Individualized immunosuppression after renal transplantation in childhood

Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.

Relationship between quality certification and financial and non-financial performance of organizations

At present, many countries have either embraced ISO9001 or used it as the basis of their national quality certification systems. However, few studies have been conducted to examine the benefits companies’ gain from achieving and implementing ISO9001 standards (Chikuku et al. 2012; Psomas et al. 2013; Sampaio et al. 2011a,b). Analysis has brought much more confused and uneven results across the countries. Turning to the experience of Malaysia, this country has witnessed a spectacular growth at an average rate of 9.89% per annum of ISO certificates issued to companies operating within its borders (ISO Survey 2012). While many companies rush to be ISO 9001 certified whether this brings about better benefits (both the financial and the non-financial) is still an open question. In this study, the research problems were first formulated from the literature and then a questionnaire survey was conducted to test the hypotheses. A survey was administered to chief executives officers and managers across manufacturing and service organizations in Malaysia. Multivariate analysis and SPSS macro developed by Preacher and Hayes were used as statistical techniques to the financial and non-financial benefits of ISO9001 certification. The survey instrument was a two-page questionnaire comprising three sections. The first section of the questionnaire covered the company’s profile. The second section consisted of 25 items on internal benefits and third section consisted of 7 items on external benefits measured on 1–5 Likert scale to assess the benefits of ISO9001 certification. Total 201 valid responses were received. Results of the study indicate that there was no significant direct relationship between ISO9001 certification and organizational financial performance, while strong statistical evidence was found to support the direct relationship between ISO9001 certification and non-financial performance. The findings of the study discovered that financial performance is actually directly related to two non-financial measures, namely quality performance and local and international business performance, which are directly and significantly influenced by ISO9001 certification. Therefore non-financial performance measures are involved in the mediational process. The findings will assist practitioners in taking right courses of action that make the implementation of this standard more effective. For example, the study findings study suggests that companies should put emphasize on nonfinancial factors to improve their financial performance.

Relationship between annual rainfall and tree mortality in a tropical dry forest: Results of a 19-year study at Mudumalai, southern India

Variability in rainfall is known to be a major influence on the dynamics of tropical forests, especially rates and patterns of tree mortality. In tropical dry forests a number of contributing factors to tree mortality, including dry season fire and herbivory by large herbivorous mammals, could be related to rainfall patterns, while loss of water potential in trees during the dry season or a wet season drought could also result in enhanced rates of death. While tree mortality as influenced by severe drought has been examined in tropical wet forests there is insufficient understanding of this process in tropical dry forests. We examined these causal factors in relation to inter-annual differences in rainfall in causing tree mortality within a 50-ha Forest Dynamics Plot located in the tropical dry deciduous forests of Mudumalai, southern India, that has been monitored annually since 1988. Over a 19-year period (1988-2007) mean annual mortality rate of all stems >1 cm dbh was 6.9 +/- 4.6% (range = 1.5-17.5%); mortality rates broadly declined from the smaller to the larger size classes with the rates in stems >30 cm dbh being among the lowest recorded in tropical forest globally. Fire was the main agent of mortality in stems 1-5 cm dbh, elephant-herbivory in stems 5-10 cm dbh, and other natural causes in stems > 10 cm dbh. Elephant-related mortality did not show any relationship to rainfall. On the other hand, fire-related mortality was significantly negatively correlated to quantity of rainfall during the preceding year. Mortality due to other causes in the larger stem sizes was significantly negatively correlated to rainfall with a 2-3-year lag, suggesting that water deficit from mild or prolonged drought enhanced the risk of death but only with a time lag that was greater than similar lags in tree mortality observed in other forest types. In this respect, tropical dry forests growing in regions of high rainfall variability may have evolved greater resistance to rainfall deficit as compared to tropical moist or temperate forests but are still vulnerable to drought-related mortality.

Essential nursing care of the critically ill patient

This chapter is about essential nursing care. Because it is often referred to as basic nursing, nurses may not always perceive it as deserving of priority. Yet, how well patients are cared for has a direct effect on their sense of wellbeing and their recovery. ‘Interventional patient hygiene’ is a systematic, evidence-based approach to nursing actions designed to improve patient outcomes using a framework of hygiene, catheter care, skin care, mobility and oral care.1 This chapter focuses on the physical care, infection control, preventative therapies and transport of critically ill patients. The first two areas are closely linked: poor-quality physical care increases the risk of infection. The final areas are essential features of critical care nursing.

