Antibiotic prophylaxis in invasive urodynamics, a Delphi consensus of the Italian Society of Urodynamics (SIUD).

INTRODUCTION: Although antibiotic prophylaxis (AB) demonstrated a statistically significant reduction in bacteriuria after invasive urodynamics (UDS), no significant decrease in the incidence of urinary tract infections (UTI) has been confirmed. No absolute recommendations on the use of AB in case of relevant potential risk of UTI have been reported, though some categories of patients at increased infective probability after UDS have been recognized. The aim of this study is to report the experts' consensus on the best practice for the use of AB before UDS in the main categories of patients at potential risk of developing UTI. MATERIALS AND METHODS: A systematic literature review was performed on AB before UDS in males and females. A panel of experts from the Italian Society of Urodynamics, Continence, Neuro-Urology, and Pelvic Floor (SIUD) assessed the review data and decided by a modified Delphi method on 16 statements proposed and discussed by the panel. The cut-off percentage for the consensus was a ≥70% of positive responses to the survey. The study was a Delphi consensus with experts' opinions, not a clinical trial involving directly patients. RESULTS: The panel group was composed of 57 experts in functional urology and UDS, mainly urologists, likewise gynaecologists, physiatrists, infectivologists, pediatric urologists, and nurses. A positive consensus was achieved on 9/16 (56.25%) of the statements, especially on the need for performing AB before UD in patients with neurogenic bladder and immunosuppression. Urine analysis and urine culture before UDS are mandatory, and in the event of their positivity, UDS should be postponed. A consensus was reached on avoiding AB in menopausal status, diabetes, age, gender, bladder outlet obstruction, high postvoid residual, chronic catheterization, previous urological surgery, lack of urological abnormalities, pelvic organ prolapse, and negative urine analysis. CONCLUSIONS: Antibiotic prophylaxis is not recommended for patients without notable risk factors and with a negative urine test due to the potential morbidities that may result from antibiotic administration. However, AB can be used for risk categories such as neurogenic bladder and immunosuppression. The evaluation of urine analysis and urine culture and postponing UDS in cases of positive tests were considered good practices, as well as performing AB in the neurogenic bladder and immunosuppression.

Role of lateral suspension for the treatment of pelvic organ prolapse: a Delphi survey of expert panel.

INTRODUCTION AND HYPOTHESIS: Lateral suspension is an abdominal prosthetic surgical procedure used to correct apical prolapse. The procedure involves the placement of a T-shaped mesh on the anterior vaginal wall and on the isthmus or uterine cervix that is suspended laterally and posteriorly to the abdominal wall. Since its description in the late 90s, modifications of the technique have been described. So far, no consensus on the correct indications, safety, advantages, and disadvantages of this emerging procedure has been reached. METHODS: A modified Delphi process was used to build consensus within a group of 21 international surgeons who are experts in the performance of laparoscopic lateral suspension (LLS). The process was held with a first online round, where the experts expressed their level of agreement on 64 statements on indications, technical features, and other aspects of LLS. A subsequent re-discussion of statements where a threshold of agreement was not reached was held in presence. RESULTS: The Delphi process allowed the identification of several aspects of LLS that represented areas of agreement by the experts. The experts agreed that LLS is a safe and effective technique to correct apical and anterior prolapse. The experts highlighted several key technical aspects of the procedure, including clinical indications and surgical steps. CONCLUSIONS: This Delphi consensus provides valuable guidance and criteria for the use of LLS in the treatment of pelvic organ prolapse, based on expert opinion by large volume surgeons' experts in the performance of this innovative procedure.

Structure-Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents.

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

Investigations of Antioxidant and Anti-Cancer Activities of 5-Aminopyrazole Derivatives.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1-4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4). All new derivatives 1-4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents.

Robot-assisted pelvic floor reconstructive surgery: an international Delphi study of expert users.

