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Abstract Background Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. The prevalence of IBS in Asian countries varies from 2.9% to 15.6%. IBS does not result in increased mortality, but is associated with psychological distress and disruption of work and sleep. Consequently, the evaluation of health-related quality of life (HRQoL) is an important outcome measure for patients with IBS since it provides a holistic assessment of the patient's emotional, social and physical function. However, some HRQoL tools can be time-consuming to apply. EQ-5D is a brief HRQoL tool which has been validated in the Western IBS population but has thus far not been used in Asia. This study was conducted to determine whether persons with self-reported symptoms that met the Rome III criteria for IBS had a poorer quality of life than those without these symptoms. We also aimed to determine which specific aspects of quality of life were most affected and whether any risk factors distinguished those with and without IBS. Methods Self-administered questionnaires which included the Rome III diagnostic questionnaire modules for IBS and the EQ-5D questionnaire were obtained from participants of a health symposium in Singapore on 31th October 2010. IBS was diagnosed based on the Rome III Criteria. The main outcome measure was the EQ-5D index score. The relationship between the presence of IBS and the EQ-5D index score, individual dimensions of EQ-5D and demographic risk factors were examined. Results 449 completed questionnaires were analyzed. The mean EQ-5D index score for IBS was 0.739 which was a significant reduction compared to non-IBS participants [−0.11 (95% CI: -0.15 to −0.07), p Conclusion IBS sufferers have significantly poorer quality of life. Assessment of HRQoL in IBS using the EQ-5D should be considered in further studies and routine clinical practice.

Background: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.Methods: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848.Findings: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred.Interpretation: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.Funding: GlaxoSmithKline Biologicals (Belgium). [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by skeletal muscle weakness and atrophy. Patients with SMA types 1 and 2 develop severe disabilities conferring substantial patient and caregiver burden. Caregiver treatment characteristic preferences are useful for informing treatment choices and improving adherence. We aimed to identify drivers of SMA treatment preference from the perspective of caregivers of patients with SMA types 1 or 2 in the United States. We quantified the relative importance of different treatment characteristics and compared preferences for hypothetical treatment scenarios. Treatment attributes and attribute levels elicited were based on a literature search and interviews with caregivers and health care professionals. The most important treatment characteristics from the perspective of health care professionals and caregivers were identified and used in a survey to quantify relative importance for caregivers. Caregivers completed surveys regarding their preferences using swing weighting methodology. These results were used to estimate the relative value of four hypothetical SMA treatment scenarios exploring different modes of treatment administration. The swing weighting survey, completed by 20 caregivers, demonstrated that the attributes driving treatment preference were reduction in permanent ventilation needs and risk of severe adverse events, followed by treatment access (including cost coverage and availability), increased ability to sit without support, and less treatment administration burden. The hypothetical SMA treatment scenarios with the highest relative value offered an easier mode of administration, lowest risk of severe adverse events, less need of permanent ventilation, and highest ability of patients to feed and sit without support. Our findings suggest that caregivers prefer a treatment with reduced clinical burden and risk in which the cost is covered and treatment is available in the short term. These results can provide important contextual information for decision-makers and help promote patient-centered care for patients with SMA., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Anish Patel, Walter Toro, Sandra P. Reyna, and Omar Dabbous are employees of Novartis Gene Therapies, Inc., and own stock and options. Siobhan Bourke, Yemi Oluboyede, Sylvaine Barbier, and Natalyia Bogoeva are employees of Putnam Associates and were contracted by Novartis Gene Therapies, Inc., as part of this research and analysis. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Patel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Hemophilia-associated bleeding and resultant joint pain and mobility restrictions can predispose patients to poor health-related quality of life (HRQoL). Therefore, efficacy of a treatment needs to address more than just annualized bleed rates., Objectives: Describe the evolution of HRQoL, pain, and activity in patients with hemophilia A, treated with efmoroctocog alfa prophylaxis., Design: A post hoc analysis from Kids A-LONG (NCT01458106), A-LONG (NCT01181128), and long-term extension study ASPIRE (NCT01454739) assessed change in pain and activity-related patient-reported outcomes (PROs)., Methods: Physical health, pain, and HRQoL were assessed by PROs for a cumulative treatment duration of up to ~6 years. The primary endpoint was change from baseline in EuroQoL (EQ)-5D and Haemophilia Quality of Life Questionnaire (Haem-A-QoL)., Results: 118 adult/adolescents and 71 pediatric patients were included. The proportion of adults and adolescents reporting no problem in the EQ-5D analysis of ' pain/discomfort ' significantly increased from A-LONG baseline (35.04%; 41/117) to ASPIRE month 30 (44.68%; 21/47; p  = 0.024). Mean (standard deviation) Haem-A-QoL subdomain scores for ' feeling ' and ' physical health ' at A-LONG baseline improved by -3.24 (15.13; p  = 0.018) and -3.85 (23.07; p  = 0.047), respectively, at study end. Proportion of pediatric patients reporting no problem on the EQ-5D analysis of ' pain/discomfort ', significantly increased from A-LONG baseline (75.0%; 42/56) to ASPIRE baseline (95.56%; 43/45; p  = 0.046). Satisfaction levels for pediatric patients were high at A-LONG baseline and maintained until study end., Conclusion: Long-term efmoroctocog alfa prophylaxis reduces pain and improves HRQoL in adult and adolescent patients with hemophilia A. In pediatric patients, it reduces perceived pain and maintains satisfaction levels., Trial Registration: NCT01458106, NCT01181128, NCT01454739., Competing Interests: PR has received travel support to attend conferences from CSL Behring and Takeda; speaker and/or consultancy honoraria from Pfizer, Sobi, and Idogen. NK, LB, and DE are employees of SOBI AB. SL has received honoraria for speaking and reimbursement for attending symposia or congresses from Roche, Sobi, Novo Nordisk, CSL Behring, Takeda, and Sanofi. KA, SB, and MM have no conflicts to disclose., (© The Author(s), 2024.)

