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Nuno Martinho,1–3 Liana C Silva,1,4 Helena F Florindo,1 Steve Brocchini,2 Mire Zloh,3 Teresa S Barata2 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; 2Department of Pharmaceutics, UCL School of Pharmacy, London, 3School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK; 4Centro de Química-Física Molecular and IN – Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal Abstract: Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure–activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(L-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system. Keywords: dendrimers, peptide dendrimers, molecular dynamics, fluorescence, CHARMM, structure-activity, surface properties

Self‐supporting concrete shell structures are highly efficient in distributing loads, which can result in very reduced thicknesses (ultra‐thin), giving them remarkable slenderness. Due to their geometric complexity, it is difficult to predict how they interact with wind action. The main aim of the present study is to assess the mean surface pressure coefficient distribution in a shell with a triangular plan shape and three supports for different angles of wind incidence. To determine the distribution of surface pressure coefficients and lift and drag force coefficients, an experimental study was carried out in a wind tunnel, and a numerical simulation study was performed through computational fluid dynamics. The experimental and numerical results were analyzed and compared, and making it possible to identify the most critical surface zones and wind incidences when the shell is under the wind action. [ABSTRACT FROM AUTHOR]

Aim: To compare the vaginal wall thickness (VWT) measurement by two-dimensional ultrasound (2D-US) and pelvic floor muscle morphometry by four-dimensional translabial ultrasound (4D-TLUS) in women with vaginal laxity (VL) who underwent treatment with radiofrequency (RF) or pelvic floor muscle training (PFMT) after 30 days and 6 months., Methods: A secondary analysis of a randomized clinical trial that occurred between February 2020 and December 2021 was performed. Women with VL were enrolled and treated with RF or PFMT for 12 weeks. Ultrasound examiners were blinded for the groups. Transabdominal (TAUS) and transvaginal (TVUS) ultrasound were performed with 2D-US analysis. The 4D-TLUS was used for PFM morphometry assessment. We performed per-protocol and intention-to-treat analysis (5% significance)., Results: Women with ballooning presented significantly worse scoring in sexual function (p = 0.037) and vaginal symptoms (p = 0.007) than women without ballooning. Analysis of variance among 2D-US, intervention groups and assessment periods has shown that measurements of the TAUS proximal vagina increased in the PFMT group after 6 months (from 9.90 ± 3.14 mm to 10.53 ± 2.71 mm; p = 0.006). TAUS/TVUS distal vagina measurements were reduced after 6 months of RF (TAUS from 11.79 ± 3.67 mm to 10.51 ± 2.51 mm; p = 0.018/TVUS from 7.94 ± 1.83 mm to 7.32 ± 2.10 mm; p = 0.037). On the other hand, 4D-TLUS measurements did not present differences according to the intervention and/or groups., Conclusion: Women with ballooning on 4D-TLUS presented significantly worse scoring in sexual function and vaginal symptoms. 2D-US found that RF reduced the VWT of the distal vagina after 6 months and PFMT increased the VWT of the proximal vagina after 6 months., Clinical Trial Registration: Registro Brasileiro de Ensaios Clínicos-REBEC-RBR-2zdvfp as a clinical trial., (© 2025 Wiley Periodicals LLC.)

