Single-Incision Mini-Slings for Stress Urinary Incontinence in Women.

BACKGROUND: Until recently, synthetic midurethral slings (made of mesh or tape) were the standard surgical treatment worldwide for female stress urinary incontinence, if conservative management failed. Data comparing the effectiveness and safety of newer single-incision mini-slings with those of standard midurethral slings are limited. METHODS: We performed a pragmatic, noninferiority, randomized trial comparing mini-slings with midurethral slings among women at 21 U.K. hospitals during 36 months of follow-up. The primary outcome was patient-reported success (defined as a response of very much or much improved on the Patient Global Impression of Improvement questionnaire) at 15 months after randomization (approximately 1 year after surgery). The noninferiority margin was 10 percentage points. RESULTS: A total of 298 women were assigned to receive mini-slings and 298 were assigned to receive midurethral slings. At 15 months, success was reported by 212 of 268 patients (79.1%) in the mini-sling group and by 189 of 250 patients (75.6%) in the midurethral-sling group (adjusted risk difference, 4.6 percentage points; 95% confidence interval [CI], -2.7 to 11.8; P<0.001 for noninferiority). At the 36-month follow-up, success was reported by 177 of 246 patients (72.0%) and by 157 of 235 patients (66.8%) in the respective groups (adjusted risk difference, 5.7 percentage points; 95% CI, -1.3 to 12.8). At 36 months, the percentage of patients with groin or thigh pain was 14.1% with mini-slings and 14.9% with midurethral slings. Over the 36-month follow-up period, the percentage of patients with tape or mesh exposure was 3.3% with mini-slings and 1.9% with midurethral slings, and the percentage who underwent further surgery for stress urinary incontinence was 2.5% and 1.1%, respectively. Outcomes with respect to quality of life and sexual function were similar in the two groups, with the exception of dyspareunia; among 290 women responding to a validated questionnaire, dyspareunia was reported by 11.7% in the mini-sling group and 4.8% in the midurethral-sling group. CONCLUSIONS: Single-incision mini-slings were noninferior to standard midurethral slings with respect to patient-reported success at 15 months, and the percentage of patients reporting success remained similar in the two groups at the 36-month follow-up. (Funded by the National Institute for Health Research.).

Social determinants of chronic diseases reporting among slum dwellers in Egypt.

The high prevalence of chronic diseases in urban slums poses increasing challenges to future social and economic development for these disadvantaged areas. Assessing the health status of slum residents offers guidance for formulating appropriate policies and interventions to improve slum residents' health outcomes. This research aimed to identify the social determinants of chronic diseases reporting among slum dwellers in Egypt. A cross-sectional survey was conducted from March to December 2021 in three slum areas in Giza governorate, Egypt, including 3,500 individuals. We constructed an asset index and a welfare index to measure the economic status and living conditions of slum residents, respectively. We used these indices, along with demographic and socio-economic factors, as independent variables in the analysis. We modeled factors associated with health status using a two-level mixed logistic model to control the effects of slum areas and the potential correlation between household members. The study contributed significantly to a better understanding of the context in which slum dwellers live and the interlinkages among poor living conditions, low economic status, and health outcomes. The results showed a high rate of self-reported chronic diseases among adults aged 18 and older, reaching more than 22%, while it did not exceed 2.0% among children in the slum areas. Therefore, measuring the determinants of chronic diseases was limited to adults. The sample size was 2530 adults after excluding 970 children. The prevalence of chronic diseases among adults ranged between 16.3% in Zenin and 22.6% in Bein El Sarayat. Our findings indicated that low socio-economic status was significantly associated with reporting chronic diseases. Future policies should be dedicated to improving living conditions and providing necessary healthcare services for these vulnerable areas.