Neovascular age-related macular degeneration (nAMD) is a prevalent cause of permanent vision loss and blindness in the elderly worldwide, with a significant impact on patients' daily lives. However, burdens related to nAMD from the patients' perspective have not been well documented. Here we developed a new questionnaire after eliciting nAMD patients' daily challenges followed by a pilot survey. Seven daily life burden domains were identified, and a quantitative survey was conducted using the questionnaire in the real-world clinic. Of the total 153 participants (mean age, 76.3 ± 8.3 years), 67 (43.8%) had bilateral nAMD, and 79 (52.7%) were classified into severe nAMD according to the best-corrected visual acuity with cut-off value of 0.52 in logMAR. Patients with bilateral and severe nAMD had significantly higher burden scores across all domains. Network models for the bilateral and severe disease subgroups identified the interactions between "activity of daily living" and "hand-eye coordination" and between "use of electronic devices" and "face recognition" domains, which were considered to be important burdens for the patients. These results can advance ophthalmologists' understanding of the impact of nAMD on patients' daily lives and the importance of active and continuing treatment for patients with nAMD., (© 2024. The Author(s).)

Large strides have been made in designing an ever-increasing set of modern organic materials of high functionality and thus, often, of high complexity, including semiconducting polymers, organic ferroelectrics, light-emitting small molecules, and beyond. Here, we review how broadly applied thermal analysis methodologies, especially differential scanning calorimetry, can be utilized to provide unique information on the assembly and solid-state structure of this extensive class of materials, as well as the phase behavior of intrinsically intricate multicomponent systems. Indeed, highly relevant insights can be gained that are useful, e.g., for further materials-discovery activities and the establishment of reliable processing protocols, in particular if combined with X-ray diffraction techniques, spectroscopic tools, and scanning electron microscopy enabled by vapor-phase infiltration staining. We, hence, illustrate that insights far richer than simple melting point- and glass-transition identification can be obtained with differential scanning calorimetry, rendering it a critical methodology to understand complex matter, including functional macromolecules and blends.

Background: Pain is a common symptom of hemophilia that may adversely affect patients' quality of life (QoL). Previous post hoc analyses of prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) have been published for adults and adolescents, demonstrating improvements in health-related QoL (HRQoL) when assessed by the haemophilia-specific QoL (HaemAQoL) questionnaire., Objective: To describe in depth the evolution of QoL, pain- and activity-related domains and questions for pediatric, adolescent, and adult patients with hemophilia B treated with rFIXFc prophylaxis., Design: A post hoc analysis of data from a series of clinical trials., Methods: This post hoc , long-term analysis assessed patient-reported outcomes (PROs) from the Kids B-LONG (NCT01440946: pediatric) and B-LONG (NCT01027364: adults and adolescents) parent studies and the B-YOND (NCT01425723: all age groups) extension study., Results: Ninety-two adult and adolescent patients that started in the B-LONG study were assessed, with a median (range) duration of follow-up of 58.9 (0.0-78.4) months. The Haem-A-QoL total score was significantly reduced from baseline by 4.45 ( p  ⩽ 0.01), as were the subdomains 'physical health' (9.10; p  = 0.001), 'sports and leisure' (11.25; p  ⩽ 0.01), 'treatment' (2.69; p  = 0.05), and 'view of self' (5.81; p  = 0.002). Thirty pediatric patients that started in the Kids B-LONG study were assessed, with a median (min-max) duration of follow-up of 36.7 (9.0-59.9) months. The high level of satisfaction demonstrated by the PROs at baseline was maintained., Conclusion: rFIXFc prophylaxis reduced perceived pain and increased levels of physical activity with sustained, long-term improvements in QoL in adult and adolescent patients with hemophilia B and maintained high QoL scores in pediatric patients., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J. Astermark reports research support from Sobi, CSL Behring, Takeda/Shire and Bayer; honoraria for consulting and lectures from Octapharma, Novo Nordisk, Pfizer, Bayer, Sobi, CSL Behring, Takeda/Shire, BioMarin, uniQure and Spark Therapeutics. C. Hermans has received consultancy and/or lecture fees from Bayer, Takeda, Roche, CSL Behring, Novo Nordisk, Pfizer, Sobi, LFB, OctaPharma, Uniqure and Biomarin within the last year. M. Ezzalfani, S. Barbier, and A. Sidhom are employees of Creativ-Ceutical, a consultancy company that received funding from Sobi for this research. N. Kragh, D. Eriksson and A. Falk are employees of Sobi., (© The Author(s), 2023.)

