Blood Pressure Complexity in Primate Pregnancy

This thesis explores the effect of antihypertensive drugs commonly used in pregnancy (labetalol, methyldopa, hydralazine) on blood pressure (BP) response in an experimental model of preeclampsia (EPE) whilst awake, during sleep, during the early morning BP surge (EMS) and in the context of stressors including general anaesthesia (ketamine, propofol, sevoflurane), noise, eating and during enclosure cleaning. The EPE was established in Papio hamadryas (n = 9) by reducing uteroplacental blood flow. The EPE was confirmed by the presence of proteinuria (urine protein creatinine ratio), elevated BP (telemeter) and raised soluble fms-like tyrosine kinase receptor-1 (sFLT-1) (ELISA). Continuous BP readings were collected via telemetry before and after antihypertensive treatment was established. Equipotent doses of labetalol, methyldopa and hydralazine equivalent to starting dose rates in humans were given. The BP response to these antihypertensive agents was established whilst awake, during sleep, during EMS and in the context of stressors including general anaesthesia (ketamine, propofol, sevoflurane), noise, eating and enclosure cleaning. The BP response was evaluated using a multidimensional approach involving assessment of BP average, BP load, short- and long-term BP variability and a published chaos algorithm classifying BP data as stochastic, periodic or chaotic. All animals developed EPE. The different BP metrics revealed diverse BP patterns in the various experimental contexts. The key findings were that the combination of sevoflurane and labetalol, or sevoflurane and hydralazine created the most preferable BP dynamics during anaesthesia. Further, labetalol was the most effective overall at controlling BP when exposed to the range of stressors in the EPE model. Labetalol, methyldopa or hydralazine created similar BP dynamics during the EMS period

Gender equality and religion:a multi-faith exploration of young adults’ narratives

This paper presents findings from research on young adults in the UK from diverse religious backgrounds. Utilizing questionnaires, interviews, and video diaries it assesses how religious young adults understood and managed the tensions in popular discourse between gender equality as an enshrined value and aspirational narrative, and religion as purportedly instituting gender inequality. We show that, despite varied understandings, and the ambivalence and tension in managing ideal and practice, participants of different religious traditions and genders were committed to gender equality. Thus, they viewed gender-unequal practices within their religious cultures as an aberration from the essence of religion. In this way, they firmly rejected the dominant discourse that religion is inherently antithetical to gender equality

Hodgkin lymphoma:hypodense lesions in mediastinal masses

Hypodense volumes (HDV) in mediastinal masses can be visualized in a computed tomography scan in Hodgkin lymphoma. We analyzed staging CT scans of 1178 patients with mediastinal involvement from the EuroNet-PHL-C1 trial and explored correlations of HDV with patient characteristics, mediastinal tumor volume and progression-free survival. HDV occurred in 350 of 1178 patients (29.7%), typically in larger mediastinal volumes. There were different patterns in appearance with single lesions found in 243 patients (69.4%), multiple lesions in 107 patients (30.6%). Well delineated lesions were found in 248 cases (70.1%), diffuse lesions were seen in 102 cases (29.1%). Clinically, B symptoms occurred more often in patients with HDV (47.7% compared to 35.0% without HDV (p = 0.039)) and patients with HDV tended to be in higher risk groups. Inadequate overall early-18F-FDG-PET-response was strongly correlated with the occurrence of hypodense lesions (p &lt; 0.001). Patients with total HDV &gt; 40 ml (n = 80) had a 5 year PFS of 79.6% compared to 89.7% (p = 0.01) in patients with HDV &lt; 40 ml or no HDV. This difference in PFS is not caused by treatment group alone. HDV is a common phenomenon in HL with mediastinal involvement.</p

Infants and newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB registry: a unique and challenging population

SIMPLE SUMMARY: Malignant rhabdoid tumors (MRT) are deadly tumors that predominantly affect infants and young children. Even when considering the generally young age of these patients, the treatment of infants below the age of six months represents a particular challenge due to the vulnerability of this patient population. The aim of our retrospective study was to assess the available information on prognostic factors, genetics, toxicity of treatment and long-term outcomes of MRT. We confirmed that, in a cohort of homogenously treated infants with MRT, significant predictors of outcome were female sex, localized stage, absence of a GLM and maintenance therapy, and these significantly favorably influence prognosis. Stratification-based biomarker-driven tailored trials may be a key option to improve survival rates. ABSTRACT: Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population

Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification

Memory as acquaintance with the past: some Lessons from Russell, 1912-1914

Russell's theory of memory as acquaintance with the past seems to square uneasily with his definition of acquaintance as the converse of the relation of presentation of an object to a subject. We show how the two views can be made to cohere under a suitable construal of 'presentation', which has the additional appeal of bringing Russell's theory of memory closer to contemporary views on direct reference and object-dependent thinking than is usually acknowledged. The drawback is that memory as acquaintance with the past falls short of fulfilling Russell's requirement that knowledge by acquaintance be discriminating knowledge - a shortcoming shared by contemporary externalist accounts of knowledge from memory.A teoria russelliana da memória como contato (acquaintance) com o passado parece coadunar-se mal com definição do contato (acquaintance) como a conversa da relação de apresentação de um objeto a um sujeito. Mostramos como as duas concepções podem ser conciliadas mediante uma interpretação apropriada de 'apresentação', que tem a vantagem adicional de salientar uma proximidade maior que a usualmente reconhecida entre a teoria da memória de Russell e idéias contemporâneas sobre referência direta e pensamentos dependentes de objeto. O preço a pagar é o reconhecimento de que a memória como contato (acquaintance) com o passado não satisfaz o requisito russelliano de que o conhecimento por contato deva ser discriminativo - uma limitação que é compartilhada pelas abordagens externalistas contemporâneas do conhecimento derivado da memória

Flood hazard assessment from alluvial sediments: data from sedimentology to place names

Floods are a natural component of our environment, and are constantly changing due to both natural and human factors. However, they leave physical and societal evidence in sediments and place names