Incorporating Ceragenins into Coatings Protects Peripherally Inserted Central Catheter Lines against Pathogen Colonization for Multiple Weeks.

Healthcare-acquired infections and multi-drug resistance in pathogens pose a major crisis for the healthcare industry. Novel antibiotics which are effective against resistant strains and unlikely to elicit strong resistance are sought after in these settings. We have previously developed synthetic mimics of ubiquitous antimicrobial peptides and have worked to apply a lead compound, CSA-131, to the crisis. We aimed to generate a system of CSA-131-containing coatings for medical devices that can be adjusted to match elution and compound load for various environments and establish their efficacy in preventing the growth of common pathogens in and around these devices. Peripherally inserted central catheter (PICC) lines were selected for our substrate in this work, and a polyurethane-based system was used to establish coatings for evaluation. Microbial challenges by methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans were performed and SEM was used to evaluate coating structure and colonization. The results indicate that selected coatings show activity against selected planktonic pathogens that extend between 16 and 33 days, with similar periods of biofilm prevention.

Abdominal fat quantification using convolutional networks.

OBJECTIVES: To present software for automated adipose tissue quantification of abdominal magnetic resonance imaging (MRI) data using fully convolutional networks (FCN) and to evaluate its overall performance-accuracy, reliability, processing effort, and time-in comparison with an interactive reference method. MATERIALS AND METHODS: Single-center data of patients with obesity were analyzed retrospectively with institutional review board approval. Ground truth for subcutaneous (SAT) and visceral adipose tissue (VAT) segmentation was provided by semiautomated region-of-interest (ROI) histogram thresholding of 331 full abdominal image series. Automated analyses were implemented using UNet-based FCN architectures and data augmentation techniques. Cross-validation was performed on hold-out data using standard similarity and error measures. RESULTS: The FCN models reached Dice coefficients of up to 0.954 for SAT and 0.889 for VAT segmentation during cross-validation. Volumetric SAT (VAT) assessment resulted in a Pearson correlation coefficient of 0.999 (0.997), relative bias of 0.7% (0.8%), and standard deviation of 1.2% (3.1%). Intraclass correlation (coefficient of variation) within the same cohort was 0.999 (1.4%) for SAT and 0.996 (3.1%) for VAT. CONCLUSION: The presented methods for automated adipose-tissue quantification showed substantial improvements over common semiautomated approaches (no reader dependence, less effort) and thus provide a promising option for adipose tissue quantification. CLINICAL RELEVANCE STATEMENT: Deep learning techniques will likely enable image-based body composition analyses on a routine basis. The presented fully convolutional network models are well suited for full abdominopelvic adipose tissue quantification in patients with obesity. KEY POINTS: • This work compared the performance of different deep-learning approaches for adipose tissue quantification in patients with obesity. • Supervised deep learning-based methods using fully convolutional networks  were suited best. • Measures of accuracy were equal to or better than the operator-driven approach.

Anthropometric estimators of abdominal fat volume in adults with overweight and obesity.

BACKGROUND/OBJECTIVES: To evaluate anthropometric measures for the prediction of whole-abdominal adipose tissue volumes VXAT (subcutaneous VSAT, visceral VVAT and total VTAT) in patients with obesity. SUBJECTS/METHODS: A total of 181 patients (108 women) with overweight or obesity were analyzed retrospectively. MRI data (1.5 T) were available from independent clinical trials at a single institution (Integrated Research and Treatment Center of Obesity, University of Leipzig). A custom-made software was used for automated tissue segmentation. Anthropometric parameters (AP) were circumferences of the waist (WC) and hip (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and the (hypothetical) hip-to-height ratio (HHtR). Agreement was evaluated by standard deviations sd% of percent differences between estimated volumes (using results of linear AP-VXAT regression) and measured ones as well as Pearson's correlation coefficient r. RESULTS: For SAT volume estimation, the smallest sd% for all patients was seen for HC (25.1%) closely followed by HHtR (25.2%). Sex-specific results for females (17.5% for BMI and 17.2% for HC) and males (20.7% for WC) agreed better. VAT volumes could not be estimated reliably by any of the anthropometric measures considered here. TAT volumes in a mixed population could be best estimated by BMI closely followed by WC (roughly 17.5%). A sex-specific consideration reduced the deviations to around 16% for females (BMI and WC) and below 14% for males (WC). CONCLUSIONS: We suggest the use of sex-specific parameters-BMI or HC for females and WC for males-for the estimation of abdominal SAT and TAT volumes in patients with overweight or obesity.

