Spectropolarimetry of Galactic stars with anomalous extinction sightlines

Highly reddened type Ia Supernovae (SNe Ia) with low total-to-selective visual extinction ratio values, $R_V$, also show peculiar linear polarization wavelength dependencies with peak polarizations at short wavelengths ($\lambda_{max} \lesssim 0.4 \mu m$). It is not clear why sightlines to SNe Ia display such different continuum polarization profiles from interstellar sightlines in the Milky Way with similar $R_V$ values. We investigate polarization profiles of a sample of Galactic stars with low $R_V$ values, along anomalous extinction sightlines, with the aim to find similarities to the polarization profiles that we observe in SN Ia sightlines. We undertook spectropolarimetry of 14 stars, and used archival data for three additional stars, and run dust extinction and polarization simulations to infer a simple dust model that can reproduce the observed extinction and polarization curves. Our sample of Galactic stars with low $R_V$ values and anomalous extinction sightlines displays normal polarization profiles with an average $\lambda_{max} \sim 0.53 {\mu m}$, and is consistent within 3$\sigma$ to a larger coherent sample of Galactic stars from literature. Despite the low $R_V$ values of dust towards the stars in our sample, the polarization curves do not show any similarity to the continuum polarization curves observed towards SNe Ia with low $R_V$ values. There is a correlation between the best-fit Serkowski parameters $K$ and $\lambda_{max}$, but we did not find any significant correlation between $R_V$ and $\lambda_{max}$. Our simulations show that the $K-\lambda_{max}$ relationship is an intrinsic property of polarization. Furthermore, we have shown that in order to reproduce polarization curves with normal $\lambda_{max}$ and low $R_V$ values, a population of large (a $\geq 0.1 \mu m$) interstellar silicate grains must be contained in the dust's composition.Comment: accepted for publication in A&

Seasonality of respiratory viruses causing hospitalizations for acute respiratory infections in children in Nha Trang, Vietnam.

BACKGROUND: Acute respiratory infections (ARIs) are the most common causes of death in children under 5 years of age. While the etiology of most pneumonia and ARI episodes is undiagnosed, a broad range of ARI-causing viruses circulate widely in South East Asia. However, the patterns and drivers of the seasonal transmission dynamics are largely unknown. Here we identify the seasonal patterns of multiple circulating viruses associated with hospitalizations for ARIs in Nha Trang, Vietnam. METHODS: Hospital based enhanced surveillance of childhood ARI is ongoing at Khanh Hoa General Hospital in Nha Trang. RT-PCR was performed to detect 13 respiratory viruses in nasopharyngeal samples from enrolled patients. Seasonal patterns of childhood ARI hospital admissions of various viruses were assessed, as well as their association with rainfall, temperature, and dew point. RESULTS: Respiratory syncytial virus peaks in the late summer months, and influenza A in April to June. We find significant associations between detection of human parainfluenza 3 and human rhinovirus with the month's mean dew point. Using a cross-wavelet transform we find a significant out-of-phase relationship between human parainfluenza 3 and temperature and dew point. CONCLUSIONS: Our results are important for understanding the temporal risk associated with circulating pathogens in Southern Central Vietnam. Specifically, our results can inform timing of routing seasonal influenza vaccination and for when observed respiratory illness is likely viral, leading to judicious use of antibiotics in the region

Early indication for a reduced burden of radiologically confirmed pneumonia in children following the introduction of routine vaccination against Haemophilus influenzae type b in Nha Trang, Vietnam.

