bluuebunny/crossref_metadata_2025 huggingface dataset:
O13 JAK inhibitors to restore skin barrier function in ARCI
Authors: Giusto Elena , Enjalbert Florence , Rognoni Emanuel  , Caley Matthew , O’Toole Edel 
Published: July 2023

The autosomal recessive congenital ichthyoses (ARCI) are a group of chronic conditions where there is unmet therapeutic need. Harlequin ichthyosis (HI) is the most severe form of ARCI, with aberrant differentiation of the epidermis leading to a severe barrier defect. It is caused by mutations in ABCA12, a lipid transporter involved in the transport of glucosylceramides from the lamellar body to the lipid lamellae. Lamellar ichthyosis is caused by mutations in TGM1. Several Janus kinase (JAK) inhibitors (JAKi) inhibiting the JAK–STAT pathway are now licensed for atopic dermatitis. Previous work from our group in an in vitro HI model showed that tofacitinib had a restorative effect on the lipid barrier. We hypothesized that JAKi A, B and C could restore the epidermal barrier in both HI three-dimensional (3D) organotypic models (OTs) made using ABCA12 CrispR-Cas9 knockout and wild-type keratinocytes and ARCI 3D OTs generated with short hairpin RNA knock down of TGM1. The JAKi were tested at three concentrations in the 3D models (20, 50 and 500 nmol L–1 for JAKiA; 10, 50 and 250 nmol L–1 for JAKiB; 2, 25 and 125 nmol L–1 for JAKiC) and vehicle only was used as the control. The OTs were stained with haematoxylin and eosin, Nile red and differentiation markers such as K10, K14, transglutaminase 1 (TGM1) and involucrin. All three JAKi had a positive effect on the epidermal barrier. The epidermal structure looked more organized and uniform, with an increase in neutral and polar lipids in the upper epidermis. The differentiation markers showed normalization of the expression of involucrin, K10 and TGM1 at the same drug concentrations. These results suggest that JAKi have a generalized positive effect on the skin barrier and will be further investigated in an in vivo mouse model of HI.
P02 Potential for the loss of endothelial AMBRA1 expression in the tumour microenvironment to identify high-risk patient subsets with nonulcerated AJCC stage I/II melanoma
Authors: Stout Roisin , Best Katie , Cosgarea Ioana , Lovat Penny  , Armstrong Jane
Published: July 2023

With the recent inclusion of adjuvant therapy for the management of patients with AJCC stage II melanomas there is increased emphasis on the identification of both prognostic and companion biomarkers for early-stage tumours. The expression of AMBRA1 and loricrin (AMBLor) in the epidermis overlying early-stage nonulcerated primary melanomas has recently been identified as a prognostic biomarker able to identify genuinely low-risk tumour subsets. Pilot data also show that loss of AMBLor is associated with loss of AMBRA1 expression in the surrounding tumour endothelium. The aim of the present study was therefore to define the potential of endothelial AMBRA1 expression to identify AJCC stage I/II melanomas at risk of metastasis. Endothelial AMBRA1 expression was determined in a cohort of 48 AJCC stage I/II melanomas previously subjected to automated immunohistochemical analysis for AMBRA1 expression and defined as tumours with loss of AMBLor. Endothelial AMBRA1 expression determined by positive pixel count using Aperio Image-Scope and normalized to vessel area, revealed variable AMBRA1 expression in the intra- and/or peritumoral vessels within 500 µm of the tumour mass. Further analysis revealed a significantly increased proportion of intra-/peritumoral vessels (23.7%) with low AMBRA1 (< 50% of mean total vessel expression) in melanomas that metastasized vs. 12.4% of vessels with low AMBRA1 expression in tumours that remained localized (P = 0.002). Kaplan–Meier analysis additionally demonstrated a significant reduction in 5-year recurrence-free survival (RFS) to 33% for patients with melanomas with > 12% intra-/peritumoral vessels with reduced AMBRA1 expression vs. 76% RFS for patients with < 12% intra-/peritumoral vessels in which AMBRA1 expression was reduced (hazard ratio 5.16, 95% confidence interval 2.05–13; P = 0.003). Collectively, these data suggest that endothelial AMBRA1 expression may serve as a prognostic and companion biomarker to identify and stratify high-risk subsets of patients with early-stage melanoma for adjuvant treatment.
P04 Skin concentration of 7-dehydrocholesterol is not a limiting factor for vitamin D3 synthesis in older versus younger adults, and a similar response occurs to UVR in these age groups
Authors: Borecka Oktawia , Dutton John J , Tang Jonathan C Y   , Fraser William D , Rhodes Lesley E
Published: July 2023

Skin exposure to ultraviolet radiation (UVR) triggers conversion of precursor 7-dehydrocholesterol (7DHC) to vitamin D3, which then enters the bloodstream. The aim of this study was to assess if skin 7DHC concentration differs between younger and older adults, and to explore the impact of solar-simulated UVR (SSR) on 7DHC (in skin) and vitamin D3 (cholecalciferol; in serum) in these age groups. Younger (n = 10, 18–40 years) and older (n = 11; 65–89 years) adults of skin phototype I–III were exposed to a suberythemal dose of SSR (95% UVA, 5% UVB, 1.3 standard erythemal dose) over 35% body surface area in the UK winter. Six 5-mm buttock skin punch biopsies were taken: two from unexposed skin, two immediately post-UVR and two at 24 h post-UVR. Blood was taken at baseline, 24 h and 7 days post-UVR. Skin and serum samples were assayed using high-performance liquid chromatography–tandem mass spectrometry. Baseline mean (SD) 7DHC concentrations were 0.22 (0.07) µg mg–1 and 0.25 (0.08) µg mg–1 in younger and older adults, respectively. Immediately post-UVR, 7DHC concentrations were 0.27 (0.10) µg mg–1 and 0.22 (0.08) µg mg–1 in younger and older adults, respectively, and 24 h post-UVR they were 0.27 (0.08) µg mg–1 and 0.28 (0.13) µg mg–1, respectively. Baseline serum vitamin D3 concentrations in younger adults were 1.5 (1.5) nmol L–1 vs. 1.5 (1.7) nmol L–1 in older adults; 24 h post-UVR they were 3.1 (2.0) nmol L–1 in younger adults vs. 2.5 (2.0) nmol L–1 in older adults and 7 days post-UVR they were 2.0 (2.1) vs. 1.7 (1.2) nmol L–1, respectively. No significant difference was seen in any parameter between age groups. Thus, in contrast to previous assumptions, skin 7DHC concentration is not a limiting factor for vitamin D3 synthesis in healthy older adults relative to younger adults. The early vitamin D3 biosynthetic pathway does not appear to differ between these age groups.
P20 Engineered peptide for KLK5 inhibition – therapeutic intervention for atopic dermatitis
Authors: Mah Jeffrey , Macmillan Derek , Di Wei-Li
Published: July 2023

