The effectiveness of adjustable trans-obturator male system (ATOMS) in radiated patients is reduced: A propensity score-matched analysis.

Objectives: This study aimed to compare the effectiveness and safety of the adjustable trans-obturator male system (ATOMS®) to treat post-prostatectomy incontinence (PPI) in radiated patients compared with non-radiated patients, using propensity score-matching analysis to enhance the validity of the comparison. Patients and methods: Consecutive men with PPI treated with silicone-covered scrotal port ATOMS (A.M.I., Feldkirch, Austria) in nine different institutions between 2016 and 2022 were included. Preoperative assessment evaluated 24-h pad usage, urethroscopy and urodynamics, if indicated. Propensity score-matching analysis was based on age, length of follow-up, previous PPI treatment, previous bladder neck stricture, androgen deprivation and pad usage. The primary endpoint was dry rate, defined as no pads post-operatively with a security pad allowed. The secondary endpoints were complications, device removal and self-perceived satisfaction with the Patient Global Impression of Improvement (PGI-I) scale. Results: Of the 710 included patients, 342 were matched, and the study groups were balanced for the baseline matched variables. The mean baseline 24-h pad was 4.8 in both groups (p = 0.48). The mean follow-up was 27.5 ± 18.6 months, which was also equivalent between groups (p = 0.36). The primary outcome was achieved in 73 (42.7%) radiated patients and in 115 (67.3%) non-radiated patients (p < 0.0001). The mean pad count at the last follow-up was 1.5 and 0.8, respectively (p < 0.0001). There was no significant difference in complications (p = 0.94), but surgical revision and device explant rates were higher (p = 0.03 and p = 0.01, respectively), and the proportion of patients highly satisfied (PGI-I = 1) was lower in the radiated group (p = 0.01). At sensitivity analysis, the study was found to be reasonably robust to hidden bias. Conclusion: ATOMS implantation significantly outperformed in patients without adjuvant radiation over radiated patients.

Dietary Salicornia ramosissima improves the European seabass (Dicentrarchus labrax) inflammatory response against Photobacterium damselae piscicida.

Introduction: Modern fish farming faces challenges in sourcing feed ingredients, most related with their prices, 21 availability, and specifically for plant protein sources, competition for the limited cultivation space for 22 vegetable crops. In that sense, halophytes have the added value of being rich in valuable bioactive compounds and salt tolerant. This study assessed the inclusion of non-food fractions of S. ramosissima in European seabass diets. Methods: Different levels (2.5%, 5%, and 10%) were incorporated into seabass diets, replacing wheat meal (diets ST2.5, ST5, and ST10) or without inclusion (CTRL). Experimental diets were administered to seabass juveniles (8.62 ± 0.63 g) for 34 and 62 days and subsequent inflammatory responses to a heat-inactivated Photobacterium damselae subsp. piscicida (Phdp) were evaluated in a time-course manner (4, 24, 48, and 72 h after the challenge). At each sampling point, seabass haematological profile, plasma immune parameters, and head-kidney immune-related gene expression were evaluated. Results: After both feeding periods, most parameters remained unaltered by S. ramosissima inclusion; nonetheless, seabass fed ST10 showed an upregulation of macrophage colony-stimulating factor 1 receptor 1 (mcsf1r1) and cluster of differentiation 8 (cd8ß) compared with those fed CTRL after 62 days of feeding. Regarding the inflammatory response, seabass fed ST10 showed lower plasma lysozyme levels than their counterparts fed ST2.5 and ST5 at 24 h following injection, while 4 h after the inflammatory stimulus, seabass fed ST10 presented higher numbers of peritoneal leucocytes than fish fed CTRL. Moreover, at 4 h, fish fed ST2.5, ST5, and ST10 showed a higher expression of interleukin 1ß (il1ß), while fish fed ST5 showed higher levels of ornithine decarboxylase (odc) than those fed CTRL. An upregulation of macrophage colony-stimulating factor 1 receptor 1 (mcsf1r1) and glutathione peroxidase (gpx) was also observed at 72 h in fish fed ST10 or ST5 and ST10 compared with CTRL, respectively. Discussion: In conclusion, incorporating up to 10% of the non-food fraction S. ramosissima in feed did not compromise seabass growth or immune status after 62 days, aligning with circular economy principles. However, S. ramosissima inclusion improved the leucocyte response and upregulated key immune-related genes in seabass challenged with an inactivated pathogen.

Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Detrusor Overactivity After Partial Bladder Outlet Obstruction Is Associated With High Urinary Adenosine Triphosphate Levels in Female Wistar Rats.

PURPOSE: Bladder outlet obstruction (BOO) commonly causes detrusor overactivity (DO). In this study, a post hoc analysis of previous obtained data, we investigate if DO occurring in initial phases of BOO is associated with changes in urinary adenosine triphosphate (ATP) levels. METHODS: Adult female Wistar rats were submitted to partial BOO (pBOO) or to sham obstruction. Cystometry was performed at 3 or 15 days after pBOO and saline voided was collected for ATP determination. Normality was tested using Shapiro-Wilk test. The mean frequency of voiding contractions (VCs) of the sham-operated animals at 15 days after surgery, plus or minus 3 standard deviations, was used to represent the normal range. Statistical analyses were performed using the chi-square and Mann-Whitney tests. RESULTS: DO was indicated by a VC frequency greater than or equal to 0.9 VCs/min. DO was observed in 63% of animals at 3 days and in 33% at 15 days following pBOO. ATP levels were significantly higher in rats with DO compared to those without DO. CONCLUSION: The DO phenotype, occurring in the initial phases of BOO, is associated with comparatively high urinary ATP levels.

Modern anthropogenic drought in Central Brazil unprecedented during last 700 years.

A better understanding of the relative roles of internal climate variability and external contributions, from both natural (solar, volcanic) and anthropogenic greenhouse gas forcing, is important to better project future hydrologic changes. Changes in the evaporative demand play a central role in this context, particularly in tropical areas characterized by high precipitation seasonality, such as the tropical savannah and semi-desertic biomes. Here we present a set of geochemical proxies in speleothems from a well-ventilated cave located in central-eastern Brazil which shows that the evaporative demand is no longer being met by precipitation, leading to a hydrological deficit. A marked change in the hydrologic balance in central-eastern Brazil, caused by a severe warming trend, can be identified, starting in the 1970s. Our findings show that the current aridity has no analog over the last 720 years. A detection and attribution study indicates that this trend is mostly driven by anthropogenic forcing and cannot be explained by natural factors alone. These results reinforce the premise of a severe long-term drought in the subtropics of eastern South America that will likely be further exacerbated in the future given its apparent connection to increased greenhouse gas emissions.

Humid and cold forest connections in South America between the eastern Andes and the southern Atlantic coast during the LGM.

The presence of Andean plant genera in moist forests of the Brazilian Atlantic Coast has been historically hypothesized as the result of cross-continental migrations starting at the eastern Andean flanks. Here we test hypotheses of former connections between the Atlantic and Andean forests by examining distribution patterns of selected cool and moist-adapted plant arboreal taxa present in 54 South American pollen records of the Last Glacial Maximum (LGM), ca. 19-23 cal ka, known to occur in both plant domains. Pollen taxa studied include Araucaria, Drimys, Hedyosmum, Ilex, Myrsine, Podocarpus, Symplocos, Weinmannia, Myrtaceae, Ericaceae and Arecaceae. Past connectivity patterns between these two neotropical regions as well as individual ecological niches during the LGM were explored by cluster analysis of fossil assemblages and modern plant distributions. Additionally, we examined the ecological niche of 137 plant species with shared distributions between the Andes and coastal Brazil. Our results revealed five complex connectivity patterns for South American vegetation linking Andean, Amazonian and Atlantic Forests and one disjunction distribution in southern Chile. This study also provides a better understanding of vegetation cover on the large and shallow South American continental shelf that was exposed due to a global sea level drop.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of Short QT Syndrome type 3.

