Incidence and Predictors of Cancer Following Kidney Transplantation in Childhood.

Cancer risk is increased substantially in adult kidney transplant recipients, but the long-term risk of cancer in childhood recipients is unclear. Using the Australian and New Zealand Dialysis and Transplant Registry, the authors compared overall and site-specific incidences of cancer after transplantation in childhood recipients with population-based data by using standardized incidence ratios (SIRs). Among 1734 childhood recipients (median age 14 years, 57% male, 85% white), 289 (16.7%) developed cancer (196 nonmelanoma skin cancers, 143 nonskin cancers) over a median follow-up of 13.4 years. The 25-year cumulative incidences of any cancer were 27% (95% confidence intervals 24-30%), 20% (17-23%) for nonmelanoma skin cancer, and 14% (12-17%) for nonskin cancer (including melanoma). The SIR for nonskin cancer was 8.23 (95% CI 6.92-9.73), with the highest risk for posttransplant lymphoproliferative disease (SIR 45.80, 95% CI 32.71-62.44) and cervical cancer (29.4, 95% CI 17.5-46.5). Increasing age at transplantation (adjusted hazard ratio [aHR] per year 1.10, 95% CI 1.06-1.14), white race (aHR 3.36, 95% CI 1.61-6.79), and having a functioning transplant (aHR 2.27, 95% CI 1.47-3.71) were risk factors for cancer. Cancer risk, particularly for virus-related cancers, is increased substantially after kidney transplantation during childhood.

Obesity and hypertension in Australian young people: results from the Australian Health Survey 2011-2012.

BACKGROUND: Few studies have focused on the prevalence of obesity and hypertension among young people (ages 15-24). AIM: To characterise the prevalence of obesity and systolic hypertension in young people aged 15-24 years across Australia. METHODS: Using data from the 2011-2012 Australian Health Survey, a national cross-sectional population-based survey, we included 2163 young people aged 15-24 years. Risk factors were estimated using multinomial logistic regression. RESULTS: The prevalence of obesity increased from 8% to 15% through the ages of 15-24 among males, but the prevalence of overweight and obesity were both 14% for females across all age groups. Low levels of physical activity were a strong risk factor for obesity for both males (odds ratio (OR) 5.95, 95% confidence intervals (CI)1.83-19.36) and females (OR 3.20 95% CI 0.69-14.87). Low socioeconomic status was associated with obesity among females only (first quintile OR 4.65, 95% CI 1.97-10.99). Although the prevalence of hypertension was low (4% males, 3% females), the prevalence of high normal blood pressure was substantial, especially among males (28% males, 14% females). CONCLUSIONS: Overweight, obesity and high normal blood pressure were highly prevalent among Australian young people. Low levels of physical activity were identified as a risk factor for obesity for both male and females. Programmes targeting physical activity participation may need to be tailored differently for males and females, with a focus on females during early adolescence but early adult life for males.

Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection.

BACKGROUND: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with chronic kidney disease (CKD), with no evidence of an excess risk of cancer or death from any non-vascular cause. However, non-randomized data have suggested that statin therapy may have effects (both adverse and beneficial) on particular non-vascular conditions that do not cause death. METHODS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) daily versus matching placebo. Participants were followed up at least 6 monthly and all post-randomization serious adverse events (SAEs) were recorded. This supplementary analysis reports the effects of treatment on non-vascular SAEs, overall, by system of disease, by baseline characteristics, and by duration of follow-up. RESULTS: During a median of 4.9 years follow-up, similar numbers of participants in the two groups experienced at least one non-vascular SAE (3551 [76.4%] simvastatin/ezetimibe vs 3537 [76.6%] placebo; risk ratio [RR] 0.99, 95% confidence interval [CI] 0.95-1.04). There was no good evidence of any significant effect of simvastatin/ezetimibe on SAEs attributed to any particular nonvascular disease system (of 43 comparisons, only 3 yielded an uncorrected p value < 0.05, of which the smallest was p = 0.02). The relative risk of any nonvascular SAE did not vary significantly among particular prognostic subgroups or by duration of follow-up. CONCLUSIONS: In the SHARP trial, allocation to simvastatin/ezetimibe combination therapy was not associated with any significant non-vascular hazard. TRIALS REGISTRATION: SHARP was retrospectively registered after the first participant was enrolled in 2003 at ISRCTN (ISRCTN54137607 on 31 January 2005: http://www.isrctn.com/ISRCTN54137607) and ClinicalTrials.gov (NCT00125593 on 29 July 2005: https://clinicaltrials.gov/ct2/show/NCT00125593).

