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Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): PREFER Introduction With the increased prevalence of chronic diseases, non-healing wounds place a significant burden on the health system, with a prevalence of 2-5%, similar to the one of heart failure. They are persistent full-thickness skin lesions that affect patients suffering from vascular disorders, such as diabetes and peripheral artery disease. Skin implants and substitutes are currently applied to promote the closure of non-healing wounds. However, both approaches are poorly effective because of lack of appropriate vascularization. Purpose To promote the neo-vascularization of non-healing wounds, we use Stromal Vascular Fraction (SVF) as innovative therapeutic opportunity for wound treatment. Here, we aim to 1) characterize and demonstrate the pro-angiogenic role of SVF cells and 2) provide pre-clinical evidence of the therapeutic efficacy of the human SVF in promoting the neo-vascularization in a new mouse model of ischemic, non-healing wound. Methods To assess capacity of SVF-derived cells to improve wound revascularization, we created a new model of non-healing wound generated by wounding an ischemic limb in mice. Human and mouse SVF was purified from adipose tissue and seeded on a clinical-grade skin substitute prior to its implantation on the ischemic wound of a recipient animal. The transplantation of human SVF into NSG immunodeficient mice was verified using species-specific antibodies, while the use of genetically modified mice allowed us to trace the fate of both endothelial and non-endothelial cells upon their transplantation into syngeneic recipient animals. The function of SVF-induced vessels was assessed by systemic injection of biotinylated lectin and by Single Photon Emission Tomography (SPECT) of the treated limb. Results At day 7 the implanted mouse SVF gives rise to a widespread vascular network composed by arteries, capillaries, veins, as well as lymphatic vessels. Similarly, human SVF-derived endothelial cells formed hybrid human-mouse vessels that were stabilized by perivascular cells. At both histological and functional analysis, these vessels were connected with the host circulatory system and determined a 2-fold increase in tissue perfusion. The comparison of the activity of human SVF from different donors allowed us to disclose its dual mechanisms of action. Conclusions Here we demonstrated the efficacy of the SVF in promoting neo-vascularization of a skin substitute in a mouse model of ischemic, non-healing wounds. Its therapeutic efficacy relies on dual mechanisms of action. On the one hand, SVF-derived ECs engraft and expand, directly forming new vascular units that colonize the scaffold and extend into surrounding tissues. On the other hand, the mesenchymal progenitors stimulate the expansion of the host vasculature, which extends into the scaffold, with the eventual appearance of donor-host hybrid vessels. Collectively, these data support the use of human SVF as a powerful cell therapy to treat non-healing wounds. Open in new tab Download slide SVF promotes neo-vascularization [ABSTRACT FROM AUTHOR]

Background: In the Venetian Tumour Registry a substantial quota of cases (55%) is accepted using an algorithm that automatically evaluates diagnostic evidence: this study aims at assessing the reliability of the information produced in this way. Methods: A reabstraction study was conducted, which put a stratified sample of 1539 automatically accepted cases through a double-blind manual revision. Results: A significantly higher proportion of prevalent cases were found among breast, prostate and larynx cancer cases without microscopic confirmation, while there is a clear strong inverse relationship between the number of concordant diagnostic sources and the proportions of discordant diagnoses: cases based only on a single cytology record are particularly unreliable. A small number of multiple cancers are not detected because of one of the rules applied. Conclusion: The overall proportion of incorrect decisions is not high and similar to those reported by other registries, but errors are correlated to the diagnostic evidence pattern. As a further check, we decided to revise clinical cases for the three sites mentioned manually, in order to reduce the numbers proportion of both prevalent cases, and all cytology-based diagnoses, so as to reduce the number of 'false positives'. Coverage of hospital discharge source has been extended in order to decrease the proportion of cases based only on pathology records. [ABSTRACT FROM AUTHOR]

Abstract Background It has been well established that prolactin (PRL) signals through the long form of its receptor (PRL-RL) and activates the Jak/Stat pathway for transcription of PRL target genes. However, signaling pathways mediated through the short PRL-R isoform (PRL-RS) remains controversial. Our recent finding that PRL signaling through PRL-RS represses two transcription factors critical for follicular development lead us to examine other putative PRL/PRL-RS target transcription factors in the decidua and ovary, two well-known target tissues of PRL action in reproduction. Methods In this investigation we used mice expressing PRL-RS on a PRL-R knockout background and a combo protein/DNA array to study the transcription factors regulated by PRL through PRL-RS only. Results We show that PRL activation of the PRL-RS receptor either stimulates or inhibits the DNA binding activity of a substantial number of transcription factors in the decidua as well as ovary. We found few transcription factors to be similarly regulated in both tissues, while most transcription factors are oppositely regulated by PRL in the decidua and ovary. In addition, some transcription factors are regulated by PRL only in the ovary or only in the decidua. Several of these transcription factors are involved in physiological pathways known to be regulated by PRL while others are novel. Conclusion Our results clearly indicate that PRL does signal through PRL-RS in the decidua as well as the ovary, independently of PRL-RL, and activates/represses transcription factors in a tissue specific manner. This is the first report showing PRL/PRL-RS regulation of specific transcription factors. Many of these transcription factors were not previously known to be PRL targets, suggesting novel physiological roles for this hormone.

Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over 6 months and the average litter size of SIK2GCKD mice were similar to controls, although in SIK3GCKD mice were significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice resulted in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. These data point to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Faecal immunochemical test (FIT)-based screening is effective in reducing colorectal cancer (CRC) incidence, but its sensitivity for proximal lesions remains low., Objectives: We compared age-adjusted CRC surgical resection rates across anatomic sites (proximal colon, distal colon, rectum), age groups and sex over 20 years in a large Italian population. We particularly focused on changes in trends following FIT-screening implementation in the target population (50-69 years)., Design: This retrospective study analysed data from the Veneto Region's administrative Hospital Discharge Dataset, involving over 54 000 patients aged 40-89 (43.4% female) who underwent CRC surgery between 2002 and 2021., Results: Overall, surgery rates increased until 2007 (annual percentage changes: 2.5% in males, 2.9% in females) and then declined (-4.2% in males, -3.4% in females). This decline was steeper for distal and rectal cancers compared with proximal cancer, suggesting a shift towards more right-sided CRC surgery.In males, the prescreening increase in proximal surgery was reversed after screening implementation (slope change: -6%) while the prescreening decline accelerated for distal (-4%) and rectal (-3%) surgeries. In females, stable prescreening trends shifted downward for all sites (-5% for proximal, -8% for distal and -7% for rectal surgery). However, the change in trends between prescreening and postscreening periods was not different across anatomic sites for either sex (all slope change differences in pairwise comparisons were not statistically significant)., Conclusion: The shift towards proximal surgery may not be entirely due to the FIT's low sensitivity but may reflect an underlying upward trend in proximal cancers independent of screening., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Skin-sparing mastectomy (SSM) entails complete removal of the breast tissue and the nipple and areola complex (NAC) with preservation of as much of the overlying skin as possible. The preservation of the natural skin envelope during SSM improves the aesthetic outcome of immediate breast reconstruction, but the lack of NAC determines that the reconstructed breast remains anatomically incomplete with not always satisfactory final results. For this purpose, the aim of the present study was to investigate and evaluate the impact of nipple reconstruction after skin sparing and skin reducing mastectomy on the patients' perception and intimate life., Materials and Method: This was a comparative single-center prospective study that involved 42 patients underwent NAC reconstruction after SSM. A pre- and postoperative quality-of-life and psychological questionnaires Breast-Q questionnaire (Breast Conserving therapy module) were given to all the patients before the surgery and 6 months after. The statistical analysis with chi-square test was performed., Results: After 6 months a prevalence of patients reported to be very satisfied in regard to shape, appearance, naturalness, projection, position and symmetry. The study shows an overall improvement in all the psychological items analyzed with statistically significant difference regarding: "patient's satisfaction," "self-confidence," "appearance of the breast.", Conclusion: The authors believe that the NAC reconstruction has useful functional and aesthetic results particularly appreciated by patients who feel demoralized after breast demolition surgery., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: We investigated whether there are differences in cancer incidence by geographical area of origin in North-eastern Italy., Methods: We selected all incident cases recorded in the Veneto Tumour Registry in the period 2015-2019. Subjects were classified, based on the country of birth, in six geographical areas of origin (Italy, Highly Developed Countries-HDC, Eastern Europe, Asia, Africa, South-central America). Age-standardized incidence rates and incidence rate ratio (IRR) were calculated, for all cancer sites and for colorectal, liver, breast and cervical cancer separately., Results: We recorded 159,486 all-site cancer cases; 5.2% cases occurred in subjects born outside Italy, the majority from High Migratory Pressure Countries (HMPC) (74.3%). Incidence rates were significantly lower in subjects born in HMPC in both sexes. Immigrants, in particular born in Asia and Africa, showed lower rates of all site cancer incidence. The lowest IRR for colorectal cancer was observed in males from South-Central America (IRR 0.19, 95%CI 0.09-0.44) and in females from Asia (IRR 0.32, 95%CI 0.18-0.70). The IRR of breast cancer appeared significantly lower than Italian natives in all female populations, except for those coming from HDC. Females from Eastern Europe showed a higher IRR for cervical cancer (IRR 2.02, 95%CI 1.57-2.61)., Conclusion: Cancer incidence was found lower in subjects born outside Italy, with differences in incidence patterns depending on geographical area of origin and the cancer type in question. Further studies, focused on the country of birth of the immigrant population, would help to identify specific risk factors influencing cancer incidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ferroni, Guzzinati, Andreotti, Baracco, Baracco, Bovo, Carpin, Dal Cin, Greco, Fiore, Memo, Monetti, Rizzato, Stocco, Stocco, Zamberlan and Zorzi.)

