies or benign conditions by means of a radiation source placed close to or into the tumor or treatment site. This practice parameter refers only to the use of radionuclide brachytherapy. Brachytherapy alone or combined with external beam therapy plays an important role in the management and treatment of patients with cancer. Low-dose-rate (LDR) brachytherapy has traditionally been used for treating prostate, head and neck, breast, cervical, and endometrial cancers as well as obstructive bile duct, esophageal, or bronchial lesions. It has been practiced for over a century with a variety of sources including radium-226, cesium-137, and, more recently, iridium- 192, iodine-125, and palladium-103. Low-dose-rate (LDR) brachytherapy can be given as interstitial, intracavitary, intraluminal, and/or plesiotherapy to a wide variety of treatment sites. This practice parameter addresses sealed sources as they are used for LDR brachytherapy. It is recognized that unsealed sources (e.g., yttrium-90) are also a form of LDR brachytherapy.



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The American College of Radiology and the American Brachytherapy Society practice parameter for the performance of radionuclide-based high-dose-rate brachytherapy

Publication date: January–February 2017
Source:Brachytherapy, Volume 16, Issue 1
Author(s): Beth A. Erickson, Nathan H.J. Bittner, Manjeet Chadha, Firas Mourtada, D. Jeffrey Demanes
Brachytherapy is a radiation therapy method in which radionuclide sources are used to deliver a radiation dose at a distance of up to a few centimeters by surface, intracavitary, intraluminal, or interstitial application. This practice parameter refers only to the use of radionuclides for brachytherapy. Brachytherapy alone or combined with external beam therapy plays an important role in the management and treatment of patients with cancer. High-dose-rate (HDR) brachytherapy uses radionuclides such as iridium-192 at dose rates of 20 cGy per minute (12 Gy per hour) or more to a designated target point or volume. High-dose-rate (HDR) brachytherapy is indicated for treating malignant or benign tumors where the treatment volume or targeted points are defined and accessible.



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Evaluation of Metal Ion Concentration in Hard Tissues of Teeth in Residents of Central Poland

Objectives. The aim of the study was an assessment of the content of trace elements in enamel and dentin of teeth extracted in patients residing in urban and agricultural areas of Poland. Methods. The study included 30 generally healthy patients with retained third molars. 65 samples of enamel and dentin from individuals living in urban areas and 85 samples of enamel and dentin from individuals living in agricultural areas were prepared. The content of manganese, lead, cadmium, and chromium in the studied enamel and dentin samples from retained teeth was determined by Graphite Furnace Atomic Absorption Spectrometry. In the process of statistical hypothesis testing, the level of significance was assumed at . Results. A comparative analysis of the data showed that enamel and dentin of inhabitants of industrialized areas contain significantly higher amounts of lead and cadmium than hard tissues of teeth in residents of agricultural areas and comparable amounts of manganese and chromium. Significance. It appears that hard tissues of retained teeth may constitute valuable material for assessment of long-term environmental exposure to metal ions. The study confirms that the risk of exposure to heavy metals depends on the place of residence and environmental pollution.

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Mechanism of Reduced Susceptibility to Fosfomycin in Escherichia coli Clinical Isolates

In recent years, multidrug resistance of Escherichia coli has become a serious problem. However, resistance to fosfomycin (FOM) has been low. We screened E. coli clinical isolates with reduced susceptibility to FOM and characterized molecular mechanisms of resistance and reduced susceptibility of these strains. Ten strains showing reduced FOM susceptibility (MIC ≥ 8 μg/mL) in 211 clinical isolates were found and examined. Acquisition of genes encoding FOM-modifying enzyme genes (fos genes) and mutations in murA that underlie high resistance to FOM were not observed. We examined ability of FOM incorporation via glucose-6-phosphate (G6P) transporter and sn-glycerol-3-phosphate transporter. In ten strains, nine showed lack of growth on M9 minimum salt agar supplemented with G6P. Eight of the ten strains showed fluctuated induction by G6P of uhpT that encodes G6P transporter expression. Nucleotide sequences of the uhpT, uhpA, glpT, ptsI, and cyaA shared several deletions and amino acid mutations in the nine strains with lack of growth on G6P-supplemented M9 agar. In conclusion, reduction of uhpT function is largely responsible for the reduced sensitivity to FOM in clinical isolates that have not acquired FOM-modifying genes or mutations in murA. However, there are a few strains whose mechanisms of reduced susceptibility to FOM are still unclear.

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Numerical Study on the Local Buckling Behaviour of Bolted Steel Plates in Steel Jacketing

A numerical simulation was conducted to investigate the local buckling behaviour of the bolted steel plates in steel jacketing technique. The numerical model was firstly validated by the results of a previous experimental study. Then a parametric study was conducted to investigate the influence of different restraint measures on the local buckling behaviour and the sensitivity of the buckling behaviour to the initial imperfection. Fitted formulae were developed to calculate the structural field capacity of the bolted steel plates, and recommended values of stiffener size were also provided to facilitate the strengthening design of steel jacketing.

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Boundedness of the Segal-Bargmann Transform on Fractional Hermite-Sobolev Spaces

Let and . We prove that the Segal-Bargmann transform is a bounded operator from fractional Hermite-Sobolev spaces to fractional Fock-Sobolev spaces .

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The Prevalence of Anti-Aquaporin 4 Antibody in Patients with Idiopathic Inflammatory Demyelinating Diseases Presented to a Tertiary Hospital in Malaysia: Presentation and Prognosis

Background. There have been inconsistent reports on the prevalence and pathogenicity of anti-Aquaporin 4 (AQP4) in patients presented with idiopathic inflammatory demyelinating diseases (IIDDs). Objective. To estimate the prevalence of anti-AQP4 antibody in patients with IIDDs presented to University Malaya Medical Centre in terms of patients’ clinical and radiological presentations and prognoses. Methods. Retrospective data review of IIDDs patients presented from 2005 to 2015. Patients were classified into classical multiple sclerosis (CMS), opticospinal (OS) presentation, optic neuritis (ON), transverse myelitis (TM), brainstem syndrome (BS), and tumefactive MS. Anti-Aquaporin 4 antibody was tested using the Indirect Immunofluorescence Test (IIFT) cell-based assay. Statistical analysis was done using the SPSS version 20. Results. Anti-AQP4 antibody was detected in 53% of patients presented with IIDDs. CMS was more common in the seronegative group, 27/47 (57.45%; ). Conversely, OS involvement was more common in the seropositive group, 26/53 (49.06%; ). Longitudinally extensive spinal cord lesions (LESCLs) on MRI were also more common in the seropositive group, 29/40 (72.50%; ). Only 2/40 (5.00%) had MRI evidence of patchy or multiple short-segment spinal cord lesions in the AQP4-positive group (). The relapse rate and Expanded Disability Status Scale (EDSS) were also higher in the seropositive group (5.43 versus 3.17, ; 4.07 versus 2.51, , resp.). Typical clinical presentations that defined NMO were also seen in the seronegative patients, but in a lower frequency. Conclusion. Our cohort of patients had a higher prevalence of seropositivity of anti-AQP4 antibody as compared to those in Western countries. This was also associated with a more typical presentation of opticospinal involvement with LESCLs on MRI, a higher rate of relapse, and EDSS.

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Molecular Mutations and Their Cooccurrences in Cytogenetically Normal Acute Myeloid Leukemia

Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making. The recent advances in clinical genomics have led to the recategorization of CN-AML into favorable or unfavorable subgroups. The relapsing nature of AML is thought to be due to clonal heterogeneity that includes founder or driver mutations present in the leukemic stem cell population. In this article, we summarize the clinical outcomes of relevant molecular mutations and their cooccurrences in CN-AML, including NPM1, FLT3ITD, DNMT3A, NRAS, TET2, RUNX1, MLLPTD, ASXL1, BCOR, PHF6, CEBPAbiallelic, IDH1, IDH2R140, and IDH2R170, with an emphasis on their relevance to the leukemic stem cell compartment. We have reviewed the available literature and TCGA AML databases (2013) to highlight the potential role of stem cell regulating factor mutations on outcome within newly defined AML molecular subgroups.

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Similarity Solutions of the MHD Boundary Layer Flow Past a Constant Wedge within Porous Media

The two-dimensional magnetohydrodynamic flow of a viscous fluid over a constant wedge immersed in a porous medium is studied. The flow is induced by suction/injection and also by the mainstream flow that is assumed to vary in a power-law manner with coordinate distance along the boundary. The governing nonlinear boundary layer equations have been transformed into a third-order nonlinear Falkner-Skan equation through similarity transformations. This equation has been solved analytically for a wide range of parameters involved in the study. Various results for the dimensionless velocity profiles and skin frictions are discussed for the pressure gradient parameter, Hartmann number, permeability parameter, and suction/injection. A far-field asymptotic solution is also obtained which has revealed oscillatory velocity profiles when the flow has an adverse pressure gradient. The results show that, for the positive pressure gradient and mass transfer parameters, the thickness of the boundary layer becomes thin and the flow is directed entirely towards the wedge surface whereas for negative values the solutions have very different characters. Also it is found that MHD effects on the boundary layer are exactly the same as the porous medium in which both reduce the boundary layer thickness.

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Cooperative Output Regulation of Multiagent Linear Parameter-Varying Systems

The output regulation problem is examined in this paper for a class of heterogeneous multiagent systems whose dynamics are governed by polytopic linear parameter-varying (LPV) models. The dynamics of the agents are decoupled from each other but the agents’ controllers are assumed to communicate. To design the cooperative LPV controllers, analysis conditions for closed-loop system are first established to ensure stability and reference tracking. Then, the LPV control synthesis problem is addressed, where the offline solution to a time-varying Sylvester equation will be used to determine and update in real time the controller state-space matrices. Two numerical examples will be finally given to demonstrate the efficacy of the proposed cooperative design method.

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Hierarchical Group Based Mutual Authentication and Key Agreement for Machine Type Communication in LTE and Future 5G Networks

In view of the exponential growth in the volume of wireless data communication among heterogeneous devices ranging from smart phones to tiny sensors across a wide range of applications, 3GPP LTE-A has standardized Machine Type Communication (MTC) which allows communication between entities without any human intervention. The future 5G cellular networks also envisage massive deployment of MTC Devices (MTCDs) which will increase the total number of connected devices hundredfold. This poses a huge challenge to the traditional cellular system processes, especially the traditional Mutual Authentication and Key Agreement (AKA) mechanism currently used in LTE systems, as the signaling load caused by the increasingly large number of devices may have an adverse effect on the regular Human to Human (H2H) traffic. A solution in the literature has been the use of group based architecture which, while addressing the authentication traffic, has their share of issues. This paper introduces Hierarchical Group based Mutual Authentication and Key Agreement (HGMAKA) protocol to address those issues and also enables the small cell heterogeneous architecture in line with 5G networks to support MTC services. The aggregate Message Authentication Code based approach has been shown to be lightweight and significantly efficient in terms of resource usage compared to the existing protocols, while being robust to authentication message failures, and scalable to heterogeneous network architectures.

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Herbal Compound “Jiedu Huayu” Reduces Liver Injury in Rats via Regulation of IL-2, TLR4, and PCNA Expression Levels

Aim of the Study. To investigate the preventative effects of Jiedu Huayu (JDHY) on D-galactosamine (D-GalN) and lipopolysaccharide-induced acute liver failure (ALF) and to evaluate the possible mechanisms of action. Materials and Methods. ALF was induced in Wistar rats by administrating D-GalN (900 mg/kg) and lipopolysaccharide (10 μg/kg). After treatment with JDHY granules, the levels of blood alanine aminotransferase, aspartate aminotransferase, total bilirubin, and prothrombin time were determined. Proliferating cell nuclear antigen was detected by immunohistochemistry staining. The expression of interleukin-2 (IL-2) and toll-like receptor 4 (TLR4) was examined by fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. Results. JDHY treatment dramatically improved liver function and increased survival rates in an ALF model in rats. We observed a decrease in IL-2 and TLR4 expression following treatment with JDHY in liver cells from ALF rats using qRT-PCR and Western blot analysis. Conclusion. We hypothesize that the therapeutic potential of JDHY for treating ALF is due to its modulatory effect on the suppression of inflammation and by promoting hepatocyte regeneration. Our results contribute towards validation of the traditional use of JDHY in the treatment of liver disease.

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Costello Syndrome and Umbilical Ligament Rhabdomyosarcoma in Two Pediatric Patients: Case Reports and Review of the Literature

Costello syndrome is caused by heterozygous de novo missense mutations in the protooncogene HRAS with tumor predisposition, especially rhabdomyosarcoma. We here report two pediatric patients with Costello syndrome and umbilical ligament rhabdomyosarcoma. A review of the literature published in English in MEDLINE from January 1971 to June 2016 using the search terms “Costello syndrome” and “rhabdomyosarcoma” was performed, including two new cases that we describe. Twenty-six patients with Costello syndrome and rhabdomyosarcoma were recorded with mean age of diagnosis of 2 years and 8 months. The most common tumor location was the abdomen/pelvis, including four out of ten of those in the umbilical ligament. The most common histological subtype was embryonal rhabdomyosarcoma. Overall survival was 43%. A total of 17 rhabdomyosarcomas in pediatric patients arising in the umbilical ligament were recorded with mean age of diagnosis of 3 years and 4 months. Overall survival was 69%. Costello syndrome is a poorly known disorder in pediatric oncology but their predisposition to malignancies implies the need for a new perspective on early diagnosis and aggressive medical and surgical treatment.

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Swirling Flow in a Permeable Tube at Slowly Expanding and Contracting Wall

The swirling flow inside a circular elastic tube with expanding and contracting permeable wall in the presence of a uniform magnetic field is studied analytically. The tube is also assumed to be rotating around its axis with an angular velocity. The governing equations for this multidimensional flow are reduced to nonlinear differential equations with similarity transformations. An analytic series solution is obtained by homotopy analysis method (HAM). The effects of physical parameters on various flow characteristics, such as the velocity, skin friction, and pressure variation, have been analysed briefly. The impact of surface expansion/contraction and rotation has been investigated on the internal boundary-layer flow inside the tube of uniform cross-section.

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The Use of Laparoscopy Simulation to Explore Gender Differences in Resident Surgical Confidence

Background. The objective of this study was to determine whether female surgical residents underestimate their surgical abilities relative to males on a standardized test of laparoscopic skill. Methods. Twenty-six male and female general surgery residents and 25 female obstetrics and gynecology residents at two academic centers were asked to predict their score prior to undergoing the Fundamentals of Laparoscopic Surgery standardized skills exam. Actual and predicted score as well as delta values (predicted score minus actual score) were compared between residents. Multivariate linear regression was used to determine variables associated with predicted score, actual score, and delta scores. Results. There was no difference in actual score based on residency or gender. Predicted scores, however, were significantly lower in female versus male general surgery residents (25.8 ± 13.3 versus 56.0 ± 16.0; ) and in female obstetrics and gynecology residents versus male general surgery residents (mean difference 20.9, 95% CI 11.6–34.8; ). Male residents more accurately predicted their scores while female residents significantly underestimated their scores. Conclusion. Gender differences in estimating surgical ability exist that do not reflect actual differences in performance. This finding needs to be considered when structuring mentorship in surgical training programs.

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Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome

Abstract

We present a patient with poikiloderma, severe osteoporosis and a mild intellectual disability. At the age of 9 years, this patient was proposed to suffer from a novel disease entity designated as calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnormalities (COPS) syndrome. At the age of 35, he was diagnosed with Hodgkin’s lymphoma. Recently, biallelic pathogenic variants in the RECQL4 gene were detected (c.1048_1049delAG and c.1391-1G>A), confirming a diagnosis of Rothmund-Thomson syndrome (RTS). In the brother of this patient, who had a milder phenotype, a similar diagnosis was made.

Conclusion: We conclude that COPS syndrome never existed as a separate syndrome entity. Instead, osteoma cutis may be regarded as a novel feature of RTS, whereas mild intellectual disability and lymphoma may be underreported parts of the phenotype.

What is new:

• Osteoma cutis was not a known feature in Rothmund-Thomson patients.

• Intellectual disability may be considered a rare feature in RTS; more study is needed.

What is known:

• RTS is a well-described syndrome caused by mutations in the RECQL4 gene.

• Patients with RTS frequently show chromosomal abnormalities like, e.g. mosaic trisomy 8.

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The secret to an easier allergy season » - Harvard Health

Harvard Health

The secret to an easier allergy season » Harvard Health "More inflammatory cells are recruited to the nose and sinuses, symptoms become more severe, and it's difficult to treat them." Instead, he suggests that it's better to block the reaction before it begins, which prevents symptoms or lessens their ...

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A bibliometric analysis of two decades of aromatherapy research

Quantitative data are lacking on the profile of published research in aromatherapy. The objective of the study was to investigate the profile of original and review articles under the topic aromatherapy using ...

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Lipoxin A4 stimulates endothelial miR-126-5p expression and its transfer via microvesicles [Research]

The proresolution lipid mediator lipoxin (LX)A₄ bestows protective bioactions on endothelial cells. We examined the impact of LXA₄ on transcellular endothelial signaling via microRNA (miR)-containing microvesicles. We report LXA₄ inhibition of MV release by TNF-α-treated HUVECs, associated with the down-regulation of 18 miR in endothelial microvesicles (EMVs) and the up-regulation of miR-126-5p, both in HUVECs and in EMVs. LXA₄ up-regulated miR-126-5p by ~5-fold in HUVECs and promoted a release of microvesicles (LXA₄-EMVs) that enhanced miR-126-5p by ~7-fold in recipient HUVECs. In these cells, LXA₄-EMVs abrogated the up-regulation of VCAM-1, induced in recipient HUVECs by EMVs released by untreated or TNF-α-treated HUVECs. LXA₄-EMVs also reduced by ~40% the expression of SPRED1, which we validated as an miR-126-5p target, whereas they stimulated monolayer repair in an in vitro wound assay. This effect was lost when the EMVs were depleted of miR-126-5p. These results provide evidence that changes in miR expression and microvesicle packaging and transfer represent a mechanism of action of LXA₄, which may be relevant in vascular biology and inflammation.—Codagnone, M., Recchiuti, A., Lanuti, P., Pierdomenico, A. M., Cianci, E., Patruno, S., Mari, V. C., Simiele, F., Di Tomo, P., Pandolfi, A., Romano, M. Lipoxin A₄ stimulates endothelial miR-126-5p expression and its transfer via microvesicles.

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Multicellular hypothesis for the pathogenesis of Alzheimers disease [Hypothesis]

Extensive abnormal interactions among microglia, astrocytes, and neurons of the CNS have been observed in proteinopathic neurodegenerative dementias of the elderly. These multicellular interactions are initiated by insoluble tangles of phosphorylated tau protein and plaques of amyloid peptides. Most research has focused on these neurotoxic proteins, but much less is known about the pathogenic roles of the responding resident and recruited neural cells. Principal interactions among the major 3 sets of CNS cells are herein considered at several levels in relation to cellular phenotypic alterations, mechanisms of cellular communication, and extent of involvement in the pathogenesis of Alzheimer’s disease and related proteinopathic dementias. It remains to be determined which of these abnormal neurocellular phenomena are primary events and sufficiently contributory to neurodegeneration to be useful targets for therapy of senile dementias.—Goetzl, E. J., Miller, B. L. Multicellular hypothesis for the pathogenesis of Alzheimer’s disease.

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Fluid shear stress increases transepithelial transport of Ca2+ in ciliated distal convoluted and connecting tubule cells [Research]

In kidney, transcellular transport of Ca²⁺ is mediated by transient receptor potential vanilloid 5 and Na⁺-Ca²⁺ exchanger 1 proteins in distal convoluted and connecting tubules (DCT and CNT, respectively). It is not yet understood how DCT/CNT cells can adapt to differences in tubular flow rate and, consequently, Ca²⁺ load. This study aims to elucidate the molecular mechanisms by which DCT/CNT cells sense fluid dynamics to control transepithelial Ca²⁺ reabsorption and whether their primary cilia play an active role in this process. Mouse primary DCT/CNT cultures were subjected to a physiologic fluid shear stress (FSS) of 0.12 dyn/cm². Transient receptor potential vanilloid 5 and Na⁺-Ca²⁺ exchanger 1 mRNA levels were significantly increased upon FSS exposure compared with static controls. Functional studies with ⁴⁵Ca²⁺ demonstrated a significant stimulation of transepithelial Ca²⁺ transport under FSS compared with static conditions. Primary cilia removal decreased Ca²⁺ transport in both static and FSS conditions, a finding that correlated with decreased expression of genes involved in transepithelial Ca²⁺ transport; however, FSS-induced stimulation of Ca²⁺ transport was still observed. These results indicate that nephron DCT and CNT segments translate FSS into a physiologic response that implicates an increased Ca²⁺ reabsorption. Moreover, primary cilia influence transepithelial Ca²⁺ transport in DCT/CNT, yet this process is not distinctly coupled to FSS sensing by these organelles.—Mohammed, S. G., Arjona, F. J., Latta, F., Bindels, R. J. M., Roepman, R., Hoenderop, J. G. J. Fluid shear stress increases transepithelial transport of Ca²⁺ in ciliated distal convoluted and connecting tubule cells.

