Urinary beta 3-adrenoceptor as a diagnostic biomarker for overactive bladder in women.

This study was to investigate urinary beta 3-adrenoceptor concentration as a biomarker for overactive bladder (OAB) and predictor of treatment outcomes in women receiving the beta 3-adrenoceptor agonist mirabegron. The study comprised 50 women identified with OAB and 35 women considered as healthy controls. All women with OAB received daily dosage of 50 mg of mirabegron for 12 weeks. Bladder diaries, OAB-related questionnaires, and global response assessment scale (GRAS) data were collected. Urinary beta 3-adrenoceptor concentration was measured through enzyme-linked immunosorbent assay. All OAB-related questionnaires and GRAS indicated improved posttreatment urinary health. After mirabegron treatment, the frequency of micturition and urgency episodes decreased, but the urinary beta 3-adrenoceptor/creatinine (Cr) ratio increased. The urinary beta 3-adrenoceptor/creatinine ratio was identified as a sensitive biomarker for OAB with a confidence interval of 0.656 to 0.856 (p < 0.001). A negative correlation (- 0.431, p = 0.040) between this biomarker and health-related quality of life (HRQL) scores. The Beta 3-adrenoceptor/Cr levels increased significantly in the treatment-responsive group, while they remained unchanged in the unsatisfactory outcome group. This study shows that 12 weeks of mirabegron treatment improves OAB symptoms and HRQL. Furthermore, urinary beta 3-adrenoceptor concentration may be a diagnostic biomarker for OAB.

Group 3 innate lymphoid cells secret neutrophil chemoattractants and are insensitive to glucocorticoid via aberrant GR phosphorylation.

BACKGROUND: Patients with neutrophil-mediated asthma have poor response to glucocorticoids. The roles and mechanisms of group 3 innate lymphoid cells (ILC3s) in inducing neutrophilic airway inflammation and glucocorticoid resistance in asthma have not been fully clarified. METHODS: ILC3s in peripheral blood were measured by flow cytometry in patients with eosinophilic asthma (EA) and non-eosinophilic asthma (NEA). ILC3s were sorted and cultured in vitro for RNA sequencing. Cytokines production and signaling pathways in ILC3s after IL-1ß stimulation and dexamethasone treatment were determined by real-time PCR, flow cytometry, ELISA and western blot. RESULTS: The percentage and numbers of ILC3s in peripheral blood was higher in patients with NEA compared with EA, and negatively correlated with blood eosinophils. IL-1ß stimulation significantly enhanced CXCL8 and CXCL1 production in ILC3s via activation of p65 NF-κB and p38/JNK MAPK signaling pathways. The expression of neutrophil chemoattractants from ILC3s was insensitive to dexamethasone treatment. Dexamethasone significantly increased phosphorylation of glucocorticoid receptor (GR) at Ser226 but only with a weak induction at Ser211 residues in ILC3s. Compared to human bronchial epithelial cell line (16HBE cells), the ratio of p-GR S226 to p-GR S211 (p-GR S226/S211) was significantly higher in ILC3s at baseline and after dexamethasone treatment. In addition, IL-1ß could induce Ser226 phosphorylation and had a crosstalk effect to dexamethasone via NF-κB pathway. CONCLUSIONS: ILC3s were elevated in patients with NEA, and associated with neutrophil inflammation by release of neutrophil chemoattractants and were glucocorticoid (GC) resistant. This paper provides a novel cellular and molecular mechanisms of neutrophil inflammation and GC-resistance in asthma. Trial registration The study has been prospectively registered in the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900027125).

Correlation between overactive bladder and detrusor overactivity: a retrospective study.

INTRODUCTION: The primary objective of this study is to determine the prevalence of overactive bladder (OAB) and detrusor overactivity (DO) in female patients who were referred for urodynamic study (UDS) because of lower urinary tract symptoms (LUTS). The secondary objective is to determine the subjective and objective differences between female OAB patients with and without DO. MATERIALS AND METHODS: All female patients who underwent UDS for LUTS between June 2016 and September 2019 were retrospectively reviewed. Personal history, medical history, physical examination, and validated questionnaires were collected. One-hour pad test and multichannel urodynamic study was performed. All statistical analyses were conducted by SAS 9.4. P-value < 0.05 was considered statistically significant. RESULTS: A total of 4184 female patients underwent UDS because of LUTS between June 2016 and September 2019; 1524 patients were analyzed for OAB or DO. The occurrence of OAB was 36.4%. The overall incidence of DO in OAB patients was 15.5%; 9.5% of all patients had DO findings on UDS, and 4.6% were incidental findings. There were significant differences among mean age, parity, ICIQ-UI SF, OABSS, POPDI-6, and all UDS parameters (except for maximal urethral pressure and pressure transmission ratio) between patients with and without DO. In patients with DO, there were no significant differences among age, parity, and BMI with or without OAB symptoms. However, there were significant differences among mean OABSS, ICIQ-UI SF, UDI-6, POPDI-6, IIQ-7, and pad test. CONCLUSIONS: Patients with DO are associated with older age, increased parity, greater urine leakage, and worse storage and micturition functions on UDS. Combinations of subjective and objective measurements are better predictive models for OAB patients.

Use of low-intensity extracorporeal shock wave therapy in the management of interstitial cystitis/bladder pain syndrome patients: A thirty case study in a tertiary medical center.

INTRODUCTION: Low-energy extracorporeal shock wave therapy (LiESWT) is a new potential treatment for intractable interstitial cystitis/bladder pain syndrome (IC/BPS), and this paper will evaluate its therapeutic effects on IC/BPS. MATERIALS AND METHODS: This prospective clinical trial enrolled 30 women who have been diagnosed with IC/PBS to receive LiESWT treatment at an intensity of 0.25 mJ/mm2 and a frequency of 3 pulses/second, for a total of 3000 pulses within 8 weeks. And we assessed questionnaires (including O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI)), 3-day voiding diary, and urodynamic study at the following intervals: 4 weeks of LiESWT (W4), 8 weeks of LiESWT (W8), 1-month follow-up (F1), 3-month follow-up (F3) after LiESWT, and 1 year follow-up (F12). RESULTS: The primary outcome of questionnaires showed significant improvement of symptoms compared to baseline (W0), especially on ICSI(12.87 ± 3.44 before treatment and 7.87 ± 5.27 at F12, p < 0.05). 3-day voiding diary also revealed significant decrease in daytime voiding frequency (15.57 ± 5.22 times before treatment and 10.70 ± 4.21 times at F1, p < 0.05) and significant increase on average voiding volume (95.85 ± 35.30 mL before treatment and 161.27 ± 74.21 mL at F1, p < 0.05). However, there were no significant differences in all parameters of the urodynamic study. CONCLUSION: LiESWT can mitigate pain and lower urinary tract symptoms and improve the quality of life in IC/PBS patients, but does not increase the maximal cystometric capacity.

Combing pre-workshop, web-based learning and hands-on workshop as a flipped classroom clinical skill training model during the COVID-19 pandemic.