Background: The last phase of folliculogenesis is driven by follicle-stimulating hormone (FSH) and locally produced insulin-like growth factors (IGFs), both essential for forming preovulatory follicles., Methods: This review discusses the molecular crosstalk of the FSH and IGF signaling pathways in regulating follicular granulosa cells (GCs) during the antral-to-preovulatory phase., Main Findings: IGFs were considered co-gonadotropins since they amplify FSH actions in GCs. However, this view is not compatible with data showing that FSH requires IGFs to stimulate GCs, that FSH renders GCs sensitive to IGFs, and that FSH signaling interacts with factors downstream of AKT to stimulate GCs. New evidence suggests that FSH and IGF signaling pathways intersect at several levels to regulate gene expression and GC function., Conclusion: FSH and locally produced IGFs form a positive feedback loop essential for preovulatory follicle formation in all species. Understanding the mechanisms by which FSH and IGFs interact to control GC function will help design new interventions to optimize follicle maturation, perfect treatment of ovulatory defects, improve in vitro fertilization, and develop new contraceptive approaches., Competing Interests: The authors declare no conflict of interest could be perceived as prejudicing the impartiality of the research reported., (© 2024 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Ovulation is the pinnacle of folliculogenesis, a process that requires an interplay between the oocyte, the granulosa cells, and the theca cells (TCs). TCs are the only source of ovarian androgens, which play a vital role in female fertility. However, abnormally elevated androgen levels reduce fertility. Therefore, uncovering novel mechanisms regulating androgen synthesis in TCs is of great significance. We have shown that salt-inducible kinases (SIKs) regulate granulosa cell steroidogenesis. Here, we investigated whether SIKs regulate androgen production in TCs. SIK2 and SIK3 were detected in the TCs of mouse ovaries and isolated TCs. Next, TCs in culture were treated with luteinizing hormone (LH) in the presence or absence of a highly specific SIK inhibitor. SIK inhibition enhanced the stimulatory effect of LH on steroidogenic gene expression and androgen production in a concentration-dependent manner. SIK inhibition alone stimulated the expression of steroidogenic genes and increased androgen production. Activation of adenylyl cyclase with forskolin or emulation of increased intracellular cyclic AMP levels stimulated steroidogenesis, an effect that was enhanced by the inhibition of SIK activity. The stimulatory effect of downstream targets of cyclic AMP was also significantly augmented by SIK inhibition, suggesting that SIKs control targets downstream cyclic AMP. Finally, it is shown that SIK2 knockout mice have higher circulating testosterone than controls. This evidence shows that TCs express SIKs and reveal novel roles for SIKs in the regulation of TC function and androgen production. This information could contribute to uncovering therapeutic targets to treat hyperandrogenic diseases., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Breast-conserving surgery (BCS) is a valid method for the reconstruction of partial breast defects, however, there is a great variety of final aesthetic outcomes depending on the location of the tumor in the breast and also on the initial breast volume and the degree of ptosis. Specifically, defects affecting the upper inner/central quadrant represent a reconstructive challenge with not always satisfactory final results. For this purpose, the authors investigated the use of the central mound technique in breast-conserving surgery. The aim of the study was to apply the central mound as an oncoplastic technique and assess the satisfaction rate of the patients., Materials and Methods: This was a retrospective study that involved 40 patients (80 breast) underwent breast conserving surgery and contextual bilateral breast remodeling with central mound technique. A pre- and postoperative Breast-Q questionnaire (breast conserving therapy module) was given to all the patients before the surgery, 