The goal of this study was to determine the efficacy of retropubic urethrolysis without resuspension for the surgical treatment of postoperative urinary retention.
A retrospective chart review was ...done of six women with posturethropexy urinary retention or voiding dysfunction who underwent retropubic urethrolysis between July 1999 and June 2000.
An average of 27.0 (+/- 19.6) months elapsed between obstructive incontinence procedure and urethrolysis. The mean maximum detrusor pressure during voiding was elevated at 52.7 (+/- 31.7) cm H2O. The mean maximum flow rate during voiding was decreased at 16.3 (+/- 10.8) cm H2O. The average postvoid residual volume was 152.9 +/- 71.6 mL, significantly decreased postoperatively to 36.9 +/- 40.0 mL (t = 3.37, p = 0.043). Postoperative cystourethroscopy showed a completely free and mobile urethra. In the short-term, all patients had resolution of their symptoms. No patient had return of stress incontinence in a mean clinical follow-up of 3.3 +/- 2.3 months.
Our results are comparable to other series of urethrolyses, despite omission of resuspension. Retropubic urethrolysis offers favorable relief of persistent postoperative urinary retention and voiding dysfunction, particularly after retropubic urethropexy.
To evaluate epicutaneous application of 5% lidocaine-prilocaine and 30% lidocaine cream anesthetics for neonatal circumcision.
The efficacy of 5% lidocaine-prilocaine and 30% lidocaine creams was ...compared in a randomized, double-blind, placebo-controlled trial. Sixty-one neonates were randomly assigned to one of three groups: 5% prilocaine-lidocaine (n = 20), 30% lidocaine (n = 20), and a control group that received an acid-mantle cream (n = 21). Heart rate, oxygen saturation, and crying time were monitored before, during, and after circumcision. Blood pressure was measured before and after circumcision.
Mean peak heart rates for the 5% lidocaine-prilocaine, 30% lidocaine, and control groups (+/- standard deviation) were 146 +/- 16, 157 +/- 10, and 164 +/- 16 beats per minute, respectively. During four of six active phases of circumcision, the 5% lidocaine-prilocaine group suppressed significant increases in heart rate better than 30% lidocaine, which was more effective than control (dorsal clamp, P < .001; bell clamp on, P = .001; tightening, P = .001; bell clamp off, P < .001). During tightening of the bell clamp, significantly less crying was seen in the 5% lidocaine-prilocaine group (13 +/- 12 seconds) compared with 30% lidocaine (24 +/- 14 seconds) and controls (38 +/- 27 seconds) (P < .001). The group that received 5% lidocaine-prilocaine also had no significant increase in systolic (t = 1.6, P = .12) or diastolic (t = 1.9, P = .067, respectively) blood pressure, unlike the group receiving 30% lidocaine (t = 4.8, P = .001 and t = 2.9, P = .009, respectively) and the placebo group (t = 2.5, P = .023 and t = 2.3, P = .032). There were no significant differences in oxygen saturation (alpha = .05, power 0.79).
Epicutaneous 5% lidocaine-prilocaine was more effective than 30% lidocaine for neonatal circumcision, better reducing neonatal stress indicators. Lidocaine-prilocaine significantly shortened crying time during one of the most painful phases of circumcision. Both topical anesthetics were more effective than placebo in attenuating the behavioral and physiologic indicators of neonatal pain.
Individual variability has clear effects upon the outcome of therapies and treatment approaches. The customization of healthcare options to the individual patient should accordingly improve treatment ...results. We propose a novel approach to brain interventions based on personalized brain network models derived from non-invasive structural data of individual patients. Along the example of a patient with bitemporal epilepsy, we show step by step how to develop a Virtual Epileptic Patient (VEP) brain model and integrate patient-specific information such as brain connectivity, epileptogenic zone and MRI lesions. Using high-performance computing, we systematically carry out parameter space explorations, fit and validate the brain model against the patient's empirical stereotactic EEG (SEEG) data and demonstrate how to develop novel personalized strategies towards therapy and intervention.
•A novel approach to brain interventions is proposed based on personalized large-scale brain network models.•The approach relies on the fusion of structural data of individual patients and mathematical modeling of brain activations.•Personalization is achieved by integrating patient specific brain connectivity, epileptogenic zone and MRI lesions.•High-performance computing enables systematic parameter space explorations, fitting and validation of the brain model.•Large-scale brain models foster the development of personalized strategies towards therapy and intervention.
The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with ...multiple endogenous peptides that can interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca(2+) mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.
Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address ...this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two ...independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention.
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•Therapeutic resistance to ACT in cancer patients is poorly characterized•T cell tumor trafficking and T cell cytotoxicity are impaired in glycolytic tumors•Glycolysis inhibition enhances antitumor activity of tumor-reactive T cells•Melanomas from ACT-refractory patients exhibit higher glycolytic activity
Cascone et al. identify tumor glycolysis to be associated with immune resistance to adoptive T cell therapy (ACT). In ACT-treated patients, increased tumor glycolytic activity is associated with lower therapeutic response, highlighting the therapeutic potential of combining glycolysis inhibition with ACT in cancer patients.
The purpose of this study was to describe the distribution of pelvic organ support in a gynecologic clinic population to define the clinical disease state of pelvic organ prolapse and to analyze its ...epidemiologic condition.
This was a multicenter observational study. Subjects who were seen at outpatient gynecology clinics who required an annual gynecologic examination underwent a pelvic organ prolapse quantification examination and completed a prolapse symptom questionnaire. Receiver operator characteristic curves were used to define pelvic organ prolapse with the use of symptoms and pelvic organ prolapse quantification examination measures. Standard age-adjusted univariate and multivariate logistic regression analysis were used to evaluate various relationships.
The population consisted of 1004 women who were aged 18 to 83 years. The prevalence of pelvic organ prolapse quantification stages was 24% (stage 0), 38% (stage 1), 35% (stage 2), and 2% (stage 3). The definition of pelvic organ prolapse that was determined by the receiver operator characteristic curve was the leading edge of their vaginal wall that was −0.5 cm above the hymenal remnants. Multivariate analysis revealed age, Hispanic race, increasing body mass index, and the increasing weight of the vaginally delivered fetus as risk factors for pelvic organ prolapse, as defined in this population.
The results from this population suggest that there is a bell-shaped distribution of pelvic organ support in a gynecologic clinic population. Advancing age, Hispanic race, increasing body mass index, and the increasing weight of the vaginally delivered fetus have the strongest correlations with prolapse.
Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this ...study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy.
To identify genes mediating resistance to T-cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous tumor-infiltrating lymphocytes (TIL).
The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti-PD-1-treated melanoma patient tumor samples suggested that higher
expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3' untranslated region (UTR) of
to destabilize the mRNA.
MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of
to destabilize the
mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells.
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