BACKGROUND: Robotic surgery has gained popularity for the reconstruction of pelvic floor defects. Nonetheless, there is no evidence that robot-assisted reconstructive surgery is either appropriate or superior to standard laparoscopy for the performance of pelvic floor reconstructive procedures or that it is sustainable. The aim of this project was to address the proper role of robotic pelvic floor reconstructive procedures using expert opinion. METHODS: We set up an international, multidisciplinary group of 26 experts to participate in a Delphi process on robotics as applied to pelvic floor reconstructive surgery. The group comprised urogynecologists, urologists, and colorectal surgeons with long-term experience in the performance of pelvic floor reconstructive procedures and with the use of the robot, who were identified primarily based on peer-reviewed publications. Two rounds of the Delphi process were conducted. The first included 63 statements pertaining to surgeons' characteristics, general questions, indications, surgical technique, and future-oriented questions. A second round including 20 statements was used to reassess those statements where borderline agreement was obtained during the first round. The final step consisted of a face-to-face meeting with all participants to present and discuss the results of the analysis. RESULTS: The 26 experts agreed that robotics is a suitable indication for pelvic floor reconstructive surgery because of the significant technical advantages that it confers relative to standard laparoscopy. Experts considered these advantages particularly important for the execution of complex reconstructive procedures, although the benefits can be found also during less challenging cases. The experts considered the robot safe and effective for pelvic floor reconstruction and generally thought that the additional costs are offset by the increased surgical efficacy. CONCLUSION: Robotics is a suitable choice for pelvic reconstruction, but this Delphi initiative calls for more research to objectively assess the specific settings where robotic surgery would provide the most benefit.

Five actions for five people: emergency cesarean section protocol.

OBJECTIVE: The scope of this work is to evaluate an operative protocol for emergency C-section to improve teamwork and reduce surgical setup time. METHODS: Sixty-six health care operators working together in the delivery ward (gynecologists, midwives, anesthesiologists) simulated an emergency scenario applying a "five actions for each operator" protocol. For each simulation, the decision to delivery interval was considered and the perception of each operator as a team worker was analyzed with specific tests. RESULTS: The "five actions for five people" protocol significantly reduces the decision to delivery interval (p < 0.001) for emergency C-section. At the same time, a simple and codified scheme improves communication among team members, avoids overlapping roles. Indeed, all the operators become more aware of being helpful to the team (p < 0.001). CONCLUSION: The use of a standardized, simple, and immediately usable protocol improves the performance of the delivery room team in terms of the urgency and quality of the operator's participation in the event. Procedures of this type should be favored within emergency obstetric settings. TRIAL REGISTRATION NUMBER: CEAVNO 19-01-23. Local ethical Committee (COMITATO ETICO REGIONALE PER LA SPERIMENTAZIONE CLINICA - Sezione autonoma Area Vasta Nord Ovest -CEAVNO) approved this study as simulation training study. All the operators participated voluntary during their working time.

Cationic Polystyrene-Based Hydrogels as Efficient Adsorbents to Remove Methyl Orange and Fluorescein Dye Pollutants from Industrial Wastewater.

Water pollution from dyes is harmful to the environment, plants, animals, and humans and is one of the most widespread problems afflicting people throughout the world. Adsorption is a widely used method to remove contaminants derived from the textile industry, food colorants, printing, and cosmetic manufacturing from water. Here, aiming to develop new low-cost and up-scalable adsorbent materials for anionic dye remediation and water decontamination by electrostatic interactions, two cationic resins (R1 and R2) were prepared. In particular, they were obtained by copolymerizing 4-ammonium methyl and ethyl styrene monomers (M1 and M2) with dimethylacrylamide (DMAA), using N-(2-acryloylamino-ethyl)-acrylamide (AAEA) as cross-linker. Once characterized by several analytical techniques, upon their dispersion in an excess of water, R1 and R2 provided the R1- and R2-based hydrogels (namely R1HG and R2HG) with equilibrium degrees of swelling (EDS) of 900% and 1000% and equilibrium water contents (EWC) of 90 and 91%, respectively. By applying Cross' rheology equation to the data of R1HG and R2HG's viscosity vs. shear rate, it was established that both hydrogels are shear thinning fluids with pseudoplastic/Bingham plastic behavior depending on share rate. The equivalents of -NH3+ groups, essential for the electrostatic-based absorbent activity, were estimated by the method of Gaur and Gupta on R1 and R2 and by potentiometric titrations on R1HG and R2HG. In absorption experiments in bulk, R1HG and R2HG showed high removal efficiency (97-100%) towards methyl orange (MO) azo dye, fluorescein (F), and their mixture (MOF). Using F or MO solutions (pH = 7.5, room temperature), the maximum absorption was 47.8 mg/g in 90' (F) and 47.7 mg/g in 120' (MO) for R1, while that of R2 was 49.0 mg/g in 20' (F) and 48.5 mg/g in 30' (MO). Additionally, R1HG and R2HG-based columns, mimicking decontamination systems by filtration, were capable of removing MO, F, and MOF from water with a 100% removal efficiency, in different conditions of use. R1HG and R2HG represent low-cost and up-scalable column packing materials that are promising for application in industrial wastewater treatment.

Hydrogel Formulations of Antibacterial Pyrazoles Using a Synthesized Polystyrene-Based Cationic Resin as a Gelling Agent.

Here, to develop new topical antibacterial formulations to treat staphylococcal infections, two pyrazoles (3c and 4b) previously reported as antibacterial agents, especially against staphylococci, were formulated as hydrogels (R1-HG-3c and R1HG-4b) using a cationic polystyrene-based resin (R1) and here synthetized and characterized as gelling agents. Thanks to the high hydrophilicity, high-level porosity, and excellent swelling capabilities of R1, R1HG-3c and R1HG-4b were achieved with an equilibrium degree of swelling (EDS) of 765% (R1HG-3c) and 675% (R1HG-4b) and equilibrium water content (EWC) of 88% and 87%, respectively. The chemical structure of soaked and dried gels was investigated by PCA-assisted attenuated total reflectance (ATR) Fourier transform infrared (FTIR) spectroscopy, while their morphology was investigated by optical microscopy. Weight loss studies were carried out with R1HG-3c and R1HG-4b to investigate their water release profiles and the related kinetics, while their stability was evaluated over time both by monitoring their inversion properties to detect possible impairments of the 3D network and by PCA-assisted ATR-FTIR spectroscopy to detect possible structural changes. The flow and dynamic rheological characterization of the gels was assessed by determining their viscosity vs. shear rate, applying the Cross rheological equation to achieve the curves of shear stress vs. shear rate, and carrying out amplitude and frequency sweep experiments. Finally, their content in NH3+ groups was determined by potentiometric titrations. Due to their favorable physicochemical characteristic and the antibacterial effects of 3c and 4b possibly improved by the cationic R1, the pyrazole-enriched gels reported here could represent new weapons to treat severe skin and wound infections sustained by MDR bacteria of staphylococcal species.

Coordinated Prefrontal State Transition Leads Extinction of Reward-Seeking Behaviors.

