Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs.

BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/objectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty-seven client-owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT

‘Organised’ cervical screening 45 years on: How consistent are organised screening practices?

Organised screening programmes have been remarkably successful in reducing incidence and mortality from cervical cancer, while opportunistic screening varies in its effectiveness. Experts recommend that cervical screening or HPV testing be carried out only in the context of an organised programme. We sought to answer the following study questions: What does it mean for a cervical screening programme to be organised? Is there a place for opportunistic screening (in an organised programme)? We reviewed 154 peer-reviewed papers on organised and opportunistic approaches to cervical screening published between 1970 and 2014 to understand how the term ‘organised’ is used, formally and in practice. We found that despite broad recognition of a prescriptive definition of organisation, in practice the meaning of organisation is much less clear. Our review revealed descriptions of organised programmes that differ significantly from prescribed norms and from each other, and a variety of ways that opportunistic and organised programmes intersect. We describe the breadth of the variation in cervical cancer screening programmes and examine the relationships and overlaps between organised and opportunistic screening. Implications emerging from the review include the need to better understand the breadth of organisation in practice, the drivers and impacts of opportunistic screening and the impact of opportunistic screening on population programme outcomes. Appreciation of the complexity of cervical screening programmes will benefit both screeners and women as programmes are changed to reflect a partially vaccinated population, new evidence and new technologies

Information provision in cervical screening in Australia

• The National Cervical Screening Program, and associated state and territory organisations, are responsible for promoting cervical screening. Communication via multiple media channels encourages women to be screened. • Some communications are not clear about misrepresent the risk of cervical cancer and the protective capacity and reliability of the Pap smear. The potential harms of screening are rarely presented. • Participation is a key performance indicator for the Program. • Women receive Pap tests from clinicians, mostly general practitioners (GPs) who often screen opportunistically during already-busy appointments. Incentive Payments encourage high screening rates. • Consent is an important ethical principle in the delivery of all health care. Provision of material information is one of the elements of valid consent. • The combination of arguably ambiguous misleading communications, screening participation targets, and opportunistic testing under time pressure seems likely to undermine opportunities for women participating in the cervical cancer screening program to be informed. • Of particular concern are women who are less likely to benefit, women who are more likely to experience harm, and some groups of disadvantaged women. • Improved communications could include the absolute risk of cervical cancer and the morbidity and mortality benefits and harms of screening. Screening programs internationally have begun providing such information. • Performance indicators could value evidence of discussion or informing. • Areas for further research include the appropriate roles of the program, screeners, and individuals in providing and seeking information. Such work would identify the optimum method for informing women in the screening process

Persistent unexplained congenital clitoromegaly in females born extremely prematurely

Objective: Unexplained clitoromegaly is a rare but well recognised feature in girls born premature. Although detected at birth, girls may re-present during childhood to paediatric urologists and gynaecologists who should be aware of this condition. The aim of the study was to describe the clinical findings and management of a series of girls presenting with persistent congenital clitoromegaly associated with prematurity. / Materials and methods: This was a retrospective notes review set in a tertiary referral centre for Paediatric and Adolescent Gynaecology (PAG). / Results: Eight girls with a mean age of 6 years were seen over an eight year period. In all cases a Disorder of Sex Development (DSD) had been previously excluded. The main symptoms were discomfort or concern about appearance. On examination five girls had excess skin over the clitoris and three had enlarged corporal tissue. Management included reassurance and simple measures to ease discomfort. In two cases the parents requested referral to a paediatric urologist to consider clitoral surgery. / Conclusion: As survival rates for extreme prematurity improve, paediatric urologists and gynaecologists are likely to see more of these cases. Clinicians must be familiar with this condition to ensure children are managed appropriately

The effect of alpha(+)-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya

BACKGROUND: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete. METHODS AND FINDINGS: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). CONCLUSIONS: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes

An optimised region and boundary classifier for head movement classification

University of Technology, Sydney. Faculty of Engineering and Information Technology.The use of Artificial Neural Network (ANN) classifiers in real-time applications that could be considered critical, such as head movement classification for the control of a powered wheelchair, naturally raises questions over safety due to performance accuracy. One inherent characteristic of an ANN is that the placement of classification boundaries within the decision space is arbitrary and ultimately unknown. The result of this characteristic is to give unpredictable results when presented with data outside the boundary of the training set and is therefore considered as a major source of uncertainty. The problem is one of accuracy and predictability and to address this a novel algorithm termed an Optimised Region and Boundary Classifier (RBC) was created to provide improvements in accuracy and predictability over a conventionally trained ANN. To improve accuracy the RBC requires the formation of effective boundaries, which relies on the training set containing data that is both representative of all types of data likely to be input to the classifier and is complementary (data either side of an implied boundary). To achieve this the original training set consisting of commands only (forward, back, left, and right) was augmented with “data outside the boundary”, which consisted of seventeen types of non-command data that the classifier was likely to see. To improve predictability the RBC uses explicit boundaries, which is achieved using kmeans clustering techniques to define Hyper-Rectangles. Also, two additional regions (vertical and horizontal null regions) are extracted from the Hyper-Rectangles and added to the classifier. To further improve accuracy and predictability an optimisation process is used that expands the Hyper-Rectangles for each of the classes to be classified (forward, back, left, and right) until the associated training error for sensitivity and specificity is optimal. To show that the RBC could provide improvements in performance comparisons were made between the RBC trained on the augmented training set and ANN’s trained on both the original training set and the augmented training set. The performance for each type of classifier was assessed using the 0.632+ Bootstrap Method and Receiver Operating Characteristics (ROC) analysis (area under the curve, sensitivity, and specificity). Results showed that the RBC provided significant improvements in performance when compared with an ANN trained on the original training set (up to 9% improvement in mean sensitivity and 30% improvement in mean specificity). When compared with the ANN that was trained on the same augmented training data only small improvements in mean sensitivity and specificity could be seen (up to 3%). However, the RBC was clearly the best performing classifier algorithm overall. The significance of the Optimised Region and Boundary Classifier is that it addresses both accuracy and predictability and therefore it is potentially an inherently safer classification algorithm. This would enable its use with more confidence in applications where safety is critical, such as in Medical Devices

Hormone replacement treatment choices in complete androgen insensitivity syndrome: an audit of an adult clinic

OBJECTIVE: To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. DESIGN: Retrospective review. PATIENTS: Women with CAIS identified from our database. RESULTS: The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1-53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. CONCLUSIONS: In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone

The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study.

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance

Multidisciplinary approach to the management of children with female genital mutilation (FGM) or suspected FGM: service description and case series

OBJECTIVE: To describe the first dedicated clinic in the UK for children with suspected or confirmed female genital mutilation (FGM) including referral patterns, clinical findings and subsequent management. DESIGN AND SETTING: A prospective study of all children seen in a dedicated multidisciplinary FGM clinic for children over a 1-year period. POPULATION: Patients aged under 18 years referred for clinical assessment or for a second opinion on Digital Versatile Disc (DVD) images. METHODS AND MAIN OUTCOME MEASURES: Data were collected on reasons for referral, demography, genital examination findings including FGM type, and clinical recommendations. RESULTS: 38 children were referred of whom 18 (47%) had confirmed FGM; most frequently type 4 (61%). Social care and police referred 78% of cases. According to UK law FGM had been performed illegally in three cases. Anonymous information given to the police led to the referral of six children, none of whom had had FGM. CONCLUSIONS: Mandatory reporting and increased media attention may increase the numbers of referrals of children with suspected FGM. This patient group have complex needs and management in a dedicated multidisciplinary service is essential. Paediatricians and gynaecologists should have the skills to carry out the consultation and detect all types of FGM including type 4 which was the most common type seen in this series. This is the first dedicated FGM service for children in the UK and similar clinics in high-prevalence areas should be established

Experimental Tests of General Relativity

Einstein's general theory of relativity is the standard theory of gravity, especially where the needs of astronomy, astrophysics, cosmology and fundamental physics are concerned. As such, this theory is used for many practical purposes involving spacecraft navigation, geodesy, and time transfer. Here I review the foundations of general relativity, discuss recent progress in the tests of relativistic gravity in the solar system, and present motivations for the new generation of high-accuracy gravitational experiments. I discuss the advances in our understanding of fundamental physics that are anticipated in the near future and evaluate the discovery potential of the recently proposed gravitational experiments.Comment: revtex4, 30 pages, 10 figure