Grading bias and young adult mental health.

We study exposure to grading bias and provide novel evidence of its impact on mental health. Grading bias, which we interpret as over-grading, is constructed as the residual of final upper secondary school grades having controlled for results in a standardized test, itself not subject to grading leniency. Grading bias is further isolated by considering only within-school variation in over-grading and controlling for prior grades and school production. Using Swedish individual-level register data for individuals graduating from upper secondary school in the years 2001-2004, we show that over-grading has substantial significant protective impacts on the mental health of young adults, but only among female students. That grades themselves, independent of knowledge, substantially impact the production of health highlights an important health production mechanism, and implies that any changes to the design of grading systems must consider these wider health implications.

Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma.

BACKGROUND: Ovarian carcinoma is the eighth most common cause of cancer death in women worldwide. The disease is predominantly diagnosed at a late stage. This contributes to high recurrence rates, eventually leading to the development of treatment-resistant disease. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor and regulator of growth factor signaling. LRIG1 levels have not been investigated in human plasma previously. MATERIALS AND METHODS: A quantitative LRIG1-specific single molecule array assay was developed and validated. LRIG1 levels were quantified in plasma samples from 486 patients with suspicious ovarian masses. RESULTS: Among women with ovarian carcinoma, LRIG1 levels were significantly elevated compared to women with benign or borderline type tumors. High LRIG1 plasma levels were associated with worse overall survival and shorter disease-free survival both in the group of all malignant cases and among the stage 3 cases only. LRIG1 was an independent prognostic factor in patients with stage 3 ovarian carcinoma. CONCLUSION: LRIG1 plasma levels were elevated in patients with ovarian carcinoma, and high levels were associated with poor prognosis, suggesting that LRIG1 might be an etiologic factor and a potentially useful biomarker in ovarian carcinoma.

Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo.

BACKGROUND: Prostate cancer (PC) metastasizes to the skeleton forming predominantly sclerotic lesions, and there is currently no cure for bone metastatic disease. The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated as a metastatic driver, but its potential as therapeutic target in bone metastasis has not been investigated. In this study, we evaluated for the first time a STAT3 inhibitor, Napabucasin, as a therapeutic option for bone metastatic PC. METHODS: Effects of STAT3 inhibitors, Stattic and Napabucasin, on metastatic potential in PC cells were studied in vitro by assessment of migration capacity, self-renewal potential, and tumorsphere formation. For evaluation of the role of STAT3 in initial skeletal establishment of PC cells as well as in progressed castration-resistant PC (CRPC) in bone, human VCaP prostate cancer cells were inoculated in the tibia of mice which subsequently were treated with the STAT3 inhibitor Napabucasin. Bone specimens were analyzed using computed tomography (CT), immunohistochemistry, and quantitative polymerase chain reaction. RESULTS: The small molecule STAT3 inhibitors Stattic and Napabucasin both effectively impaired metastatic potential of PC cells in vitro. Furthermore, treatment with Napabucasin prevented metastatic establishment in tibial bones in vivo and thereby also the tumor-induced sclerotic bone response seen in vehicle-treated VCaP xenografts. In addition, treatment with Napabucasin of established bone CRPC significantly decreased both tumor burden and tumor-induced trabecular bone volume compared with effects seen in vehicle-treated animals. Anti-mitotic effects were confirmed by decreased Ki67 staining in Napabucasin-treated xenografts compared with vehicle-treated xenografts. Alterations of gene expression in the femoral bone marrow (BM) niche toward the maintenance of hematopoietic stem cells and the myeloid lineage were demonstrated by quantitative real-time polymerase chain reaction and were further reflected by a substantial increase in the number of erythrocytes in BM of Napabucasin-treated mice. Furthermore, a unique pattern of STAT3 phosphorylation in osteoblasts/stromal cells surrounding the areas of tumor cells was demonstrated immunohistochemically in bone xenograft models using several different PC cell lines. CONCLUSION: Inhibition of STAT3 activity disrupts the bone metastatic niche and targets both the skeletal establishment of PC and advanced bone metastatic CRPC in mice, suggesting STAT3 as a candidate for molecular targeted therapies of skeletal metastatic disease.

Evaluation of Sialyl-Lactotetra as a Marker for Epithelial Ovarian Tumors.

