Elevated fibrosis burden as assessed by MRI predicts cryoballoon ablation failure.

INTRODUCTION: Late-gadolinium enhancement magnetic resonance (LGE-MRI) imaging is increasingly used in management of atrial fibrillation (AFib) patients. Here, we assess the usefulness of LGE-MRI-based fibrosis quantification to predict arrhythmia recurrence in patients undergoing cryoballoon ablation. Our secondary goal was to compare two widely used fibrosis quantification methods. METHODS: In 102 AF patients undergoing LGE-MRI and cryoballoon ablation (mean age 62 years; 64% male; 59% paroxysmal AFib), atrial fibrosis was quantified using the pixel intensity histogram (PIH) and image intensity ratio (IIR) methods. PIH segmentations were completed by a third-party provider as part of the standard of care at our hospital; Image intensity ratio (IIR) segmentations of the same scans were carried out in our lab using a commercially available software package. Fibrosis burdens and spatial distributions for the two methods were compared. Patients were followed prospectively for recurrent arrhythmia following ablation. RESULTS: Average PIH fibrosis was 15.6 ± 5.8% of the left atrial (LA) volume. Depending on threshold (IIRthr ), the average IIR fibrosis (% of LA wall surface area) ranged from 5.0 ± 7.2% (IIRthr = 1.2) to 37.4 ± 10.9% (IIRthr = 0.97). An IIRthr of 1.03 demonstrated the greatest agreement between the methods, but spatial overlap of fibrotic areas delineated by the two methods was modest (Sorenson Dice coefficient: 0.49). Fourty-two patients (41.2%) had recurrent arrhythmia. PIH fibrosis successfully predicted recurrence (HR 1.07; p = .02) over a follow-up period of 362 ± 149 days; regardless of IIRthr , IIR fibrosis did not predict recurrence. CONCLUSIONS: PIH-based volumetric assessment of atrial fibrosis was modestly predictive of arrhythmia recurrence following cryoballoon ablation in this cohort. IIR-based fibrosis was not predictive of recurrence for any of the IIRthr values tested, and the overlap in designated areas of fibrosis between the PIH and IIR methods was modest. Caution must therefore be exercised when interpreting LA fibrosis from LGE-MRI, since the values and spatial pattern are methodology-dependent.

Epicardial adipose tissue is associated with left atrial volume and fibrosis in patients with atrial fibrillation.

Background: Obesity is a risk factor for atrial fibrillation (AF) and strongly influences the response to treatment. Atrial fibrosis shows similar associations. Epicardial adipose tissue (EAT) may be a link between these associations. We sought to assess whether EAT is associated with body mass index (BMI), left atrial (LA) fibrosis and volume. Methods: LA fibrosis and EAT were assessed using late gadolinium enhancement, and Dixon MRI sequences, respectively. We derived 3D models incorporating fibrosis and EAT, then measured the distance of fibrotic and non-fibrotic areas to the nearest EAT to assess spatial colocalization. Results: One hundred and three AF patients (64% paroxysmal, 27% female) were analyzed. LA volume index was 54.9 (41.2, 69.7) mL/m2, LA EAT index was 17.4 (12.7, 22.9) mL/m2, and LA fibrosis was 17.1 (12.4, 23.1)%. LA EAT was significantly correlated with BMI (R = 0.557, p < 0.001); as well as with LA volume and LA fibrosis after BSA adjustment (R = 0.579 and R = 0.432, respectively, p < 0.001 for both). Multivariable analysis showed LA EAT to be independently associated with LA volume and fibrosis. 3D registration of fat and fibrosis around the LA showed no clear spatial overlap between EAT and fibrotic LA regions. Conclusion: LA EAT is associated with obesity (BMI) as well as LA volume and fibrosis. Regions of LA EAT did not colocalize with fibrotic areas, suggesting a systemic or paracrine mechanism rather than EAT infiltration of fibrotic areas.

Opportunistic osteoporosis screening using routine computed tomography images to identify bone loss in gynecologic cancer survivors.

OBJECTIVE: Cancer treatment-induced bone loss is a known side effect of cancer therapy. Computed tomography (CT) bone mineral density screening is a novel tool for identifying bone loss. This study aims to use routine CT images to determine long-term bone mineral density changes and osteoporosis risk among women with gynecologic cancers. METHODS: Bone loss was evaluated in a retrospective cohort of women ≤65 years old with gynecologic cancer who underwent oophorectomy from January 2010 to December 2014. Opportunistic CT-based bone mineral density measurements (Hounsfield units, HU) were performed at baseline and intervals up to 5 years after cancer diagnosis. Osteoporosis risk was categorized by HU. Bivariate and multivariate analyses were performed to compare baseline to follow-up bone mineral density at 1, 3, and 5 years and to identify predictors of bone loss following diagnosis. RESULTS: A total of 185 patients (median age 53 years, range 23-65 years, 78.1% ovarian cancer) were included. Bone mineral density significantly decreased between baseline and 1 year (p<0.001), 3 years (p<0.001), and 5 years (p<0.001). Half with normal bone mineral density at baseline had risk for osteopenia or osteoporosis at 5 years. Four percent had osteoporosis risk at baseline compared with 1 year (7.4%), 3 years (15.7%), and 5 years (18.0%). Pre-treatment bone mineral density was a significant predictor at 1 and 5 years (1 year: p<0.01; 5 years: p<0.01). History of chemotherapy predicted bone loss at 1 year (p=0.03). More lifetime chemotherapy cycles were associated with increased risk of osteoporosis at 1 year (p=0.03) and 5 years (p=0.01). CONCLUSIONS: Women with gynecologic cancers may experience accelerated cancer treatment-induced bone loss. Routine CT imaging is a convenient screening modality to identify those at highest risk for osteoporosis who warrant further evaluation with dual-energy X-ray absorptiometry. Routine bone mineral density assessments 1 year following oophorectomy for cancer treatment may be warranted in this population.

Improving Obstetric Provider Congenital Cytomegalovirus Knowledge and Practices.

Background: Congenital cytomegalovirus infection (cCMV) is the most common congenital infection. Antenatal education is proven to reduce cCMV risk. Little is known about obstetric provider knowledge and practice patterns around cCMV. Objectives: To evaluate obstetric provider knowledge and practice patterns regarding cCMV at baseline and again after a brief educational intervention. Methods: Obstetric providers (N = 53) at a US academic community hospital were invited to complete a survey regarding their knowledge and practice patterns around cCMV. Providers attended a brief presentation about cCMV and later were invited to repeat the same survey. Univariate statistics were calculated for baseline data, and prepost intervention comparison analyses were conducted. Results: Baseline cCMV knowledge was low at 49% (M = 17.54 out of a possible 36, SD 6.4), with most providers (51%) reporting never counseling pregnant patients about cCMV. Post intervention, overall cCMV knowledge increased to 80% (M = 29.33, SD 4.1, p < .001); provider intention to counsel about cCMV prevention increased to 100%. Conclusions: Obstetric provider knowledge about cCMV is low, which likely impacts their antenatal counseling. Educational initiatives to increase awareness about cCMV may increase antenatal education and thereby decrease the risk of cCMV.

Evaluation of an activated carbon disposal system for safe disposal of model prescription sedative medications.

Lack of a safe and convenient disposal method for expired and unused medications may lead to many problems such as accidental exposure, intentional misuse, and food and water contamination. Activated carbon can offer safe disposal of medications due to its highly porous structure, which exerts strong physical adsorption forces with chemicals. This study aimed to evaluate the efficiency of an activated carbon-based drug disposal system for deactivating three model sedative prescription medications. Deactivation was performed by mixing the medication, activated carbon, and tap water. Desorption was evaluated by exposing the deactivation system to wash-out solutions. Rapid, precise, accurate, and sensitive HPLC-UV method for each drug was successfully developed, validated and employed. Results of the 28-day deactivation study showed that on average, more than 94.00% of drugs were rapidly deactivated within 8 hours. All drugs reached more than 99.00% deactivation by the end of 28-day period. Desorption study demonstrated that all medications were retained by the system, with insignificant amount of drug (0.25%) leached into the washout solutions within 24 hours. In conclusion, activated carbon rapidly and successfully deactivated the medications tested, suggesting activated carbon-based drug disposal system provides a convenient, secure, and effective method for unused medication.

Barriers to College and Health Care Careers Among US Students From a Rural Community.

INTRODUCTION: Despite rural origin being a strong predictor of rural practice for health care professionals, rural students face educational barriers and are underrepresented in medical schools. The aim of this study was to identify rural high school students' perceived barriers to college and health-related careers and compare whether perceptions were similar based on gender, socioeconomic status (SES), and parental education. METHODS: We performed a cross-sectional survey of all high school students from one rural Michigan community. The survey included 13 multiple-choice and 5 short-answer questions. We compared results using χ2 analysis and logistic regression. Free-text answers were grouped thematically and analyzed for patterns. RESULTS: Survey response rate was 97.1% (506/521); 45.3% (229/506) of students were contemplating health care careers. Rural females were more likely to plan on college (females 83.9%, males 75.6%, P=0.03) and to contemplate a health care career (females 64.1%, males 25.2%, P<0.01). Students of lower SES and those who would be first-generation college students were less likely to plan on college (SES: low 76.8%, high 84.7%, P=.04; parental college: yes 84.4%, no 72.0%, P<0.01), although they were equally likely as other students to consider a health care career. Gender and parental education were significant independent predictors of plans for college; female gender was the only significant predictor for health care interest. The most frequently reported barrier to post-high school education was financial, and for health care training, it was academic success. CONCLUSIONS: Rural students are interested in health-related careers. Addressing perceived academic and financial barriers for students from high-need rural communities may inform targeted interventions to increase the rural health care workforce.

The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study.

BACKGROUND: Statins are thought to possess antineoplastic properties related to their effect on cell proliferation and steroidogenesis. Progression to castrate resistant prostate cancer (CaP) includes de-regulation of androgen synthesis suggesting a role for statins in this setting. Our goal was to assess the role of statin use on oncologic outcomes in patients with advanced CaP being treated with androgen deprivation therapy (ADT). METHODS: The national VA database was used to identify all men diagnosed with CaP who were treated with ADT for at least 6 months between 2000 and 2008 with follow-up through May 2016. Our cohort was stratified based on statin use of at least 6 months duration during the same time. Multivariable Cox proportional hazards analyses with inverse propensity score weighted (IPSW) adjustment were calculated to assess for primary outcomes of CaP-specific survival (CSS), overall survival (OS) and skeletal related events (SREs). RESULTS: A total of 87,346 patients on ADT were included in the study cohort, 53,360 patients used statins and 33,986 did not. Statin users were younger in age (median 73 vs. 76, P < 0.001), more likely to have a higher Charlson comorbidity index (CCI) >3 (3.1% vs. 2.5%, P < 0.001) and more likely to have a high grade (Gleason score 8-10) cancer (12.3% vs. 10.9%, P < 0.001). Statin users had longer OS (median 6.5 vs. 4.0 years P < 0.001) and decreased death from CaP (5-year CSS 94.0% vs. 87.3%, P < 0.001). Statin use was also associated with longer time to a SRE (median 5.9 vs. 3.7 years, P < 0.001). On multivariable Cox proportional hazards analysis with inverse propensity score weighted, statin use was an independent predictor of improved OS (hazard ratio [HR] 0.66, confidence interval [CI] 0.63-0.68; P < 0.001), CSS (HR 0.56, 95% CI 0.53-0.60; P < 0.001), and SREs (HR 0.64, 95%CI 0.59-0.71; P < 0.001) when controlling for age, race, Charlson comorbidity index, prostate-specific antigen, and Gleason score. CONCLUSION: The use of statins in men on ADT for CaP is associated with improved CSS and OS. Statins are inexpensive, well-tolerated medications that offer a promising adjunct to ADT, but require further prospective studies.

Development of Disposal Systems for Deactivation of Unused/Residual/Expired Medications.

PURPOSE: The objective of this work was to identify deactivation agents and develop a disposal system for unused/ residual/ expired medications. METHODS: Deactivation agents screened included oxidizing agent-sodium percarbonate, hydrolysis agent- sodium carbonate and adsorbants- zeolite and activated carbon. Deactivation studies using these agents were performed on four active pharmaceutical agents (APIs) including ketoprofen, dexamethasone sodium phosphate, metformin hydrochloride and amoxicillin trihydrate. Disposal systems were also designed for deactivation studies on dexamethasone pills, amoxicillin trihydrate capsules and fentanyl transdermal patches (Duragesic®). Briefly, APIs/ dosage forms were allowed to be in close contact with deactivation agents for a specified period of time and percentage decrease in the amount of API from the initial amount was measured. RESULTS: Sodium percarbonate and sodium carbonate were only successful in deactivation of amoxicillin trihydrate API. Adsorption agents resulted in more universal deactivation with activated carbon resulting in efficient deactivation of most APIs and all dosage forms tested. Also adsorption of oral dosage medications on activated carbons was maintained even on dilution and shaking and no desorption was observed. CONCLUSIONS: Deactivation systems containing activated carbon are promising for efficient, safe and environment friendly disposal of unused/residual/expired medications.

A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis.

The nature of Alzheimer's disease limits the effectiveness of available oral treatments. The aim of this study was to assess the feasibility of transdermal iontophoretic delivery of donepezil in a hairless rat model as a potential treatment modality in Alzheimer's and to evaluate the effect of current densities on its pharmacokinetics. Donepezil loaded integrated Wearable Electronic Drug Delivery (WEDD(®)) patches supplied current levels of 0, 0.13, 0.26 and 0.39 mA. Plasma extracted donepezil was analyzed by HPLC. Noncompartmental analysis was used to characterize disposition of the drug. The amount delivered across hairless rat skin and areas under the curve (AUC) were found to rise in proportion to the current levels. Peak plasma levels of 0.094, 0.237 and 0.336 µg/ml were achieved at 0.13, 0.26 and 0.39 mA respectively. Time to peak plasma concentrations was after termination of current and same for all current levels. Transdermal elimination half-life was significantly increased from the true value of 3.2h due to depot formation, prolonging complete absorption of the drug. Donepezil was successfully delivered iontophoretically at levels sufficient to produce pharmacodymanic effect. Pharmacokinetic analysis demonstrated linear kinetics at the current levels used and flip flop kinetics following iontophoretic administration.

Investigation of drug delivery by iontophoresis in a surgical wound utilizing microdialysis.

PURPOSE: This study investigated the penetration of lidocaine around and through a sutured incision following the application of iontophoretic and passive patches in the CD Hairless rat. MATERIALS AND METHODS: Concentrations in localized areas (suture, dermis, subcutaneous, and vascular) were determined using microdialysis sampling followed by analysis using liquid chromatography with UV detection. RESULTS: Iontophoresis significantly enhanced the dermal penetration of lidocaine. In an intact skin model, dermal concentrations were 40 times greater following iontophoretic delivery compared to passive delivery. In a sutured incision model, iontophoresis enhanced localized concentrations in the dermis, suture, and subcutaneous regions by 6-, 15-, and 20-fold, respectively. Iontophoretic delivery to a region containing a sutured incision was focused to the incision resulting in a greater increase in the suture concentration and in the subcutaneous region directly below the incision. CONCLUSIONS: The four microdialysis probe design was successful in the determination of localized drug penetration in a sutured incision model. Iontophoresis enhanced skin penetration and allowed for site specific delivery when applied to a sutured incision.

Dermal, subdermal, and systemic concentrations of granisetron by iontophoretic delivery.

PURPOSE: The purpose of this work was to demonstrate the iontophoretic delivery of granisetron hydrochloride by novel, self-contained iontophoretic patches and to determine the subcutaneous and dermal absorption kinetics using microdialysis. METHODS: In vitro iontophoretic delivery of granisetron hydrochloride was evaluated at 5, 10, or 20 mg/ml concentrations of donor using Franz diffusion cells and hairless rat skin as a membrane. In vivo studies were performed in hairless rats. Animals received either subcutaneous or dermal microdialysis probes and iontophoretic patches filled with drug formulation were applied on the abdominal area such that the probe lies below the anode chamber. Blood and microdialysate samples were collected at different time intervals. Intravenous administration of granisetron was also done to determine the basic pharmacokinetic parameters. RESULTS: Iontophoretic patches delivered current constantly throughout the patch application. The patches delivered granisetron hydrochloride at a rate of 14.91+/-4.53 microg/min/kg. Similar concentrations of granisetron hydrochloride in dermal and subcutaneous tissue were observed. Depot formation was identified in the subcutaneous and dermal profiles, indicating that subcutaneous structures are also responsible for the depot formation of the drug in the dermis. CONCLUSION: The patches successfully delivered granisetron hydrochloride by iontophoresis and depot formation was observed in the dermal and subcutaneous structures in the skin.

In vivo iontophoretic delivery and pharmacokinetics of salmon calcitonin.

In vivo iontophoretic delivery of salmon calcitonin (SCT) in hairless rats using a self-contained wearable and disposable iontophoretic patch was investigated. Iontophoretic patches with built-in proprietary Zn/AgCl electrodes were used. SCT was formulated in citrate buffer (50mM, pH 4.0) to impart a positive charge for anodal iontophoresis. SCT was delivered intravenously to determine primary pharmacokinetic parameters. Pharmacokinetics of iontophoretic delivery of SCT was compared with subcutaneous route of administration. Blood samples were collected through tail vein and analyzed for serum SCT and calcium levels. Pharmacokinetic parameters were calculated by non-compartmental analysis. An average current of 0.43+/-0.01 mA was maintained during patch application. Iontophoretic patches delivered SCT at an average infusion rate of 177.9+/-58.7 ng/(min kg) and an average steady state concentration of 7.58+/-1.35 ng/ml was achieved. There was no difference between the calcium lowering effect of iontophoretic patch and subcutaneous injection (p>0.05). Clearance and half-life of SCT after IV administration were found to be 16.8+/-0.9 ml/(min kg) and 33.5+/-3.3 min, respectively. The iontophoretic delivery of SCT was well defined by a one-compartment model with zero-order infusion. Iontophoretic patch delivered therapeutically relevant concentrations of SCT in hairless rats and delivery was comparable to conventional routes.

Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention.

BACKGROUND AND PURPOSE: Iontophoresis is a process that uses bipolar electric fields to propel molecules across intact skin and into underlying tissue. The purpose of this study was to describe and experimentally examine an iontophoresis drug delivery model. SUBJECTS AND METHODS: A mechanistic model describing delivery was studied in vitro using agarose gels and was further tested in vivo by evaluation of cutaneous vasoconstriction following iontophoresis in human volunteers. RESULTS: In vitro cathodic iontophoresis at 4 mA and 0.1 mA each delivered dexamethasone/dexamethasone phosphate (DEX/DEX-P) from a 4-mg/mL donor solution to a depth of 12 mm following a 40 mA minute stimulation dosage. Delivery of DEX/DEX-P to at least the depths of the vasculature in humans was confirmed by observation of cutaneous vasoconstriction. This cutaneous vasoconstriction was longer lasting and greater in magnitude when using low-current, long-duration (approximately 0.1 mA) iontophoresis compared with equivalent dosages delivered by higher-current, shorter-duration (1.5-4.0 mA) iontophoresis. DISCUSSION AND CONCLUSION: From data gathered with the gel model, the authors developed a model of a potential mechanism of drug depot formation following iontophoresis. The authors believe this drug depot formation to be due to exchange of drug ions for chloride ions as the ionic current carriers. Furthermore, diffusion, not magnitude of current, appears to govern the depth of drug penetration. Although the authors did not address the efficacy of the drug delivered, the results of human experiments suggest that current magnitude and duration should be considered as factors in treating musculoskeletal dysfunctions with iontophoresis using DEX/DEX-P at a concentration of 4 mg/mL.

Quantification of total dexamethasone phosphate delivery by iontophoresis.

The total amount of dexamethasone phosphate transferred into the human body as a function of iontophoresis has not previously been determined, despite its widespread clinical use in the treatment of localized inflammation. The objective of this study was to document the optimal parameters required for clinical iontophoresis of dexamethasone phophate. Results were achieved by the experiment of in vitro evalutations of dexamethasone phosphate iontophoresis and by in vivo estimations of drug amounts (milligrams) iontophoresed into healthy human volunteers. The in vitro evaluations were conducted to quantify total dexamethasone phosphate amounts transferred as a function of dosage (milliAmp-minutes), to evaluate the efficiency of the delivery based on dexamethasone phosphate only (pure) donor solutions compared with dexamethasone phosphate + salts (coformulated) donor solutions, and to compare the delivery from the negative electrode (cathode) with that from the positive electrode (amode). The in vivo drug amounts were estimated by the use of the formulation conditions determined from the in vivo testing. The in vitro evaluations were conducted with side-by-side glass diffusion cells, which measured iontophoretic and passive delivery across an ultrafiltration membrane. The in vivo experiments were conducted on five healthy human volunteers who were wearing a low-voltage iontophoreses system. Total drug delivery was ascertained by the difference between the initial drug load and a final residual amount determined by extraction. The in vitro results demonstrated increased dexamethasone phosphate delivery with higher iontophoretic dosages and with the pure dexamethasone phosphate formulation. Delivery from the anode was significantly lower than that from the cathode. After an 80-mA-minute drug-delivery was administered, the in vivo iontophoretic delivery was measured to be 1.40 +/- 0.23 mg, and the corresponding passive delivery was 0.26 +/-0.16 mg. The in vitro experiments confirm iontophoretic delivery of dexamethasone phosphate across artificial membranes, and the in vivo experiments suggest that drug is delivered into human skin.