Toward Optimization of Imaging System and Lymphatic Tracer for Near-Infrared Fluorescent Sentinel Lymph Node Mapping in Breast Cancer

Near-infrared (NIR) fluorescent sentinel lymph node (SLN) mapping in breast cancer requires optimized imaging systems and lymphatic tracers. A small, portable version of the FLARE imaging system, termed Mini-FLARE, was developed for capturing color video and two semi-independent channels of NIR fluorescence (700 and 800 nm) in real time. Initial optimization of lymphatic tracer dose was performed using 35-kg Yorkshire pigs and a 6-patient pilot clinical trial. More refined optimization was performed in 24 consecutive breast cancer patients. All patients received the standard of care using (99m)Technetium-nanocolloid and patent blue. In addition, 1.6 ml of indocyanine green adsorbed to human serum albumin (ICG:HSA) was injected directly after patent blue at the same location. Patients were allocated to 1 of 8 escalating ICG:HSA concentration groups from 50 to 1000 mu M. The Mini-FLARE system was positioned easily in the operating room and could be used up to 13 in. from the patient. Mini-FLARE enabled visualization of lymphatic channels and SLNs in all patients. A total of 35 SLNs (mean = 1.45, range 1-3) were detected: 35 radioactive (100%), 30 blue (86%), and 35 NIR fluorescent (100%). Contrast agent quenching at the injection site and dilution within lymphatic channels were major contributors to signal strength of the SLN. Optimal injection dose of ICG:HSA ranged between 400 and 800 mu M. No adverse reactions were observed. We describe the clinical translation of a new NIR fluorescence imaging system and define the optimal ICG:HSA dose range for SLN mapping in breast cancer.EndocrinologyOV5Oncologic ImagingImaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Income inequality and alcohol attributable harm in Australia

<p>Abstract</p> <p>Background</p> <p>There is little research on the relationship between key socioeconomic variables and alcohol related harms in Australia. The aim of this research was to examine the relationship between income inequality and the rates of alcohol-attributable hospitalisation and death at a local-area level in Australia.</p> <p>Method</p> <p>We conducted a cross sectional ecological analysis at a Local Government Area (LGA) level of associations between data on alcohol caused harms and income inequality data after adjusting for socioeconomic disadvantage and remoteness of LGAs.</p> <p>The main outcome measures used were matched rate ratios for four measures of alcohol caused harm; acute (primarily related to the short term consequences of drinking) and chronic (primarily related to the long term consequences of drinking) alcohol-attributable hospitalisation and acute and chronic alcohol-attributable death. Matching was undertaken using control conditions (non-alcohol-attributable) at an LGA level.</p> <p>Results</p> <p>A total of 885 alcohol-attributable deaths and 19467 alcohol-attributable hospitalisations across all LGAs were available for analysis. After weighting by the total number of cases in each LGA, the matched rate ratios of acute and chronic alcohol-attributable hospitalisation and chronic alcohol-attributable death were associated with the squared centred Gini coefficients of LGAs. This relationship was evident after adjusting for socioeconomic disadvantage and remoteness of LGAs. For both measures of hospitalisation the relationship was curvilinear; increases in income inequality were initially associated with declining rates of hospitalisation followed by large increases as the Gini coefficient increased beyond 0.15. The pattern for chronic alcohol-attributable death was similar, but without the initial decrease. There was no association between income inequality and acute alcohol-attributable death, probably due to the relatively small number of these types of death.</p> <p>Conclusion</p> <p>We found a curvilinear relationship between income inequality and the rates of some types of alcohol-attributable hospitalisation and death at a local area level in Australia. While alcohol-attributable harms generally increased with increasing income inequality, alcohol-attributable hospitalisations actually showed the reverse relationship at low levels of income inequality. The curvilinear patterns we observed are inconsistent with monotonic trends found in previous research making our findings incompatible with previous explanations of the relationship between income inequality and health related harms.</p

BCG Revaccination Does Not Protect Against Leprosy in the Brazilian Amazon: A Cluster Randomised Trial

BCG is a vaccine developed and used to protect against tuberculosis, but it can also protect against leprosy. In Brazil, children receive BCG at birth, and since 1996 a trial has been conducted to find out if a second dose of BCG administered to schoolchildren gives additional protection against tuberculosis. We use this trial to find out if such vaccination protects against leprosy. The trial was conducted in the Brazilian Amazon, involving almost 100,000 children aged 7–14 years who had received neonatal BCG. Half of them received a second dose of BCG at school, and the other half did not. We followed the children for 6 years and observed that there were as many new cases of leprosy in the vaccinated children as in the unvaccinated children. Therefore, we concluded that a second dose of BCG given at school age in the Brazilian Amazon offers no additional protection against leprosy