3 months and 9 months after. The statistical analysis with chi-square test was performed., Results: After 9 months the author found a major increase of all BREAST-Q parameters; the most valuable increments concerned the "Satisfaction with breast" and "Psychosocial well-being." None of the patients experienced a decreased in the quality of life related to the surgical procedure., Conclusion: The authors believe that this technique has useful functional and aesthetic results particularly appreciated by patients with upper pole lesion who have a slightly or moderately breast ptosis and a small cup size., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nonhealing wounds place a significant burden on both quality of life of affected patients and health systems. Skin substitutes are applied to promote the closure of nonhealing wounds, although their efficacy is limited by inadequate vascularization. The stromal vascular fraction (SVF) from the adipose tissue is a promising therapy to overcome this limitation. Despite a few successful clinical trials, its incorporation in the clinical routine has been hampered by their inconsistent results. All these studies concluded by warranting pre-clinical work aimed at both characterizing the cell types composing the SVF and shedding light on their mechanism of action. Here, we established a model of nonhealing wound, in which we applied the SVF in combination with a clinical-grade skin substitute. We purified the SVF cells from transgenic animals to trace their fate after transplantation and observed that it gave rise to a mature vascular network composed of arteries, capillaries, veins, as well as lymphatics, structurally and functionally connected with the host circulation. Then we moved to a human-in-mouse model and confirmed that SVF-derived endothelial cells formed hybrid human-mouse vessels, that were stabilized by perivascular cells. Mechanistically, SVF-derived endothelial cells engrafted and expanded, directly contributing to the formation of new vessels, while a population of fibro-adipogenic progenitors stimulated the expansion of the host vasculature in a paracrine manner. These data have important clinical implications, as they provide a steppingstone toward the reproducible and effective adoption of the SVF as a standard care for nonhealing wounds., (© 2023. The Author(s).)

Introduction: This study assesses the risk of infection and clinical outcomes in a large consecutive population of cancer and non-cancer patients tested for SARS-CoV-2 status., Methods: Study patients underwent SARS-CoV-2 molecular-testing between 22 February 2020 and 31 July 2020, and were found infected (CoV2+ ve ) or uninfected. History of malignancy was obtained from regional population-based cancer registries. Cancer-patients were distinguished by time between cancer diagnosis and SARS-CoV-2 testing (<12/⩾12 months). Comorbidities, hospitalization, and death at 15 September 2020 were retrieved from regional population-based databases. The impact of cancer history on SARS-CoV-2 infection and clinical outcomes was calculated by fitting a multivariable logistic regression model, adjusting for sex, age, and comorbidities., Results: Among 552,362 individuals tested for SARS-CoV-2, 55,206 (10.0%) were cancer-patients and 22,564 (4.1%) tested CoV2+ ve . Irrespective of time since cancer diagnosis, SARS-CoV-2 infection was significantly lower among cancer patients (1,787; 3.2%) than non-cancer individuals (20,777; 4.2% - Odds Ratio (OR)=0.60; 0.57-0.63). CoV2+ ve cancer-patients were older than non-cancer individuals (median age: 77 versus 57 years; p<0.0001), were more frequently men and with comorbidities. Hospitalizations (39.9% versus 22.5%; OR=1.61; 1.44-1.80) and deaths (24.3% versus 9.7%; OR=1.51; 1.32-1.72) were more frequent in cancer-patients. CoV2+ ve cancer-patients were at higher risk of death (lung OR=2.90; 1.58-5.24, blood OR=2.73; 1.88-3.93, breast OR=1.77; 1.32-2.35)., Conclusions: The risks of hospitalization and death are significantly higher in CoV2+ ve individuals with past or present cancer (particularly malignancies of the lung, hematologic or breast) than in those with no history of cancer.

