Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example.

The effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (C(p)) and trough (C(t)) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based on C(p) and C(t) to model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110 C(p)-C(t) combination pairs. The C(p) time points were in 15-min increments between 0.5 h and 3 h and C(t) in 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identify C(p)-C(t) pairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily on C(p), and use of a daptomycin C(p) 1.5 h to 3 h from the start of infusion was associated with a bias of <10% and an R(2) of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use of C(p) ≥1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycin C(p) approximately 2 h from the start of infusion and a C(t) within an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC

Clinical and economic comparison of an individualised immunoglobulin protocol vs. standard dosing for chronic inflammatory demyelinating polyneuropathy

Background The clinical and economic implications of an individualised intravenous immunoglobulin (IVIg) protocol for chronic inflammatory demyelinating polyneuropathy (CIDP) are unknown. Comparison with standard dosing regimens has not been performed. Methods We retrospectively studied 47 IVIg-treated subjects with CIDP over 4 years with an individualised, outcome-measured, dose-modifying protocol. We evaluated responder and remission rates, clinical improvement levels and dose requirements. We compared clinical benefits and costs with those reported with standard dosing at 1 g/kg every 3 weeks. Results The IVIg-responder rate was 83% and the 4-year remission rate was 25.6%. Mean IVIg dose requirements were 22.06 g/week (SD:15.29) in patients on ongoing therapy. Dose range was wide (5.83–80 g/week). Mean infusion frequency was every 4.34 weeks (SD:1.70) and infusion duration of 2.79 days (SD:1.15). Mean Overall Neuropathy Limitation Scale improvement was 2.54 (SD:1.89) and mean MRC sum score improvement of 12.23 (SD:7.17) in IVIg-responders. Mean modified-INCAT (Inflammatory Neuropathy Cause and Treatment) score improvement was similar (p = 0.47) and mean MRC sum score improvement greater (p < 0.001) in our cohort, compared to the IVIg-treated arm of the ICE Study. Mean drug costs were GBP 37,660/patient/year (€ 43,309) and mean infusion-related costs of GBP 17,115/patient/year (€ 19,682), totalling GBP 54,775/patient/year (€ 62,991). Compared to standard dosing using recorded weight, mean savings were of GBP 13,506/patient/year (€ 15,532). Compared to standard dosing using dosing weight, savings were of GBP 6,506/patient/year (€ 7,482). Conclusion Our results indicate that an individualised IVIg treatment protocol is clinically non-inferior and 10–25% more cost-effective than standard dosing regimens in CIDP

QuantiFERON®-TB gold in-tube performance for diagnosing active tuberculosis in children and adults in a high burden setting.

To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania. Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB. Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline. QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting

The need for nursing instruction in patients receiving steroid pulse therapy for the treatment of autoimmune diseases and the effect of instruction on patient knowledge

<p>Abstract</p> <p>Background</p> <p>Many patients who receive steroid pulse therapy go home the same day or the day after steroid administration. Nursing instructions are important for improving patient knowledge related to their diseases and treatments, but the short hospital stay often prevents complete education and guidance regarding the given therapy. The purpose of this study was to investigate the need for nursing instruction in patients receiving steroid pulse therapy for the treatment of autoimmune diseases and the effect of instruction on patient knowledge of their disease and treatment.</p> <p>Methods</p> <p>Patients with systemic lupus erythematosus (SLE) and systemic sclerosis receiving steroid pulse therapy (N = 63) were recruited from a medical center in Taipei. A structured questionnaire was used for data collection before and after nursing instruction, and 1 week as well as 2 weeks after therapy. The need for nursing instruction and knowledge levels were validated using Cronbach's α reliability test.</p> <p>Results</p> <p>There was a significant difference (<it>P </it>< 0.001) in the need for nursing instruction among the 4 time points. There was a positive correlation between the need for nursing instruction and body weight change, frequency of treatment, and distress, but there was a negative correlation with knowledge level (β = -0.012, <it>P </it>= 0.003) regarding symptoms. The knowledge level of subjects after nursing instruction was significantly higher than before nursing instruction (80 ± 14.31 vs. 70.06 ± 17.23, <it>P </it>< 0.001).</p> <p>Conclusions</p> <p>This study indicates that nursing instruction is needed by patients receiving steroid pulse therapy, and that by designing and administering nursing instructions according to the priority of patient symptoms, nurses can improve patient knowledge related to their diseases and treatments. In addition, the need for nursing instruction can be affected by patient characteristics.</p

Isoniazid prophylaxis differently modulates T-cell responses to RD1-epitopes in contacts recently exposed to Mycobacterium tuberculosis: a pilot study

RATIONALE: Existing data on the effect of treatment of latent tuberculosis infection (LTBI) on T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens are contradictory. Differences in technical aspects of the assays used to detect this response and populations studied might explain some of these discrepancies. In an attempt to find surrogate markers of the effect of LTBI treatment, it would be important to determine whether, among contacts of patients with contagious tuberculosis, therapy for LTBI could cause changes in MTB-specific immune responses to a variety of RD1-antigens. METHODS AND RESULTS: In a longitudinal study, 44 tuberculin skin test(+ )recent contacts were followed over a 6-month period and divided according to previous exposure to MTB and LTBI treatment. The following tests which evaluate IFN-gamma responses to RD1 antigens were performed: QuantiFERON TB Gold, RD1 intact protein- and selected peptide-based assays. Among the 24 contacts without previous exposure that completed therapy, we showed a significant decrease of IFN-gamma response in all tests employed. The response to RD1 selected peptides was found to be more markedly decreased compared to that to other RD1 antigens. Conversely, no significant changes in the response to RD1 reagents were found in 9 treated subjects with a known previous exposure to MTB and in 11 untreated controls. CONCLUSION: These data suggest that the effect of INH prophylaxis on RD1-specific T-cell responses may be different based on the population of subjects enrolled (recent infection versus re-infection) and, to a minor extent, on the reagents used