INTRODUCTION: Despite the global success of Hib vaccination in reducing disease and mortality, uncertainty about the disease burden and the potential impact of Hib vaccination in Southeast Asia has delayed the introduction of vaccination in some countries in the region. Hib vaccination was introduced throughout Vietnam in July 2010 without catch-up. In an observational, population based surveillance study we estimated the impact of routine Hib vaccination on all cause radiologically confirmed childhood pneumonia in Nha Trang, Vietnam. MATERIALS AND METHODS: In 2007 active hospital based surveillance was established in Khanh Hoa General Hospital, the only hospital in Nha Trang, Khanh Hoa province. Nasopharyngeal samples and chest radiographs are taken routinely from all children diagnosed with acute respiratory illness on admission. For admissions between 02/2007 and 03/2012 chest radiographs were interpreted for the presence of WHO primary endpoint pneumonia and nasopharyngeal swabs were analysed by PCR for the presence of Influenza A or B, RSV and rhinovirus. We employed Poisson regression to estimate the impact of Hib vaccination on radiologically confirmed pneumonia (RCP) while statistically accounting for potential differences in viral circulation in the post vaccination era which could have biased the estimate. RESULTS: Of 3151 cases admitted during the study period, 166 had RCP and major viruses were detected in 1601. The adjusted annual incidence of RCP in children younger than 5 years declined by 39% (12-58%) after introduction of Hib vaccination. This decline was most pronounced in children less than 2 years old, adjusted IRR: 0.52 (0.33-0.81), and no significant impact was observed in the 2-4 years old who were not eligible for vaccination, adjusted IRR: 0.96 (0.52-1.72). DISCUSSION: We present early evidence that the burden of Hib associated RCP in Nha Trang before vaccination was substantial and that shortly after introduction to the routine childhood immunisation scheme vaccination has substantially reduced that burden

Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

SummaryAmong the cytokines linked to inflammation-associated cancer, interleukin (IL)-6 drives many of the cancer “hallmarks” through downstream activation of the gp130/STAT3 signaling pathway. However, we show that the related cytokine IL-11 has a stronger correlation with elevated STAT3 activation in human gastrointestinal cancers. Using genetic mouse models, we reveal that IL-11 has a more prominent role compared to IL-6 during the progression of sporadic and inflammation-associated colon and gastric cancers. Accordingly, in these models and in human tumor cell line xenograft models, pharmacologic inhibition of IL-11 signaling alleviated STAT3 activation, suppressed tumor cell proliferation, and reduced the invasive capacity and growth of tumors. Our results identify IL-11 signaling as a potential therapeutic target for the treatment of gastrointestinal cancers

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Once the shovel hits the ground : Evaluating the management of complex implementation processes of public-private partnership infrastructure projects with qualitative comparative analysis

Much attention is being paid to the planning of public-private partnership (PPP) infrastructure projects. The subsequent implementation phase – when the contract has been signed and the project ‘starts rolling’ – has received less attention. However, sound agreements and good intentions in project planning can easily fail in project implementation. Implementing PPP infrastructure projects is complex, but what does this complexity entail? How are projects managed, and how do public and private partners cooperate in implementation? What are effective management strategies to achieve satisfactory outcomes? This is the fi rst set of questions addressed in this thesis. Importantly, the complexity of PPP infrastructure development imposes requirements on the evaluation methods that can be applied for studying these questions. Evaluation methods that ignore complexity do not create a realistic understanding of PPP implementation processes, with the consequence that evaluations tell us little about what works and what does not, in which contexts, and why. This hampers learning from evaluations. What are the requirements for a complexity-informed evaluation method? And how does qualitative comparative analysis (QCA) meet these requirements? This is the second set of questions addressed in this thesis

The role of aberrant GP130 signalling in the development and progression of gastric cancer