Preovulatory granulosa cell (GC) differentiation is essential for the maturation and release of oocytes from the ovary. We have previously demonstrated that follicle-stimulating hormone (FSH) and insulin-like growth factors (IGFs) closely interact to control GC function. Similarly, we showed that GATA4 mediates FSH actions and it is required for preovulatory follicle formation. This report aimed to determine in vivo the effect of FSH on GATA4 phosphorylation and to investigate whether FSH and IGF1 interact to regulate GATA4 activity. In rat ovaries, treatment with equine chorionic gonadotropin (eCG) increased the phosphorylation of GATA4, which was confined to the nucleus of GCs. Using primary rat GCs, we observed that GATA4 phosphorylation at serine 105 increases the transcriptional activity of this transcription factor. Like FSH, IGF1 stimulated GATA4 phosphorylation at serine 105. Interestingly, GATA4 phosphorylation was significantly higher in cells cotreated with FSH and IGF1 when compared to FSH or IGF1 alone, suggesting that IGF1 augments the effects of FSH on GATA4. It was also found that the enhancing effect of IGF1 requires AKT activity and is mimicked by the inhibition of glycogen synthase kinase-3 β (GSK3β), suggesting that AKT inhibition of GSK3β may play a role in the regulation of GATA4 phosphorylation. The data support an important role of the IGF1/AKT/GSK3β signaling pathway in the regulation of GATA4 transcriptional activity and provide new insights into the mechanisms by which FSH and IGF1 regulate GC differentiation. Our findings suggest that GATA4 transcriptional activation may, at least partially, mediate AKT actions in GCs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Population-based cancer registration methods are subject to internationally-established rules. To ensure efficient and effective case recording, population-based cancer registries widely adopt digital processing (DP) methods. At the Veneto Tumor Registry (RTV), about 50% of all digitally-identified (putative) cases of cancer are further profiled by means of registrars' assessments (RAs). Taking these RAs for reference, the present study examines how well the registry's DP performs. A series of 1,801 (putative) incident and prevalent cancers identified using DP methods were randomly assigned to two experienced registrars (blinded to the DP output), who independently re-assessed every case. This study focuses on the concordance between the DP output and the RAs as concerns cancer status (incident versus prevalent), topography, and morphology. The RAs confirmed the cancer status emerging from DP for 1,266/1,317 incident cancers (positive predictive value [PPV] = 96.1%) and 460/472 prevalent cancers (PPV = 97.5%). This level of concordance ranks as "optimal", with a Cohen's K value of 0.91. The overall prevalence of false-positive cancer cases identified by DP was 2.9%, and was affected by the number of digital variables available. DP and the RAs were consistent in identifying cancer topography in 88.7% of cases; differences concerned different sites within the same anatomo-functional district (according to the International Agency for Research on Cancer [IARC]) in 9.6% of cases. In short, using DP for cancer case registration suffers from only trivial inconsistencies. The efficiency and reliability of digital cancer registration is influenced by the availability of good-quality clinical information, and the regular interdisciplinary monitoring of a registry's DP performance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Guzzinati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The optimal development of preovulatory follicles needs follicle-stimulating hormone (FSH). Recent findings revealed that salt-inducible kinases (SIKs) inhibit FSH actions in humans and rodents. This report seeks to increase our understanding of the molecular mechanisms controlled by SIKs that participate in the inhibition of FSH actions in primary rat granulosa cells (GCs). The results showed that FSH causes a transient induction of Sik1 mRNA. In contrast, SIK inhibition had no effects on FSH receptor expression. Next, we determined whether SIK inhibition enhances the effect of several sequential direct activators of the FSH signaling pathway. The findings revealed that SIK inhibition stimulates the induction of steroidogenic genes by forskolin, cAMP, protein kinase A (PKA), and cAMP-response element-binding protein (CREB). Strikingly, FSH stimulation of CREB and AKT phosphorylation was not affected by SIK inhibition. Therefore, we analyzed the expression and activation of putative CREB cofactors and demonstrated that GCs express CREB-regulated transcriptional coactivators (CRTC2) and that FSH treatment and SIK inhibition increase the nuclear expression of this factor. We concluded that SIKs target the FSH pathway by affecting factors located between cAMP/PKA and CREB and propose that SIKs control the activity of CRTC2 in ovarian GCs. The findings demonstrate for the first time that SIKs blunt the response of GCs to FSH, cAMP, PKA, and CREB, providing further evidence for a crucial role for SIKs in regulating ovarian function and female fertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Armouti, Rodriguez-Esquivel and Stocco.)