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Isoform-specific mechanisms of {alpha}3{beta}4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1 [Research]

This study investigates—for the first time to our knowledge—the existence and mechanisms of functional interactions between the endogenous mammalian prototoxin, lynx1, and α3- and β4-subunit–containing human nicotinic acetylcholine receptors (α3β4*-nAChRs). Concatenated gene constructs were used to express precisely defined α3β4*-nAChR isoforms (α3β4)₂β4-, (α3β4)₂α3-, (α3β4)₂α5(398D)-, and (α3β4)₂α5(398N)-nAChR in Xenopus oocytes. In the presence or absence of lynx1, α3β4*-nAChR agonist responses were recorded by using 2-electrode voltage clamp and single-channel electrophysiology, whereas radioimmunolabeling measured cell-surface expression. Lynx1 reduced (α3β4)₂β4-nAChR function principally by lowering cell-surface expression, whereas single-channel effects were primarily responsible for reducing (α3β4)₂α3-nAChR function [decreased unitary conductance (≥50%), altered burst proportions (3-fold reduction in the proportion of long bursts), and enhanced closed dwell times (3- to 6-fold increase)]. Alterations in both cell-surface expression and single-channel properties accounted for the reduction in (α3β4)₂α5-nAChR function that was mediated by lynx1. No effects were observed when α3β4*-nAChRs were coexpressed with mutated lynx1 (control). Lynx1 is expressed in the habenulopeduncular tract, where α3β4*-α5*-nAChR subtypes are critical contributors to the balance between nicotine aversion and reward. This gives our findings a high likelihood of physiologic significance. The exquisite isoform selectivity of lynx1 interactions provides new insights into the mechanisms and allosteric sites [α(–)-interface containing] by which prototoxins can modulate nAChR function.—George, A. A., Bloy, A., Miwa, J. M., Lindstrom, J. M., Lukas, R. J., Whiteaker, P. Isoform-specific mechanisms of α3β4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.

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High school football: Marengo alum Derek Caskey, 20, dies - Northwest Herald

Northwest Herald

High school football: Marengo alum Derek Caskey, 20, dies Northwest Herald He had several hours of surgery last summer during which medical personnel had to remove his tongue, which was filled with the cancer. Parents Patrick and Rae Caskey remained strong and positive while their son was home trying to recover through the ...

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Bortezomib Triplet Improves Outcomes in Newly Diagnosed Multiple Myeloma

Adding bortezomib to lenalidomide and dexamethasone improved progression-free and overall survival in patients with newly diagnosed multiple myeloma who were not planned for immediate stem-cell transplant. (Source: CancerNetwork)

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Predicting brain metastases for non-small cell lung cancer based on magnetic resonance imaging

Abstract

In this study the relationship between brain structure and brain metastases (BM) occurrence was analyzed. A model for predicting the time of BM onset in patients with non-small cell lung cancer (NSCLC) was proposed. Twenty patients were used to develop the model, whereas the remaining 69 were used for independent validation and verification of the model. Magnetic resonance images were segmented into cerebrospinal fluid, gray matter (GM), and white matter using voxel-based morphometry. Automatic anatomic labeling template was used to extract 116 brain regions from the GM volume. The elapsed time between the MRI acquisitions and BM diagnosed was analyzed using the least absolute shrinkage and selection operator method. The model was validated using the leave-one-out cross validation (LOOCV) and permutation test. The GM volume of the extracted 11 regions of interest increased with the progression of BM from NSCLC. LOOCV test on the model indicated that the measured and predicted BM onset were highly correlated (r = 0.834, P = 0.0000). For the 69 independent validating patients, accuracy, sensitivity, and specificity of the model for predicting BM occurrence were 70, 75, and 66%, respectively, in 6 months and 74, 82, and 60%, respectively, in 1 year. The extracted brain GM volumes and interval times for BM occurrence were correlated. The established model based on MRI data may reliably predict BM in 6 months or 1 year. Further studies with larger sample size are needed to validate the findings in a clinical setting.

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Relationship of long-term prognosis to MMP and TIMP polymorphisms in patients after ST elevation myocardial infarction

Abstract

The influence of polymorphisms in the large group of MMP and TIMP genes on clinical outcomes in patients after ST elevation myocardial infarction (STEMI) treated with primary PCI was analysed. In total, 550 consecutive Caucasian patients with STEMI were included in the present study, with a median of 32 months. We analysed 19 polymorphisms in the genes coding MMP and TIMP genes. The MMP-1 -519A/G and -422A/T polymorphisms are associated with combined endpoint after myocardial infarction. The hazard ratio for AT variant of MMP-1 -422A/T was 1.75 (p < 0.001); the variants with at least one A allele of MMP-1 -519A/G have less risk of combined endpoint. The TT variants of -1562C/T MMP-9 and at least one T allele of +92C/T MMP-13 were considered in a trend to affect disease progression and long-term survival after myocardial infarction. According to reclassification analysis NRI and IDI, long-term risk stratification using MMP-1 -422A/T and -519A/G polymorphisms gives additional information to the commonly used GRACE risk score. Patient stratification after myocardial infraction (MI) according to risk genotypes of MMP-1 polymorphisms could have important clinical implications for identification of patients at risk and therapeutic strategies.