Epidermal proteases, such as human tissue kallikrein-related peptidase, regulate skin barrier function through keratinocyte desquamation, antimicrobial defence, inflammatory response and barrier maintenance. It has been reported that the activity of kallikreins (KLKs) is upregulated in inflammatory skin disorders, including atopic dermatitis (AD; eczema). AD is a very common, chronic and relapsing inflammatory skin disease affecting 15–20% of children in the UK. Studies have shown that enhanced KLK5 results in AD-like skin architecture with an impaired skin barrier function. In this study, we aimed to develop a potent and selective inhibitor that targets KLK5 and restores epidermal barrier dysfunction in AD. Nature-based sunflower trypsin inhibitor 1 (SFTI), a small, circular peptide exhibiting wide-ranging serine protease inhibition can be engineered and modified to become a potent inhibitor specific for tissue kallikreins; our previous study also indicated that it was able to permeate through the outermost layer to exert its inhibitory action on serine proteases. In this study, we wanted to develop a more potent and specific inhibitor of KLK5 based on a lead SFTI analogue (‘analogue 6’) that was previously developed by our research group. Computer modelling was employed to assess the structure and binding affinity between KLK5 and SFTI-1. Designed SFTI analogues were then synthesized using solid phase peptide synthesis. The inhibitory effect was evaluated by its half maximal inhibitory concentration (IC50) against KLK5 using a 7-amido-4-methylcoumarin assay and further tested by protease-activated receptor 2-dependent intracellular calcium influx assay in keratinocytes. Computer modelling then indicated that an endogenous inhibitor was comparable with the analogue 6 we developed previously. Analogue 6 was further modified, based on the endogenous inhibitor structure, and synthesized. The new analogue achieved an IC50 of 14 nmol L–1 for KLK5, which was a fourfold increase in potency compared to analogue 6 (IC50 56 nmol L–1) and a 16-fold increase vs. SFTI-1 wild type (IC50 230 nmol L–1). Further, the new analogue could inhibit proteinase-activated receptor 2 (PAR2)-dependent intracellular calcium influx by modulating the activation of PAR2 receptor, a KLK5 downstream molecule in keratinocytes at a minimum inhibitor-to-enzyme molar ratio of 1:1. The novel potent inhibitor for KLK5 could be a potential therapeutic intervention for AD and other inflammatory skin conditions with enhanced KLK5.
P23 Inducible E-cadherin ablation drives malignant progression in HK1.ras.fos.PTENflx/flx carcinogenesis and induces conversion of HK1.fos.PTENflx/flx keratoacanthoma
Authors: Zaweia Rema , Alyamani Abdullah , McMenemy Carol  , Quinn Jean , Greenhalgh David 
Published: July 2023

Inducible ablation of E-cadherin expression has been investigated in mouse skin carcinogenesis driven by Ras and Fos activation (HK1.ras; HK1.fos), and conditional (cre/lox) PTEN knockout exclusively in the epidermis. Previously, analysis of endogenous E-cadherin expression in stage-specific HK1.ras/fos/Δ5PTEN tumours showed E-cadherin expression became reduced at the invasive front of well-differentiated squamous cell carcinomas (wdSCCs) following p53 loss, and where retention of p21 minimized Akt activation and further progression. To validate stage-specific causality of E-cadherin loss, RU486-inducible conditional E-cadherin knockout was introduced into HK1.ras/fos/Δ5PTENflx/flx genotypes employing the cre/LoxP system (K14cre-ΔE-cadflx/flx). Initial observations in RU486-treated compound HK1.ras/fos/ΔPTENflx/flx-ΔE-cadflx/flx mice found that E-cadherin ablation appeared to accelerate malignant conversion, again associated with p53 loss; however, the main effect was on malignant progression and invasion, as wdSCCs displayed rapid progression to aggressive SCCs. Malignant progression also implicated β-catenin activation, finding increased nuclear expression, alongside loss of membranous expression, in the invasive basal layer keratinocytes, together with loss of p21 and increased p-Akt1 activity. In addition, preliminary data for E-cadherin loss in HK1.fos/Δ5PTEN keratoacanthoma aetiology now showed malignant conversion to invasive wdSCC, again associated with increased β-catenin activation. These wdSCCs may have retained a degree of correct adhesion signalling, as basal layer HK1.fos/Δ5PTEN-ΔE-cadflx/flx keratinocytes exhibited both membranous and nuclear p-β-catenin expression; hence, in the absence of Ras, progression stalled at wdSCC. Collectively, these data show that, in some contexts (hyperplasia/papillomas), E-cadherin loss can be tolerated via increased differentiation, while in carcinogenesis, following overt tumour appearance, conditional ablation of E-cadherin drives invasion and malignant progression, consistent with roles in cell–cell adhesion and deregulated signalling to β-catenin.
P24 Emollient use and effects on cutaneous allergen reactions: a preliminary study
Authors: Katibi Oludolapo Sherifat , Andrew Paul , Poyner Anna  , Pinnock Abigail , Brown Kirsty , Byers Rob  , Cork Michael , Danby Simon
Published: July 2023