Background: Lidocaine hydrochloride is frequently used for management of painful wounds. This prospective, multicentre study examined the effects of 5% lidocaine cream on wound pain relief., Material and Methods: The study included 78 patients with painful wounds treated with 5% Lidocaine cream for two weeks in two Italian Hospitals. Patients' perception of pain was recorded by, using the 5-point Visual Rate Scale and the 11-point Numerical Pain Rating Scale. All medications and adverse events were evaluated in a daily diary. The primary outcome of the study was establishing the wound pain relief based on the results of 5-VRS and pain intensity based on the 11-NPRS testing from baseline to the end of treatment. Clinical aspects and adverse events were also collected., Results: Seventy-eight patients had a median age of 67.5 years (range 18-96 years). 62.8% were women. The wounds included traumatic wounds (n = 39), venous ulcers (n = 25), post-surgical wounds (n = 6) pyoderma gangrenosum (n = 6), vasculitis (n = 1) and pressure ulcer (n = 1). The intensity of pain significantly decreased from the baseline level established at the beginning of treatment (mean score 6.7 - 1.90) - to the level at end of treatment (3.0 - 2.23-; p < 0.0001). 9 patients prematurely stopped the treatment for healing (n = 4), wound improvement (n = 2) and adverse events related to the treatment. (n = 3). 13 patients presented a total of 25 adverse events, 4 of them were related to the treatment., Conclusion: The treatment of painful wounds with 5% Lidocaine Cream for 14 days resulted in reduced pain intensity, and showed high safety and tolerability.

Background: An early, comprehensive rhythm-control therapy is needed in order to treat atrial fibrillation (AF) effectively and to improve ablation outcomes., Methods: A total of 153 consecutive patients from the CHARISMA registry undergoing AF ablation at eight centers were included. Patients with de novo PVI were classified as having undergone early treatment (ET) if the procedure was performed within 6 months after the first AF episode, and as having undergone delayed treatment (DT) if ablation was performed over 6 months after the first AF episode., Results: One-hundred fifty-three patients were enrolled (69.9% male, 59 ± 10 years, 61.4% paroxysmal AF, 38.6% persistent AF). The time from the first AF episode to the ablation procedure was 1034 ± 1483 days. The ET group comprised 36 patients (25.3%), the DT group 60 (39.2%) and Redo cases were 57 (37.3%). During a mean follow-up of 366 ± 130 days, 18 patients (11.8%) suffered an AF/AT recurrence. More DT patients than ET patients suffered recurrences (15.7% vs. 2.2%, p = 0.0452) and the time to AT/AF recurrence was shorter in the group of patients who received an ablation treatment after 6 months (HR = 6.19, 95% CI: 1.7 to 21.9; p = 0.0474). On multivariate Cox analysis, only hypertension (HR = 4.86, 95% CI: 1.6 to 14.98, p = 0.0062) was independently associated with recurrences. Beyond the hypertension risk factor, ET was associated with a low risk of recurrence; recurrence rate ranged from 0% (ET patients without hypertension) to 25.0% (DT patients with hypertension)., Conclusions: An early rhythm-control ablation therapy in the absence of common risk factors was associated with the lowest rate of recurrences., (© 2021 Wiley Periodicals LLC.)

The loss of skin integrity has always represented a major challenge for clinicians dealing with dermal defects, such as ulcers (diabetic, vascular and chronic), postoncologic resections (i.e., radical vulvectomy) or dermatologic disorders. The introduction in recent decades of acellular dermal matrices (ADMs) supporting the repair and restoration of skin functionality represented a significant step toward achieving clean wound repair before performing skin grafts. Hard-to-heal ulcers generally depend on local ischemia and nonadequate vascularization. In this context, one possible innovative approach could be the prevascularization of matrices with vessel-forming cells (inosculation). This paper presents a comparative analysis of the most widely used dermal templates, i.e., Integra ® Bilayer Matrix Wound Dressing, PELNAC ® , PriMatrix ® Dermal Repair Scaffold, Endoform ® Natural Dermal Template, and Myriad Matrix ® , testing their ability to be colonized by human adult dermal microvascular endothelial cells (ADMECs) and to induce and support angiogenesis in vitro and in vivo. By in vitro studies, we demonstrated that Integra ® and PELNAC ® possess superior pro-adhesive and pro-angiogenetic properties. Animal models allowed us to demonstrate the ability of preseeded ADMECs on Integra ® to promote the engraftment, integration and vascularization of ADMs at the site of application.