Ovarian carcinoma is a heterogeneous disease with distinct molecular and histological profiles, ranging from low grade atypia to highly aggressive tumors associated with a poor prognosis. In the present study, glycosphingolipids were isolated from human high-grade serous ovarian carcinoma, whereby the novel stem cell marker Sialyl-lactotetra (S-Lc4) was characterized in two out of three cases. The presence and level of S-Lc4 was further evaluated immunohistochemically in a cohort of patients with ovarian tumors ranging from benign lesions to high grade serous carcinoma (n = 478). Its expression was assessed in association with tumor grade, stage, histology, and survival. The data showed that S-Lc4 is most common and highly expressed in borderline type tumors and carcinomas with low levels of aggressiveness, such as mucinous, endometrioid, and low grade serous. Accordingly, S-Lc4-positivity was associated with better disease-free survival. The expression of S-Lc4 was seemingly associated with lineage continuity and could be traced from premalignant lesions to carcinoma, suggesting inheritance by a stem cell lineage that gives rise to generally indolent tumors.

Education, immigration and rising mental health inequality in Sweden.

Educational and income gradients in health are well established in the literature but there is need for a better understanding of how mental health inequalities change over time, and what drives the development. We aim to study how psychiatric diagnosis and its income-related inequality have changed over time in Sweden and to make a first attempt at disentangling the development by decomposing any changes in terms of changes in two important demographic characteristics: education and migration background. We use administrative patient data to study psychiatric inpatient diagnosis in the years 1994 and 2011. The study population comprises all individuals aged 31-64 years living in Sweden. Income-related inequalities are measured by the Concentration Index (CI). We decompose changes in the probability of receiving a diagnosis and changes in income-related inequality over time to understand the role of changing demographics. Our results show that over the study period the probability of receiving a psychiatric inpatient diagnosis increased by 12.6%, while the relative and absolute income-related inequalities in diagnosis increased by 48.2% and 66.7% respectively. In 2011, more than half of psychiatric inpatients were found among the poorest fifth of the population. The decomposition results suggest that changes in education and migration background have not played a substantial role in determining these increases. Education levels increased substantially over the study period which would be expected to protect against mental ill-health. Instead, we find that diagnoses have become more concentrated amongst the lowest educated individuals and the lowest income families, groups who appear to be increasingly disadvantaged. The growing proportion of individuals with foreign background in Sweden does, in fact, predict small increases in the probability of diagnosis, while the impact on diagnosis inequality varies depending on the definition of foreign background.

Heterogeneity in the associations between common mental disorders and labour outcomes - a population study from southern Sweden.

BACKGROUND: Previous research has shown that Common Mental Disorders (CMD) are unequally distributed between population subgroups, but we know less about how labour outcomes following such disorders are distributed. Our aim is to investigate how the labour outcomes following a CMD diagnosis differ over sex, age, schooling and country of birth. METHODS: We use a population sample from southern Sweden of patients diagnosed with CMD during calendar years 2009-2011, and a matched general population control group, to study labour market outcomes three years following diagnosis. Logistic regression is used to study the associations between a CMD diagnosis and outcomes in employment, sick leave, and disability pension. Interaction analysis is used to study heterogeneity in these associations. RESULTS: CMD diagnosis is associated with reduced employment and increased odds of sick leave and disability pension. Following a CMD diagnosis, men and higher educated individuals have higher odds of non-employment and sick leave compared to women and the lower educated. Foreign-born individuals have higher odds of non-employment and lower odds of sick leave, compared to individuals born in Sweden. Heterogeneity appears to be present also based on age. Younger age is associated with higher odds of non-employment and disability pension and lower odds of sick leave, following a CMD diagnosis. CONCLUSIONS: Heterogeneity in labour outcomes following a CMD diagnosis sometimes contributes to and sometimes mitigates inequalities in employment, sick leave and disability pension between population subgroups. When developing new strategies to tackle mental ill-health in the population, it may therefore be motivated to consider not only inequalities in the prevalence of mental disorders but also heterogeneity in associated adverse labour outcomes.

RGS2 is prognostic for development of castration resistance and cancer-specific survival in castration-resistant prostate cancer.

