Development of a quantitative morphological assessment of toxicant‐treated zebrafish larvae using brightfield imaging and high‐content analysis

One of the rate‐limiting procedures in a developmental zebrafish screen is the morphological assessment of each larva. Most researchers opt for a time‐consuming, structured visual assessment by trained human observer(s). The present studies were designed to develop a more objective, accurate and rapid method for screening zebrafish for dysmorphology. Instead of the very detailed human assessment, we have developed the computational malformation index, which combines the use of high‐content imaging with a very brief human visual assessment. Each larva was quickly assessed by a human observer (basic visual assessment), killed, fixed and assessed for dysmorphology with the Zebratox V4 BioApplication using the Cellomics® ArrayScan® V^TI high‐content image analysis platform. The basic visual assessment adds in‐life parameters, and the high‐content analysis assesses each individual larva for various features (total area, width, spine length, head–tail length, length–width ratio, perimeter–area ratio). In developing the computational malformation index, a training set of hundreds of embryos treated with hundreds of chemicals were visually assessed using the basic or detailed method. In the second phase, we assessed both the stability of these high‐content measurements and its performance using a test set of zebrafish treated with a dose range of two reference chemicals (trans‐retinoic acid or cadmium). We found the measures were stable for at least 1 week and comparison of these automated measures to detailed visual inspection of the larvae showed excellent congruence. Our computational malformation index provides an objective manner for rapid phenotypic brightfield assessment of individual larva in a developmental zebrafish assay. Copyright © 2016 John Wiley & Sons, Ltd.     

A new immunodeficient retinal dystrophic rat model for transplantation studies using human-derived cells

Graefe's Archive for Clinical and Experimental Ophthalmology - To create new immunodeficient Royal College of Surgeons (RCS) rats by introducing the defective MerTK gene into athymic nude rats....     

Is surgical PD catheter insertion safe for urgent‐start peritoneal dialysis?

Urgent‐start peritoneal dialysis (USPD) is increasingly seen as a viable alternative to hemodialysis through a central venous catheter for late‐presenting end‐stage renal disease patients. However, concerns remain about starting dialysis early following the surgical implantation of the peritoneal dialysis (PD) catheter; urgent PD is often thought to be a safe option only after minimally invasive percutaneous catheter insertions. Analysis of the cumulative data from published literature presented in this review appears to negate this general perception and shows that compared to the percutaneous catheter insertions, starting PD urgently following surgically placed catheter is not associated with more catheter leaks, dysfunctions, or other complications. The outcome of USPD is independent of the mode of catheter insertion. Instead, measures to minimize intra‐peritoneal pressure including using the low initial dwell volume based on patient's weight and body habitus and keeping patients in strict supine posture during exchanges in the first 2 weeks of treatment are the two most important factors ensuring a minimization of the risk of catheter‐related complications.     

A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

Objective

To create a prognostic tool to quantify the 5‐year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease.

Methods

We reviewed CV outcomes during the long‐term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort.

Results

Seventy‐four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11–1.90), diastolic hypertension (OR 1.97, 95% CI 0.98–3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20–0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80).

Conclusion

Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status.     

Predictors of delayed culture conversion in patients treated for multidrug-resistant tuberculosis in Pakistan

Culture conversion is an interim monitoring tool for treatment of multidrug-resistant tuberculosis (MDR-TB). We evaluated the time to and predictors of culture conversion in pulmonary MDR-TB patients enrolled in the community-based MDR-TB management program at the Indus Hospital in Karachi, Pakistan. Despite strict daily directly observed therapy, monthly food incentives and patient counseling, the median time to culture conversion was 196 days (range 32-471). The cumulative probabilities of culture conversion by 2, 4, 6 and 12 months were respectively 6%, 33%, 47%, and 73%. Smoking, high smear grade at baseline and previous use of second-line drugs delayed culture conversion.     

Long-term survivor of brain metastases from malignant melanoma

Malignant melanoma is notorious for distant metastases. Median survival for stage IV melanoma is 6-10 months and 5 year survival is less than 5%. Median survival for melanoma with brain metastases is even lower i.e. 2 to 9 months. Here a case is reported who was treated for melanoma of sole of left foot with ipsilateral inguinal adenopathy and brain metastases in 2001 and is still surviving disease-free after a lapse of 8 years.     

Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study

Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AI therapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D(3) (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was <30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15-2.20 %] bone loss at LS (0.017 g/cm(2) [0.012-0.024], P < 0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to -0.3 %], adjusted P = 0.0001), and those who reached levels ≥40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4-3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (<30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI-associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.     

Late Effects in Cancer Survivors: “The Shared Care Model”

Advances continue to be made in the field of pediatric oncology ever since treatment for childhood cancer began in 1948. Since then, there has been exponential progress in the care for children with cancer as reflected in the current survival rates, which approach 90%. With such incredible survival rates, the number of childhood cancer survivors has increased significantly, with present estimates being above 300,000 in the United States alone. This success has, however, not been without cost. Long-term studies of cancer survivors have brought to light specific adverse effects of therapy, which often present years after treatment is finished, termed “late effects.” Over the years, it has become apparent that monitoring for and treating these late effects of treatment is essential for the continuing health of young cancer survivors. It is now well recognized that childhood cancer survivors require long-term follow-up care given by an integrated team of qualified and invested specialty-care providers in collaboration with their primary caregivers. These teams deliver care using a risk-based approach, following a systematic plan for lifelong screening, surveillance, and prevention that incorporates risks based on the previous cancer, cancer therapy, genetic predispositions, lifestyle behaviors, and co-morbid health conditions.     

Personalized Activity Intelligence (PAI) for Prevention of Cardiovascular Disease and Promotion of Physical Activity

Purpose

To derive and validate a single metric of activity tracking that associates with lower risk of cardiovascular disease mortality.