Within-host dynamics of antigenic variation.

Genomes of some parasites contain dozens of alternative and highly diverged surface antigens, of which only a single one is expressed in any cell. Individual cells occasionally change expression of their surface antigen, allowing them to escape immune surveillance. These switches appear to occur in a partly random way, creating a diverse set of antigenic variants. In spite of this diversity, the parasitemia develops as a series of outbreaks, in which each outbreak is dominated by relatively few antigenic types. Host-specific immunity eventually clears the dominant antigenic types, and a new outbreak follows from antigenic types that have apparently been present all along at low frequency. This pattern of sequential dominance by different antigenic types remains unexplained. We review the five most prominent theories, which have developed mainly from studies of the protozoans Trypanosoma and Plasmodium, and the bacterial spirochete Borrelia. The most promising theories depend on some combination of mechanisms to create favored connectivity pathways through the matrix of transitions between variants. Favored pathways may arise from biased switches at the molecular level of gene expression or from biases imposed by immune selection. We illustrate the concept of connectivity pathways by reanalysis of data on transitions between variants from Borrelia hermsii.     

Sexual function in patients presenting to a urogynecology practice

The purpose of this study was to evaluate sexual function in women referred to a urogynecology practice. All new patients were mailed an optional female sexual function index (FSFI) in conjunction with their history forms; other sexual function information was obtained during the physician interview. Over 6 months, four hundred fifty new patients were enrolled. Of these, 243 (54%) were not sexually active. Reasons listed for sexual inactivity included partner problems/no partner (32%), low desire (14%), prolapse (10%), and pain (10%). There were several differences between sexually active and non-sexually active participants; however, after a multivariate analysis, only age, marital status, and stage/grade 1–2 of prolapse remained significant. One hundred nine sexually active patients completed the FSFI; the majority was sexually active two to four times per month. Female sexual dysfunction was noted in 70 (64%) patients. Lowest scores were noted for the domain of desire, followed by arousal, orgasm, lubrication, satisfaction, and pain. Reduced frequency of intercourse was the only factor significantly associated with dysfunction. Ninety-four percent were not embarrassed by the survey. Overall, sexual inactivity is common in patients presenting for urogynecologic care. Those that are sexually active report low rates of sexual activity and high rates of sexual dysfunction. Most sexually active patients will accept a sexual function questionnaire as part of their routine assessment.This research was presented at the American College of Obstetricians and Gynecologists annual clinical meeting, May 10, 2005, San Francisco, CA, USA.     

Validation of a simplified technique for using the POPQ pelvic organ prolapse classification system

Our objective was to determine the inter-examiner agreement of a simplified pelvic organ prolapse quantification (POPQ) exam and to assess its correlation with the standard POPQ exam. This study consists of two parts; both were preformed in a prospective, randomized, blinded fashion on women presenting with complaints attributed to pelvic organ support defects. The first study was done to determine the inter-examiner reliability of a simplified POPQ exam. The simplified POPQ exam is based on the POPQ with similar ordinal staging but with only four points measured instead of nine. Forty-eight women underwent exams by five different investigators. The order of exams was randomized and the examiners were blinded to the results of each other’s findings. The results of these two exams were compared using weighted kappa statistics. The second part of the study was done to determine the inter-system agreement between the simplified vs standard POPQ exam. A group of 49 women were examined by four different investigators: one using the simplified and the other using standard POPQ exams. The order of the exams was randomized and the examiners were blinded to the results of each other’s exam. Kendall’s tau-b statistics were used to determine the inter-system agreement. For the inter-examiner reliability of the POPQ exam, the average age was 60±13 years. The weighted kappa statistics for the inter-examiner reliability of the simplified prolapse classification system were 0.86 for the overall stage, 0.89 and 0.86 for the anterior and posterior vaginal walls, respectively, 0.82 for the apex/cuff, and 0.72 for the cervix. All demonstrate significant agreement. For the inter-system association between the simplified POPQ and standard POPQ, the average age was 61±15 year. The Kendall’s tau-b value for overall stage was 0.90, 0.83, and 0.87 for the anterior and posterior walls respectively, and 0.78 for the cuff/apex and 0.98 for the cervix. There is good inter-examiner agreement of a simplified POPQ classification system and it appears to have good inter-system association with the POPQ.IUGA Standardization of Terminology Committee members: Robert Freeman MD (chairman), Steven Swift, Eckhard Petri MD, Richard J. Scotti MD, and Peter Dwyer MD.     

Increasing the efficiency of Monte Carlo cohort simulations with variance reduction techniques.

The authors discuss techniques for Monte Carlo (MC) cohort simulations that reduce the number of simulation replications required to achieve a given degree of precision for various output measures. Known as variance reduction techniques, they are often used in industrial engineering and operations research models, but they are seldom used in medical models. However, most MC cohort simulations are well suited to the implementation of these techniques. The authors discuss the cost of implementation versus the benefit of reduced replications.     

Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized,Double‐Blind,Placebo‐Controlled Clinical Trial

Objective. The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial. Materials and Methods. Patients (169 ziconotide, 86 placebo) with severe chronic nonmalignant pain unresponsive to conventional therapy and a visual analog scale of pain intensity (VASPI score) ≥ 50 mm were treated over a 6‐day period in an inpatient hospital setting. Initial starting dose was 0.4 µg/hour and was titrated to analgesia or intolerance (maximum dose 7.0 µg/hour). The starting and maximum doses were reduced to 0.1 µg/hour and 2.4 µg/hour, respectively, due to adverse events (AEs). Results. The mean percent reduction in VASPI score from baseline was 31.2% and 6.0% for ziconotide‐ and placebo‐treated patients, respectively (p ≤ 0.001). During the initial titration phase, a significantly greater percentage of patients in the ziconotide group compared to the placebo group reported AEs, including abnormal gait, amblyopia, dizziness, nausea, nystagmus, pain, urinary retention, and vomiting. Conclusion. Ziconotide provided significant analgesia in patients for whom conventional therapy failed. However, there was a considerable incidence of ziconotide‐associated AEs due to the rapid titration and high doses administered.