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Abstract Background Vessel-sparing anastomotic repair (vsAR) has been developed as a less traumatic alternative to transecting anastomotic repair (tAR) to treat isolated short bulbar urethral strictures. This vessel-sparing technique could result in improved functional outcomes without jeopardizing the excellent surgical outcome after (transecting) anastomotic repair. The purpose of this study is to directly compare vsAR and tAR for both surgical and functional outcomes. Methods This trial is a prospective, interventional, multi-center, single-blinded, 1:1 randomized, controlled, non-inferiority, phase II trial. Sample size calculation resulted in a required sample size of 100 patients (50 patients per arm). Trial participants will be randomized by an independent third party using a computer-based random sequence generator with permuted blocks of variable size. The primary objective of this trial is to show that vsAR is non-inferior to tAR in terms of failure-free survival after 24 months of follow-up, considering a non-inferiority limit of 10%. Failure is defined as the inability to pass a 16-Fr flexible cystoscope through the reconstructed area without damaging the urethral mucosa. Secondary end-points mainly include differences in postoperative complications and changes in functional outcome parameters, which will be assessed with validated questionnaires. All participants are scheduled for follow-up at 3, 12, and 24 months postoperatively. Discussion This trial will provide level Ib evidence about the differences in both surgical and functional outcome between vsAR and tAR, which may importantly scape the future of bulbar urethral reconstruction. Depending on the trial results, this phase II trial may generate a larger phase III trial with more statistical power and a lower alpha value. Trial registration This trial is registered at clinicaltrials.gov ( NCT03572348 ) and in the Belgian Clinical Trial Registry (B670201837335). The trial was registered prospectively. Registered on 28 June 2018.

Between 1910 and 1912, copies of some sixty burial chambers of the catacombs of Rome were reconstructed on the Valkenburg estate of the client, Jan Diepen. To ensure the integrity of the project, an ‘Archeological Advisory Committee’ was assembled under the chairmanship of the architect P.J.H. (Pierre) Cuypers. In response to a historiographical critique by the liturgical scholar Paul Post, this article demonstrates that among the members of the client’s entourage the Valkenburg catacomb reproductions were associated not only with devotional or liturgical matters but also with art-theoretical issues. In 1916 the members of the group of advisers chaired by Cuypers published a Festschrift to celebrate the fifth anniversary of the catacomb complex. The first sections of this article discuss and analyse the contents and structure of that publication. It is clear from the Festschrift that both the devotional and the art-theoretical significance of Christian archaeology were acknowledged. In the Festschrift contributions, the symbolic heart of the undertaking, the Salvatore Olandese fresco discovered by Diepen, is not only dealt with as a devotional object, but is also described as an art-historical transitional fresco. The devotional and art-theoretical intent resonated even more clearly in the articles about the complex that appeared in the Dutch press. The reports in the De Tijd newspaper of the opening of the first wing and of an episcopal visitation, confirm that not only the religious but also the artistic ideas associated with the reproductions in the Festschrift, were actually experienced and communicated in the catacomb complex. Finally, the manuscript of the 1917 eulogy dedicated to Cuypers in the name of Diepen’s advisers, reveals that the latter were also cognizant of what the project might mean for Cuypers’ oeuvre. While the Salvatore Olandese connected the Valkenburg reproductions with their Roman models, the manuscript shows that the members of Diepen’s entourage also hoped that their catacombs would connect Rome with Cuypers’ neo-Gothic architecture.

Abstract Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity‐on‐Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF‐based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T‐cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8‐targeted type I interferon AcTakine. Co‐treatment with a CD13‐targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible.

Simulations of high-density deuterium plasmas in a lower single-null magnetic configuration based on a TCV discharge are presented. We evolve the dynamics of three charged species (electrons, $\textrm{D}^+$ and $\textrm{D}_2^+$ ), interacting with two neutrals species ( $\textrm{D}$ and $\textrm{D}_2$ ) through ionization, charge-exchange, recombination and molecular dissociation processes. The plasma is modelled by using the drift-reduced fluid Braginskii equations, while the neutral dynamics is described by a kinetic model. To control the divertor conditions, a $\textrm{D}_2$ puffing is used and the effect of increasing the puffing strength is investigated. The increase in fuelling leads to an increase of density in the scrape-off layer and a decrease of the plasma temperature. At the same time, the particle and heat fluxes to the divertor target decrease and the detachment of the inner target is observed. The analysis of particle and transport balance in the divertor volume shows that the decrease of the particle flux is caused by a decrease of the local neutral ionization together with a decrease of the parallel velocity, caused by the lower plasma temperature and the increase in momentum losses. The relative importance of the different collision terms is assessed, showing the crucial role of molecular interactions, as they are responsible for increasing the atomic neutral density and temperature, since most of the $\textrm{D}$ neutrals are produced by molecular activated recombination and $\textrm{D}_2$ dissociation. The presence of strong electric fields in high-density plasmas is also shown, revealing the role of the E × B drift in setting the asymmetry between the divertor targets. Simulation results are in agreement with experimental observations of increased density decay length, attributed to a decrease of parallel transport, together with an increase of plasma blob size and radial velocity.

We study structured multiarmed bandits, which is the problem of online decision-making under uncertainty in the presence of structural information. In this problem, the decision-maker needs to discover the best course of action despite observing only uncertain rewards over time. The decision-maker is aware of certain convex structural information regarding the reward distributions; that is, the decision-maker knows that the reward distributions of the arms belong to a convex compact set. In the presence of such structural information, the decision-maker then would like to minimize his or her regret by exploiting this information, where the regret is its performance difference against a benchmark policy that knows the best action ahead of time. In the absence of structural information, the classical upper confidence bound (UCB) and Thomson sampling algorithms are well known to suffer minimal regret. However, as recently pointed out by Russo and Van Roy (2018) and Lattimore and Szepesvari (2017), neither algorithm is capable of exploiting structural information that is commonly available in practice. We propose a novel learning algorithm that we call "DUSA," whose regret matches the information-theoretic regret lower bound up to a constant factor and can handle a wide range of structural information. Our algorithm DUSA solves a dual counterpart of the regret lower bound at the empirical reward distribution and follows its suggested play. We show that this idea leads to the first computationally viable learning policy with asymptotic minimal regret for various structural information, including well-known structured bandits such as linear, Lipschitz, and convex bandits and novel structured bandits that have not been studied in the literature because of the lack of a unified and flexible framework. Funding: N. Golrezaei was supported in part by the Young Investigator Program (YIP) Award from the Office of Naval Research (ONR) [Grant N00014-21-1-2776] and the MIT Research Support Award. This paper was accepted by Chung Piaw Teo, Optimization [ABSTRACT FROM AUTHOR]

Plasmodium falciparum circumsporozoite protein (PfCSP) and Pfs25 are leading candidates for the development of pre-erythrocytic and transmission-blocking vaccines (TBV), respectively. Although considerable progress has been made in developing PfCSP- and Pfs25-based vaccines, neither have elicited complete protection or transmission blocking in clinical trials. The combination of antigens targeting various life stages is an alternative strategy to develop a more efficacious malaria vaccine. In this study, female and male mice were immunized with DNA plasmids encoding PfCSP and Pfs25, administered alone or in combination via intramuscular in vivo electroporation (EP). Antigen-specific antibodies were analyzed for antibody titers, avidity and isotype by ELISA. Immune protection against sporozoite challenge, using transgenic P. berghei expressing PfCSP and a GFP-luciferase fusion protein (PbPfCSP-GFP/Luc), was assessed by in vivo bioluminescence imaging and blood-stage parasite growth. Transmission reducing activity (TRA) was evaluated in standard membrane feeding assays (SMFA). High levels of PfCSP- and Pfs25-specific antibodies were induced in mice immunized with either DNA vaccine alone or in combination. No difference in antibody titer and avidity was observed for both PfCSP and Pfs25 between the single DNA and combined DNA immunization groups. When challenged by PbPfCSP-GFP/Luc sporozoites, mice immunized with PfCSP alone or combined with Pfs25 revealed significantly reduced liver-stage parasite loads as compared to mice immunized with Pfs25, used as a control. Furthermore, parasite liver loads were negatively correlated with PfCSP-specific antibody levels. When evaluating TRA, we found that immunization with Pfs25 alone or in combination with PfCSP elicited comparable significant transmission reduction. Our studies reveal that the combination of PfCSP and Pfs25 DNAs into a vaccine delivered by in vivo EP in mice does not compromise immunogenicity, infection protection and transmission reduction when compared to each DNA vaccine individually, and provide support for further evaluation of this DNA combination vaccine approach in larger animals and clinical trials.

