Risk Factors for West Nile Virus Neuroinvasive Disease, California, 2005

In 2005, 880 West Nile virus cases were reported in California; 305 case-patients exhibited neuroinvasive disease, including meningitis, encephalitis, or acute flaccid paralysis. Risk factors independently associated with developing neuroinvasive disease rather than West Nile fever included older age, male sex, hypertension, and diabetes mellitus

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Styrning av lagerhållning och artikelplacering

Examensarbetet är utfört på Lifco Dental, som är ett distributionsföretag i Enköping undervårterminen 2013 och omfattar 30 högskolepoäng. Lifco Dentals huvudsakliga verksamhet ärlagerhantering av tandläkarartiklar och det rör sig om cirka 40 000 artiklar i varierandestorlek.Examensarbetet avser i första hand styrning av lagerhållning och artikelplacering. Andraområden som har bearbetas är ergonomi och personalfrågor. Arbetet kretsar kring följandeforskningsfrågor;1. Enligt vilka principer kan man placera artiklar?2. Hur kan man utforma arbetssättet på lager både kostnadseffektivt och ergonomiskt?3. Hur kan materialflödet effektiviseras?från källor som artiklar, litteratur, internet och direktkontakt med personal har samlats in.Behandling av information har baserats på författarnas tidigare kunskaper och vägledning avhögskolans handledare.Valda vertyg och metod är; Read a Plant, värdeflödeskartläggning, spagettidiagram,Paretodiagram, 5-Varför, benchmarking och intervjuer av personal, säljbolag och tandläkare.Dessa verktyg har hjälpt att analysera nuläget i verksamheten och identifiera slöserier samtförbättringsområden. En del verktyg har varit mer relevant för att kunna besvaraforskningsfrågorna.Bäst artikelplacering torde uppnås med ABC-principen. Undersökning av tre identifieradeergonomiska riskmoment gjordes enligt arbetsmiljöverkets bedömningsmall, vilket påvisadeatt man genom att ha rätt resurser, hjälpmedel och klara direktiv kan undvika skador. Dettakan man åstadkomma bland annat genom visuellt ledningssystem och investering i nyaergonomiska verktyg. Resultatet från värdeflödeskartläggning och paretodiagram tyder påbristande fördelning av resurser och identifierar flaskhalsar i flödet. En kontrolleradfördelning av anpassade resurser reducerar ojämnheter och underlättar styrningen.Författarna har baserad på analysen rekommenderat principer för artikelplacering ochlagerflöde samt rekommendationer kring personalmotivering, engagemang och ergonomi.This Master of Science thesis has been conducted at Lifco Dental, a logistics company inEnköping, Sweden, during the spring term of 2013, encompassing 30 credits. Lifco Dental’score operation is logistics and inventory management of dental products, a sum total ofapproximately 40,000 articles in various sizes.The thesis is primarily concerned with inventory management and article placement. Otherareas of interest have been ergonomics and human resource management. The main researchareas have been;1. According to which principles can articles be placed?2. How can the inventory be managed to be cost efficient and have good ergonomics?3. How can material flows be streamlined?Information from sources such as articles, literature, the internet and direct interaction withemployees has been gathered. This information has been processed based on the authors’prior experience as well as extensive guidance from the MDH supervisor.The authors´ chosen tools and methods have been Read a Plant; Value Stream Mapping;Spaghetti diagram; Pareto diagram; 5Why; benchmarking and interviews with employees,sales staff and dentists. These tools and methods have aided us in analyzing the current stateof operations and in identifying waste as well as areas of opportunity. Some tools have provenmore relevant than others in producing relevant research answers.Optimal article placement can be achieved with the ABC principle. Studies of threeergonomically problematic operations, utilizing templates provided by Arbetsmiljöverket,showed that correct resources and aids as well as clear directives reduces the risks of injuries.This can be achieved by deploying a visual management system and more ergonomical toolsand aids. Results from the Value Stream Mapping and Pareto diagram suggest deficiencies inthe allocation of resources and identifies bottlenecks in the material flow. Controlledallocation of resources reduces inbalances and enhances control.Based on the analysis the authors have recommended principles for article placement andinventory flow as well as recommendations regarding staff motivation, commitment andergonomics

Diagnostic Challenges of Central Nervous System Tuberculosis

Central nervous system tuberculosis (TB) was identified in 20 cases of unexplained encephalitis referred to the California Encephalitis Project. Atypical features (encephalitic symptoms, rapid onset, age) and diagnostic challenges (insensitive cerebrospinal fluid [CSF] TB PCR result, elevated CSF glucose levels in patients with diabetes, negative result for tuberculin skin test) complicated diagnosis

Cellular and genomic disease signature of peripheral blood mononuclear cells in patients with malignant pleural mesothelioma

Background: Recent data on the incidence malignant pleural mesothelioma (MPM) and the continued large-scale use of asbestos throughout the developing world portends an epidemic of asbestos-related disease. MPM is an aggressive and fatal cancer with few treatment options. Recent advances in large scale genomic and high throughput cellular analyses now provide the tools to more easily attain markers of disease status and potential responsiveness to immunotherapeutics. Materials and Methods: Here we present pre-treatment cellular and genomic biomarker data on a cohort of chemotherapy-naïve MPM patients, and demographically matched healthy donors (HD). MPM patients were enrolled in a Phase 1b study utilizing CRS-207, a live, attenuated Listeria monocytogenes strain engineered to express the tumor-associated antigen, mesothelin. Four different multi-color flow cytometry panels were used to provide resolution on major immune cell populations of T cells, γδ T cells, B Cells, dendritic cells, monocytes, and natural killer cells. Together, these panels provided deeper resolution on 39 distinct subpopulations of major immune cell subsets. RNA from these cells was used to perform multiplex gene expression analysis on 770 genes using the Nanostring nCounter PanCancer Pathway Panel. Results: FACS analysis yielded numerous subpopulations with statistically significant differences between MPM patients and healthy controls. Differences in immune populations were analyzed by median and significant findings included populations of CD4+ T cells, CD8+ T cells, B cells, classical monocytes, and monocytic myeloid derived suppressor cells*. Class comparison and hierarchical clustering of gene expression data revealed genomic markers that were significantly expressed in MPM compared to healthy controls. Immune subset deconvolution of gene expression data provided similar findings as FACS analysis and corroborated this disease signature across experimental platforms. Conclusions: Understanding a patient’s biological disease signature can aide in diagnosis, as well as in making informed choices about therapies amidst the complex and broadening immunotherapeutic landscape. Until recently, existing biomarker data in MPM has been limited to a small number of serological markers and limited immune analysis. Here, we present the first comprehensive report of a MPM disease signature from the cellular and genomic perspectives. Correlation of patient baseline disease signatures with treatment outcome may yield biomarkers predictive of treatment efficacy. Predictive signatures are being investigated in the on-going Phase 1b study of CRS-207 and chemotherapy, as well as in the Phase 2 study of CRS-207 with pembrolizumab in MPM patients who failed prior treatment. *Inclusion of additional subjects confirmed the significance of all immune cell subsets except for MDSCs