Abstract Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed “resistant/refractory CMV” and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of “resistant” and “refractory” CMV. These definitions have emerged from the Working Group’s review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

It has been emphasized that the anterior cruciate ligament plays an important role in the proprioceptive feedback system. The anterior cruciate ligament-hamstring reflex has been revealed in animal experiments, but it has not been established in humans. The purpose of this study was to demonstrate direct evidence of the anterior cruciate ligament-hamstring reflex arc. Nine knees in nine healthy subjects were investigated. The anterior cruciate ligament was stimulated by the use of wire electrodes inserted using an arthroscopic technique. Electromyographic signals from the biceps femoris and the semitendinosus muscles were recorded with surface electrodes. The change in electromyographic activity was analyzed after electrical stimulation in the normal knee condition, and again after intraarticular sensation had been interrupted with a local anesthetic. After electrical stimulation, subjects demonstrated increased electromyographic activity of the hamstring muscles in the normal knee condition. This response indicates the existence of an anterior cruciate ligament-hamstring reflex arc. Conversely, there was no change in activity for the hamstring muscle in the anesthetized knee because the afferent impulse from the neural elements of the anterior cruciate ligament had been removed.

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