The "Aberdeen Home Continence Stress Test": a novel objective assessment tool for female stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Clinical trials for stress urinary incontinence (SUI) require a robust, reliable, and responsive tool for objective assessment of SUI post-intervention. The Aberdeen Home Continence Stress Test (HCST) is a novel patient-reported objective assessment tool, aimed to be patient-friendly and reduce attrition rates by avoiding hospital appointments and prolonged pad-wearing. We aim to describe the HCST for the first time and evaluate its reliability, diagnostic accuracy, and response to change. METHODS: A secondary analysis of the Single-Incision Mini-Slings (SIMS) study (a prospective multicentre randomised control trial (RCT) comparing two surgical treatments of SUI was performed. In SIMS (n = 600 women), the objective outcome was assessed by the 24-h pad test, while the patient-reported success rates were assessed using the Patient Global Impression of Improvement (PGI-I) at 15 months, 2 years and 3 years post-randomisation. Participants were instructed to perform the HCST before and after the 24-h pad test. The HCST was analysed in relation to reliability, validity, and the relationship between the 24-h pad test and HCST results and finally with regard to its responsiveness to change in PGI-I. (Trial registration-number ISRCTN93264234, registration date 14/01/2014). RESULTS: Compared to the 24-h pad test, the sensitivity of the HCST ranged from 0.81-0.95, specificity was 0.76-0.79, negative predictive value was 0.96-0.99 and positive predictive value was 0.32-0.43. Reliability was indicated by high-performing Cronbach's alpha value (> 0.7). An improvement of ≥ 2 leakage groups on the HCST (for example from Large at baseline to Small leakage at follow-up) was strongly associated with patient-reported success on PGI-I (OR 4.38, 95% CI 2.31, 8.31). CONCLUSIONS: The HCST is a valid and reliable patient-reported objective assessment tool that can be used for assessing SUI in surgical trials with good specificity, sensitivity, and consistency.

Novel clinically meaningful scores for the ICIQ-UI-SF and ICIQ-FLUTS questionnaires in women with stress incontinence.

AIM: To establish, for the first time, the clinically important differences for the ICIQ-UI-SF and ICIQ-FLUTS questionnaires following surgical and conservative treatments for stress-predominant urinary incontinence in women. METHODS: Data from the SIMS and OPAL randomised controlled trials were analysed using an anchor-based method. Clinically important difference (CID; score change indicating a successful outcome) and minimal important difference (MID; score change indicating the smallest noticeable difference) were estimated using the PGI-I scale as the anchor. RESULTS: For ICIQ-UI-SF, following surgical management, CIDs were 5.0 (95%CI 4.3, 5.6) at 1 year and 4.9 points (95%CI 4.2, 5.5) at 3 years, while following conservative management, CIDs were 4.0 (95%CI 3.4, 4.5) at 1 year and 4.6 points (95%CI 4.0, 5.2) at 2 years. For ICIQ-FLUTS, the CID was 3.4 points (95%CI 2.9, 4.0) at 1 year for both surgical and conservative management. MIDs for ICIQ-UI-SF, after surgical treatment, were 4.7 (95% CI 3.2, 6.1) at 1 year and 1.6 points (95%CI -0.2, 3.0) at 3 years, and after conservative treatment they were 1.7 (95% CI 1.0, 2.5) at 1 year and 1.9 points (95%CI 1.1, 2.7) at 2 years. For ICIQ-FLUTS, MIDs were 1.8 (95% CI 0.6, 3.1) at 1 year and 3.2 points (95%CI 2.0, 4.4) at 2 years after surgical treatment, and 1.3 (95%CI 0.6, 1.9) at 1 year and 1.9 points (95%CI 1.1, 2.6) at 2 years after conservative treatment. CONCLUSION: Our study is the first to establish the CID for the ICIQ-UI-SF and ICIQ-FLUTS that women would associate with a successful outcome 3-years post-surgery and 2-years post-conservative treatment of stress-predominant urinary incontinence. The MID was lower following conservative compared to surgical treatment.

In vitro and in vivo assessment of the anti-inflammatory activity of olive leaf extract in rats.

