Predefined Target Level Research Articles

Effects of Individualized Anemia Therapy on Hemoglobin Stability: A Randomized Controlled Pilot Trial in Patients on Hemodialysis.

Anemia is common among hemodialysis patients. Maintaining stable hemoglobin levels within predefined target levels can be challenging, particularly in patients with frequent hemoglobin fluctuations both above and below the desired targets. We conducted a multi-center, randomized, controlled trial comparing our anemia therapy assistance software against a standard population-based anemia treatment protocol. We hypothesized that personalized dosing of erythropoiesis stimulating agents (ESA) improves hemoglobin target attainment. Ninety-six patients undergoing hemodialysis and receiving methoxy polyethylene glycol-epoetin beta were randomized 1:1 to the intervention group (personalized ESA dose recommendations computed by the software) or the standard of care group for twenty-six weeks. The therapy assistance software combined a physiology-based mathematical model and a model predictive controller designed to stabilize hemoglobin levels within a tight target range (10 to 11 g/dl). The primary outcome measure was the percentage of hemoglobin measurements within the target. Secondary outcome measures included measures of hemoglobin variability and ESA utilization. The intervention group showed an improved median percentage of hemoglobin measurements within target at 47% (IQR 39 to 58), with a 10 percentage points median difference between the two groups (95% CI: 3 to 16; P=0.008). The odds ratio of being within the hemoglobin target in the standard of care group compared to the group receiving the personalized ESA recommendations was 0.68 (95% CI: 0.51 to 0.92). The variability of hemoglobin levels decreased in the intervention group, with the percentage of patients experiencing fluctuating hemoglobin levels being 45% vs 82% in the standard of care group. ESA usage was reduced by about 25% in the intervention group. Our results demonstrated an improved hemoglobin target attainment and variability by employing personalized ESA recommendations using the physiology-based anemia therapy assistance software.

Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples.

Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs. Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC). Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies. There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms. There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

The influence of selective attention to specific emotions on the processing of faces as revealed by event-related brain potentials.

Event-related potential studies using affective words have indicated that selective attention to valence can increase affective discrimination at early perceptual stages. This effect most likely relies on neural associations between perceptual features of a stimulus and its affective value. Similar to words, emotional expressions in human faces are linked to specific visual elements. Therefore, selectively attending to a given emotion should allow for the preactivation of neural networks coding for the emotion and associated first-order visual elements, leading to enhanced early processing of faces expressing the attended emotion. To investigate this, we employed an expression detection task (N = 65). Fearful, happy, and neutral faces were randomly presented in three blocks while participants were instructed to respond only to one predefined target level of expression in each block. Reaction times were the fastest for happy target faces, which was accompanied by an increased occipital P1 for happy compared with fearful faces. The N170 yielded an arousal effect (emotional > neutral) while both components were not modulated by target status. In contrast, the early posterior negativity (EPN) arousal effect tended to be larger for target compared with nontarget faces. The late positive potential (LPP) revealed large effects of status and expression as well as an interaction driven by an increased LPP specifically for nontarget fearful faces. These findings tentatively indicate that selective attention to facial affect may enhance early emotional processing (EPN) even though further research is needed. Moreover, late controlled processing of facial emotions appears to involve a negativity bias.

The opportunistic newsvendor problem: Defining the optimal purchase quantity of resalable items, whose value may appreciate

With Newsvendor Problem (NvP) we refer to a specific class of inventory management problems, valid for a single item with stochastic demand over a single period. In the standard version, the newsvendor is allowed to issue a single order, before he or she can observe the actual demand. Since the newsvendor can face both overage and underage costs, due to lost sales or residual stock, the objective is to define the optimal order size that maximizes the expected profit. In this paper, we consider a specific version of the NvP, in which the buyer has the opportunity to make a last and single order for opportunistic reasons. Specifically, we consider discontinued, collectible items, for which demand will not vanish and whose value might appreciate. Hence, the objective is to define the optimal quantity that should be purchased, just before the item is retired from the market or sold-out, and that should be sold as soon as the price rises over a predefined target level. An optimal solution, maximizing the expected profit, is obtained both in case of negligible and non-negligible stockholding costs. In the latter case, to obtain the optimal solution in implicit form, some simplifying assumptions are needed. Hence, a thorough numerical analysis is finally performed, as a way to empirically demonstrate both the robustness and the accuracy of the model, in several scenarios differentiated in terms of costs and customers’ demand.

Transcranial direct current stimulation leads to faster acquisition of motor skills, but effects are not maintained at retention.

Practice is required to improve one’s shooting technique in basketball or to play a musical instrument well. Learning these motor skills may be further enhanced by transcranial direct current stimulation (tDCS). We aimed to investigate whether tDCS leads to faster attainment of a motor skill, and to confirm prior work showing it improves skill acquisition and retention performance. Fifty-two participants were tested; half received tDCS with the anode on primary motor cortex and cathode on the contralateral forehead while concurrently practicing a sequential visuomotor isometric pinch force task on Day 1, while the other half received sham tDCS during practice. On Day 2, retention of the skill was tested. Results from a Kaplan-Meier survival analysis showed that participants in the anodal group attained a pre-defined target level of skill faster than participants in the sham group (χ2 = 9.117, p = 0.003). Results from a nonparametric rank-based regression analysis showed that the rate of improvement was greater in the anodal versus sham group during skill acquisition (F(1,249) = 5.90, p = 0.016), but there was no main effect of group or time. There was no main effect of group or time, or group by time interaction when comparing performance at the end of acquisition to retention. These findings suggest anodal tDCS improves performance more quickly during skill acquisition but does not have additional benefits on motor learning after a period of rest.

Interactions of ignored and attended valence in a valence-detection task with emotional words support the model of evaluative space: an ERP study

ABSTRACT In a valence-detection task with emotional adjectives, 57 participants selectively responded to a predefined target level of valence (negative, positive, or neutral). Event-related potentials of ignored nontargets were examined for a novel type of emotion–attention interaction between a nontarget’s valence and valence of the attentional set. Findings support an extension of the model of evaluative space [Cacioppo, J. T., Gardner, W. L., & Berntson, G. G. (1997). Beyond bipolar conceptualizations and measures: The case of attitudes and evaluative space. Personality and Social Psychology Review, 1(1), 3–25. https://doi.org/10.1207/s15327957pspr0101_2], proposing associations of negative and positive stimuli/attentional sets with high and low arousal, respectively. Consistently, in the neutral attentional set involving low arousal, false alarms were more frequent and an average-referenced EPN-like posterior negativity (150–250 ms) was smaller for positive than negative nontarget words. The late positive potential was reduced for positive nontargets in the negative attentional set, but not the reverse, indicating conjoint effects of a negativity bias and distractor-target distance in terms of valence. Finally, data suggest a sensitivity of mastoid-referenced lateral-posterior N170 to inhibition of task-irrelevant affect.

Attention to affect 2.0: Multiple effects of emotion and attention on event-related potentials of visual word processing in a valence-detection task.

Here we continue recent work on the specific mental processes engaged in a valence-detection task. Fifty-seven participants responded to one predefined target level of valence (negative, neutral, or positive), and ignored the remaining two levels. This enables more precise fine-tuning of neuronal pathways, compared to valence categorization where attention is divided between different levels of valence. Our group recently used valence detection with emotional words. Posterior P1 and N170 effects in the event-related potential (ERP) supported the idea of valent word forms that can be tuned by selective attention to valence. Here we report findings on three distinct posterior N2 components, P300, N400, and the late positive potential (LPP). Target but not nontarget words showed an arousal effect (emotional > neutral) on left-side early posterior negativity (180-280 ms). In contrast, an arousal effect on a sharp N2 deflection in left-minus-right difference ERPs (230-270 ms), suggesting facilitation of lexical access for emotional words, was independent of target status. This also applied to increased medial parieto-occipital N2 (260-300 ms) specific to negative words, indicating attentional capture. Medial-central N400 was specifically enhanced for negative nontarget words, further supporting attentional capture. The typical LPP arousal effect was observed, being stronger and more left-lateralized in target words. An exploratory finding concerned a broad component-overarching ERP valence effect (250-650 ms). Independent of target status, ERPs were more positive for positive than negative words. Combined with our previous results, data suggest multiple loci of emotion-attention interactions in valence detection.

