Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naive patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-alpha (pegIFN-alpha), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-alpha, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-alpha. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10) IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10) IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-alpha and thus shortened treatment duration (P <0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P <0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an antiviral effect differently regulated across IL28B genotypes.Peer reviewe

Type 2 Diabetes Is Associated with Altered NF-κB DNA Binding Activity, JNK Phosphorylation, and AMPK Phosphorylation in Skeletal Muscle after LPS

Systemic inflammation is often associated with impaired glucose metabolism. We therefore studied the activation of inflammatory pathway intermediates that interfere with glucose uptake during systemic inflammation by applying a standardised inflammatory stimulus in vivo. After ethical approval, informed consent and a thorough physical examination, 10 patients with type 2 diabetes and 10 participants with normal glucose tolerance (NGT) were given an intravenous bolus of E. coli lipopolysaccharide (LPS) of 0.3 ng/kg. Skeletal muscle biopsies and plasma were obtained at baseline and two, four and six hours after LPS. Nuclear factor (NF)-κB p65 DNA binding activity measured by ELISA, tumor necrosis factor-α and interleukin-6 mRNA expression analysed by real time reverse transcription polymerase chain reaction, and abundance of inhibitor of NF-κB (IκB)α, phosphorylated c-Jun-N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase measured by Western blotting were detected in muscle biopsy samples. Relative to subjects with NGT, patients with type 2 diabetes exhibited a more pronounced increase in NF-κB binding activity and JNK phosphorylation after LPS, whereas skeletal muscle cytokine mRNA expression did not differ significantly between groups. AMPK phosphorylation increased in volunteers with NGT, but not in those with diabetes. The present findings indicate that pathways regulating glucose uptake in skeletal muscle may be involved in the development of inflammation-associated hyperglycemia. Patients with type 2 diabetes exhibit changes in these pathways, which may ultimately render such patients more prone to develop dysregulated glucose disposal in the context of systemic inflammation

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010)info:eu-repo/semantics/publishedVersio

A Smartphone app For Self-Management of Urgency and Mixed Urinary Incontinence : a Randomized Controlled Trial

Hypothesis / aims of study: Urgency (UUI) and mixed (MUI) urinary incontinence are common clinical problems. They account for almost half of all cases of urinary incontinence (UI) in women [1], and have a potentially large impact on quality of life. Nonetheless, many women are reluctant to seek treatment, sometimes due to UI being a stigmatized condition. The recommended first-line treatment for UUI and MUI is pelvic floor muscle training (PFMT) and lifestyle advice [2], with bladder training as a valuable complement to the treatment. Previous studies have shown that a smartphone app was an effective form of self-management for women with stress urinary incontinence (SUI), both in terms of treatment efficacy [3] and cost-effectiveness. On-going studies show promising results of the app once it was made freely available for download, and a further study of the user experience of the app found that the app provided an appreciated and satisfactory experience. In this study, we aimed to evaluate whether a new smartphone app for the self-management of UUI and MUI in women was effective, in comparison to app-based information only. Study design, materials and methods: Between April 2017 and March 2018, women were consecutively recruited to this randomized controlled trial (RCT) via a screening questionnaire on the homepage of the research project. The trial has been Clinical Trials registered. The inclusion criteria were as follows: woman (gender self-stated and sex assigned at birth), ≥18 years, UUI or MUI with ≥2 leakages/week and ≥12 months of symptom duration. Pregnant women or women who used another PFMT app or anti-muscarinic drugs were not eligible to participate in the study. In order to identify and redirect cases that were better suited to receive usual care, an algorithm was developed by a team of professionals with both clinical and scientific experience from fields such as urogynecology, general practice, urology and incontinence care. The algorithm included questions on the person’s history of cancer in the pelvic region, diabetes, and neurological symptoms and diseases, as well as questions on certain alarm symptoms (e.g. painful urges, dysuria, haematuria, metrorrhagia, recurring urinary tract infections, bladder-emptying difficulties and pyelonephritis). The presence of any alarm symptom led to the respondent being classified as not eligible for the study and instead recommended to contact their usual medical care provider. Women who passed the screening questionnaire and submitted an email address received information about the study, and were asked to fill in an Informed Consent form, a two-day bladder diary and a baseline questionnaire which included the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form (ICIQ-UI SF), which provides a validated UI symptom score (range 0 - 21 points) with questions on frequency, amount and overall impact. Respondents were then contacted by telephone for an interview during which the symptom-based diagnosis of UUI or MUI was determined, and questions about alarm symptoms and UI symptoms were asked to ensure that the respondent was truly eligible for the study. Throughout the study, there was no face-to-face contact between the research group and the participants, only communication by email and telephone. The participants were randomized 1:1 to the two groups using sealed opaque envelopes prepared by an independent administrator who generated the randomization plan via the online randomization tool at http://www.randomization.com. Women randomized to the intervention group received access to the Treatment App, a smartphone app built on four themes: PFMT; bladder training; psychological education; and lifestyle information (Figure 1). The PFMT and bladder training parts of the app included 11-step and 7-step training programmes, respectively, in addition to information on pelvic floor anatomy and bladder physiology. The psychological education contained information on psychological topics related to UI, and three optional exercises. The Treatment App also offered an option to set three different times for reminder notifications, as well as an automated feedback function. In addition, the app included individual advice based on information from questionnaires and the bladder diary. The advice was generated via a pre-designed template and offered guidance to the most relevant parts of the app for each user. The control group received access to the Information App, a very limited version of the app, containing only brief information on the different topics and no training programmes or other features. Three months after randomization, the participants were asked to fill in a follow-up questionnaire and another bladder diary. In this abstract we present the results of the analysis of the primary outcome measure, the ICIQ-UI SF, measured at baseline and follow-up. Analyses of secondary outcomes, including incontinence episode frequency, are currently on-going and will be presented at a later date. Sample size calculation: Based on the findings of previous studies, improvements in the ICIQ-UI SF of 2.5 points in the Treatment App group and 0.9 points in the Information App group were assumed. To detect this difference with 80% power, 2-side test and a significance of 0.05, a sample size of 49 women was needed in each group. To allow for a dropout rate of 20%, each group needed to include 60 participants, and we therefore aimed to recruit 120 women in total. Statistical analysis: We performed Intention to Treat analysis by using a linear mixed model to estimate the difference between the groups in the ICIQ-UI SF at follow-up. A paired t-test was used for within-groups comparisons of the mean ICIQ-UI SF scores at baseline and follow-up. Results: 123 women were randomized to receive the Treatment App (n=60) or the Information App (n=63). The groups did not differ significantly in baseline measures (e.g. age, BMI, education level) nor in the mean ICIQ-UI SF scores. The mean age was 58.30 (SD 9.55) years and the mean BMI was 26.17 (SD 4.47) kg/m². The symptom-based diagnosis of MUI was more common (n=88) than that of UUI (n=35), and this distribution was equal across the two groups. The majority of women had moderate (n=73), severe (n=43) or very severe (n=4) incontinence, based on the ICIQ-UI SF scores. Two women, both in the Treatment App group, were lost to follow-up. Participants in both groups improved with regard to the mean ICIQ-UI SF score at follow-up (Treatment App group -4.67 (-5.65 to -3.69, 95% CI, p <0.001) and Information App group -1.64 (-2.31 to -0.96, 95% CI, p <0.001)). The improvement was significantly larger in the Treatment App group (p = 0.001) (Figure 2). Interpretation of results: Self-management of UUI or MUI using a mobile app led to highly significant improvements in incontinence symptoms with a significant difference compared to a control group. Thus the findings in this study show that the use of an app that includes treatment with PFMT, bladder training, psychological education and lifestyle advice was effective for women with UUI or MUI. Concluding message: Previous studies have shown that a smartphone app is an effective, easily accessible and appreciated first-line treatment option for women with SUI. The findings in the current study indicate that, provided that certain alarm symptoms or risk factors are not present, a smartphone app may be a useful addition to first-line treatment options for women with UUI or MUI who are interested in eHealth self-management

Temperature-responsive inclusion complex of cationic PNIPAAM diblock copolymer and gamma-cyclodextrin

Aqueous mixtures of gamma-cyclodextrin (gamma-CD) and the thermosensitive cationic diblock copolymer poly(N-isopropylacrylamide)-b-poly(3-acrylamidopropyl)trimethylammonium chloride (PNIPAAM(24)-b-PAMPTAM(+)(9)) or the PNIPAAM homopolymer PNIPAAM(47) have been investigated using various experimental methods. Solid g-CD-polymer inclusion complexes (pseudopolyrotaxanes) form at ambient temperatures in fairly concentrated CD solutions. The NMR measurements showed that the stoichiometry of the inclusion complexes is close to two NIPAAM units per CD molecule. The cationic block of the copolymer is not incorporated into the CD cavity. Synchrotron radiation X-ray diffraction spectra of the solid inclusion complexes indicate a compact columnar structure of CD molecules threaded onto the PNIPAAM chains. In water, square-shaped cyclodextrin aggregates were found to co-exist with single cyclodextrin molecules. In mixed solutions of gamma-CD and PNIPAAM(24)-b-PAMPTAM(+)(9) these aggregates disintegrate with time as inclusion complexes are formed and the kinetics was studied using time-resolved static and dynamic light scattering and cryo-TEM. Steady-state fluorescence spectroscopy measurements reveal that the CD molecules dethread from the PNIPAAM chains upon increasing the temperature to 40 degrees C, which is above the lower critical solution temperature of PNIPAAM

Influenza vaccination in breast cancer patients during subcutaneous trastuzumab in adjuvant setting

Background Despite the current recommendation for influenza vaccination in cancer patients with active oncological therapy, limited data are available on the efficacy of vaccination in cancer patients receiving targeted therapies. We aimed to investigate the immunogenicity and tolerability of influenza vaccination in breast cancer patients treated with trastuzumab in adjuvant setting. Methods A prospective open-label multicenter study was performed including patients with breast cancer during trastuzumab treatment in adjuvant setting and healthy controls. Blood samples were taken before, 4 weeks after, and 12 weeks after a single dose of trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Hongkong4801/2014 (H3N2), and B/Brisbane/60/2008. Levels of serum antibody titers to hemagglutinin for H1N1 and influenza B strains were measured. Results Twenty breast cancer patients and 37 controls were included in the study. No difference in seroprotection rate between trastuzumab-treated patients and controls was observed for either H1N1 (100% in both groups) or B strain (78.9% vs. 89.2%,pvalue = 0.423). A statistically significant increase in geometric mean titers from baseline was seen in both groups and was evident both 4 weeks and 12 weeks after vaccination. Adverse events in the trastuzumab-treated group were uncommon and mild with only one serious adverse event not related to vaccination. Conclusion Breast cancer patients treated with trastuzumab in adjuvant setting seem to benefit from influenza vaccination in terms of immunogenicity without increasing the risk for adverse events. The current data support the recommendation to offer influenza vaccination in breast cancer patients treated with this type of targeted therapy

Physical Activity and Mobile Phone Apps in the Preschool Age: Perceptions of Teachers and Parents

Background: Physical activity (PA) is already beneficial at the preschool age. In many countries, young children spend most of their days in the preschool setting, making it a common arena for PA interventions. Mobile health tools are becoming increasingly popular to promote PA in different populations; however, little is known about the interest for and how the preschool setting could incorporate such a tool. Objective: This study aimed to examine how teachers and parents perceive PA in preschool-aged children in general and their perceptions of how a mobile phone app could be used to promote PA in the preschool setting. Methods: Semistructured interviews were conducted with 15 teachers (93%, [14/15] women, mean age 43.5 years, 47%, [7/15] with a university degree and 10 parents [91%, 9/10] women, mean age 38.9 years, all with a university degree) recruited from 2 urban preschools in central Sweden. The interviews were recorded, fully transcribed, coded, and analyzed using thematic analysis by means of an inductive approach. Results: The analysis revealed 4 themes: (1) children are physically active by nature, (2) the environment as a facilitator or a barrier, (3) prerequisites of the adult world, and (4) an app in the preschool setting-challenges and possibilities. Parents and teachers perceived preschoolers as being spontaneously physically active; however, high-intensity PA was perceived as low. The PA was specifically performed during the day in the preschool. Identified facilitators of PA were access to safe and engaging outdoor environments such as forests, spacious indoor areas, and adult involvement. Adult involvement was considered especially important for children preferring sedentary activities. Identified barriers for PA were restricted indoor and outdoor space, rules for indoor activities, and lack of adult involvement because of time constraints. The teachers perceived that they had limited skills and experiences using apps in general, although they also acknowledged the increasing role of technological tools in the curriculum. Thus, the teachers expressed an interest for an app designed as a support tool for them, especially for situations when PA was limited because of perceived barriers. They suggested the app to include accessible information regarding the health benefits of PA in children linked to a library of activities for different settings and seasons. Parents suggested interactive app features including problem-solving tasks and music and dance, but not video clips as they made children passive. Conclusions: Vigorous PA was perceived as low in preschool-aged children. Future tailoring of interventions in the preschool setting should work around barriers and support facilitators to PA, especially PA of high intensity. In such work, an app could serve as a source of inspiration for PA in different ages, settings, and seasons and thus reduce environmental and structural inequalities in the preschool setting

Cell Surface Orifices of Caveolae and Localization of Caveolin to the Necks of Caveolae in Adipocytes

Caveolae are noncoated invaginations of the plasma membrane that form in the presence of the protein caveolin. Caveolae are found in most cells, but are especially abundant in adipocytes. By high-resolution electron microscopy of plasma membrane sheets the detailed structure of individual caveolae of primary rat adipocytes was examined. Caveolin-1 and -2 binding was restricted to the membrane proximal region, such as the ducts or necks attaching the caveolar bulb to the membrane. This was confirmed by transfection with myc-tagged caveolin-1 and -2. Essentially the same results were obtained with human fibroblasts. Hence caveolin does not form the caveolar bulb in these cells, but rather the neck and may thus act to retain the caveolar constituents, indicating how caveolin participates in the formation of caveolae. Caveolae, randomly distributed over the plasma membrane, were very heterogeneous, varying in size between 25 and 150 nm. There was about one million caveolae in an adipocyte, which increased the surface area of the plasma membrane by 50%. Half of the caveolae, those larger than 50 nm, had access to the outside of the cell via ducts and 20-nm orifices at the cell surface. The rest of the caveolae, those smaller than 50 nm, were not open to the cell exterior. Cholesterol depletion destroyed both caveolae and the cell surface orifices