BACKGROUND: Regulator of G-protein signaling 2 (RGS2) is a multifaceted protein with a prognostic value in hormone-naïve prostate cancer (PC). It has previously been associated with the development of castration resistance. However, RGS2 expression in clinical specimens of castration-resistant prostate cancer (CRPC) and its clinical relevance has not been explored. In the present study, RGS2 was assessed in CRPC and in relation to the development of castration resistance. METHODS: In the present study, RGS2 expression was evaluated with immunohistochemistry in patient materials of hormone-naïve and castration-resistant primary tumors, also in matched specimens before and after 3 months of androgen deprivation therapy (ADT). Cox regression and Kaplan-Meier curves were used to evaluate the clinical significance of RGS2 expression. RGS2 expression in association to castration-resistant growth was assessed experimentally in an orthotopic xenograft mouse model of CRPC. In vitro, hormone depletion of LNCaP and enzalutamide treatment of LNCaP, 22Rv1, and VCaP was performed to evaluate the association between RGS2 and the androgen receptor (AR). Stable RGS2 knockdown was used to evaluate the impact of RGS2 in association to PC cell growth under hormone-reduced conditions. Gene and protein expression were evaluated with quantitative polymerase chain reaction and Western blot analysis, respectively. RESULTS: RGS2 expression is increased in CRPC and enriched under ADT. Furthermore, a high RGS2 level is prognostic for poor cancer-specific survival for CRPC patients and significantly reduced failure-free survival (FFS) after an initiated ADT. Additionally, the prognostic value of RGS2 outperforms prostate-specific antigen (PSA) in terms of FFS. The present study furthermore suggests that RGS2 expression is reflective of AR activity. Moreover, low RGS2-expressing cells display hampered growth under hormone-reduced conditions, in line with the poor prognosis associated with high RGS2 expression. CONCLUSIONS: High levels of RGS2 are associated with aggressive forms of castration-resistant PC. The results demonstrate that a high level of RGS2 is associated with poor prognosis in association with castration-resistant PC growth. RGS2 alone, or in association with PSA, has the potential to identify patients that require additional treatment at an early stage during ADT.

Inequalities in the economic consequences of depression and anxiety in Europe: a systematic scoping review.

BACKGROUND: Depression and anxiety are associated with adverse outcomes in educational achievements and economic performances. Moreover, the prevalence of these disorders is unequally distributed among different population subgroups. Our objective is to investigate whether the economic consequences of depression and anxiety differ between population subgroups of different gender, socioeconomic status (SES), ethnicity and age, in Europe. METHODS: A systematic scoping literature review was performed to identify studies where exposure to depression or anxiety was identified at baseline and consequences in education, sickness absence, disability pension, unemployment and income/earnings were measured at follow-up. RESULTS: Seventeen articles were included in this review and most of these were conducted in the Nordic countries. The consequences of depression and anxiety were stratified by gender in most of the articles. However, only in a few studies, the findings were stratified by SES, age and ethnicity. The negative consequences of depression in educational performance, disability pension and income are larger for men compared to women. Moreover, low SES individuals have more depression- and anxiety-related absence from work than high SES individuals. CONCLUSION: Our findings imply that the economic consequences of depression differ between population subgroups in Europe. This could have an impact on social stratification, shifting people who experience mental ill-health to lower SES groups or reinforcing an already disadvantaged position. More research is needed on unequal economic consequences of depression and anxiety in different population subgroups in Europe.

Analysis of regulator of G-protein signalling 2 (RGS2) expression and function during prostate cancer progression.

Prostate cancer (PC) represents the second highest cancer-related mortality among men and the call for biomarkers for early discrimination between aggressive and indolent forms is essential. Downregulation of Regulator of G-protein signaling 2 (RGS2) has been shown in PC, however the underlying mechanism has not been described. Aberrant RGS2 expression has also been reported for other carcinomas in association to both positive and negative prognosis. In this study, we assessed RGS2 expression during PC progression in terms of regulation and impact on tumour phenotype and evaluated its prognostic value. Our experimental data suggest that the RGS2 downregulation seen in early PC is caused by hypoxia. In line with the common indolent phenotype of a primary PC, knockdown of RGS2 induced epithelial features and impaired metastatic properties. However, increased STAT3, TWIST1 and decreased E-cadherin expression suggest priming for EMT. Additionally, improved tumour cell survival and increased BCL-2 expression linked decreased RGS2 levels to fundamental tumour advantages. In contrast, high RGS2 levels in advanced PC were correlated to poor patient survival and a positive metastatic status. This study describes novel roles for RGS2 during PC progression and suggests a prognostic potential discriminating between indolent and metastatic forms of PC.

Circulating Tumor Cells as a Marker for Progression-free Survival in Metastatic Castration-naïve Prostate Cancer.

