The short- and long-term impact of multi-disciplinary clinics in addition to standard nephrology care on patient outcomes.

BACKGROUND: This two country case control study of incident dialysis patients evaluates the outcomes of patients exposed to formalized multi-disciplinary clinic (MDC) programmes vs standard nephrologist care. METHODS: Patients commencing dialysis in two centres (Vancouver, Canada and Cremona, Italy) were evaluated at and after dialysis start, as a function of MDC exposure vs nephrologist care alone. Only chronic kidney disease patients, with longer than 3 months of exposure to nephrology care, who had not previously received kidney replacement therapy were included. Study outcomes included laboratory parameters and survival. The MDC was similar in both countries and average exposure was 6-8 h per patient-year, as compared to 2-4 h for standard care. All patients had equal access to resources prior to dialysis and with respect to dialysis start, as all had been referred to the same local nephrology practices. RESULTS: During the evaluation period 288 patients commenced dialysis after receiving more than 3 months nephrology care prior to dialysis. There were no major demographic differences between the cohorts. Mean duration of nephrology care prior to dialysis was 42 months, and dialysis was initiated at similar low glomerular filtration rate (GFR), though statistically significantly different (7.0 and 8.4 ml/min/m2, P = 0.001). The MDC patients had higher haemoglobin (102 vs 90 g/l, P<0.0001), albumin (37.0 vs 34.8 g/l, P = 0.002) and calcium levels (2.29 vs 2.16 mmol/l, P<0.0001) at dialysis start. Survival was significantly better in the MDC group demonstrated by Kaplan-Meier analysis (P = 0.01). Cox proportional hazards analysis demonstrated standard nephrology clinic vs MDC attendance was a statistically significant independent predictor of death (hazards ratio = 2.17, 95% confidence interval 1.11-4.28) after adjusting for other variables known to impact outcomes. CONCLUSIONS: This analysis of outcomes in two different countries suggests that despite equal and long exposure to nephrology care prior to dialysis, there appears to be an association of survival advantage for those patients exposed to formalized clinic care in addition to standard nephrologist follow-up. While other known predictors of survival such as adequacy of dialysis and severity of illness measures were not included in the model, those parameters require time on dialysis to be accumulated. Thus, the data do suggest that knowledge of patient status at the time of dialysis start is important. Further research is needed to determine which specific components of care both prior to dialysis and after its commencement are most important with respect to outcomes.     

Biosensor technology for real‐time detection of the cystic fibrosis W1282X mutation in CFTR

In the present paper, biospecific interaction analysis (BIA) was performed using surface plasmon resonance (SPR) and biosensor technologies to detect the Trp1282Ter mutation (W1282X) of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene. We first immobilized on a SA5 sensor chip a single‐stranded biotinylated oligonucleotide containing the sequence involved in this mutation, and the efficiency of hybridization of oligonucleotide probes differing in length was determined. Second, we immobilized on different SA5 sensor chips biotinylated polymerase‐chain reaction (PCR) products from a normal subject as well as from heterozygous and homozygous W1282X samples. The results obtained show that both allele‐specific 10‐ and 12‐mer oligonucleotides are suitable probes to detect W1282X mutations of the cystic fibrosis gene under standard BIA experimental conditions. During the association phase performed at 25°C, discrimination between mismatched and full matched hybrids was readily and reproducibly observed by using the 10‐mer W1282X probes. By contrast, when the 12‐mer DNA probes were employed, discrimination between mismatched and full matched hybrids was observed during the dissociation phase. Taken together, the results presented suggest that BIA is an easy, speedy, and automatable approach to detect point mutations leading to cystic fibrosis. By this procedure, it is possible to perform real‐time monitoring of hybridization between target single stranded PCR products obtained by using as substrates DNA isolated from normal or heterozygous subjects, and homozygous W1282X CF samples and oligonucleotide probes, therefore enabling a one‐step, non‐radioactive protocol to perform diagnosis. Hum Mutat 18:70–81, 2001. © 2001 Wiley‐Liss, Inc.     

Synthesis and screening of 2-(2-(4-substituted piperazine-1-yl)-5-phenylthiazol-4-yl)-3-aryl quinazolinone derivatives as anticancer agents

