Evaluation of clinical performance and safety for the rechargeable InterStim Micro device in overactive bladder subjects: 6-month results from the global postmarket ELITE study.

AIMS: Sacral neuromodulation (SNM) is an advanced therapy option for the treatment of overactive bladder (OAB), nonobstructive urinary retention, and fecal incontinence. The aim of this ongoing prospective, multicenter, global, postmarket study is to confirm safety and clinical performance of the InterStimTM Micro system for SNM in all indications. Reported here are the results for the OAB cohort through 6-month follow-up. METHODS: Eligible OAB subjects that had a successful therapy evaluation were enrolled after implant of an InterStim Micro implantable pulse generator (IPG). Subjects completed voiding diaries and the Overactive Bladder Quality of Life questionnaire (OAB-q) at baseline and follow-up visits occurring at 3 months and 6 months postimplant. Safety was evaluated as device-, procedure-, or therapy-related adverse events. The primary objective for the OAB cohort was to demonstrate an improvement in OAB-q Health Related Quality of Life (HRQL) total score at 3 months postimplant compared to baseline. RESULTS: Sixty-eight OAB subjects were enrolled and implanted with an InterStim Micro IPG. Of those, 67 and 66 subjects completed the 3- and 6-month follow-up visits, respectively. The OAB-q HRQL demonstrated a statistically significant improvement from baseline to 3-month follow-up with an average increase of 33 ± 24 points (n = 67, p < 0.001). The change was also observed at 6-months with an average increase of 31 ± 23 points (n = 65) compared to baseline. Eighty-two percent of subjects achieved the minimally important difference in HRQL score at 3- and 6-month, respectively, with a change of 10 points or greater. The majority of subjects reported that their bladder condition was better at 3-month (92.5%, 62/67) and 6-month (89%, 59/66) compared to before they were treated with SNM therapy delivered by the InterStim Micro system. For subjects with urgency urinary incontinence (UUI), the average change from baseline to follow-up in UUI episodes/day was -3.6 (95% CI: -4.7, -2.6; n = 62) at 3-month and -3.7 (95% CI: -4.7, -2.7; n = 61) at 6-month. Among subjects with urgency-frequency (UF), the average change from baseline to follow up in voids/day was -4.5 (95% CI: -6.3, -2.7; n = 52) at 3-months and -4.4 (95% CI: -6.0, -2.7; n = 52) at 6-month. The cumulative incidence of device-, procedure-, or therapy- related adverse events was 7.4% (5/68). Out of these five related adverse events, there was one serious adverse event (1.5%, implant site pain) at the time of database snapshot. CONCLUSIONS: These data confirm the safety and clinical performance of the InterStim Micro device for subjects with OAB by demonstrating a significant improvement in OAB-q HRQL score at 3-month. Similar improvements were observed at 6 months in addition to an incidence of adverse events that is comparable to previously reported rates for SNM.

Prospective, multicenter study to evaluate performance and safety of a re-engineered temporary lead for InterStim™ therapy evaluation.

AIMS: The basic evaluation or percutaneous nerve evaluation (PNE) is a method to assess pre-implantation therapeutic response in patients considering sacral neuromodulation for the treatment of refractory overactive bladder. A new PNE lead with a more robust design and greater distensibility designed to reduce the possibility of lead migration has recently been introduced to the market. The aim of this prospective, multicenter, global, postmarket study was to evaluate the clinical performance and safety of the new InterStim PNE lead with the foramen needle. METHODS: Patients with overactive bladder were enrolled in this study. The primary objective of this study was to determine the proportion of subjects who demonstrated motor or sensory response(s) during lead placement using the InterStim PNE lead. Additional measures included the Patient Global Impression of Improvement (PGI-I), patient satisfaction at the end of therapy evaluation, and change in bladder symptoms from baseline to the end of therapy evaluation (1-week follow-up visit). RESULTS: One-hundred and ten subjects met the inclusion and exclusion criteria and underwent a lead implant procedure. Of those, 108 had a successful procedure and 107 completed the 1-week follow-up visit. Ninety-nine percent of subjects (109/110) had a motor or sensory response during needle placement (95% confidence interval [CI]: 95%-100%) and 97% of subjects (107/110) had a motor or sensory response during lead placement (95% CI: 92%-99%). The majority of subjects (88%, 95/108) reported their bladder condition was better at the follow-up visit compared to before the PNE implant procedure, as reported in PGI-I. Subjects reported being satisfied with how the therapy impacted their voiding symptoms (82%, 88/108) and that they would recommend this therapy (87%, 94/108) to other patients. Symptom improvement was demonstrated with urinary urge incontinence subjects having an average of 4.2 ± 3.4 urinary incontinence episodes/day at baseline and 2.2 ± 2.5 at follow-up, and urinary frequency subjects having an average of 12.5 ± 4.4 voids/day at baseline and 10.5 ± 4.3 voids/day at follow-up. Lead removal was deemed to be easy and safe by the implanting physician, with a total of three adverse device effects in 3/110 subjects. No event was categorized as serious and all were resolved without sequelae. CONCLUSIONS: The updated InterStim PNE lead with a more robust design and greater distensibility designed to reduce migration was shown to have a high rate of motor or sensory response during lead placement. Furthermore, subjects reported high rates of global improvements and amelioration of symptoms, and the lead was easy to remove with minimal morbidity.

Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach.

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p ≤ 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 × 10-8), was nominally a cis-expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor ß (TGFß)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 × 10-5). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations.

Rationale and design of an implant procedure and pivotal study to evaluate safety and effectiveness of Medtronic's tibial neuromodulation device.

Percutaneous tibial neuromodulation is a medical guideline recommended therapy for treating symptoms of overactive bladder. Stimulation is delivered to the tibial nerve via a thin needle placed percutaneously for 30 min once a week for 12-weeks, and monthly thereafter. Studies have shown that this therapy can effectively relieve symptoms of overactive bladder; however, the frequent office visits present a barrier to patients and can impact therapy effectiveness. To mitigate the burden of frequent clinic visits, small implantable devices are being developed to deliver tibial neuromodulation. These devices are implanted during a single minimally invasive procedure and deliver stimulation intermittently, similar to percutaneous tibial neuromodulation. Here, we describe the implant procedure and design of a pivotal study evaluating the safety and effectiveness for an implantable tibial neuromodulation device. The Evaluation of Implantable Tibial Neuromodulation (TITAN 2) pivotal study is a prospective, multicenter, investigational device exemption study being conducted at up to 30 sites in the United States and enrolling subjects with symptoms of overactive bladder.

Maternally-derived antibody to fibroblast growth factor-23 reduced dietary phosphate requirements in growing chicks.

Phosphate in manure of monogastric animals pollutes the environment if improperly applied to soil. Strategies that reduce phosphate inputs into animal production systems reduce environmental pollution. Using a novel vaccine to fibroblast growth factor-23 (FGF-23), we induced neutralizing antibodies that reduced the phosphate requirement of growing chickens. Breeding hens were injected with a FGF-23 peptide (AFLPGMNP) conjugate. Antibody was passively transferred from hen to chick and chick response to deficient dietary phosphate intake was determined. Chicks without passive anti-FGF-23 antibody had a 43% and 21% reduction in blood phosphate and bone ash, respectively, when fed a phosphate deficient diet and compared to chicks fed a phosphate replete diet (P<0.05). Chicks with circulating anti-FGF-23 antibodies fed the phosphate deficient diet had plasma phosphate and bone ash that did not differ from chicks fed the phosphate replete diet (P>0.05). Neutralization of FGF-23 offers a new approach to reduce phosphate requirements of farmed animals and may provide a new means to reduce phosphate pollution related to animal farming.

Diagnosis of urolithiasis and rate of spontaneous passage during pregnancy.

PURPOSE: Due to imaging limitations little is known about the true rate of spontaneous stone passage during pregnancy. We evaluated the accuracy of urolithiasis diagnosis during pregnancy and the rate of spontaneous passage. MATERIALS AND METHODS: We retrospectively reviewed the records of patients diagnosed with urolithiasis during pregnancy from 1997 to 2009. Patients were evaluated for a confirmed stone event, defined as a stone visualized on imaging or at surgery, or passed with visualization. RESULTS: We identified 112 women diagnosed with urolithiasis during pregnancy, including 5 with multiple episodes for a total of 117 events. Stones were visualized by imaging in 63 of 117 events. Another 22 patients without imaging confirmation passed a stone spontaneously. In 1 patient the stone was diagnosed at surgical removal during pregnancy and postpartum imaging identified another 4 patients. Thus, 90 of 117 events (77%) represented confirmed stones. Of the 90 patients 27 (30%) underwent temporizing or definitive surgical intervention during pregnancy. Postpartum definitive surgical management was necessary in 29 women (25%). Overall only 43 of 90 women (48%) spontaneously passed the stone. Mean followup of those with confirmed stones was 51 months. Urolithiasis recurred in 26 of the 90 patients (29%). The most common primary component of analyzed stones was calcium phosphate (81%). CONCLUSIONS: We found that almost a quarter of pregnant women diagnosed with urolithiasis are diagnosed inaccurately. The inappropriate diagnosis of urolithiasis may contribute to the misconception that most stones pass with conservative management during pregnancy.

Variants in the CYP2B6 3'UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs.

CYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 activity. Emerging evidence has shown that genetic variants in the 3'UTR may explain variable drug response by altering microRNA regulation. Five 3'UTR variants were associated with significantly altered efavirenz AUC0-48 (8-OH-EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR-1275, was associated with a 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA (P < 0.05)). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing an 11.3% decrease in activity compared to the AG allele when treated with miR-1275 (P = 0.0035). Our results show that a 3'UTR variant contributes to variability in CYP2B6 activity.

Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes.

UNLABELLED: Membrane drug transporters contribute to the disposition of many drugs. In human liver, drug transport is controlled by two main superfamilies of transporters, the solute carrier transporters (SLC) and the ATP Binding Cassette transporters (ABC). Altered expression of these transporters due to drug-drug interactions can contribute to differences in drug exposure and possibly effect. In this study, we determined the effect of rifampin on gene expression of hundreds of membrane transporters along with all clinically relevant drug transporters. METHODS: In this study, primary human hepatocytes (n = 7 donors) were cultured and treated for 24 h with rifampin and vehicle control. RNA was isolated from the hepatocytes, mRNA expression was measured by RNA-seq, and miRNA expression was analyzed by Taqman OpenArray. The effect of rifampin on the expression of selected transporters was also tested in kidney cell lines. The impact of rifampin on the expression of 410 transporter genes from 19 different transporter gene families was compared with vehicle control. RESULTS: Expression patterns of 12 clinically relevant drug transporter genes were changed by rifampin (FDR < 0.05). For example, the expressions of ABCC2, ABCB1, and ABCC3 were increased 1.9-, 1.7-, and 1.2-fold, respectively. The effects of rifampin on four uptake drug transporters (SLCO1B3, SLC47A1, SLC29A1, SLC22A9) were negatively correlated with the rifampin effects on specific microRNA expression (SLCO1B3/miR-92a, SLC47A1/miR-95, SLC29A1/miR-30d#, and SLC22A9/miR-20; r < -0.79; p < 0.05). Seven hepatic drug transporter genes (SLC22A1, SLC22A5, SLC15A1, SLC29A1, SLCO4C1, ABCC2, and ABCC4), whose expression was altered by rifampin in hepatocytes, were also present in a renal proximal tubular cell line, but in renal cells rifampin did not alter their gene expression. PXR expression was very low in the kidney cells; this may explain why rifampin induces gene expression in a tissue-specific manner. CONCLUSION: Rifampin alters the expression of many of the clinically relevant hepatic drug transporters, which may provide a rational basis for understanding rifampin-induced drug-drug interactions reported in vivo. The relevance of its effect on many other transporters remains to be studied.

Robotic/Laparoscopic prolapse repair and the role of hysteropexy: a urology perspective.

Approximately 11% of women will undergo a surgical procedure for the treatment of pelvic organ prolapse (POP) or urinary incontinence by age 80 years. Abdominal sacrocolpopexy has been found in multiple studies to have high long-term success rates for repair of severe vault prolapse. Robotic or laparoscopic sacrocolpopexy offer similar success to an open approach. This article describes the techniques of laparoscopic sacrocolpopexy and robotic sacrocolpopexy. The role of hysteropexy for the treatment of POP is also discussed.