Late results after paediatric cardiac surgery

Background: Congenital heart defects include a wide range of inborn malformations. Depending on the defect, the life expectancy of a newborn with cardiac anomaly varies from a few days to a normal life span. In most instances surgery, is the only treatment available. The late results of surgery have not been comprehensively investigated. Aims: Mortality, morbidity and the life situation of all Finnish patients who had been operated on for congenital heart defect during childhood were investigated. Methods: Patient and surgical data were gathered from all hospitals that had performed heart surgeries on children. Late mortality and survival data were obtained from the population registry, and the causes of deaths from Statistics Finland. Morbidity of patients operated on during 1953-1989 was assessed by the usage of medicines. The pharmacotherapy data of patients and controls were obtained from the Social Insurance Institute. The life situation of patients was surveyed by mailed questionnaire. Survival, causes of deaths and life situation of patients were compared with those of the general population. Results: A total of 7240 cardiac operations were performed on 6461 children during the first 37 years of cardiac surgery (1953-1989). The number of procedures constantly rose during this period, and the increase continued in later years. The patient material varied over time, as more defects became surgically treatable. During 1953-1989 the operative mortality (death within 30 days of surgery) was 6.9%. In the 1990s a slight rise occurred in early mortality, as increasingly complicated patients were surgically treated. During 2000-2003 practically no defects were beyond the operative range. Thus, the operative mortality of 4.4% was excellent, decreasing even further to 2.0% in 2004-2007. The overall 45-year survival of patients operated on in 1953-1989 was 78%, and the corresponding figure for the general population was 93%. Survival depended on the defect, being worst among patients with univentricular heart. Late survival was also better during the 1990s and at the beginning of the 21st century. Of the 6028 early survivors, 592 died late (>30 days) after surgery. A total of 397 deaths (67%) were related and 185 (31%) unrelated to congenital heart defect. The cause of death was unknown in 10 cases. Of those 5774 patients who survived their first operation and had complete follow-up, 16% were operated on several times. Seventeen percent of patients used medicines for cardiac symptoms (heart failure, arrhythmia, hypertension and coronary disease). Patients risk of using cardiac medicines was 2.16 (Cl 1.97-2.37) times higher than that of controls. Patients also had more genetic syndromes and mental retardation and more often used medicines for asthma and epilepsy. Adult patients who had been operated on as children had coped surprisingly well with their defects. Their level of education was similar and their employment level even higher than expected, and they were living in a steady relationship as often as the general population. Conclusions: Cardiac surgery developed rapidly, and nowadays practically all defects can be treated. The overall survival of all operated patients was 78%, 16% less than that of the general population. However, it was significantly better than the anticipated natural survival. However, many patients had health problems; 16% needed reoperations and 17% cardiac medicines to maintain their condition. Most of the patients assessed their general health as good and lived a normal life.

The impact of communication technologies on life and relationship satisfaction

Previous studies have shown a relationship between the use of communications technology and well-being, particularly mediated through its effect on personal relationships. However, there is some debate over whether this effect is positive or negative. The present study explored this issue further, examining whether the effect varies depending on the type of communications technology, and the nature of the personal relationship. An online survey was conducted with 3,421 participants in three countries (Australia, UK and US). It examined the use of ten communication methods, overall satisfaction with life and satisfaction with four different kinds of relationships (close and extended family, and close and distant friends). Results indicate that richer communication methods, which include non-verbal cues, were positively associated with both overall satisfaction with life and satisfaction with relationships. These methods included face-to-face communication, and phone and video calls. Conversely, more restricted methods, such as text messaging and instant messaging, were negatively associated with both variables. Social networking was negatively associated with overall satisfaction, but not with satisfaction with relationships. The strength of the association between a communications method and satisfaction with a relationship varied depending on the type of relationship, but whether it was positive or negative did not change.

Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a valid screening tool in chemotherapy outpatients

