Predictive modeling of the outcomes of chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim (MONITOR-GCSF study).

BACKGROUND: Risk models of chemotherapy-induced (CIN) and febrile neutropenia (FN) have to date focused on determinants measured at the start of chemotherapy. We extended this static approach with a dynamic approach of CIN/FN risk modeling at the start of each cycle. DESIGN: We applied predictive modeling using multivariate logistic regression to identify determinants of CIN/FN episodes and related hospitalizations and chemotherapy disturbances (CIN/FN consequences) in analyses at the patient ('ever' during the whole period of chemotherapy) and cycle-level (during a given chemotherapy cycle). Statistical dependence of cycle data being 'nested' under patients was managed using generalized estimation equations. Predictive performance of each model was evaluated using bootstrapped c concordance statistics. RESULTS: Static patient-level risk models of 'ever' experiencing CIN/FN adverse events and consequences during a planned chemotherapy regimen included predictors related to history, risk factors, and prophylaxis initiation and intensity. Dynamic cycle-level risk models of experiencing CIN/FN adverse events and consequences in an upcoming cycle included predictors related to history, risk factors, and prophylaxis initiation and intensity; as well as prophylaxis duration, CIN/FN in prior cycle, and treatment center characteristics. CONCLUSIONS: These 'real-world evidence' models provide clinicians with the ability to anticipate CIN/FN adverse events and their consequences at the start of a chemotherapy line (static models); and, innovatively, to assess risk of CIN/FN adverse events and their consequences at the start of each cycle (dynamic models). This enables individualized patient treatment and is consistent with the EORTC recommendation to re-appraise CIN/FN risk at the start of each cycle. Prophylaxis intensity (under-, correctly-, or over-prophylacted relative to current EORTC guidelines) is a major determinant. Under-prophylaxis is clinically unsafe. Over-prophylaxis of patients administered chemotherapy with intermediate or low myelotoxicity levels may be beneficial, both in patients with and without risk factors, and must be validated in future studies.

Differences in Medication Adherence between Living and Deceased Donor Kidney Transplant Patients.

BACKGROUND: Literature review suggests that adherence to immunosuppressive drugs may be lower in recipients of living than of deceased donor kidney grafts, possibly because of profile differences. OBJECTIVE: To compare the level of immunosuppressive adherence levels between patients with deceased and living (-related; -unrelated) donor grafts in Switzerland. METHODS: Using data from two similar cross-sectional studies at two transplant centers in Switzerland, the level of adherence between the two groups was compared. Medication adherence was assessed by self-report or electronic monitoring. Possible explanatory factors included age, beliefs regarding immunosuppressive drugs, depressive symptomatology, pre-emptive transplantation, and the number of transplants received, were also considered. Data were analyzed using logistic regression analysis. RESULTS: Unadjusted non-adherence odds were 2 to 3 times higher in living-related than deceased donor transplantation (ORs: 2.09-3.05; p<0.05). Adjustment for confounders showed that these differences were associated most with the younger age of living-related subjects and the belief that immunosuppressive drugs are less important for living-related donations. CONCLUSION: There is a lower immunosuppressive adherence in recipients of living-related donor kidneys, possibly owing to differences in patient profile (ie, health beliefs regarding their immunosuppressive needs), knowledge of which may enhance adherence if addressed.

Contextual factors associated with pain response of preterm infants to heel-stick procedures.

BACKGROUND: Evidence indicates that medical and demographic contextual factors (cFs) impact pain responses in preterm neonates, but the existing evidence is very heterogeneous. AIM: To explore the effect of cFs on pain responses to heel-stick procedures of preterm infants. METHODS: This study was a secondary analysis of data collected during a randomized controlled trial examining pain response to non-pharmacological interventions across repeated heel sticks. Five heel sticks across the first 14 days of life were videotaped. Pain response was rated with the Bernese Pain Scale for Neonates (BPSN) by four raters blinded to the heel-stick phases (baseline, heel stick, recovery). Demographic and medical cFs were extracted from medical charts. Mixed single and multiple regression analyses were performed controlling for the intervention group, site and heel-stick phase. RESULTS: Apgar scores at 1 min were negatively associated with behavioural (p = 0.002) BPSN scores, while Apgar scores at 5 min after birth were positively associated with behavioural (p = 0.006) scores. Accumulated number of painful procedures (p = 0.002) and gender (p = 0.02) were positively associated with physiological scores while continuous positive airway pressure CPAP (p = 0.009) and mechanical ventilation (p = 0.005) were negatively associated. CONCLUSION: Higher exposure to painful procedures, male infants and having CPAP or mechanical ventilation were cFs associated with physiological response. The only variables significantly associated with behavioural BPSN scores were Apgar scores but these relationships were inconsistent.

Sensitive cardiac troponin in the diagnosis and risk stratification of acute heart failure.

BACKGROUND: The aim of our study was to investigate the diagnostic and prognostic value of a sensitive cardiac troponin I (s-cTnI) assay in patients with acute heart failure (AHF). METHODS: Sensitive cardiac troponin I was measured in 667 consecutive patients at presentation to the emergency department with acute dyspnoea. Three s-cTnI strata were predefined: below the limit of detection (<0.01 µg L(-1) , undetectable), detectable but still within the normal range (0.01-0.027 µg L(-1) ) and increased (≥0.028 µg L(-1) , ≥99th percentile). The final diagnosis was adjudicated by two independent cardiologists blinded to the s-cTnI levels. Median follow-up in patients with AHF was 371 days. RESULTS: Levels of s-cTnI were higher in patients with AHF (n = 377, 57%) compared to patients with noncardiac causes of acute dyspnoea (median 0.02 vs. <0.01 µg L(-1) , P < 0.001). In patients with AHF, in-hospital mortality increased with increasing s-cTnI in the three strata (2%, 5% and 14%, P < 0.001). One-year mortality also increased with increasing s-cTnI (21%, 33% and 47%, P < 0.001). s-cTnI remained an independent predictor of 1-year mortality [adjusted odds ratio 1.03 for each increase of 0.1 µg L(-1) , 95% confidence interval (CI) 1.02-1.05, P < 0.001] after adjustment for other risk factors including B-type natriuretic peptide. The net reclassification improvement was 68% (P < 0.001), and absolute integrated discrimination improvement was 0.18 (P < 0.001). The diagnostic accuracy of s-cTnI for the diagnosis of AHF as quantified by the area under the receiver operating characteristic curve was 0.78 (95% CI, 0.75-0.82). CONCLUSIONS: Sensitive cardiac troponin I is a strong predictor of short- and long-term prognosis in AHF that helps to reclassify patients in terms of mortality risk. Detectable levels of s-cTnI, even within the normal range, are independently associated with mortality.

Variability in pain response to a non-pharmacological intervention across repeated routine pain exposure in preterm infants: a feasibility study.

AIM: To explore the variability in pain response in preterm infants across time who received sucrose during routine heel stick. METHOD: Single group, exploratory repeated measures design. SETTING: Two tertiary level neonatal intensive care units (NICU) in Switzerland. SUBJECTS: Nine preterm infants born between 28 2/7 and 31 4/7 weeks of gestation during their first 14 days of life. MEASUREMENTS: Pain was assessed by the Bernese Pain Scale for Neonates (BPSN), the Premature Infant Pain Profile (PIPP) and the Visual Analogue Scale (VAS). Salivary cortisol was analysed. RESULTS: 72-94% of the variability was within-subject variability, indicating inconsistency of pain responses across the 5 heel sticks. Interrater agreement was highest during heel sticks 1-3 and decreased during heel stick 4 and 5, indicating a possible alteration of pain patterns. No significant differences in the amount of cortisol could be detected before and after the heel sticks (p = 0.55), indicating no stress-induced peak after the painful intervention. However, a general gradual decrease of cortisol levels across time could be detected. CONCLUSION: A high variability in pain response among preterm neonates across time could be described. Consistency of cortisol levels before and after the heel sticks could indicate the effectiveness of sucrose across time.

Diagnostic accuracy of measurement methods to assess non-adherence to immunosuppressive drugs in kidney transplant recipients.

Valid assessment of immunosuppressive therapy non-adherence (NAH) is vital: NAH is associated with negative transplantation outcomes. We studied the diagnostic accuracy of assay, patient self-reports and clinicians' collateral reports and composite adherence scores using electronic monitoring (EM) as a reference standard. This cross-sectional study included a convenience sample of 249 adult kidney transplant recipients (Ktx) (female: 43.4%; mean age 53.6 [SD: 12.7], median 7 years [IQR: 9 years] post-Ktx). NAH was assessed using EM over 3 months (i.e. reference standard), assays of cyclosporine, tacrolimus, mycophenolat-mofetil, patients' self-reports and clinicians' collateral reports. The constructed composite adherence score included assay, self-reports and collateral reports. NAH's prevalence across the measurement methods was EM: 17.3%; assay: 33% (cyclosporine: 25.8%; tacrolimus: 35.1%; mycophenolat-mofetil: 40.2%); self-report: 12.4%; collateral reports: 24.9% and composite adherence score: 38.9%, respectively. The composite adherence score and collateral reports showed the highest and lowest sensitivities to NAH (72.1% and 15.8%, respectively). Specificity was highest for collateral reports of at least three clinicians (93.1%). Likelihood ratio of a positive test was 2.74 for composite adherence score. No measures showed high sensitivity alongside high specificity. Combining measures increased diagnostic accuracy, indicating the relevance of combined measures for clinical and research purposes.

Prevalence and risk factors of non-adherence with immunosuppressive medication in kidney transplant patients.

Non-adherence with immunosuppressive regimen is a major risk factor for poor outcome after kidney transplantation. Identifying patients at risk for non-adherence requires understanding the risk factors for non-adherence. This prospective study included a convenience sample of 249 adult kidney transplant patients >1 year post-transplant. Non-adherence was monitored electronically using MEMS(R). Selected socio-economic, therapy-, patient-, condition- and healthcare team-related risk factors for non-adherence were assessed. Period prevalences were expressed as the percent of prescribed doses taken (taking adherence), the percent of correctly dosed days (dosing adherence), the percentage of inter-dose intervals not exceeding 25% of the prescribed interval (timing adherence), and the number of drug holidays per 100 days (no intake for > 48 h if once daily or for > 24 h if twice daily intake). Testing occurred by simple mixed logistic regression analysis. Factors significant after correction for multiple testing were entered into a multiple logistic regression model. Mean taking, dosing, timing adherence, and drug holidays were 98%, 96%, 93%, and 1.1 days, respectively. Non-adherence was associated with lower self-efficacy, higher self-reported non-adherence, no pillbox usage, and male gender. Adherence declined between Monday and Sunday. This study provides a framework for identifying patients at risk for non-adherence and for developing adherence-enhancing interventions.