Methods for a multicenter randomized trial for mixed urinary incontinence: rationale and patient-centeredness of the ESTEEM trial

Introduction and hypothesis

Mixed urinary incontinence (MUI) can be a challenging condition to manage. We describe the protocol design and rationale for the Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM) trial, designed to compare a combined conservative and surgical treatment approach versus surgery alone for improving patient-centered MUI outcomes at 12 months.

Methods

ESTEEM is a multisite, prospective, randomized trial of female participants with MUI randomized to a standardized perioperative behavioral/pelvic floor exercise intervention plus midurethral sling versus midurethral sling alone. We describe our methods and four challenges encountered during the design phase: defining the study population, selecting relevant patient-centered outcomes, determining sample size estimates using a patient-reported outcome measure, and designing an analysis plan that accommodates MUI failure rates. A central theme in the design was patient centeredness, which guided many key decisions. Our primary outcome is patient-reported MUI symptoms measured using the Urogenital Distress Inventory (UDI) score at 12 months. Secondary outcomes include quality of life, sexual function, cost-effectiveness, time to failure, and need for additional treatment.

Results

The final study design was implemented in November 2013 across eight clinical sites in the Pelvic Floor Disorders Network. As of 27 February 2016, 433 total/472 targeted participants had been randomized.

Conclusions

We describe the ESTEEM protocol and our methods for reaching consensus for methodological challenges in designing a trial for MUI by maintaining the patient perspective at the core of key decisions. This trial will provide information that can directly impact patient care and clinical decision making.

     

Physiologically based controller for generating overground locomotion using functional electrical stimulation

The physiological control of stepping is governed both by signals descending from supraspinal systems and by circuitry residing within the lumbosacral spinal cord. The goal of this study was to evaluate the capacity of physiologically based controllers to restore functional overground locomotion after neurological damage, such as spinal cord injury when used in conjunction with functional electrical stimulation. For this purpose we implemented and tested two controllers: 1) an intrinsically timed system that generated a predetermined rhythmic output and 2) a sensory-based system that used feedback signals to make appropriate transitions between the unloaded (flexion) and loaded (extension) phases of the gait cycle. A third controller, a combination of the intrinsically timed and sensory-driven controllers, was implemented and two sessions were conducted to demonstrate the functional advantages of this approach. The controllers were tested in anesthetized cats, implanted with intramuscular electrodes in six major extensor and flexor muscles of the hindlimbs. The cats were partially supported on a sliding trolley that was propelled by the hindlimbs along a 2.5-m instrumented walkway. Ground reaction forces and limb positions were measured by force plates in the walkway and by accelerometers secured to the legs of the cat, respectively. The controllers were used to generate patterns of stimulation that would elicit alternating flexor (swing) and extensor (stance) movements in the hindlimbs. Using either the intrinsically timed or sensory-driven controllers, the cats were able to travel a distance of 2.5 m, taking five to 12 steps. Functional stepping sequences were more easily achieved using the intrinsically timed controller as the result of a lower sensitivity to the selection of initial stimulation parameters. However, unlike the sensory-driven controller, the intrinsically timed controller was unable to adjust to overcome walkway resistance and muscle fatigue. Neither system was consistently able to ensure load-bearing stepping. Therefore we propose the use of a "combined controller" that relies heavily on intrinsic timing but that can be reset based on sensory signals. A combined controller such as this one may provide the best solution for restoring robust overground locomotion after spinal cord injury.     

Common Deficiencies of <Emphasis Type="Italic">in vitro</Emphasis> Binding Bioequivalence (BE) Studies Submitted in Abbreviated New Drug Applications (ANDAs)