OBJECTIVE: Due to the COVID-19 pandemic, there is a dramatic drop in in-person residency training due to the implementation of isolation and triage measurements. Here, we propose a new flipped classroom clinical skill training model utilizing a combination of pre-workshop, web-based learning and hands-on workshop that shortens in-person contact time to maintain residency training during the pandemic. Effectiveness of this training model was evaluated with a pre-test and post-test skills competency assessment, two-way feedback, and a five-point Likert scale structured survey questionnaire. MATERIALS AND METHODS: The workshop was conducted in a flipped classroom fashion by the obstetrics and gynecology (OBGYN) department of a single tertiary teaching medical center covering topics from five OBGYN subspecialities. Every topic consisted of a pre-workshop, web-based, mini lecture (PWML) followed by a hands-on workshop (HW). All first to fourth year OBGYN residents were invited to attend the workshop. All the trainees were required to complete the PWML prior to the day of HW. The workshop consisted of rotational station for each topic and was conducted within one afternoon. A 0-100-point scale pre-test and post-test skills competency evaluation were performed for each station and was assessed by the attending doctor or fellow doctor of each subspeciality. Two-way feedback was done after the post-test evaluation. A five-point Likert scale structured survey instrument consisting of participant's perceptions of the workshop design, relevance to clinical practice, and quality of instructors and materials was created during the curriculum development process and sent to each participant one month after the workshop. RESULTS: A total of 19 residents including five first-year, six second-year, three third-year, and five fourth-year residents completed the entire pre-workshop lecture, workshop, pre-test, and post-test. For all residents, the average post-test score of 5 stations was 95 and was significantly higher than the pre-test score of 60 (p < 0.001). For both junior residents and senior residents, the average post-test scores of 5 stations were also significantly higher than pre-test scores (p < 0.001). Survey generated one month after the workshop showed a high overall satisfaction with the workshop instructors on their professional knowledge, communication skills, and interactions between the instructors and trainees. The average satisfaction scores for manipulation of vaginal breech delivery (VBD), semen analysis (SA), cervical conization (CC), obstetrics anal sphincter injury (OASIS), and laparoscopic suture techniques (LST) were 4.84, 4.96, 4.92, 4.88, and 4.92, respectively The average score for practical application of the training materials, class design and teaching method, overall satisfaction of the session, and time scheduling was 4.84, 4.96, 4.96, and 4.48, respectively. The entire HW was completed within 180 min and was carried out within half a day. CONCLUSION: With the implementation of isolation and triage measures in the COVID-19 pandemic, there is a dramatic drop in in-person exposure to all aspects of the residency training, in particular, non-emergent surgeries. Utilization of PWML saved 1/3 of in-person time and the entire workshop was completed within 180 min that could be carried out within half a day. The decrease of person-to-person contact time during the COVID-19 pandemic is necessary while still providing curriculum-based residency training in spite of decreased hands-on experience.

Ultrasonography and clinical outcomes following anti-incontinence procedures (Solyx™ tape): a 3-year post-operative review.

INTRODUCTION AND HYPOTHESIS: Our primary objective was to study objective and subjective outcomes of patients with urodynamic stress incontinence (USI) following Solyx™ at 3-year follow-up. Our secondary objective was to evaluate ultrasonographic tape and bladder neck position and mobility. METHODS: Records of 88 women who received Solyx™ surgery between September 2015 and December 2017 were reviewed. Ultrasonographic sling evaluation was performed at 6 months and 3 years postoperatively. Primary outcomes were objective and subjective cure of stress incontinence, defined as no involuntary urine leakage during filling cystometry, 1-h pad test < 2 g and negative response to Urogenital Distress Inventory-6 Question 3. RESULTS: Subjective and objective cure rates at 3 years were 85.2% and 87.5%, respectively, with no complications reported. QOL improvements were maintained. Bladder neck position and mobility had no significant change between 6-month and 3-year follow-up. Tape position demonstrated significant shifts in the y-axis at both rest and Valsalva and in the x-axis at Valsalva between 6 months and 3 years; overall mobility was unchanged. Percentile of sling location remained unchanged at 60.1%, as did percentage of urethral kinking (67.9%) achieved. Risk factors for failure were bladder neck hypomobility postoperatively and no urethral kinking postoperatively. CONCLUSIONS: There was good sustained objective and subjective cure with improved QOL in women who underwent Solyx™ for USI at 3-year follow-up. Ultrasonographic evaluation showed a tape position shift upwards and backwards with unchanged tape and bladder neck mobility. Percentile of sling location and rates of dynamic kinking were maintained.

Immunochemical and urodynamic outcomes after polypropylene mesh explant from the pelvic wall of rats.

INTRODUCTION AND HYPOTHESIS: To analyze the immunochemical and urodynamic outcomes after partial versus complete excision of transvaginal polypropylene mesh (PPM) from pelvic walls of rats. METHODS: Forty-eight female Sprague-Dawley (SD) rats were randomly distributed into seven groups: control, mesh total removal 60 days (M-T 60D), mesh total removal 180 days (M-T 180D), mesh partial removal 60 days (M-H 60D), mesh partial removal 180 days (M-H 180D), sham 60 days (Sham 60D), and sham 180 days (Sham 180D). In the mesh groups, PPM was inserted and partially (0.3 × 0.3 cm) or completely removed 30 days later. In the Sham group, the space between the vagina and bladder was dissected without placing or removing the synthetic mesh at day 1 and day 30 later. Urodynamic studies, immunochemical analysis, and Western blot were done at days 60 and 180. RESULTS: The M-T 60D voiding pressure was significantly decreased compared to the Sham 60D and M-H 60D. The voiding interval of M-T 60D was significantly shorter than that of M-H 60D. In the M-T 60D and M-T 180D groups, the leak point pressure was significantly less than in their corresponding sham groups. IL-1 and TNF-α were significantly more intense in M-T 60D compared to M-H 60D and Sham 60D. NGF was significantly greater in M-T 60D compared to Sham 60D. There were no significant differences in MMP-2 and CD-31s throughout the group. CONCLUSION: Total mesh excision incites a host inflammatory response and transitory lower urinary tract dysfunction. Despite the good outcomes after total excision, the invasiveness and surgical risk associated with repeated procedures should not be underestimateded.

Difficulties of Prenatal Genetic Counseling for a Subsequent Child in a Family With Multiple Genetic Variations.

Many parents with a disabled child caused by a genetic condition appreciate the option of prenatal genetic diagnosis to understand the chance of recurrence in a future pregnancy. Genome-wide tests, such as chromosomal microarray analysis and whole-exome sequencing, have been increasingly used for prenatal diagnosis, but prenatal counseling can be challenging due to the complexity of genomic data. This situation is further complicated by incidental findings of additional genetic variations in subsequent pregnancies. Here, we report the prenatal identification of a baby with a MECP2 missense variant and 15q11.2 microduplication in a family that has had a child with developmental and epileptic encephalopathy caused by a de novo KCNQ2 variant. An extended segregation analysis including extended relatives, in addition to the parents, was carried out to provide further information for genetic counseling. This case illustrates the challenges of prenatal counseling and highlights the need to understand the clinical and ethical implications of genome-wide tests.

De novo detrusor overactivity and urgency after mid-urethral slings for urodynamic stress incontinence.

INTRODUCTION AND HYPOTHESIS: The objective was to identify incidence and risk factors of de novo urgency and detrusor overactivity (DO) following mid-urethral slings (MUS) in patients with urodynamic stress incontinence (USI) without urgency. METHODS: A total of 688 women between January 2004 and July 2017 were reviewed retrospectively. De novo urgency was established with a positive response to question 2 on the Urogenital Distress Inventory-6 questionnaire (UDI-6). Objective cure of USI is no involuntary urine leakage during filling cystometry and pad test < 2 g. Subjective cure of stress urinary incontinence (SUI) is defined as a negative response to question 3 on UDI-6. Multivariate logistic regression was used to identify risk factors for failure. RESULTS: Forty-four out of 688 women (6.4%) developed de novo urgency, with 16 out of 688 (2.3%) demonstrating de novo DO. Subjective cure for women with de novo urgency was significantly lower at 35 out of 44 (79.5%) compared with 556 out of 644 (86.3%) in those with no urgency (p < 0.001). Objective cure for women with de novo DO was significantly lower at 8 out of 16 (50%) compared with 599 out of 672 (89.1%) in those with detrusor stability (p < 0.001). Quality of life improved for all. Age ≥ 66 (OR, 1.23; 1.07), increased bladder sensation (OR, 4.18; 3.80), lower bladder capacity (OR, 5.28; 4.97), lower maximum urethral closure pressure (OR, 2.32; 5.20), and pad test > 100 g (OR, 1.08; 1.15) were independent risk factors for de novo urgency and DO. Diabetes (OR, 1.32) was an independent predictor of de novo urgency. CONCLUSION: Cure is significantly reduced in women who report symptoms of de novo urgency or demonstrate DO after MUS at 1 year. Independent risk factors include age ≥ 66, increased bladder sensation, lower bladder capacity, lower maximum urethral closure pressure, greater pad loss, and diabetes.

Anterior-Apical Transvaginal Mesh (Surelift) for Advanced Urogenital Prolapse: Surgical and Functional Outcomes at 1 Year.

STUDY OBJECTIVE: To determine the objective and subjective outcomes of pelvic organ prolapse (POP) surgery using a modified Surelift system (Neomedic International, Barcelona, Spain) and to evaluate surgical complications and postoperative impact on quality of life (QOL) and lower urinary tract symptoms. DESIGN: Retrospective cohort study. SETTING: Tertiary-care university hospital. PATIENTS: Patients with symptomatic anterior or apical POP stage III and above. INTERVENTIONS: All patients underwent pelvic reconstructive surgery with a modified Surelift transvaginal mesh kit. MEASUREMENTS AND MAIN RESULTS: Eighty-three women who underwent pelvic reconstructive surgery with a modified Surelift for symptomatic anterior or apical prolapse stage III and above from April 2018 to January 2019 were reviewed retrospectively. All completed a 72-hour voiding diary, urodynamic study, and multiple validated QOL questionnaires at baseline and at between 6 and 12 months postoperatively. Descriptive statistics were used for demographics and perioperative data. Paired-samples t test and the McNemar test were applied for comparison of pre- and postoperative continuous and categoric data, respectively. The primary outcomes were the objective cure of POP, defined as anterior and apical prolapse Pelvic Organ Prolapse Quantification System ≤ stage I, and subjective cure on the basis of negative answers to Pelvic Organ Prolapse Distress Inventory 6. The objective and subjective cure rates at 1 year were 97.6% and 92.8%, respectively. There were significant improvements in QOL scores postoperatively. Although bladder outlet obstruction improved, de novo urodynamic stress incontinence and stress urinary incontinence were increased at 18.9% and 21.6%, respectively, at 1-year follow-up. The mesh extrusion rate was 4.8%. CONCLUSION: A modified Surelift has good objective and subjective cure rates at 1 year postoperatively with 4.8% mesh extrusion rate. There was significant improvement in lower urinary tract symptoms and QOL. De novo urodynamic stress incontinence at 6 months to 12 months was increased, but it was not sufficiently bothersome to warrant surgery.

Mid Urethral Slings for the Treatment of Urodynamic Stress Incontinence in Overweight and Obese Women: Surgical Outcomes and Preoperative Predictors of Failure.

PURPOSE: We evaluated mid urethral sling outcomes in overweight and obese patients compared to normal weight patients and identified risk factors for failure in this population. MATERIALS AND METHODS: Records of 688 women between January 2004 and July 2017 were retrospectively reviewed. Patients received urodynamic studies, 1-hour pad test, Urogenital Distress Inventory-6 and Incontinence Impact Questionnaire-7, and were divided into normal weight, overweight and obese. Objective cure at 1 year was defined as no involuntary urine leakage during filling cystometry and pad test less than 2 gm. Subjective cure was established by negative response to question 3 on Urogenital Distress Inventory-6. McNemar's test, chi-square test, Mann-Whitney U and Fisher's exact test were used for paired categorical variables. Independent samples t-tests and paired t-test were used for continuous parametric variables. Multivariate logistic regression was used to identify risk factors for failure. RESULTS: Objective and subjective cure in normal, overweight and obese patients was 91.4% and 89.1%, 87.5% and 86%, and 76% and 70.1%, respectively. There was no difference in surgical complications. Obese patients had worse quality of life scores preoperatively and postoperatively. Risk factors in obese patients with failed mid urethral sling included 66 years old or older (OR 2.02, 1.56-3.98), menopause (OR 4.21, 1.21-14.22), previous prolapse surgery (OR 4.57, 2.36-8.52), diabetes (OR 2.79, 1.61-5.99) and intrinsic sphincter deficiency (OR 5.06, 3.08-9.64). CONCLUSIONS: Obese women with mid urethral sling had lower objective and subjective cure at 1 year and worse quality of life scores compared to normal and overweight women. Risk factors for failure include age, diabetes, menopause, previous prolapse surgery and intrinsic sphincter deficiency.

The Phospholipid:Diacylglycerol Acyltransferase-Mediated Acyl-Coenzyme A-Independent Pathway Efficiently Diverts Fatty Acid Flux from Phospholipid into Triacylglycerol in Escherichia coli.

Researchers have long endeavored to accumulate triacylglycerols (TAGs) or their derivatives in easily managed microbes. The attempted production of TAGs in Escherichia coli has revealed barriers to the broad applications of this technology, including low TAG productivity and slow cell growth. We have demonstrated that an acyl-CoA-independent pathway can divert phospholipid flux into TAG formation in E. coli mediated by Chlamydomonas reinhardtii phospholipid:diacylglycerol acyltransferase (CrPDAT) without interfering with membrane functions. We then showed the synergistic effect on TAG accumulation via the acyl-CoA-independent pathway mediated by PDAT and the acyl-CoA-dependent pathway mediated by wax ester synthase/acyl-CoA:diacylglycerol acyltransferase (WS/DGAT). Furthermore, CrPDAT led to synchronous TAG accumulation during cell growth, and this could be enhanced by supplementation of arbutin. We also showed that rationally mutated CrPDAT was capable of decreasing TAG lipase activity without impairing PDAT activity. Finally, ScPDAT from Saccharomyces cerevisiae exhibited similar activities as CrPDAT in E. coli Our results suggest that the improvement in accumulation of TAGs and their derivatives can be achieved by fine-tuning of phospholipid metabolism in E. coli Understanding the roles of PDAT in the conversion of phospholipids into TAGs during the logarithmic growth phase may enable a novel strategy for the production of microbial oils.IMPORTANCE Although phospholipid:diacylglycerol acyltransferase (PDAT) activity is presumed to exist in prokaryotic oleaginous bacteria, the corresponding gene has not been identified yet. In this article, we have demonstrated that an acyl-CoA-independent pathway can divert phospholipid flux into TAG formation in Escherichia coli mediated by exogenous CrPDAT from Chlamydomonas reinhardtii without interfering with membrane functions. In addition, the acyl-CoA-independent pathway and the acyl-CoA-dependent pathway had the synergistic effect on TAG accumulation. Overexpression of CrPDAT led to synchronous TAG accumulation during cell growth. In particular, CrPDAT possessed multiple catalytic activities, and the rational mutation of CrPDAT led to the decrease of TAG lipase activity without impairing acyltransferase activity. The present findings suggested that applying PDAT in E. coli or other prokaryotic microbes may be a promising strategy for accumulation of TAGs and their derivatives.

Urodynamics mixed type urinary incontinence with advanced pelvic organ prolapse, management and outcomes.

Patients with pelvic organ prolapse (POP) often have accompanying lower urinary tract symptoms. Symptoms such as stress urinary incontinence(SUI-UD) and detrusor overactivty(DO) would co-exist in a number of patients. Management entails relieving the obstructive element. To determine the clinical outcome of patients with urodynamics mixed type urinary incontinence(MUI-U) after vaginal pelvic reconstructive surgery(PRS), a retrospective study was conducted. MUI-U was defined as having urodynamic findings of both of DO/DOI (derusor overactivity incontinence) and SUI-UD. Main outcome measures: Objective cure- absence of involuntary detrusor contraction on filling cystometry and no demonstrable leakage of urine during increased abdominal pressure; Subjective cure- assessment index score of <1 on UDI-6 question #2 and #3. Of the 82 patients evaluated, 14 underwent vaginal PRS with concomitant mid-urethral sling(MUS) insertion while 68 had vaginal PRS alone. Pre-operatively, 49(60%) patients had stage III and 33(40%) had stage IV prolapse. Post-operatively, 1-year data shows an objective cure of 56% (46/82) and subjective cure of 54% (44/82). MUI-U was significantly improved. Improvement of SUIUD and results of the 1-hour pad test were more pronounced in patients with concomitant MUS insertion. Ergo, vaginal PRS cures symptoms of MUI-U in >50% of patients and concomitant MUS can be offered to SUI predominant MUI.

Ex utero intrapartum treatment for extremely low birth-weight neonates requiring resuscitation at birth.

OBJECTIVE: Difficulties often encountered during intubation in extremely low birth-weight (ELBW) neonates requiring resuscitation at birth because of the smaller airway and the pressure from the limited number of attempts before hemodynamic instability occurs. CASE REPORT: We evaluated two pregnant women at 26 weeks of gestation with premature rupture of membranes and evidence of chorioamnionitis and applied the concept of ex utero intrapartum treatment, which involved delaying cord clamping (DCC) after establishing a secured airway with adequate ventilation during cesarean delivery. The resuscitative procedure was smooth and all three neonates had favorable outcomes at one month of age. CONCLUSION: When cesarean delivery is indicated in ELBW infants and intubation after birth is anticipated, DCC after establishing a secured airway may help maintain neonatal cardiovascular stability and allow physicians to resolve the technical difficulties of intubation.