Comparing Medications in a Therapeutic Area Using an NNT Model

OBJECTIVES: Clinicians are told to use the number needed to treat (NNT) to compare the benefits of therapeutic strategies, and researchers are asked to report results this way, generally without considering differences among the studies from which these were derived. METHODS: The crude NNT currently advocated is compared to the NNT standardized for a common outcome, follow-up time, study population and comparator. An NNT model for cardiovascular disease is described as an example that addresses differences among studies of secondary prevention of cardiovascular disease. Crude NNTs are compared to those obtained from the model. RESULTS: Follow-up in the 18 trials identified varied from 1.0 to 6.2 years; rates of cardiovascular events in the untreated subgroups ranged from 4.8% to 45.9%. The crude NNTs were more variable (9.1-163.7) than those obtained from the model (9.1-75.2). The effect of standardization was substantial in some cases, with proportional changes ranging from a 91% decrease to a 223% increase. CONCLUSION: Using an NNT model to account for differences in study design allows for more meaningful comparisons.     

De novo microduplication of the FMR1 gene in a patient with developmental delay,epilepsy and hyperactivity

Loss-of-function due to expansion of a CGG repeat located in the 5''UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.     

Potassium Balance in Dialysis Patients

The advent of dialytic therapy has enabled nephrologists to provide life‐saving therapy, but potassium balance continues to be an ever present challenge in the ESRD population. Although a small percent of patients are chronically hypokalemic, hyperkalemia is by far the most common abnormality in dialysis patients. It is associated with increased all‐cause mortality, cardiovascular mortality, and arrhythmogenic death. Although alterations of the dialysis bath may decrease predialysis potassium, potassium baths <2 mEq/l are associated with a higher risk of sudden cardiac death. Studies show that patients are aware of the risks of hyperkalemia, but adherence to a low potassium diet is suboptimal. ACEI, ARBs, and spironolactone may cause slight increases in potassium even in anuric patients, requiring increased surveillance. Fludrocortisone and potassium binders have not been proven to be beneficial in lowering interdialytic potassium levels. Frequent hemodialysis may be a viable option, and studies of prophylactic placement of implantable cardioverter/defibrillators are underway.     

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells, and, because of this, we observe that the malaria parasite Plasmodium falciparum is highly sensitive to the inhibition of components of this protein quality control system. Inhibitors that specifically target a putative protease component of ERAD, signal peptide peptidase (SPP), have high selectivity and potency for P. falciparum. By using a variety of methodologies, we validate that SPP inhibitors target P. falciparum SPP in parasites, disrupt the protein’s ability to facilitate degradation of unstable proteins, and inhibit its proteolytic activity. These compounds also show low nanomolar activity against liver-stage malaria parasites and are also equipotent against a panel of pathogenic protozoan parasites. Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential pan-protozoan drug target.     

Terapia con estimulación del nervio vago en pacientes con epilepsia fármaco-resistente y callosotomía previa

ObjectiveTo analyse the results of vagus nerve stimulation in patients with drug-resistant epilepsy and previous corpus callosotomy.Materials and methodsWe prospectively reviewed data from patients with drug-resistant epilepsy who showed persistence of disabling seizures after undergoing corpus callosotomy, in whom it was not possible to identify an epileptogenic focus and who were subsequently treated with vagus nerve stimulation.Variables analysed included: age, gender, aetiology of epilepsy, frequency and characteristics of the crises and Engel scale classification, before and after vagal stimulator implant. Furthermore, the percentage differences in seizure frequency changes were also calculated.ResultsFour patients were identified: two male and two female. The total seizure frequency had decreased between 20% and 81% after corpus callosotomy in three patients and one of them did not show any favourable response (Engel IVB). Following implantation of the stimulator they became reduced to between 57% and 100% after a mean follow-up period of 8.3 months (range: 3 to 12 months). Generalised seizures decreased between 71.4% and 100%, and focal seizures between 57.7% and 100%.ConclusionsVagus nerve stimulation therapy proved to be an alternative for the reduction of seizure frequency in patients with drug-resistant epilepsy who suffered disabling seizures despite undergoing corpus callosotomy as primary surgery.     

Evidence-Based Practice Implementation Within a Theory of Planned Behavior Framework

Although significant progress has been made in the identification of youth evidence-based practices, the adoption of these interventions into community-based mental health care remains limited. Dissemination and implementation (DI) research has the potential to bridge this science-practice gap in clinical psychology. The theory of planned behavior (TPB) offers a useful conceptualization of individual behavior change including behavioral intention as defined by attitudes, subjective norms, and perceived behavioral control. To facilitate application of this model to DI efforts, the current study explores perspectives about using evidence-based practice from stakeholders in the field of youth mental health (including clinical supervisors, case managers, administrators at the departments of health and education, and direct service providers in clinic-based, school-based, and intensive in-home settings) within the TPB framework. A set of instrument items was created from this rich qualitative data using a rigorous mixed-method content validation approach. Instrument items are provided for future use in DI research.     

Molecular Investigation of Tularemia Outbreaks,Spain, 1997–2008

Tularemia outbreaks occurred in northwestern Spain in 1997–1998 and 2007–2008 and affected >1,000 persons. We assessed isolates involved in these outbreaks by using pulsed-field gel electrophoresis with 2 restriction enzymes and multilocus variable number tandem repeat analysis of 16 genomic loci of Francisella tularensis, the cause of this disease. Isolates were divided into 3 pulsotypes by pulsed-field gel electrophoresis and 8 allelic profiles by multilocus variable number tandem repeat analysis. Isolates obtained from the second tularemia outbreak had the same genotypes as isolates obtained from the first outbreak. Both outbreaks were caused by genotypes of genetic subclade B.Br:FTNF002–00, which is widely distributed in countries in central and western Europe. Thus, reemergence of tularemia in Spain was not caused by the reintroduction of exotic strains, but probably by persistence of local reservoirs of infection.