SNIP/p140Cap mRNA expression is an unfavourable prognostic factor in breast cancer and is not expressed in normal breast tissue

The prevalence and clinical relevance of SNIP/p140Cap has not been extensively investigated. Here SNIP/p140Cap mRNA expression was studied in 103 breast tumour biopsies, where it was detected in ∼37% of tumour specimens, but not in any normal breast specimens. Expression correlated significantly with unfavourable overall survival. This suggests that SNIP/p140Cap may be a useful diagnostic and prognostic marker for breast cancer and its expression in breast cancer, but not in normal breast tissue, suggests that it may have potential as a therapeutic target

A Role for Antimicrobial Stewardship in Clinical Sepsis Pathways: A Prospective Interventional Study

© 2017 by The Society for Healthcare Epidemiology of America. All rights reserved. OBJECTIVE To evaluate the impact of early infectious diseases (ID) antimicrobial stewardship (AMS) intervention on inpatient sepsis antibiotic management. DESIGN Interventional, nonrandomized, controlled study. SETTING Tertiary-care referral hospital, Sydney, Australia. PATIENTS Consecutive, adult, non-intensive care unit (non-ICU) inpatients triggering an institutional clinical sepsis pathway from May to August 2015. INTERVENTION All patients reviewed by an ID Fellow within 24 hours of sepsis pathway trigger underwent case review and clinic file documentation of recommendations. Those not reviewed by an ID Fellow were considered controls and received standard sepsis pathway care. The primary outcome was antibiotic appropriateness 48 hours after sepsis trigger. RESULTS In total, 164 patients triggered the sepsis pathway: 6 patients were excluded (previous sepsis trigger); 158 patients were eligible; 106 had ID intervention; and 52 were control cases. Of these 158 patients, 91 (58%) had sepsis, and 15 of these 158 (9.5%) had severe sepsis. Initial antibiotic appropriateness, assessable in 152 of 158 patients, was appropriate in 80 (53%) of these 152 patients and inappropriate in 72 (47%) of these patients. In the intervention arm, 93% of ID Fellow recommendations were followed or partially followed, including 53% of cases in which antibiotics were de-escalated. ID Fellow intervention improved antibiotic appropriateness at 48 hours by 24% (adjusted risk ratio, 1.24; 95% confidence interval, 1.04-1.47; P=.035). The appropriateness agreement among 3 blinded ID staff opinions was 95%. Differences in intervention and control group mortality (13% vs 17%) and median length of stay (13 vs 17.5 days) were not statistically significant. CONCLUSION Sepsis overdiagnosis and delayed antibiotic optimization may reduce sepsis pathway effectiveness. Early ID AMS improved antibiotic management of non-ICU inpatients with suspected sepsis, predominantly by de-escalation. Further studies are needed to evaluate clinical outcomes. Infect Control Hosp Epidemiol 2017;38:1032-1038

Multiple line arrays for the characterization of aeroacoustic sources using a time-reversal method

This letter investigates the use of multiple line arrays (LAs) in a Time-Reversal Mirror for localizing and characterizing multipole aeroacoustic sources in a uniform subsonic mean flow using a numerical Time-Reversal (TR) method. Regardless of the original source characteristics, accuracy of predicting the source location can be significantly improved using at least two LAs. Furthermore, it is impossible to determine the source characteristics using a single LA, rather a minimum of two are required to establish either the monopole or dipole source nature, while four LAs (fully surrounding the source) are required for characterizing a lateral quadrupole source.A. Mimani, C. J. Doolan, and P. R. Medwel

Anomalies in T cell function are associated with individuals at risk of mycobacterium abscessus complex infection

The increasing global incidence and prevalence of non-tuberculous mycobacteria (NTM) infection is of growing concern. New evidence of person-to-person transmission of multidrug-resistant NTM adds to the global concern. The reason why certain individuals are at risk of NTM infections is unknown. Using high definition flow cytometry, we studied the immune profiles of two groups that are at risk of Mycobacterium abscessus complex infection and matched controls. The first group was cystic fibrosis (CF) patients and the second group was elderly individuals. CF individuals with active M. abscessus complex infection or a history of M. abscessus complex infection exhibited a unique surface T cell phenotype with a marked global deficiency in TNFa production during mitogen stimulation. Importantly, immune-based signatures were identified that appeared to predict at baseline the subset of CF individuals who were at risk of M. abscessus complex infection. In contrast, elderly individuals with M. abscessus complex infection exhibited a separate T cell phenotype underlined by the presence of exhaustion markers and dysregulation in type 1 cytokine release during mitogen stimulation. Collectively, these data suggest an association between T cell signatures and individuals at risk of M. abscessus complex infection, however, validation of these immune anomalies as robust biomarkers will require analysis on larger patient cohorts