Vision is superior to touch in shape perception even with equivalent peripheral input.

Results from previous studies suggest that two-dimensional spatial patterns are processed similarly in vision and touch when the patterns are equated for effective size or when visual stimuli are blurred to mimic the spatial filtering of the skin. In the present study, we measured subjects' ability to perceive the shape of familiar and unfamiliar visual and tactile patterns to compare form processing in the two modalities. As had been previously done, the two-dimensional tactile and visual patterns were adjusted in size to stimulate an equivalent number of receptors in the two modalities. We also distorted the visual patterns, using a filter that accurately mimics the spatial filtering effected by the skin to further equate the peripheral images in the two modalities. We found that vision consistently outperformed touch regardless of the precise perceptual task and of how familiar the patterns were. Based on an examination of both the earlier and present data, we conclude that visual processing of both familiar and unfamiliar two-dimensional patterns is superior to its tactile counterpart except under very restricted conditions.

The differential effect of socio-economic status, birth weight and gender on body mass index in Australian Aboriginal Children.

BACKGROUND: Adult Aboriginal Australians have 1.5-fold higher risk of obesity, but the trajectory of body mass index (BMI) through childhood and adolescence and the contribution of socio-economic factors remain unclear. Our objective was to determine the changes in BMI in Australian Aboriginal children relative to non-Aboriginal children as they move through adolescence into young adulthood, and to identify risk factors for higher BMI. METHODS: A prospective cohort study of Aboriginal and non-Aboriginal school children commenced in 2002 across 15 different screening areas across urban, regional and remote New South Wales, Australia. Socio-economic status was recorded at study enrolment and participants' BMI was measured every 2 years. We fitted a series of mixed linear regression models adjusting for age, birth weight and socio-economic status for boys and girls. RESULTS: In all, 3418 (1949 Aboriginal) participants were screened over a total of 11 387 participant years of follow-up. The prevalence of obesity was higher among Aboriginal children from mean age 11 years at baseline (11.6 vs 7.6%) to 16 years at 8 years follow-up (18.6 vs 12.3%). The mean BMI increased with age and was significantly higher among Aboriginal girls compared with non-Aboriginal girls (P<0.01). Girls born of low birth weight had a lower BMI than girls born of normal birth weight (P<0.001). Socio-economic status and low birth weight had a differential effect on BMI for Aboriginal boys compared with non-Aboriginal boys (P for interaction=0.01). Aboriginal boys of highest socio-economic status, unlike those of lower socio-economic status, had a higher BMI compared with non-Aboriginal boys. Non-Aboriginal boys of low birth weight were heavier than Aboriginal boys. CONCLUSIONS: Socio-economic status and birth weight have differential effects on BMI among Aboriginal boys, and Aboriginal girls had a higher mean BMI than non-Aboriginal girls through childhood and adolescence. Intervention programs need to recognise the differential risk for obesity for Aboriginal and non-Aboriginal boys and girls to maximise their impact.

Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise.

Critical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued. Peripheral fatigue appears to be constant across O2 delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise. We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development and W '. Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O2 delivery conditions for small muscle mass exercise. W ' appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe-intensity exercise. The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ') have not been investigated. Six men (age: 25 ± 4 years, body mass: 82 ± 10 kg, height: 179 ± 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post-exercise blood flow occlusion (Con + Occ), and Occ with 5 min post-exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements and W ' were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 ± 5.1% vs. 22.7 ± 6.0%) and central (42.6 ± 3.9% vs. 4.9 ± 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 ± 4.2% vs. 69.0 ± 6.2%) and central (65.5 ± 14.6% vs. 18.6 ± 4.1%) fatigue occurred for Occ + Occ than for Con + Occ. W ' was significantly related to the magnitude of global (r = 0.91) and peripheral (r = 0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post-exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest that W ' may be determined by the magnitude of fatigue accrued during exercise.

Family perspectives on deceased organ donation: thematic synthesis of qualitative studies.

A major barrier to meeting the needs for organ transplantation is family refusal to give consent. This study aimed to describe the perspectives of donor families on deceased donation. We conducted a systematic review and thematic synthesis of qualitative studies. Electronic databases were searched to September 2012. From 34 studies involving 1035 participants, we identified seven themes: comprehension of sudden death (accepting finality of life, ambiguity of brain death); finding meaning in donation (altruism, letting the donor live on, fulfilling a moral obligation, easing grief); fear and suspicion (financial motivations, unwanted responsibility for death, medical mistrust); decisional conflict (pressured decision making, family consensus, internal dissonance, religious beliefs); vulnerability (valuing sensitivity and rapport, overwhelmed and disempowered); respecting the donor (honoring the donor's wishes, preserving body integrity) and needing closure (acknowledgment, regret over refusal, unresolved decisional uncertainty, feeling dismissed). Bereaved families report uncertainty about death and the donation process, emotional and cognitive burden and decisional dissonance, but can derive emotional benefit from the "lifesaving" act of donation. Strategies are needed to help families understand death in the context of donation, address anxieties about organ procurement, foster trust in the donation process, resolve insecurities in decision making and gain a sense of closure.

Living kidney donor assessment: challenges, uncertainties and controversies among transplant nephrologists and surgeons.

The assessment of living kidney donors presents unique ethical challenges and complex psychosocial implications. This study aimed to ascertain the perspectives of transplant nephrologists and surgeons on living kidney donor assessment. Semi-structured, face-to-face interviews were conducted with 110 transplant nephrologists and surgeons from 43 transplant units in 12 countries from Europe, Australasia and North America. The challenge of defining acceptable risk to the donor was central to five themes identified: burden of responsibility (personal accountability, policing morality, democratic decision making, meeting legal obligations, optimizing outcomes and innovation, relinquished control); medical protectiveness (prognostic uncertainty, skepticism of donor risk perception, avoidance of undue coercion, concerns for dubious motivations and coercion, safeguard donor well-being, ethical information disclosure); respecting donor autonomy (facilitate informed-decision making, concede to donor risk acceptance, benefit of the doubt, donor mandate to maintain health, acceptable altruism); driving ideologies (preserving equity, championing living donation, cognizance of anti-paternalism) and contextual pressures (evolving donor demographic, resource limitations). Living kidney donor assessment involves complex interactions between safeguarding the donors' welfare and respecting their autonomy. In our opinion, authoritative and well-described transplant unit, hospital and public policy positions that make explicit the considerations that are often implicit may reduce the uncertainty within which living donors are assessed today.

Qualitative research in organ transplantation: recent contributions to clinical care and policy.

Qualitative studies remain relatively uncommon in the transplant literature but are an important approach contributing unique strengths in some areas of research. With the increased focus on patient-centered research and decision-making, it is timely to review qualitative research in the context of transplantation. While quantitative research addresses questions about the effectiveness of interventions or associations between risk factors and outcomes, qualitative research has an equal and complementary role in providing understanding about people's behaviors, attitudes, and values. Qualitative research has provided insights into some of the important but elusive questions in transplantation, including the sources of barriers to organ donation and inequities in access to transplantation, nonadherence to immunosuppressive regimens, and complex psychosocial outcomes. This review highlights recent contributions of qualitative research to transplantation practice and policy, and identifies key principles to guide qualitative research appraisal.

Donor cancer transmission in kidney transplantation: a systematic review.

Transplantation of any biological material from a donor to a host will carry some inherent risk of disease transmission. Our aims were to summarize the totality of the published evidence about donor cancer transmission among kidney transplant recipients and to determine the cancer-specific survival of these patients. We systematically reviewed all case reports, case series and registry studies that described the outcomes of kidney transplant recipients with donor cancer transmission published to December 2012. A total of 69 studies with 104 donor-transmitted cancer cases were identified. The most common transmitted cancer types were renal cancer (n = 20, 19%), followed by melanoma (n = 18, 17%), lymphoma (n = 15, 14%) and lung cancer (n = 9, 9%). Patients with melanoma and lung cancers had the worst prognosis, with less than 50% of recipients surviving after 24 months from transplantation. Recipients with transmitted renal cancers had the best outcomes, with over 70% of recipients surviving for at least 24 months after transplantation. Overall, the risk of donor transmission of cancer appears low, but there is a high likelihood of reporting bias. Our findings support the current recommendations for rejecting organs from donors with a history of melanoma and lung cancer, but suggest that the use of donor kidneys with a history of small, incidental renal cell cancer may be reasonable.

Consistency and completeness of reported outcomes in randomized trials of primary immunosuppression in kidney transplantation.

Inconsistent and incomplete outcome reporting may make estimates of treatment effects from published randomized trials unreliable. We aimed to determine outcome reporting practices and source of differences in reporting quality among randomized trials of primary immunosuppression in kidney transplantation. We searched the Cochrane Renal Group's Specialized Register, 2000-2012, specified four core outcomes we expected trials to report, and recorded if and how completely each was reported. We identified 179 trials. One hundred sixty-eight (94%) reported death, 145 (81%) as number dead and 119 (66%) as time to death. One hundred sixty-five (92%) reported graft loss, 158 (88%) as number with graft loss and 127 (71%) as time to graft loss. One hundred twenty-one (68%) reported creatinine and 114 (64%) estimated GFR (eGFR). One hundred forty-one (79%) provided complete reports of number dead, 95 (53%) censored and 99 (55%) uncensored number with graft loss. Seventy-three (41%) provided complete reports of time to death, 67 (37%) censored and 31 (17%) uncensored time to graft loss. Complete reporting of graft function was infrequent: 62 (35%) eGFR and 50 (28%) creatinine. All four outcomes were reported in any form in 61 (34%) and completely in 28 (16%) trials. No single trial or journal characteristic was consistently associated with complete outcome reporting. Outcome reporting in kidney transplant trials is inconsistent and frequently incomplete, and published estimates of treatment effects may be unreliable.

Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney-pancreas transplant recipients.

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney-pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add-on test to qualitative polyoma NAT for the diagnosis of BK virus-associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10(3) serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1-99.8) and specificity 79.1% (95%: CI 67.4-88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8-57.7%) and 98.6% (95% CI: 98.3-99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85-0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add-on test to qualitative polyomavirus NAT for kidney and kidney-pancreas transplant recipients at risk of BKVAN.

A comparison of doctors', parents' and children's reports of health states and health-related quality of life in children with chronic conditions.

BACKGROUND: Health-related quality of life is an important outcome. Self-report is the gold standard, but in the paediatric setting we often rely on proxy reporting. Our understanding of the differences between self- and proxy reports and the factors that influence them is limited. These differences can impact on treatment choices and the patient-doctor relationship. OBJECTIVE: To evaluate differences between children's, parents' and doctors' perceptions of health states and health-related quality of life in children with chronic illness and explore factors which explain these differences. METHODS: Consecutive families attending eligible clinics at a tertiary paediatric centre were invited to complete the Health Utilities Index (HUI) 23 questionnaire. Percentage agreement and kappas were calculated as a measure of the agreement between pairs. Chi-squared tests or Fisher's exact test, if appropriate, were performed to determine if there was an association between level of agreement and participant variables. RESULTS: Data were collected for 130 parent-doctor pairs, 59 child-parent pairs and 59 child-doctor pairs. Overall health-related quality of life scores did not differ between responders, but there was poorer agreement for subjective domains. Doctor-child agreement was lower than parent-child agreement. Children with a diagnosis of cerebral palsy or chronic neurological condition were more likely to have lower inter-rater agreement for both subjective and objective domains. On the HUI2, agreement was lower for parent-child pairs when the father was the respondent. For child-doctor pairs, an increased frequency of patient-doctor visits and doctors' seniority were predictors of poorer agreement on the HUI3 and HUI2 respectively. CONCLUSIONS: We identified factors associated with level of agreement for self- and proxy reporting on the HUI23. Parent-child agreement was higher than doctor-child agreement. Patients with significant pain or emotional distress and patients with a diagnosis of severe cerebral palsy or chronic neurological conditions were more susceptible to under-reporting of subjective aspects of well-being by doctors and parents and may benefit from formal assessment of health-related quality of life in the clinical setting.

Parental perspectives on caring for a child with chronic kidney disease: an in-depth interview study.

BACKGROUND: Children diagnosed with chronic kidney disease (CKD) depend on their parents for complex, continuous and intensive support. The study aimed to explore the experiences of parents who have children with CKD. METHODS: Parents of 20 children with CKD, recruited from two paediatric hospitals in Australia, participated in an in-depth interview, qualitative study. RESULTS: Four major themes were identified: (1) absorbing the clinical environment: parents struggled to accept the diagnosis and permanence of CKD, felt traumatized watching their child undergo invasive clinical procedures, battled to meet appointments, negotiated with staff for their child's needs and felt disempowered; (2) medicalizing parenting: parents became caregivers, a role which was stressful, exhausting and overwhelming. Dialysis was unrelenting and consumed the time, thoughts and energy of parents who felt at fault if their child developed infections and other complications. Parents struggled with their child's psychological problems and episodic aggressive behaviour; (3) disrupting family norms: CKD caused spousal tension, sibling neglect and influenced family planning; (4) coping strategies and support structures: Parents depended on support from their health care providers and valued meeting and learning from other parents of CKD children. Parents also expressed information needs and suggested methods of communicating information. CONCLUSIONS: Despite facing profound and pervasive difficulties, parents strived to fulfil their dual parental and health care provider responsibilities. Parents appear to need better support structures to help them cope with the difficulties encountered during all stages of their child's illness.

Vibrotactile pattern perception: extraordinary observers.

Two sighted peopled showed a remarkable ability to perceive vibrotactile patterns generated by the Optacon, a reading aid for the blind. These individuals were able to read at very high rates, 70 to 100 words per minute, through their fingertips. Additional testing showed them to be much better than other people at discriminating and recognizing vibrotactile patterns.

C-Glucuronidation of the acetylenic moiety of ethchlorvynol in the rabbit.

An acetylenic C-glucuronide of the sedative-hypnotic drug ethchlorvynol was isolated from rabbit urine as the major metabolite. The C-glucuronide represents a novel metabolic pathway for acetylenes and is a rare example of the formation of a carbon-glucuronide bond in mammalian systems.

Nicotine in breast fluid of nonlactating women.

Using a combination of gas chromatography, mass spectrometry, and selected ion recording techniques, we have identified nicotine and its major metabolite, continine, in the breast fluid of nonlactating women smokers. As little as 25 picograms could be measured by using the deuterated variants, [5',5'-2H]nicotine and [3,3-2H]cotinine, both as internal standards and as carriers in an inverse isotope dilution method.

Rational design of peptide-based HIV proteinase inhibitors.

A series of peptide derivatives based on the transition-state mimetic concept has been designed that inhibit the proteinase from the human immunodeficiency virus (HIV). The more active compounds inhibit both HIV-1 and HIV-2 proteinases in the nanomolar range with little effect at 10 micromolar against the structurally related human aspartic proteinases. Proteolytic cleavage of the HIV-1 gag polyprotein (p55) to the viral structural protein p24 was inhibited in chronically infected CEM cells. Antiviral activity was observed in the nanomolar range (with one compound active below 10 nanomolar) in three different cell systems, as assessed by p24 antigen and syncytium formation. Cytotoxicity was not detected at 10 and 5 micromolar in C8166 and JM cells, respectively, indicating a high therapeutic index for this new class of HIV proteinase inhibitors.

Managing cancer risk and decision making after kidney transplantation.

Kidney transplant recipients are at higher risk of cancer at most sites, and cancer after transplantation causes considerable morbidity and mortality. To optimize long-term patient outcomes, clinicians balance the prospect of graft failure and dialysis, with competing risks of diabetes, cardiovascular and cerebrovascular disease and the risk of malignancy. In this paper we critically examine the assumptions underpinning primary prevention, immunization, chemoprevention and screening programs, and highlight considerations when applying evidence to the kidney transplant population, and suggest a clinical research agenda that aims to define a rational approach to managing posttransplant cancer risk.

The tactile perception of stimulus orientation.

Studies of the visual system suggest that, at an early stage of form processing, a stimulus is represented as a set of contours and that a critical feature of these local contours is their orientation. Here, we characterize the ability of human observers to identify or discriminate the orientation of bars and edges presented to the distal fingerpad. The experiments were performed using a 400-probe stimulator that allowed us to flexibly deliver stimuli across a wide range of conditions. Orientation thresholds, approximately 20 degrees on average, varied only slightly across modes of stimulus presentation (scanned or indented), stimulus amplitudes, scanning speeds, and different stimulus types (bars or edges). The tactile orientation acuity was found to be poorer than its visual counterpart for stimuli of similar aspect ratio, contrast, and size. This result stands in contrast to the equivalent spatial acuity of the two systems (at the limit set by peripheral innervation density) and to the results of studies of tactile and visual letter recognition, which show that the two modalities yield comparable performance when stimuli are scaled appropriately.