Metformin inhibits nerve growth factor-induced sympathetic neuron differentiation through p35/CDK5 inhibition.

The authors' previous research has shown the pivotal roles of cyclin-dependent kinase 5 (CDK5) and its regulatory protein p35 in nerve growth factor (NGF)-induced differentiation of sympathetic neurons in PC12 cells. During the process of differentiation, neurons are susceptible to environmental influences, including the effects of drugs. Metformin is commonly used in the treatment of diabetes and its associated symptoms, particularly in diabetic neuropathy, which is characterized by dysregulation of the sympathetic neurons. However, the impacts of metformin on sympathetic neuronal differentiation remain unknown. In this study, we investigated the impact of metformin on NGF-induced sympathetic neuronal differentiation using rat pheochromocytoma PC12 cells as a model. We examined the regulation of TrkA-p35/CDK5 signaling in NGF-induced PC12 differentiation. Our results demonstrate that metformin reduces NGF-induced PC12 differentiation by inactivating the TrkA receptor, subsequently inhibiting ERK and EGR1. Inhibition of this cascade ultimately leads to the downregulation of p35/CDK5 in PC12 cells. Furthermore, metformin inhibits the activation of the presynaptic protein Synapsin-I, a substrate of CDK5, in PC12 differentiation. In addition, metformin alters axonal and synaptic bouton formation by inhibiting p35 at both the axons and axon terminals in fully differentiated PC12 cells. In summary, our study elucidates that metformin inhibits sympathetic neuronal differentiation in PC12 cells by disrupting TrkA/ERK/EGR1 and p35/CDK5 signaling. This research contributes to uncovering a novel signaling mechanism in drug response during sympathetic neuronal differentiation, enhancing our understanding of the intricate molecular processes governing this critical aspect of neurodevelopment.NEW & NOTEWORTHY This study unveils a novel mechanism influenced by metformin during sympathetic neuronal differentiation. By elucidating its inhibitory effects from the nerve growth factor (NGF) receptor, TrkA, to the p35/CDK5 signaling pathways, we advance our understanding of metformin's mechanisms of action and emphasize its potential significance in the context of drug responses during sympathetic neuronal differentiation.

Metformin alters dendrite development and synaptic plasticity in rat cortical neurons.

Synaptic plasticity is crucial as it dynamically molds the strength and connectivity of neural circuits, influencing learning, memory, and the development of neurological disorders. Metformin, a widely prescribed anti-diabetic medication, has been shown to readily cross the blood-brain barrier (BBB) and the placenta. However, its prolonged impact on neuronal morphology and functions remains underexplored. In this study, we investigated the influence of metformin on dendrite development and synaptic plasticity in embryonic brains and primary rat cortical neurons. Our findings reveal a negative modulation of dendrite development by metformin, as evidenced by altered dendritic arborization, impaired dendritic spine morphology and disruptions in synaptic plasticity, suggesting a potential link between metformin exposure and aberrations in neuronal connectivity. In addition, we extend our insights to the impact of maternal metformin exposure on embryonic brains, revealing a significant inhibition of dendrite development in E18.5 rat brains. In conclusion, this study adds to the expanding knowledge base on the non-metabolic effects of metformin, emphasizing the significance of assessing its potential influence on both neuronal structure and function. There is an urgent need for further investigations into the enduring impact of prolonged metformin administration on the structural and functional aspects of neurons.

The prevalence of overt, occult, and no-demonstrated stress urinary incontinence and their clinical and urodynamic findings in women with advanced-stage cystoceles.

OBJECTIVES: To elucidate the prevalence of overt, occult and no demonstrated (ND) stress urinary incontinence (SUI) in women with advanced-stage cystoceles. STUDY DESIGN: Between November 2011 and January 2017, all women with ≥stage 2 cystoceles were retrospectively enrolled. Overt SUI was diagnosed before the prolapse reduction test, and occult SUI was diagnosed when urine leakage was noted after a reduction test with vaginal gauze. Otherwise, a diagnosis of ND-SUI was made. MAIN OUTCOME MEASURES: The prevalence, clinical and urodynamic findings of overt SUI, occult SUI, and ND-SUI. RESULTS: In 480 enrolled women, 62% had overt SUI, 17% had occult SUI, and 21% had ND-SUI. The occult SUI group had the most advanced prolapse. The pad weight results after prolapse reduction (37.3 ± 44.3 vs. 13.4 ± 21.9, p < 0.05), the bladder capacity (243 ± 54 vs. 273 ± 48, p < 0.001), and questionnaires regarding life quality were significantly different between the overt SUI and the occult SUI groups. Bladder oversensitivity (BO) was the most common urodynamic diagnosis (389/480, 81%), especially in overt SUI, while urodynamic stress incontinence (56/480, 12%) and detrusor overactivity (60/480, 13%) were uncommon. The cutoff value of stage 3 uterine prolapse was the strongest predictor for predicting occult SUI (sensitivity = 30.3%, specificity = 78.5%; area = 0.60, 95% CI: 0.52-0.68). CONCLUSIONS: SUI occurs in a ratio of 3:1:1 among cases with overt, occult, and no demonstrable symptoms. BO is the most common urodynamic diagnosis. Pad test with prolapse reduction remains an important tool, especially for coexistent stage 3 uterine prolapse.

RAGE potentiates EGFR signaling and interferes with the anticancer effect of gefitinib on NSCLC cells.

The receptor for advanced glycation end-products (RAGE) has been implicated in tumorigenesis, whereas epidermal growth factor receptor (EGFR) signaling plays a vital role in lung cancer progression. Both RAGE and EGFR are transmembrane receptors that transmit intracellular signals through ligand binding, and their downstream signaling cascades show substantial overlap. However, the interplay between these two molecules remains poorly understood. In the present study, we evaluated the correlation between RAGE and EGFR in the tumorigenesis of non-small cell lung cancer (NSCLC) and evaluated the impact of RAGE on the response of NSCLC cells to gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). The expression and activation of EGFR and the phosphorylation of its downstream molecules, signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (Erk), were increased in RAGE-overexpressed A549 (A549-RAGE) cells. Notably, ligand-triggered activation of EGFR signaling was significantly greater in A549-RAGE compared with A549-parental cells. In addition, gefitinib had less effect on the inhibition of EGFR signaling in A549-RAGE cells. These findings were validated in other NSCLC cell lines, H1299 and H1975. Furthermore, upon gefitinib administration, the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) expression was upregulated in A549-RAGE cells, whereas the apoptotic markers Bcl-2 associated X protein (Bax) and Bcl-2 interacting mediator (Bim) remained at lower levels compared with A549-parental cells. Importantly, our findings provide evidence that RAGE interferes with the anticancer effect of gefitinib by modulating the activation of EGFR-STAT3 and EGFR-Erk pathways. Overall, these significant findings deepen our understanding of the intricate relationship between RAGE and EGFR signaling in NSCLC tumorigenesis and provide new considerations for the clinical treatment of NSCLC.NEW & NOTEWORTHY This study represents a pioneering endeavor in comprehending the intricate interplay between RAGE and EGFR signaling within NSCLC. The findings reveal that RAGE serves to enhance EGFR phosphorylation and activation, consequently modulating apoptosis regulators through the EGFR-STAT3 and EGFR-Erk1/2 signaling pathways. Through this mechanism, RAGE potentially imparts resistance to the toxicity induced by EGFR-TKIs in NSCLC cells.

Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update.

Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.