Background: Vaginal laxity (VL) is a complaint of excessive vaginal looseness with a prevalence ranging from 24% to 38% across studies., Aim: The study sought to compare the effect of radiofrequency (RF) and pelvic floor muscle training (PFMT) on the treatment of women with VL., Methods: From February 2020 to December 2021, a prospective, parallel, noninferiority, randomized clinical trial was carried out in women ≥18 years of age and complaining of VL in a tertiary hospital. Two groups (RF and PFMT) were evaluated at the beginning of the study and 30 days and 6 months postintervention. A total of 42 participants per arm was sufficient to demonstrate a difference in sexual function on the Female Sexual Function Index at 90% power, 1-sided type 1 error of 0.025 with a noninferiority margin of 4 on the FSFI total score. Analysis was intention-to-treat and per-protocol based., Outcomes: The primary endpoint was the change of FSFI score after treatment, and the secondary outcomes were improvement in symptoms of VL and changes in questionnaire scores of sexual distress, vaginal symptoms, and urinary incontinence, in the quantification of pelvic organ prolapse, and pelvic floor muscle (PFM) contraction., Results: Of 167 participants recruited, 87 were included (RF: n = 42; PFMT: n = 45). All questionnaires improved (P < .05) their total scores and subscales in both groups and during the follow-ups. After 30 days of treatment, RF was noninferior to PFMT to improving FSFI total score (mean difference -0.08 [95% confidence interval, -2.58 to 2.42]) in the per-protocol analysis (mean difference -0.46 [95% confidence interval, -2.92 to 1.99]) and in the intention-to-treat analysis; however, this result was not maintained after 6 months of treatment. PFM contraction improved significantly in both groups (RF: P = .006, 30 days; P = .049, 6 months; PFMT: P < .001, 30 days and 6 months), with better results in the PFMT group., Clinical Implications: Sexual, vaginal, and urinary symptoms were improved after 30 days and 6 months of treatment with RF and PFMT; however, better results were observed in the PFMT group after 6 months., Strengths & Limitations: The present randomized clinical trial used several validated questionnaires evaluating quality of life, sexual function and urinary symptoms, in addition to assessing PFM contraction and classifying the quantification of pelvic organ prolapse aiming at anatomical changes in two follow-up periods. The limitations were the lack of a sham-controlled group (third arm) and the difficulty of blinding researchers to assess treatments due to the COVID-19 pandemic., Conclusion: After 30 days and 6 months of treatment, sexual, vaginal, and urinary symptoms improved with RF and PFMT; however, better results were observed in the PFMT group after 6 months. RF was noninferior to PFMT in improving FSFI total score after 30 days; however, this result was not maintained after 6 months of treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Polymers, including non-linear copolymers, have great potential in the development of drug delivery systems with many advantages, but the design requires optimizing polymer-drug interactions. Molecular dynamics (MD) simulations can provide insights into polymer-drug interactions for designing delivery systems, but mimicking formulation processes such as drying is often not included in in silico studies. This study demonstrates an MD approach to model drying of systems comprising either hydrophilic tinidazole or hydrophobic clotrimazole drugs with amphiphilic hyperbranched copolyethers. The simulated drying protocol was critical for elucidating drug encapsulation and binding mechanisms. Experimentally, two polymers were synthesized and shown to encapsulate clotrimazole with up to 83% efficiency, guided by interactions with the hydrophobic core observed in simulations. In contrast, tinidazole is associated with surface regions, indicating capacity differences between drug types. Overall, this work highlights MD simulation of the drying process as an important tool for predicting drug-polymer complex behaviour. The modelled formulation protocol enabled high encapsulation efficiency and opened possibilities for the design of delivery systems based on computationally derived binding mechanisms. This demonstrates a computational-experimental approach where simulated drying was integral to elucidating interactions and developing optimized complexes, emphasizing the value of molecular modelling for the development of drug delivery formulations.

Urease is a metalloenzyme that catalyzes the hydrolysis of urea, and its modulation has an important role in both the agricultural and medical industry. Even though numerous molecules have been tested against ureases of different species, their clinical translation has been limited due to chemical and metabolic stability as well as side effects. Therefore, screening new compounds against urease would be of interest in part due to rising concerns regarding antibiotic resistance. In this work, we collected and curated a diverse set of 2640 publicly available small-molecule inhibitors of jack bean urease and developed a classifier using a random forest machine learning method with high predictive performance. In addition, the physicochemical features of compounds were paired with molecular docking and protein-ligand fingerprint analysis to gather insight into the current activity landscape. We observed that the docking score could not differentiate active from inactive compounds within each chemical family, but scores were correlated with compound activity when all compounds were considered. Additionally, a decision tree model was built based on 2D and 3D Morgan fingerprints to mine patterns of the known active-class compounds. The final machine learning model showed good prediction performance against the test set (81% and 77% precision for active and inactive compounds, respectively). Finally, this model was employed, as a proof-of-concept, on an in-house library to predict new hits that were then tested against urease and found to be active. This is, to date, the largest, most diverse dataset of compounds used to develop predictive in silico models. Overall, the results highlight the usefulness of using machine learning classifiers and molecular docking to predict novel urease inhibitors.

