Medications that Regulate Gastrointestinal Transit Influence Inpatient Blood Glucose.

Objective: A multitude of factors affect a hospitalized individual's blood glucose (BG), making BG difficult to predict and manage. Beyond medications well established to alter BG, such as beta-blockers, there are likely many medications with undiscovered effects on BG variability. Identification of these medications and the strength and timing of these relationships has potential to improve glycemic management and patient safety. Materials and Methods: EHR data from 103,871 inpatient encounters over 8 years within a large, urban health system was used to extract over 500 medications, laboratory measurements, and clinical predictors of BG. Feature selection was performed using an optimized Lasso model with repeated 5-fold cross-validation on the 80% training set, followed by a linear mixed regression model to evaluate statistical significance. Significant medication predictors were then evaluated for novelty against a comprehensive adverse drug event database. Results: We found 29 statistically significant features associated with BG; 24 were medications including 10 medications not previously documented to alter BG. The remaining five factors were Black/African American race, history of type 2 diabetes mellitus, prior BG (mean and last) and creatinine. Discussion: The unexpected medications, including several agents involved in gastrointestinal motility, found to affect BG were supported by available studies. This study may bring to light medications to use with caution in individuals with hyper- or hypoglycemia. Further investigation of these potential candidates is needed to enhance clinical utility of these findings. Conclusion: This study uniquely identifies medications involved in gastrointestinal transit to be predictors of BG that may not well established and recognized in clinical practice.

Spatial analysis and characteristics of persistent late potentials after ablation of scar-related VT substrate- implications for late potential elimination as a procedural endpoint with high-resolution mapping.

BACKGROUND: Late potential elimination has been proposed as a surrogate endpoint for scar-related VT ablation procedures. The characteristics, distribution, and predictors of persistent LPs (pLP) after ablation have not been studied. OBJECTIVE: We sought to characterize the spatial distribution and features of pLP after catheter ablation of VT substrate with high-resolution mapping. METHODS: Cases of scar-related VT ablation with adequate pre- and post-ablation electroanatomical maps (EAM) acquired exclusively using a high-density grid (HDG) catheter were reviewed from 2021-2023. RESULTS: A total of 62 EAM (pre- and post-ablation) from 31 cases using HDG were reviewed. Persistent late potentials (pLP) were observed in 19 cases after ablation (61%). New LP, spatially distinct from pre-ablation LP, at the periphery of the ablation area comprised the majority of pLP (16/19, 84%). Isolated pLP were more prevalent than fractionated pLP with a median amplitude of 0.26mV (0.09-0.59mV). The presence of pLP was associated with a significantly lower LVEF and septal ablation but not low voltage, late potential, or ablation area as compared to absence of pLP (22.8±7.8% vs 31.5±8.0% [p =0.008] for LVEF, and 83% vs 44% [p = 0.033] for septal ablation). CONCLUSIONS: Formation of spatially distinct new LP after targeted VT ablation is common especially in patients with lower LVEF and septal substrate independent of ablation burden. This finding highlights the limitations of complete LP elimination as an endpoint to VT ablation procedures.

Urinary Incontinence Care in the Academic and Safety-Net Primary Care Settings: Opportunities to Improve Quality of Care.

OBJECTIVE: To compare the quality of urinary incontinence (UI) care for women in the safety-net and nonsafety-net settings prior to referral to a specialist. METHODS: We performed a retrospective review of 200 women from two nonsafety-net hospitals and 188 women from two safety-net hospitals who were referred to Urogynecology and Reconstructive Surgery specialists for bothersome UI between March 2017 and March 2020. We evaluated the care that women received 12 months prior to referral, by measuring adherence to a set of previously developed quality indicators (QIs), for example, the performance of a urinalysis or pelvic exam. RESULTS: Women seen in safety-net hospitals were more likely to receive QI-compliant care than women in the nonsafety-net hospitals prior to referral, with 55.53% of appropriate care given in the safety-net vs 40.3% in the nonsafety-net setting (P <.01). Clinicians in the safety-net hospitals were more likely to adhere to QIs in patients with general, stress, and urgency incontinence. CONCLUSION: Women were more likely to receive timely, quality-based UI care in the safety net compared to the nonsafety-net setting. This may be in part due to aspects unique to the safety-net system, including an eConsult referral system, which guides referring clinicians in appropriate management steps that should be taken prior to the specialist visit, as well as women's health-focused primary care clinics.

Characteristics associated with blood transfusion among women undergoing laparoscopic myomectomy: a National Surgical Quality Improvement Program study.

BACKGROUND: Uterine fibroids are the most common benign tumors that affect females. A laparoscopic myomectomy is the standard surgical treatment for most women who wish to retain their uterus. The most common complication of a myomectomy is excessive bleeding. However, risk factors for hemorrhage during a laparoscopic myomectomy are not well studied and no risk stratification tool specific for identifying the need for a blood transfusion during a laparoscopic myomectomy currently exists in the literature. OBJECTIVE: This study aimed to identify risk factors for intraoperative and postoperative blood transfusion during laparoscopic myomectomies and to develop a risk stratification tool to determine the risk for requiring a blood transfusion. STUDY DESIGN: This was a retrospective cohort study of the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2020. Women who underwent a laparoscopic (conventional or robotic) myomectomy were included. Women who received 1 or more blood transfusions within 72 hours after the start time of a laparoscopic myomectomy were compared with those who did not require a blood transfusion. A multivariable analysis was performed to identify risk factors independently associated with the risk for transfusion. Two risk stratification tools to determine the need for a blood transfusion were developed based on the multivariable results, namely (1) based on preoperative factors and (2) based on preoperative and intraoperative factors. RESULTS: During the study period, 11,498 women underwent a laparoscopic myomectomy. Of these, 331(2.9%) required a transfusion. In a multivariable regression analysis of the preoperative factors, Black or African American and Asian races, Hispanic ethnicity, bleeding disorders, American Society of Anesthesiologists class III or IV classification, and a preoperative hematocrit value ≤35.0% were independently associated with the risk for transfusion. Identified intraoperative factors included specimen weight >250 g or ≥5 intramural myomas and an operation time of ≥197 minutes. A risk stratification tool was developed in which points are assigned based on the identified risk factors. The mean probability of transfusion can be calculated based on the sum of the points. CONCLUSION: We identified preoperative and intraoperative independent risk factors for a blood transfusion among women who underwent a laparoscopic myomectomy. A risk stratification tool to determine the risk for requiring a blood transfusion was developed based on the identified risk factors. Further studies are needed to validate this tool.

Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia.

Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. CLN6 encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red + lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC). White matter involvement has been recently noted in several CLN6 animal models and several CLN6 subjects had neuroimaging was consistent with leukodystrophy. CLN6 patient-derived induced pluripotent stem cells (IPSCs) were generated from several of these subjects. IPSCs were differentiated into oligodendroglia or neurons using well-established small-molecule protocols. A doxycycline-inducible transgenic system expressing neurogenin-2 (the I3N-system) was also used to generate clonal IPSC-lines (I3N-IPSCs) that could be rapidly differentiated into neurons (I3N-neurons). All CLN6 IPSC-derived neural cell lines developed significant storage material, CLN6-I3N-neuron lines revealed significant Nile Red + and SUBC + storage within three and seven days of neuronal induction, respectively. CLN6-I3N-neurons had decreased tripeptidyl peptidase-1 activity, increased Golgi area, along with increased LAMP1 + in cell bodies and neurites. SUBC + signal co-localized with LAMP1 + signal. Bulk-transcriptomic evaluation of control- and CLN6-I3N-neurons identified >1300 differentially-expressed genes (DEGs) with Gene Ontogeny (GO) Enrichment and Canonical Pathway Analyses having significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways. These findings indicate that CLN6-IPSCs and CLN6-I3N-IPSCs are appropriate cellular models for this disorder. These I3N-neuron models may be particularly valuable for developing therapeutic interventions with high-throughput drug screening assays and/or gene therapy.

A randomized controlled trial of a proactive analgesic protocol demonstrates reduced opioid use among hospitalized adults with inflammatory bowel disease.

Most hospitalized patients with inflammatory bowel disease (IBD) experience pain. Despite the known risks associated with opioids in IBD including risk for misuse, overdose, infection, readmission, and even death, opioid use is more prevalent in IBD than any other chronic gastrointestinal condition. Most hospitalized IBD patients receive opioids; however, opioids have not been shown to improve pain during hospitalization. We conducted a randomized controlled trial in hospitalized patients with IBD to evaluate the impact of a proactive opioid-sparing analgesic protocol. Wearable devices measured activity and sleep throughout their hospitalization. Chronic opioid users, post-operative, and pregnant patients were excluded. The primary endpoint was a change in pain scores from admission to discharge. Secondary endpoints included opioid use, functional activity, sleep duration and quality, and length of stay. Of 329 adults with IBD evaluated for eligibility, 33 were enrolled and randomized to the intervention or usual care. Both the intervention and control group demonstrated significant decreases in pain scores from admission to discharge (- 2.6 ± 2.6 vs. - 3.0 ± 3.2). Those randomized to the intervention tended to have lower pain scores than the control group regardless of hospital day (3.02 ± 0.90 vs. 4.29 ± 0.81, p = 0.059), used significantly fewer opioids (daily MME 11.8 ± 15.3 vs. 30.9 ± 42.2, p = 0.027), and had a significantly higher step count by Day 4 (2330 ± 1709 vs. 1050 ± 1214; p = 0.014). There were no differences in sleep duration, sleep quality, readmission, or length-of-stay between the two groups. A proactive analgesic protocol does not result in worsening pain but does significantly reduce opioid-use in hospitalized IBD patients.Clinical trial registration number: NCT03798405 (Registered 10/01/2019).

Bladder instillation patterns in a cohort of women with interstitial cystitis/bladder pain syndrome.

Purpose: To determine intravesical instillation patterns among women receiving treatment for interstitial cystitis/bladder pain syndrome (IC/BPS). Methods: Using the Veterans Affairs Informatics and Computing Infrastructure, active female users of the Veterans Affairs system with an ICD-9 diagnosis of IC/BPS (595.1) were randomly sampled. Patients were considered to have IC/BPS (by chart review) if they had two visits complaining of bladder-centric pain in the absence of positive urine culture ≥6 weeks apart or history of bladder pain with one additional visit for bladder-centric pain. We abstracted the dates of intravesical instillations for each patient. A "course" of instillations was defined as ≥1 instillations made with <21 days between visits. Results: We identified 641 women with confirmed diagnosis of IC/BPS, 78 of whom underwent a total of 344 intravesical instillations. On average each subject had 1.5 +/- 0.8 courses between October 2004-July 2016. Each course was an average of 3.1 +/- 2.6 instillations. 55% of courses consisted of one instillation. Only 22% of courses had 6 or more instillations, the number typically recommended to achieve clinical response. Each instillation within a course was an average of 9.4 +/- 4.0 days apart. Most instillations (77%) were a cocktail of two or more drugs. Conclusions: In our cohort, few women with IC/BPS received a recommended treatment course of six weekly instillations, with most receiving only one per course. Future studies are needed to determine if instillation courses were altered from the guideline due to provider practice patterns, early improvement, or poor tolerance of instillations.

Simultaneous Bladder Drainage via Suprapubic and Urethral Catheters: Which Drains More Completely and Why?

Background: Reconstructive urologists often place both a urethral and suprapubic catheter intraoperatively to prevent extravasation of undrained urine across anastomosis sutures. As no consensus exists on which catheter drains the bladder more completely, many surgeons leave one catheter to gravity drainage and cap the other postoperatively. We sought to identify differences in catheter urine outflow during dual bladder drainage with suprapubic and urethral catheters in postoperative urology patients. Methods: Urine output (UOP) from transgender men who underwent Stage II Phalloplasty with urethral lengthening was retrospectively reviewed. Both 16 French urethral and suprapubic catheters were placed to gravity drainage postoperatively. Urine output from each catheter was recorded separately, twice daily. Mixed model regression modeling tested for differences in urine output by time of day (day/night) and activity status (Bedrest: Postop Day 0-2, Ambulatory: Postop Day 3+). Results: The aggregate number of 12-hour shift urine output observations was 250 (125 for urethral and 125 for suprapubic catheters) across 14 inpatients. Suprapubic catheters had a mean 410 ml higher output than urethral catheters per 12-hour shift (p=0.002; 95% CI: 185, 636 ml). During daytime, Suprapubic catheters demonstrated higher UOP than urethral catheters per 12-hour shift (Estimated Difference: 464 ml; p=0.002; 95% CI: 211, 718 ml). During nighttime, a similar phenomenon was observed (Estimated Difference: 356 ml; p=0.009; 95% CI: 104, 606 ml). When comparing mean UOP from each catheter during the Bedrest Phase, suprapubic catheters averaged an estimated 295 ml higher UOP compared to urethral catheters per 12-hour shift with a trend toward statistical significance (p=0.052; 95% CI -3, 594 ml). During the Ambulatory Phase, mean suprapubic catheter UOP was an estimated 472 ml higher than urethral catheters per 12-hour shift (p=0.009; 95% CI 142, 802 ml). Conclusions: Simultaneous bladder drainage with urethral and suprapubic catheters shows greater drainage from the suprapubic catheter (35% vs 65%). When using two catheters, both can be placed to gravity to maximize bladder drainage as the suprapubic catheter can drain residual urine not adequately drained by the urethral catheter.

Diet modification reverses diastolic dysfunction in rats with heart failure and preserved ejection fraction.

Dahl Salt-Sensitive (DSS) rats develop heart failure with preserved ejection fraction (HFpEF) when fed a high-salt (8 % NaCl) diet. Hypertension-induced inflammation and subsequent ventricular fibrosis are believed to underlie the development of HFpEF. We investigated the role of diet modification in the progression of HFpEF using male DSS rats, fed either a high-salt diet from7 weeks of age to induce HFpEF, ora normal-salt (0.3% NaCl) diet as controls. After echocardiographic confirmation of diastolic dysfunction at 14-15 weeks of age along with HF manifestations, the HFpEF rats were randomly assigned to either continue a high-salt diet or switch to a normal-salt diet for an additional 4 weeks. HFpEF rats with diet modification showed improved diastolic function (reduced E/E' ratio in echocardiogram), increased functional capacity (increased treadmill exercise distance), and reduced pulmonary congestions (lung/body weight ratio), compared to high-salt-fed HFpEF rats. Systolic blood pressure remained high (~200 mmHg), and ventricular hypertrophy remained unchanged. Ventricular arrhythmia inducibility (100 % inducible) and corrected QT interval (on ECG) did not change in HFpEF rats after diet modification. HFpEF rats with diet modification showed prolonged survival and reduced ventricular fibrosis (Masson's trichrome staining) compared to high-salt-fed HFpEF rats. Hence, the modification of diet (from high-salt to normal-salt diet) reversed HFpEF phenotypes without affecting blood pressure or ventricular hypertrophy.

The Streaming Web-Based Exercise at Home Study for Breast and Prostate Cancer Survivors: A Feasibility Study Protocol.

BACKGROUND: Despite the known benefits of physical activity in cancer survivors, adherence to exercise guidelines remains low. Known barriers to adhering to guidelines include a lack of time and an unwillingness to return to treatment facilities. Virtual exercise programming could assist in mitigating these barriers. This protocol presents a single arm pilot study exploring the feasibility of personalized Zoom-delivered exercise training for breast and prostate cancer survivors. A secondary objective is to determine the preliminary efficacy of participation on body composition, estimated VO2max, hand grip, one repetition maximum leg press, resting heart rate, resting blood pressure, exercise self-efficacy, and intentions to remain active. METHODS: Breast (n = 10) and prostate (n = 10) cancer survivors will participate in a 24-week feasibility study, including (1) 12 weeks of one-on-one virtual personal training with an exercise physiologist (EP) via Zoom, and (2) individual exercise for a 12-week follow-up period using recordings of Zoom sessions for guidance. Physical assessments and surveys will be implemented at baseline, 12 weeks, and at the end of the study (24 weeks from baseline). CONCLUSIONS: While virtual exercise programming became popularized during the pandemic, evidence is still required to understand whether it can successfully address barriers and promote participation.

A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

Anatomic maps of erogenous sensation and pleasure in the penis: are there difference between circumcised and uncircumcised men?

BACKGROUND: The effects of male circumcision on sexual function remain controversial. Heterogeneity across previous studies and low-quality scientific evidence have resulted in poor understanding of the effects of circumcision on erogenous sensation of the penis and orgasm function. AIM: In this study we sought to describe and assess differences in erogenous genital sensation and reported orgasm function in circumcised compared with uncircumcised men. METHODS: Adult male subjects who were recruited on a paid anonymous online survey platform were shown illustrations of 12 anatomic regions of the penis. Subjects were prompted to designate regions as pleasurable when touched during partnered sex and to rate each on a 1-10 scale, with higher erogeneity scores correlating with greater pleasure. Subjects were also asked to characterize their orgasms across 6 experiential domains. OUTCOMES: Outcomes were differences between circumcised and uncircumcised men in the probabilities that regions would be designated as pleasurable, average pleasure scores, and self-reported orgasm parameters. RESULTS: In total, 227 circumcised (mean [SD] age 46.6 [17.7] years) and 175 uncircumcised men (47.8 [18.1] years) completed the survey. There were no significant differences in average ratings across all regions between circumcised and uncircumcised men. However, significantly more circumcised men reported preferences for the tip of the penis (38% vs 17%, P = .02) and the middle third of the ventral penile shaft (63% vs 48%, P = .04). Additionally, there were no significant differences in orgasm quality and function across all queried domains between circumcised and uncircumcised cohorts. CLINICAL IMPLICATIONS: Our findings suggest that circumcision does not change how men describe erogenous genital sensation or how they experience orgasm. STRENGTHS AND LIMITATIONS: In this study we expanded upon existing literature regarding comparison of sexual function in circumcised and uncircumcised men in its scale and investigation of diverse domains. Limitations include the survey format of data collection. CONCLUSION: We found no differences in reported erogenous ratings or orgasm function between circumcised and uncircumcised men. These findings suggest that male circumcision does not negatively impact penile erogeneity or orgasm function.

National prevalence of IC/BPS in women and men utilizing veterans health administration data.

Importance: Interstitial cystitis/bladder pain syndrome (IC/BPS) is an immense burden to both patients and the American healthcare system; it is notoriously difficult to diagnose. Prevalence estimates vary widely (150-fold range in women and >500-fold range in men). Objectives: We aimed to create accurate national IC/BPS prevalence estimates by employing a novel methodology combining a national population-based dataset with individual chart abstraction. Study design: In this epidemiological survey, all living patients, with ≥2 clinic visits from 2016 to 2018 in the Veterans Health Administration, with an ICD-9/10 code for IC/BPS (n = 9,503) or similar conditions that may represent undiagnosed IC/BPS (n = 124,331), were identified (other were controls n = 5,069,695). A detailed chart review of random gender-balanced samples confirmed the true presence of IC/PBS, which were then age- and gender-matched to the general US population. Results: Of the 5,203,529 patients identified, IC/BPS was confirmed in 541 of 1,647 sampled charts with an IC/BPS ICD code, 10 of 382 charts with an ICD-like code, and 3 of 916 controls. After age- and gender-matching to the general US population, this translated to national prevalence estimates of 0.87% (95% CI: 0.32, 1.42), with female and male prevalence of 1.08% (95% CI: 0.03, 2.13) and 0.66% (95% CI: 0.44, 0.87), respectively. Conclusions: We estimate the prevalence of IC/BPS to be 0.87%, which is lower than prior estimates based on survey data, but higher than prior estimates based on administrative data. These potentially represent the most accurate estimates to date, given the broader and more heterogeneous population studied and our novel methodology of combining in-depth chart abstraction with administrative data.

Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty.

INTRODUCTION: No nomogram exists to predict maximum achievable neovaginal depth before penile inversion vaginoplasty (PIV) based on available penile & scrotal skin (SS). Maximal depth is important to patients and is determined by available skin and available anatomic space within the pelvis and varies with surgical technique. AIM: We endeavored to create a nomogram to predict expected postoperative vaginal depth. METHODS: Retrospective review of all patients undergoing primary PIV at a single institution from June 2017 to February 2020 (n = 60). Pre-op: Dorsal penile and midline scrotal skin length were measured. Intra-op: Tubularized scrotal skin length measured on a dilator. Immediate post-op: Final vaginal depth measured with a dilator. OUTCOMES: The amount of available penile and scrotal skin was not associated with vaginal depth. The only variable that did significantly increase depth was the use of penile + scrotal skin, as compared to penile skin alone. (P < .001) RESULTS: In patients who underwent PIV-SS, the final vaginal depth (13.3 ± 1.9 cm) was 87% of pre-op measured penile skin length (15.3 ±- 3.0 cm). In patients who underwent PIV+SS, pre-op penile skin length was 11.1 ± 4.7±cm and pre-op midline scrotal length was 22.8 ± 2.6 cm. with a final post-op vaginal canal depth of 15.2 ± 1.3 cm. In 45/46 (98%) surgeries utilizing SS grafts, SS tube length exceeded the length necessary to achieve maximal vaginal depth, and required trimming and discard. Given that in most cases there was an excess of SS, final post-op depth equaled the maximal vaginal depth that could be surgically dissected, and was not limited by the amount of available skin. CLINICAL IMPLICATIONS: Our findings suggest that for most patients it should not be necessary to include additional tissue sources (eg, peritoneum) to create a vaginal canal during primary vaginoplasty. STRENGTHS AND LIMITATIONS: Any penile skin that was discarded due to poor quality (eg, tight phimosis, poor viability) was not measured and accounted for. This likely resulted in a slight overestimation of the contribution of the penile skin to the final vaginal depth, but did not change the overall finding that final depth was not limited by available skin. CONCLUSION: SS grafts, when harvested and tubularized using optimized technique, supplied an excess of skin necessary to line a vaginal canal space of maximal achievable depth. We found that additional tissue sources can, instead, be reserved for future salvage surgery if it becomes necessary to augment depth. Smith SM, Yuan N, Stelmar J, et al. Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty. Sex Med 2022;10:100569.

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial.

Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3-5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

Measures of glucose homeostasis during and after duodenal exclusion using a duodenal-jejunal bypass liner in a normoglycemic, nonobese canine model.

BACKGROUND: Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. OBJECTIVES: To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. SETTING: Academic laboratory setting. METHODS: An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. RESULTS: Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. CONCLUSION: These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients.

Atrial fibrillation mechanisms before and after pulmonary vein isolation characterized by noncontact charge density mapping.

BACKGROUND: The interaction of the pulmonary vein (PV) and putative nonpulmonary triggers of atrial fibrillation (AF) remains unclear and has yet to translate into patient-tailored ablation strategies. OBJECTIVE: The purpose of this study was to use noncontact mapping to detail the global conduction patterns in paroxysmal and persistent AF and how they are modified during PV ablation. METHODS: Forty patients during AF ablation underwent mapping using a noncontact catheter (AcQMap, Acutus Medical, Inc., Carlsbad, CA) before and after PV isolation (PVI). Propagation history maps were analyzed postprocedure for each patient to categorize conduction patterns into focal, organized reentrant, and disorganized patterns (F-Patterns, O-Patterns, and D-Patterns, respectively). RESULTS: Activation patterns identified by using a noncontact mapping system can be subclassified from 3 main patterns into subtypes (macroreentrant and localized reentrant [MR and LR] subtypes and disorganized 1 and disorganized 2 [D1 and D2] subtypes). Persistent AF demonstrated more D-Patterns and less O-Patterns and F-Patterns than did paroxysmal AF. In addition, patients with PAF inducible after PVI demonstrated a higher region number and higher prevalence of MR subtypes than did those noninducible. PVs remained the critical region and included almost one-third of all patterns across any AF types. PVI was effective to eliminate PV-related functional phenotypes and affected recurrence with other patterns. CONCLUSION: Activation patterns identified using AcQMap can be classified into 3 main patterns (F-Patterns, O-Patterns, and D-Patterns) as well as subtypes (MR and LR subtypes and D1 and D2 subtypes). PerAF was different from PAF in demonstrating a higher region number and higher prevalence of D-Patterns but a lower region number and lower prevalence of O-Patterns and F-Patterns.

Do medication prescription patterns follow guidelines in a cohort of women with interstitial cystitis/bladder pain syndrome?

OBJECTIVE: To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines. METHODS: We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression. RESULTS: There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression. CONCLUSIONS: Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.

AAV9-MCT8 Delivery at Juvenile Stage Ameliorates Neurological and Behavioral Deficits in a Mouse Model of MCT8-Deficiency.

Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.