Background: The impact of intrauterine growth restriction (IUGR) on lung function in very preterm children is largely unknown as current evidence is mainly based on studies in children born small for gestational age but not necessarily with IUGR., Methods: Spirometry, transfer factor of the lung for carbon monoxide (TLco), and lung clearance index (LCI) were cross-sectionally evaluated at 8.0-15.0 years of age in children born <32 weeks of gestation with IUGR (n = 28) and without IUGR (n = 67). Controls born at term (n = 67) were also included., Results: Very preterm children with IUGR had lower mean forced expired volume in the first second (FEV 1 ) z-score than those with normal fetal growth (∆ -0.66, 95% confidence interval (CI) -1.12, -0.19), but not significant differences in LCI (∆ +0.24, 95% CI -0.09, 0.56) and TLco z-score (∆ -0.11, 95% CI -0.44, 0.23). The frequency of bronchopulmonary dysplasia (BPD) in the two groups was, respectively, 43% and 10% (P = 0.003). IUGR was negatively associated with FEV 1 (B = -0.66; P = 0.004), but the association lost significance (P = 0.05) when adjusting for BPD., Conclusions: IUGR has an impact on conducting airways function of very preterm children at school age, with part of this effect being mediated by BPD. Ventilation inhomogeneity and diffusing capacity, instead, were not affected., Impact: IUGR does not necessarily imply a low birthweight for gestational age (and vice versa). While a low birthweight is associated with worse respiratory outcomes, the impact of IUGR on lung function in premature children is largely unknown. IUGR affects conducting airways function in school-age children born <32 weeks with IUGR, but not ventilation inhomogeneity and diffusing capacity. The impact of IUGR on FEV 1 seems mainly related to the higher risk of BPD in this group., (© 2020. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Several different flaps can reconstruct intraoral defects or lower limb deficits after free fibula osteo-cutaneous flap harvesting for jaw reconstructions. However, commonly used options may not be available for various reasons and can be associated with significant morbidity. We hypothesized that flaps supplied by the superficial peroneal nerve accessory artery (SPNAA) could be a viable alternative reconstructive option., Methods: We describe the SPNAA's anatomy using 20 human cadaveric leg dissections and report eight cases involving SPNAA-based perforator flap reconstructions (six propeller flaps and two free flaps) in a retrospective case series. Patient-specific baseline variables and intraoperative and postoperative outcomes are described., Results: Cadaveric dissection suggests that the location of the SPNAA is reliable but its origin varies, with 40% (N = 8) of SPNAAs being of type I origin, 20% type II (N = 4), and 40% (N = 8) type III in our series. All reconstructions were successful. No intraoperative complications occurred during propeller or free-flap reconstructions. No flap failures occurred. One propeller reconstruction showed distal superficial skin necrosis and one donor site wound dehisced; both were successfully managed conservatively. No other short-term or long-term complications occurred., Conclusions: Flaps based on SPNAA perforators appear effective, reliable, and safe reconstructive methods for covering fibula osteocutaneous donor site defects and for intraoral reconstructions. Controlled trials are required to compare its effectiveness and safety with other reconstructive methods., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Secreted frizzled-related protein-4 (SFRP4) belongs to a family of soluble ovarian-expressed proteins that participate in female reproduction, particularly in rodents. In humans, SFRP4 is highly expressed in cumulus cells (CCs). However, the mechanisms that stimulate SFRP4 in CCs have not been examined. We hypothesise that oocyte-secreted factors such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are involved in the regulation of SFRP4. Human CCs were collected from patients undergoing fertility treatments and treated with GDF9 or BMP15 or their combination in the presence of FSH or vehicle. FSH treatment significantly decreased SFRP4 mRNA levels when compared with nontreated cells. However, SFRP4 mRNA levels were increased significantly by GDF9 plus BMP15 in a concentration-dependent manner in the presence or absence of FSH. The combination of GDF9 plus BMP15 also increased SFRP4 protein levels and decreased the activity of the β-catenin/T cell factor-responsive promoter significantly. GDF9 plus BMP15 inhibited steroidogenic acute regulatory protein and LH/hCG receptor stimulation by FSH, while treatment with SFRP4 blocked the stimulatory effect of FSH on these genes. The evidence demonstrates that GDF9 and BMP15 act in coordination to stimulate SFRP4 expression and suggests that SFRP4 mediates the anti-luteinising effects of the oocyte in human CCs., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Surgical site infection in implant-based breast reconstruction is a complication with variable