Parkinson's disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in the motor symptoms, NMS and dyskinesias in PD patients. In this study, we investigated the effects of a selective mGlu5 negative allosteric modulator (NAM), dipraglurant, in a rodent motor symptoms model of PD, but also in models of anxiety, depression and obsessive-compulsive disorder, all of which are among the most prevalent NMS symptoms. Dipraglurant is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and exhibits a high correlation between plasma concentration and efficacy in behavioral models. In vivo, dipraglurant dose-dependently reduced haloperidol-induced catalepsy, increased punished licks in the Vogel conflict-drinking model, decreased immobility time in the forced swim test, decreased the number of buried marbles in the marble-burying test, but had no effect on rotarod performance or locomotor activity. These findings suggest that dipraglurant may have benefits to address some of the highly problematic comorbid non-motor symptoms of PD, in addition to its antidyskinetic effect demonstrated in PD-LID patients.

Introduction: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan., Methods: We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week., Results: Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively., Conclusion: This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer., (© 2023. The Author(s).)

In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models. Mixed and joint models were compared in a real MCT ( N = 225 mice) to estimate the effect of a chemotherapy and a simulation study. Mixed models assume that death is predictable by observed tumor volumes (data missing at random, MAR) while the joint models assume that death depends on nonobserved tumor volumes (data missing not at random, MNAR). In the real dataset, of 103 deaths, 97 mice were sacrificed when reaching a predetermined tumor size (MAR data). Joint and mixed model estimates of tumor growth slopes differed significantly [0.24 (0.13;0.36)log(mm 3 )/week for mixed model vs. -0.02 [-0.16;0.11] for joint model]. By disrupting the MAR process of mice deaths (inducing MNAR process), the estimate of the joint model was 0.24 [0.04;0.45], close to mixed model estimation for the original dataset. The simulation results confirmed the bias in the slope estimate from the joint model. Using a MCT example, we show that joint model can provide biased estimates under MAR mechanisms of dropout. We thus recommend to carefully choose the statistical model according to nature of mice deaths., Significance: This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models., Competing Interests: H. Savel reports other from Ipsen during the conduct of the study; other from Ipsen outside the submitted work. F. Meyer-Losic reports other from Ipsen during the conduct of the study. L. Richert reports grants from Ipsen during the conduct of the study. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)

In Belarus and several EECA countries, periodic population-based chest X-ray "fluorography programme" use as a mass screening tool for the diagnosis of tuberculosis (TB) has been used for decades. This mass screening has also often been justified for the early detection of lung cancer (LC), although no mortality benefits were demonstrated by screening with chest X-ray in international randomized trials. In Belarus, fluorography testing is mandatory every one to three years for all adults depending on age and the so-called "risk groups". The World Bank and WHO estimate that Belarus spends USD11 million annually on mass fluorography screening and advocate for more targeted screening approaches to increase diagnostic yield for TB and not to use it for screening for LC. The study is a retrospective review of medical records to assess the yield of fluorography to detect true cases of LC and/or TB in asymptomatic patients in two rural and two urban districts in Belarus for 2015-2017 with positive screening results for presumed of TB or LC. The study provided the rationale to implement the improved policy and practices regarding the role of fluorography in the early detection of LC and TB in Belarus and elsewhere.

Purpose : Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design : Three paired PDAC preclinical models-patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)-were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results : PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions : Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance : The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.