Extinction learning suppresses conditioned reward responses and is thus fundamental to adapt to changing environmental demands and to control excessive reward seeking. The medial prefrontal cortex (mPFC) monitors and controls conditioned reward responses. Abrupt transitions in mPFC activity anticipate changes in conditioned responses to altered contingencies. It remains, however, unknown whether such transitions are driven by the extinction of old behavioral strategies or by the acquisition of new competing ones. Using in vivo multiple single-unit recordings of mPFC in male rats, we studied the relationship between single-unit and population dynamics during extinction learning, using alcohol as a positive reinforcer in an operant conditioning paradigm. To examine the fine temporal relation between neural activity and behavior, we developed a novel behavioral model that allowed us to identify the number, onset, and duration of extinction-learning episodes in the behavior of each animal. We found that single-unit responses to conditioned stimuli changed even under stable experimental conditions and behavior. However, when behavioral responses to task contingencies had to be updated, unit-specific modulations became coordinated across the whole population, pushing the network into a new stable attractor state. Thus, extinction learning is not associated with suppressed mPFC responses to conditioned stimuli, but is anticipated by single-unit coordination into population-wide transitions of the internal state of the animal.SIGNIFICANCE STATEMENT The ability to suppress conditioned behaviors when no longer beneficial is fundamental for the survival of any organism. While pharmacological and optogenetic interventions have shown a critical involvement of the mPFC in the suppression of conditioned responses, the neural dynamics underlying such a process are still largely unknown. Combining novel analysis tools to describe behavior, single-neuron response, and population activity, we found that widespread changes in neuronal firing temporally coordinate across the whole mPFC population in anticipation of behavioral extinction. This coordination leads to a global transition in the internal state of the network, driving extinction of conditioned behavior.

Microglia modulate hippocampal synaptic transmission and sleep duration along the light/dark cycle.

Microglia, the brain's resident macrophages, actively contribute to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor-1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice. Our data demonstrate that almost complete microglial depletion increases the duration of NREM sleep and reduces the hippocampal excitatory neurotransmission. The fractalkine receptor CX3CR1 plays a relevant role in these effects, because cx3cr1GFP/GFP mice recapitulate what found in PLX5622-treated mice. Furthermore, during the light phase, microglia express lower levels of cx3cr1 and a reduction of cx3cr1 expression is also observed when cultured microglial cells are stimulated by ATP, a purinergic molecule released during sleep. Our findings suggest that microglia participate in the regulation of sleep, adapting their cx3cr1 expression in response to the light/dark phase, and modulating synaptic activity in a phase-dependent manner.

Granzyme A and CD160 expression delineates ILC1 with graded functions in the mouse liver.

Type 1 innate lymphoid cells (ILC1) are tissue-resident lymphocytes that provide early protection against bacterial and viral infections. Discrete transcriptional states of ILC1 have been identified in homeostatic and pathological contexts. However, whether these states delineate ILC1 with different functional properties is not completely understood. Here, we show that liver ILC1 are heterogeneous for the expression of distinct effector molecules and surface receptors, including granzyme A (GzmA) and CD160, in mice. ILC1 expressing high levels of GzmA are enriched in the liver of adult mice, and represent the main hepatic ILC1 population at birth. However, the heterogeneity of GzmA and CD160 expression in hepatic ILC1 begins perinatally and increases with age. GzmA+ ILC1 differ from NK cells for the limited homeostatic requirements of JAK/STAT signals and the transcription factor Nfil3. Moreover, by employing Rorc(γt)-fate map (fm) reporter mice, we established that ILC3-ILC1 plasticity contributes to delineate the heterogeneity of liver ILC1, with RORγt-fm+ cells skewed toward a GzmA- CD160+ phenotype. Finally, we showed that ILC1 defined by the expression of GzmA and CD160 are characterized by graded cytotoxic potential and ability to produce IFN-γ. In conclusion, our findings help deconvoluting ILC1 heterogeneity and provide evidence for functional diversification of liver ILC1.

Technical features, perioperative and anatomical outcomes of a standardized suturing pattern for robotic sacrocolpopexy.