Increasing evidence suggests a critical role of lipids in both the mechanisms of toxicity and resistance of cells to platinum(II) complexes. In particular, cisplatin and other analogues were reported to interact with lipids and transiently promote lipid phase changes both in the bulk membranes and in specific membrane domains. However, these processes are complex and not fully understood. In this work, cisplatin and its cationic species formed at pH 7.4 in low chloride concentrations were tested for their ability to induce phase changes in model membranes with different lipid compositions. Fluorescent probes that partition to different lipid phases were used to report on the fluidity of the membrane, and a leakage assay was performed to evaluate the effect of cisplatin in the permeability of these vesicles. The results showed that platinum(II) complex effects on membrane fluidity depend on membrane lipid composition and properties, promoting a stronger decrease in the fluidity of membranes containing gel phase. Moreover, at high concentration, these complexes were prone to alter the permeability of lipid membranes without inducing their collapse or aggregation.

The efficacy of conventional antimicrobials is falling to critical levels and raising alarming concerns around the globe. In this scenery, engineered nanoparticles emerged as a solid strategy to fight growing deadly infections. Here, we show the in vitro and in vivo performance of pharmadendrimers, a novel class of engineered polyurea dendrimers that are synthetic mimics of antibacterial peptides, against a collection of both Gram-positive and Gram-negative bacteria and fungi. These nanobiomaterials are stable solids prepared by low-cost and green processes, display a dense positively charged core-shell, and are biocompatible and hemocompatible drugs. Mechanistic data, corroborated by coarse-grained molecular dynamics simulations, points towards a fast-killing mechanism via membrane disruption, triggered by electrostatic interactions. Altogether this study provides strong evidence and support for the future use of polyurea pharmadendrimers in antibacterial and antifungal nanotherapeutics.

The fast spreading of the SARS-CoV-2 virus led to a significant increase in the demand for personal protective equipment (PPE). Healthcare professionals, mainly dentists, work near the patients, increasing their risk of infection. This paper investigates the effectiveness of an air-curtain sealing effect in a newly designed visor developed to reduce the risk of contracting a respiratory infection. This PPE was developed by computational fluid dynamics (CFD) modeling. CFD results show that the aerodynamic sealing in this PPE device effectively protects the user's face by 43% from a contaminated environment. The experiments considered two different tests: one using a tracer gas (CO 2 ) to simulate a gaseous contaminant inside and outside the PPE face shield and a second test using smoke to simulate aerosol transport and evaluate the PPE efficiency. The particle concentration within the aerodynamically sealed PPE was evaluated and compared with the protection efficiency of other PPE. Results show similar protection levels for particles in the 1-5 μm range between the prototype and a KN95 respirator. The combined use of this novel PPE with aerodynamic sealing and a physical mask (KN95 or surgical) produced protection efficiency values within the range of 57%-70% for particles greater than 0.5 μm. This study reveals the potential of using an air curtain combined with a face shield to reduce the risks from contaminated environments., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Blocking the catalytic activity of urease has been shown to have a key role in different diseases as well as in different agricultural applications. A vast array of molecules have been tested against ureases of different species, but the clinical translation of these compounds has been limited due to challenges of potency, chemical and metabolic stability as well as promiscuity against other proteins. The design and development of new compounds greatly benefit from insights from previously tested compounds; however, no large-scale studies surveying the urease inhibitors' chemical space exist that can provide an overview of developed compounds to data. Therefore, given the increasing interest in developing new compounds for this target, we carried out a comprehensive analysis of the activity landscape published so far. To do so, we assembled and curated a data set of compounds tested against urease. To the best of our knowledge, this is the largest data set of urease inhibitors to date, composed of 3200 compounds of diverse structures. We characterized the data set in terms of chemical space coverage, molecular scaffolds, distribution with respect to physicochemical properties, as well as temporal trends of drug development. Through these analyses, we highlighted different substructures and functional groups responsible for distinct activity and inactivity against ureases. Furthermore, activity cliffs were assessed, and the chemical space of urease inhibitors was compared to DrugBank. Finally, we extracted meaningful patterns associated with activity using a decision tree algorithm. Overall, this study provides a critical overview of urease inhibitor research carried out in the last few decades and enabled finding underlying SAR patterns such as under-reported chemical functional groups that contribute to the overall activity. With this work, we propose different rules and practical implications that can guide the design or selection of novel compounds to be screened as well as lead optimization.