Background: Regional variations in gastric cancer incidence are not explained by prevalence of Helicobacter pylori, the main cause of the disease, with several areas presenting high H. pylori prevalence but low gastric cancer incidence. The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk., Methods: We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1-69 years old and provided interviews and blood for anti-H. pylori antibodies (IgG, VacA, CagA, others) and atrophy biomarkers (pepsinogens)., Results: H. pylori seroprevalence (Age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years. The comparison of the prevalence of known and potential H. pylori cofactors in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products was significantly higher in Valdivia and daily non-green vegetable consumption was more common in Antofagasta. Pepsinogen levels suggestive of gastric atrophy were significantly more common and occurred at earlier ages in Valdivia, the higher risk area. In a multivariate model combining both study sites, age, chili consumption and CagA were the main risk factors for gastric atrophy., Conclusions: The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area. Dietary factors could partly explain higher rates of atrophy and gastric cancer in Valdivia., Impact: The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC., Methods and Analysis: Women aged 30-64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre., Ethics and Dissemination: The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings., Trial Registration Number: NCT01881659., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Bluetongue virus (BTV) is a Culicoides -borne pathogen infecting both domestic and wild ruminants. In Europe, the Red Deer ( Cervus elaphus ) (RD) is considered a potential BTV reservoir, but persistent sylvatic cycle has not yet been demonstrated. In this paper, we explored the dynamics of BTV1 and BTV8 serotypes in the RD in France, and the potential role of that species in the re-emergence of BTV8 in livestock by 2015 (i.e., 5 years after the former last domestic cases). We performed 8 years of longitudinal monitoring (2008-2015) among 15 RD populations and 3065 individuals. We compared Culicoides communities and feeding habits within domestic and wild animal environments (51,380 samples). Culicoides diversity (>30 species) varied between them, but bridge-species able to feed on both wild and domestic hosts were abundant in both situations. Despite the presence of competent vectors in natural environments, BTV1 and BTV8 strains never spread in RD along the green corridors out of the domestic outbreak range. Decreasing antibody trends with no PCR results two years after the last domestic outbreak suggests that seropositive young RD were not recently infected but carried maternal antibodies. We conclude that RD did not play a role in spreading or maintaining BTV in France.

Background: Evidence on long term effectiveness of public health strategies for lowering blood pressure (BP) is scarce. In the Control of Blood Pressure and Risk Attenuation (COBRA) Trial, a 2 x 2 factorial, cluster randomized controlled trial, the combined home health education (HHE) and trained general practitioner (GP) intervention delivered over 2 years was more effective than no intervention (usual care) in lowering systolic BP among adults with hypertension in urban Pakistan. However, it was not clear whether the effect would be sustained after the cessation of intervention. We conducted 7 years follow-up inclusive of 5 years of post intervention period of COBRA trial participants to assess the effectiveness of the interventions on BP during extended follow-up., Methods: A total of 1341 individuals 40 years or older with hypertension (systolic BP 140 mm Hg or greater, diastolic BP 90 mm Hg or greater, or already receiving treatment) were followed by trained research staff masked to randomization status. BP was measured thrice with a calibrated automated device (Omron HEM-737 IntelliSense) in the sitting position after 5 minutes of rest. BP measurements were repeated after two weeks. Generalized estimating equations (GEE) were used to analyze the primary outcome of change in systolic BP from baseline to 7- year follow-up. The multivariable model was adjusted for clustering, age at baseline, sex, baseline systolic and diastolic BP, and presence of diabetes., Findings: After 7 years of follow-up, systolic BP levels among those randomised to combined HHE plus trained GP intervention were significantly lower (2.1 [4.1-0.1] mm Hg) compared to those randomised to usual care, (P = 0.04). Participants receiving the combined intervention compared to usual care had a greater reduction in LDL-cholesterol (2.7 [4.8 to 0.6] mg/dl., Conclusions: The benefit in systolic BP reduction observed in the original cohort assigned to the combined intervention was attenuated but still evident at 7- year follow-up. These findings highlight the potential for scaling-up simple strategies for cardiovascular risk reduction in low- and middle- income countries., Trial Registration: ClinicalTrials.gov NCT00327574.