Mindfulness or meditation therapy for Parkinson's disease: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Mindfulness and meditation therapies have been demonstrated as effective alternative treatments for patients with neurological disorders. However, the effects of mindfulness and meditation therapies on PD remain unclear. This meta-analysis investigated the effects of mindfulness and meditation therapies in PD patients. METHODS: A literature search was conducted using PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials comparing mindfulness and meditation therapies with control treatments in patients with PD. RESULTS: Nine articles involving eight trials were included, with a total of 337 patients. Our meta-analysis revealed that mindfulness and meditation therapies significantly improved Unified Parkinson's Disease Rating Scale-Part III score (mean difference [MD] = -6.31, 95% confidence interval [95% CI] = -8.57 to -4.05) and cognitive function (standard mean difference [SMD] = 0.62, 95% CI = 0.23 to 1.02). However, no significant differences were discovered between mindfulness therapies and control in gait velocity (MD = 0.05, 95% CI = -0.23 to 0.34), Parkinson's Disease Questionnaire-39 Summary Index (MD = 0.51, 95% CI = -1.12 to 2.14), activities of daily living (SMD = -1.65, 95% CI = -3.74 to 0.45), depression (SMD = -0.43, 95% CI = -0.97 to 0.11), anxiety (SMD = -0.80, 95% CI = -1.78 to 0.19), pain (SMD = 0.79, 95% CI = -1.06 to 2.63), or sleep disturbance (SMD = -0.67, 95% CI = -1.58 to 0.24). CONCLUSION: Mindfulness and meditation therapies may serve as complementary and alternative treatments for PD patients.

Efficacy of Platelet-Rich Plasma Injection on Range of Motion, Pain, and Disability in Patients With Adhesive Capsulitis: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate the therapeutic effects of platelet-rich plasma (PRP) injection on range of motion, pain, and disability in patients with adhesive capsulitis (AC). DATA SOURCES: The authors performed the literature search in the PubMed, Embase, and Cochrane Library databases in February 2023. STUDY SELECTION: Prospective studies comparing the outcomes of PRP with other intervention in patients with AC. DATA EXTRACTION: The quality of included randomized trials was assessed using the revised Cochrane Risk of Bias (RoB 2.0) tool. The Risk of Bias in Non-Randomized Studies of Interventions tool was applied to assess the quality of nonrandomized trials. The mean difference (MD) or standardized mean difference (SMD) was determined as the effect size for continuous outcomes, and outcome accuracy was determined using 95% confidence intervals (CIs). DATA SYNTHESIS: Fourteen studies involving 1139 patients were included. Our meta-analysis revealed that PRP injection can significantly improve passive abduction (MD=3.91; 95% CI, 0.84-6.98), passive flexion (MD=3.90; 95% CI, 0.15-7.84), and disability (SMD=-0.50; 95% CI, -1.29 to -0.74) within 1 month after intervention. Moreover, PRP injection can significantly improve passive abduction (MD=17.19; 95% CI, 12.38-22.01), passive flexion (MD=17.74; 95% CI, 9.89-25.59), passive external rotation (MD=12.95; 95% CI, 10.04-15.87), pain (MD=-8.40; 95% CI, -16.73 to -0.06), and disability (SMD=-1.02; 95% CI, -1.29 to -0.74) 3 months after intervention. PRP injection can also significantly improve pain (MD=-18.98; 95% CI, -24.71 to -13.26), and disability (SMD=-2.01; 95% CI, -3.02 to -1.00) 6 months after intervention. In addition, no adverse effects of PRP injection were reported. CONCLUSIONS: PRP injection may serve as an effective and safe treatment for patients with AC.

Daily Exposure to Mild Intermittent Hypoxia Reduces Blood Pressure in Male Patients with Obstructive Sleep Apnea and Hypertension.

Rationale: Daily exposure to mild intermittent hypoxia (MIH) may elicit beneficial cardiovascular outcomes. Objectives: To determine the effect of 15 days of MIH and in-home continuous positive airway pressure treatment on blood pressure in participants with obstructive sleep apnea and hypertension. Methods: We administered MIH during wakefulness 5 days/week for 3 weeks. The protocol consisted of twelve 2-minute bouts of hypoxia interspersed with 2 minutes of normoxia. End-tidal carbon dioxide was maintained 2 mm Hg above baseline values throughout the protocol. Control participants were exposed to a sham protocol (i.e., compressed air). All participants were treated with continuous positive airway pressure over the 3-week period. Results are mean ± SD. Measurements and Main Results: Sixteen male participants completed the study (experimental n = 10; control n = 6). Systolic blood pressure at rest during wakefulness over 24 hours was reduced after 15 days of MIH (142.9 ± 8.6 vs. 132.0 ± 10.7 mm Hg; P < 0.001), but not following the sham protocol (149.9 ± 8.6 vs. 149.7 ± 10.8 mm Hg; P = 0.915). Thus, the reduction in blood pressure from baseline was greater in the experimental group compared with control (-10.91 ± 4.1 vs. -0.17 ± 3.6 mm Hg; P = 0.003). Modifications in blood pressure were accompanied by increased parasympathetic and reduced sympathetic activity in the experimental group, as estimated by blood pressure and heart rate variability analysis. No detrimental neurocognitive and metabolic outcomes were evident following MIH. Conclusions: MIH elicits beneficial cardiovascular and autonomic outcomes in males with OSA and concurrent hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT03736382).

Prevalence and predictors of nocturnal polyuria in females with overactive bladder syndrome.

PURPOSE: To describe the prevalence and predictors of nocturnal polyuria (NP) in women with overactive bladder syndrome (OAB). METHODS: Between July 2009 and January 2018, women with OAB were enrolled. NP was defined when the nocturnal polyuria index (NPI) (nighttime voided volume over 24-h voided volume) was > 33% (NPI33) in women ≥ 65 years-old and > 20% (NPI20) in women < 65 years old. Repeated analysis was also performed for NP defined by the NPI33 definition at all ages. RESULTS: A total of 1071 women with OAB were analyzed. The overall prevalence of NP was 30% (319/1071), with the highest prevalence in women in the perimenopausal period (46-50 years old), while NP was diagnosed by age-dependent NPI. The overall prevalence of NP was 12% (128/1071), with an increasing trend with increasing age, while NP was diagnosed by the NPI33 definition only. Daytime frequency and nocturia episodes were both predictors for NP in both definitions. Receiver operating characteristic curve analysis revealed that more than 5 nocturia episodes noted in the 3-day bladder diary were an optimal cutoff value to predict nocturnal polyuria [(sensitivity = 85.6%, specificity = 61.0%; area = 0.80, 95% CI 0.77-0.82) and (sensitivity = 88.3%, specificity = 65.9%; area = 0.83, 95% CI 0.80-0.85), respectively, in the two definitions]. CONCLUSIONS: NP is common in women with OAB, especially in women with more than 5 nocturia episodes in their 3-day bladder diaries, and adjuvant therapy for better treatment efficacy is needed.

Telemedicine trends at a comprehensive cancer center during the first wave of the COVID-19 pandemic.

INTRODUCTION: This article reports on the effects of an early outbreak during the COVID-19 pandemic on visit volume and telehealth use by various specialists at a comprehensive cancer center. MATERIALS AND METHODS: The number of on-site and telehealth visits (THV) for medical and surgical specialties were obtained from scheduling software. RESULTS: Total visits were most drastically limited in April 2020 to a low point of 3139; THV made up 28% of all visits. For head and neck surgery, THV made up 54% and 30% of visits in April and May, respectively. Other specialties, such as psychiatry and palliative care, had higher levels of THV. For most specialties, the rebound in June through September did not make up for visits lost during the outbreak, and fiscal year  (FY) 2020 had a 9% loss from FY 2019 with 5786 fewer total annual visits across all specialties. CONCLUSIONS: While telemedicine was a helpful part of this cancer center's response to the initial COVID-19 surge, it was not able to replace the in-person services offered at the same center. The main strategy of physicians at this cancer center was to defer care, with telemedicine being an auxiliary response.

Cumulative incidence of urinary incontinence and associated factors during pregnancy and after childbirth: a cohort study.

INTRODUCTION AND HYPOTHESIS: This study examined the associated factors (i.e., obstetric and maternal-newborn factors) related to cumulative incidence of urinary incontinence and changes in urinary incontinence during pregnancy and the first year postpartum. METHODS: This prospective, longitudinal, within-subject study included 501 women who completed the Incontinence Questionnaire-Urinary Incontinence Short Form during pre-pregnancy, early pregnancy, mid-pregnancy, and late pregnancy and at five time points during the first year postpartum. Data were analyzed by multivariate logistic regression, McNemar's and analysis of variance (ANOVA) tests. RESULTS: According to the multivariate analysis, the gestational week and number of previous vaginal deliveries increased the risk of cumulative incidence of urinary incontinence (CIUI) during pregnancy (both p < 0.05). Full-time employment, higher body mass index, vaginal delivery and UI during early pregnancy and mid-pregnancy increased the risk of CIUI during the first year postpartum (all p < 0.05). CIUI tended to increase throughout the entire pregnancy (p < 0.001) and decrease from 3 to 5 days to 6 months postpartum (p = 0.028). The prevalence rates of UI at all postpartum visits were lower than those during late pregnancy (p < 0.001-0.009) but higher than those during pre-pregnancy (p < 0.001). CONCLUSIONS: The results identified the change patterns in UI and the risk factors associated with CIUI during the entire pregnancy (i.e., gestational age and number of previous vaginal deliveries) and the first year postpartum (i.e., full-time work, higher body mass index, vaginal delivery and UI during early and mid-pregnancy). Appropriate counseling should be provided to women preparing for pregnancy and during the prenatal and postpartum periods.

Clinical outcome and urodynamic changes of tailored transvaginal mesh surgery for pelvic organ prolapse: A mid-term 40 Months follow-up.

PURPOSE: To evaluate the changes in clinical outcome and urodynamic parameters after tailored anterior transvaginal mesh (ATVM) surgeries in a mid-term follow-up. METHODS: Between November 2011 and December 2015, women with ≥stage II pelvic organ prolapse (POP) who underwent ATVM surgeries were retrospectively reviewed. The data-reviewing timeframe was until December 2021. Clinical and urodynamic diagnoses regarding urinary symptoms were evaluated before and after the operation. RESULTS: A total of 160 women were included. Stress urinary incontinence decreased significantly after the operation (99% (159/160) vs. 43% (68/160), p < 0.01), as well as the pad weight (20.5 ± 2.7 vs. 9.4 ± 2.0, p < 0.001) and diagnosis of urodynamic stress incontinence (83% (132/160) vs. 51% (82/160), p < 0.01). Overactive bladder syndrome increased significantly after the operation (18% (29/160) vs. 28% (45/160), p = 0.03), even though the objective parameters, such as first and strong desire to void, bladder oversensitivity, and detrusor overactivity, were all improved after the operation. The pad weight was mostly improved significantly within the first postoperative 2 years. Eighteen (11%) women had global recurrent POP, and only one (0.6%) woman had true recurrence of cystocele. Twenty-four (15%) women had mesh extrusion, and two-thirds of them could be managed in an office setting. CONCLUSION: In women with advanced cystocele, the ATVM surgery provides a favorable anatomic reduction outcome with an acceptable mesh extrusion rate. The ATVM provides an anti-incontinence effect, both in subjective symptoms and objective parameters, but this effect might decline after postoperative 2 years.

Antrodia salmonea extract inhibits cell proliferation through regulating cell cycle arrest and apoptosis in prostate cancer cell lines.

Antrodia salmonea (AS) is a fungus, which belongs to a fungal family of Taiwanofungus salmoneus with the features of anti-oxidant, anti-inflammatory, and anticancer. Recent studies have shown that AS has anti-cancer functions in ovarian and breast cancer. However, the effects of AS on prostate cancer (PCa) proliferation remain unknown. Therefore, we investigated the role of AS in PCa proliferation through apoptosis, and cell cycle regulation in PCa cell lines. Our results showed that Antrodia salmonea extract (ASE) inhibited PCa cells growth with a dose-dependent manner. In addition, ASE decreased the anchorage-independent growth formation ability in PC3 cells. Moreover, ASE-induced cell growth inhibition in PCa cells (DU145, PC3) was correlated to decreased cell cycle-related proteins such as cyclin A/B and cyclin-dependent kinase CDK1/2/4, and increased cell cycle inhibitor proteins p21. Besides, ASE decreased the total protein level of epidermal growth factor receptor and its downstream signaling pathways Akt and Erk in both PCa cells. We found that apoptotic markers such as cleaved-PARP protein levels increased significantly in DU145 cells indicating ASE might induce apoptosis. In conclusion, our results suggest that ASE may have the ability to induce PCa cell death through regulating cell cycle arrest and apoptosis pathways.

Predictors of Clinical Outcome in Women with Pelvic Organ Prolapse Who Underwent Transvaginal Mesh Reconstruction Surgery.

Background and Objectives: To identify the predictors of clinical outcomes in women with pelvic organ prolapse (POP) who underwent transvaginal reconstruction surgery, especially with transobturator mesh fixation or sacrospinous mesh fixation. Materials and Methods: All women with POP who underwent transvaginal reconstruction surgery, especially with transobturator mesh fixation or sacrospinous mesh fixation, were reviewed. Results: Between January 2011 and May 2019, a total of 206 consecutive women were reviewed, including 68 women receiving POP reconstruction with transobturator mesh fixation and 138 women who underwent POP reconstruction with sacrospinous mesh fixation. The least experienced surgeon (hazard ratio = 804.6) and advanced stage of cystocele (hazard ratio = 8.80) were the predictors of POP recurrence, especially those women with stage 4 of cystocele. Young age (hazard ratio = 0.94) was a predictor for mesh extrusion, especially those women with age ≤67 years. Follow-up interval (odds ratio = 1.03, p = 0.02) was also an independent predictor of mesh extrusion. High maximum flow rate (Qmax, hazard ratio = 1.03) was the sole predictor of postoperative stress urinary incontinence, especially those women with Qmax ≥19.2 mL/s. Preoperative overactive bladder syndrome (hazard ratio = 3.22) were a predictor for postoperative overactive bladder syndrome. In addition, overactive bladder syndrome rate improved after surgery in the sacrospinous group (p = 0.0001). Voiding dysfunction rates improved after surgery in both sacrospinous and transobturator groups. Conclusions: Predictors of clinical outcome in women who underwent transvaginal POP mesh reconstruction are identified. The findings can serve as a guide for preoperative consultation of similar procedures.

Histological Transformation after Acquired Resistance to the Third-Generation EGFR-TKI in Patients with Advanced EGFR-Mutant Lung Adenocarcinoma.

Background and Objectives: Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is one of the standard-of-care therapies in patients with EGFR-mutant lung adenocarcinoma; however, acquired resistance inevitably developed. Despite the proposition of histological transformation being one of the resistance mechanisms, its incidence and influence on outcome remain unclear. Materials and Methods: This was a retrospective study conducted at Taichung Veterans General Hospital on patients with advanced EGFR-mutant lung adenocarcinoma receiving the third-generation EGFR-TKI. Only patients receiving rebiopsy were included in the analysis. Results: A total of 55 patients were studied. Eight patients (14.5%) showed histological transformation, including three small cell carcinoma, three squamous cell carcinoma, one large cell neuroendocrine carcinoma, and one with a mixture of adenocarcinoma and squamous cell carcinoma components. The median treatment duration of the third-generation EGFR-TKI before rebiopsy was numerically longer in patients with histological transformation than those without (16.0 vs. 10.9 months). Both the overall survival time from the start of third-generation EGFR-TKI initiation (30.8 vs. 41.2 months) and from rebiopsy (6.6 vs. 12.9 months) to mortality were numerically shorter amongst the transformed population. All patients in the transformed group did not respond to the next line of systemic treatment. One patient with histological transformation receiving local treatment for the metastatic site had a longer overall survival. Conclusions: Repeating biopsy to identify histological transformation should be considered in patients with progression to the third-generation EGFR-TKI. Histological transformations could contribute to the acquired resistance with the implication of a worse prognosis. Further studies are needed to determine the optimal therapy for these patients.

Risk factors for stress and urge urinary incontinence during pregnancy and the first year postpartum: a prospective longitudinal study.

INTRODUCTION AND HYPOTHESIS: We examined obstetric and maternal-newborn factors and UI history for stress urinary incontinence (UI) and urge UI during pregnancy and the first year postpartum. METHODS: This prospective cohort study included 1447 pregnant women who underwent prenatal examinations and completed an Incontinence Questionnaire-Urinary Incontinence Short Form before pregnancy, during early, mid- and late pregnancy, and at five visits during the first year postpartum. Data were analyzed using univariate/multivariate generalized estimating equation (GEE) logistic regression analyses. RESULTS: The prevalence rates of stress UI during late pregnancy (42.5%) and urge UI at 3-5 days postpartum (10.4%) were the highest throughout pregnancy and the first year postpartum. After adjusting for covariates, gestational age increased the risks of stress UI (p < 0.001) and urge UI (p = 0.003); stress UI during pre-pregnancy, number of previous vaginal deliveries and concurrent high body mass index (BMI) increased stress UI (all p < 0.05); urge UI during pre-pregnancy and full-time work increased urge UI (both p < 0.05) during pregnancy. During the postpartum period, vaginal delivery increased stress UI (p < 0.001) and urge UI (p = 0.041); stress UI during pre-pregnancy and pregnancy, women aged ≥ 30 years and vacuum extraction/forceps delivery increased stress UI (all p < 0.05). Urge UI during early, mid- and late pregnancy increased stress UI (all p < 0.05). CONCLUSIONS: Gestational age increased stress and urge UI, while previous vaginal deliveries and high BMI increased stress UI; full-time work increased urge UI during pregnancy. Vaginal delivery increased both UIs, and vacuum/forceps delivery and maternal age increased stress UI during postpartum.

Fellow selection protocols in sleep surgery: a national survey of sleep surgery program directors.

PURPOSE: To determine the factors that sleep medicine/surgery fellowship program directors look for in applicants. METHODS: Program directors from 9 sleep medicine/surgery fellowship programs in the USA were sent an anonymous online survey. They were asked to select the five most important academic factors (of a list of 17) when evaluating potential fellowship candidates, then rank those five in order of importance. They were then asked to do the same for the most important subjective criteria (of a list of 12). RESULTS: Eight of 10 survey responses met inclusion criteria. Of the academic factors, strength of letters of recommendation, reputation of letter writer, and letters from sleep surgeons ranked highest. As for the subjective criteria, faculty assessment of the applicant on interview was ranked highest, followed by initiative and personality "fit" with the program. The reputation of an applicant's residency was ranked as more important than the reputation of their medical school. An applicant's performance in residency was assessed as more predictive of their performance in fellowship than performance during the interview process or position on the rank order list for the match. Only one program has a United States Medical Licensing Examination (USMLE) Step, and a different program has an Otolaryngology Training Examination (OTE) score cutoff. CONCLUSION: Letters of recommendation and interview are the most important factors in the selection process for hybrid sleep medicine and surgery fellowship programs, followed by research and residency program reputation. Sleep surgery-specific experience is helpful.

Aqueous Ocimum gratissimum extract induces cell apoptosis in human hepatocellular carcinoma cells.

Treatment of advanced hepatocellular carcinoma (HCC) has exhibited a poor overall survival rate of only six to ten months, and the urgency of the development of more effective novel agents is ever present. In this line of research, we aimed to investigate the effects and inhibitive mechanisms of aqueous Ocimum gratissimum leaf extract (OGE), the extract of Ocimum gratissimum, which is commonly used as a therapeutic herb for its numerous pharmacological properties, on malignant HCC cells. Our results showed that OGE decreased the cell viability of HCC SK-Hep1 and HA22T cells in a dose-dependent manner (from 400 to 800 µg/mL), while there is little effect on Chang liver cells. Moreover, cell-cycle analysis shows increased Sub-G1 cell count in SK-Hep1 and HA22T cells which is not observed in Chang liver cells. These findings raise suspicion that the OGE-induced cell death may be mediated through proteins that regulate cell cycle and apoptosis in SK-Hep1 and HA22T cells, and further experimentation revealed that OGE treatment resulted in a dose-dependent decrease in caspase 3 and PARP expressions and in CDK4and p-ERK1/2expressions. Moreover, animal tests also exhibited decreased HCC tumor growth by OGE treatment. We therefore suggest that the inhibition of cell viability and tumor growth induced by OGE may be correlated to the alteration of apoptosis-related proteins.

Predictors of an improvement in the severity of concomitant urodynamic stress incontinence after transvaginal mesh surgery for pelvic organ prolapse.

BACKGROUND/PURPOSE: Factors affecting the anti-incontinence efficacy of a tailored anterior transvaginal mesh (ATVM) surgery are undetermined. Thus, our aim was to investigate predictors for anti-incontinence efficacy of this ATVM surgery. METHODS: Medical records of women with pelvic organ prolapse and concomitant evident or occult urodynamic stress incontinence, who underwent the ATVM surgery but without concomitant anti-incontinence surgery, were reviewed. RESULTS: A total of 134 women were reviewed, including those who underwent ATVM only (n = 45), ATVM and posterior transvaginal mesh surgery (n = 88), and ATVM with total vaginal hysterectomy (n = 1). Multivariable analysis revealed that stage of cystocele (coefficient = 56.4), functional profile length (cm, coefficient = 61.1) and the score of general health perceptions in the King's Health Questionnaire (coefficient = -3.3) were independent predictors of the percentage change in pad weight from baseline. Seven (5.2%) women were found to have recurrent or persistent stress urinary incontinence, and 6 of the above 7 women underwent transobturator mid-urethral sling procedure. Free of further anti-incontinence surgery probabilities were 94.7% and 89.2% at 3 and 6 years after surgery, respectively. Functional profile length (hazard ratio = 2.61) was also identified as a predictor for further anti-incontinence surgery. CONCLUSION: Lesser degree of cystocele, shorter functional profile length and poorer general health perceptions were predictors of greater anti-incontinence effect after the tailored ATVM surgery. Besides, longer functional profile length was also a predictor for further anti-incontinence surgery after the ATVM surgery.

Prevalence of detrusor underactivity and bladder outlet obstruction in women with cystocele and changes in voiding function after cystocele repair.

PURPOSE: To evaluate the prevalence of detrusor underactivity (DU) and bladder outlet obstruction (BOO) in women with high-grade cystocele and the impacts of cystocele repair. METHODS: Between November 2010 and September 2018, women with ≥stage II cystocele were included. DU (detrusor pressure at maximum flow rate (PdetQmax) < 20 cmH2O, maximum flow rate (Qmax) < 15 mL/s, and bladder voiding efficiency < 90%) and BOO (PdetQmax ≥ 40 cmH2O and Qmax < 12 mL/s) were diagnosed by urodynamic study (UDS). Women who underwent cystocele repair were further analyzed with preoperative and postoperative comparisons. RESULTS: A total of 623 women were included. Forty-four (7%) and 17 (3%) women were diagnosed with DU and BOO, respectively. Among the 314 operatively treated women, a significant increase in DU (7% vs. 15%, p = 0.0007), especially in those with stage III cystocele, and a slightly decreased rate of BOO were noted postoperatively. UDS revealed that the postvoid residual volume, functional profile length, maximum urethral closure pressure (MUCP), and pressure transmission ratio at the MUCP decreased significantly, as did the pad weight. Nearly all lower urinary tract symptoms (LUTS) improved significantly, except nocturnal enuresis. Among bladder diary parameters, nocturia episodes, daytime frequency, urgency episodes, and incontinence episodes decreased significantly after the operation. CONCLUSION: The prevalence rates of DU and BOO in women with high-grade cystocele were 7% and 3%, respectively. After cystocele repair, the rate of DU increased. Most LUTS improved subjectively on questionnaires and objectively on UDS and bladder diary parameters after operation.