Introduction and Hypothesis: The female pelvic floor muscles (PFM) play an important role in sexual function. We hypothesize that there is a relation between PFM strength and sexual function in women with and without sexual dysfunction., Methods: Retrospective multicentric cross-sectional study including women with and without sexual dysfunction [Female Sexual Function Index (FSFI) cutoff point < 26.55], analyzed by age range, considering demographic, clinical, anthropometric and PFM strength [Modified Oxford Scale (MOS)] data. Chi-square, Mann-Whitney test and linear regression (ranks) were used, with 5% significance (SAS 9.4)., Results: Out of 1013 medical records, 982 women with an average age of 45.76 (± 15.25) were included in the study. Of these, 679 (69.14%) presented FSFI score < 26.55, while 303 (30.86%) presented FSFI ≥ 26.55. It was identified that the higher scores were among white women, < 45 years old, single, with higher education, family income > 4 minimum wages, body mass index < 25 kg/m 2 , lower parity, regular physical activity practitioner and higher PFM strength (MOS: 4-5). Desire, arousal, lubrication and orgasm domains were higher among women with MOS 4-5, while satisfaction and pain domains were higher among those with MOS 3-5., Conclusion: Demographic, clinical and anthropometric conditions can influence both PFM strength and female sexual function. Our findings demonstrate that women with higher PFM strength present fewer complaints about sexual dysfunction., (© 2021. The International Urogynecological Association.)

Background: Vaginal laxity is an underreported condition that negatively affects women's sexual function and their relationships. Evidence-based studies are needed to better understand this complaint and to discuss its treatment options. Thus, we present a study protocol to compare the effect of radiofrequency and pelvic floor muscle training in the treatment of women with complaints of vaginal laxity., Methods/design: This is a prospective, parallel-group, two-arm, randomized clinical trial (Registry: RBR-2zdvfp-REBEC). Participants will be randomly assigned to one of the two groups of intervention (Radiofrequency or Pelvic Floor Muscle Training). The study will be performed in the Urogynecology outpatient clinic and in the physiotherapy outpatient clinic at the State University of Campinas-UNICAMP and will include women aged ≥ 18 years and with self-reported complaints of vaginal laxity. Participants will be assessed at baseline (pre-intervention period) and will be followed up in two periods: first follow-up (30 days after intervention) and second follow-up (six months after intervention)., Expected Results: The results of this randomized clinical trial will have a positive impact on the participants' quality of life, as well as add value to the development of treatment options for women with complaints of vaginal laxity., Trial Registration: Registry: RBR-2zdvfp-Registro Brasileiro de Ensaios Clínicos-REBEC (19/02/2020)., Competing Interests: The authors declare no competing Interests.

Introduction and Hypothesis: We hypothesized that anatomical changes in the pelvic floor muscles (PFM) could be detected using four-dimensional translabial ultrasound (4D TLUS) in patients with cervical (CC) or endometrial cancer (EC) who underwent pelvic radiotherapy (RT) as digital palpation may present sensitivity limitations., Methods: This was a cross-sectional study that included 64 women (26 with CC and 38 with EC). PFM function was assessed by digital palpation, grading muscle strength according to the Modified Oxford Scale and by 4D TLUS. Ultrasonographic variables were: levator plate angle, hiatal area, puborectalis muscle thickness, puborectalis strain and levator ani muscle integrity. These variables were also correlated with clinical and sociodemographic data from all these patients. A 5% significance level was adopted., Results: When assessed by digital palpation, no significant difference was found in PFM strength between women with CC and those with EC (p = 0.747). However, when assessed by 4D TLUS, women with CC presented greater thickening of the left (p = 0.039) and right (p = 0.014) lower portion of the puborectalis muscle during PFM contraction compared to those with EC. After pooling the groups, higher cancer staging (p = 0.028) was associated with smaller narrowing in the symphysis-levator distance, and shorter RT finishing duration (< 60 months) was associated with higher thickening in the left (p = 0.029) and right (p = 0.013) upper portion of the puborectalis muscle during PFM contraction as well as a shorter menopause duration (p = 0.007 and p = 0.002, respectively)., Conclusions: Anatomical changes in the puborectalis muscle during PFM contraction were detected by 4D TLUS within gynecological cancer patients after pelvic RT.