Recently, there has been some evidence of an increased incidence of food allergy in infants regularly applying some types of emollients. Considering that emollient vehicles can modify the delivery of ‘actives’ into the skin, it is important to examine their effects on epicutaneous sensitization to environmental allergens. The aim was to determine the effects of regular emollient use on cutaneous reactions to house dust mite allergen. An observer-blind within-participant multilateral controlled interventional study in 40 adults with confirmed house dust mite allergy was carried out. Participants underwent 4 weeks of treatment with olive oil, coconut oil and a basic emollient cream (no added moisturizers) applied to three different areas of both forearms with a fourth area left as a no-treatment control (NTC). At the end of treatment, skin barrier integrity was assessed by performing transepidermal water loss (TEWL) measurements in conjunction with tape-stripping. At adjacent locations, atopy patch tests (APTs) using house dust mite allergen were performed. This interim analysis includes data from the first 16 participants. Skin barrier integrity was reduced by all three treatments relative to NTC as indicated by elevated TEWL [mean (SD) olive oil 35.10 (15.17), coconut oil 36.56 (17.17) and emollient cream 39.18 (20.91) vs. NTC 28.76 (13.06) g m–2 h–1; P < 0.05]. Pretreatment of the skin had a significant effect on APT reactions (P = 0.0401, graded from 0 to 4). The strongest reactions were seen following pretreatment with emollient cream [2.31 (1.12)], olive oil [2.22 (0.91)] and coconut oil [1.94 (0.91)] vs. NTC [1.50 (0.80)]. These preliminary results suggest that some commonly used emollients decrease skin barrier integrity and increase the severity of reactions to house dust mite allergens. This implies that regular use of emollients that damage the skin may directly affect allergy development arising from epicutaneous sensitization. Some sophisticated emollients (with moisturizers) have been shown to improve skin barrier function. Clinical trials are therefore needed to determine if they impart protection against epicutaneous sensitization.
P27 Uncovering the roles of lysosomal protease cathepsin H in atopic dermatitis
Authors: Tachie-Menson Theresa , Azizah Atqiya , Hughes Aaron  , O'Shaughnessy Ryan
Published: July 2023

Atopic dermatitis (AD) is a persisting skin condition characterized by recurring eczematous lesions and pruritus. It is ranked as a nonfatal disease with the fifteenth-highest global burden. The causes of AD are diverse: a defective epidermal barrier, epidermal inflammation, an altered epidermal microbiome and genetics. However, much of the treatment for AD focuses on reducing inflammation. Further understanding on how the epidermal barrier maintains its integrity may be useful in developing treatments that specifically help to restore the defective epidermal barrier. We have identified cathepsin H, a lysosomal protease with aminopeptidase activity, as a protease with key roles in maintaining the integrity of the epidermal barrier. Ctsh+/– mice exhibit reduced corneocyte integrity, a reduction in the expression of the cornified envelope protein loricrin, reduced filaggrin processing and altered skin immunity, among other defects. These highlight the significant roles of cathepsin H within the epidermal barrier and terminal differentiation process of epidermal keratinocytes. To investigate the roles of cathepsin H in the epidermal barrier we have used patient biopsies, patient tape-strip samples and rat epidermal keratinocytes (REKs), a keratinocyte cell line that spontaneously undergoes differentiation and recapitulates the complete differentiation process of human epidermal keratinocyte. Using REKs, we have generated Ctsh knockdown cell lines, from which we have derived three-dimensional organotypic cultures, as well as cathepsin H and cathepsin B stable overexpression cell lines. Moreover, we have performed mass spectrometry analysis of tape-strip samples from patients with AD exhibiting a high or low expression of cathepsin H. Our research aims to uncover the protein targets of cathepsin H in the epidermis and its ensuing functions in the epidermal barrier.
P33 Investigating the utility and exploring biological targets of micro-wound healing compounds in 2D and 3D skin models
Authors: Gorkic Metka , Messenger David , Wainwright Linda  , Connelly John , Bishop Cleo L  
Published: July 2023

An injury to the epidermis can result in a micro-wound, characterized by its localization above the dermal–epidermal junction and an absence of vessel damage. Re-epithelialization is driven by keratinocytes, which organize into overlapping migrating and proliferating zones to ensure faithful micro-wound closure. Although still relatively unexplored, keratinocyte-mediated cytokine secretion is thought to be a feature of the micro-wound re-epithelialization response. A failure to re-epithelize, also characteristic of chronic wounds, can lead to reoccurring infections and hyperpigmentation. Although wound healing has been extensively researched, there are gaps in our understanding of the cellular mechanisms involved in the onset and completion of re-epithelization, leading to a scarcity of available enhanced micro-wound healing compounds (MHCs). To investigate the utility of a panel of putative MHCs, a new high-throughput scratch assay method was devised. A guide for multichannel pipette scratches was produced by three-dimensional printing an autoclavable 96-well plate lid with custom-made lengthwise slits. Using an immortalized keratinocyte cell line (N/TERT), the rate of scratch healing was characterized. Critical re-epithelization time points have been determined, and markers of migration are being explored within the identified periods. Moreover, known keratinocyte migration-inducing compounds are being tested to serve as a positive control for enhanced MHC screening. Any putative MHC hits will be further explored using proteomic approaches to elucidate the signalling pathways involved in the onset and completion of re-epithelization. This analysis will assist in the identification of novel enhanced MHC targets and further our understanding of keratinocyte re-epithelization.
Troubled and Troublesome Teenagers: Towards Critical and Relationship-based Practice
Authors: McDonald Lisa , Rogowski Steve
Published: July 2023