Synthesis of novel quinazolinone derivatives was performed from the reaction of N-benzoyl substituted piperazine-1-carbothioamide with 2-chloromethyl quinazolinone derivatives and screened for their in vitro cytotoxic activity by MTT assay. The cell lines used were NCI (human lung cancer cell), MCF 7 (Breast cancer cell), and HEK 293 (Normal epidermal kidney cell). Result of screening on cell line showed moderate to good anticancer activity for all the compounds. Compound 3d (IC₅₀ = 1.1 ± 0.03 μM) was found to be the most active compared to standard methotrexate (IC₅₀ = 2.20 ± 0.18 μM) and 5-florouracil (IC₅₀ = 2.30 ± 0.49 μM). Structure activity relationship of synthesized analogs suggested that the presence of NH linker with aryl moiety at the third position of quinazolinone ring was important for potent anticancer activity. Electron donating group on phenyl ring at the third position of quinazolinone ring gave better anticancer activity then unsubstituted phenyl and electron withdrawing group. Activity by substituted piperazine at 2nd position of thiazole linked with quinazolinone scaffold gave better activity in the order of H > CH₃ > CO–C₆H₅. Our findings may impart new direction to medicinal chemists and biochemists for further investigations of quinazolinone-thiazole containing anticancer agents.     

Client satisfaction as a driver of quality improvement in services for older people: A Western Australian case study

This paper aims to describe a practical example of the use of adapted versions of a resident satisfaction questionnaire for quality improvement purposes in a large aged care service organisation. Residential care and home care questionnaires each covered 11 aspects, the ‘housing’ questionnaire nine. Each aspect included Likert scale‐type satisfaction questions. Questionnaires were distributed for completion by residents or by a friend/family member where a resident was unable to self‐complete (e.g. because of dementia). Over the six separate customer satisfaction surveys conducted by the organisation since 1999, the analysis scheme has been refined and forms the basis of a report to the Board highlighting major findings and making recommendations regarding future actions. Most recently, the Board has decided to focus on three main areas, with actions identified for each, namely satisfaction with staff (e.g. enhanced staff training), social activities and involvement (e.g. increased occupational therapy), and opportunities for enhanced feedback.     

Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter,Open-Label,Noninferiority, Randomized Controlled Trial

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1–16 years who had developed SDNS in the previous 6–12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m²; intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m² per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6–13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.     

Modeling Survival of Arteriovenous Accesses for Hemodialysis: Semiparametric versus Parametric Methods

Background and objectives: Comparing outcomes of arteriovenous grafts and fistulas is challenging because the pathophysiology of access dysfunction and failure rate profiles differ by access type. Studying how risks vary over time may be important.Design, setting, participants, & measurements: Longitudinal data from 535 incident hemodialysis patients were used to study the relationship between access type and access survival, without (semiparametric Cox modeling) and with specification of the underlying hazard function (parametric Weibull modeling).Results: The hazard for failure of fistulas and grafts declined over time, becoming proportional only after 3 months from surgery, with a graft versus fistula hazard ratio of 3.2 (95% confidence interval 1.9 to 5.3; Cox and Weibull estimation) and time ratio of 0.11 (i.e., the estimated access survival time was approximately one tenth shorter in grafts; 95% confidence interval 0.04 to 0.28; Weibull estimation only). Considering the entire observation period, grafts had slower hazard decline (P < 0.001) with shorter median survival times than fistulas (8.4 versus 38.3 months; Weibull regression only).Conclusions: Parametric models of arteriovenous access survival may provide relevant information about temporal risk profiles and predicted survival times.Cox regression and its extensions have become standard methods for survival analysis (1). These are semiparametric models because they estimate the covariate coefficients (i.e., risk ratios, or effects on the risk scale) without specification of the instantaneous risk (hazard) distribution. In contrast, parametric models specify also how the hazard varies over time (hazard shape or profile, or underlying hazard), which may provide insights into certain disease processes and guidance on how best to compare outcomes (2). For example, comparing outcomes of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) is challenging because the temporal profile of their hazard for failure differs, probably reflecting differences in the underlying pathophysiology (3–7). This hazard is highest immediately after placement of either access and then declines over time, decreasing more quickly in AVFs than in AVGs (8), with nonconstant (nonproportional) hazard ratios (HRs) (9). Cox regression can still be used in such circumstances to estimate time-dependent risk ratios, but information about the hazard profile is not directly accessible.Parametric methods may offer other complementary information to standard survival analyses (10). Most parametric models have a time metric formulation, whereby the coefficients estimate the extent to which survival time accelerates or decelerates as the covariate varies (“time ratio”). Although the HR is a more familiar measure of association, this interpretation has an intuitive appeal for describing disease processes and intervention effects. Finally, when events repeat in the same subject (e.g., access thromboses), parametric models can help investigators study the individual tendency to fail and how this individual frailty affects the frailty of the studied population (frailty effect).We report data from incident hemodialysis patients who were followed in centers where local policies favor AVF creation, early transition from catheters to arteriovenous accesses, and limited use of AVGs (11). We studied access survival using both Cox and parametric models. We highlight the merits of both methods, focusing on objectives that are directly addressed by parametric models (i.e., underlying hazard modeling, frailty effect, time ratio interpretation, and survival times prediction).