INTRODUCTION AND HYPOTHESIS: Several technical alternatives to repair mesh using laparoscopic sacrocolpopexy exist. We aim to describe the outcomes and surgical technique of robotic-assisted colpo-/cervicosacropexy using a standardized suturing scheme to repair the mesh. METHODS: We retrospectively reported data of 60 consecutive cases of robotic-assisted colpo-/cervicosacropexy for advanced multicompartmental prolapse using a standardized suturing design. We placed three non-absorbable stitches on the cervix or three absorbable stitches on the apex of the vaginal vault, six long-term absorbable stitches on the anterior vaginal wall deep to the basis of the vesical trigone, six similar posterior stitches with the deeper row of sutures down to the levator ani plane and three non-absorbable stitches on the sacral promontory as the cranial support for Y-shaped polypropylene mesh. RESULTS: Median operative time was 188 ± 43 min. All the procedures were successfully performed using a Da Vinci Si platform in a three-arm configuration, and no conversion to open or traditional laparoscopic surgery was needed. The length of hospital stay was 1.2 ± 1.7 days, and no readmission within 30 postoperative days was reported. At a follow-up of 12 and 24 months, no case of extrusion or exposure of the mesh occurred, and the retreatment rate was 6.7%. CONCLUSIONS: Our suturing technique is safe and effective, with negligible risk of complications and good medium-term results. It is plausible that robotic systems may facilitate precise, accurate and reproducible placement of the stitches, thereby favoring wider diffusion of minimally invasive treatment of advanced prolapse.

The Development of FAK Inhibitors: A Five-Year Update.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

A Self-Forming Hydrogel from a Bactericidal Copolymer: Synthesis, Characterization, Biological Evaluations and Perspective Applications.

Objects touched by patients and healthcare workers in hospitals may harbor pathogens, including multi-drug resistant (MDR) staphylococci, enterococci (VRE), Escherichia coli, Acinetobacter, and Pseudomonas species. Medical devices contaminated by these pathogens may also act as a source of severe and difficult-to-treat human infections, thus becoming a critical public health concern requiring urgent resolutions. To this end, we recently reported the bactericidal effects of a cationic copolymer (CP1). Here, aiming at developing a bactericidal formulation possibly to be used either for surfaces disinfection or to treat skin infections, CP1 was formulated as a hydrogel (CP1_1.1-Hgel). Importantly, even if not cross-linked, CP1 formed the gel upon simple dispersion in water, without requiring gelling agents or other additives which could be skin-incompatible or interfere with CP1 bactericidal effects in possible future topical applications. CP1_1.1-Hgel was characterized by attenuated-total-reflectance Fourier transform infrared (ATR-FTIR) and UV-Vis spectroscopy, as well as optic and scanning electron microscopy (OM and SEM) to investigate its chemical structure and morphology. Its stability was assessed by monitoring its inversion properties over time at room temperature, while its mechanical characteristics were assessed by rheological experiments. Dose-dependent cytotoxicity studies performed on human fibroblasts for 24 h with gel samples obtained by diluting CP_1.1-Hgel at properly selected concentrations established that the 3D network formation did not significantly affect the cytotoxic profile of CP1. Also, microbiologic investigations carried out on two-fold serial dilutions of CP1-gel confirmed the minimum inhibitory concentrations (MICs) previously reported for the not formulated CP1.Selectivity indices values up to 12 were estimated by the values of LD50 and MICs determined here on gel samples.

Microwave-Assisted and Conventional Extractions of Volatile Compounds from Rosa x damascena Mill. Fresh Petals for Cosmetic Applications.

Rosa x damascena Mill. essential oil is mainly used in the cosmetics and perfumery industry, but it also finds application in the food industry as a flavoring agent. The chemical composition of essential oils is affected by environment, soil, harvesting technique, storage condition, and extraction methods. Nowadays, the study and design of greener, more efficient, and sustainable extractive procedures is the main and strategic focus in the chemical research and development of botanical derivatives, especially as regards fragrances and essential oils. Several technologies are available, and the best method to use depends on the desired chemicals, but conventional extractive processes are often laborious and time-consuming, involve large amounts of solvents, and may cause the partial loss of volatiles, affecting the quality of the final product. In the last decade, microwave irradiation has been successfully applied to classical techniques, often improving the general extractive efficiency and extract quality. In the present paper, as a preliminary analytical screening approach, two microwave-mediated techniques, Solvent-Free Microwave Extraction (SFME) and Microwave Hydrodiffusion and Gravity (MHG), and two conventional procedures, Hydrodistillation (HD) and Steam Distillation (SD), were applied and compared for the extraction of volatile compounds from R. x damascena fresh petals to highlight differences and advantages of the selected procedure and of the obtained extracts useful in a cosmetic context as fragrances or active ingredients. The chemical composition of the extracts was investigated by GC-MS and GC-FID. Sixty-one components, distributed in the four techniques, were identified. SD and HD are dominated by oxygenated terpenes (59.01% and 50.06%, respectively), while MHG and SFME extracts are dominated by alcohols (61.67% and 46.81%, respectively). A relevant variability in the composition of the extracts relating to the extraction techniques used was observed. To point out the correlation between the process and composition of the obtained natural products, principal component analysis (PCA) of the data extracted from GC-FID was used. Taking into account a cosmetic application, SFME shows several advantages when compared with the other procedures. The extract (obtained in a significantly higher amount) contains a meaningful lower level of potential fragrance allergenic compounds and quite a double amount of benzyl alcohol and 2-phenyl ethanol that can also enhance the preservative action in personal care products.