The presence of genotoxic impurities in active pharmaceutical ingredients (APIs) is a major concern for the pharmaceutical industry. Acetamide is a common genotoxic byproduct found in synthetic routes of many APIs, mainly due to acetonitrile hydrolysis, and selective scavenging is a still a challenging task. Herein, as a proof-of-concept, we evaluate polyurea (PURE) biodendrimers as strategic nanopolymers to prepare safe drug nanoformulations from mixtures containing acetamide, using (S)-ibuprofen (IBF) as a model drug. Furthermore, computational molecular dynamics (MD) simulations were conducted to rationalize in vitro results and to identify the key intermolecular interactions within mixtures. Experimental data were corroborated by MD simulations which showed that acetamide, IBF and carboxyfluorescein interactions with PURE biodendrimers are mostly at the surface. Also, PURE nanoformulations appear to be driven by hydrogen bonding, electrostatic and hydrophobic interactions.

Background: Pelvic floor muscle function has been shown to be inversely associated with pelvic organ prolapse in Western women, however differences have been documented between ethnic groups., Objective: To determine if pelvic floor muscle strength and thickness and hiatal area are associated with pelvic organ prolapse in Nepali women., Methods: This cross-sectional study included non-pregnant Nepali women ≥18 years attending an outpatient gynecology clinic in Kathmandu, Nepal. A clinical examination included the pelvic organ prolapse quantification (POP-Q)- system examination and Modified Oxford Scale. Puborectalis muscle thickness and hiatal area were assessed using 3D/4D translabial ultrasound. Statistical analysis included Pearson's correlation and multiple regression (p<0.05)., Results: Of the 123 women; 14 (11%) had POP-Q stage 0 prolapse, 29 (24%) stage I, 69 (56%) stage II, 8 (7%) stage III, and 3 (2%) stage IV. Mean±SD Modified Oxford Scale was 3.37±0.48 and muscle thickness was 1.14±0.21cm, hiatal area at rest was 14.67±3.11cm 2 and on contraction was 11.29±2.51cm 2 . No associations were found between pelvic floor muscle strength or thickness and POP-Q stages 0-IV. There was a positive correlation found between hiatal area at rest and pelvic organ prolapse stage (r=0.34, p<0.001)and hiatal area on contraction and prolapse stage (r=0.30, p<0.001) and a negative correlation between pelvic floor muscle strength and hiatal area on contraction (r=-0.36, p<0.001)., Conclusion: In contrast to previous findings, pelvic floor muscle strength and thickness are not associated with pelvic organ prolapse in this sample of Nepali women. It is important to consider these findings when developing pelvic organ prolapse treatment and management strategies in this population., (Copyright © 2020 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Vulvodynia is a disabling condition in which pelvic floor muscles' (PFM) hypertonicity plays an important role., Aim: To evaluate biometric changes in PFM in women with vulvodynia undergoing kinesiotherapy treatment protocol (KTP)., Methods: A single-blinded randomized controlled trial of 57 women with vulvodynia randomly assigned to either KTP + amitriptyline or amitriptyline alone (controls) for treatment. Four-dimensional translabial ultrasound assessed PFM regarding symphysis-levator distance at rest, anorectal angle at rest, excursion of the levator plate angle, and levator hiatal narrowing. Volunteers underwent a vaginal examination for a cotton swab test (CST), fulfillment of Friedrich criteria score and PFM power of contraction, and completed a diary of sexual pain and frequency of vaginal intercourse. Outcomes were assessed at baseline and after 8 weeks of treatment., Outcomes: Primary outcomes were differences in biometric parameters assessed by four-dimensional translabial ultrasound after treatment, between groups. Secondary outcomes were changes in clinical variables (CST, Friedrich criteria, PFM power of contraction, frequency of intercourse, and intensity of sexual pain) between groups and correlation analysis between biometric parameters and clinical variables., Results: Only the KTP group had statistically significant changes in biometric parameters after treatment (symphysis-levator distance: 0.22 ± 0.2, 95% CI = 0.1-0.4, P = .008; levator hiatal narrowing: -0.33 ± 0.2, 95% CI = -1 to -0.2, P = .04). Comparisons between groups showed that symphysis-levator distance (0.3, 95% CI = 0.2-0.6, P = .005) and excursion of levator plate angle (4.9, 95% CI = -0.4 to 10.1, P = .02) improved significantly after KTP treatment. Clinical variables showed