Aim: This study aims to determine the risk factors associated with glycaemic control of ambulatory patients with type 2 diabetes mellitus (T2DM) who are managed in primary care., Method: The data was retrieved from a primary care site within the Singapore Consortium of Cohort Studies-Diabetes Cohort (SCCS-DC). Demographic and clinical variables were described, in association with the risk of having a deteriorating glycaemic control (defined as an absolute increase of at least 1% HbA1c from one year to a subsequent year). Next, multivariate model was performed to define the independent effect of each factor. The longitudinal analysis of the HbA1c was performed using Generalised Estimating Equation (GEE)., Results: The 5 year longitudinal data of 1256 patients (54% Chinese, 25% Malays, 12% Indians, 9% others) were analysed. Their mean HbA1c decreased by <0.1% in the initial 3 years, but increased thereafter. 12% of them had absolute HbA1c increment of ≥1% in the first year, and 22% over 5 years. Based on GEE analysis, insulin, was associated with an increase of HbA1c (≥1%) from one year to another (all p<0.05). Compared with Chinese patients, Malays had higher HbA1c (+0.3%), Indians (+0.3%), and others (+0.2%), (all p<0.01). Patients with retinopathy had higher HbA1c (+0.2%) and those with cataract had lower mean HbA1c (-0.2%) (p<0.01)., Conclusion: Most cohort patients achieved glycaemic control within the initial 3 years. Patients of Malay and Indian ethnicity and those with retinopathy were associated with subsequent risk of glycaemic control deterioration. Those with cataract were associated with trend towards improved glycaemic control., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Hand foot mouth disease (HFMD) is a common childhood infection that can potentially lead to serious complications. The aim of this study is to identify risk factors of acquiring severe HFMD in our population., Methods: We performed a case control study using patients admitted to our hospital from August 2004 to July 2014. Cases were patients with severe HFMD disease while controls were age-matched patients obtained from the same year, in a 2:1 ratio. Data comprising demographic characteristics, clinical symptoms and signs, and lab findings were collected. Conditional univariable logistic regression was performed to determine risk factors for severe disease., Results: A total of 24 cases of severe HFMD were identified and matched with 48 controls. Seventeen (70.8%) cases had central nervous system complications. Seven (29.2%) had cardiovascular complications without evidence of myocarditis. One patient died of encephalitis. The overall mortality of severe disease is 4%. Evidence of hypoperfusion, seizure, altered mentation, meningeal irritation, tachycardia, tachypnea, raised absolute neutrophil count and EV-A71 (Enterovirus A71) positivity were significantly associated with a severe course of HFMD., Conclusion: In managing children with HFMD, physicians should consider these factors to help identify patients at risk for severe disease.

Background: Interventions to prevent readmissions of patients at highest risk have not been rigorously evaluated. We conducted a randomised controlled trial to determine if a post-discharge transitional care programme can reduce readmissions of such patients in Singapore., Methods: We randomised 840 patients with two or more unscheduled readmissions in the prior 90 days and Length of stay, Acuity of admission, Comorbidity of patient, Emergency department utilisation score ≥10 to the intervention programme (n = 419) or control (n = 421). Patients allocated to the intervention group received post-discharge surveillance by a multidisciplinary integrated care team and early review in the clinic. The primary outcome was the proportion of patients with at least one unscheduled readmission within 30 days after discharge., Results: We found no statistically significant reduction in readmissions or emergency department visits in patients on the intervention group compared to usual care. However, patients in the intervention group reported greater patient satisfaction (p < 0.001)., Conclusion: Any beneficial effect of interventions initiated after discharge is small for high-risk patients with multiple comorbidity and complex care needs. Future transitional care interventions should focus on providing the entire cycle of care for such patients starting from time of admission to final transition to the primary care setting., Trial Registration: Clinicaltrials.gov, no NCT02325752.

The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and β-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of β-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by β-catenin nuclear translocation after 15 days. As a consequence, increased expression of β-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic β-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.

Introduction and Aim: Head injuries are a common complaint among children presenting to the emergency department (ED). This study is part of an ongoing prospective surveillance of head injured children presenting to a paediatric ED. We aim to derive predictors for moderate to severe head injury in our population., Materials and Methods: We performed an unmatched case-control study. Cases were defined as those who presented to the ED with moderate to severe head injury, during the period from 2006 to 2014. Controls were obtained from the prospective surveillance head injury database and were children who presented to the ED with head injury but who remained well on follow up. We compared variables from demographics, mechanism of injury, history, and physical examination., Results: There were 39 cases and 1173 controls. In the prospective database, our event rate was 0.5% and our computed tomography (CT) rate was 1%. Among those with moderate to severe head injury, they were more likely to be involved in road traffic accidents, have a history of difficult arousal, confusion or disorientation and a history of seizure. On physical examination, cases were more likely to have the presence of altered mental status, base of skull fracture, scalp hematoma and anisocoria. On multivariable analysis, the following 4 predictors remained statistically significant: Involvement in road traffic accident (p<0.001), difficult arousal (p<0.001), vomiting (p=0.003) and signs of base of skull fracture (p<0.001). Using these 4 variables, the Area under Curve was 0.97 {Sensitivity 92.3% (79.1-98.4%), Specificity 93.0% (91.4-94.4%), positive predictive value 30.5% (22-40%), negative predictive value 99.7% (99.2-99.9%)}., Conclusion: Involvement in road traffic accident, difficult arousal, base of skull fracture and vomiting are independent predictors for moderate to severe head injury in our paediatric population., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Pediatric traumatic brain injury (TBI) constitutes a significant burden and diagnostic challenge in the emergency department (ED). While large North American research networks have derived clinical prediction rules for the head injured child, these may not be generalizable to practices in countries with traditionally low rates of computed tomography (CT). We aim to study predictors for moderate to severe TBI in our ED population aged < 16 years., Methods: This was a retrospective case-control study based on data from a prospective surveillance head injury database. Cases were included if patients presented from 2006 to 2014, with moderate to severe TBI. Controls were age-matched head injured children from the registry, obtained in a 4 control: 1 case ratio. These children remained well on diagnosis and follow up. Demographics, history, and physical examination findings were analyzed and patients followed up for the clinical course and outcome measures of death and neurosurgical intervention. To predict moderate to severe TBI, we built a machine learning (ML) model and a multivariable logistic regression model and compared their performances by means of Receiver Operating Characteristic (ROC) analysis., Results: There were 39 cases and 156 age-matched controls. The following 4 predictors remained statistically significant after multivariable analysis: Involvement in road traffic accident, a history of loss of consciousness, vomiting and signs of base of skull fracture. The logistic regression model was created with these 4 variables while the ML model was built with 3 extra variables, namely the presence of seizure, confusion and clinical signs of skull fracture. At the optimal cutoff scores, the ML method improved upon the logistic regression method with respect to the area under the ROC curve (0.98 vs 0.93), sensitivity (94.9% vs 82.1%), specificity (97.4% vs 92.3%), PPV (90.2% vs 72.7%), and NPV (98.7% vs 95.4%)., Conclusions: In this study, we demonstrated the feasibility of using machine learning as a tool to predict moderate to severe TBI. If validated on a large scale, the ML method has the potential not only to guide discretionary use of CT, but also a more careful selection of head injured children who warrant closer monitoring in the hospital.