There are several drug products that bind phosphate or bile acid in the gastrointestinal (GI) tract to exert their therapeutic efficacy. In vitro binding studies are used to assess bioequivalence (BE) of these products. The objective of this study is to identify the common deficiencies in Abbreviated New Drug Applications (ANDAs) for these products. Deficiencies were compiled from ANDAs containing in vitro binding BE studies. The deficiencies were classified into eight categories: Pre-Study Method Validation, During-Study Sample Analysis, Study Design, Study Procedure, Dissolution/Disintegration, Analytical Site Inspection, Data Submission, and Formulations. Within each category, additional subcategories were defined to characterize the deficiencies. A total of 712 deficiencies from 95 ANDAs for 11 drug products were identified and included in the analysis. The four categories with the most deficiencies were During-Study Sample Analysis (27.8%), Pre-Study Method Validation (17.3%), Data Submission (16.7%), and Study Design (15.7%). For the During-Study Sample Analysis category, failure to submit complete raw data or analytical runs ranked as the top deficiency (32.8%). For the Study Design category, using an unacceptable alternate study design (26.8%) was the most common deficiency. Within this category, other commonly occurring deficiencies included incorrect/insufficient number of absorbent concentrations, failure to pre-treat drug product with acid, insufficient number of replicates in study, incorrect calculation of k1 and k2 values, incorrect dosage form or pooled samples used in the study, and incorrect pH of study medium. The review and approval of these products may be accelerated if these common deficiencies are addressed in the original ANDA submissions.     

Reversal of resistance in microorganisms by help of non-antibiotics

Intracellular efflux pumps have been largely the research focus in multidrug-resistant (MDR) Gram-positive and Gram-negative microorganisms and parasites including cancers. However, drug efflux mechanisms other than pumps per se have been observed, supported by the effects of isomeric, non-antibiotic depressant (DPR), phenothiazines and thixenes, and antidepressant (ADPR) phenylpiperidine neurotropic drugs, alone or in combination with classical antimicrobials on MDR Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes and Streptococcus pneumoniae. Of the non-antibiotics we investigated, the DPR l-thioridazine, trans-clopenthixol and isomers of phenylpiperidines NNC 20-4962 (isomer of femoxetine) and NNC 20-7052 (isomer of paroxetine) were potent antimicrobials with the least neurotropic activity, pointing to a possible general isomeric structure-activity relationship. These compounds may be regarded as new efflux inhibitors. Moreover, these isomers have considerably reduced, in some cases absent, neurotropism and reduced mammalian toxicity. This may alleviate concerns about adverse effects and therapeutic safety for infected patients in life-threatening situations where the non-antibiotic dosage would be in the lower, non-chronic dosage ranges generally prescribed for individuals with mild mental health problems. The results point to the prokaryotic and eukaryotic microorganisms' phospholipid/protein domain involvement of the cationic, amphiphilic, non-antibiotic DPR and ADPR, with the phospholipids being the initial sites attracting and concentrating the neurotropes to induce a form of suspended animation, followed by gross changes of cell wall and membrane structure, and thereby potentiating their destructive or immobilizing effects on various as yet only hinted at resistance and efflux mechanisms. Combination of appropriate isomeric non-antibiotic DPR and ADPR of low neurotropism and toxicity with conventional and classical antimicrobials promises early, new therapeutic strategies salutary against microbial resistance, resistance development, pathogenicity and virulence.     

The mechanisms and evidence of efficacy of electrical stimulation for healing of pressure ulcer: A systematic review

The objective of this article is to provide a systematic review of the efficacy of electrical stimulation in healing pressure ulcer and to review its mechanism of action. The Cochrane Library, PubMed, CINAHL, Medline, EMBASE, and NHS EED were searched for relevant interventional studies including randomized controlled trials (RCTs) and observational studies. A best‐evidence synthesis was performed to summarize the results of the included studies. A total of seven RCTs and two observational studies met the inclusion criteria. Moderate level of evidence of efficacy with low risk of bias was shown in all seven RCTs. Although some studies have used continuous direct current, most other investigators opted to use high‐voltage pulsed current to minimize the risk of skin burn and to achieve greater current penetration. Overall, the incidence of adverse effects was very low. Two studies that assessed the economic impacts of electrical stimulation revealed substantial health care cost savings. The mechanisms through which electrical stimulation exerts a positive effect on pressure ulcer healing are reasonably well established. Clinical trials have revealed a moderate level of evidence to support its use as an ancillary treatment modality for healing pressure ulcer. Recommendations regarding the optimal electrical stimulation parameters and dosage of use are provided. Further studies to investigate potential barriers that may impede widespread use in different clinical settings are needed.