greater improvement in the group treated with KTP for CST (difference of -3.7, 95% CI = -7 to -0.4, P = .01), Friedrich criteria (difference of -1.9, 95% CI = -3.2 to -0.6, P = .003), PFM power of contraction (0.3, 95% CI = 0.1-0.6, P = .05) and intensity of sexual pain (reduction of 1.7, 95% CI = -3.1 to -0.2, P = .01). Some clinical and biometric variables correlated positively, for example, frequency of vaginal intercourse and anorectal angle (P = .04; r = 0.25), or inversely, for example, pain intensity at CST and anorectal angle (P = .004, r = -0.31)., Clinical Implications: This study provides evidence on efficiency of a physical therapy protocol for improvement of symptoms of vulvodynia and hypertonicity changes., Conclusion: This pilot study suggests that KTP for women with vulvodynia promoted significant changes in PFM biometric measures, consistent with alterations in hypertonicity and clinical improvement. Bardin MG, Giraldo PC, Martinho N. Pelvic Floor Biometric Changes Assessed by 4D Translabial Ultrassound in Women With Vulvodynia Submitted to Physical Therapy: A Pilot Study of a Randomized Controlled Trial. J Sex Med 2020;17:2236-2246., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate whether pelvic floor muscle (PFM) morphological changes obtained through four-dimensional translabial ultrasound (4D TLUS) correlate with a PFM contraction as evaluated by digital palpation and PFM electromyographic activity evaluated by surface electromyography (sEMG). The secondary objective was to investigate which ultrasound parameter is more strongly associated with digital palpation., Methods: This cross-sectional study included 210 women and their PFMs were evaluated by digital palpation (graded according to the Modified Oxford Scale), sEMG and 4D TLUS. Offline analysis of ultrasound volume datasets was performed for measuring the change in levator plate angle, bladder neck elevation, hiatal area narrowing, puborectalis strain, and puborectalis muscle thickness at rest and during PFM contraction. Statistical analysis included Kruskal-Wallis, Dunn, and Spearman's tests in addition to univariate and multivariate logistic regression, adopting a significance level of 5%., Results: A weak but significant correlation between the change in levator plate angle and sEMG (P = .04; r = 0.14) was found. All 4D TLUS measurements, except the puborectalis muscle thickness, significantly correlated with digital palpation (P < .0001); with the puborectalis strain and the change in levator plate angle having the strongest combined parameters associated with digital palpation (R 2  = 21.77%), despite the low coefficient of determination., Conclusion: We found that 4D TLUS significantly correlates with digital palpation and sEMG, being the change in the levator plate angle the parameter that best correlates with both methods. While digital palpation is essential during a PFM functional assessment, 4D TLUS is recommended as a beneficial noninvasive clinical tool for a more in-depth evaluation., (© 2019 Wiley Periodicals, Inc.)

Introduction and Hypothesis: Birthweight seems to be a risk factor for levator ani muscle (LAM) avulsion and a predictive factor for pelvic organ prolapse (POP). Most trauma seems due to first vaginal birth., Methods: One thousand one hundred twenty-five women with at least two vaginal deliveries underwent a physician-directed interview, followed by clinical examination (digital palpation and Pelvic Organ Prolapse Quantification-POPQ) and 4D translabial ultrasound. Ultrasound volume data were obtained at rest, on pelvic floor contraction and Valsalva. The investigator, blinded to all other data, performed offline analysis of the LAM integrity and hiatal area on Valsalva. We tested for associations between birthweight of the first and of the largest vaginally born baby on the one hand and avulsion and symptoms/signs of prolapse on the other hand., Results: Between July 2014 and July 2017, 1575 patients were seen. After exclusion of nulliparae and women with just one vaginal birth, 1202 remained. Another 77 were excluded due to missing data, leaving 1125. A significant association was found between birthweight and LAM avulsion as well as significant prolapse on POPQ. The birthweight of the first vaginally born baby was at least as predictive for avulsion as the birthweight of any subsequent births, even when adjusted for maternal age at first delivery and use of forceps., Conclusions: The birthweight of the first vaginally born baby is associated with levator avulsion and subsequent POP. Maximum weight of vaginal births does not seem to be a stronger predictor.