A shrinkage approach for Sharpe ratio optimal portfolios with estimation risks

We consider the problem of maximizing the out-of-sample Sharpe ratio when portfolio weights have to be estimated. We apply an improved bootstrap-based estimator, and an approximative estimator derived from a Taylor series. In a simulation study and empirical analysis with 15 datasets the proposed estimators outperform the minimum variance and equally weighted portfolio strategies. Out-of-sample Sharpe ratios improve by 15 and 32 percent on average, respectively, in the empirical analysis. While effectively dealing with estimation risks, the estimators produce considerable amounts of turnover. Realized net Sharpe ratios improve by 40 percent on average when the effects of accruing transaction costs are incorporated ex-ante into estimation of portfolio weights. When adding a risk-free asset, net Sharpe ratios remain of the same magnitude and portfolio volatility does not exceed a predefined target level.

Optimal load rating-based inspection planning of corroded steel girders using Markov decision process

Steel girder bridges are vulnerable to corrosion. To maintain their safety above a predefined target level, the load rating can be computed from the inspection results and guide the following maintenance actions. Optimizing inspection and maintenance based on load ratings has substantial practical and economic relevance. Load rating-based strategies can be categorized based on whether the inspection interval and replacement criteria are fixed or flexible. Existing studies focus on fixed inspection intervals throughout the service life. In general, their results are not optimal for inspection planning. To reduce life-cycle cost, aged steel girders may be inspected and repaired in an adaptive manner. To this end, a method based on Markov decision process (MDP) is proposed to compare the life-cycle cost of four load rating-based policies (i.e. uniform or adaptive non-uniform inspection interval, and fixed or adaptive replacement threshold). Load rating-based inspection planning is formulated as MDP and the optimal plans are obtained using dynamic programming. The conventional approach to discretize states cannot accurately approximate the non-stationary deterioration process, while state augmentation is successful in doing this but will increase computational cost. A comparison of two approaches is made to investigate their effects on life-cycle cost. A bridge girder under corrosion attack is used as an illustrative example. The results show that the load rating-based plan with an adaptive non-uniform inspection interval and fixed replacement threshold obtained using the state augmentation technique can be near-optimal.

A two‐stage inverse data envelopment analysis approach for estimating potential merger gains in the US banking sector

Mergers and acquisitions are mainly due to financial and technological innovations but could also be due to changes in the structure of the economy, which alters the optimal production functions of banks. Banks that seek to be operationally efficient would focus more on expanding their asset size, in the face of bad loans, leading to the acquisition of less efficient banks. This paper develops two‐stage inverse data envelopment analysis (DEA) models for estimating potential gains from bank mergers for the top US commercial banks. The results show additional intermediate and final outputs at different predefined target levels of technical efficiencies.

New Clamp-PID Algorithm for Automated Glucose Clamps Improves Clamp Quality.

In automated glucose clamp experiments, blood glucose (BG) concentrations are kept close to a predefined target level using variable glucose infusion rates (GIRs) determined by implemented algorithms. Clamp quality (ie, the ability to keep BG close to target) highly depends on the quality of these algorithms. We developed a new Clamp algorithm based on the proportional-integral-derivative (PID) approach and compared clamp quality between this and the established Biostator (BS) algorithm. In numerical simulations, the PID-based algorithm was optimized in silico. The optimized Clamp-PID algorithm was tested in in vitro experiments and finally validated in vivo in a small (n = 5) clinical study. In silico, in vitro, and in vivo experiments showed better clamp quality for the new Clamp-PID algorithm compared with the BS algorithm: precision and absolute control deviation (ACD) decreased from 3.7% to 1.1% and from 2.9 mg/dL to 0.6 mg/dL, respectively, in the numerical simulation. The in vitro validation demonstrated reductions in precision (from 3.3% ± 0.1% (mean ± SD) to 1.4% ± 0.4%) and in ACD (from 2.3 mg/dL ± 0.4 mg/dL to 0.8 mg/dL ± 0.2 mg/dL), respectively. In the clinical study, precision and ACD improved from 6.5% ± 1.3% to 4.0% ± 1.1% and from 3.6 mg/dL ± 0.9 mg/dL to 2.2 mg/dl ± 0.6 mg/dl, respectively. The quality parameter utility did not change. The new Clamp-PID algorithm improves the clamp quality parameters precision and ACD versus the BS algorithm.