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Structure of the Z ring associated protein, ZapD, bound to the C-terminal domain of the tubulin-like protein, FtsZ, suggests mechanism of Z ring stabilization through FtsZ crosslinking [Microbiology]

Cell division in most bacteria is mediated by the tubulin-like FtsZ protein, which polymerizes in a GTP-dependent manner to form the cytokinetic Z ring. A diverse repertoire of FtsZ binding proteins affect FtsZ localization and polymerization to ensure correct Z ring formation. Many of these proteins bind the C-terminal domain (CTD) of FtsZ, which serves as a hub for FtsZ regulation. FtsZ ring-associated proteins, ZapA-D (Zaps), are important FtsZ regulatory proteins that stabilize FtsZ assembly and enhance Z ring formation by increasing lateral assembly of FtsZ protofilaments, which then form the Z ring. There are no structures of a Zap protein bound to FtsZ, hence how these proteins affect FtsZ polymerization has been unclear. Recent data showed ZapD binds specifically to the FtsZ CTD. Thus, to obtain insight into the ZapD-CTD interaction and how it may mediate FtsZ protofilament assembly, we determined the Escherichia coli ZapD-FtsZ CTD structure to 2.67 Angstrom resolution. The structure shows that the CTD docks within a hydrophobic cleft in the ZapD helical domain and adopts an unusual structure composed of two turns of helix separated by a proline kink. FtsZ CTD residue Phe377 inserts into the ZapD pocket, anchoring the CTD in place and permitting hydrophobic contacts between FtsZ residues Ile374, Pro375 and Leu378 with ZapD residues Leu74, Trp77, Leu91 and Leu174. The structural findings were supported by mutagenesis coupled with biochemical and in vivo studies. The combined data suggest that ZapD acts as a molecular crosslinking reagent between FtsZ protofilaments to enhance FtsZ assembly.

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Cool-associated tyrosine phosphorylated protein-1 is required for the anchorage-independent growth of cervical carcinoma cells by binding paxillin and promoting AKT activation [Cell Biology]

Cool-associated tyrosine phosphorylated protein-1 (Cat-1) is a signaling scaffold, as well as an ADP-ribosylation factor-GTPase-activating protein (ARF-GAP). Although best known for its role in cell migration, we recently showed that the ability of Cat-1 to bind paxillin, a major constituent of focal complexes, was also essential for the anchorage-independent growth of HeLa cervical carcinoma cells. Here, we set out to learn more about the underlying mechanism by which Cat-paxillin interactions mediate this effect. We show that knocking-down paxillin expression in HeLa cells promoted their ability to form colonies in soft-agar, whereas ectopically expressing paxillin in these cells inhibited this transformed growth phenotype. While knocking-down Cat-1 prevents HeLa cells from forming colonies in soft agar, when paxillin is knocked-down together with Cat-1, the cells are again able to undergo anchorage-independent growth. These results suggested that the requirement of Cat-1 for this hallmark of cellular transformation is coupled to its ability to bind paxillin and abrogate its actions as a negative regulator of anchorage-independent growth. We further show that knocking-down Cat-1 expression in HeLa cells leads to a reduction in Akt activation, which can be reversed by knocking-down paxillin. Moreover, expression of constitutively active forms of Akt1 and Akt2 restores the anchorage-independent growth capability of HeLa cells depleted of Cat-1 expression. Together, these findings highlight a novel mechanism, whereby interactions between Cat-1 and its binding partner paxillin are necessary to ensure sufficient Akt activation, such that cancer cells are able to grow under anchorage-independent conditions.

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Structure-activity relationship of {alpha} mating pheromone from the fungal pathogen Fusarium oxysporum [Protein Structure and Folding]

During sexual development, ascomycete fungi produce two types of peptide pheromones termed a and α. The α pheromone from the budding yeast Saccharomyces cerevisiae, a thirteen residue peptide which elicits cell cycle arrest and chemotropic growth, has served as paradigm for the interaction of small peptides with their cognate G protein-coupled receptors (GPCRs). However, no structural information is currently available for α pheromones from filamentous ascomycetes, which are significantly shorter and share almost no sequence similarity with the S. cerevisiae homolog. High-resolution structure of synthetic α-pheromone from the plant pathogenic ascomycete Fusarium oxysporum revealed the presence of a central β-turn resembling that of its yeast counterpart. Disruption of the fold by D-alanine substitution of the conserved central Gly6-Gln7 residues or by random sequence scrambling demonstrated a crucial role for this structural determinant in chemoattractant activity. Unexpectedly, the growth inhibitory effect of Fusarium oxysporum α-pheromone was independent of the cognate GPCR Ste2 and of the central β-turn but instead required two conserved Trp1-Cys2 residues at the N-terminus. These results indicate that, in spite of their reduced size, fungal α-pheromones contain discrete functional regions with a defined secondary structure that regulate diverse biological processes such as polarity reorientation and cell division.

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Targeted Fc{gamma}R mediated clearance by a biparatopic bispecific antibody [Cell Biology]

Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. While monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6 mediated signaling. The BiSAb formed large immune complexes with IL-6 that can bind FcγRs on phagocytic cells and are rapidly internalized. In addition, rapid clearance of the BiSAb-IL-6 complex was observed in mice while the parental antibodies prolonged the serum half-life of IL-6. Intravital imaging of liver in mice confirmed that the rapid clearance of these large immune complexes was associated with FcγR-dependent binding to Kupffer cells in the liver. The approach described here provides a general strategy for therapeutic antibodies with the ability to not only neutralize, but also actively drive clearance of their soluble antigens.

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Crystallographic snapshots of Class A {beta}-lactamase catalysis reveal structural changes that facilitate {beta}-lactam hydrolysis [Enzymology]

β-lactamases confer resistance to β-lactam-based antibiotics. There is great interest in understanding their mechanisms to enable the development of β-lactamase-specific inhibitors. The mechanism of Class A β-lactamases has been studied extensively, revealing Lys73 and Glu166 as general bases that assist the catalytic residue Ser70. However, the specific roles of these two residues within the catalytic cycle remains not fully understood. To help resolve this question, we first identified a Glu166His mutant that is functional but kinetically slowed. We then carried out time-resolved crystallographic study of a full cycle of the catalytic reaction. We obtained structures that represent apo, ES*-acylation and ES*-deacylation states and analyzed the conformational changes of His166. The "in" conformation in the apo structure allows His166 to form a hydrogen bond with Lys73. The unexpected "flipped-out" conformation of His166 in the ES*-acylation structure was further examined by molecular dynamics simulations, which suggested deprotonated Lys73 serving as the general base for acylation. The "revert-in" conformation in the ES*-deacylation structure aligns His166 toward the water molecule that hydrolyzes the acyl adduct. Finally, when the acyl adduct is fully hydrolyzed, His166 rotates back to the "in" conformation of the apo state, restoring the Lys73-His166 interaction. Using His166 as surrogate, our study identifies distinct conformational changes within the active site during catalysis. We suggest that the native Glu166 executes similar changes in a less constricted way. Taken together, this structural series improves our understanding of β-lactam hydrolysis in this important class of enzymes.