Cisplatin and other platinum(II) analogs are widely used in clinical practice as anti-cancer drugs for a wide range of tumors. The primary mechanism by which they exert their action is through the formation of adducts with genomic DNA. However, multiple cellular targets by platinum(II) complexes have been described. In particular, the early events occurring at the plasma membrane (PM), i.e., platinum-membrane interactions seem to be involved in the uptake, cytotoxicity and cell-resistance to cisplatin. In fact, PM influences signaling events, and cisplatin-induced changes on membrane organization and fluidity were shown to activate apoptotic pathways. This review critically discusses the sequence of events caused by lipid membrane-platinum interactions, with emphasis on the mechanisms that lead to changes in the biophysical properties of the membranes (e.g., fluidity and permeability), and how these correlate with sensitivity and resistance phenotypes of cells to platinum(II) complexes.

Introduction and Hypothesis: We used clinical examination and transperineal 3D/4D ultrasound (US) to evaluate pelvic floor muscles (PFM) after different delivery modes., Methods: Women were surveyed using validated questionnaires. PFM were evaluated and classified according to the Modified Oxford Scale following 3D/4D transperineal US. For statistical analysis, Kruskal-Wallis, Mann-Whitney, chi-square, and Fisher exact tests were used., Results: Fifty-three women were evaluated: 32 with previous vaginal delivery (VD) and 21 with cesarean section (CS) (8 nonelective and 13 elective). No significant difference among groups was observed regarding urinary incontinence (UI) after delivery (p = 0.39), loss of muscle strength referred by the patient (p = 0.48), or evaluated through digital examination (p = 0.87). No patient with elective CS had avulsion, with difference between VD and elective CS (p = 0.008). US evaluation identified no differences in bladder-neck elevation (p = 0.69) or descent (p = 0.65) , and no difference in genital hiatus size (p = 0.35), levator ani thickness (p = 0.35 -0.44), or presence of major or minor levator ani avulsion (p = 0.10)., Conclusions: We evaluated primiparous women within 12 to 24 months of delivery and found that VD was associated with PFM avulsion. There was no difference among VD and nonelective or elective CS in symptomatology or other anatomic alterations evaluated through 3D/4D transperineal US.

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.

Objectives: The aim of this work is to synthesize a novel stable and biodegradable nitric oxide (NO) donor polymer based on a chitosan backbone. This polymer needed to be linked to glutathione (GSH), which was nitrosated in a second step. This polymer has been developed as an NO delivery platform that could be further evaluated for an oral delivery in Crohn's disease., Methods: The new polymer (named S-nitrosoglutathione-oligosaccharide-chitosan or SNOC) was obtained using a two-step procedure involving the linkage of GSH to chitosan via an amidine reaction followed by a post-nitrosation with NaNO2. The GSH linkage was assessed using NMR, FTIR and an Ellman's test, whereas the final NO amount was determined by the Griess and Saville method., Results: Polymers with different numbers of NO groups were obtained (159.04 ± 64.16 µmol/g of polymer for SNOC G1 and 525.08 ± 151.35 µmol/g of polymer for SNOC G2) depending on the procedure used for production. When tested in an Ussing chamber, SNOC G2 had a sustained release of NO and nitrites for at least 6 h., Conclusion: We believe that this type of polymer is adapted for the development of various formulations, including microparticles.