Automated Titration of Vasopressor Infusion Using a Closed-loop Controller: In Vivo Feasibility Study Using a Swine Model.

Intraoperative hypotension has been associated with adverse postoperative outcomes.A randomized controlled trial of individualized blood pressure management in patients undergoing major abdominal surgery found reduced postoperative adverse events in patients in the blood pressure management intervention group versus the standard of care group. In this study of pigs with normovolemic hypotension induced by administration of sodium nitroprusside, an automated closed-loop vasopressor administration device was able to maintain mean arterial pressure within 5 mmHg of 80 mmHg for 98% of the intraoperative period. This suggests that norepinephrine can be accurately titrated using an automated infusion device in order to maintain target blood pressure. Multiple studies have reported associations between intraoperative hypotension and adverse postoperative complications. One of the most common interventions in the management of hypotension is vasopressor administration. This approach requires careful and frequent vasopressor boluses and/or multiple adjustments of an infusion. The authors recently developed a closed-loop controller that titrates vasopressors to maintain mean arterial pressure (MAP) within set limits. Here, the authors assessed the feasibility and overall performance of this system in a swine model. The authors hypothesized that the closed-loop controller would be able to maintain MAP at a steady, predefined target level of 80 mmHg for greater than 85% of the time. The authors randomized 14 healthy anesthetized pigs either to a control group or a closed-loop group. Using infusions of sodium nitroprusside at doses between 65 and 130 µg/min, we induced four normovolemic hypotensive challenges of 30 min each. In the control group, nothing was done to correct hypotension. In the closed-loop group, the system automatically titrated norepinephrine doses to achieve a predetermined MAP of 80 mmHg. The primary objective was study time spent within ±5 mmHg of the MAP target. Secondary objectives were performance error, median performance error, median absolute performance error, wobble, and divergence. The controller maintained MAP within ±5 mmHg of the target for 98 ± 1% (mean ± SD) of the time. In the control group, the MAP was 80 ± 5 mmHg for 14.0 ± 2.8% of the time (P< 0.0001). The MAP in the closed-loop group was above the target range for 1.2 ± 1.2% and below it for 0.5 ± 0.9% of the time. Performance error, median performance error, median absolute performance error, wobble, and divergence were all optimal. In this experimental model of induced normovolemic hypotensive episodes in pigs, the automated controller titrated norepinephrine infusion to correct hypotension and keep MAP within ±5 mmHg of target for 98% of management time.

Replacement therapy during surgery in von Willebrand disease needs personalization.

Replacement therapy during surgery in von Willebrand disease needs personalization.

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment

Patients with Von Willebrand disease (VWD) are regularly treated with VWF-containing concentrates in case of acute bleeding, trauma and dental or surgical procedures. In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate® P) in patients with VWD was evaluated. Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII-based treatment regimens were compared to predefined target levels in national guidelines. In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act. High VWF:Act and accumulation of FVIII were observed after perioperative FVIII-based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment.

Improved Algorithm for Automated Glucose Clamps

In glucose clamp experiments, blood glucose concentrations (BGs) are kept as close as possible to a predefined target level using variable glucose infusion rates (GIRs). In automated clamps, GIRs are calculated by algorithms implemented in the device (e.g., the Biostator). Low BG- and GIR-variability is needed for high clamp quality. We therefore tried to reduce oscillations in both BG and GIR with an improved algorithm implemented in ClampArt, a modern clamp device. The Biostator algorithm was first improved by numerical simulations of glucose clamps (in silico). With the results of the simulations, we started in vitro experiments using the ClampArt device and a container with water and glucose as "test subject." After a small pilot in vivo study, a larger clinical study was performed to compare the original with the optimized algorithm. With the improved algorithm, in silico, in vitro, and in vivo experiments showed reduced oscillations in both BG and GIR. In the clinical study, the coefficient of variation (CV) of BG values was lowered from 6.0% (4.6%-7.8%) [median (interquartile range)] to 4.2% (3.6%-5.0%), P < 0.0001 and the CV of GIR from 60.7% (49.6%-82.0%) to 43.5% (32.8%-57.2%), P < 0.0001. Other clamp quality parameters did not change substantially, median deviation from target slightly increased from 0.6% (0.2%-1.0%) to 1.1% (0.7%-1.5%), P = 0.0005, whereas utility did not change [97.0% (93.4%-100.0%) vs. 97.0% (94.0%-98.8%), P = 0.57]. With the improved algorithm, all experiments confirmed a reduction in BG- and GIR-oscillations without a major impact on other glucose clamp parameters. The optimized algorithm has been implemented in ClampArt for all future glucose clamp studies.