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De novo sphingolipid biosynthesis is required for adipocyte survival and metabolic homeostasis [Metabolism]

Sphingolipids are a diverse class of essential cellular lipids that function as structural membrane components and as signaling molecules. Cells acquire sphingolipids by both de novo biosynthesis and recycling of exogenous sphingolipids. The individual importance of these pathways for the generation of essential sphingolipids in differentiated cells is not well understood. To investigate the requirement for de novo sphingolipid biosynthesis in adipocytes, a cell type with highly regulated lipid metabolism, we generated mice with an adipocyte-specific deletion of Sptlc1. Sptlc1 is an obligate subunit of serine palmitoyltransferase, the enzyme responsible for the first and rate-limiting step of de novo sphingolipid biosynthesis. These mice, which initially developed adipose tissue, exhibited a striking age-dependent loss of adipose tissue accompanied by evidence of adipocyte death, increased macrophage infiltration, and tissue fibrosis. Adipocyte differentiation was not affected by the Sptlc1 deletion. The mice also had elevated fasting blood glucose, fatty liver, and insulin resistance. Collectively, these data indicate that de novo sphingolipid biosynthesis is required for adipocyte cell viability and normal metabolic function, and that reduced de novo sphingolipid biosynthesis within adipocytes is associated with adipocyte death, adipose tissue remodeling, and metabolic dysfunction.

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Loss of Cyclin Dependent Kinase 2 in the Pancreas Links Primary {beta}-cell Dysfunction to Progressive Depletion of {beta}-cell Mass and Diabetes [Molecular Bases of Disease]

The failure of pancreatic islet β-cells is a major contributor to the etiology of Type 2 diabetes. β-cell dysfunction and declining β-cell mass are two mechanisms that contribute to this failure, although it is unclear if they are molecularly linked. Here, we show that the cell cycle regulator, cyclin-dependent kinase 2 (Cdk2), couples primary β-cell dysfunction to the progressive deterioration of β-cell mass in diabetes. Mice with pancreas-specific deletion of Cdk2 are glucose intolerant primarily due to defects in glucose-stimulated insulin secretion. Accompanying this loss of secretion are defects in β-cell metabolism and perturbed mitochondrial structure. Persistent insulin secretion defects culminate in progressive deficits in β-cell proliferation, reduced β-cell mass and diabetes. These outcomes may be mediated directly by the loss of Cdk2, which binds to and phosphorylates the transcription factor Foxo1 in a glucose-dependent manner. Further, we identified a requirement for Cdk2 in the compensatory increases in β-cell mass that occur in response to age- and diet-induced stress. Thus, Cdk2 serves as an important nexus linking primary β-cell dysfunction to progressive β-cell mass deterioration in diabetes.

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Telix Pharmaceuticals and Atlab Pharma Conclude Therapeutic Product Development Agreement for Prostate Cancer - P&T Community

Telix Pharmaceuticals and Atlab Pharma Conclude Therapeutic Product Development Agreement for Prostate Cancer P&T Community Small molecule and peptide therapies targeting PSMA, with various isotopes, have demonstrated serious off-target effects, such as pancreatitis, nephrotoxicity and permanent salivary gland ablation. These considerations are particularly important for ...

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Author's 'Guide' to Human Body Addresses Nagging Medical Questions - Chicago Tonight | WTTW

Chicago Tonight | WTTW

Author's 'Guide' to Human Body Addresses Nagging Medical Questions Chicago Tonight | WTTW The pus around the contact lens can drain into a person's sinuses and spread into their pharynx. This has happened to me. I thought my contact had just fallen out, but no. Six days later, it came out. In the interim, I got pretty ... Tobacco companies ...

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Intranasal azelastine and mometasone exhibit a synergistic effect on a murine model of allergic rhinitis

The purpose of this study was to compare the anti-allergic effects of the combination of azelastine and mometasone with those of either agent alone in a Dermatophagoides farinae (Derf)-induced murine model of allergic rhinitis (AR).

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Two-stage CO2-laser-assisted bilateral cordectomy for cT1b glottic carcinoma

The aim of the present paper was to investigate the oncological safety of two-stage bilateral cordectomy for the treatment of cT1b glottic SCC, and to compare its oncological outcome and synechia development rate with those of single-stage procedures.

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Laryngeal alveolar soft part sarcoma: A case report of a rare malignancy in an atypical location

Laryngeal sarcoma is a rare and potentially aggressive malignancy. In this case report, we present a 23year-old-male with four-years of progressive hoarseness who was found to have a large left paraglottic mass. A partial laryngectomy was successful at completely excising the lesion. Final pathology returned as alveolar soft part sarcoma. Alveolar soft part sarcomas of the larynx are extremely rare with only five cases published in the current literature. This article provides a case presentation with literature review of alveolar soft part sarcoma of the head and neck.

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Tongue Retaining Devices for Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis

Obstructive Sleep Apnea (OSA) remains a prevalent and difficult disease to treat [1–4]. Treatment modalities range from the most non-invasive form such as lifestyle modifications to surgical procedures that permanently change the patient’s anatomy [5–8]. Selection of a specific type of treatment remains largely based on parameters to address specific physiologic and anatomic variables that contribute to the obstructive etiology [4]. In this fashion, Continuous Positive Airway Pressure (CPAP) serves as the gold standard in effectively addressing the obstruction throughout the upper airway [4,7].

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Inpatient Injection Laryngoplasty for Vocal Fold Immobility: When is it Really Necessary?

To compare pulmonary and swallow outcomes of injection laryngoplasty when performed in the acute versus subacute setting in head & neck and thoracic cancer patients presenting with new onset unilateral vocal fold immobility.

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Adenoid cystic carcinoma of the base of tongue: A population-based study

The objective was to assess demographic and survival patterns in patients with adenoid cystic carcinoma of the base of tongue.

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Cortactin and phosphorylated cortactin tyr466 expression in temporal bone carcinoma

Cortactin is a multidomain protein engaged in several cellular mechanisms involving actin assembly and cytoskeletal arrangement. Cortactin overexpression in several malignancies has been associated with increased cell migration, invasion, and metastatic potential. Cortactin needs to be activated by tyrosine or serine/threonine phosphorylation. The role of cortactin and phosphorylated cortactin (residue tyr466) was investigated in temporal bone squamous cell carcinoma (TBSCC).

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Reconstruction of Midface Defect from Idiopathic Destructive Process Using Medpor Implant

Reconstruction of the midface remains a challenging task for even the most experienced surgeon, with a host of reconstructive options including free tissue transfer, allografts, or prosthetic implants. Presented here is a case of idiopathic bony destruction of the right midface in a 19 year old female, creating a unique defect requiring repair.

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Rethinking surgical technique and priorities for pediatric tonsillectomy

The past 100 years have witnessed dramatic shifts in the concept of ideal surgical goals and operative technique in tonsil surgery. Surgeons are reviving a technique of intracapsular tonsillectomy with increasing precision thanks to modern technology. With intracapsular tonsillectomy, pediatric patients recover faster, use less pain medication, and have a lower risk of dehydration and hemorrhage. Various considerations will dictate the adoption of this technology in the coming years. This current review explores concepts and controversies surrounding tonsillectomy with a focus on quality improvement.

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Facial Nerve Sacrifice During Parotidectomy: A Cautionary Tale in Pathologic Diagnosis

The parotid gland harbors 85% of all salivary gland neoplasms. Though the majority of tumors are benign, complete surgical resection remains the mainstay of treatment. Along with adequate tumor removal, facial nerve preservation is a critical objective. Given the significant negative effects on quality of life following facial nerve sacrifice [1], every effort should be made to spare the nerve until conclusive evidence mandates its removal. Here we share observations from a case where facial nerve sacrifice was considered, but ultimately deferred due to lack of definitive intraoperative pathologic diagnosis.