In neoliberal and associated managerial times, social work in the UK is dominated by the speedy completion of bureaucracy to ration services and assess/manage risk. Concerning children and families, unless there are child protection issues little help or support is provided with parents/carers often told to change their behaviour/lifestyle or face the possibility of losing their children to adoption. To counteract this, we argue for critical and relationship-based practice, using work with troubled and troublesome teenagers as an example. Such practice involves a broad responsibility to seek equality and social justice as well as address individual problems and difficulties. Importantly, the article includes the perspective of someone who has the lived and care experience of being a troubled/troublesome teenager.
Dissociated amplitude and phase effects of alpha oscillation in a nested structure of rhythm- and sequence-based temporal expectation
Authors: Su Zhongbin , Zhou Xiaolin , Wang Lihui
Published: July 2023

The human brain can utilize various information to form temporal expectations and optimize perceptual performance. Here we show dissociated amplitude and phase effects of prestimulus alpha oscillation in a nested structure of rhythm- and sequence-based expectation. A visual stream of rhythmic stimuli was presented in a fixed sequence such that their temporal positions could be predicted by either the low-frequency rhythm, the sequence, or the combination. The behavioral modeling indicated that rhythmic and sequence information additively led to increased accumulation speed of sensory evidence and alleviated threshold for the perceptual discrimination of the expected stimulus. The electroencephalographical results showed that the alpha amplitude was modulated mainly by rhythmic information, with the amplitude fluctuating with the phase of the low-frequency rhythm (i.e. phase-amplitude coupling). The alpha phase, however, was affected by both rhythmic and sequence information. Importantly, rhythm-based expectation improved the perceptual performance by decreasing the alpha amplitude, whereas sequence-based expectation did not further decrease the amplitude on top of rhythm-based expectation. Moreover, rhythm-based and sequence-based expectations collaboratively improved the perceptual performance by biasing the alpha oscillation toward the optimal phase. Our findings suggested flexible coordination of multiscale brain oscillations in dealing with a complex environment.
Menstrually-related migraine shapes the structural similarity network integration of brain
Authors: Li Xinyu , Hao Huifen , Li Yingying , Au Lisa Wing-Chi , Du Ganqin , Gao Xiuju , Yan Junqiang , Tong Raymond Kai-Yu , Lou Wutao
Published: July 2023

Menstrually-related migraine (MM) is a primary migraine in women of reproductive age. The underlying neural mechanism of MM was still unclear. In this study, we aimed to reveal the case–control differences in network integration and segregation for the morphometric similarity network of MM. Thirty-six patients with MM and 29 healthy females were recruited and underwent MRI scanning. The morphometric features were extracted in each region to construct the single-subject interareal cortical connection using morphometric similarity. The network topology characteristics, in terms of integration and segregation, were analyzed. Our results revealed that, in the absence of morphology differences, disrupted cortical network integration was found in MM patients compared to controls. The patients with MM showed a decreased global efficiency and increased characteristic path length compared to healthy controls. Regional efficiency analysis revealed the decreased efficiency in the left precentral gyrus and bilateral superior temporal gyrus contributed to the decreased network integration. The increased nodal degree centrality in the right pars triangularis was positively associated with the attack frequency in MM. Our results suggested MM would reorganize the morphology in the pain-related brain regions and reduce the parallel information processing capacity of the brain.
GC Analysis of Metformin, Ranitidine and Famotidine from Pharmaceuticals and Human Serum
Authors: Zounr Rizwan A , Khuhawar Muhammad Y , Khuhawar Taj M J , Lanjwani Muhammad F , Khuhawar Muzamil Y
Published: July 2023

A method has been designed based on gas chromatography with flame ionization detection (FID) for the separation and analyses of ranitidine, famotidine and metformin after pre-column derivatization with trifluoroacetylacetone and ethyl chloroformate. DB-1 (30 m × 0.32 mm id) column with film thickness 0.25 μm was used for the separation at an initial temperature of column was 100°C for 2 min, and ramping at 20°C/min up to 250°C, with a hold time of 3 min. The rate of nitrogen flow was 2.5 mL/min and FID was used for detection. Complete separation was obtained between all the three drugs including excess of derivatization reagents. Linear calibration curves and detection limits were obtained in the ranges 0.1–30 μg/mL and 0.011–0.015 μg/mL. The procedure was repeatable in terms of peak heights/peak areas and retention time (n = 5) for derivatization, quantitation and separation with relative standard deviations (RSDs) within 2.0–3.0%. The approach was examined for the analyses of drug products and serum after the intake of the drugs by healthy volunteers, and recoveries were obtained within 95–98% with RSDs 2.4–3.1%.
Bioimaging of glucose analogs labeled at the C-1 or C-2 position with a fluorescent dansylamino group
Authors: Yanagida Mio , Nakano Hirofumi , Ueno Hironori
Published: July 2023