Inflammation is a complex and crucial process that protects the body against pathogens. Here in our study, we propose to scientifically justify the anti-inflammatory activity of olive leaf (OL). Initially, we ensured the safety of olive leaf extract (OLE) through acute oral administration of graded doses up to 4 g\kg in Wistar rats. Thus, the extract was considered generally safe. We also evaluated the ability of the extract to reduce carrageenan-induced rat paw edema. Compared to diclofenac sodium (10 mg/kg PO), OLE showed significant (P < 0.05) anti-inflammatory activity, showing the maximum inhibition percentage at the fifth hour of measurement at 42.31% and 46.99%, at doses of 200 and 400 m/kg, respectively, compared to 63.81% for the standard drug. To elucidate the potential mechanism, we measured TNF, IL-1, COX-2 and NO inside the paw tissue. Interestingly, OLE at all tested doses reduced the concentration of TNF and IL-1 to a level that was lower than that obtained by the standard drug. Additionally, OLE at the dose of 400 mg/kg reduced the levels of COX-2 and NO inside the paw tissue to a level that was statistically equivalent to the level observed in the normal control group. Finally, olive leaf extract at doses of 100, 200 and 400 mg/kg doses significantly (P < 0.05) inhibited the heat-induced hemolysis of RBCs membrane by 25.62, 57.40 and 73.88%, respectively, compared to 83.89% produced by aspirin. Consequently, we concluded that olive leaf extract has a significant anti-inflammatory activity through the reduction of TNF, IL-1, COX-2 and NO.

Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience.

This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/ßcatenin, Angiogenesis, EGFR, TGF-ß and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.

Planned mode of birth after previous cesarean section and risk of undergoing pelvic floor surgery: A Scottish population-based record linkage cohort study.

BACKGROUND: The global rise in cesarean sections has led to increasing numbers of pregnant women with a history of previous cesarean section. Policy in many high-income settings supports offering these women a choice between planned elective repeat cesarean section (ERCS) or planned vaginal birth after previous cesarean (VBAC), in the absence of contraindications to VBAC. Despite the potential for this choice to affect women's subsequent risk of experiencing pelvic floor disorders, evidence on the associated effects to fully counsel women is lacking. This study investigated the association between planned mode of birth after previous cesarean section and the woman's subsequent risk of undergoing pelvic floor surgery. METHODS AND FINDINGS: A population-based cohort study of 47,414 singleton term births in Scotland between 1983 to 1996 to women with 1 or more previous cesarean sections was conducted using linked Scottish national routine datasets. Cox regression was used to investigate the association between planned as well as actual mode of birth and women's subsequent risk of having any pelvic floor surgery and specific types of pelvic floor surgery adjusted for sociodemographic, maternal medical, and obstetric-related factors. Over a median of 22.1 years of follow-up, 1,159 (2.44%) of the study population had pelvic floor surgery. The crude incidence rate of any pelvic floor surgery per 1,000 person-years was 1.35, 95% confidence interval (CI) 1.27 to 1.43 in the overall study population, 1.75, 95% CI 1.64 to 1.86 in the planned VBAC group and 0.66, 95% CI 0.57 to 0.75 in the ERCS group. Planned VBAC compared to ERCS was associated with a greater than 2-fold increased risk of the woman undergoing any pelvic floor surgery (adjusted hazard ratio [aHR] 2.38, 95% CI 2.03 to 2.80, p < 0.001) and a 2- to 3-fold increased risk of the woman having surgery for pelvic organ prolapse or urinary incontinence (aHR 3.17, 95% CI 2.47 to 4.09, p < 0.001 and aHR 2.26, 95% CI 1.79 to 2.84, p < 0.001, respectively). Analysis by actual mode of birth showed these increased risks were only apparent in the women who actually had a VBAC, with the women who needed an in-labor non-elective repeat cesarean section having a comparable risk of pelvic floor surgery to those who had an ERCS. The main limitation of this study is the potential for misclassification bias. CONCLUSIONS: This study suggests that among women with previous cesarean section giving birth to a singleton at term, planned VBAC compared to ERCS is associated with an increased risk of the woman subsequently undergoing pelvic floor surgery including surgery for pelvic organ prolapse and urinary incontinence. However, these risks appear to be only apparent in women who actually give birth vaginally as planned, highlighting the role of vaginal birth rather than labor in pelvic floor dysfunction requiring surgery. The findings provide useful additional information to counsel women with previous cesarean section about the risks and benefits associated with their future birth choices.