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Treatment Outcomes in Veterans with HPV-Positive Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) caused by the human papilloma virus (HPV) has an improved prognosis relative to HPV-negative tumors. Patients with HPV-positive disease may benefit from different treatment modalities in order to optimize survival and quality of life. We sought to investigate HPV-positive HNSCC within the military veteran population, and analyze the role of treatment modality in outcomes of patients with HPV-positive and HPV-negative tumors.

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Application of tissue-engineered bone grafts for alveolar cleft osteoplasty in a rodent model

Abstract

Objectives

The clinical standard for alveolar cleft osteoplasty is augmentation with autologous bone being available in limited amounts and might be associated with donor site morbidity. The aim of the present study was the creation of tissue-engineered bone grafts and their in vivo evaluation regarding their potential to promote osteogenesis in an alveolar cleft model.

Materials and methods

Artificial bone defects with a diameter of 3.3 mm were created surgically in the palate of 84 adult Lewis rats. Four experimental groups (n = 21) were examined: bovine hydroxyl apatite/collagen (bHA) without cells, bHA with undifferentiated mesenchymal stromal cells (MSC), bHA with osteogenically differentiated MSC. In a control group, the defect remained empty. After 6, 9 and 12 weeks, the remaining defect volume was assessed by cone beam computed tomography. Histologically, the remaining defect width and percentage of bone formation was quantified.

Results

After 12 weeks, the remaining defect width was 60.1% for bHA, 74.7% for bHA with undifferentiated MSC and 81.8% for bHA with osteogenically differentiated MSC. For the control group, the remaining defect width measured 46.2% which was a statistically significant difference (p < 0.001).

Conclusions

The study design was suitable to evaluate tissue-engineered bone grafts prior to a clinical application. In this experimental set-up with the described maxillary defect, no promoting influence on bone formation of bone grafts containing bHA could be confirmed.

Clinical relevance

The creation of a sufficient tissue-engineered bone graft for alveolar cleft osteoplasty could preserve patients from donor site morbidity.

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What is involved in medicines management across care boundaries? A qualitative study of healthcare practitioners' experiences in the case of acute kidney injury

Objectives

To examine the role of individual and collective cognitive work in managing medicines for acute kidney injury (AKI), this being an example of a clinical scenario that crosses the boundaries of care organisations and specialties.

Design

Qualitative design, informed by a realist perspective and using semistructured interviews as the data source. The data were analysed using template analysis.

Setting

Primary, secondary and intermediate care in England.

Participants

12 General practitioners, 10 community pharmacists, 7 hospital doctors and 7 hospital pharmacists, all with experience of involvement in preventing or treating AKI.

Results

We identified three main themes concerning participants' experiences of managing medicines in AKI. In the first theme, challenges arising from the clinical context, AKI is identified as a technically complex condition to identify and treat, often requiring judgements to be made about renal functioning against the context of the patient's general well-being. In the second theme, challenges arising from the organisational context, the crossing of professional and organisational boundaries is seen to introduce problems for the coordination of clinical activities, for example by disrupting information flows. In the third theme, meeting the challenges, participants identify ways in which they overcome the challenges they face in order to ensure effective medicines management, for example by adapting their work practices and tools.

Conclusions

These themes indicate the critical role of cognitive work on the part of healthcare practitioners, as individuals and as teams, in ensuring effective medicines management during AKI. Our findings suggest that the capabilities underlying this work, for example decision-making, communication and team coordination, should be the focus of training and work design interventions to improve medicines management for AKI or for other conditions.

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Prevalence and clinical impact of recreational drug consumption in people living with HIV on treatment: a cross-sectional study

Objectives

Drug interactions, poor adherence to medication and high-risk sexual behaviour may occur in individuals with HIV using recreational drugs. Thus, we aimed to assess the prevalence of recreational drugs use and to explore its clinical impact in HIV patients on treatment.

Methods

Observational, cross sectional, study conducted in a 700 bed university hospital, Barcelona, Spain. A total of 208 adults living with HIV on treatment were included. A questionnaire was administered by clinical pharmacists, including evaluation of sociodemographic variables, past 12-month drug consumption, adherence to antiretrovirals (Simplified Medication Adherence Questionnaire) and high-risk sexual behaviour (condomless sex/multiple partners). Additional data were obtained from clinical records. Recreational drug-antiretroviral interactions were checked in reference databases. Prevalence was calculated for 5% precision and 95% CI. Crude and adjusted binary logistic regressions were performed to identify associations between recreational drug use and adherence problems, and between recreational drug use and high-risk sexual behaviour.

Results

From the overall sample, 92 participants (44.2%) consumed recreational drugs over the past 1 year. Of these, 44 (48.8%) had used different types of recreational drugs in this period. We detected 11 recreational substances, including sildenafil and nitrites. The most consumed drugs were: cannabis (68.5%), cocaine (45.5%), nitrites (31.5%), sildenafil (28.3) and ecstasy (19.6%). Relevant interactions occurred in 46 (50%) of the individuals consuming drugs. Recreational drug consumption was found to be related to adherence problems with antiretrovirals (OR: 2.51 (95% CI 1.32 to 4.77) p=0.005) and high-risk sexual behaviour (OR: 2.81 (95% CI 1.47 to 5.39) p=0.002).

Conclusions

Recreational drugs are frequently used by HIV patients on treatment. Classical drugs and new substances consumed in sexual context are usual. Recreational drug consumption interferes with several clinical outcomes, including potentially relevant interactions between drugs and antiretrovirals, adherence problems and high-risk sexual behaviour. Thus, there is the urgent need of implementing patient-centred care involving recreational drug consumption.

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Investigation of the degree of organisational influence on patient experience scores in acute medical admission units in all acute hospitals in England using multilevel hierarchical regression modelling

Objectives

Previous studies found that hospital and specialty have limited influence on patient experience scores, and patient level factors are more important. This could be due to heterogeneity of experience delivery across subunits within organisations. We aimed to determine whether organisation level factors have greater impact if scores for the same subspecialty microsystem are analysed in each hospital.

Setting

Acute medical admission units in all NHS Acute Trusts in England.

Participants

We analysed patient experience data from the English Adult Inpatient Survey which is administered to 850 patients annually in each acute NHS Trusts in England. We selected all 8753 patients who returned the survey and who were emergency medical admissions and stayed in their admission unit for 1–2 nights, so as to isolate the experience delivered during the acute admission process.

Primary and secondary outcome measures

We used multilevel logistic regression to determine the apportioned influence of host organisation and of organisation level factors (size and teaching status), and patient level factors (demographics, presence of long-term conditions and disabilities). We selected ‘being treated with respect and dignity’ and ‘pain control’ as primary outcome parameters. Other Picker Domain question scores were analysed as secondary parameters.