Background: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides., Methods and Findings: In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease., Conclusions: Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL.

Background: Self-management plays an important role in maintaining good control of diabetes mellitus, and mobile phone interventions have been shown to improve such self-management. The Health Promotion Board of Singapore has created a caloric-monitoring mobile health app, the "interactive Diet and Activity Tracker" (iDAT)., Objective: The objective was to identify and describe short-term (8-week) trajectories of use of the iDAT app among patients with type 2 diabetes mellitus in a primary care setting in Singapore, and identify patient characteristics associated with each trajectory., Methods: A total of 84 patients with type 2 diabetes mellitus from a public primary care clinic in Singapore who had not previously used the iDAT app were enrolled. The app was demonstrated and patients' weekly use of the app was monitored over 8 weeks. Weekly use was defined as any record in terms of food entry or exercise workout entry in that week. Information on demographics, diet and exercise motivation, diabetes self-efficacy (Diabetes Empowerment Scale-Short Form), and clinical variables (body mass index, blood pressure, and glycosylated hemoglobin/HbA1c) were collected at baseline. iDAT app use trajectories were delineated using latent-class growth modeling (LCGM). Association of patient characteristics with the trajectories was ascertained using logistic regression analysis., Results: Three iDAT app use trajectories were observed: Minimal Users (66 out of 84 patients, 78.6%, with either no iDAT use at all or use only in the first 2 weeks), Intermittent-Waning Users (10 out of 84 patients, 11.9%, with occasional weekly use mainly in the first 4 weeks), and Consistent Users (8 out of 84 patients, 9.5%, with weekly use throughout all or most of the 8 weeks). The adjusted odds ratio of being a Consistent User, relative to a Minimal User, was significantly higher for females (OR 19.55, 95% CI 1.78-215.42) and for those with higher exercise motivation scores at baseline (OR 4.89, 95% CI 1.80-13.28). The adjusted odds ratio of being an Intermittent-Waning User relative to a Minimal User was also significantly higher for those with higher exercise motivation scores at baseline (OR 1.82, 95% CI 1.00-3.32)., Conclusions: This study provides insight into the nature and extent of usage of a caloric-monitoring app among patients with type 2 diabetes and managed in primary care. The application of LCGM provides a useful framework for evaluating future app use in other patient populations.

