Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients

Background Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed

Applied system analysis and technology of designing the software

An analogy is made between the stages of applied system analysis and the stages of software Engineerin

Hypertension, Microvascular Pathology, and Prognosis After an Acute Myocardial Infarction

The rationale for our study was to investigate the pathophysiology of microvascular injury in patients with acute ST-segment–elevation myocardial infarction in relation to a history of hypertension. We undertook a cohort study using invasive and noninvasive measures of microvascular injury, cardiac magnetic resonance imaging at 2 days and 6 months, and assessed health outcomes in the longer term (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850). Three hundred twenty-four patients with acute myocardial infarction (mean age, 59 [12] years; blood pressure, 135 [25] / 79 [14] mm Hg; 237 [73%] male, 105 [32%] with antecedent hypertension) were prospectively enrolled during emergency percutaneous coronary intervention. Compared with patients without antecedent hypertension, patients with hypertension were older (63 [12] years versus 57 [11] years; P<0.001) and a lower proportion were cigarette smokers (52 [50%] versus 144 [66%]; P=0.007). Coronary blood flow, microvascular resistance within the culprit artery, infarct pathologies, inflammation (C-reactive protein and interleukin-6) were not associated with hypertension. Compared with patients without antecedent hypertension, patients with hypertension had less improvement in left ventricular ejection fraction at 6 months from baseline (5.3 [8.2]% versus 7.4 [7.6]%; P=0.040). Antecedent hypertension was a multivariable associate of incident myocardial hemorrhage 2-day post-MI (1.81 [0.98–3.34]; P=0.059) and all-cause death or heart failure (n=47 events, n=24 with hypertension; 2.53 [1.28–4.98]; P=0.007) postdischarge (median follow-up 4 years). Severe progressive microvascular injury is implicated in the pathophysiology and prognosis of patients with a history of hypertension and acute myocardial infarction

Gendering the careers of young professionals: some early findings from a longitudinal study. in Organizing/theorizing: developments in organization theory and practice

Wonders whether companies actually have employees best interests at heart across physical, mental and spiritual spheres. Posits that most organizations ignore their workforce – not even, in many cases, describing workers as assets! Describes many studies to back up this claim in theis work based on the 2002 Employment Research Unit Annual Conference, in Cardiff, Wales

Case report: Cutaneous pseudolymphoma caused by a Leishmania infantum infection in a patient treated with anti-TNF antibody for plaque psoriasis

For psoriasis, which affects up to 2% of the population and adalimumab is approved from the age of 4 years. Here, we present a middle-aged Italian man with long-term history of plaque psoriasis and psoriasis arthropathica and adalimumab therapy. He developed ulcers or nodules within the psoriatic plaques, resembling cutaneous infection with Leishmania infantum. TNF and other cytokines such as IL-12 and IFN-γ are central in the early control of the infection. Discontinuation of the anti-TNF-treatment resolved the infection without specific therapy

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer

IntroductionBreast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study.Methods and analysesPatients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated.RegistrationThe study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221)

Software-assisted structured reporting and semi-automated TNM classification for NSCLC staging in a multicenter proof of concept study

Objectives : In this multi-center study, we proposed a structured reporting (SR) framework for non-small cell lung cancer (NSCLC) and developed a software-assisted tool to automatically translate image-based findings and annotations into TNM classifications. The aim of this study was to validate the software-assisted SR tool for NSCLC, assess its potential clinical impact in a proof-of-concept study, and evaluate current reporting standards in participating institutions. Methods : A framework for SR and staging of NSCLC was developed in a multi-center collaboration. SR annotations and descriptions were used to generate semi-automated TNM classification. The SR and TNM classification tools were evaluated by nine radiologists on n = 20 representative [18F]FDG PET/CT studies and compared to the free text reporting (FTR) strategy. Results were compared to a multidisciplinary team reference using a generalized linear mixed model (GLMM). Additionally, participants were surveyed on their experience with SR and TNM classification. Results : Overall, GLMM analysis revealed that readers using SR were 1.707 (CI: 1.137–2.585) times more likely to correctly classify TNM status compared to FTR strategy (p = 0.01) resulting in increased overall TNM correctness in 71.9% (128/178) of cases compared to 62.8% (113/180) FTR. The primary source of variation in classification accuracy was explained by case complexity. Participants rated the potential impact of SR and semi-automated TNM classification as positive across all categories with improved scores after template validation. Conclusion : This multi-center study yielded an effective software-assisted SR framework for NSCLC. The SR and semi-automated classification tool improved TNM classification and were perceived as valuable. Critical relevance statement : Software-assisted SR provides robust input for semi-automated rule-based TNM classification in non-small-cell lung carcinoma (NSCLC), improves TNM correctness compared to FTR, and was perceived as valuable by radiology physicians