In Brazil, the parasitoid Cotesia flavipes (Cameron) has been used as a biological control agent against Diatraea saccharalis (F.) since 1976, because of its effectiveness in reducing populations of this pest. Three million plastic cups are used annually to release C. flavipes, which remain in the environment. This study aimed to develop fully biodegradable packaging, so that releases occur without damaging the environment. The biological characteristics of C. flavipes were studied for five generations in the packaging developed (biodegradable boxes) and in the packaging currently used (non-biodegradable plastic cups and biodegradable cups), as were the costs. The results demonstrated the feasibility of using completely biodegradable and inexpensive packaging for the rearing, transport, and release of adult C. flavipes in the field., (© The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Molecular modeling techniques provide a powerful tool to study the properties of molecules and their interactions at the molecular level. The use of computational techniques to predict interaction patterns and molecular properties can inform the design of drug delivery systems and therapeutic agents. Dendrimers are hyperbranched macromolecular structures that comprise repetitive building blocks and have defined architecture and functionality. Their unique structural features can be exploited to design novel carriers for both therapeutic and diagnostic agents. Many studies have been performed to iteratively optimise the properties of dendrimers in solution as well as their interaction with drugs, nucleic acids, proteins and lipid membranes. Key features including dendrimer size and surface have been revealed that can be modified to increase their performance as drug carriers. Computational studies have supported experimental work by providing valuable insights about dendrimer structure and possible molecular interactions at the molecular level. The progress in computational simulation techniques and models provides a basis to improve our ability to better predict and understand the biological activities and interactions of dendrimers. This review will focus on the use of molecular modeling tools for the study and design of dendrimers, with particular emphasis on the efforts that have been made to improve the efficacy of this class of molecules in biomedical applications.

Objective: The aim of this study was to evaluate a formulation made of poly(lactide-co-glycolide) (PLGA) nanoparticles containing azelaic acid for potential acne treatment., Methods: Azelaic acid-loaded PLGA nanoparticles were prepared by spontaneous emulsification processes using poloxamer 188 as stabilizer. Several manufacturing parameters such as stirring rate, concentration of stabilizer and different recovery methods were investigated. Nanoparticles were evaluated in terms of size, zeta potential, encapsulation efficiency, release kinetics and permeation kinetics in vitro. Furthermore, in vitro toxicological studies were performed in Saccharomyces cerevisiae model., Results: The results showed that by adjusting some formulation conditions it was possible to obtain nanoparticles with high loading and a controlled drug release. Freeze-dried recovery altered the nanoparticles structure by enhancing porous structures and mannitol was required to control the mean particle size. The centrifugation recovery was found to be the best approach to nanoparticles recovery. Similar toxicity profiles were observed for both drug-free and azelaic acid-loaded nanoparticles, with concentration-dependent decreases in cell viability., Conclusion: These results indicate a potential formulation for controlled release delivery of azelaic acid to the follicular unit.

Azelaic acid (AzA) is used in the treatment of acne. However, side effects and low compliance have been associated with several topical treatments with AzA. Nanotechnology presents a strategy that can overcome these problems. Polymeric nanoparticles can control drug release and targeting and reduce local drug toxicity. The aim of this study was to produce and evaluate an innovative topical treatment for acne with AzA-loaded poly-DL-lactide/glycolide copolymer nanoparticles. A soft white powder of nanoparticles was prepared. The mean size of loaded nanoparticles was < 400 nm and zeta potential was negative. Spherical nanoparticles were observed by scanning electron microscopy. Encapsulation efficiency was around 80% and a strong interaction between the polymer and the drug was confirmed by differential scanning calorimetric analysis. In vitro drug release studies suggested a controlled and pulsatile release profile. System efficacy tests suggested similar results between the loaded nanoparticles and the nonencapsulated drug against the most common bacteria associated with acne. Cytotoxicity of AzA-loaded nanoparticles was concentration dependent, although not pronounced. The occluded patch test seemed to indicate that the formulation excipients were safe and thus AzA-loaded nanoparticles appear to be an efficient and safe treatment for acne.

Effective formulation for peptide and protein delivery through the oral route has always been the critical effort with the advent of biotechnology. Stability, enzymatic degradation and ineffective absorption are common difficulties found for conventional dosage forms. As a result, new drug-delivery approaches are used to circumvent these limitations and enhance effective oral drug delivery. Some of these technologies have reached late stages of clinical trials and promising results will be available in the near future. This review covers, in general, the recent carriers reported in literature.