Aim: The main treatment for meibomian gland dysfunction (MGD), a major cause of dry eye, is eyelid warming. Lack of compliance is the main reason for treatment failure. This has led to the development of eyelid-warming devices that are safe, effective and convenient. To obtain robust evidence demonstrating their efficacy, the authors conducted a 3-arm randomized clinical study., Methods: The authors conducted a 3-month assessor-blinded, randomized, controlled trial of patients from the Singapore National Eye Centre experiencing at least one of eight dry eye symptoms 'often' or 'all the time'. Patients who wore contact lenses, had an active infection or known diagnosis of thyroid dysfunction and rheumatoid arthritis were excluded from the study. MGD participants were randomly assigned to warm towel (n = 25), EyeGiene(®) (Eyedetec Medical Inc., Danville, CA, USA) (n = 25) and Blephasteam(®) (Spectrum Thea Pharmaceuticals LTD, Macclesfield, UK) (n = 25) treatments. The primary efficacy and safety outcomes included the proportions of participants with improved symptoms and changes in best corrected visual acuity (BCVA), respectively. Other outcomes included tear break up time (TBUT), Schirmer test, corneal fluorescein dye staining and number of visibly occluded meibomian gland (MG) orifices., Results: The study population was 53.5 ± 11.1 years old and predominantly Chinese. For severity of symptom after 3 months of treatment, 78.3% Blephasteam(®) participants reported improvement compared to 45.5% warm towel participants (p = 0.023). The corresponding proportions for improvement in the frequency of symptoms were 82.6% and 50.0%, respectively (p = 0.020). The proportions of improvement of symptoms in EyeGiene(®) patients were not significantly different from warm towel intervention. At 1 month of treatment, the crude odds ratio of improvement of severity of irritation for Blephasteam(®) compared to control was 3.0 (95% CI 0.88-10.18). However, the odds ratio adjusted by age was 5.67 (1.30-24.66). The lid-warming treatments did not significantly change the TBUT, Schirmer test results or number of visibly occluded MGs in the study period. All treatment modalities did not worsen BCVA after 3 months., Conclusion: Blephasteam(®) is more effective than warm towel for MGD treatment, with warm towel and EyeGiene(®) being comparable effective. Older age might predict for treatment efficacy. All studied therapies were safe for visual acuity (VA) for 3 months of treatment.

Background: Disability is prevalent among patients treated in Internal Medicine (IM), but its impact on length of inpatient stay (LOS) is unknown. Current systems of patient management and resource allocation are disease-focused with scant attention paid to functional impairment. Earlier studies in selected cohorts suggest that disability prolongs LOS., Objective: To investigate the relationship of disability with LOS in IM, controlling for comorbidity., Design: Prospective cohort study., Patients: We charted 448 patients from an IM team admitted between 2008 and 2012 for sociodemographic, disease, biochemical and functional characteristics. Each IM team is on duty for one month annually, and patients were hence recruited for one month each year., Main Measures: Disability was measured using the Functional Independence Measure (FIM) recorded at discharge. Comorbidity was measured using the Charlson Comorbidity Index (CCI)., Key Results: Of the 448 patients, 57.4 % were male with mean age 68.6 years. The mean LOS was 9.58 days. The mean motor and cognitive FIM scores were 57.1 and 25.7, respectively. The mean CCI score was 2.69. Thirty-four percent had major social issues impacting discharge plans. The five most common diagnoses for admission were pneumonia (8.9 %), urinary tract infection (7.8 %), cellulitis (7.6 %), heart failure (7.1 %) and falls (6.0 %). Both cognitive and motor FIM scores were negatively correlated with longer LOS (P < 0.001). On multivariate analysis, variables independently associated with longer LOS included the motor FIM score (P < 0.001), presence of social issues such as caregiver unavailability (P < 0.001), non-realistic patient expectations (P = 0.001) and administrative issues impeding discharge (P = 0.016)., Conclusion: Disability predicts LOS in IM patients, and thus their comprehensive care should involve functional assessment. As social and administrative factors were also independently associated with LOS, there is a need to involve social workers and administrators in a multidisciplinary approach towards optimizing LOS.

Purpose: The primary healthcare setting is well placed for health screening. Tear fluid composition gives valuable information about the eye and systemic health, and there is now significant interest in the potential application of tears as a tool for health screening; however, the acceptability of tear collection in the primary healthcare setting as compared with other methods of human sample collection has not been previously addressed. The objective of this study was to evaluate the patient acceptability of tear collection in a primary healthcare setting., Methods: This was a cross-sectional study on 383 adult patients seeking primary healthcare, who were not diabetic and were not attending for an eye-related complaint. Tear collection was done using Schirmer strips, and an interviewer-administered questionnaire was conducted to collate information on the pain score (0-10) of the Schirmer tear collection, as well as to score the pain associated with their previous experience of antecubital venous puncture and finger prick test., Results: The pain score for Schirmer tear collection was significantly lower (p < 0.001) than antecubital venous puncture but higher (p < 0.001) than finger prick. The pain scores for all three procedures were significantly higher in participants of younger age, female gender, and higher education level. Among the participants, 70% did not mind their tears being collected to screen for eye problems, whereas only 38% did not mind this procedure being performed for general health screening. Nevertheless, 69% of the participants preferred tear to urine collection, and 74% of participants preferred tear to blood collection., Conclusions: Tear collection using Schirmer strips is a highly acceptable form of investigation that has the potential for use in health screening in the primary healthcare setting. This study has implications on using tear collection as a method of ocular and systemic health screening in the primary healthcare setting.

Background: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand., Methods and Findings: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported., Conclusions: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings., Trial Registration: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.