© 2011 Dr. Stefan ThiemGastric cancer (GC) is one of the leading causes of cancer-related deaths. There is no cure, and current treatments are not particularly successful. Therefore, there is an urgent need to develop novel therapies. Our laboratory has previously characterized the gp130Y757F/Y757F mouse (referred to as gp130FF) as a robust model for inflammation-associated gastric tumourigenesis akin to human intestinal-type GC. In this model, a knock-in mutation triggers spontaneous gastric tumour formation driven by interleukin- (IL) 11-mediated hyper-activation of the latent transcription factor signal transducer and activator of transcription 3 (Stat3). This mediator of cell proliferation, survival and angiogenesis is hyper-activated in many types of solid epithelial cancers and also plays a key role in cancer-associated chronic inflammation. The aim of this study was to explore the molecular mechanisms underlying inflammation-associated gastric tumourigenesis in gp130FF mice in three different projects by: 1. identifying Stat3 target genes in gp130FF tumours through microarray and chromatin immunoprecipitation/high throughput sequencing (ChIP-Seq) analysis; 2. examining the role of phosphoinositide 3-kinase (PI3K) signalling and the therapeutic potential of inhibiting the associated mammalian target of rapamycin (mTor) pathway; and 3. generating a novel preclinical mouse model using bacterial artificial chromosome (BAC) transgenesis to confer inducible Cre-recombinase-mediated gene (in-)activation to the gastric epithelium. The combined use of ChIP-Seq, microarray and quantitative PCR analysis revealed genomic Stat3 binding sites in gp130FF tumour cells and associated genes that respond to the pro-inflammatory cytokines IL6 and/or IL11. Careful analysis identified candidate genes that play important roles in oncogenesis, including c-myc. Genetic deletion of c-myc in gp130FF mice resulted in a significantly reduced tumour burden demonstrating that c-myc function is crucial for Stat3-mediated tumour development. Thus, this approach may provide a basis for the identification of novel therapeutic targets for the treatment of Stat3-dependent cancers. The PI3K and mTor signalling pathways promote tumour growth, survival and vascularization and are commonly deregulated in human cancer. In this study, it was demonstrated that mTor complex 1 (mTorc1) and Stat3 are strongly co-activated in human and gp130FF gastric tumours. Furthermore, it was shown that stimulation of mutant gp130 can induce PI3K and mTorc1 signalling, independently of Stat3. Importantly, therapeutic treatment of gp130FF mice with the rapamycin analogue RAD001 (everolimus) suppressed mTorc1 activity and reduced tumour number and burden through inhibition of proliferation and tumour vascularization. Moreover, prophylactic treatment of gp130FF mice alleviated tumour formation. When RAD001 treatment was stopped, mTorc1 activity was re-activated and tumour growth resumed. These findings suggest that inflammation-associated tumour development and progression in gp130FF mice are critically dependent on both Stat3 and mTorc1 activity. Therefore, inhibition of mTOR activity alone or in combination with STAT3 and/or PI3K inhibition may have therapeutic potential. A novel gastric-specific and inducible Cre expressing mouse line, Tg(Tff1/2-CreERT2; Tff3-Luc), was generated and analysed. These mice express the CreERT2 recombinase as well as the firefly luciferase as part of a BAC containing the cis-regulatory elements of the three trefoil factor (Tff) genes. The Tff1 and Tff2 loci confer CreERT2 expression to normal and (on the gp130FF background) neoplastic epithelial cells of the glandular stomach, thus allowing conditional mutagenesis specifically in these cells. The development of the Tg(Tff1/2-CreERT2; Tff3-Luc) mouse provides a novel and powerful tool to study gene functions in the gastric epithelium and identify molecular mechanisms leading to tumour formation. Moreover, intestinal-specific expression of the Tff3-driven luciferase allows in vivo monitoring of intestinal homeostasis and mucosal damage. In order to establish a preclinical model of GC progression, this strain was further used to generate novel compound mutant mice. These are based on the activation of oncogenic mutations associated with invasive human gastric adenocarcinomas and metastasis

Who's afraid of the GOATs? - Shadow effects of tennis superstars*

Deutscher C, Neuberg L, Thiem S. Who's afraid of the GOATs? - Shadow effects of tennis superstars*. Journal of Economic Psychology. 2023;99: 102663.In multi-stage tournaments, anticipated competition in future stages might affect the outcome of competition in the current stage. In particular, the presence of superstars might demotivate the next-best competitors from seeking to advance to later rounds, where they ultimately are likely to face a superstar. Data from men's professional tennis tournaments held between 2004 and 2019 affirm that the participation of superstars (Djokovic, Nadal, Federer, and Murray) reduces the probability that the remaining Top 20 players win their matches. Such shadow effects arise even in very early tournament stages, in which favoured players lose more often than expected, given their ability. The effects are more pronounced when multiple superstars compete in the tournament and disappear once all superstars have been eliminated from competition. Furthermore, shadow effects increase the probability of retirement of strong but non-superstar competitors and disappear once superstar performance is not dominant