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Abstract Background There is limited data on client preferences for different HIV self-testing (HIVST) and provider-delivered testing options and associated factors. We explored client preferences for oral-fluid-based self-testing (OFBST), blood-based self-testing (BBST) and provider-delivered blood-based testing (PDBBT) among different populations. Methods At clinics providing HIV testing services to general populations (1 urban, 1 rural clinic), men seeking voluntary medical male circumcision (VMMC, 1 clinic), and female sex workers (FSW, 1 clinic), clients had the option to test using OFBST, BBST or PDBBT. A pre-test questionnaire collected information on demographics and testing history. Two weeks after collecting a self-test kit, participants responded to a questionnaire. We used logistic regression to determine predictors of choices. We also conducted 20 in-depth interviews to contextualise quantitative findings. Results May to June 2019, we recruited 1244 participants of whom 249 (20%), 251 (20%), 244 (20%) and 500 (40%) were attending urban general, rural, VMMC and FSW clinics, respectively. Half (n = 619, 50%) chose OFBST, 440 (35%) and 185 (15%) chose BBST and PDBBT, respectively. In multivariable analysis comparing those choosing HIVST (OFBST and BBST combined) versus not, those who had never married aOR 0.57 (95% CI 0.34–0.93) and those previously married aOR0.56 (0.34–0.93) were less likely versus married participants to choose HIVST. HIVST preference increased with education, aOR 2.00 (1.28–3.13), 2.55 (1.28–5.07), 2.76 (1.48–5.14) for ordinary, advanced and tertiary education, respectively versus none/primary education. HIVST preference decreased with age aOR 0.97 (0.96–0.99). Urban participants were more likely than rural ones to choose HIVST, aOR 9.77 (5.47–17.41), 3.38 (2.03–5.62) and 2.23 (1.38–3.61) for FSW, urban general and VMMC clients, respectively. Comparing those choosing OFBST with those choosing BBST, less literate participants were less likely to choose oral fluid tests, aOR 0.29 (0.09–0.92). Conclusions Most testing clients opted for OFBST, followed by BBST and lastly, PDBBT. Those who self-assessed as less healthy were more likely to opt for PDBBT which likely facilitated linkage. Results show importance of continued provision of all strategies in order to meet needs of different populations, and may be useful to inform both HIVST kit stock projections and tailoring of HIVST programs to meet the needs of different populations.

Abstract Background Dental materials science is an important subject, but research on curriculum mapping in preclinical dental materials science courses is still scarce. The present study aimed to conduct a curriculum mapping in analysing elements and suggesting recommendations for an institutional dental materials science course. Methods Curriculum mapping was conducted for the Year 2 undergraduate dental materials science course (Bachelor of Dental Surgery programme) in a Malaysian dental school. Based on Harden’s framework, the following steps were used to map the curriculum of the institutional dental materials science course: (1) scoping the task; (2) deciding the mapping format; (3) populating the windows, and (4) establishing the links. Two analysts reviewed the curriculum independently. Their respective analyses were compared, and discrepancies were discussed until reaching a consensus. A SWOT analysis was also conducted to evaluate the strengths, weaknesses, opportunities, and threats associated with the curriculum. Results Course learning outcomes, course contents, levels of cognitive and psychomotor competencies, learning opportunities, learning resources, learning locations, assessments, timetable, staff, curriculum management and students’ information were successfully scoped from the institutional dental materials science course. The present curriculum’s strengths included comprehensiveness, alignment with standards, adequate learning opportunities, well-defined assessment methods, and sufficient learning resources. However, the identified weaknesses were repetition in curriculum content, limited emphasis on the psychomotor domain, dependency on a single academic staff, and limited integration of technology. The SWOT analysis highlighted the opportunities for curriculum improvement, such as revising repetitive content, emphasising the psychomotor domain, and incorporating advanced teaching strategies and technology. Conclusions The present dental materials science curriculum demonstrated several strengths with some areas for improvement. The findings suggested the need to revise and optimise the course content to address gaps and enhance student learning outcomes. Ongoing monitoring and evaluation are necessary to ensure the curriculum remains aligned with emerging trends and advancements in dental materials science.

Abstract Background The integration of artificial intelligence (AI) in dentistry has the potential to revolutionise the field of dental technologies. However, dental technicians’ views on the use of AI in dental technology are still sparse in the literature. This qualitative study aimed to explore the perceptions of dental technicians regarding the use of AI in their dental laboratory practice. Methods Twelve dental technicians with at least five years of professional experience and currently working in Malaysia agreed to participate in the one-to-one in-depth online interviews. Interviews were recorded, transcribed verbatim and translated. Thematic analysis was conducted to identify patterns, themes, and categories within the interview transcripts. Results The analysis revealed two key themes: “Perceived Benefits of AI” and “Concerns and Challenges”. Dental technicians recognised the enhanced efficiency, productivity, accuracy, and precision that AI can bring to dental laboratories. They also acknowledged the streamlined workflow and improved communication facilitated by AI systems. However, concerns were raised regarding job security, professional identity, ethical considerations, and the need for adequate training and support. Conclusion This research sheds light on the potential benefits and challenges associated with the integration of AI in dental laboratory practices. Understanding these perceptions and addressing the challenges can support the effective integration of AI in dental laboratories and contribute to the growing body of literature on AI in healthcare.

Abstract Background The dental workforce plays a crucial role in delivering quality oral healthcare services, requiring continuous training and education to meet evolving professional demands. Understanding the impact of dental workforce training and education programmes on policy evolution is essential for refining existing policies, implementing evidence-based reforms and ensuring the growth of the dental profession. Therefore, this study protocol aims to assess the influence of dental workforce training and education programmes on policy evolution in Malaysia. Methods A mixed-method research design will be employed, combining quantitative surveys and qualitative interviews. Stakeholder theory and policy change models will form the theoretical framework of the study. Participants from various stakeholder groups will be recruited using purposive sampling. Data collection will involve surveys and one-on-one semi-structured interviews. Descriptive statistics, inferential analysis and thematic analysis will be used to analyse the data. Integration of quantitative and qualitative data will be used to provide a comprehensive understanding of the data. Discussion This study will shed light on factors influencing policy decisions related to dental education and workforce development in Malaysia. The findings will inform evidence-based decision-making, guide the enhancement of dental education programmes and improve the quality of oral healthcare services. Challenges related to participant recruitment and data collection should be considered, and the study’s unique contribution to the existing body of knowledge in the Malaysian context will be discussed.