BACKGROUND: Analysis of circulating tumor cells (CTC) is a promising prognostic marker in castration-resistant prostate cancer (CRPC). The aim of this study was to investigate CTC detection and phenotyping as prognostic biomarkers for response to primary androgen deprivation therapy (ADT) of metastatic prostate cancer (PC). METHODS: PC patients presenting with a prostate specific antigen (PSA) >80 ng/ml and/or metastatic disease, intended for ADT were enrolled in the study. CTCs were analysed for expression of PSA prostate specific membrane antigen (PSMA) and epidermal growth factor receptor (EGFR) before and three months after ADT and related to progression. RESULTS: At inclusion, 46 out of 53 patients (87%) were CTC-positive with a sensitivity and specificity for distant metastases (M1) of 98% and 75%, respectively. In patients with M1-disease, EGFR-detection in CTC was an independent prognostic marker for progression-free survival, whereas PSA and alkaline phosphatase serum levels, Gleason score, or T-stage were not. EGFR-positive patients had significantly shorter time to progression (5 months) compared to EGFR-negative patients (11 months) (P < 0.05). CONCLUSIONS: In this explorative study, CTCs were detected in 98% of M1 patients and detection of EGFR in CTCs was strongly associated with poor outcome, which indicated that phenotypical analysis of CTC could be a promising prognostic marker of ADT-response in castration-naïve metastatic PC patients. Prostate 77:849-858, 2017. © 2017 Wiley Periodicals, Inc.

Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region.

BACKGROUND: Several reports indicate a commonly deleted chromosomal region independent from, and distal to the TP53 locus in a variety of human tumors. In a previous study, we reported a similar finding in a rat tumor model for endometrial carcinoma (EC) and through developing a deletion map, narrowed the candidate region to 700 kb, harboring 19 genes. In the present work real-time qPCR analysis, Western blot, semi-quantitative qPCR, sequencing, promoter methylation analysis, and epigenetic gene expression restoration analyses (5-aza-2'-deoxycytidine and/or trichostatin A treatments) were used to analyze the 19 genes located within the candidate region in a panel of experimental tumors compared to control samples. RESULTS: Real-time qPCR analysis suggested Hic1 (hypermethylated in cancer 1), Inpp5k (inositol polyphosphate-5-phosphatase K; a.k.a. Skip, skeletal muscle and kidney enriched inositol phosphatase) and Myo1c (myosin 1c) as the best targets for the observed deletions. No mutation in coding sequences of these genes was detected, hence the observed low expression levels suggest a haploinsufficient mode of function for these potential tumor suppressor genes. Both Inpp5k and Myo1c were down regulated at mRNA and/or protein levels, which could be rescued in gene expression restoration assays. This could not be shown for Hic1. CONCLUSION: Innp5k and Myo1c were identified as the best targets for the deletions in the region. INPP5K and MYO1C are located adjacent to each other within the reported independent region of tumor suppressor activity located at chromosome arm 17p distal to TP53 in human tumors. There is no earlier report on the potential tumor suppressor activity of INPP5K and MYO1C, however, overlapping roles in phosphoinositide (PI) 3-kinase/Akt signaling, known to be vital for the cell growth and survival, are reported for both. Moreover, there are reports on tumor suppressor activity of other members of the gene families that INPP5K and MYO1C belong to. Functional significance of these two candidate tumor suppressor genes in cancerogenesis pathways remains to be investigated.

Impact of the surgeon's experience on the postoperative outcome--a retrospective analysis of non-melanoma skin cancers of the head and neck region.

BACKGROUND: Treatment of choice for non-melanoma skin cancers is surgical excision. No study has analyzed the impact of the dermatologic surgeon's experience on the postoperative outcome. PATIENTS AND METHODS: In a single center, retrospective study, 196 cases of non-melanoma skin cancer of the head and neck treated with micrographically-controlled surgery were categorized with regard to type of tumor, location, size of defect, number of stages, complications, recurrence rate and cosmetic result. These data were analyzed in respect of the surgeon's experience (dermatology attendings [AT], senior residents with experience in dermatosurgery [SR], junior residents with less experience in dermatosurgery [JR]). RESULTS: AT and SR excised tumors in toto at roughly the same rate (AT: 42/75; SR: 59/104), JR less frequently (3/6). The patients graded 97% of the scars as very good to satisfactory. The grading of smaller defects (< 4 cm(2)) was not influenced by the surgeon's experience. Larger defects were graded equally in the two groups AT and SR. The complication rate was similar in all three groups, even though larger defects were treated by the attendings (AT). CONCLUSIONS: Micrographically-controlled surgery followed by plastic reconstruction is the treatment of choice for non-melanoma skin tumors of the head and neck area. Cosmetic results are excellent. Minor procedures can be performed by residents during their training; larger defects require more experience in dermatosurgery.