Results

The proportion of overall variance attributable at organisational level was small; 0.5% (NS) for respect and dignity, 0.4% (NS) for pain control. Long-standing conditions and consequent disabilities were associated with low scores. Other item scores also showed that most influence was from patient level factors.

Conclusions

When a single microsystem, the acute medical admission process, is isolated, variance in experience scores is mainly explainable by patient level factors with limited organisational level influence. This has implications for the use of generic patient experience surveys for comparison between Trusts and should prompt further research to explore if more discriminant surveys can be developed.

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Ageing and mental health: changes in self-reported health due to physical illness and mental health status with consecutive cross-sectional analyses

Objectives

It is known that self-reported health (SRH) declines with increasing age and that comorbidity increases with age. We wished to examine how age transfers its effect to SRH through comorbid disease and mental illness and whether these processes remained stable from 1994 until 2008. The hypothesis is that ageing and/or the increased age-related burden of pathology explains the declining SRH.

Setting

The Tromsø Study (TS) is a cohort study using a survey approach with repeated physical examinations. It was conducted in the municipality of Tromsø, Norway, from 1974 to 2008.

Participants

A total of 21 199 women and 19 229 men participated.

Primary and secondary outcome measures

SRH is the outcome of interest. We calculated and compared the effect sizes of age, comorbidity and mental health symptoms using multimediator analysis based on OLS regression.

Results

Ageing had a negative impact on SRH, but the total effect of age decreased from 1994 to 2007. We assessed the direct effect of age and then the proportion of indirect age-related effects through physical illness and mental health symptoms on the total effect. The direct effect of age represented 79.3% of the total effect in 1994 and decreased to 58.8% in 2007. Physical illness emerged as an increasingly important factor and increased its influence from 15.7% to 41.2% of the total effect. Age alone had a protective effect on mental health symptoms and this increased (2.5% to 17.3%), but we found a stronger association between mental health symptoms and physical disease in the later waves of the study (increasing from 3.7% to 14.8%).

Conclusions

The results suggest that the effect on SRH of mental health symptoms caused by physical illness is an increasing public health problem. Treatment and care for specific medical conditions must therefore focus more strongly on how these conditions affect the patient's mental health and address these concerns accordingly.

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Effect of socioeconomic disadvantage, remoteness and Indigenous status on hospital usage for Western Australian preterm infants under 12 months of age: a population-based data linkage study

Objectives

Our primary objective was to determine the incidence of hospital admission and emergency department presentation in Indigenous and non-Indigenous preterm infants aged postdischarge from birth admission to 11 months in Western Australia. Secondary objectives were to assess incidence in the poorest infants from remote areas and to determine the primary causes of hospital usage in preterm infants.

Design

Prospective population-based linked data set.

Setting and participants

All preterm babies born in Western Australia during 2010 and 2011.

Main outcome measures

All-cause hospitalisations and emergency department presentations.

Results

There were 6.9% (4211/61 254) preterm infants, 13.1% (433/3311) Indigenous preterm infants and 6.5% (3778/57 943) non-Indigenous preterm infants born in Western Australia. Indigenous preterm infants had a higher incidence of hospital admission (adjusted incident rate ratio (aIRR) 1.24, 95% CI 1.08 to 1.42) and emergency department presentation (aIRR 1.71, 95% CI 1.44 to 2.02) compared with non-Indigenous preterm infants. The most disadvantaged preterm infants (7.8/1000 person days) had a greater incidence of emergency presentation compared with the most advantaged infants (3.1/1000 person days) (aIRR 1.61, 95% CI 1.30 to 2.00). The most remote preterm infants (7.8/1000 person days) had a greater incidence of emergency presentation compared with the least remote preterm infants (3.0/1000 person days; aIRR 1.82, 95% CI 1.49 to 2.22).

Conclusions

In Western Australia, preterm infants have high hospital usage in their first year of life. Infants living in disadvantaged areas, remote area infants and Indigenous infants are at increased risk. Our data highlight the need for improved postdischarge care for preterm infants.

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Prevalence, impact and cost of multimorbidity in a cohort of people with chronic pain in Ireland: a study protocol

Introduction

Multimorbidity (MM) refers to the coexistence of two or more chronic conditions within one person, where no one condition is considered primary. As populations age and healthcare provision improves, MM is becoming increasingly common and poses a challenge to the single morbidity approach to illness management, usually adopted by healthcare systems. Indeed, recent research has shown that 66.2% of the people in primary care in Ireland are living with MM. Healthcare usage and cost is significantly associated with MM, and additional chronic conditions lead to exponential increases in service usage and financial costs, and decreases in physical and mental well-being. Certain conditions, for example, chronic pain, are highly correlated with MM. This study aims to assess the extent, profile, impact and cost of MM among Irish adults with chronic pain.

Methods and analysis

Using cluster sampling, participants aged 18 years and over will be recruited from Irish pain clinics and provided an information package and questionnaire asking them to participate in our study at three time points, 1 year apart. The questionnaire will include our specially developed checklist to assess the prevalence and impact of MM, along with validated measures of quality of life, pain, depression and anxiety, and illness perception. Economic data will also be collected, including direct and indirect costs.

Ethics and dissemination

Ethical approval has been granted by the Research Ethics Committee of the National University of Ireland, Galway. Dissemination of results will be via journal articles and conference presentations.

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Healthcare organisation and delivery for people with dementia and comorbidity: a qualitative study exploring the views of patients, carers and professionals

Objectives

People living with dementia (PLWD) have a high prevalence of comorbidty. The aim of this study was to explore the impact of dementia on access to non-dementia services and identify ways of improving service delivery for this population.

Design

Qualitative study involving interviews and focus groups. Thematic content analysis was informed by theories of continuity of care and access to care.

Setting

Primary and secondary care in the South and North East of England.

Participants

PLWD who had 1 of the following comorbidities—diabetes, stroke, vision impairment, their family carers and healthcare professionals (HCPs) in the 3 conditions.

Results

We recruited 28 community-dwelling PLWD, 33 family carers and 56 HCPs. Analysis resulted in 3 overarching themes: (1) family carers facilitate access to care and continuity of care, (2) the impact of the severity and presentation of dementia on management of comorbid conditions, (3) communication and collaboration across specialities and services is not dementia aware. We found examples of good practice, but these tended to be about the behaviour of individual practitioners rather than system-based approaches; current systems may unintentionally block access to care for PLWD.

Conclusions

This study suggests that, in order to improve access and continuity for PLWD and comorbidity, a significant change in the organisation of care is required which involves: coproduction of care where professionals, PLWD and family carers work in partnership; recognition of the way a patient's diagnosis of dementia affects the management of other long-term conditions; flexibility in services to ensure they are sensitive to the changing needs of PLWD and their family carers over time; and improved collaboration across specialities and organisations. Research is needed to develop interventions that support partnership working and tailoring of care for PLWD and comorbidity.

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