Abstract Background Effective teaching of dental materials science is crucial for dental students to develop a comprehensive understanding of materials used in clinical practice. However, literature on educators’ views on teaching this subject is still scarce. This qualitative study aimed to explore the lived experiences of dental educators in teaching dental materials science subjects, thereby addressing potential gaps and enhancing teaching practices. Methods Thirteen dental educators from East and Southeast Asian countries (Malaysia, China, Indonesia, Thailand, South Korea, and Japan) participated in the present study. The present study adopted a transcendental phenomenological approach. One-to-one semi-structured online interviews were conducted. Interviews were recorded and transcribed verbatim. Thematic analysis was employed to identify patterns in the educators’ experiences. Results Three themes emerged from the present study. First, perceptions of the importance of dental materials science, highlighting its relevance in clinical practice, patient care, and lifelong learning. Second, the challenges faced in teaching dental materials science include limited instructional time, complex content, and insufficient resources. Third, specific strategies, such as applying interactive teaching methods, integrating clinical scenarios, and promoting critical thinking skills have been suggested to enhance teaching and learning. Conclusion Understanding dental educators’ experiences can improve dental materials science education, curriculum development, teaching methods, and faculty training programmes, ultimately enhancing the knowledge and skills of dental students in this field.

Abstract Background Paediatric dentistry is a branch of dental specialty that focuses on dental care for children from infancy through adolescence. However, there is no standardised national undergraduate paediatric dental curriculum in Malaysia. The present study aimed to identify relevant topics for undergraduate paediatric dental curricula and to determine the appropriate cognitive and psychomotor levels for each topic based on the consensus among paediatric dental experts. Methods Potential relevant undergraduate paediatric dentistry topics were initially drafted and revised according to the revised national competency statement. The final draft included 65 topics clustered under 18 domains. A fuzzy Delphi method was used and experts who fulfilled the inclusion criteria were invited to anonymously ranked the importance of relevant topics using a five-point Likert scale and proposed suitable cognitive and psychomotor levels for each topic. Fuzzy evaluation was then performed, and experts were considered to have reached a consensus if the following three conditions were achieved: (a). the difference between the average and expert rating data was ≤ 0.2; (b). the average expert consensus was ˃70%; and (c). the average fuzzy number was ≥ 0.5. Subsequently, the mean ratings were used to determine the cognitive and psychomotor levels. Results 20 experts participated in the survey. 64 out of 65 paediatric dentistry topics were deemed acceptable. The average fuzzy number ranged from 0.36 to 0.85, while the average Likert score ranged from 3.05 to 5.00. The topic “Dental amalgam” was rejected based on expert consensus since the average fuzzy number was 0.36. The most significant topic was “Pit and fissure sealant”, followed by “Preventive advice”, “Early childhood caries”, “Dental caries in children & adolescent”, “Management of dental caries in paediatric patients”, and “Consent” which were equally ranked as the second most important topics. According to Bloom’s and Simpson’s taxonomies, most of the paediatric dentistry topics were rated adequate for undergraduate students at the cognitive level of “Apply” (C3) and a psychomotor level of “Guided response” (P3). Conclusion The current study successfully identified relevant undergraduate paediatric dentistry topics using the fuzzy Delphi method, which can facilitate future educators to improve existing Malaysian undergraduate paediatric dental curricula.

Abstract Background Feedback is regarded as a key component of formative assessment and one of the elements with the greatest impact on students’ academic learning. The present study aimed to evaluate and compare students’ perceptions of the use of two feedback models, namely feedback sandwich and Ask-Tell-Ask (ATA), in teaching dental materials science courses. Methods All undergraduate second-year dental students were invited to participate in the dental materials science practical session and were randomly allocated into two groups: Group 1 (feedback) sandwich and Group 2 (ATA). The session began with the teacher giving a short briefing on the commonly used dental materials, followed by a short demonstration of the manipulation of those materials. Students were then allowed to mix and manipulate the materials, and teachers provided feedback accordingly. At the end of the session, 16 close-ended (five-point Likert scales) and an open-ended questionnaire were distributed to students to evaluate their perceptions of the feedback given. Internal reliability of the questionnaire items was evaluated using Cronbach’s alpha. Mean feedback scores were analysed using an independent t-test with ANCOVA for controlling gender and ethnicity. Thematic analysis was used to code the qualitative data. Results Sixty-nine students participated in the present study with the majority being females (72.5%) and Chinese (79.7%). Cronbach’s alpha analysis suggested removing three Likert-scale items, with the remaining 13 items being accepted. Generally, no significant difference was noted between the two groups (p = 0.197), but three items were found to be significant (p

Abstract Background Double reading (DR) in screening mammography increases cancer detection and lowers recall rates, but has sustainability challenges due to workforce shortages. Artificial intelligence (AI) as an independent reader (IR) in DR may provide a cost-effective solution with the potential to improve screening performance. Evidence for AI to generalise across different patient populations, screening programmes and equipment vendors, however, is still lacking. Methods This retrospective study simulated DR with AI as an IR, using data representative of real-world deployments (275,900 cases, 177,882 participants) from four mammography equipment vendors, seven screening sites, and two countries. Non-inferiority and superiority were assessed for relevant screening metrics. Results DR with AI, compared with human DR, showed at least non-inferior recall rate, cancer detection rate, sensitivity, specificity and positive predictive value (PPV) for each mammography vendor and site, and superior recall rate, specificity, and PPV for some. The simulation indicates that using AI would have increased arbitration rate (3.3% to 12.3%), but could have reduced human workload by 30.0% to 44.8%. Conclusions AI has potential as an IR in the DR workflow across different screening programmes, mammography equipment and geographies, substantially reducing human reader workload while maintaining or improving standard of care. Trial registration ISRCTN18056078 (20/03/2019; retrospectively registered).

Abstract Background Dental materials science is an important core course in undergraduate dental programs which integrates foundational concepts of chemical engineering and materials science into clinical dentistry. The present study aimed to identify relevant dental materials science topics for Malaysian undergraduate dental curricula and to determine their appropriate competency levels in terms of cognitive and psychomotor taxonomies. Methods Potential dental materials science topics were drafted in alignment with the revised national competency statement. The list of topics was further amended after comparing it with those recommended topics in the literature. Fuzzy Delphi method was applied. Experts were selected based on the different inclusion criteria. They ranked the topics using a five-point Likert scale and recommended the appropriate cognitive and psychomotor levels. Next, fuzzy evaluation was performed. Consensus was deemed for a topic to be included if (a) the average expert agreement was ≥ 75%, (b) the d-construct threshold value for each topic was ≤ 0.2 and (c) the average fuzzy number was ≥ 0.5. Results Sixty-two experts participated in the study. They accepted 33 out of 36 potential dental materials science topics. The average Likert score and fuzzy number ranged from 3.63 to 4.92 and 0.526 to 0.784, respectively. Furthermore, “Endodontic materials” was ranked as the most significant topic. Meanwhile, many topics required dental students to demonstrate a cognitive level of “Apply” and a psychomotor level of “Guided response”. Based on mean scores, “Impression materials” was rated as the most cognitively demanding topic, whilst “Temporary restorative materials” was the most demanding topic for psychomotor taxonomy. Conclusion The present study has identified relevant dental materials science topics and their appropriate cognitive and psychomotor levels using the Fuzzy Delphi approach. The findings of the present study form the basis for future studies to develop measurable learning outcomes, design corresponding innovative pedagogy and propose assessment criteria for each topic.

Abstract Background Supportive periodontal therapy (SPT) is the key for a stable periodontal health following active treatment. Likewise, implant maintenance is crucial following implant placement. This systematic review aimed to assess clinical outcomes, patients’ perception, and cost-effectiveness of repeated periodontal therapy with air polishing devices (APDs) in comparison with hand instruments and/or power-driven instruments (conventional interventions) in SPT and implant maintenance. Methods Electronic search for randomised controlled clinical trials with minimum 6 months follow-up for SPT and implant maintenance programme was conducted for data published from 01 January 2000 to 30 April 2020 using multiple databases and hand searching. Risk of bias was assessed using the Revised Cochrane Risk-of-Bias tool (RoB 2). Results A total of 823 articles were screened. 4 SPT and 2 implant maintenance studies were eligible for inclusion. For SPT, repeated APDs interventions revealed no statistically significant difference when compared to the conventional interventions (weighted mean difference [WMD] 0.11 mm, p = 0.08). Likewise, no statistical difference was noted in terms of percentage of bleeding on probing (BOP) and clinical attachment level (CAL) gain. APDs were associated with lower pain score (based on Visual Analogue Scale) and higher patient acceptance in SPT studies. For implant maintenance, APDs resulted in reduction in PPD and percentage of BOP. However, CAL gain was comparable between the two groups. In terms of patient reported outcomes, no implant maintenance studies recorded any forms of patient reported outcomes. In addition, no studies reported on economic evaluation of APDs in both SPT and implant maintenance. Conclusion Within the limitations of this systematic review and meta-analysis, repeated subgingival debridement using APDs in SPT resulted in similar clinical outcomes but better patients’ comfort when compared to the conventional interventions. For implant maintenance, there is limited evidence to show that repeated application of APDs leads to improved clinical outcomes when compared to conventional treatments.

Abstract A retrospective study was carried out to investigate the causes of disease and death in a population of foals in Ireland during their first 12 months post partum. Foaling and veterinary records from 343 foals on four farms born between January 1, 2004 and May 30, 2008 were reviewed. Among 343 foals, 22 did not survive to 12 months of age. Over the five-year period, the incidence of stillbirth was 1.5% (5/343), mortality 5% (17/338) and overall morbidity was 88.5% (299/338). Morbidity was calculated to include all new conditions brought to the attention of the attending veterinary surgeon, no matter how minor. Of foals born alive: congenital abnormalities were the most common cause of death (35.3% 6/17 foals) followed by musculoskeletal trauma (5/17, 29.4%). Of 711 separate incidents of disease, 46.5% (331/711) were due to an infectious process, 25% (178/711) due to non-infectious musculoskeletal issues; and 14.9% (106/711) related to non-infectious gastrointestinal problems. Respiratory infection was the single most common disease accounting for 27.8% (178/711) of all disease incidents in this population. Findings from this study provide information regarding the causes and incidence of death and disease in the young Irish Thoroughbred population.

This report presented a brief overview of the literature on the perinatal asphyxia syndrome (PAS) in foals as a prelude to a description of the investigation and treatment of acute onset seizures in a 24-hour-old Thoroughbred colt foal. PAS can cause a wide variety of clinical abnormalities, of which seizures due to encephalopathy are the most significant. The structural and biochemical components of CNS neurones are disrupted by the shift from oxidative to anaerobic metabolism, with a resultant deficit in cellular energy. The cells succumb to the combined effects of acidosis, neurotoxic activities of glutamate, nitric oxide and free radicals, lipid peroxidation, accumulation of intracellular calcium and destructive overactivity of intracellular enzymes. Concurrently, the hypoxia affects other organ systems and management of foals presenting with CNS signs requires the veterinarian to undertake a thorough clinical examination and to institute appropriate therapy for the various derangements induced by the hypoxic-ischaemic episode. Diazepam (0.1 to 0.2 mg/kg bwt) can be used for short-term control of seizures; phenobarbital (2 to 10 mg/kg bwt) may be required for more prolonged treatment of recurrent seizures. The needs of the affected foal for nutrients, fluids and electrolytes, antimicrobial therapy and ancillary therapies were discussed in the literature review and illustrated in the case report.

Right dorsal colitis (RDC) is an ulcerative inflammatory bowel disorder of the horse that has been associated with the administration of non-steroidal anti-inflammatory drugs (NSAIDs), particularly in horses treated when dehydrated or toxaemic. The acute form of RDC may result in profuse diarrhoea, severe colic, dehydration, endotoxic shock and even death; the chronic form may be manifest by mild to moderate intermittent colic, ventral oedema and weight loss with or without diarrhoea. The most consistent laboratory findings are anaemia, hypoproteinaemia, hypoalbuminaemia and hypocalcaemia. Medical management of RDC requires avoidance of NSAIDs, of stressful experiences and of large-volume diets. Specific medications such as sucralfate and metronidazole have been used to treat RDC in the horse. The use of dietary additions such as psyllium and corn oil has been mentioned in the literature. RDC has not been reported previously in Ireland or Britain; here we report that the condition was diagnosed in three horses in Ireland on the bases of a history of phenylbutazone therapy, clinical signs, clinical pathology and ultrasonography. In two of the three horses the diagnosis was confirmed by direct inspection of the affected colon at celiotomy.

Abstract Background Family-based cardiac screening programmes for persons at risk for genetic cardiac diseases are now recommended. However, the psychological wellbeing and health related quality of life (QoL) of such screened patients is poorly understood, especially in younger patients. We sought to examine wellbeing and QoL in a representative group of adults aged 16 and over in a dedicated family cardiac screening clinic. Methods Prospective survey of consecutive consenting patients attending a cardiac screening clinic, over a 12 month period. Data were collected using two health measurement tools: the Short Form 12 (version 2) and the Hospital Anxiety and Depression Scale (HADS), along with baseline demographic and screening visit-related data. The HADS and SF-12v.2 outcomes were compared by age group. Associations with a higher HADS score were examined using logistic regression, with multi-level modelling used to account for the family-based structure of the data. Results There was a study response rate of 86.6%, with n=334 patients providing valid HADS data (valid response rate 79.5%), and data on n=316 retained for analysis. One-fifth of patients were aged under 25 (n=61). Younger patients were less likely than older to describe significant depression on their HADS scale (p Conclusions High levels of anxiety were seen amongst patients attending a family-based cardiac screening clinic.Younger patients also had high rates of clinically significant anxiety. Higher levels of anxiety and depression tends to run in families, and this has implications for family screening and intervention programmes.