Purpose In the oncology population where malnutrition prevalence is high, more descriptive screening tools can provide further information to assist triaging and capture acute change. The Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a component of a nutritional assessment tool which could be used for descriptive nutrition screening. The purpose of this study was to conduct a secondary analysis of nutrition screening and assessment data to identify the most relevant information contributing to the PG-SGA SF to identify malnutrition risk with high sensitivity and specificity. Methods This was an observational, cross-sectional study of 300 consecutive adult patients receiving ambulatory anti-cancer treatment at an Australian tertiary hospital. Anthropometric and patient descriptive data were collected. The scored PG-SGA generated a score for nutritional risk (PG-SGA SF) and a global rating for nutrition status. Receiver operating characteristic curves (ROC) were generated to determine optimal cut-off scores for combinations of the PG-SGA SF boxes with the greatest sensitivity and specificity for predicting malnutrition according to scored PG-SGA global rating. Results The additive scores of boxes 1–3 had the highest sensitivity (90.2 %) while maintaining satisfactory specificity (67.5 %) and demonstrating high diagnostic value (AUC = 0.85, 95 % CI = 0.81–0.89). The inclusion of box 4 (PG-SGA SF) did not add further value as a screening tool (AUC = 0.85, 95 % CI = 0.80–0.89; sensitivity 80.4 %; specificity 72.3 %). Conclusions The validity of the PG-SGA SF in chemotherapy outpatients was confirmed. The present study however demonstrated that the functional capacity question (box 4) does not improve the overall discriminatory value of the PG-SGA SF.

Patient exposure monitoring and radiation qualities in two-dimensional digital x-ray imaging

The methods for estimating patient exposure in x-ray imaging are based on the measurement of radiation incident on the patient. In digital imaging, the useful dose range of the detector is large and excessive doses may remain undetected. Therefore, real-time monitoring of radiation exposure is important. According to international recommendations, the measurement uncertainty should be lower than 7% (confidence level 95%). The kerma-area product (KAP) is a measurement quantity used for monitoring patient exposure to radiation. A field KAP meter is typically attached to an x-ray device, and it is important to recognize the effect of this measurement geometry on the response of the meter. In a tandem calibration method, introduced in this study, a field KAP meter is used in its clinical position and calibration is performed with a reference KAP meter. This method provides a practical way to calibrate field KAP meters. However, the reference KAP meters require comprehensive calibration. In the calibration laboratory it is recommended to use standard radiation qualities. These qualities do not entirely correspond to the large range of clinical radiation qualities. In this work, the energy dependence of the response of different KAP meter types was examined. According to our findings, the recommended accuracy in KAP measurements is difficult to achieve with conventional KAP meters because of their strong energy dependence. The energy dependence of the response of a novel large KAP meter was found out to be much lower than with a conventional KAP meter. The accuracy of the tandem method can be improved by using this meter type as a reference meter. A KAP meter cannot be used to determine the radiation exposure of patients in mammography, in which part of the radiation beam is always aimed directly at the detector without attenuation produced by the tissue. This work assessed whether pixel values from this detector area could be used to monitor the radiation beam incident on the patient. The results were congruent with the tube output calculation, which is the method generally used for this purpose. The recommended accuracy can be achieved with the studied method. New optimization of radiation qualities and dose level is needed when other detector types are introduced. In this work, the optimal selections were examined with one direct digital detector type. For this device, the use of radiation qualities with higher energies was recommended and appropriate image quality was achieved by increasing the low dose level of the system.

Tumour islet Foxp3+ T-cell infiltration predicts poor outcome in nonsmall cell lung cancer

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis. Tumour- and stroma-infiltrating CD3+, CD8+ and forkhead box P3 (Foxp3)+ T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined. There was a positive association between overall survival and increased CD8+ TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3+ TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8+ islet (HR 0.48, p<0.001) and Foxp3+ stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3+ and CD8+ stromal counts and high Foxp3+ islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8+ TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3+ TI/S ratio was associated with worse survival (HR 3.91, p<0.001). Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.

Morbid obesity in total hip arthroplasty: Redefining outcomes for operative time, length of stay, and readmission

Background The incidence of obesity amongst patients presenting for elective Total Hip Arthroplasty (THA) has increased in the last decade and the relationship between obesity and the need for joint replacement has been demonstrated. This study evaluates the effects of morbid obesity on outcomes following primary THA by comparing short-term outcomes in THA between a morbidly obese (BMI ≥40) and a normal weight (BMI 18.5 - <25) cohort at our institution between January 2003 and December 2010. Methods Thirty-nine patients included in the morbidly obese group were compared with 186 in the normal weight group. Operative time, length of stay, complications, readmission and length of readmission were compared. Results Operative time was increased in the morbidly obese group at 122 minutes compared with 100 minutes (p=0.002). Post-operatively there was an increased 30-day readmission rate related to surgery of 12.8% associated with BMI ≥40 compared with 2.7% (p= 0.005) as well as a 5.1 fold increase in surgery related readmitted bed days - 0.32 bed days per patient for normal weight compared with 1.64 per patient for the morbidly obese (p=0.026). Conclusion Morbidly obese patients present a technical challenge and likely this and the resultant complications are underestimated. More work needs to be performed in order to enable suitable allocation of resources.