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives

Research priorities for freshwater mussel conservation assessment

Freshwater mussels are declining globally, and effective conservation requires prioritizing research and actions to identify and mitigate threats impacting mussel species. Conservation priorities vary widely, ranging from preventing imminent extinction to maintaining abundant populations. Here, we develop a portfolio of priority research topics for freshwater mussel conservation assessment. To address these topics, we group research priorities into two categories: intrinsic or extrinsic factors. Intrinsic factors are indicators of organismal or population status, while extrinsic factors encompass environmental variables and threats. An understanding of intrinsic factors is useful in monitoring, and of extrinsic factors are important to understand ongoing and potential impacts on conservation status. This dual approach can guide conservation status assessments prior to the establishment of priority species and implementation of conservation management actions.NF-R was supported by a post-doctoral fellowship (Xunta de Galicia Plan I2C 2017-2020, 09.40.561B.444.0) from the government of the autonomous community of Galicia. BY was supported by the Ministry of Science and Higher Education (no. 0409-2016-0022). DLS was supported by the G. E. Hutchinson Chair at the Cary Institute of Ecosystem Studies. AO was supported by the Russian Foundation for Basic Research (no. 17-44-290016). SV was funded by European Investment Funds by FEDER/COMPETE/POCI- Operacional Competitiveness and Internacionalization Programme, under Project POCI-01-0145-FEDER-006958 and National Funds by FCT-Portuguese Foundation for Science and Technology, under the project UID/AGR/04033/2013. NF-R is very grateful to the University of Oklahoma Biological Survey for providing space to work in the U.S. and especially to Vaughn Lab members. Authors are very grateful to Akimasa Hattori, Allan K. Smith, Andrew Roberts, Daniel Graf, David Stagliano, David T. Zanatta, Dirk Van Damme, Ekaterina Konopleva, Emilie Blevins, Ethan Nedeau, Frankie Thielen, Gregory Cope, Heinrich Vicentini, Hugh Jones, Htilya Sereflisan, Ilya Vikhrev, John Pfeiffer, Karen Mock, Mary Seddon, Katharina Stockl, Katarzyna Zajac, Kengo Ito, Marie Capoulade, Marko Kangas, Michael Lange, Mike Davis, Pirkko-Liisa Luhta, Sarina Jepsen, Somsak Panha, Stephen McMurray, G. Thomas Watters, Wendell R. Haag, and Yoko Inui for their valuable contribution in the initial selection and description of extrinsic and intrinsic factors. We also wish to thank Dr. Amanda Bates, Chase Smith, and two anonymous reviewers for comments on earlier drafts of this manuscript. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government

Diarrhoea Episodes and Treatment-seeking Behaviour in a Slum Area of North Jakarta, Indonesia

Visits to household during a census in an impoverished area of north Jakarta were used for exploring the four-week prevalence of diarrhoea, factors associated with episodes of diarrhoea, and the patterns of healthcare use. For 160,261 urban slum-dwellers, information was collected on the socioeconomic status of the household and on diarrhoea episodes of individual household residents in the preceding four weeks. In households with a reported case of diarrhoea, the household head was asked which form of healthcare was used first. In total, 8,074 individuals (5%)\uaf13% of children aged less than five years and 4% of adults\uafhad a diarrhoea episode in the preceding four weeks. The two strongest factors associated with a history of diarrhoea were a diarrhoea episode in another household member in the four weeks preceding the interview (adjusted odds ratio [OR] 11.1; 95% confidence interval [CI] 10.4- 11.8) and age less than five years (adjusted OR 3.4; 95% CI 3.2-3.5). Of the 8,074 diarrhoea cases, 1,969 (25%) treated themselves, 1,822 (23%) visited a public-health centre (PHC), 1,462 (18%) visited a private practitioner or a private clinic, 1,318 (16%) presented at a hospital, 753 (9%) bought drugs from a drug vendor, and 750 (9%) used other healthcare providers, such as belian (traditional healers). Children with diarrhoea were most often brought to a PHC, a private clinic, or a hospital for treatment. Compared to children, adults with diarrhoea were more likely to treat themselves. Individuals from households in the lowest-income group were significantly more likely to attend a PHC for treatment of diarrhoea compared to individuals from households in the middle- and higher-income groups

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk