Synergistic inhibition of Haemonchus contortus exsheathment by flavonoid monomers and condensed tannins

This study investigated the separate and combined anthelmintic (AH) effects of different phenolic compounds, including condensed tannins and flavonoids, all of which are known to occur in willow leaves, a potentially valuable dry season feed. A range of contrasting model tannins, which span the whole range of willow tannins, were isolated from tilia flowers, goat willow leaves, black currant leaves and red currant leaves. All together, the tested compounds represented the major tannin types (procyanidins and prodelphinidins) and flavonoid types (flavonols, flavones and flavanones). The larval exsheathment inhibition assay (LEIA) was used to assess their in vitro effects on Haemonchus contortus third stage larvae. Arbutin, vanillic acid, and taxifolin proved to be ineffective whereas naringenin, quercetin and luteolin were highly effective at 250 μM concentrations. Procyanidin (PC) tannins tended to be less active than prodelphinidin tannins (PD). Experiments with combinations of tannins and quercetin or luteolin revealed for the first time the existence of synergistic AH effects between tannins and flavonoid monomers. They also provided evidence that synergistic effects appear to occur at slightly lower concentrations of PC than PD. This suggests that the AH activity of condensed tannins can be significantly enhanced by the addition of quercetin or luteolin. This information may prove useful for plant breeding or selection and for designing optimal feed mixtures

Risk Factors for Urgency Incontinence in Women Undergoing Stress Urinary Incontinence Surgery

Objective. To determine baseline variables associated with urgency urinary incontinence (UUI) in women presenting for stress urinary incontinence (SUI) surgery. Methods. Baseline data from two randomized trials enrolling 1,252 women were analyzed: SISTEr (fascial sling versus Burch colposuspension) and TOMUS (retropubic versus transobturator midurethral sling). Demographic data, POP-Q measures, and validated measures of symptom severity and quality of life were collected. Charlson Comorbidity Index (CCI) and Patient Health Questionnaire-9 were measured in TOMUS. Multivariate models were constructed with UUI and symptom severity as outcomes. Results. Over two-thirds of subjects reported bothersome UUI at baseline. TOMUS patients with more comorbidities had higher UDI irritative scores (CCI score 0 = 39.4, CCI score 1 = 42.1, and CCI score 2+ = 51.0, P=0.0003), and higher depression scores were associated with more severe UUI. Smoking, parity, prior incontinence surgery/treatment, prolapse stage, and incontinence episode frequency were not independently associated with UUI. Conclusions. There were no modifiable risk factors identified for patient-reported UUI in women presenting for SUI surgery. However, the direct relationships between comorbidity level, depression, and worsening of UUI/urgency symptoms may represent targets for preoperative intervention. Further research is necessary to elucidate the pathophysiologic mechanisms that explain the associations between these medical conditions and bladder function

High-Energy Collision of Quarks and Mesons in the Schwinger Model: From Tensor Networks to Circuit QED

With the aim of studying nonperturbative out-of-equilibrium dynamics of high-energy particle collisions on quantum simulators, we investigate the scattering dynamics of lattice quantum electrodynamics in 1+1 dimensions. Working in the bosonized formulation of the model and in the thermodynamic limit, we use uniform-matrix-product-state tensor networks to construct multi-particle wave-packet states, evolve them in time, and detect outgoing particles post collision. This facilitates the numerical simulation of scattering experiments in both confined and deconfined regimes of the model at different energies, giving rise to rich phenomenology, including inelastic production of quark and meson states, meson disintegration, and dynamical string formation and breaking. We obtain elastic and inelastic scattering cross sections, together with time-resolved momentum and position distributions of the outgoing particles. Furthermore, we propose an analog circuit-QED implementation of the scattering process that is native to the platform, requires minimal ingredients and approximations, and enables practical schemes for particle wave-packet preparation and evolution. This study highlights the role of classical and quantum simulation in enhancing our understanding of scattering processes in quantum field theories in real time.Comment: 5+12 pages, 4+6 figures, close to published versio

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma.

PurposeGDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma.Patients and methodsGDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.ResultsForty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of >1 and >0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable.ConclusionsGDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier

The prevention of lower urinary tract symptoms (PLUS) research consortium: A transdisciplinary approach toward promoting bladder health and preventing lower urinary tract symptoms in women across the life course

Lower urinary tract symptoms (LUTS) are highly prevalent in women, and are expected to impose a growing burden to individuals and society as the population ages. The predominance of research related to LUTS has focused on underlying pathology, disease mechanisms, or the efficacy of treatments for women with LUTS. Although this research has been vital for helping to reduce or ameliorate LUTS conditions, it has done little to prevent the onset of LUTS. Health promotion and prevention require an expansion of scientific inquiry beyond the traditional paradigm of studying disease mechanisms and treatment to the creation of an evidence base to support recommendations for bladder health promotion and, in turn, prevention of LUTS. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) introduced the concept of prevention as an important priority for women's urologic research as a prelude to supporting the formation of the Prevention of Lower Urinary Tract Symptoms (PLUS) research consortium. In this article, we introduce the PLUS research consortium to the scientific community; share the innovative paradigms by which the consortium operates; and describe its unique research mission: to identify factors that promote bladder health across the life course and prevent the onset of LUTS in girls and women

Palliative gastrostomy in the setting of voluminous ascites

Objective: We report the indications, methods, and complications of percutaneous gastrostomy/gastrojejunostomy (G/GJ) in patients with voluminous ascites. Methods: Following institutional review board approval, 69 patients (14 male, 55 female, mean age 58±12 years, range 32–89 years) who underwent percutaneous G/GJ with paracentesis were identified from a prospectively acquired database. Electronic medical record data extracted included diagnosis, method of G/GJ insertion, clinical course, and complications, which were graded by The Society of Interventional Radiology (SIR) criteria. Statistics were performed using Graphpad Instat. Results: Sixty-six G and three GJ catheters were placed in 62 patients with malignant and 7 patients with benign disease; 47 procedures were conducted using fluoroscopy and 22 using computed tomography (CT; 10 patients had failed fluoroscopy). Sixty-six patients had 1980±1371 mL (range, 20–5000 mL) ascites drained (more in males, p=0.01) 0.8±1.6 days (range, 0–5 days) prior to placement. Forty-one patients had significantly less ascites (1895±1426 mL; range, 100–5400 mL) drained after G/GJ (p>0.0.5). Mean survival after insertion was 43±57 days (range, 1–252 days) among 38 patients for whom data were available. Fifty-six patients had a mean postprocedure hospital stay of 8.6±8.4 days (range, 0–45 days); 3 were outpatients and 10 patients died in the hospital. Successful gastropexy was confirmed on subsequent cross-sectional imaging in 22 of 25 patients. There were 25 tube maintenance issues that included catheter displacement and leakage, one patient experienced hemorrhage, and there were two deaths. All except one patient had satisfactory gastrostomy function. Conclusion: Effective G/GJ placement is possible in most patients with voluminous ascites provided ascites is drained and gastrocutaneous fistula formation occurs. Caution is advised; placement is generally for fragile terminal patients, and fluoroscopy or CT guidance is required

Oral human papillomavirus is common in individuals with Fanconi anemia

Fanconi anemia is a rare genetic disorder resulting in a loss of function of the Fanconi anemia-related DNA repair pathway. Individuals with Fanconi anemia are predisposed to some cancers, including oropharyngeal and gynecologic cancers, with known associations with human papillomavirus (HPV) in the general population. As individuals with Fanconi anemia respond poorly to chemotherapy and radiation, prevention of cancer is critical. METHODS: To determine whether individuals with Fanconi anemia are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with Fanconi anemia and 162 unaffected first-degree family members for 37 HPV types. RESULTS: Fourteen individuals (11.1%) with Fanconi anemia tested positive, significantly more (P = 0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with Fanconi anemia (17.7% vs. 2.4% in family; P = 0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in Fanconi anemia vs. 2.9% in siblings). Indeed, having Fanconi anemia increased HPV positivity 4.9-fold (95% CI, 1.6-15.4) considering age and sexual experience, but did not differ by other potential risk factors. CONCLUSION: Our studies suggest that oral HPV is more common in individuals with Fanconi anemia. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time. IMPACT: HPV vaccination should be emphasized in those with Fanconi anemia as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine whether the level of protection it offers in this population is adequate