C-Reactive Protein (CRP) Gene Polymorphisms, CRP Levels, and Risk of Incident Coronary Heart Disease in Two Nested Case-Control Studies

Background: C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD). Methods and Findings: We conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses' Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A greater than T and 4741G greater than C, but associated with lower CRP levels for SNPs 2667G greater than C and 3872C greater than T. SNP 2667G greater than C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01–2.44); p = 0.047] and men [1.93 (95% CI 1.30–2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations. Conclusions: Common variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene

Correcting for Mortality Among Patients Lost to Follow Up on Antiretroviral Therapy in South Africa: A Cohort Analysis

Loss to follow-up (LTF) challenges the reporting of antiretroviral treatment (ART) programmes, since it encompasses patients alive but lost to programme and deaths misclassified as LTF. We describe LTF before and after correction for mortality in a primary care ART programme with linkages to the national vital registration system

Hands-on time during cardiopulmonary resuscitation is affected by the process of teambuilding: a prospective randomised simulator-based trial

BACKGROUND: Cardiac arrests are handled by teams rather than by individual health-care workers. Recent investigations demonstrate that adherence to CPR guidelines can be less than optimal, that deviations from treatment algorithms are associated with lower survival rates, and that deficits in performance are associated with shortcomings in the process of team-building. The aim of this study was to explore and quantify the effects of ad-hoc team-building on the adherence to the algorithms of CPR among two types of physicians that play an important role as first responders during CPR: general practitioners and hospital physicians. METHODS: To unmask team-building this prospective randomised study compared the performance of preformed teams, i.e. teams that had undergone their process of team-building prior to the onset of a cardiac arrest, with that of teams that had to form ad-hoc during the cardiac arrest. 50 teams consisting of three general practitioners each and 50 teams consisting of three hospital physicians each, were randomised to two different versions of a simulated witnessed cardiac arrest: the arrest occurred either in the presence of only one physician while the remaining two physicians were summoned to help ("ad-hoc"), or it occurred in the presence of all three physicians ("preformed"). All scenarios were videotaped and performance was analysed post-hoc by two independent observers. RESULTS: Compared to preformed teams, ad-hoc forming teams had less hands-on time during the first 180 seconds of the arrest (93 +/- 37 vs. 124 +/- 33 sec, P > 0.0001), delayed their first defibrillation (67 +/- 42 vs. 107 +/- 46 sec, P > 0.0001), and made less leadership statements (15 +/- 5 vs. 21 +/- 6, P > 0.0001). CONCLUSION: Hands-on time and time to defibrillation, two performance markers of CPR with a proven relevance for medical outcome, are negatively affected by shortcomings in the process of ad-hoc team-building and particularly deficits in leadership. Team-building has thus to be regarded as an additional task imposed on teams forming ad-hoc during CPR. All physicians should be aware that early structuring of the own team is a prerequisite for timely and effective execution of CPR

IP-10 response to RD1 antigens might be a useful biomarker for monitoring tuberculosis therapy

Background There is an urgent need of prognosis markers for tuberculosis (TB) to improve treatment strategies. The results of several studies show that the Interferon (IFN)-γ-specific response to the TB antigens of the QuantiFERON TB Gold (QFT-IT antigens) decreases after successful TB therapy. The objective of this study was to evaluate whether there are factors other than IFN-γ [such as IFN-γ inducible protein (IP)-10 which has also been associated with TB] in response to QFT-IT antigens that can be used as biomarkers for monitoring TB treatment. Methods In this exploratory study we assessed the changes in IP-10 secretion in response to QFT-IT antigens and RD1 peptides selected by computational analysis in 17 patients with active TB at the time of diagnosis and after 6 months of treatment. The IFN-γ response to QFT-IT antigens and RD1 selected peptides was evaluated as a control. A non-parametric Wilcoxon signed-rank test for paired comparisons was used to compare the continuous variables at the time of diagnosis and at therapy completion. A Chi-square test was used to compare proportions. Results We did not observe significant IP-10 changes in whole blood from either NIL or QFT-IT antigen tubes, after 1-day stimulation, between baseline and therapy completion (p = 0.08 and p = 0.7 respectively). Conversely, the level of IP-10 release to RD1 selected peptides was significantly different (p = 0.006). Similar results were obtained when we detected the IFN-γ in response to the QFT-IT antigens (p = 0.06) and RD1 selected peptides (p = 0.0003). The proportion of the IP-10 responders to the QFT-IT antigens did not significantly change between baseline and therapy completion (p = 0.6), whereas it significantly changed in response to RD1 selected peptides (p = 0.002). The proportion of IFN-γ responders between baseline and therapy completion was not significant for QFT-IT antigens (p = 0.2), whereas it was significant for the RD1 selected peptides (p = 0.002), confirming previous observations. Conclusions Our preliminary study provides an interesting hypothesis: IP-10 response to RD1 selected peptides (similar to IFN-γ) might be a useful biomarker for monitoring therapy efficacy in patients with active TB. However, further studies in larger cohorts are needed to confirm the consistency of these study results