Background: Choline is an essential nutrient involved in a wide range of physiological functions. It occurs in water- and lipid-soluble forms in the body and diet. Foods with a known high choline content are eggs, beef, chicken, milk, fish, and selected plant foods. An adequate intake has been set in the US and Europe, however, not yet in the Nordic countries. A higher intake of lipid-soluble choline forms has been associated with increased risk of acute myocardial infarction, highlighting the need for knowledge about food sources of the individual choline forms. In general, little is known about the habitual intake and food sources of choline, and individual choline forms.Objective: Investigate foods contributing to the intake of total choline and individual choline forms.Design: The study population consisted of 1,929 patients with stable angina pectoris from the Western Norway B Vitamin Intervention Trial. Dietary intake data was obtained through a 169-item food frequency questionnaire. Intake of total choline and individual choline forms was quantified using the USDA database, release 2.Results: The geometric mean (95% prediction interval) total choline intake was 287 (182, 437) mg/d. Phosphatidylcholine accounted for 42.5% of total choline intake, followed by free choline (25.8%) and glycerophosphocholine (21.2%). Phosphocholine and sphingomyelin contributed 4.2 and 4.5%, respectively. The main dietary choline sources were eggs, milk, fresh vegetables, lean fish, and bread. In general, animal food sources were the most important contributors to choline intake.Conclusion: This study is, to the best of our knowledge, the first to assess the intake of all choline forms and their dietary sources in a European population. Most choline was consumed in the form of phosphatidylcholine and animal food sources contributed most to choline intake. There is a need for accurate estimates of the dietary intake of this essential nutrient to issue appropriate dietary recommendations.

Background: Red and processed meat intake have been associated with increased risk of morbidity and mortality, and a restricted intake is encouraged in patients with cardiovascular disease. However, evidence on the association between total meat intake and clinical outcomes in this patient group is lacking.Objectives: To investigate the association between total meat intake and risk of all-cause mortality, acute myocardial infarction, cancer, and gastrointestinal cancer in patients with stable angina pectoris. We also investigated whether age modified these associations.Materials and Methods: This prospective cohort study consisted of 1,929 patients (80% male, mean age 62 years) with stable angina pectoris from the Western Norway B-Vitamin Intervention Trial. Dietary assessment was performed by the administration of a semi-quantitative food frequency questionnaire. Cox proportional hazards models were used to investigate the association between a relative increase in total meat intake and the outcomes of interest.Results: The association per 50 g/1,000 kcal higher intake of total meat with morbidity and mortality were generally inconclusive but indicated an increased risk of acute myocardial infarction [HR: 1.26 (95% CI: 0.98, 1.61)] and gastrointestinal cancer [1.23 (0.70, 2.16)]. However, we observed a clear effect modification by age, where total meat intake was associated with an increased risk of mortality and acute myocardial infarction among younger individuals, but an attenuation, and even reversal of the risk association with increasing age.Conclusion: Our findings support the current dietary guidelines emphasizing a restricted meat intake in cardiovascular disease patients but highlights the need for further research on the association between meat intake and health outcomes in elderly populations. Future studies should investigate different types of meat separately in other CVD-cohorts, in different age-groups, as well as in the general population.

This qualitative study explored how adolescent boys with autism spectrum disorder experience their sexuality. Previous research has demonstrated that sexuality is a developmental task for boys with autism spectrum disorder, as it is for their peers. Case studies have suggested a relation between autism spectrum disorder and atypical sexual development; empirical studies on this subject, however, are scant and inconsistent. This study is based on interviews with eight boys, aged 16-20 years, with Asperger's disorder or autistic disorder. Interpretative phenomenological analysis of the data revealed three major themes relating to (a) how they experience sexual feelings, think about sexuality and think about themselves as sexual beings; (b) how they perceive messages relating to sexuality in their surroundings; and (c) how they experience finding and having a partner and partnered sex. We believe that attention to these themes is needed in assessment, education and further research.

Introduction and Objectives: Kidney autotransplantation can be performed in patients with complex renal or ureteral pathology not suitable for in situ reconstruction, such as renal vasculature anomalies, patients with proximal or long complex ureteral strictures, or complex oncological cases. Robot-assisted surgery allows for a high-quality vascular and ureteral anastomosis and faster patient recovery. Robot-assisted kidney autotransplantation (RAKAT) is performed in two phases: nephrectomy and pelvic transplantation. In-between, extraction of the kidney allows for vascular reconstruction or kidney modification on the bench and safe cold ischemia can be established. If no bench reconstruction is needed, total intracorporeal RAKAT (tiRAKAT) is feasible. One case report in Europe has been described; however, to our knowledge no surgical video is available.Methods: A 58 year-old woman suffered from right mid- and distal ureteral stenosis following pelvic radiotherapy 10 years prior for cervical cancer. A JJ stent was placed, but she suffered from recurrent urinary tract infections, and ultimately a nephrostomy was placed. Renogram demonstrated 43% relative right kidney function. As her bladder volume was low following radiotherapy, no Boari flap was possible and the patient refused life-long nephrostomy or nephrectomy. Therefore, tiRAKAT was performed using the DaVinci Xi system.Results: We describe our surgical technique including a video. Surgical time (skin-to-skin) was 5 h and 45 min. Warm ischemia time was 4 min, cold ischemia 55 min, and rewarming ischemia 15 min. The abdominal catheter and bladder catheter were removed on the first and second postoperative day, respectively. The JJ stent was removed after 4 weeks. The patient suffered from pulmonary embolism on the second postoperative day, for which therapeutic low molecular weight heparin was started. No further complications occurred during the first 90 postoperative days. After 7 months, overall kidney function remained stable, right kidney function dropped non-significantly from 27 to 25.2 mL/min (−6.7%) on renal scintigraphy.Conclusion: We demonstrated feasibility and, for the first time, a surgical video of tiRAKAT highlighting patient positioning, trocar placement, and intracorporeal cold ischemia technique.

Plasma concentrations of trimethylamine N-oxide (TMAO) have been linked to cardiovascular disease (CVD) risk and mortality. TMAO is formed through the bacterial conversion of trimethylamine which is obtained either directly from food, generated from dietary precursors (e.g. choline) or derived from endogenous trimethyllysine (TML) production. In a previous article, we reported an increased risk of acute myocardial infarction with increased total choline intake in patients with stable angina pectoris. Due to the close link between TMAO, TML, choline metabolism and possibly CVD, we investigated whether plasma TMAO and TML modified the effect of total choline intake on acute myocardial infarction (AMI) risk in a post-hoc analysis. We found plasma TMAO and TML do not modify the association between higher dietary choline intake and increased AMI risk. Additionally, this association is not mediated via TMAO.

Abstract Nonsuicidal self-injury (NSSI) is a complex behaviour and occurs most commonly during adolescence. This developmental period is characterized by the drive to establish an equilibrium between personal autonomy and connectedness with primary caregivers. When an adolescent self-injures, caregivers often experience confusion about how to react. Reports of feeling guilt, fear, and shame are common in the wake of learning about a child’s self-injury. This cascade of negative feelings and self-appraisals may lead to hypervigilance and increased caregiver efforts to control the child’s behaviour. The adolescent may experience this as an intrusion, leading to worse family functioning and increased risk of NSSI. This cascade is not well acknowledged or articulated in current literature. This article remedies this gap by presenting the NSSI Family Distress Cascade.