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OBJECTIVE: To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. METHODS: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule-1 (VCAM-1) binding were assessed using flow cytometry. RESULTS: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 109 to 3.5 × 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 109 vs 3.5 × 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. CONCLUSIONS: Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.

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A professional skydiver underwent aortic valve and ascending aorta replacement complicated by infective endocarditis with root abscess and pacemaker implantation. He then enrolled in the Baylor Heart and Vascular Hospital cardiac rehabilitation (CR) program as part of its specificity of testing and exercise training facility. He performed specific skydiving cardiovascular and muscular strength tests at the beginning and the end of the CR program. His pacemaker was interrogated to ascertain any arrhythmias or lead displacement over the course of the CR program. Daily exercise training was customized to match the physical demands of skydiving, including two sessions at iFLY Dallas. Upon completion of the daily exercise sessions, the patient performed a simulated free-fall drop test. He then performed a true jump at Dallas Skydive Center and subsequently traveled to Arizona for a skydiving competition, where he performed 35 true jumps with no adverse events or symptoms. This case illustrates how CR, tailored to a patient's specific needs, can aid in the return to rigorous activity.

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Natalizumab, a human immunoglobulin monoclonal antibody that targets α4ß1/α4ß7 integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure-response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count provided a superior goodness of fit. The mean (95% confidence interval) slopes from the exposure-Gd lesion count model and exposure-ARR model are -0.0903 (-0.100, -0.081) and -0.0222 (-0.026, -0.015) (mg/L)-1, respectively. From these slopes, it can be inferred that both Gd lesion count and ARR decrease with increasing exposure to natalizumab in MS subjects. Model-based simulations demonstrated that although reductions in Gd lesion count and ARR were observed with lower doses (75, 150, or 200 mg), only the dose of 300 mg every 4 weeks (q4w) was associated with an ARR ≤0.25 and was considered clinically effective. The results from the exposure-Gd lesion count and exposure-ARR models thus support the appropriateness of the approved natalizumab dose (300 mg q4w) in MS subjects.

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BACKGROUND: The mortality rate due to Acinetobacter baumannii nosocomial meningitis (ANM) is high. OBJECTIVE: The aim of this study was to evaluate the factors that have influence over the outcomes in ANM patients. METHODS: A retrospective analysis of 22 cases of ANM was conducted in a hospital with high incidence of multidrug resistance. RESULTS: The mean age of patients was 43 years (21 to 91) and 54.5 percent were male. All ANM cases occurred within 60 days of admission and the mean duration of illness was of 18.2 days. All cases were associated with previous neurosurgical procedures: elective surgery (27.2 percent), external shunt (54.4 percent) and emergency surgery due to trauma (18.1 percent). Imipenem resistance was observed in 40.9 percent of cases, but ampicillin/sulbactam resistance was lower (27.2 percent). The mortality rate of ANM patients was of 72.7 percent. The only risk factor associated with mortality was inappropriate therapy within five days after CSF collection. All patients who survived the meningitis episode had received appropriate therapy, in contrast to only 69.2 percent of those who did not survive (OR = 5.15; IC = 0.45-54.01). CONCLUSIONS: The high mortality rate observed in our study suggests the need for aggressive empirical treatment with addition of drugs, including intrathecal therapy, where multi-resistant A. baumannii is endemic.

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BACKGROUND: The mortality rate due to Acinetobacter baumannii nosocomial meningitis (ANM) is high. OBJECTIVE: The aim of this study was to evaluate the factors that have influence over the outcomes in ANM patients. METHODS: A retrospective analysis of 22 cases of ANM was conducted in a hospital with high incidence of multidrug resistance. RESULTS: The mean age of patients was 43 years (21 to 91) and 54.5% were male. All ANM cases occurred within 60 days of admission and the mean duration of illness was of 18.2 days. All cases were associated with previous neurosurgical procedures: elective surgery (27.2%), external shunt (54.4%) and emergency surgery due to trauma (18.1%). Imipenem resistance was observed in 40.9% of cases, but ampicillin/sulbactam resistance was lower (27.2%). The mortality rate of ANM patients was of 72.7%. The only risk factor associated with mortality was inappropriate therapy within five days after CSF collection. All patients who survived the meningitis episode had received appropriate therapy, in contrast to only 69.2% of those who did not survive (OR = 5.15; IC = 0.45-54.01). CONCLUSIONS: The high mortality rate observed in our study suggests the need for aggressive empirical treatment with addition of drugs, including intrathecal therapy, where multi-resistant A. baumannii is endemic.

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