Characteristics of tumor-infiltrating lymphocytes prior to and during immune checkpoint inhibitor therapy

The tumor immune contexture plays a major role for the clinical outcome of patients. High densities of CD45RO + T helper 1 cells and CD8 + T cells are associated with improved survival of patients with various cancer entities. In contrast, a higher frequency of tumor-infiltrating M2 macrophages is correlated with poor prognosis. Recent studies provide evidence that the tumor immune architecture also essentially contributes to the clinical efficacy of immune checkpoint inhibitor (CPI) therapy in patients. Pretreatment melanoma samples from patients who experienced a clinical response to anti-programmed cell death protein 1 (PD-1) treatment show higher densities of infiltrating CD8 + T cells compared to samples from patients that progressed during therapy. Anti-PD-1 therapy results in an increased density of tumor-infiltrating T lymphocytes in treatment responders. In addition, elevated frequencies of melanoma-infiltrating TCF7 + CD8 + T cells are correlated with beneficial clinical outcome of anti-PD-1-treated patients. In contrast, a high density of tumor-infiltrating, dysfunctional PD-1 + CD38 hi CD8 + cells in melanoma patients is associated with anti-PD-1 resistance. Such findings indicate that comprehensive tumor immune contexture profiling prior to and during CPI therapy may lead to the identification of underlying mechanisms for treatment response or resistance, and the design of improved immunotherapeutic strategies. Here, we focus on studies exploring the impact of intratumoral T and B cells at baseline on the clinical outcome of CPI-treated cancer patients. In addition, recent findings demonstrating the influence of CPIs on tumor-infiltrating lymphocytes are summarized

Prevention and contrast of child abuse and neglect in the practice of European paediatricians: a multi-national pilot study

Background: Child abuse and neglect, or maltreatment, is a serious public health problem, which may cause long-term effects on children's health and wellbeing and expose them to further adulthood vulnerabilities. Studies on child maltreatment performed in Europe are scarce, and the number of participants enrolled relatively small. The aim of this multi-national European pilot study, was to evaluate the level of understanding and perception of the concepts of child abuse and neglect by European paediatricians working in different medical settings, and the attitude toward these forms of maltreatment in their practice. Methods: The study was performed by a cross-sectional, descriptive, online survey, made available online to European paediatricians members of 50 national paediatric, who belonged to four different medical settings: hospital, family care, university centres and private practice. The questionnaire, designed as a multiple choice questions survey, with a single answer option consisted of 22 questions/statements. Frequency analyses were applied. Most of the data were described using univariate analysis and Chi-squared tests were used to compare the respondents and answers and a significance level of p ≤ 0.05 applied. Results: Findings show that European paediatricians consider the training on child maltreatment currently provided by medical school curricula and paediatric residency courses to be largely insufficient and continuing education courses were considered of great importance to cover educational gaps. Physical violence was recognized by paediatricians mostly during occasional visits with a significant correlation between detecting abuse during an occasional visit and being a primary care paediatrician. Results also showed a reluctance by paediatricians to report cases of maltreatment to the competent judicial authorities. Conclusions: Data of this study may provide useful contribution to the current limited knowledge about the familiarity of European paediatricians with child maltreatment and their skills to recognize, manage and contrast abusive childhood experiences in their practice. Finally, they could provide local legislators and health authorities with information useful to further improve public health approaches and rules able to effectively address shared risk and protective factors, which could prevent child abuse and neglect from ever occurring

Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV

Young F. Schligel\u27s Political Thought : German Jacobinism and the German Early Romanticism

1.カロリーネの影響とG・フォルスターの共和主義, 2.シュレーゲルの革命思想批判と民主的共和主

Clinical effects of erdosteine in the treatment of acute respiratory tract diseases in children

Erdosteine has positive effects on mucus rheology and transport due to the active metabolite (Metabolite 1) which contains a free thiol group. Erdosteine inhibits bacterial adhesiveness and has antioxidant properties. A synergistic effect of erdosteine with various antibiotics has been demonstrated in pharmacological and clinical studies. The present study was multicenter, randomized, double-blind and placebo-controlled. The aims of the study were to compare a combination of erdosteine with amoxicillin against an amoxicillin-placebo combination in pediatric patients with acute lower respiratory tract disease. A total of 158 patients (78 in the erdosteine group and 80 in the placebo group) were treated for 7 2 days. The efficacy parameters were cough (primary), polypnea, rhonchi, rales and body temperature (all measured at baseline, on Day 3 and at the end of treatment). Safety was assessed by strictly monitoring the occurrence of adverse events and using standard laboratory parameters. The results of the intention-to-treat analysis showed that the severity of cough was decreased by 47% at Day 3 in the erdosteine group with a statistically significant difference compared to placebo, the difference was still significant at the final visit. The decrease in the severity of rales was significantly greater at Day 3 in the erdosteine group than in the placebo group. The incidence of polypnea and rhonchi in the two groups showed similar decreases, an improvement mainly due to the antibiotic. No adverse events occurred and no adverse changes in laboratory parameters were observed. It is concluded that the combination of erdosteine and amoxicillin is a safe medication which is clinically superior to that of the antibiotic combined with placebo, especially in regard to the effects on cough

Low 2016/17 season vaccine effectiveness against hospitalised influenza A(H3N2) among elderly: Awareness warranted for 2017/18 season

In a multicentre European hospital study we measured influenza vaccine effectiveness (IVE) against A(H3N2) in 2016/17. Adjusted IVE was 17% (95% confidence interval (CI): 1 to 31) overall; 25% (95% CI: 2 to 43) among 65–79-year-olds and 13% (95% CI: −15 to 30) among those ≥ 80 years. As the A(H3N2) vaccine component has not changed for 2017/18, physicians and public health experts should be aware that IVE could be low where A(H3N2) viruses predominate

Global-scale evaluation of 22 precipitation datasets using gauge observations and hydrological modeling

We undertook a comprehensive evaluation of 22 gridded (quasi-)global (sub-)daily precipitation (P) datasets for the period 2000–2016. Thirteen non-gauge-corrected P datasets were evaluated using daily P gauge observations from 76,086 gauges worldwide. Another nine gauge-corrected datasets were evaluated using hydrological modeling, by calibrating the conceptual model HBV against streamflow records for each of 9053 small to medium-sized (<50,000 km2) catchments worldwide, and comparing the resulting performance. Marked differences in spatio-temporal patterns and accuracy were found among the datasets. Among the uncorrected P datasets, the satellite- and reanalysis-based MSWEP-ng V1.2 and V2.0 datasets generally showed the best temporal correlations with the gauge observations, followed by the reanalyses (ERA-Interim, JRA-55, and NCEP-CFSR) and the satellite- and reanalysis-based CHIRP V2.0 dataset, the estimates based primarily on passive microwave remote sensing of rainfall (CMORPH V1.0, GSMaP V5/6, and TMPA 3B42RT V7) or near-surface soil moisture (SM2RAIN-ASCAT), and finally, estimates based primarily on thermal infrared imagery (GridSat V1.0, PERSIANN, and PERSIANN-CCS). Two of the three reanalyses (ERA-Interim and JRA-55) unexpectedly obtained lower trend errors than the satellite datasets. Among the corrected P datasets, the ones directly incorporating daily gauge data (CPC Unified and MSWEP V1.2 and V2.0) generally provided the best calibration scores, although the good performance of the fully gauge-based CPC Unified is unlikely to translate to sparsely or ungauged regions. Next best results were obtained with P estimates directly incorporating temporally coarser gauge data (CHIRPS V2.0, GPCP-1DD V1.2, TMPA 3B42 V7, and WFDEI-CRU), which in turn outperformed the one indirectly incorporating gauge data through another multi-source dataset (PERSIANN-CDR V1R1). Our results highlight large differences in estimation accuracy, and hence, the importance of P dataset selection in both research and operational applications. The good performance of MSWEP emphasizes that careful data merging can exploit the complementary strengths of gauge-, satellite- and reanalysis-based P estimates