Simulation training program for vacuum application to improve technical skills in vacuum-assisted vaginal delivery.

OBJECTIVE: evaluation of technical skills of the operators during the obstetrical device application for operative vaginal delivery, named kiwi-cup in a simulation training program. METHODS: Thirty-five residents in obstetrics and gynecology of the University of Pisa, Italy were recruited and evaluated with an assessment scale on technical skills from 0 to 55 points. They performed various operative vaginal delivery simulations with kiwi-cup and were evaluated at time 0 by a tutor. After 8 weeks, simulation training was repeated and trainees were re-evaluated by the same tutor. RESULTS: after 8 weeks from the first simulation session, trainees have been shown to increase technical skills (46.27 ± 4.6 with p-value < 0.0001), the successful application rate (85.71% with p-value 0.0161).) and to reduce the time to complete the procedure (86.2 ± 29.9 s with p-value < 0.0001). CONCLUSION: simulation training on operational vaginal delivery significantly increases technical skills, improves successful rate, and reduces the time taken to complete the procedure. CLINICAL TRIAL REGISTRATION: Not applicable.

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective.

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective.

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

The Development of BTK Inhibitors: A Five-Year Update.

Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "BTK" and "BTK inhibitors" as keywords.

Medium-term outcomes after robotic-assisted lateral suspension with mesh for advanced multi-compartmental prolapse.

INTRODUCTION AND HYPOTHESIS: Robotic abdominal lateral suspension (RALS) is an innovative mini-invasive surgical technique that allows treating apical and anterior prolapse. The safety and efficacy of this strategy have not yet been tested. METHODS: We completed a prospective case series of 115 RALS to treat apical and anterior prolapse stage III or IV, with no or minimal (stage I) posterior defect. Clinical evaluation was performed with a simplified POP quantification system (POP-Q). Mean follow-up was 28 ± 4 months. Primary outcomes were objective and subjective cure; secondary outcomes were reoperation rate for recurrence, erosion rate and complications. Objective cure was defined as POP-Q ≤ 1. Subjective cure was defined as absence of vaginal bulge. Patient's satisfaction was measured using the Patient Global Impression of Improvement Scale (PGI-I). RESULTS: There was a significant improvement in POP-Q score in all treated compartments with an objective cure rate of 88.7% for the anterior and 93.1% for the apical compartment (p < 0.0001). Subjective cure rate was 82%. The emergence of de novo high rectoceles was not significant in the cohort, as much as the development of de novo stress or urge urinary incontinence. Reoperation rate for POP was 11.3% (8 recurrent cystoceles without apical descent and 5 apical and anterior relapses). No postoperative complications of Clavien-Dindo grade ≥ 3a were seen. Mesh exposure rate was 0.9%; 58.2% patients compiled a PGI-I score at 18-24 months post-surgery, reporting high satisfaction rates. CONCLUSIONS: RALS is highly effective at a mid-term follow-up for the treatment of advanced apical and anterior POP.