Glucose is the most important energy source in all organisms; however, our understanding of the pathways and mechanisms underlying glucose transportation and localization in living cells is incomplete. Here, we prepared two glucose analogs labeled with a dansylamino group at the C-1 (1-Dansyl) or C-2 (2-Dansyl) position; the dansyl group is a highly fluorescent moiety that is characterized by a large Stokes shift between its excitation and emission wavelengths. We then examined the cytotoxicity of the two glucose analogs in mammalian fibroblast cells and in the ciliated protozoan Tetrahymena thermophila. In both cell types, 2-Dansyl had no negative effects on cell growth. The specificity of cellular uptake of glucose analogs was confirmed using an inhibitor of glucose transporter in NIH3T3 cells. In NIH3T3 cells and T. thermophila, fluorescence microscopy revealed that the glucose analogs localized throughout the cytoplasm, but especially at the periphery of the nucleus. In T. thermophila, we also found that swimming speed was comparable in media containing non-labeled glucose or one of the glucose analogs, which provided more evidence not only that the analogs were not cytotoxic in these cells but also that the analogs had no negative effect on the ciliary motion. Together, the present results suggest that the glucose analogs have low toxicity and will be useful for bioimaging of glucose-related systems.
Unequal racial distribution of immunotherapy for late-stage non–small cell lung cancer
Authors: Chang Annie , Flores Raja M , Taioli Emanuela
Published: July 2023

Immunotherapy has increased survival for non–small cell lung cancer (NSCLC), especially for those diagnosed with late-stage disease. However, it is not known if its use is equally distributed across races. We assessed immunotherapy use in 21 098 pathologically confirmed stage IV NSCLC patients according to race in the Surveillance Epidemiology, and End Results–Medicare linked dataset. Multivariable models were conducted to evaluate the independent association of receipt of immunotherapy with race and overall survival according to race. Black patients had statistically significantly lower odds of receiving immunotherapy (adjusted odds ratio = 0.60, 95% confidence interval = 0.44 to 0.80); receipt of immunotherapy was lower in Asian and Hispanic patients but not statistically significant. When immunotherapy was received, survival was similar across races. Immunotherapy for NSCLC is not used equally among races, underscoring the racial disparities that exist in access to the newest cancer treatment. Efforts should be directed toward expanding access to novel, efficacious treatments for advanced stage lung cancer.
(165) PAROXETINE COMBINED WITH ATLAS987 DOES NOT INHIBIT SEXUAL BEHAVIOR IN SEROTONIN TRANSPORTER KNOCKOUT RATS
Authors: Prof. Jocelien D Olivier , Jolijn Hogenbirk , Stephen Stephen De Prêtre , Prof. Berend Olivier
Published: July 2023

Objectives

Enduro is a drug that combines paroxetine with the 5-HT1A-receptor antagonist Atlas987. In rats this drug successfully acutely inhibits the sexual behavior, making it relevant for on demand treatment of lifelong premature ejaculation in men. Because the serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the latency to ejaculate in men with premature ejaculation, we were interested to test this drug in an animal model without the serotonin transporter, the serotonin transporter knockout (SERT-/-) rat. We hypothesized that SERT-/- rats would not respond to an SSRI, but that the 5-HT1A-receptor antagonist Atlas987 would inhibit sexual behavior as previously shown with the reference 5-HT1A-receptor antagonist WAY100635.

Methods

Wildtype (SERT+/+) and SERT-/- male Wistar rats were trained in a 30-minute weekly sexual performance test, for ten weeks. Rats with a high number of ejaculations (10 SERT+/+ and 10 SERT-/-) were selected. Atlas987 (s.c.) was dose-dependently administered with either placebo (saline) or Paroxetine (10 mg/kg; i.p.). Acute responses on sexual behavior assessed in both SERT+/+ and SERT-/- rats.

Results

A clear reduction in the number of ejaculations was found in SERT-/- rats compared with SERT+/+ rats. As shown before, the combination of Atlas987 and paroxetine acutely reduced the number of ejaculations in wildtype rats. No effects of paroxetine and Atlas987 were found in SERT-/- rats. In addition, Atlas987 alone did not influence the number of ejaculations in both SERT+/+ and SERT-/- rats. This suggests that the 5-HT1A receptor involved with sexual behavior is desensitized in SERT-/- animals.

Conclusions

Enduro successfully inhibited sexual behavior in SERT+/+ rats, but had no effects on SERT-/- rats. Knocking out the serotonin transporter gene probably decreased the sensitivity to a 5-HT1A antagonist in sexual behavior.

Conflicts of Interest

All authors declare to have no conflicts of interest.
(145) VITAMIN D DEFICIENCY IS ASSOCIATED WITH SEXUAL FUNCTION IMPAIRMENT: FINDINGS FROM A CROSS SECTIONAL STUDY
Authors: Dr. Luca Boeri , Dr. Edoardo Pozzi , Dr. Federico Belladelli , Dr. Giuseppe Fallara , Dr. Simone Cilio , Dr. Francesco Lanzaro , Dr. Alessandro Bertini , Dr. Luigi Candela , Massimiliano Raffo , Fausto Negri , Alessia d'Arma , Ludovica Cella , Margherita Fanton , Dr. Christian Corsini , Dr. Paolo Capogrosso , Prof. Francesco Montorsi , Prof. Andrea Salonia
Published: July 2023

Objectives

Vitamin D (vitD) is an antioxidant molecule involved in endothelial protection. Previous studies have investigated the association between vitD and erectile dysfunction (ED) with conflicting findings. We aimed to investigate the association between vitD levels and erectile function in a cohort of men seeking medical help for ED as their primary compliant.

Methods

Data from 540 men were analyzed. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF) and the Beck Inventory for Depression (BDI). Circulating hormones and VitD levels were measured in every patient [deficiency for vitD was defined as <20 ng/mL (group A); vitD insufficiency for vitD levels between 20 and 30 ng/mL (group B); normal level for vitD >30 ng/ml (Group C)]. Descriptive statistics and linear regression models tested the association between clinical variables and sexual functioning.

Results

Overall, 211 (39.1%), 197 (36.5%) and 132 (24.4%) patients were in group A, B and C, respectively. Groups were similar for age, BMI, CCI, sex steroids, smoking and alcohol habits. IIEF-EF domain score was lower in group A compared to group B (p<0.01) and group C (p<0.01). Severe ED was more frequently observed in group A men than the other groups [47.5% vs. 29.2% vs. 23.3% for group A, B and C, respectively (p=0.03)]. Group A patients reported lower scores of IIEF-sexual desire (p=0.03) and IIEF-overall satisfaction (p<0.01) domains than those in group C. BDI score was comparable among groups. At multivariable linear regression analysis younger age (beta -0.1, p=0.01), lower CCI (beta -1.3, p=0.04) and BDI scores (beta -0.2, p<0.001) and vitD deficiency (beta -2.5, p=0.02) were significantly associated with IIEF-EF, after accounting for total testosterone and smoking status.

Conclusions

VitD deficiency is associated with overall sexual function impairment. The association between vitD and EF is even independent from clinical characteristics.

Conflicts of Interest

No conflicts of interest to declare.
(213) TESTOSTERONE SUPPLEMENTATION AND BONE PARAMETERS: A SYSTEMATIC REVIEW AND META-ANALYSIS STUDY
Authors: Dr. Walter Vena , Prof. Giovanni Corona , Dr. Alessandro Pizzocaro , Dr. Vito Angelo Giagulli , Dr. Davide Francomano , Dr. Giulia Rastrelli , Prof. Gherardo Mazziotti , Dr. Alessandro Brunetti , Prof. Antonio Aversa , Dr. Andrea Isidori , Prof. Rosario Pivonello , Prof. Linda Vignozzi , Edoardo Mannucci , Prof. Mario Maggi , Prof. Alberto Ferlin
Published: July 2023

Objectives

The role of testosterone (T) replacement therapy (TRT) in subjects with late onset hypogonadism is still the object of an intense debate.

Methods

All observational studies and placebo-controlled or -uncontrolled randomized trials (RCTs) comparing the effect of TRT on different bone parameters were considered.

Results

Out of 349 articles, 36 were considered, including 3103 individuals with a mean trial duration of 66.6 weeks. TRT improves areal bone mineral density (aBMD) at the spine and femoral neck levels in observational studies, whereas placebo-controlled RTCs showed a positive efect of TRT only at lumber spine and when trials included only hypogonadal patients at baseline (total testosterone<12 nM). The effects on aBMD were more evident in subjects with lower T levels at baseline and increased as a function of trial duration and a higher prevalence of diabetic subjects. Either T or estradiol increase at endpoint contributed to aBMD improvement. TRT was associated with a signifcant reduction of bone resorption markers in observational but not in controlled studies.

Conclusions

TRT is able to inhibit bone resorption and increase bone mass, particularly at the lumbar spine level and when the duration is long enough to allow the anabolic efect of T and estrogens on bone metabolism to take place.

Conflicts of Interest

The authors declare no confict of interest.
(196) A MORPHOMETRIC ANALYSIS OF THE PENIS BEFORE AND AFTER PROSTAGLANDIN INJECTION: IS “SHOWER” AND “GROWER” EVEN A THING
Authors: Dr. Manuel Alonso-Isa , Dr. Borja García-Gómez , Dr. Guillermo Celada-Luis , Dr. Alessandro Fiorillo , Dr. Daniel Tueti-Silva , Dr. Esther García-Rojo , Eduard García-Cruz , Javier Romero-Otero
Published: July 2023

Objectives

The colloquial terms “grower” and “shower” refer to those men whose penis change significantly without or with erection, and those whose penis don't. We aim to analyze the morphometric changes in the penis after prostaglandin injection, detect if there are different patterns and which factors might be related to those patterns.

Methods

The retrospectively review a total of 225 patients from February 2021 to October 2022 who underwent penile ultrasonography with prostaglandin injection (10 mcg). Demographic, vascular and other relevant variables were recorded for analysis. A history of Peyronie disease or penile surgery (excluding postectomy and frenuloplasty) were exclusion criteria. We measured penile length (in cm) and tunica albuginea thickness (in mm) in flaccid and erect state. Only grade 3 of Erection Hardness Score (EHS) and EHS 4 were included.

Results

Mean age 48 (range 17-98). Mean penis size (flaccid) 10.07cm (range 4-17). Mean SFLP (stretch flaccid penile length) 15.32 cm (range 10.4-19.7). Mean EPL (erect penile length) 14.37 cm (range 9-19.5)

Median penile growth (PG) 42.6 % (range 3.57-264.1). PG has a normal distribution, based on 1 SD:

PG<30.94% can be considered “shower”.

PG >55.73% can be considered “grower”.

Intermediate results would be the “grey area”.

“Growers” have a thinner albuginea (0,9 mm; p < 0,05) and a greater albuginea reduction (28%; p < 0,05) in erection compared to “showers” (1,2 mm and 16,2%) respectively.

Conclusions

We have established growth ranges from which we can consider a penis grower, shower or grey zone. The size of the albuginea and its reduction during erection is related to the growth of the erect penis.

Conflicts of Interest

Authors have no potential conflict of interest to report.
(175) IMPACT OF PELVIC FLOOR DYSFUNCTIONS IN FEMALE SEXUALITY
Authors: Dr. Sònia Anglès-Acedo , Lorena López-Frías , Carolina Carmona-Guerrero , Esther Benito-García , Sílvia Escura-Sancho , Dr. Eduardo Bataller-Sánchez , Dr. Cristina Ros-Cerro , Dr. Montserrat Espuña-Pons
Published: July 2023

Objectives

To analyse female sexuality of women who seek care for pelvic floor dysfunctions.

Methods

Cross-sectional study about female sexuality of women attended the first consultation to assess and treat pelvic floor dysfunctions (urinary incontinence-IU, anal incontinence-IA, pelvic organ prolapse-POP). Urinary, anal and prolapse symptoms were assessed with B-SAQ, ICIQ-UI-SF, PFDI-20. PISQ-IR, a condition-specific questionnaire, was used for assessing sexuality in both non-sexually active (NSA) and sexually active (SA) patients.

Results

We included 131 participants, 89.3% reported UI, 37.4% AI and 30.5% had a symptomatic POP. The more frequently isolated pelvic floor dysfunction was UI (39.7%). 26% of the participants informed double incontinence. 46% of women presented 2 pelvic floor dysfunctions, whereas 8.4% had 3 of them. Table 1 shows the baseline characteristics.

NSA rate was 45%. The main reason for sexual inactivity was lack of interest (70.7%), followed by not having a partner (53.4%). The pelvic floor dysfunction, other health issues and the pain were the inactivity reason in a lower proportion (12.1%, 10.3% y 10.3%, respectively). 25.8% NSA women reported avoidance of sexual activity due to fear related to UI/AI or POP. 75.9% of NSA participants were satisfied with their sexual life.

Related to SA women (n=72), 36.5% informed about UI/AI during sexual activity, however, 57.7% of the SA participants limited sexual activity due to fear related to UI /AI or POP. Dyspareunia was present in 52.3% SA women. 59.1% of SA women were satisfied with their sexual life.

Conclusions

Most of our sample are interested in their sexuality assessment. Pelvic floor dysfunctions may affect sexual activity among NSA and SA women, as well as worsen sexual function on SA women. So, satisfaction with the sexual life could be impaired. PISQ-IR permits to identify the subgroup of patients with unsatisfied sexual life due to pelvic floor dysfunctions and, then, to individualized treatment according patient’s expectations.

Conflicts of Interest

No conflict of interest.
(229) FEMALE GENITAL SELF-IMAGE SCALE-SPANISH (FGSIS-S): PROPOSAL FOR A CUT-OFF SCORE
Authors: Dr. Alba Bartolomé , Cecilia Villalaín , Alvaro Tejerizo
Published: July 2023

Objectives

To explore cut-off scores for Female Genital Self-Image Scale-Spanish (FGSIS-S) to discriminate women concerned about their genital appearance and/or considering female genital cosmetic surgery (FGCS), most frequently labiaplasty.

Methods

FGSIS-S is a Spanish validated, 6-item scale, developed from original FGSIS. It measures women’s genital image self-perception. Total score varies from 6 to 24 and higher scores resemble a more positive attitude towards genital self-image.

Answers from 200 women taking part, through an online survey, in the FGSIS-S validation original study were analyzed. Participants were 18-70 years old, native Spanish-speakers, non-pregnant, without vulvar disease, attending general gynecology consults in Hospital 12 de Octubre, from march to may 2021.

Questions “Have you ever been concerned about your genital appearance?” and “Have you ever considered undergoing genital cosmetic surgery?” were validated and used for stratification of FGSIS-S scores.

Sensitivity and specificity analysis was performed through logistic regression and plot of the area under the ROC curve (AUC).

Results

Overall FGSIS-S score was able to predict women’s concern with an AUC of 0.80 (95% CI 0.74 – 0.86); and those considering FGCS with AUC 0.78 (95% CI 0.69 – 0.86).

A 90% sensitivity cut-off for the detection of women concerned was found at 21 and 17 for 90% specificity. Best trade-off between sensitivity (51.6%) and specificity (91.6%) was found at 17.

To detect women considering FGCS, cut-offs were found at 21 (90% sensitivity) and 15 (90% specificity). Best trade-off was found again at 17 (sensitivity 72.0%, specificity 81.1%)

Cut-off scores are shown in FIgure 1.

Conclusions

We consider 17 could be a good cut-off to refer women to specialized counselling as they probably represent the most extreme group of those concerned and considering surgery.

Further studies are needed to validate cut-off scores as well as establish the total score increment required to obtain clinical benefit from interventions.

Conflicts of Interest

The authors report no conflicts of interest.
(49) HIV KNOWLEDGE AND STIGMA TOWARDS HIV-POSITIVE PEOPLE: AN EMPIRICAL STUDY
Authors: Dr. Sofia Falaschi , Paolo Antonelli , Dr. Daniel Giunti , Dr. Gioele A Salvatori , Prof. Davide Dèttore
Published: July 2023

Objectives

Our study investigates the Italian population’s level of knowledge about HIV and how it influences the perceived stigma towards HIV-positive people. Specifically, we evaluated the association between socio-demographic variables and the level of knowledge regarding transmission, high-risk behaviors and prevention with respect to HIV, and the association between such variables and the perceived stigma towards HIV-positive individuals. We hypothesized that knowledge about HIV would be negatively correlated with participants’ age and with the perceived stigma towards HIV-positive people.

Methods

5256 individuals took part in the study, 54 of whom reported being HIV-positive. Participants were given a questionnaire aimed at gathering socio-demographic information, at investigating knowledge on the topic of HIV, and at assessing the level of stigma they perceived towards HIV-positive individuals.

Results

Participants answered correctly to an average of 86.4% of the answers, but the percentage was lower for seronegative respondents (82.6%) compared to seropositive ones (90.2%). Significant but weak positive correlations were observed between knowledge regarding HIV, on one side, and, on the other, participant’s age and perceived stigma. A higher level of knowledge about HIV was associated with a higher education and with the main source of information on the matter, with those relying mostly on the media being the least informed. Moreover, condom use tends to decrease with age. As regards HIV-positive respondents, the younger their age the more they felt that their serostatus negatively impacted their self-image.

Conclusions

Our study highlights that, although our sample showed a good overall knowledge about HIV, several areas resulted lacking and should be the target of future sensibilization campaigns. Perceived stigma resulted weakly correlated with the variables we considered, but future research should aim at gaining a deeper understanding of the factors that influence it.

Conflicts of Interest

The authors declare no conflict of interest.
(62) TUNNELING IN A CASE OF SEVERE CAVERNOUS FIBROSIS AFTER PENILE IMPLANT INFECTION
Authors: Dr. Maurizio D'Anna , Josep Torremadé , Dr. Meritxell Costa , Dr. Roger Matheu , Lluis Peri , Prof. Antonio Alcaraz
Published: July 2023

Objectives

Penile implant can be a challenging procedure when cavernosal fibrosis is encountered. In some cases, a second incision and more aggressive maneuvers may be necessary, such as fibrotic tissue ressection, widening of the corporotomies, and grafting in order to close the cavernous bodies. Tunneling is a less invasive technique that allows the development of a space inside the cavernous body to implant the prosthesis.

Methods

We present a case of a 36-year-old patient who underwent suspensory ligament section and, later on, an implant of a two-piece inflatable penile prosthesis. He presented to our hospital a month later, with sepsis and a penoscrotal abscess. After urgent removal of the prosthesis and skin debridement, the patient developed a urethrocutaneous fistula that was subsequently repaired. A physical examination was performed, fibrosis didn’t allow penile stretching. Patient was scheduled for a three-piece inflantable penile prostesis implant.

Results

In this video we show a step-wise management of a patient with cavernosal fibrosis. After development of a space with Metzembaum scissors, tunneling is performed with Mooreville Uramix dilators and Rosselló cavernotomes. This made possible the implantation of a Titan Touch narrow-base penile prosthesis.

Conclusions

Tunneling of the cavernosal bodies is a useful technique in cases with extensive cavernosal fibrosis due to previous infection.

Conflicts of Interest

No conflict of interest.
(277) A CASE OF PENILE-SCROTAL RECONSTRUCTION DUE TO MALE GENITAL LYMPHOEDEMA
Authors: Matthew Megson , Prof. David Ralph
Published: July 2023

Objectives

This is a case of scrotal lymphoedema in a 36 year old gentleman who had had 3 years of recurrent infections. Due to the extent of the disease he required an excision of the lymphoedematous tissue and a scrotoplasty to reconstruct his scrotum from unaffected skin.

Methods

This is a video demonstrating the steps of the excision of the lymphoedematous tissue and subsequent reconstructive. Steps of the procedure start with marking of the lymphoedematous tissue. The surgeon the dissects down the isolate the cords and delivers the testes. The penile shaft can then be isolated and all lymphoedematous tissue excised. With the important structures now isolated, the scrotal lymphoedematous tissue can be removed. Care must be taken to keep the unaffected skin on the lateral aspects of the wounds, as these have a different lymphatic drainage and are therefore not involved in the pathology. This creates an ideal tissue for reconstruction as this allows primary closure of the neo-scrotum. The lymphoedematous tissue tends to be extremely vascular with large feeding vessels, therefore care much be taken with haemostasis. Due to the lymphoedematous tissue extending into the patients perineum he was then placed into lithotomy to allow better access to this area. Care was taken to avoid injury to the anus and rectum. Prior to the close of the neo-scrotum an Orchidopexy was performed to stop testicular retraction. The lateral skin was then closed to create a neo-scrotum over drains.

Results

The video shows a typical operation for male genital lymphoedema and the usual end results. The patient is happy with his final result. The histology showed an anogenital granulomatosis lymphoedema.

Conclusions

A variety of treatment options for anogenital granulomatosis exist though if left to become severe then surgery is required before any of these medications would improve future outcomes.

Conflicts of Interest

No conflict of interest to declare.
(128) EVALUATION OF DONOR-SITE MORBIDITY AFTER RADIAL FOREARM FLAP ELEVATION FOR TOTAL PHALLIC RECONSTRUCTION IN TRANSGENDER MEN
Authors: Marco Falcone , Dr. Mirko Preto , Dr. Davide Ciclamini , Dr. Federica Peretti , Dr. Lorenzo Cirigliano , Dr. Ilaria Ferro , Dr. Natalia Plamadeala , Dr. Carlo Ceruti , Prof. Paolo Gontero
Published: July 2023

Objectives

Radial artery forearm free-flap (RAFFF) phalloplasty is the main technique used to total phallic construction (TPC) in transgender men. Donor-site morbidity has been rarely investigated. The study aims to evaluate the surgical and functional outcomes of donor site reconstruction.

Methods

It is a retrospective analysis of TPC with RAFFF performed from 2016 to 2022. Were considered as outcome measures: duration of the procedure, hospital stay, size of the donor-site defect, and postoperative complication rate. Validated tools and questionnaires used for functional outcomes evaluation were: Vancouver and POSAS scale, Scar Pinch Test, and aROM. Patient-reported outcomes were inquired using a 3 items ad-hoc created questionnaire. A subanalysis was made according to the donor site reconstruction technique: Group A a full-thickness skin graft (FTSG); Group B a single-layer dermal matrix with split-thickness skin (STSG) graft.

Results

Group A included 18 (53%) patients, whereas group B 16 (47%) patients. Mean follow-up was 24 months (IQR 11-40). The median donor-site defect was 302 cc (IQR 306-323, p=0.21). Early postoperative complications were described in 23.5% of cases. Mean graft take was 91%. A complete graft take was detected in 58.9% of the patients, with a significant advantage for group B (93.8%) respect to group A (27.8%) (p= 0.0001). In Group B a significantly shorter operative time (310min vs 447min p= 0.0001) and a reduced median hospital stay (8 days vs 10 days p= 0.001) were detect. Overall 80% of patients were satisfied with the appearance of the arm, and 92% with the post-surgery functionality. The analysis reveals that Group B reached a significantly higher satisfaction rate for arm appearance compared to group A (94% vs 66% p = 0.048).

Conclusions

FTSG or single layer dermal matrix with STSG for donor-site reconstruction after RAFFF provides satisfactory surgical, functional and aesthetic outcomes.

Conflicts of Interest

None to declare.