Tuberous sclerosis clinical factors in long term outcome

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Mobilizing for total war : the National Socialist leadership and social and labour prerequisites for intensifying the German war effort, 1941-1945

This thesis examines the differing concepts of total war, and the resulting policies and strategies for their acceptance pursued from 1941 to 1945 by four prominent National Socialist leaders, Martin Bormann, Heinrich Himmler, Joseph Goebbels and Albert Speer. Speer and Goebbels suggested, and later historians have agreed, that the National Socialist government only reluctantly oriented its economic and social production to the war effort. A study of the policies and ideas of these men is important to see whether this was the case. In examining the policies of the leadership, the thesis argues that previous interpretations of the National Socialist political system as either polycratic or monocratic have become too polarised. Instead it shows the existence at this level of both monocratic and polycratic elements of authority; but finally it emphasizes the importance of Hitler's authority for the pursuit of total war policies. It suggests the origins of this authority should be seen in the charismatic nature of his rule. The changing policies which these men pursued both in their own areas of responsibility and in the wider German society indicate that they supported total war. There were differences in the emphasis on the policies to be followed. Early efforts to win more German workers to the armaments industry and the front in 1941-42 foundered on the availability of foreign labour and a failure to realize the seriousness of Germany's position. Speer and Goebbels supported a more economically efficient and rational use of resources and labour in the period 1943-44. Their efforts to make women liable for labour and to close inessential businesses met with some support from Hitler after Stalingrad, when a Committee of Three was set up to enforce the measures. This committee failed to make all the changes the two men thought necessary but their expectations were unrealistic. From 1943 on there was also support in the leadership for ideological mobilization and, eventually, paramilitary forces as a contribution to preventing defeat. In addition to their emphasis on the economically rational use of resources, Goebbels and Speer were also aware of the need for burdens of the war to appear to be equally distributed. Himmler supported total war but his interpretation was more ideological. He supported administrative simplification and sought to increase the role of the SS in economic production. By 1944 he was willing to abandon certain ideological precepts to prolong the life of the regime. Bormann's view of the need to orient the home front for the pursuit of the war was also more ideological; he also represented Hitler's opinions. For Goebbels in particular the policies of total war were to be combined with moves towards a compromise peace to allow the regime to remove itself from the war. The thesis demonstrates that these members of the leadership did agree on the need for total war; in particular on the need for administrative simplification and greater use of labour reserves. Some of their policies foundered on opposition from Hitler; in other cases their expectations of what else could be achieved were unrealistic or foundered on other systemic constraints

The invasion of Greece in 1941 and the Nazi hordes that never were...

Includes image: 'landscape with three figures', 1935.AbstractDespite the significance of the German invasion of Greece in 1941 within the international history of the Second World War, relatively little research has yet been conducted into many of its operational aspects. As a consequence, over the last 70 years a number of serious misconceptions have developed and been used to explain (or explain-away) British defeat within this campaign. Foremost is the notion of a huge disparity in numbers - against which Commonwealth troops, despite their courage and stoic resolve, could never stand. This key explanation is mistaken. By no means and by no measure did overwhelming German numbers push Imperial troops unwillingly out of Greece

Community Roles for Supporting Emerging Education Researchers

DBER attracts many faculty from other STEM disciplines, and these faculty have little or no specific training in DBER. DBER requires a mastery of quantitative, qualitative, and/or mixed methodologies, and also a nuanced understanding of breadth of topic, research questions, and theoretical frameworks. This interdisciplinarity is particularly challenging for emerging DBER researchers who often switch into DBER with only discipline specific content and research training. As part of a large study about how STEM faculty become involved with DBER, we interviewed a number of emerging DBER faculty about their pathways into DBER. We conducted a thematic analysis of these interviews grounded in the theoretical frameworks of the reasoned action approach and conjecture mapping. Based on our analysis we identified 3 roles that support new faculty entering DBER. These roles are the peer, the subject matter expert, and the project manager

Prednisolone or tetracosactide depot for infantile epileptic spasms syndrome? A prospective analysis of data embedded within two randomised controlled trials

OBJECTIVE: To report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS). METHODS: Individual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13-14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14-42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks. RESULTS: 126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13-14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14-42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = -0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33). SIGNIFICANCE: With hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome

RAC1(P29S) Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification