Breast Tumor Identification in Ultrafast MRI Using Temporal and Spatial Information

Purpose: To investigate the feasibility of using deep learning methods to differentiate benign from malignant breast lesions in ultrafast MRI with both temporal and spatial information. Methods: A total of 173 single breasts of 122 women (151 examinations) with lesions above 5 mm were retrospectively included. A total of 109 out of 173 lesions were benign. Maximum intensity projection (MIP) images were generated from each of the 14 contrast-enhanced T1-weighted acquisitions in the ultrafast MRI scan. A 2D convolutional neural network (CNN) and a long short-term memory (LSTM) network were employed to extract morphological and temporal features, respectively. The 2D CNN model was trained with the MIPs from the last four acquisitions to ensure the visibility of the lesions, while the LSTM model took MIPs of an entire scan as input. The performance of each model and their combination were evaluated with 100-times repeated stratified four-fold cross-validation. Those models were then compared with models developed with standard DCE-MRI which followed the same data split. Results: In the differentiation between benign and malignant lesions, the ultrafast MRI-based 2D CNN achieved a mean AUC of 0.81 ± 0.06, and the LSTM network achieved a mean AUC of 0.78 ± 0.07; their combination showed a mean AUC of 0.83 ± 0.06 in the cross-validation. The mean AUC values were significantly higher for ultrafast MRI-based models than standard DCE-MRI-based models. Conclusion: Deep learning models developed with ultrafast breast MRI achieved higher performances than standard DCE-MRI for malignancy discrimination. The improved AUC values of the combined models indicate an added value of temporal information extracted by the LSTM model in breast lesion characterization

Mortality After Clinical Management of Aids-Associated Cryptococcal Meningitis in Kenya

Background: Cryptococcal meningitis (CM) is an increasingly prevalent  infection among HIV/AIDS patients and is becoming a leading cause of  morbidity and mortality in Africa. The short-term prognosis and  management of patients with CM may be improved by identifying factors leading to mortality in patients with CM.Objective: To assess the clinical management and mortality associated with cryptococcal meningitis (CM) in patients with acquired  immunodeficiency syndrome (AIDS) in Kenya.Design: A retrospective study.Setting: Kenyatta National Hospital and Mbagathi District Hospital, between August 2008 and March 2009.Subjects: Seventy six HIV-infected patients confirmed to be CM positive.Results: Results show that 30 (40%) of 76 patients diagnosed with CM died during hospitalisation after a median hospital stay of ten days (range, 2-73 days). Significant predictors of mortality in the univariate model were Mycobacterium tuberculosis (TB) co-infection (P = 0.04), having been diagnosed with a co-morbid condition such as diabetes mellitus, oral candidiasis and hypertension (P = 0.01), and a low median CD4+ T lymphocyte count (P < 0.001). The multivariable model revealed that male sex, previous or current anti-retroviral therapy (ART) at admission and CD4+ T lymphocyte count less than 50 were significant predictors of mortality. Conversely, a minimum of two weeks of amphotericin B treatment (P < 0.001), initiation of ART (P = 0.007) and monitoring of creatinine and electrolyte levels (P = 0.02) were significantly associatedwith survival in the univariate model.Conclusions: CM-associated mortality in Kenya is high; there is an  opportunity to improve the management and the short-term outcomes of hospitalised HIV positive patients with CM in Kenya

Comparison of contact patterns relevant for transmission of respiratory pathogens in Thailand and the Netherlands using respondent-driven sampling

Understanding infection dynamics of respiratory diseases requires the identification and quantification of behavioural, social and environmental factors that permit the transmission of these infections between humans. Little empirical information is available about contact patterns within real-world social networks, let alone on differences in these contact networks between populations that differ considerably on a socio-cultural level. Here we compared contact network data that were collected in the Netherlands and Thailand using a similar online respondent-driven method. By asking participants to recruit contact persons we studied network links relevant for the transmission of respiratory infections. We studied correlations between recruiter and recruited contacts to investigate mixing patterns in the observed social network components. In both countries, mixing patterns were assortative by demographic variables and random by total numbers of contacts. However, in Thailand participants reported overall more contacts which resulted in higher effective contact rates. Our findings provide new insights on numbers of contacts and mixing patterns in two different populations. These data could be used to improve parameterisation of mathematical models used to design control strategies. Although the spread of infections through populations depends on more factors, found similarities suggest that spread may be similar in the Netherlands and Thailand

Health related quality of life six months following surgical treatment for secondary peritonitis – using the EQ-5D questionnaire

Background: To compare health related quality of life (HR-QoL) in patients surgically treated for secondary peritonitis to that of a healthy population. And to prospectively identify factors associated with poorer (lower) HR-QoL. Design: A prospective cohort of secondary peritonitis patients was mailed the EQ-5D and EQ-VAS 6-months following initial laparotomy. Setting: Multicenter study in two academic and seven regional teaching hospitals. Patients: 130 of the 155 eligible patients (84%) responded to the HR-QoL questionnaires. Results: HR-QoL was significantly worse on all dimensions in peritonitis patients than in a healthy reference population. Peritonitis characteristics at initial presentation were not associated with HR-QoL at six months. A more complicated course of the disease leading to longer hospitalization times and patients with an enterostomy had a negative impact on the mobility (p = 0.02), self-care (p <0.001) and daily activities: (p = 0.01). In a multivariate analysis for the EQ-VAS every doubling of hospital stay decreases the EQ-VAS by 3.8 points (p = 0.015). Morbidity during the six-month follow-up was not found to be predictive for the EQ-5D or EQ-VAS. Conclusion: Six months following initial surgery, patients with secondary peritonitis report more problems in HR-QoL than a healthy reference population. Unfavorable disease characteristics at initial presentation were not predictive for poorer HR-QoL, but a more complicated course of the disease was most predictive of HR-QoL at 6 month

Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-beta and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-beta and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-beta plaques or both amyloid-beta plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-beta load and localized to amyloid-beta plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies

Magnesium Inhibits Wnt/β-Catenin Activity and Reverses the Osteogenic Transformation of Vascular Smooth Muscle Cells

Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved

Developing Symptom Lists for People with Cancer Treated with Targeted Therapies

Background: Targeted Therapies (TTs) have revolutionised cancer treatment with their enhanced specificity of action. Compared with conventional therapies, TTs are delivered over a longer period and often have unusual symptom profiles. Patient reported outcome measures such as symptom side-effect lists need to be developed in a time-efficient manner to enable a rapid and full evaluation of new treatments and effective clinical managementObjective: the aim of this study is to develop a set of TT-related symptoms and identify the optimal method for developing symptom lists. Patients and Methods: symptoms from TT treatment in the context of Chronic Myeloid Leukaemia (CML), HER2 positive breast cancer, or Gastrointestinal Stromal Tumours (GIST) were identified through literature reviews, interviews with health care professionals (HCPs) and patients, and patient focus groups. The symptom set was then pilot tested in patients across the three cancer diagnoses: The number of items derived from each source (literature, patients, or HCPs) were compared. Results: a total of 316 patients and 86 HCPs from 16 countries participated. An initial set of 209 symptoms was reduced to 61 covering 12 symptom categories. Patient interviews made the greatest contribution to the item set.Conclusions: symptom lists should be created based on input from patients. The item set described will be applicable to the assessment of new TTs, and in monitoring treatment.<br/

Colonies of the fungus Aspergillus niger are highly differentiated to adapt to local carbon source variation

Saprobic fungi, such as Aspergillus niger, grow as colonies consisting of a network of branching and fusing hyphae that are often considered to be relatively uniform entities in which nutrients can freely move through the hyphae. In nature, different parts of a colony are often exposed to different nutrients. We have investigated, using a multi-omics approach, adaptation of A. niger colonies to spatially separated and compositionally different plant biomass substrates. This demonstrated a high level of intra-colony differentiation, which closely matched the locally available substrate. The part of the colony exposed to pectin-rich sugar beet pulp and to xylan-rich wheat bran showed high pectinolytic and high xylanolytic transcript and protein levels respectively. This study therefore exemplifies the high ability of fungal colonies to differentiate and adapt to local conditions, ensuring efficient use of the available nutrients, rather than maintaining a uniform physiology throughout the colony.Peer reviewe

Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal

Tuberous sclerosis complex (TSC) is caused by inactivating variants in TSC1 and TSC2. Somatic mosaicism, as well as the size and complexity of the TSC1 and TSC2 loci, makes variant identification challenging. Indeed, in some individuals with a clinical diagnosis of TSC, diagnostic testing fails to identify an inactivating variant. To improve TSC1 and TSC2 variant detection, we screened the TSC1 and TSC2 genomic regions using targeted HaloPlex custom capture and next-generation sequencing (NGS) in genomic DNA isolated from peripheral blood of individuals with definite, possible or suspected TSC in whom no disease-associated variant had been identified by previous diagnostic genetic testing. We obtained &gt;95% target region coverage at a read depth of 20 and &gt;50% coverage at a read depth of 300 and identified inactivating TSC1 or TSC2 variants in 83/155 individuals (54%); 65/113 (58%) with clinically definite TSC and 18/42 (43%) with possible or suspected TSC. These included 19 individuals with deep intronic variants and 54 likely cases of mosaicism (variant allele frequency 1-28%; median 7%). In 13 cases (8%), we identified a variant of uncertain significance (VUS). Targeted genomic NGS of TSC1 and TSC2 increases the yield of inactivating variants found in individuals with suspected TSC.</p