Does gender moderate the relationship between polydrug use and sexual risk-taking among Australian secondary school students under 16 years of age?

Introduction and Aims This study examines the association of alcohol and polydrug use with risky sexual behaviour in adolescents under 16 years of age and if this association differs by gender. Design and Methods The sample consisted of 5412 secondary school students under 16 years of age from Victoria, Australia. Participants completed an anonymous and confidential survey during class time. The key measures were having had sex before legal age of consent (16 years), unprotected sex before 16 (no condom) and latent-class derived alcohol and polydrug use variables based on alcohol, tobacco, cannabis, inhalants and other illegal drug use in the past month. Results There were 7.52% and 2.55% of adolescents who reported having sex and having unprotected sex before 16 years of age, respectively. After adjusting for antisocial behaviours, peers' drug use and family and school risk factors, girls were less likely to have unprotected sex (odds ratio = 0.31, P = 0.003). However, the interaction of being female and polydrug use (odds ratio = 4.52, P = 0.004) was significant, indicating that girls who engaged in polydrug use were at higher risk of having unprotected sex. For boys, the effect of polydrug use was non-significant (odds ratio = 1.44, P = 0.310). Discussion and Conclusions For girls, polydrug use was significantly associated with unprotected sex after adjusting for a range of risk factors, and this relationship was non-significant for boys. Future prevention programs for adolescent risky sexual behaviour and polydrug use might benefit from a tailored approach to gender differences.

Metabolomic and proteomic analysis of breast cancer patient samples suggests that glutamate and 12-HETE in combination with CA15-3 may be useful biomarkers reflecting tumour burden

Evaluation of protein and metabolite expression patterns in blood using mass spectrometry and high-throughput antibody-based screening platforms has potential for the discovery of new biomarkers for managing breast cancer patient treatment. Previously identified blood-based breast cancer biomarkers, including cancer antigen 15.3 (CA15-3) are useful in combination with imaging (computed tomography scans, magnetic resonance imaging, X-rays) and physical examination for monitoring tumour burden in advanced breast cancer patients. However, these biomarkers suffer from insufficient levels of accuracy and with new therapies available for the treatment of breast cancer, there is an urgent need for reliable, non-invasive biomarkers that measure tumour burden with high sensitivity and specificity so as to provide early warning of the need to switch to an alternative treatment. The aim of this study was to identify a biomarker signature of tumour burden using cancer and non-cancer (healthy controls/non-malignant breast disease) patient samples. Results demonstrate that combinations of three candidate biomarkers from Glutamate, 12-Hydroxyeicosatetraenoic acid, Beta-hydroxybutyrate, Factor V and Matrix metalloproteinase-1 with CA15-3, an established biomarker for breast cancer, were found to mirror tumour burden, with AUC values ranging from 0.71 to 0.98 when comparing non-malignant breast disease to the different stages of breast cancer. Further validation of these biomarker panels could potentially facilitate the management of breast cancer patients, especially to assess changes in tumour burden in combination with imaging and physical examination.

The relationship between class participation and law students' learning, engagement and stress: Do demographics matter?

Student participation in the classroom has long been regarded as an important means of increasing student engagement and enhancing learning outcomes by promoting active learning. However, the approach to class participation common in U.S. law schools, commonly referred to as the Socratic method, has been criticised for its negative impacts on student wellbeing. A multiplicity of American studies have identified that participating in law class discussions can be alienating, intimidating and stressful for some law students, and may be especially so for women, and students from minority backgrounds. Using data from the Law School Student Assessment Survey (LSSAS), conducted at UNSW Law School in 2012, this Chapter provides preliminary insights into whether assessable class participation (ACP) at an Australian law school is similarly alienating and stressful for students, including the groups identified in the American literature. In addition, we compare the responses of undergraduate Bachelor of Laws (LLB) and graduate Juris Doctor (JD) students. The LSSAS findings indicate that most respondents recognise the potential learning and social benefits associated with class participation in legal education, but remain divided over their willingness to participate. Further, in alignment with general trends identified in American studies, LLB students, women, international students, and non-native English speakers perceive they contribute less frequently to class discussions than JD students, males, domestic students, and native English speakers, respectively. Importantly, the LSSAS indicates students are more likely to be anxious about contributing to class discussions if they are LLB students (compared to their JD counterparts), and if English is not their first language (compared to native English speakers). There were no significant differences in students’ self-reported anxiety levels based on gender, which diverges from the findings of American research.