Objective: Through the eyes of those depressed, the world may appear dull and gray. Visual contrast sensitivity has recently been reported to be lower in depressed patients compared to healthy controls. We aimed to examine the consistency of this finding and to explore the underlying retinal electrophysiology., Methods: Twenty subjects with major depressive disorder and 20 matched healthy controls were studied. Pattern electroretinogram (PERG) and subjective visual contrast test were used to assess visual contrast sensitivity. Full-field electroretinography (ffERG) was additionally used to assess retinal neurophysiology. Depression was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and depression severity was measured using standard psychometric scales., Results: Visual contrast sensitivity was significantly lower in depressed patients compared to controls based on the Landolt C visual contrast test, but no difference was found between groups using PERG and ffERG. Greater severity of depressive symptoms correlated (r=0.49, p=0.001) with poorer visual contrast sensitivity., Conclusions: Depressed subjects had reduced visual contrast discrimination performance, but this finding could not be consistently determined using PERG. The neurobiological link between major depressive disorder and visual contrast sensitivity warrants further investigation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The potential of laser-induced breakdown spectroscopy (LIBS) for the rapid determination of platinum in liquid silicone oils has been evaluated in the framework of on-line process control. A comparison of LIBS sensitivity between three setups designed for liquid analysis (static, liquid jet and flowing liquid) was performed using a 266 nm Nd/YAG laser irradiation. Best results were obtained using the flowing liquid setup and a similar limit of detection was obtained using the liquid jet. The effect of different buffer gases (Ar, He, N(2), etc.) on the signal sensitivity was studied in liquid jet analysis and best values were obtained with a nitrogen sheath gas. Detection limits were in the 100 mg/kg range for both setups. Quantitative determination of platinum in real liquid samples was also investigated using both liquid jet and flowing liquid setups. Calibration curves were plotted for Pt with the liquid jet and the flowing liquid setups under optimised temporal acquisition parameters (delay time and gate width). A normalisation using a silicon line was applied and recovery ranged from 3 to 15% for Pt in catalyst samples with both setups showing that LIBS is a sensitive and accurate method for on-line applications.

Background: Mid-regional pro-atrial natriuretic peptide (MR-proANP) increases with severity in community-acquired pneumonia (CAP). We investigated whether changes of MR-proANP correlated to bacteremia., Methods: 392 adult patients with CAP visiting emergency department from a prospective observational multicenter study., Results: MR-proANP levels increased in patients with positive bacteremia (92.8 pmol/L vs. 84.3 pmol/L, p = 0.04). Performance of MR-proANP to detect bacteremia (0.60) was equivalent to CRP (0.59) but less accurate than PCT (0.69)., Conclusion: MR-ANP poorly predicts bacteremia in CAP patients.

Introduction: Mid-regional pro-atrial natriuretic peptide (MRproANP) increases during systemic infections and could possibly correlate with bacteremia., Methods: We determined the characteristics of MRproANP for accuracy to detect positive blood culture., Results: Bacteremia was positive in 58 (15%) of 347 patients. MRproANP levels increased in patients with bacteremia (98.4 pmol/L [interquartile range (IQR) 68.2-153.1] vs. 66.4 pmol/L [IQR 51.0-90.3], p <0.01). Performance of MRproANP to predict bacteremia [AUC = 0.69, 95%CI: 0.61-0.77] was equivalent to C-reactive protein (0.66 [95%CI: 0.59-0.74], p = 0.53) but less accurate than procalcitonin (0.78 [95%CI: 0.72-0.84], p <0.001)., Conclusion: Although MRproANP increased in bacteremic patients with acute pyelonephritis, results of likelihood ratios discarded its use at bedside to predict bacteremia.

A new approach for the interactive simulation of viscoelastic object cutting is presented. Two synchronized geometrical models at different resolutions are used, both derived from medical images. In contrast with most previous approaches, the blade deforms the object, and cutting occurs once a contact pressure threshold is exceeded. Moreover, we achieve interactive simulation rates by embedding a high-resolution geometry within a regular grid with arbitrary resolution. This allows to trade off accuracy for speed in the computation of deformations. The input data is a high-resolution volumetric model of the objects. The surface model of the object, used for rendering as well as collision detection and response, is a polygonal level set of the volumetric data. It is embedded in the volume model using barycentric coordinates. Cutting is performed by removing voxels at the fine level, and updating the surface and volume models accordingly. We introduce a new data structure, which we call a Dynamic Branched Grid, in order to preserve the fine-level topology at the coarse level. When an element of the coarse volumetric model is cut, it is replaced by a number of superimposed elements with the same size and at the same rest position as the original one. Each new element is assigned a part of material contained in the original one, and the mass and stiffness are recomputed accordingly. The well-known problem of creating small, ill-shaped finite elements while remeshing is thus completely avoided., (Copyright © 2010 Elsevier Ltd. All rights reserved.)