Community wide electronic distribution of summary health care utilization data

BACKGROUND: In recent years, the use of digital technology has supported widespread sharing of electronic health care data. Although this approach holds considerable promise, it promises to be a complicated and expensive undertaking. This study described the development and implementation of a community wide system for electronic sharing of summary health care utilization data. METHODS: The development of the community wide data system focused on the following objectives: ongoing monitoring of the health care system, evaluation of community wide individual provider initiatives, identification and development of new initiatives. The system focused on the sharing of data related to hospital acute care, emergency medical services, long term care, and mental health. It was based on the daily distribution of reports among all health care providers related to these services. RESULTS: The development of the summary reports concerning health care utilization produced a system wide view of health care in Syracuse, New York on a daily basis. It was not possible to isolate the results of these reports because of the impact of specific projects and other factors. At the same time, the reports were associated with reduction of hospital inpatient stays, improvement of access to hospital emergency departments, reductions in stays for patients discharged to nursing homes, and increased access of mental health patients to hospital inpatient units. CONCLUSION: The implementation of the system demonstrated that summary electronic utilization data could provide daily information that would support the improvement of health care outcomes and efficiency. This approach could be implemented in a simple, direct manner with minimal expenses

CD161 expression defines new human γδ T cell subsets

γδ T cells are a highly versatile immune lineage involved in host defense and homeostasis, but questions remain around their heterogeneity, precise function and role during health and disease. We used multi−parametric flow cytometry, dimensionality reduction, unsupervised clustering, and self-organizing maps (SOM) to identify novel γδ T cell naïve/memory subsets chiefly defined by CD161 expression levels, a surface membrane receptor that can be activating or suppressive. We used middle-to-old age individuals given immune blockade is commonly used in this population. Whilst most Vδ1+subset cells exhibited a terminal differentiation phenotype, Vδ1− subset cells showed an early memory phenotype. Dimensionality reduction revealed eight γδ T cell clusters chiefly diverging through CD161 expression with CD4 and CD8 expression limited to specific subpopulations. Comparison of matched healthy elderly individuals to bronchiectasis patients revealed elevated Vδ1+ terminally differentiated effector memory cells in patients potentially linking this population with chronic proinflammatory disease

Dose ratio proton radiography using the proximal side of the Bragg peak

Purpose: In recent years there has been a movement towards single-detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single-detector technique is the dose ratio method, in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp fall-off. We investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water-equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak. Methods: Using the analytical approximation for the Bragg peak we generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, we were able to generate look-up graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these look-up graphs we investigated the applicability of the technique for a range of patient treatment sites. We validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam. Results: Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm2, for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root-mean-square-error of 1.6 mm WET. The noise in the measured images was found to be σ =1.2% (standard deviation) and theoretical predictions with a 1.96σ noise level showed good agreement with the measured errors. Conclusions: After validating the theoretical approach with measurements, we have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Utilization of genomic sequence information to develop malaria vaccines

Recent advances in the fields of genomics, proteomics and molecular immunology offer tremendous opportunities for the development of novel interventions against public health threats, including malaria. However, there is currently no algorithm that can effectively identify the targets of protective T cell or antibody responses from genomic data. Furthermore, the identification of antigens that will stimulate the most effective immunity against the target pathogen is problematic, particularly if the genome is large. Malaria is an attractive model for the development and validation of approaches to translate genomic information to vaccine development because of the critical need for effective anti-malarial interventions and because the Plasmodium parasite is a complex multistage pathogen targeted by multiple immune responses. Sterile protective immunity can be achieved by immunization with radiation-attenuated sporozoites, and anti-disease immunity can be induced in residents in malaria-endemic areas. However, the 23 Mb Plasmodium falciparum genome encodes more than 5300 proteins, each of which is a potential target of protective immune responses. The current generation of subunit vaccines is based on a single or few antigens and therefore might elicit too narrow a breadth of response. We are working towards the development of a new generation vaccine based on the presumption that duplicating the protection induced by the whole organism may require a vaccine nearly as complex as the organism itself. Here, we present our strategy to exploit the genomic sequence of P. falciparum for malaria vaccine development