Abstract Background Geopropolis is a type of propolis containing resin, wax, and soil, collected by threatened stingless bee species native to tropical countries and used in folk medicine. However, studies concerning the biological activity and chemical composition of geopropolis are scarce. In this study, we evaluated the antimicrobial and antiproliferative activity of the ethanolic extract of geopropolis (EEGP) collected by Melipona scutellaris and its bioactive fraction against important clinical microorganisms as well as their in vitro cytotoxicity and chemical profile. Methods The antimicrobial activity of EEGP and fractions was examined by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against six bacteria strains as well as their ability to inhibit Streptococcus mutans biofilm adherence. Total growth inhibition (TGI) was chosen to assay the antiproliferative activity of EEGP and its bioactive fraction against normal and cancer cell lines. The chemical composition of M. scutellaris geopropolis was identified by reversed-phase high-performance liquid chromatography and gas chromatography–mass spectrometry. Results EEGP significantly inhibited the growth of Staphylococcus aureus strains and S. mutans at low concentrations, and its hexane fraction (HF) presented the highest antibacterial activity. Also, both EEGP and HF inhibited S. mutans biofilm adherence (p < 0.05) and showed selectivity against human cancer cell lines, although only HF demonstrated selectivity at low concentrations. The chemical analyses performed suggest the absence of flavonoids and the presence of benzophenones as geopropolis major compounds. Conclusions The empirical use of this unique type of geopropolis by folk medicine practitioners was confirmed in the present study, since it showed antimicrobial and antiproliferative potential against the cancer cell lines studied. It is possible that the major compounds found in this type of geopropolis are responsible for its properties.

Abstract Background Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe3O4 magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated. Results Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting. Conclusion We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route.

Abstract Background The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.

Abstract Background The Human Papillomavirus (HPV) genome is divided into early and late coding sequences, including 8 open reading frames (ORFs) and a regulatory region (LCR). Viral gene expression may be regulated through epigenetic mechanisms, including cytosine methylation at CpG dinucleotides. We have analyzed the distribution of CpG sites and CpG islands/clusters (CGI) among 92 different HPV genomes grouped in function of their preferential tropism: cutaneous or mucosal. We calculated the proportion of CpG sites (PCS) for each ORF and calculated the expected CpG values for each viral type. Results CpGs are underrepresented in viral genomes. We found a positive correlation between CpG observed and expected values, with mucosal high-risk (HR) virus types showing the smallest O/E ratios. The ranges of the PCS were similar for most genomic regions except E4, where the majority of CpGs are found within islands/clusters. At least one CGI belongs to each E2/E4 region. We found positive correlations between PCS for each viral ORF when compared with the others, except for the LCR against four ORFs and E6 against three other ORFs. The distribution of CpG islands/clusters among HPV groups is heterogeneous and mucosal HR-HPV types exhibit both lower number and shorter island sizes compared to cutaneous and mucosal Low-risk (LR) HPVs (all of them significantly different). Conclusions There is a difference between viral and cellular CpG underrepresentation. There are significant correlations between complete genome PCS and a lack of correlations between several genomic region pairs, especially those involving LCR and E6. L2 and L1 ORF behavior is opposite to that of oncogenes E6 and E7. The first pair possesses relatively low numbers of CpG sites clustered in CGIs while the oncogenes possess a relatively high number of CpG sites not associated to CGIs. In all HPVs, E2/E4 is the only region with at least one CGI and shows a higher content of CpG sites in every HPV type with an identified E4. The mucosal HR-HPVs show either the shortest CGI size, followed by the mucosal LR-HPVs and lastly by the cutaneous viral subgroup, and a trend to the lowest CGI number, followed by the cutaneous viral subgroup and lastly by the mucosal LR-HPVs.

Abstract Background Toxoplasmosis is a disease caused by Toxoplasma gondii and at least one-third of the world’s population has detectable T. gondii antibodies. The seroprevalence of T.gondii ranges from 15% to 50% among the Mexican general population. The aim of this work was to determine the mean prevalence and weighted mean prevalence of T. gondii infection, and to evaluate the epidemiological transition of infection in Mexico. Methods Pub Med, Lilacs, Medline, Latindex, Google Scholar data bases were searched to retrieve reports from 1951 up to 2012 regarding prevalence data, diagnostic tests and risk factors of infection among the adult population. Data collection and criteria eligibility was established in order to determine the crude prevalence (proportion of positive cases) of each study, together with weighted population prevalence according to individual research group categories to limit the bias that may impose the heterogeneous nature of the reports. A Forest Plot chart and linear regression analysis were performed by plotting the prevalence of infection reported from each study over a period of sixty years. Results A total of 132 studies were collected from 41 publications that included 70,123 individuals. The average mean prevalence was 27.97%, and weighted mean prevalence was 19.27%. Comparisons among different risk groups showed that the weighted prevalence was higher in women with miscarriages (36.03%), immunocompromised patients (28.54%), mentally-ill patients (38.52%) and other risk groups (35.13%). Toxoplasma infection among the Mexican population showed a downward trend of 0.1%/year over a period of sixty years that represents a 5.8% reduction in prevalence. Conclusions This analysis showed a downward trend of infection; however, there are individuals at high risk for infection such as immunocompromised patients, mentally-ill patients and pregnant women. Further research is required to provide better prevention strategies, effective diagnostic testing and medical management of patients. Educational efforts are required to avoid the transmission of infection in populations that cannot be controlled by drugs alone.

Abstract Background Risk factors for lung cancer, such as cigarette smoking, environmental pollution, asbestos, and genetic determinants, are well-known, whereas involvement of the human papillomavirus (HPV) is still unclear. Methods We examined a series of 100 lung cancer patients from Italy and the UK for the presence of HPV DNA in both lung tumor specimens and adjacent non-tumoral specimens from the same patients. Thirty-five of the most clinically relevant HPV types were assayed using PCR amplification of the highly conserved L1 region of the viral genome followed by hybridization with specific probes. Results No HPV was detected in tumor specimens nor in normal lung tissue of any patient. Conclusions These data indicate that, in this Western series, HPV is not associated with the risk of lung cancer. Our findings will help refine estimates of lung cancer risk in patients affected by a common viral infection involved in other types of human cancer.

Abstract Background To describe the long term outcome of patients who interrupted highly active antiretroviral therapy (HAART) once, identify the variables associated with earlier need to re-start HAART, and the response when therapy was resumed. A retrospective observational cohort of 66 adult patients with HIV-1 infection who interrupted HAART with a CD4+cell count ≥350 cells/μL and undetectable viral load (VL) was performed. The pre-established CD4+ cell count for restarting therapy was 300cells/μL. Cox regression was used to analyse the variables associated with earlier HAART reinitiation. Results The median follow-up was 209 weeks (range, 64–395). Rates of HIV-related or possible HIV-related events were 0.37 (one case of acute retroviral syndrome) and 1.49 per 100 patient-years, respectively. Two patients died after re-starting therapy and having reached undetectable VL. Three patients suffered a sexually transmitted disease while off therapy. Fifty patients (76%) resumed therapy after a median of 97 weeks (range, 17–267). Age, a nadir of CD4+ 10,000 copies/ml were independent predictors for earlier re-start. The intention-to-treat success rate of the first HAART resumed regimen was 85.4%. There were no differences by regimen used, nor between regimens that were the same as or different from the one that had been interrupted. Conclusions Our data suggest highly active antiretroviral therapy may be interrupted in selected patients because in these patients, when the HAART is restarted, the viral and clinical response may be achieved.

Abstract Background Care of the polytrauma patient does not end in the operating room or resuscitation bay. The patient presenting to the intensive care unit following initial resuscitation and damage control surgery may be far from stable with ongoing hemorrhage, resuscitation needs, and injuries still requiring definitive repair. The intensive care physician must understand the respiratory, cardiovascular, metabolic, and immunologic consequences of trauma resuscitation and massive transfusion in order to evaluate and adjust the ongoing resuscitative needs of the patient and address potential complications. In this review, we address ongoing resuscitation in the intensive care unit along with potential complications in the trauma patient after initial resuscitation. Complications such as abdominal compartment syndrome, transfusion related patterns of acute lung injury and metabolic consequences subsequent to post-trauma resuscitation are presented. Methods A non-systematic literature search was conducted using PubMed and the Cochrane Database of Systematic Reviews up to May 2012. Results and conclusion Polytrauma patients with severe shock from hemorrhage and massive tissue injury present major challenges for management and resuscitation in the intensive care setting. Many of the current recommendations for “damage control resuscitation” including the use of fixed ratios in the treatment of trauma induced coagulopathy remain controversial. A lack of large, randomized, controlled trials leaves most recommendations at the level of consensus, expert opinion. Ongoing trials and improvements in monitoring and resuscitation technologies will further influence how we manage these complex and challenging patients.

Abstract Background There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. Methods/design We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will take place at baseline, 6 months and 12 months. Discussion This project is unique as it explores a fundamental question of when exercise implementation will be of most benefit and addresses both physical and psychological consequences of androgen deprivation initiation. The final outcome may be adjunct treatment which will reduce if not prevent the toxicities of androgen deprivation, ultimately resulting in reduced morbidity and mortality for men with prostate cancer. Trial registration ACTRN12612000097842

Abstract Background IFN-α contributes extensively to host immune response upon viral infection through antiviral, pro-apoptotic, antiproliferative and immunomodulatory activities. Although extensively documented in various types of human cancers and viral infections, controversy exists in the exact mechanism of action of IFN-α in human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) retroviral infections. Results IFN-α displayed strong anti-HIV-1 effects in HIV-1/HTLV-1 co-infected MT-4 cells in vitro, demonstrated by the dose-dependent inhibition of the HIV-1-induced cytopathic effect (IC50 = 83.5 IU/ml, p 50 = 1.2 IU/ml, p Conclusions Taken together, our results indicate that both the absence of in vitro antiproliferative and pro-apoptotic activity as well as the modest post-transcriptional antiviral activity of IFN-α against HTLV-1, were not due to a cell-intrinsic defect in IFN-α signalisation, but rather represents a retrovirus-specific phenomenon, considering the strong HIV-1 inhibition in co-infected cells.

Abstract Our hypothesis was that overexpression of certain lipoprotein receptors might be related to lipid accumulation in the human ischemic myocardium. Intramyocardial lipid overload contributes to contractile dysfunction and arrhythmias in cardiomyopathy. Thus, the purpose of this study was to assess the effect of hypercholesterolemic LDL and hypertrigliceridemic VLDL dose on LRP1 expression in cardiomyocytes, as well as the potential correlation between LRP1 expression and neutral lipid accumulation in the left ventricle tissue from ischemic cardiomyopathy patients. Cell culture experiments include control and LRP1-deficient cardiomyocytes exposed to lipoproteins under normoxic and hypoxic conditions. Explanted hearts from 18 ICM patients and eight non-diseased hearts (CNT) were included. Low density lipoprotein receptor-related protein 1 (LRP1), very low density lipoprotein receptor (VLDLR) and low density lipoprotein receptor (LDLR) expression was analyzed by real time PCR and Western blotting. Cholesteryl ester (CE), triglyceride (TG) and free cholesterol (FC) content was assess by thin layer chromatography following lipid extraction. Western blotting experiments showed that protein levels of LRP1, VLDLR and HIF-1α were significantly upregulated in ischemic hearts. Immunohistochemistry and confocal microscopy analysis showed that LRP1 and HIF-1α were upregulated in cardiomyocytes of ICM patients. In vitro studies showed that VLDL, LDL and hypoxia exerted an upregulatory effect on LRP1 expression and that LRP1 played a major role in cholesteryl ester accumulation from lipoproteins in cardiomyocytes. Myocardial CE accumulation strongly correlated with LRP1 levels in ischemic hearts. Taken together, our results suggest that LRP1 upregulation is key for myocardial cholesterol ester accumulation in ischemic human hearts and that LRP1 may be a target to prevent the deleterious effects of myocardial cholesterol accumulation in ischemic cardiomyopathy.

Abstract Background This study examines exposure to perceived discrimination and its association with depression among low-income, Latina male-to-female transgender women as well as evaluates the impact of sexual partner violence and mistreatment on depression. Methods A total of 220 Latina male-to-female transgender women who resided in Los Angeles, California, were recruited through community based organizations and referrals. Participants completed individual interviews using a structured questionnaire. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Perceived discrimination was assessed using a fifteen-item measure that was designed to assess the experiences of maltreatment of transgender individuals. Multinomial logistic regression was used to examine the association between perceived discrimination and depression after controlling for the presence of other variables. Results Of the sample, 35% reported significant depressive symptoms (PHQ-9 ≥ 15). Additionally, one-third of the participants indicated that in the two weeks prior to the interviews they had thought either of hurting themselves or that they would be better off dead. The extent of perceived discrimination in this population was extensive. Many of the participants experienced discrimination on a daily basis (14%) or at least once or twice a week (25%) as demonstrated by a positive response to at least 7 of 15 items in the measure of perceived discrimination. Almost six out of ten participants admitted that they had been victims of sexual partner violence. Those who reported more frequent discrimination were more likely to be identified with severe depression. There was also a notable association between self-reported history of sexual partner violence and depression severity. Conclusions A significant association between depression severity and perceived discrimination was identified. How exposure to discrimination leads to increased risk of mental health problems needs additional investigation. Models investigating the association between perceived discrimination and depression among transgender women should include sexual partner violence as a potential confounding variable.

Abstract Background The lack of information on the care for sexually transmitted infections (STI) associated syndromes may contribute for its non-inclusion as prevention and control strategy for STI in Brazil. This study aims to analyze the cases of STI – Associated Syndromes assisted in primary health care center in a city in Northeast Brazil associating them with socio-demographic and behavioral variables. Methods This is a retrospective study that analyzed 5148 consultation forms and medical records of patients assisted in a primary health care center who presented at least one genital syndrome from 1999 to 2008. Was considered as dependent variables the genital syndromes and serologies for syphilis and HIV and as independent variables the socio-demographic and behavioral aspects. It was used Pearson’s chi-square test to analyze the differences between the categorical variables, with a significance level of 5%. It was performed a multivariate analysis through the multivariate logistic regression model with the variables with p Results The most frequent syndromes were vaginal discharge and/or cervicitis (44%) and genital wart (42.2%). Most people were between 20 and 39 years old (70%) and women (74.2%). Genital ulcer was most prevalent among men (OR = 2.67; CI 95% 1.99-3.58) and people who studied more than eight years (OR = 1.33; CI 95% 1.00-1.75) and wart prevailed among men (OR = 3.92; IC 95% 3.36-4.57), people under 29 years old (OR = 1.81; CI 95% 1.59-2.07) and who studied more than eight years (OR = 1.75; CI 95% 1.54-1.99). The Venereal Disease Research Laboratory (VDRL) was positive in 7.3% of men and in 7.1% of women and the Anti-HIV in 3.1% of men and 0.7% of women. Conclusion Vaginal discharge was the most frequent syndrome assisted in primary health care, followed by genital wart. The high prevalence of genital wart justifies the greater effort for the proper follow-up of these cases. Men presented more genital wart and ulcer and reported having more sexual partners, showing their need for a greater access and inclusion in health activities developed in primary health care in Brazil.

Abstract Background The STRATIFY score is a clinical prediction rule (CPR) derived to assist clinicians to identify patients at risk of falling. The purpose of this systematic review and meta-analysis is to determine the overall diagnostic accuracy of the STRATIFY rule across a variety of clinical settings. Methods A literature search was performed to identify all studies that validated the STRATIFY rule. The methodological quality of the studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. A STRATIFY score of ≥2 points was used to identify individuals at higher risk of falling. All included studies were combined using a bivariate random effects model to generate pooled sensitivity and specificity of STRATIFY at ≥2 points. Heterogeneity was assessed using the variance of logit transformed sensitivity and specificity. Results Seventeen studies were included in our meta-analysis, incorporating 11,378 patients. At a score ≥2 points, the STRATIFY rule is more useful at ruling out falls in those classified as low risk, with a greater pooled sensitivity estimate (0.67, 95% CI 0.52–0.80) than specificity (0.57, 95% CI 0.45 – 0.69). The sensitivity analysis which examined the performance of the rule in different settings and subgroups also showed broadly comparable results, indicating that the STRATIFY rule performs in a similar manner across a variety of different ‘at risk’ patient groups in different clinical settings. Conclusion This systematic review shows that the diagnostic accuracy of the STRATIFY rule is limited and should not be used in isolation for identifying individuals at high risk of falls in clinical practice.

Abstract Background Around the globe, school closures were used sporadically to mitigate the 2009 H1N1 influenza pandemic. However, such closures can detrimentally impact economic and social life. Methods Here, we couple a decision analytic approach with a mathematical model of influenza transmission to estimate the impact of school closures in terms of epidemiological and cost effectiveness. Our method assumes that the transmissibility and the severity of the disease are uncertain, and evaluates several closure and reopening strategies that cover a range of thresholds in school-aged prevalence (SAP) and closure durations. Results Assuming a willingness to pay per quality adjusted life-year (QALY) threshold equal to the US per capita GDP ($46,000), we found that the cost effectiveness of these strategies is highly dependent on the severity and on a willingness to pay per QALY. For severe pandemics, the preferred strategy couples the earliest closure trigger (0.5% SAP) with the longest duration closure (24 weeks) considered. For milder pandemics, the preferred strategies also involve the earliest closure trigger, but are shorter duration (12 weeks for low transmission rates and variable length for high transmission rates). Conclusions These findings highlight the importance of obtaining early estimates of pandemic severity and provide guidance to public health decision-makers for effectively tailoring school closures strategies in response to a newly emergent influenza pandemic.

Abstract Background Research has shown that parental feeding styles may influence children’s food consumption, energy intake, and ultimately, weight status. We examine this relationship, among recent immigrants to the US. Given that immigrant parents and children are at greater risk for becoming overweight/obese with increased time in the US, identification of risk factors for weight gain is critical. Methods Baseline data was collected on 383 mother-child dyads enrolled in Live Well, a community-based, participatory, randomized controlled lifestyle intervention to prevent weight gain in recent immigrant mothers. Socio-demographic information together with heights and weights were collected for both mother and child. Acculturation, behavioral data, and responses to the Caregiver’s Feeding Styles Questionnaire (CFSQ) were also obtained from the mother. Results The children’s average age was 6.2 ± 2.7 years, 58% male. Mothers had been in the country for an average of 6.0 ± 3.3 years, and are Brazilian (36%), Haitian (34%) and Latino (30%). Seventy-two percent of the mothers were overweight/obese, while 43% of the children were overweight/obese. Fifteen percent of mothers reported their feeding style as being high demanding/high responsive; 32% as being high demanding/low responsive; 34% as being low demanding/high responsive and 18% as being low demanding/low responsive. In bivariate analyses, feeding styles significantly differed by child BMIz-score, ethnic group, and mother’s perceived stress. In multiple linear regression, a low demanding/high responsive feeding style was found to be positively associated (ß = 0.56) with a higher child weight as compared to high demanding/high responsive, controlling for known covariates (p = 0.01). Conclusions Most mothers report having a low demanding/high responsive feeding style, which is associated with higher child weight status in this diverse immigrant population. This finding adds to the growing literature that suggests this type of feeding style may be a risk factor for childhood obesity. Further research is needed to help understand the larger socio-cultural context and its influence on feeding dynamics among immigrant families and families of lower incomes. How parents establish a certain feeding style in their home country compared to when they move to the US “obesogenic” environment, should also be explored.