Dose-Finding Study of Omeprazole on Gastric pH in Neonates with Gastro-Esophageal Acid Reflux Using a Bayesian Sequential Approach.

ObjectiveProton pump inhibitors are frequently administered on clinical symptoms in neonates but benefit remains controversial. Clinical trials validating omeprazole dosage in neonates are limited. The objective of this trial was to determine the minimum effective dose (MED) of omeprazole to treat pathological acid reflux in neonates using reflux index as surrogate marker.DesignDouble blind dose-finding trial with continual reassessment method of individual dose administration using a Bayesian approach, aiming to select drug dose as close as possible to the predefined target level of efficacy (with a credibility interval of 95%).SettingNeonatal Intensive Care unit of the Robert Debré University Hospital in Paris, France.PatientsNeonates with a postmenstrual age ≥ 35 weeks and a pathologic 24-hour intra-esophageal pH monitoring defined by a reflux index ≥ 5% over 24 hours were considered for participation. Recruitment was stratified to 3 groups according to gestational age at birth.InterventionFive preselected doses of oral omeprazole from 1 to 3 mg/kg/day.Main outcome measuresPrimary outcome, measured at 35 weeks postmenstrual age or more, was a reflux index <5% during the 24-h pH monitoring registered 72±24 hours after omeprazole initiation.ResultsFifty-four neonates with a reflux index ranging from 5.06 to 27.7% were included. Median age was 37.5 days and median postmenstrual age was 36 weeks. In neonates born at less than 32 weeks of GA (n = 30), the MED was 2.5mg/kg/day with an estimated mean posterior probability of success of 97.7% (95% credibility interval: 90.3–99.7%). The MED was 1mg/kg/day for neonates born at more than 32 GA (n = 24).ConclusionsOmeprazole is extensively prescribed on clinical symptoms but efficacy is not demonstrated while safety concerns do exist. When treatment is required, the daily dose needs to be validated in preterm and term neonates. Optimal doses of omeprazole to increase gastric pH and decrease reflux index below 5% over 24 hours, determined using an adaptive Bayesian design differ among neonates. Both gestational and postnatal ages account for these differences but their differential impact on omeprazole doses remains to be determined.

QugSS – Qualitätsgemeinschaft Schlaganfallversorgung Schleswig-Holstein

The Quality Association for Acute Stroke Treatment Schleswig-Holstein (QugSS) continues a project which was conducted from 2004 to 2007 as part of a benchmarking programme funded by the German Health Ministry. The implementation of the benchmarking programme in 15 hospitals was intended to improve patient-related outcomes of the inpatient treatment of acute stroke. Regular reports to the Quality Association are complemented by quarterly meetings of the association members to compare and discuss the results of the participating hospitals. Quality indicators developed by the German Stroke Registries Study Group (ADSR) are used. In addition, the meetings serve as a platform for mutual exchange in the form of further training. Between April 2005 and December 2010 approx. 18,000 cases (mean age: 71.9±12.8 years/M±SD, 48.7% females) were documented. From 2008 to 2010, nine out of 12 process indicators improved significantly. Values above the pre-defined target level of the quality indicators were significantly achieved by five indicators (p<.05), almost achieved by three indicators (not significant), and were significantly failed by four indicators.

Interleukin-2 Therapy in Patients with HIV Infection

BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Interleukin-2 Therapy in Patients with HIV Infection

Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol

Objectives:To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment.Methods:Prospective, multicentre, open-label,...