Systematic review of the use of translated patient-reported outcome measures in cancer trials.

BACKGROUND: Patient-reported outcomes (PROs) are used in clinical trials to assess the effectiveness and tolerability of interventions. Inclusion of participants from different ethnic backgrounds is essential for generalisability of cancer trial results. PRO data collection should include appropriately translated patient-reported outcome measures (PROMs) to minimise missing data and sample attrition. METHODS: Protocols and/or publications from cancer clinical trials using a PRO endpoint and registered on the National Institute for Health Research Portfolio were systematically reviewed for information on recruitment, inclusion of ethnicity data, and use of appropriately translated PROMs. Semi-structured interviews were conducted with key stakeholders to explore barriers and facilitators for optimal PRO trial design, diverse recruitment and reporting, and use of appropriately translated PROMs. RESULTS: Eighty-four trials met the inclusion criteria, only 14 (17%) (n = 4754) reported ethnic group data, and ethnic group recruitment was low, 611 (13%). Although 8 (57%) studies were multi-centred and multi-national, none reported using translated PROMs, although available for 7 (88%) of the studies. Interviews with 44 international stakeholders identified a number of perceived barriers to ethnically diverse recruitment including diverse participant engagement, relevance of ethnicity to research question, prominence of PROs, and need to minimise investigator burden. Stakeholders had differing opinions on the use of translated PROMs, the impact of trial designs, and recruitment strategies on diverse recruitment. Facilitators of inclusive research were described and examples of good practice identified. CONCLUSIONS: Greater transparency is required when PROs are used as primary or secondary outcomes in clinical trials. Protocols and publications should demonstrate that recruitment was accessible to diverse populations and facilitated by trial design, recruitment strategies, and appropriate PROM usage. The use of translated PROMs should be made explicit when used in cancer clinical trials.

Retrospective study on the occurrence of canine lymphoma and associated breed risks in a population of dogs in NSW (2001-2009).

OBJECTIVE: To identify risk factors for canine lymphoma in dogs from New South Wales, Australia, and to compare factors affecting remission duration. METHODS: Client-owned dogs diagnosed with lymphoma presented to the University Veterinary Teaching Hospital (UVTH), University of Sydney, between 2001 and 2009 (n = 134) were compared with a control population of dogs seen in that period of time with a diagnosis other than lymphoma to evaluate association of explanatory variables (breed, age and sex) with the outcome (case or control status). RESULTS: The Australian Cattle Dog (odds ratio (OR) = 4.71; 95% confidence interval (Cl) 2.31-9.62; P < 0.001), Doberman (OR = 7.64; 95% Cl 2.87-20.34; P = 0.001) and Rottweiler (OR = 4.52; 95% Cl 2.09-9.73; P = 0.001) had increased odds of lymphoma among dogs attending the UVTH compared with crossbreds. The results suggested that the Border Collie (OR = 3.38; 95% Cl 1.52-7.53; P = 0.008) and Boxer (OR = 3.85; 95% Cl 1.65-8.95; P = 0.006) also have increased odds of lymphoma among the pure-breed dogs attending the UVTH when compared with crossbred dogs. CONCLUSIONS: The results of this study confirmed a breed predilection for lymphoma in dogs, with the Australian Cattle Dog and Doberman having increased odds of lymphoma.

Associations between neurologic dysfunction and lesions in canine fucosidosis.

Canine fucosidosis in English Springer spaniels is the only animal model of the neurovisceral lysosomal storage disease fucosidosis available for preclinical therapeutic trials. For this reason, it is crucial to identify critical time points in disease progression, and if there are particular lesions associated with specific aspects of neurologic dysfunction. Historical records of 53 canine fucosidosis cases from 1979 to 2009 containing a neurologic dysfunction score assessing motor, behavioral and sensory dysfunction were interrogated by statistical analysis. Motor and behavioral dysfunction scores assessing gait deficits and apprehensive behavior first significantly increased at 12-17 months, and increased at each 6-month interval thereafter. Sensory dysfunction scores, assessing hearing loss, balance and vision deterioration, did not significantly increase until 18-23 months, and coincided with a rapid decline in neurologic function. Regression analysis incorporating published neuropathology data, measured by image analysis, identified neuroinflammation and apoptotic cell death as significant informative predictors of increasing neurologic dysfunction. These findings indicate that the level of neuropathology required to induce consistent and conspicuous clinical signs in canine fucosidosis is reached by approximately 12 months of age in the absence of other disease processes. Significant association between neuroinflammation and apoptotic cell death also suggests that specifically targeting these lesions combined with enzyme replacement in future studies may reduce disease burden in fucosidosis. Overall, examining this historical clinical data to identify associations between the extent of neuropathology and degree of clinical dysfunction provides a useful reference tool for monitoring disease and evaluating therapeutic trials conducted in canine fucosidosis.