Abstract Background Contact network models have become increasingly common in epidemiology, but we lack a flexible programming framework for the generation and analysis of epidemiological contact networks and for the simulation of disease transmission through such networks. Results Here we present EpiFire, an applications programming interface and graphical user interface implemented in C++, which includes a fast and efficient library for generating, analyzing and manipulating networks. Network-based percolation and chain-binomial simulations of susceptible-infected-recovered disease transmission, as well as traditional non-network mass-action simulations, can be performed using EpiFire. Conclusions EpiFire provides an open-source programming interface for the rapid development of network models with a focus in contact network epidemiology. EpiFire also provides a point-and-click interface for generating networks, conducting epidemic simulations, and creating figures. This interface is particularly useful as a pedagogical tool.

Abstract Background Non-compliance with antidepressant treatment continues to be a complex problem in mental health care. In immigrant populations non-compliance is one of several barriers to adequate management of mental illness; some data suggest greater difficulties in adhering to pharmacological treatment in these groups and an increased risk of therapeutic failure. The aim of this study is to assess differences in the duration and compliance with antidepressant treatment among immigrants and natives in a Spanish health region. Methods Population-based (n=206,603), retrospective cohort study including all subjects prescribed ADT between 2007 and 2009 and recorded in the national pharmacy claims database. Compliance was considered adequate when the duration was longer than 4months and when patients withdrew more than 80% of the packs required. Results 5334 subjects (8.5% of them being immigrants) initiated ADT. Half of the immigrants abandoned treatment during the second month (median for natives=3months). Of the immigrants who continued, only 29.5% presented good compliance (compared with 38.8% in natives). The estimated risk of abandoning/ending treatment in the immigrant group compared with the native group, adjusted for age and sex, was 1.28 (95%CI 1.16-1.42). Conclusions In the region under study, immigrants of all origins present higher percentages of early discontinuation of ADT and lower median treatment durations than the native population. Although this is a complex, multifactor situation, the finding of differences between natives and immigrants in the same region suggests the need to investigate the causes in greater depth and to introduce new strategies and interventions in this population group.

Abstract Background The development of plant gene transfer systems has allowed for the introgression of alien genes into plant genomes for novel disease control strategies, thus providing a mechanism for broadening the genetic resources available to plant breeders. Using the tools of plant genetic engineering, a broad-spectrum antimicrobial gene was tested for resistance against head blight caused by Fusarium graminearum Schwabe, a devastating disease of wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) that reduces both grain yield and quality. Results A construct containing a bovine lactoferrin cDNA was used to transform wheat using an Agrobacterium-mediated DNA transfer system to express this antimicrobial protein in transgenic wheat. Transformants were analyzed by Northern and Western blots to determine lactoferrin gene expression levels and were inoculated with the head blight disease fungus F. graminearum. Transgenic wheat showed a significant reduction of disease incidence caused by F. graminearum compared to control wheat plants. The level of resistance in the highly susceptible wheat cultivar Bobwhite was significantly higher in transgenic plants compared to control Bobwhite and two untransformed commercial wheat cultivars, susceptible Wheaton and tolerant ND 2710. Quantification of the expressed lactoferrin protein by ELISA in transgenic wheat indicated a positive correlation between the lactoferrin gene expression levels and the levels of disease resistance. Conclusions Introgression of the lactoferrin gene into elite commercial wheat, barley and other susceptible cereals may enhance resistance to F. graminearum.

Abstract Background Cannabis use can frequently have adverse affects in those that use it and these can be amplified by various characteristics of an individual, from demographic and environmental variations to familial predisposition for mental illnesses. Methods The current study of 100 individuals, who were cannabis users during their adolescence and may still be users, was a survey of the self perceived effects of cannabis and their correlates. A reliable family member was also interviewed for determination of family history of various major mental illnesses and substance use. Results As many as 40% of cannabis users had paranoid feelings (suspiciousness) when using cannabis, although the most frequent effect was feeling relaxed (46%). Having a familial background for mental illnesses such as depression or schizophrenia did not determine the effects of cannabis nor its pattern of use, although the number of subjects with such a history was small. An age at which an individual began using cannabis did have an effect on how heavily it was used and the heavier the cannabis use, the more likely the individual was also to have had psychotic symptoms after use. There were no sex differences in effects of cannabis. These results are tempered by the reliance on self-report for many of the variables ascertained. Conclusion Cannabis can frequently have negative effects in its users, which can be amplified by certain demographic and/or psychosocial factors. Thus, users with a specific profile may be at a higher risk of unpleasant effects from cannabis use and caution should be noted when cannabis is administered to young people for medicinal purposes.

Abstract Background Canine leishmaniosis (CanL) caused by Leishmania infantum is a widespread endemic disease in the Mediterranean basin, though, so far, the north of Spain has been considered a non-endemic area. The aim of the present study was to determine the prevalence of specific antibodies to L. infantum among stray dogs living in shelters in this area, and to evaluate the clinical status (both clinical signs and clinico-pathological abnormalities) of seropositive dogs. Besides L. infantum infection, the epidemiological role of variables like sex, breed and age was also assessed. Methods Over the year 2011 a cross-sectional study was conducted on a total of 418 stray dogs. A preliminary entomological survey was carried out using CDC-light traps. The chi-squared test was used to examine relationships between L. infantum seroprevalence and the remaining variables. Results The overall seroprevalence of L. infantum infection detected was 3% in the Cantabrian coast. In Orense the seroprevalence was 35.6%. In this latter region, the presence of sand fly, Phlebotomus perniciosus was also detected. In general, seropositivity for L. infantum was related to size (large breed dogs versus small) and age, with a significantly higher seroprevalence recorded in younger (0-3 years) and older dogs (> 7 years) than adult dogs. Clinical signs of CanL were observed in 41.3% of the seropositive dogs. The seropositivity for L. infantum infection associated with the presence of clinical signs and/or abnormal laboratory findings shows a prevalence of 4.5%. Conclusion Our data provide new insight into the prevalence of CanL across northern Spain. The situation observed in Orense seems to be worsening compared to the few reports available, with figures being similar to those cited for known endemic areas of Spain. Besides, the presence of P. perniciosus in Orense points out to a risk of the spread of this zoonotic disease in this geographical area. These findings identify a need for an active search for the sand fly vectors of L. infantum across the entire northern spanish region including the rest of Galicia, Asturias, Cantabria and the Basque Country.