AIMS: Short QT Syndrome Type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. METHODS AND RESULTS: We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. CONCLUSIONS: The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.

Early in life stressful events induce chronic visceral pain and changes in bladder function in adult female mice through a mechanism involving TRPV1 and alpha 1A adrenoceptors.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder with multiple phenotypes, one of which is associated with an overactive adrenergic system. OBJECTIVE: We investigated if the maternal deprivation model (MDM) in female and male mice mimics IC/BPS phenotype and if the overstimulation of alpha 1A adrenoceptor (A1AAR) and the crosstalk with transient receptor potential vanilloid-1 (TRPV1) are involved in the generation of pain and bladder functional changes. DESIGN, SETTING, AND PARTICIPANTS: C57BL/6 female and male mice were submitted to MDM. TRPV1 knockout (KO) mice were used to study TRPV1 involvement. Silodosin administration to MDM mice was used to study A1AAR involvement. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was chronic visceral pain measured by Von Frey filaments analysis (effect size: 3 for wild type, 3.9 for TRPV1 KO). Bladder changes were secondary outcome measurements. Unpaired T test, Mann-Whitney test, one-way analysis of variance followed by Newman-Keuls multiple comparisons test, and Kruskal-Wallis followed by Dunn's multiple comparisons test were used where appropriate. RESULTS AND LIMITATIONS: MDM induces pain behavior in female and not in male mice. Bladder afferents seem sensitize as MDM also increase the number of small volume spots voided, the bladder reflex activity, and urothelial damage. These changes were similarly absent after A1AAR blockade with silodosin or by TRPV1 gene KO. The main limitation is the number/type of pain tests used. CONCLUSIONS: MDM induced in female mice is able to mimic IC/BPS phenotype, through mechanisms involving A1AAR and TRPV1. Therefore, the modulation of both receptors may represent a therapeutic approach to treat IC/BPS patients.

From Perugino to Picasso revisited: Electrophysiological responses to faces in paintings from different art styles.

Behavioral research (Ventura, et al., 2023) suggested that pictorial representations of faces varying along a realism-distortion spectrum elicit holistic processing as natural faces. Whether holistic face neural responses are engaged similarly remains, however, underexplored. In the present study, we evaluated the neural correlates of naturalist and artistic face processing, by exploring electrophysiological responses to faces in photographs versus in four major painting styles. The N170 response to faces in photographs was indistinguishable from that elicited by faces in the renaissance art style (depicting the most realistic faces), whilst both categories elicited larger N170 than faces in other art styles (post-impressionism, expressionism, and cubism), with a gradation in brain activity. The present evidence suggest that visual processing may become finer grained the more the realistic nature of the face. Despite behavioral equivalence, the neural mechanisms for holistic processing of natural faces and faces in diverse art styles are not equivalent.

Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023.

INTRODUCTION: Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. METHODS: During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. RESULTS: Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. CONCLUSIONS: The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.

Self-reported urinary incontinence in women is higher with increased age, lower educational level, lower income, number of comorbidities, and impairment of mental health. Results of a large, population-based, national survey in Portugal.

PURPOSE: Urinary incontinence (UI) is a common condition in women. The aim of this study is to analyze women with self-reported UI, focusing on socio-demographic data, health-related conditions and comorbidities, and their impact on healthcare resources. METHODS: We analyzed data from a population-based survey with a representative sample of Portuguese women aged ≥ 18 years (n = 10,465). Women with self-reported symptoms of UI were distributed according to age, education level, and household income. The comparison of comorbidities and use of healthcare resources between the UI and non-UI groups was adjusted for age, education, and body mass index. We computed weighted prevalence and adjusted prevalence ratios with 95% confidence intervals using Poisson regression. RESULTS: Female UI prevalence was 9.9%, increasing with age (6.3% for 18- to 39-year-old, 40.8% for 75- to 85-year-old women). The prevalence decreased with education level (36.8% in women with no education, 4.6% in women with more than 12 years of education) and household income (29.8% in the 2nd quintile of income, 9.9% in the 5th quintile). Women with UI had a higher level of comorbidities, especially cardiovascular, respiratory, and mental health disorders. UI was also associated with higher consumption of healthcare resources. CONCLUSION: UI is highly prevalent among Portuguese women. It increases with age, low education level, and low household income. The use of healthcare resources was higher, possibly related with associated comorbidities. Though obtained in a single European country, these data may be useful to design a comprehensive management of UI in other parts of the western world.

Trophodynamics of the Antarctic toothfish (Dissostichus mawsoni) in the Antarctic Peninsula: Ontogenetic changes in diet composition and prey fatty acid profiles.

The Antarctic toothfish (Dissostichus mawsoni) is the largest notothenioid species in the Southern Ocean, playing a keystone role in the trophic web as a food source for marine mammals and a top predator in deep-sea ecosystems. Most ecological knowledge on this species relies on samples from areas where direct fishing is allowed, whereas in areas closed to fishing, such as the Antarctic Peninsula (AP), there are still key ecological gaps to ensure effective conservation, especially regarding our understanding of its trophic relationships within the ecosystem. Here, we present the first comprehensive study of the feeding behavior of Antarctic toothfish caught in the northern tip of the AP, during two consecutive fishing seasons (2019/20 and 2020/21). Stomach content was analyzed according to size-classes, sex and season. Macroscopic morphological analysis was used to identify prey, whereas DNA analysis was used in highly digested prey items. Fatty acid analysis was conducted to determine the prey's nutritional composition. The diet mainly consisted of Macrouridae, Cephalopoda, Anotopteridae, and Channichthyidae. Other prey items found were crustaceans and penguin remains; however, these were rare in terms of their presence in stomach samples. Sex had no effect on diet, whereas size-class and fishing season influenced prey composition. From 27 fatty acid profiles identified, we observed two different prey groups of fishes (integrated by families Anotopteridae, Macrouridae and Channichthyidae) and cephalopods. Our results revealed a narrow range of prey items typical of a generalist predator, which probably consumes the most abundant prey. Understanding the diet and trophic relationships of Antarctic toothfish is critical for a better comprehension of its role in the benthic-demersal ecosystem of the AP, key for ecosystemic fisheries management, and relevant for understanding and predicting the effect of climate change on this species.

Assessing the energy recovery potential at district metered areas inlets of water supply systems: A Spanish case study.

The energy required for various processes in the water cycle can have significant economic and environmental impacts. Therefore, efficient energy management in urban water supply systems is crucial for a sustainable operation. By installing energy recovery technologies in these facilities, it is possible to reap the benefits of the infrastructure design by saving energy. In this study, a new methodology to assess the energy recovery at the inlets of district metered areas is presented, considering the city of Murcia (Spain) as case study. This methodology is based on creating a detailed model of city water supply system and calibrating such model with an experimental campaign of measurements. Then, the assessment of the hydraulic potential recovery is analysed through two different energy estimators, one considering the minimum available net head and the other assuming a variable net head. Results show that there are several points where turbines could be installed, most of them recovering in between 1000-5000 kWh, which could be used to cover the yearly energy consumption of about 24-120 m2 of a school or 10-50 traffic lights of such area. Moreover, in some points it could be recovered up to 14500 kWh. Even though these values are not high, the energy recovered could be used for self-consumption of nearby electrical loads, at the time that reduces the pressure in the system, thus leading to leak reductions. Moreover, this kind of energy recovery does not reduce the potential of other proposals for upstream energy recovery, such as replacing pressure reduction valves with turbines instead. The scripts developed to apply the proposed methodology are available in EPANET-Octave file exchange for the researcher community.

ThyroidPrint®: clinical utility for indeterminate thyroid cytology.

Molecular testing contributes to improving the diagnosis of indeterminate thyroid nodules (ITNs). ThyroidPrint® is a ten-gene classifier aimed to rule out malignancy in ITN. Post-validation studies are necessary to determine the real-world clinical benefit of ThyroidPrint® in patients with ITN. A single-center, prospective, noninterventional clinical utility study was performed, analyzing the impact of ThyroidPrint® in the physicians' clinical decisions for ITN. Demographics, nodule characteristics, benign call rates (BCRs), and surgical outcomes were measured. Histopathological data were collected from surgical biopsies of resected nodules. Of 1272 fine-needle aspirations, 109 (8.6%) were Bethesda III and 135 (10.6%) were Bethesda IV. Molecular testing was performed in 155 of 244 ITN (63.5%), of which 104 were classified as benign (BCR of 67.1%). After a median follow-up of 15 months, 103 of 104 (99.0%) patients with a benign ThyroidPrint® remained under surveillance and one patient underwent surgery which was a follicular adenoma. Surgery was performed in all 51 patients with a suspicious for malignancy as per ThyroidPrint® result and in 56 patients who did not undergo testing, with a rate of malignancy of 70.6% and 32.1%, respectively. A higher BCR was observed in follicular lesion of undetermined significance (87%) compared to atypia of undetermined significance (58%) (P < 0.05). False-positive cases included four benign follicular nodules and six follicular and four oncocytic adenomas. Our results show that, physicians chose active surveillance instead of diagnostic surgery in all patients with a benign ThyroidPrint® result, reducing the need for diagnostic surgery in 67% of patients with preoperative diagnosis of ITN.

Change detection versus change localization for faces, houses, and words.

Holistic processing aids in the discrimination of visually similar objects, but it may also come with a cost. Indeed holistic processing may improve the ability to detect changes to a face while impairing the ability to locate where the changes occur. We investigated the capacity to detect the occurrence of a change versus the capacity to detect the localization of a change for faces, houses, and words. Change detection was better than change localization for faces. Change localization outperformed change detection for houses. For words, there was no difference between detection and localization. We know from previous studies that words are processed holistically. However, being an object of visual expertise processed holistically, visual words are also a linguistic entity. Previously, the word composite effect was found for phonologically consistent words but not for phonologically inconsistent words. Being an object of visual expertise for which linguistic information is important, letter position information, is also crucial. Thus, the importance of localization of letters and features may augment the capacity to localize a change in words making the detection of a change and the detection of localization of a change equivalent.

Efficacy and Safety of Eliapixant in Overactive Bladder: The 12-Week, Randomised, Placebo-controlled Phase 2a OVADER Study.

BACKGROUND: Effective, well-tolerated novel treatments for overactive bladder (OAB) are lacking. The P2X3 receptor antagonist eliapixant demonstrated potential to reduce OAB symptoms in preclinical studies. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of eliapixant in patients with OAB with urgency urinary incontinence (UUI). DESIGN, SETTING AND PARTICIPANTS: OVADER was a 12-wk, randomised, placebo-controlled, double-blind, parallel-group, multicentre, phase 2a study (NCT04545580) conducted between 2020 and 2022 in private and institutional clinical practices. Eligible patients were aged ≥18 yr with wet OAB symptoms (urgency, urinary frequency, and urinary incontinence) for ≥3 mo before screening. INTERVENTION: Randomisation (1:1 ratio) to oral eliapixant 125 mg or placebo twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the mean change from baseline in the mean number of UUI episodes/24 h over weeks 4, 8, and 12 according to an electronic bladder diary, evaluated using a repeated-measurement model in a Bayesian framework. RESULTS AND LIMITATIONS: Of 202 patients enrolled, 85 were valid for per-protocol analysis. The primary efficacy endpoint was not met. The posterior probability for eliapixant superiority over placebo was 40% (point estimate 0.05, 95% credible interval -∞ to 0.38), which did not meet the predefined criterion of ≥90% probability. Secondary and exploratory endpoints were not met. The incidence of adverse events was similar in the eliapixant (n = 32, 63%) and placebo (n = 27, 56%) groups; most were mild and five led to discontinuation of eliapixant. CONCLUSIONS: OVADER did not meet its clinical efficacy endpoints. Potential reasons include the nonspecific OAB symptom complex, the poorly understood pathophysiology, and the coinciding COVID-19 pandemic. PATIENT SUMMARY: We tested whether a new drug called eliapixant would reduce symptoms of overactive bladder in comparison to placebo. We found that the drug did not work. More knowledge on how overactive bladder occurs is needed to find new drugs to treat this condition.