Management of post-midurethral sling voiding dysfunction. International Urogynecological Association research and development committee opinion.

Voiding dysfunction following midurethral sling procedures is not a rare event. There is no current consensus regarding management of this complication. Although it is often transient and self-limiting, chronic post-midurethral sling voiding dysfunction may lead to irreversible changes affecting detrusor function. Initial management includes intermittent catheterization, and addressing circumstantial factors interfering with normal voiding, such as pain. Early sling mobilization often resolves the dysfunction, and is associated with minimal morbidity. Sling incision or excision at a later stage, although fairly effective, could be associated with recurrence of stress urinary incontinence. There is insufficient evidence to justify urethral dilatation in this context.

Long-term outcomes of transobturator tension-free vaginal tapes as secondary continence procedures.

PURPOSE: To assess the long-term patient-reported outcomes following TO-TVT as a secondary continence procedure in women with recurrent stress urinary incontinence (R-SUI). METHODS: A secondary analysis of the 9-year follow-up of the E-TOT study was performed: 341 women with predominant SUI symptoms were randomised to undergo either Inside-out or Outside-in TO-TVT between April 2005 and April 2007. Forty-six women had R-SUI following previously failed continence surgery at time of randomisation and are the basis of this analysis as a one single cohort. Primary outcome was the patient-reported success rate defined as very/much improved on Patient's Global Impression of Improvement (PGI-I). Secondary outcomes included late adverse events and impact on women's quality of life and sexual function. Statistical analysis was performed using SPSS version 23. RESULTS: Sixty-three per cent completed the 9-year follow-up. The success based on the PGI-I was 62.1% with no significant difference between groups (OR 5.33; 95% CI 1.03, 27.76; p = 0.094). Clinically significant improvement in QoL was found in 84.2%. Adverse events included vaginal erosions (n = 3) and groin pain (n = 2). The small sample size is a limitation in this study; nevertheless, this is one of the largest cohorts reported for women with R-SUI and the first to report the long-term outcomes of TO-TVT as a secondary continence procedure. CONCLUSIONS: TO-TVT operations are associated with good patient-reported success rates (62%) in women with previous failed continence surgery with up to 9-years follow-up. There is a non-significant trend towards better outcomes with the inside-out TO-TVT.

Long-term outcomes for transobturator tension-free vaginal tapes in women with urodynamic mixed urinary incontinence.

AIMS: To assess the long-term patient reported outcomes following transobturator tension-free vaginal tapes (TO-TVT) in women with urodynamic mixed urinary incontinence (MUI). METHODS: A secondary analysis of the 9-year follow-up of the E-TOT study: 341 women with predominant stress urinary incontinence symptoms were randomized to undergo either inside-out or outside-in TO-TVT between April 2005 and April 2007. Forty-eight women had preoperative urodynamic MUI and were available for 9-year follow-up. Primary outcome was the patient-reported success rate defined as very/much improved on Patient's Global Impression of Improvement PGI-I. Secondary outcomes included impact on women's quality of life, sexual function, overactive bladder symptoms,and late adverse events. Statistical analysis was performed using SPSS v.23. RESULTS: Forty-eight women completed the 9-year follow-up, with adjusted response rate of 63%. The success based on the PGI-I was 64.6% (n = 31), with a further 14.6% (n = 7) who reported "improved." There was no significant difference between groups (OR 1.11; 95%CI 0.33, 3.70; P > 0.999). Clinically significant improvement in quality of life was found in 85.3%. Cure of urgency and UUI was reported by 35% and 41%, whereas worsening was reported in 6.5% and 2.3%, respectively. One patient reported chronic groin/leg pain. The small sample size and the sizeable loss to follow-up are limitations in this study. CONCLUSIONS: This is the first study to report the long-term outcomes of TO-TVT in women with urodynamic MUI; TO-TVT is associated with a good and sustained patient-reported success rate in women with MUI up to 9-years follow-up.

A new validated score for detecting patient-reported success on postoperative ICIQ-SF: a novel two-stage analysis from two large RCT cohorts.

INTRODUCTION AND HYPOTHESIS: The Patient Global Impression of Improvement (PGI-I) and International Consultation of Incontinence Questionnaire - Short Form (ICIQ-SF) are validated instruments for the assessment of patient reported outcome measures (PROM) following treatment of stress urinary incontinence (SUI). However, there is a paucity of evidence as to what represents a successful postintervention ICIQ-SF score. To determine the correlation between the postoperative ICIQ-SF scores with the PGI-I outcomes, the latter was considered one of the standard PROM following surgical treatment for SUI. The aim of this study was to determine, and if appropriate validate, an ICIQ-SF cut-off score that can predict a successful PROM as determined by PGI-I. METHODS: Four large datasets yielding 674 ICIQ-SF score/PGI-I outcome data pairs were used in this study for (a) determining and (b) validating the cut-off ICIQ-SF score for a successful PGI-I outcome. Two long-term follow-up datasets were used representing follow-up periods of 3 and 8 years of a randomized controlled trial (RCT) performed between April 2005 and April 2007 in a tertiary urogynaecology centre in Scotland, UK. All patients had urodynamic SUI or mixed urinary incontinence (MUI, with predominant SUI) and were randomized to treatment with either an inside-out or an outside-in transobturator tape (TVT-O or TOT, respectively) as a sole procedure. The datasets yielded 432 ICIQ-SF score/PGI-I outcome data pairs. Successful outcome was defined as "very much improved/much improved" on the PGI-I scale. SPSS v. 22.0 (IBM Corp., Armonk, NY) was used for all statistical analyses. The correlations and cut-off scores generated were then validated on two independent datasets representing the 1-year and 4-year follow-up periods of the multicentre RCT in six units in the UK. The datasets yielded 242 ICIQ-SF score/PGI-I outcome data pairs. All patients had urodynamic SUI or MUI (with predominant SUI) and were randomized to either adjustable single incision minisling (SIMS) or TVT-O. RESULTS: Significant correlations at the 0.01 level (two-tailed) were clearly demonstrated between ICIQ-SF scores at follow up and PGI-I outcomes in terms of success/failure in both the generation and validation datasets. Higher ICIQ-SF scores correlated with a 'poorer' PGI-I score. Using ROC analysis, a postoperative ICIQ-SF score of 6 was validated as approximately 90 % sensitive and 85 % specific for success/failure with a high Cohen's kappa coefficient of 0.83 (95 % CI 0.74 - 0.89). CONCLUSIONS: This two-stage study provided a robust well-validated postoperative ICIQ-SF cut-off score (of 6/21) that is likely to be associated with a patient-reported successful outcome on the PGI-I following surgical treatment with a midurethral sling in women at different stages of follow-up over 1 - 8 years. Such a cut-off score could enable the comparison of results between various studies and serve as a valuable guide for surgeons to counsel patients before and/or after surgical treatment. Our study fills a research gap in providing a way to compare trial results when baseline ICIQ-SF scores are not available.

Immune Reactivity of Synthetic Peptides Originated from Hypervariable Region 1 of Hepatitis C Synthetic Consensuses with Egyptian Sera Infected with Hepatitis C Virus Type 4.

We have studied the immune reactivity of hypervariable region 1 (HVR1) of hepatitis C virus (HCV) against HCV immune positive and negative sera. Two published HVR1 consensus nucleotide sequences (Italian and Chinese) were synthesized, and with both of them, a splicing by overlap extension polymerase chain reaction, cloning and sequencing were performed. From the corresponding amino acid sequences, 3 Italian and 1 Chinese HVR1 peptides were selected for synthesis. The 4 peptides (MB1-MB4; GenBank No.: HQ846888-HQ846891) were used to screen 47 and 31 HCV (type 4) immune positive and negative sera, respectively, by enzyme-linked immunosorbent assay (ELISA). The 3 Italian HVR1 peptides (MB1, MB2, MB3) showed reactivities of 83, 68 and 76.6%, respectively, while the Chinese HVR1 peptide (MB4) showed a reactivity of 80.8%. Our results supported that the HVR1 is an attractive target for a peptide-based vaccine as it contains neutralizing epitopes, and all of the HCV patients' sera used in this study have anti-HVR1 antibodies. Interestingly, the amino acid sequence of peptide MB1 has a close sequence similarity with the published mimotope R9, and it shows a high ELISA reactivity. So, MB1 could be tested in combination with other HCV-related peptides as a supplemental assay for HCV diagnosis.

Evaluation of transobturator tension-free vaginal tapes in the surgical management of mixed urinary incontinence: 3-year outcomes of a randomized controlled trial.

PURPOSE: We evaluate the clinical effectiveness of transobturator tension-free vaginal tape procedures in the surgical management of mixed urinary incontinence in women at 3-year followup. MATERIALS AND METHODS: In this secondary analysis of a prospective, single-blind, randomized controlled trial 83 of 341 women (24%) with mixed urinary incontinence were randomized to undergo an outside-in (Aris® transobturator sling system 42) or inside-out (TVT™-O 41) transobturator tension-free vaginal tape procedure. Patients were contacted by postal questionnaire at a minimum of 3 years postoperatively. The primary outcome was the patient reported success rate, defined as very much improved/much improved on the PGI-I (Patient Global Impression of Improvement). Secondary outcomes included improvement in quality of life, impact on preoperative urgency/urgency incontinence and repeat surgical treatment for stress urinary incontinence. Outcomes at 3 years were compared between groups (outside-in vs inside-out) and to 1-year outcomes. Analysis was performed using SPSS® version 20 with significance levels set at p = 0.05. RESULTS: A total of 66 women with mixed urinary incontinence completed the 3-year followup (outside-in 35 vs inside-out 31). In each group 2 women underwent further continence surgery. The patient reported success rate was 73.8% with no significant differences between the groups (OR 1.035, 95% CI 0.342-3.134, p = 0.951). Overall 34 (50.1%) and 26 women (56.5%) reported cure of preoperative urgency and urgency incontinence, respectively, and 52 women (86.7%) had a clinically significant improvement in quality of life (18 points or more in total KHQ [King's Health Questionnaire] score) compared to baseline. CONCLUSIONS: Transobturator tape procedures are associated with a good (73.8%) patient reported success rate at a minimum of 3 years of followup in the surgical management of mixed urinary incontinence in women with predominant stress urinary incontinence symptoms. Nearly half of the women reported cure of urgency/urgency incontinence.

Involvement of TNFα, IL-1ß, COX-2 and NO in the anti-inflammatory activity of Tamarix aphylla in Wistar albino rats: an in-vivo and in-vitro study.

BACKGROUND: With the emergence of many side effects from synthetic drugs, there is an urgent need to find a natural alternative to these products. Therefore, our primary aim was to evaluate the anti-inflammatory activity of Tamarix aphylla (TA) and investigate the potential mechanism underlying this action. METHODS: Initially, to ensure the safety of the extract and for dose selection, we performed an acute oral toxicity Assay through the oral administration of graded doses up to 4 g\kg in Wistar rats. then, we used the carrageenan-induced edema model to elucidate the anti-inflammatory activity. Using specific ELISA kits, we measured the levels of TNF-α, IL-1ß, COX-2 and NO inside the inflamed paw tissue. Finally, for the in-vitro anti-inflammatory experiment, we used the erythrocyte membrane stability test. RESULTS: Based on the acute oral toxicity assay, T. aphylla was considered generally safe and three different doses of 100, 200, and 400 mg/kg were chosen for further experiments. Additionally, TA expressed a significant (P < 0.05) anti-inflammatory activity, showing the maximum inhibition percentage at the fifth hour of measurement at 53.47% and 70.06%, at doses of 200 and 400 mg/kg respectively, compared to 63.81% for the standard drug. Similarly, we found that TA effectively reduced the levels of TNF-α and IL-1ß at all tested doses (100-200-400 mg/kg) to a greater extent than the standard drug. Moreover, at 400 mg/kg, TA was able to significantly lower the levels of COX-2 and NO inside the inflamed tissue to a level comparable (P < 0.05) with that measured inside the paw tissue of normal rats. Finally, Tamarix aphylla at 100, 200 and 400 mg/kg doses significantly (P < 0.05) inhibited the heat-induced hemolysis of RBCs membrane by 67.78, 74.82 and 82.08%, respectively, compared to 83.89% produced by Aspirin. CONCLUSION: T. aphylla produced a significant (P < 0.05) anti-inflammatory activity compared to the standard drugs either through the reduction of pro-inflammatory mediators or the protection of the lysosomal membrane.

Three-year cost utility analysis of mini versus standard slings: A trial based economic evaluation.

Objective: To report on the cost-effectiveness of adjustable anchored single-incision mini-slings (mini-slings) compared with tension-free standard mid-urethral slings (standard slings) in the surgical management of female stress urinary incontinence (SUI). Patients and Methods: Data on resource use and quality were collected from women aged ≥18 years with predominant SUI undergoing mid-urethral sling procedures in 21 UK hospitals. Resource use and quality of life (QoL) data were prospectively collected alongside the Single-Incision Mini-Slings versus standard synthetic mid-urethral slings Randomised Control Trial (SIMS RCT), for surgical treatment of SUI in women. A health service provider's (National Health Service [NHS]) perspective with 3-year follow-up was adopted to estimate the costs of the intervention and all subsequent resource use. A generic instrument, EuroQol EQ-5D-3L, was used to estimate the QoL. Results are reported as incremental costs, quality adjusted life years (QALYs) and incremental cost per QALY. Results: Base case analysis results show that although mini-slings cost less, there was no significant difference in costs: mini-slings versus standard slings: £-6 [95% CI -228-208] or in QALYs: 0.005 [95% CI -0.068-0.073] over the 3-year follow-up. There is substantial uncertainty, with a 56% and 44% probability that mini-slings and standard slings are the most cost-effective treatment, respectively, at a £20 000 willingness-to-pay threshold value for a QALY. Conclusions: At 3 years, there is no significant difference between mini-slings and standard slings in costs and QALYs. There is still some uncertainty over the long-term complications and failure rates of the devices used in the treatment of SUI; therefore, it is important to establish the long-term clinical and cost-effectiveness of these procedures.

Comparison of an adjustable anchored single-incision mini-sling, Ajust(®) , with a standard mid-urethral sling, TVT-O(TM) : a health economic evaluation.

OBJECTIVES: To assess the cost, quality of life (QoL) and cost-effectiveness of a single-incision mini-sling (SIMS; Ajust(®) , C. R. Bard Inc., New Providence, NJ, USA) compared with a standard mid-urethral sling (SMUS; TVT-O™, Ethicon Inc., Somerville, NJ, USA) in the surgical management of female stress urinary incontinence. PATIENTS AND METHODS: A total of 137 women, in a secondary care setting, were randomized between October 2009 and October 2011 to undergo SIMS placement (n = 69) under local anaesthesia as an opt-out policy or SMUS placement (n = 68) under general anaesthesia. Clinical outcome measures included the patient-reported success rate (Patient Global Impression of Improvement [PGI-I]) and the impact on the patients' QoL (King's Health Questionnaire [KHQ]). Health economic data (cost and quality-adjusted life year [QALY] data) were compared using linear regression models to generate an incremental cost per QALY estimate, in order to determine a measure of cost-effectiveness. Deterministic sensitivity analyses investigated uncertainty in the results, and non-parametric bootstrapping techniques were used to estimate a probability of cost-effectiveness. RESULTS: There were no significant differences between the groups in terms of the KHQ total score (P = 0.27) or the patient-reported success rate (P = 1.00, odds ratio: 0.895; 95% confidence interval [CI]: 0.344 to 2.330). There was no significant difference in QALYs for the SIMS group compared with the SMUS group (mean difference: -0.003; 95% CI: -0.008 to +0.002). The SIMS was on average less costly, -£142.41 95% CI: (-316.99 to 32.17) and generated cost savings of £48 419 per QALY loss with 94% probability of cost savings to the health services. Taking a wider perspective on the costing analysis by including the wider community benefit associated with the significantly earlier return to work observed in the SIMS group (P = 0.006, 95% CI: 11.756 to 17.217), there was an increase in cost savings to -£477, (95% CI: -823.65 to -129.63), with a probability of 100% of cost savings to the wider economy. CONCLUSIONS: The adjustable anchored SIMS (Ajust), performed under local anaesthesia as an opt-out policy, delivers cost savings to the health service provider when compared with the SMUS (TVT-O), and is likely to be cost-effective up to 1 year after placement. Further research should be undertaken to confirm the results of our study over longer follow-up and should explore patient preferences alongside an adequately powered non-inferiority randomized controlled trial.

An interactive SAR approach to discover novel hybrid thieno probes as ligands for D2-like receptors with affinities in the subnanomolar range.

A series of [(phenylpiperazinyl)alkyl]-isoindole-1,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with Ki values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki (D4) value of 0.62 nM, and to its butyl analog, 10a, with Ki (D4) and Ki (D3) values of 0.03 and 0.26 nM, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4-subtype-receptor selectivity.

Patient preferences for stress urinary incontinence treatments: a discrete choice experiment.

OBJECTIVES: To elicit and value patient preferences for the processes and outcomes of surgical management of stress urinary incontinence in women. DESIGN: A discrete choice experiment survey to elicit preferences for type of anaesthesia, postoperative recovery time, treatment success, adverse events, impact on daily activities and cost. An experimental design generated 40 choice tasks, and each respondent completed 1 block of 10 and 2 validity tests. Analysis was by multinomial logistical regression. SETTING: N=21 UK hospitals. PARTICIPANTS: N=325 adult women who were a subsample of those randomised to the single-incision mini-slings clinical trial. OUTCOMES: Patient preferences; valuation obtained using willingness to pay. RESULTS: N=227 of 325 (70%) returned a questionnaire, and 94% of those completed all choice tasks. Respondents preferred general anaesthesia, shorter recovery times, improved stress urinary incontinence symptoms and avoidance of adverse events. Women were willing to pay (mean (95% CI)) £76 (£33 to £119) per day of reduction in recovery time following surgery. They valued increases in Patient Global Impression of Improvement, ranging from £8173 (£5459 to £10 887) for 'improved' to £11 706 (£8267 to £15 144) for 'very much improved' symptoms, compared with no symptom improvement. This was offset by negative values attached to the avoidance of complications ranging between £-8022 (£-10 661 to £-5383) and £-10 632 (£-14 077 to £-7187) compared to no complications. Women valued treatments that reduced the need to avoid daily activities, with willingness to pay ranging from £-967 (£-2199 to £266) for rarely avoiding activities to £-5338 (£-7258 to £-3417) for frequently avoiding daily activities compared with no avoidance. CONCLUSION: This discrete choice experiment demonstrates that patients place considerable value on improvement in stress urinary incontinence symptoms and avoidance of treatment complications. Trade-offs between symptom improvement and adverse event risk should be considered within shared decision-making. The willingness to pay values from this study can be used in future cost-benefit analyses. TRIAL REGISTRATION NUMBER: ISRCTN: 93264234; Post-results.

Expanding agroforestry can increase nitrate retention and mitigate the global impact of a leaky nitrogen cycle in croplands.

The internal soil nitrogen (N) cycle supplies N to plants and microorganisms but may induce N pollution in the environment. Understanding the variability of gross N cycling rates resulting from the global spatial heterogeneity of climatic and edaphic variables is essential for estimating the potential risk of N loss. Here we compiled 4,032 observations from 398 published 15N pool dilution and tracing studies to analyse the interactions between soil internal potential N cycling and environmental effects. We observed that the global potential N cycle changes from a conservative cycle in forests to a less conservative one in grasslands and a leaky one in croplands. Structural equation modelling revealed that soil properties (soil pH, total N and carbon-to-N ratio) were more important than the climate factors in shaping the internal potential N cycle, but different patterns in the potential N cycle of terrestrial ecosystems across climatic zones were also determined. The high spatial variations in the global soil potential N cycle suggest that shifting cropland systems towards agroforestry systems can be a solution to improve N conservation.