Micro-elastometry on whole blood clots using actuated surface-attached posts (ASAPs).

We present a novel technology for microfluidic elastometry and demonstrate its ability to measure stiffness of blood clots as they form. A disposable micro-capillary strip draws small volumes (20 µL) of whole blood into a chamber containing a surface-mounted micropost array. The posts are magnetically actuated, thereby applying a shear stress to the blood clot. The posts' response to magnetic field changes as the blood clot forms; this response is measured by optical transmission. We show that a quasi-static model correctly predicts the torque applied to the microposts. We experimentally validate the ability of the system to measure clot stiffness by correlating our system with a commercial thromboelastograph. We conclude that actuated surface-attached post (ASAP) technology addresses a clinical need for point-of-care and small-volume elastic haemostatic assays.

A scoping exercise of favourable characteristics of professionals working in teenage and young adult cancer care: 'thinking outside of the box'.

A scoping exercise to define the preferred competencies of professionals involved in teenage and young adult (TYA) cancer care. Data were generated during two workshops with health professionals. In groups, they ranked skills, knowledge and attitudes, previously identified through a literature search, onto a diamond template. Data were also used from an education day with TYA professionals, who generated lists of key skills, knowledge and attitudes. Individually, professionals then selected the top five areas of competence to care for young people with cancer. The workshops generated three diamonds, which exhibited agreement of 13 principle skills, knowledge and attitudes. The top two being: 'expertise in treating paediatric and adult cancers' and 'understanding cancer'. The data from the education day suggested communication, technical knowledge and teamwork as being core role features for professionals who care for young people with cancer. Integration of both datasets; one derived inductively, the other deductively provides a comprehensive outline of core skills health professionals require to be proficient in young people's cancer care. These results will form the basis of future discussion around workforce strategies and inform a Delphi survey.

Mapping cerebellar abiotrophy in Australian Kelpies.

An autosomal recessive form of cerebellar abiotrophy occurs in Australian Kelpie dogs. Clinical signs range from mild ataxia with intention tremor to severe ataxia with seizures. A whole-genome mapping analysis was performed using Affymetrix Canine SNP array v2 on 11 affected and 19 control dogs, but there was no significant association with disease. A homozygosity analysis identified a three megabase region likely to contain the disease mutation. The region spans 29.8-33 Mb on chromosome 3, for which all affected dogs were homozygous for a common haplotype. Microsatellite markers were developed in the candidate region for linkage analysis that resulted in a logarithm of odds score suggestive of linkage. The candidate region contains 29 genes, none of which are known to cause ataxia.

Seropositive abdominal and thoracic donor organs are largely underutilized.

The aim of this study was to describe the epidemiology and utilization of anti-hepatitis B core protein(+) and anti-hepatitis C virus(+) organ donor referrals in a large organ procurement organization. Between 1995 and 2006, 3,134 deceased organ donor referrals were tested for anti-HBc and anti-HCV using commercial assays. The prevalence of anti-HCV(+) organ donor referrals significantly increased from 3.4% in 1994-1996 to 8.1% in 2003-2005 (P < .001), whereas the prevalence of anti-HBc(+) organ donor referrals remained unchanged at 3%-4% (P = .20). The 112 anti-HBc(+) (3.5%) and 173 anti-HCV(+) (5.5%) organ donor referrals were significantly older and more likely to be noncaucasian than seronegative organ donor referrals (P < .02). The procurement and utilization rates of seropositive thoracic and abdominal donor organs were significantly lower compared with seronegative organ donors (P < .0001). However, liver utilization rates significantly increased from anti-HBc(+) donors over time (21% vs 46%; P = .026), whereas utilization of anti-HCV(+) liver donors remained unchanged over time (5% vs 18%; P = .303). In summary, the proportion of anti-HCV(+) organ donor referrals has significantly increased and the proportion of anti-HBc(+) organ donor referrals has remained stable. Both thoracic and abdominal organs from seropositive donors are largely underutilized.

Sugar deprivation reduces insemination of Anopheles gambiae (Diptera: Culicidae), despite daily recruitment of adults, and predicts decline in model populations.

Our research tests the hypothesis that the inability to sugar-feed reduces the insemination rate in mosquito populations. To test this, we measured the effects of sugar availability on cumulative insemination performance of male Anopheles gambiae Giles s.s. (Diptera: Culicidae) during 10-d periods of continual emergence of equal numbers of both sexes, and we evaluated the implications at the population level with a matrix population model. On each day of each of four replicates, 20 newly emerged mosquitoes of each sex were recruited into the populations within two mesocosms, large walk-in enclosures with simulated natural conditions. Each mesocosm contained a cage to replicate the experiment on a small scale. Scented sucrose was absent or present (control). A human host was available nightly as a bloodmeal source in both mesocosms. Sugar availability and enclosure size significantly influenced female insemination. In the mesocosms, with sugar 49.7% of the females were inseminated, compared with 10.9% of the females without sugar. In the small cages, the insemination rates were 76.0 and 23.5%, respectively. In the mesocosms, cumulative survival of females after 10 d was 51.6% with sugar and 25.6% without sugar. In the cages, female survival was 95 and 73%, respectively. Sensitivity analysis of the population projection matrix shows that both reduced male survival and reduced mating capability due to a lack of sugar contributed to lower insemination rates in females, and in the absence of sugar the insemination rate was lowered to an extent that led to population decline.

How dietary plant nectar affects the survival, growth, and fecundity of a cursorial spider Cheiracanthium inclusum (Araneae: Miturgidae).

We measured the effects of plant nectar consumption on Cheiracanthium inclusum (Hentz) (Miturgidae), an agriculturally important spider. Newly emerged spiderlings were reared on the eggs of Helicoverpa zea (Boddie) at four prey densities, 1, 5, 25, or 125 eggs, three times a week, with or without nectar. Nectar came from the extrafloral nectaries of Indian almond, Terminalia cattapa L. (Combretaceae). The addition of nectar to prey (1) allowed spiderlings on the 1-egg diet to survive longer and molt many more times; (2) allowed virtually all of the spiderlings on the 5-egg diet to become small adults and 50% to mate and reproduce versus those without nectar, none of which matured to adulthood; and (3) increased fecundity of females on 5-egg and 25-egg diets to the level of females fed five times the amount of prey. These results show that spiders that feed on nectar increase their fitness with increased survival, growth, and fecundity, particularly when density of prey is inadequate or marginal.

Study of the factors affecting health-related quality of life in adolescents after liver transplantation.

The aim of the study was to identify factors affecting health-related quality of life (HRQL) in adolescents after liver transplantation. HRQL was measured using the CHQ-CF87 in 55 adolescents, aged 12-18 years. Factors associated with HRQL included allograft morbidity, psychological and family-related variables measured through standardized questionnaires. The domains of the CHQ-CF87 were reduced using factor analysis to give physical, psychological and social domains. Impacting factors were identified through stepwise, multiple regression analysis. Adolescents had significantly lower HRQL in every domain except for role/social-behavior and family cohesion compared to the general population. Adolescents experienced median 18 (range 4-31) symptoms related to immunosuppression, 40(75%) had one or more chronic illnesses related to immunosuppression and 12(22%) had a history of emotional difficulties. Self-esteem and emotional health were similar to the general population but behavior and aspects of family function were lower. Following regression analysis, the factors associated with HRQL were: age at transplant, secondary chronic illness, symptom distress, headaches, history of emotional difficulties, self-esteem and family conflict. These explained 57% of the variance in physical function, 61% of psychological function and 39% of social function. HRQL is significantly reduced in adolescents after transplantation, which could be related to immunosuppression and psychosocial factors.

Involving health professionals in the development of an advanced symptom management system for young people: the ASyMS-YG study.

PURPOSE OF THE STUDY: ASyMS is an advanced symptom management system utilising mobile phone technology for patients to report cancer chemotherapy-related symptoms. The aim of this paper is to present health professionals involvement in the development of ASyMS for use with young people (YG) and evaluate their perceptions of the system. STAGE 1: Health professionals reviewed the symptoms chosen by young people to be included on the personal digital assistant questionnaire to confirm they would have universal relevance. These included: mouth sores, nausea, diarrhoea, vomiting and weight loss. STAGE 2: Health professionals completed a questionnaire prior to the study commencing, which suggested they felt ASyMS-YG would give young people control and facilitate timely interventions when symptoms occur. Post-study perceptions were sought through semi-structured interviews and consultation sessions with 23 health professionals. These showed two over-arching themes: young people's symptoms and perceptions of ASyMS-YG; and six sub-themes: increased control for young people; enhances communication between young people and health professionals; and helps with professional early intervention; increased support for young people; improve knowledge and understanding; technology appealing to young people. CONCLUSIONS: This early development work indicates that ASyMS-YG is acceptable to health professionals and their perceptions of the system were overall very positive. Health professionals will continue to be involved in the study through developing self-care guidelines and alert system, which will be tested in an exploratory trial (stage 3) and randomised controlled trial (stage 4) in the future.

Defining, constructing and assessing learning outcomes.

Learning outcomes define the veterinary curriculum and inform students about what they must be able to demonstrate to succeed. Stakeholder consultation during their development ensures that programme learning outcomes equip graduates to contribute to the veterinary profession. Effective learning outcomes form a hierarchy linking the programme, its courses and tasks. Clear outcomes direct students towards higher quality learning by indicating the achievements intended, but leave scope for emergent learning outcomes. Defined technical competencies fit within this overarching framework, complementing higher order learning. Mapping is used to align learning outcomes horizontally and vertically so students are systematically guided towards entry-level competence and professional independence. Constructively aligned learning and assessment tasks ensure learners spend the focused time required to sequentially develop programme outcomes. Assessment by staff, peers and other stakeholders certifies achievement of intended outcomes. Effective assessment also empowers students to define and achieve their own learning outcomes, so they develop the habits of autonomous life-long learning. Evaluation of the quality and consistency of achieved outcomes informs ongoing programme improvement. If we are going to achieve the objectives of this set of papers, i.e. to improve public health education globally (Rev. sci. tech. Off. int. Epiz. 28 [2] 2009), then it is essential that they be well defined in the learning outcomes statement of all veterinary schools.

Nectar feeding by wandering spiders on cotton plants.

Spiders are assumed to be strictly carnivorous in assessments of their nutritional and energetic requirements, their habitat preferences, and their potential as biological control agents. However, members of Salticidae (jumping spiders), Thomisidae (crab spiders), and the fast-moving Miturgidae, Anyphaenidae, and Corinnidae, all non-webbuilding wandering spiders, have been observed at floral and extrafloral nectaries of plants, presumably feeding on nectar. To test spiders in the field for nectar feeding, we used a cold anthrone test to detect the presence of ingested fructose, a plant-derived sugar, in wandering spiders occupying cotton plants (Gossypium hirsutum L.), which have floral and extrafloral nectaries. Field collections focused on three ecologically similar, highly active nocturnal spiders: Cheiracanthium inclusum (Hentz) (Miturgidae), Hibana futilis (Banks), and H. arunda (Platnick) (Anyphaenidae). During 2002 and 2003, 27 and 21%, respectively, of all field-collected adults and subadults tested positive for fructose, indicating consumption of extrafloral nectar. In both years, significantly more females were positive than males (38 versus 11% in 2002; 26 versus 12% in 2003). Immatures tested positive at a lower rate than adults (3 and 13%, respectively). Smaller numbers of spiders in the Lycosidae, Oxyopidae, and Thomisidae were also tested. Among the thomisids, 38% in 2002 and 41% in 2003 tested positive for fructose. None of the lycosids (wolf spiders) tested positive; two of nine oxyopids (lynx spiders) did test positive. Oxyopidae is new to the list of nectarivorous spiders. These results suggest that nectarivory is common for foliage wandering spiders and may contribute to fitness.

Neural transplantation of human MSC and NT2 cells in the twitcher mouse model.

BACKGROUND: Accumulating evidence has demonstrated that the NT2 embryonal carcinoma cell line and multipotential stem cells found in BM, mesenchymal stromal cells (MSC), have the ability to differentiate into a wide variety of cell types. This study was designed to explore the efficacy of these two human stem cell types as a graft source for the treatment of demyelinating disorders such as Krabbe's disease and multiple sclerosis (MS). METHODS: We examined the engraftment and in vivo differentiation of adult MSC and NT2 cells after transplantation into two demyelinating environments, the neonatal and postnatal twitcher mouse brain. RESULTS: Both types of xenografts led to anatomical integration, without tumor formation, and remained viable in the normal and twitcher mouse brain, showing differentiation into neurons, astrocytes and oligodendrocytes. DISCUSSION: This study represents a platform for further stem cell transplantation studies in the twitcher model and potentially has important therapeutic implications.

Thin-foil magnetic force system for high-numerical-aperture microscopy.

Forces play a key role in a wide range of biological phenomena from single-protein conformational dynamics to transcription and cell division, to name a few. The majority of existing microbiological force application methods can be divided into two categories: those that can apply relatively high forces through the use of a physical connection to a probe and those that apply smaller forces with a detached probe. Existing magnetic manipulators utilizing high fields and high field gradients have been able to reduce this gap in maximum applicable force, but the size of such devices has limited their use in applications where high force and high-numerical-aperture (NA) microscopy must be combined. We have developed a magnetic manipulation system that is capable of applying forces in excess of 700 pN on a 1 mum paramagnetic particle and 13 nN on a 4.5 mum paramagnetic particle, forces over the full 4pi sr, and a bandwidth in excess of 3 kHz while remaining compatible with a commercially available high-NA microscope objective. Our system design separates the pole tips from the flux coils so that the magnetic-field geometry at the sample is determined by removable thin-foil pole plates, allowing easy change from experiment to experiment. In addition, we have combined the magnetic manipulator with a feedback-enhanced, high-resolution (2.4 nm), high-bandwidth (10 kHz), long-range (100 mum xyz range) laser tracking system. We demonstrate the usefulness of this system in a study of the role of forces in higher-order chromosome structure and function.

Visualization and mechanical manipulations of individual fibrin fibers suggest that fiber cross section has fractal dimension 1.3.

We report protocols and techniques to image and mechanically manipulate individual fibrin fibers, which are key structural components of blood clots. Using atomic force microscopy-based lateral force manipulations we determined the rupture force, FR, f fibrin fibers as a function of their diameter, D, in ambient conditions. As expected, the rupture force increases with increasing diameter; however, somewhat unexpectedly, it increases as FR approximately D1.30+/-0.06. Moreover, using a combined atomic force microscopy-fluorescence microscopy instrument, we determined the light intensity, I, of single fibers, that were formed with fluorescently labeled fibrinogen, as a function of their diameter, D. Similar to the force data, we found that the light intensity, and thus the number of molecules per cross section, increases as I approximately D1.25+/-0.11. Based on these findings we propose that fibrin fibers are fractals for which the number of molecules per cross section increases as about D1.3. This implies that the molecule density varies as rhoD approximately D -0.7, i.e., thinner fibers are denser than thicker fibers. Such a model would be consistent with the observation that fibrin fibers consist of 70-80% water and only 20-30% protein, which also suggests that fibrin fibers are very porous.

Nutritional support in critically ill children.

BACKGROUND & AIMS: Enteral nutrition is the feeding method of choice during critical illness, but in some cases as few as 25% are fed appropriately. The aim was to retrospectively review the administration of nutrition to critically ill children. METHODS: The notes of 95 children over the age of 1 year who were in PICU>or=3 days were reviewed and information related to the delivery of nutrition was obtained. RESULTS: Fifty-nine per cent were fed within 24h of admission. Enteral nutrition was administered 54% of the time, 10% required parenteral nutrition and 9.5% received no nutritional support. Children only received a median 58.8 (range 0-277)% of their energy requirements, which could not be optimised until the 10th intensive care day. Energy intake was greater when supplemented with parenteral nutrition. Parenteral nutrition administration was interrupted 3 times while enteral nutrition was stopped 264 times, mainly to allow other clinical procedures to take place. For 75% of the study time, children had abnormal bowel patterns. Seventy-nine per cent were constipated for 3-21 days and 43% had diarrhoea of unknown aetiology. CONCLUSION: This was a retrospective study to describe the efficiency of nutritional support in critically ill children. We have shown that it is possible to administer enteral nutrition safely. However, the difference between desirable intake and actual intake achieved suggests that a more pro-active approach should be adopted.

Basiliximab (Simulect) for the treatment of steroid-resistant rejection in pediatric liver transpland recipients: a preliminary experience.

BACKGROUND: The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients. METHODS: This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil. RESULTS: The median time from transplant to SRR was 30 days (range, 8 days-23 months). Five children received two doses of basiliximab (10 mg, 3-7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5-32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease. CONCLUSION: Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.