Results of Adjustable Trans-Obturator Male System in Patients with Prostate Cancer Treated with Prostatectomy and Radiotherapy: A Multicenter Study.

(1) Background: Treatment of male stress incontinence in patients with prostate cancer treated with radical prostatectomy and adjuvant pelvic radiation is a therapeutic challenge. The efficacy and safety of the adjustable trans-obturator male system (ATOMS) in these patients is not well established, despite the general belief that outcomes are worse than in patients without radiation. (2) Methods: Retrospective multicenter study evaluating patients treated with silicone-covered scrotal port (SSP) ATOMS implant after radical prostatectomy and radiotherapy in nine different institutions between 2016 and 2022. The primary endpoint was dry patient rate, defined as pad-test ≤ 20 mL/day. The secondary endpoints were complication rate (defined using Clavien-Dindo classification), device removal and self-perceived satisfaction using the Patient Global Impression of Improvement (PGI-I) scale. Wilcoxon rank-sum test, Fisher's exact test and logistic regression were performed using stepwise method with a 0.15 entry and 0.1 stay criteria. (3) Results: 223 patients fulfilled the criteria for inclusion and 12 (5.4%) received salvage prostatectomy after radiation and 27 (12.1%) previous devices for stress incontinence. After ATOMS adjustment, 95 patients (42.6%) were dry and 36 (16.1%) had complications of any grade (grade I, n = 20; grade II, n = 11; grade III, n = 5) during the first 3 months postoperatively. At a mean of 36 ± 21 months follow-up, the device was explanted in 26 (11.7%) patients. Regarding self-perceived satisfaction with the implant, 105 of 125 patients (84%) considered themselves satisfied (PGI-I 1 to 3). In the univariate analysis, dryness was associated to younger age (p = 0.06), primary prostatectomy (p = 0.08), no previous incontinence surgery (p = 0.02), absence of overactive bladder symptoms (p = 0.04), absence of bladder neck stricture (p = 0.001), no need of surgical revision (p = 0.008) and lower baseline incontinence severity (p = 0.0003). Multivariate analysis identified absence of surgical revision (p = 0.018), absence of bladder neck stricture (p = 0.05), primary prostatectomy (p = 0.07) and lower baseline incontinence severity (p < 0.0001) were independent predictors of dryness. A logistic regression model was proposed and internally validated. (4) Conclusions: ATOMS is an efficacious and safe alternative to treat male incontinence after radical prostatectomy and adjuvant radiotherapy. Factors predictive of dryness are identified in this complex scenario to allow for better patient selection.

The spatiotemporal extent of the Green Sahara during the last glacial period.

The Sahara Desert, one of today's most inhospitable environments, has known periods of enhanced precipitation that supported pre-historic humans. However, the Green Sahara timing and moisture sources are not well known due to limited paleoclimate information. Here, we present a multi-proxy (δ18O, δ13C, Δ17O, and trace elements) speleothem-based climate record from Northwest (NW) Africa. Our data document two Green Sahara periods during Marine Isotope Stage (MIS) 5a and the Early to Mid-Holocene. Consistency with paleoclimate records across North Africa highlights the east-west geographical extent of the Green Sahara, whereas millennial-scale North Atlantic cooling (Heinrich) events consistently resulted in drier conditions. We demonstrate that an increase in westerly-originating winter precipitation during MIS5a resulted in favorable environmental conditions. The comparison of paleoclimate data with local archaeological sequences highlights the abrupt climate deterioration and the decline in human density in NW Africa during the MIS5-4 transition, which suggests climate-forced dispersals of populations, with possible implications for pathways into Eurasia.

Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL). Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127). Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001). Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.