Abstract Background The presence of bone metastases has excluded participation of prostate cancer patients in exercise intervention studies to date and is also a relative contraindication to supervised exercise in the community setting because of concerns of fragility fracture. However, this group of patients often have developed significant muscle atrophy and functional impairments from prior and continuing androgen deprivation that is exacerbated by subsequent and more intensive interventions such as chemotherapy. The aim of this study is to determine the efficacy and safety of a modular multi-modal exercise program in prostate cancer patients with bone metastases. Methods/Design Multi-site randomized controlled trial in Western Australia and New South Wales to examine the efficacy and safety of a modular multi-modal physical exercise program in 90 prostate cancer survivors with bone metastases. Participants will be randomized to (1) modular multi-modal exercise intervention group or (2) usual medical care group. The modular multi-modal exercise group will receive a 3-month supervised exercise program based on bone lesion location/extent. Measurements for primary and secondary endpoints will take place at baseline, 3 months (end of the intervention) and 6 months follow-up. Discussion Delaying or preventing skeletal complication and improving physical function for men with bone metastases would provide clinically meaningful benefits to patients. However, exercise programs must be designed and executed with careful consideration of the skeletal complications associated with bone metastatic disease and cumulative toxicities from androgen deprivation such as osteoporosis and increased risk of fractures. The results from this study will form the basis for the development of a specific exercise prescription in this patient group in order to alleviate disease burden, counteract the adverse treatment related side-effects and enhance quality of life. Trial Registration ACTRN: ACTRN12611001158954

Abstract Background Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) especially effective in tumors with activating EGFR gene mutations while EGFR wild-type non small cell lung cancer (NSCLC) patients at present do not benefit from this treatment. The primary site of gefitinib metabolism is the liver, nevertheless tumor cell metabolism can significantly affect treatment effectiveness. Results In this study, we investigated the intracellular metabolism of gefitinib in a panel of EGFR wild-type gefitinib-sensitive and -resistant NSCLC cell lines, assessing the role of cytochrome P450 1A1 (CYP1A1) inhibition on gefitinib efficacy. Our results indicate that there is a significant difference in drug metabolism between gefitinib-sensitive and -resistant cell lines. Unexpectedly, only sensitive cells metabolized gefitinib, producing metabolites which were detected both inside and outside the cells. As a consequence of gefitinib metabolism, the intracellular level of gefitinib was markedly reduced after 12-24 h of treatment. Consistent with this observation, RT-PCR analysis and EROD assay showed that mRNA and activity of CYP1A1 were present at significant levels and were induced by gefitinib only in sensitive cells. Gefitinib metabolism was elevated in crowded cells, stimulated by exposure to cigarette smoke extract and prevented by hypoxic condition. It is worth noting that the metabolism of gefitinib in the sensitive cells is a consequence and not the cause of drug responsiveness, indeed treatment with a CYP1A1 inhibitor increased the efficacy of the drug because it prevented the fall in intracellular gefitinib level and significantly enhanced the inhibition of EGFR autophosphorylation, MAPK and PI3K/AKT/mTOR signalling pathways and cell proliferation. Conclusion Our findings suggest that gefitinib metabolism in lung cancer cells, elicited by CYP1A1 activity, might represent an early assessment of gefitinib responsiveness in NSCLC cells lacking activating mutations. On the other hand, in metabolizing cells, the inhibition of CYP1A1 might lead to increased local exposure to the active drug and thus increase gefitinib potency.

Abstract A method was developed to identify insertional mutants of Chlamydomonas reinhardtii disrupted for selected target genes. The approach relies on the generation of thousands of transformants followed by PCR-based screenings that allow for identification of strains harboring the introduced marker gene within specific genes of interest. Our results highlight the strengths and limitations of two independent screens that differed in the nature of the marker DNA used (PCR-amplified fragment containing the plasmid-free marker versus entire linearized plasmid with the marker) and in the strategies used to maintain and store transformants.

Abstract Background Prostate cancer is the most common male cancer in developed countries and diagnosis and treatment carries with it substantial morbidity and related unmet supportive care needs. These difficulties may be amplified by physical inactivity and obesity. We propose to apply a multimodal intervention approach that targets both unmet supportive care needs and physical activity. Methods/design A two arm randomised controlled trial will compare usual care to a multimodal supportive care intervention "Living with Prostate Cancer" that will combine self-management with tele-based group peer support. A series of previously validated and reliable self-report measures will be administered to men at four time points: baseline/recruitment (when men are approximately 3-6 months post-diagnosis) and at 3, 6, and 12 months after recruitment and intervention commencement. Social constraints, social support, self-efficacy, group cohesion and therapeutic alliance will be included as potential moderators/mediators of intervention effect. Primary outcomes are unmet supportive care needs and physical activity levels. Secondary outcomes are domain-specific and health-related quality of life (QoL); psychological distress; benefit finding; body mass index and waist circumference. Disease variables (e.g. cancer grade, stage) will be assessed through medical and cancer registry records. An economic evaluation will be conducted alongside the randomised trial. Discussion This study will address a critical but as yet unanswered research question: to identify a population-based way to reduce unmet supportive care needs; promote regular physical activity; and improve disease-specific and health-related QoL for prostate cancer survivors. The study will also determine the cost-effectiveness of the intervention. Trial Registration ACTRN12611000392965

Abstract Background Cardiovascular diseases (CVD) in diabetic patients have endothelial dysfunction as a key pathogenetic event. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), plays a pivotal role in endothelial dysfunction. Different natural polyphenols have been shown to preserve endothelial function and prevent CVD. In this study, we assessed the effect of silibinin, a widely used flavonolignan from milk thistle, on ADMA levels and endothelial dysfunction in db/db mice. Methods Eight-week-old db/db mice were administrated a 20 mg/Kg i.p. daily dose of silibinin (n = 6) or vehicle (n = 6) for four weeks. Heterozygous lean db/m mice served as control. Plasma, aorta and liver ADMA levels were determined by ELISA. Vascular reactivity to phenilephrine (PE), acetylcholine (ACh), sodium nitroprusside (SNP) and ADMA was assessed in isolated aortic segments, in wire myograph. Results Plasma and aorta ADMA levels were higher in db/db than in control lean mice. Silibinin administration markedly decreased plasma ADMA; consistently, aorta ADMA was reduced in silibinin-treated animals. Plasma and aorta ADMA levels exhibited a positive correlation, whereas liver ADMA was inversely correlated with both plasma and aorta ADMA concentrations. Endothelium-(NO)-dependent vasodilatation to ACh was impaired in db/db mice and was restored in the silibinin group, in accordance with the observed reduction of plasma and vascular levels of ADMA. Endothelium-independent vasodilatation to SNP was not modified by silibinin administration; contractile tone induced in isolated aorta from db/db mice by challenging with exogenous ADMA was not affected by the treatment. Conclusions Silibinin markedly improves endothelial dysfunction in db/db mice by reducing circulating and vascular ADMA levels. Clinical studies are warranted to assess the efficacy of silibinin for cardiovascular protection.