incidence reported in the literature. Due to potential loss of implant and reconstruction, it can have a strong psychological impact on patients. Background and objectives: This study aimed primarily at analyzing the current status of the surgical site infection (SSI), (type, time of onset, clinical presentation, pathogens and management) in patients who underwent implant-based breast reconstruction at our Breast Unit. Secondarily, we wanted to establish whether introduction of a new, updated evidence-based protocol for infection prevention can reduce SSI in implant-based breast reconstruction. Materials and Methods: A single-center retrospective study was performed primarily to evaluate the incidence and features of SSI after implant-based breast reconstruction from 2007 to 2020. In June 2020, a protocol for prevention of SSI in implant-based breast reconstruction was introduced in clinical practice. Secondarily, a data analysis of all patients who underwent implant-based breast reconstruction in compliance with this protocol was performed after preliminarily assessing its efficacy. Results: 756 women were evaluated after mastectomy and implant-based breast reconstruction for breast cancer. A total of 26 surgical site infections were detected. The annual incidence of SSI decreased over time (range 0-11.76%). Data relating to infections' features, involved pathogens and implemented treatments were obtained. Since the introduction of the protocol, 22 patients have been evaluated, for a total of 29 implants. No early infections occurred. Conclusions: Surgical site infection rates at our Breast Unit are comparable to those reported in the literature. The SSI rates have shown a decreasing trend over the years. No SSI has occurred since the introduction of the prevention protocol for surgical site infection in June 2020.

Despite the considerable number of studies investigating the Mediterranean diet in prostate cancer (PCa) etiology, very few focused on cancer survival. We assessed the pre-diagnostic diet and physical activity in a cohort of 777 men with PCa diagnosed between 1995 and 2002 in north-eastern Italy; adherence to the Mediterranean diet was evaluated through the Mediterranean Diet Score (MDS). Hazard ratios (HR) of death with confidence intervals (CI) were estimated using the Cox model, adjusting for potential confounders. During 10 years of follow-up, 208 patients (26.8%) died, 75 (9.7%) due to PCa. Patients reporting MDS ≥ 5 showed a higher overall survival than those with MDS < 5 (HR = 0.74; 95% CI: 0.56-0.99). Although high physical activity was not significantly associated with overall survival (HR = 0.79; 95% CI: 0.59-1.07), the HR for all-cause death was the lowest (HR = 0.58; 95% CI: 0.38-0.90) for men reporting MDS ≥ 5 and high physical activity compared to those reporting MDS < 5 and low/moderate physical activity. No association emerged for PCa specific survival. Study findings support the beneficial impact of pre-diagnostic adherence to the Mediterranean diet and physical activity on overall survival; they are mainly driven by risk reduction in non-prostate cancer mortality, which however accounts for about 80% of death in men with PCa.

This study evaluates the use of acellular dermal matrix (ADM) in conjunction with negative pressure wound therapy (NPWT) and delayed split-thickness skin graft (STSG) application as an alternative to free tissue transfer for defect coverage of the penile shaft. Five patients with genital lymphedema and one with penile skin deficiency underwent penile shaft reconstruction with a two-stage surgical procedure. The first procedure aimed to the correction of skin defect and to neodermis regeneration through the use of an ADM (Integra®, Integra Lifesciences Corp., Plainsboro, NJ, USA) and NPWT. The second procedure 3 weeks later aimed to the covering of the skin defect with an unmeshed STSG. Both the Integra and skin graft showed completely taking at 7 days postop. No major complications occurred. At 6 months grafts gained sufficient elasticity to allow the sliding of the epidermis over the dermal layer, similarly the physiological penile shaft skin. Our results suggest that combined therapy might be an alternative to free tissue transfer for defect coverage of the penile shaft, leading to a good esthetic result, an optimal shaft coverage and providing adequate extensibility during erections. For best results we advise that in these cases urologists should collaborate with plastic surgeons., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Adherence to Mediterranean diet has been consistently associated with a reduced mortality in the general population, but evidence for women with breast cancer is scanty., Methods: A cohort of 1453 women with breast cancer diagnosed between 1991 and 1994 in northern Italy was followed-up for vital status for 15 years after diagnosis. The pre-diagnostic habitual diet was assessed through a structured questionnaire and adherence to the Mediterranean diet was evaluated through the Mediterranean Diet Score. Hazard ratios (HR) of death with confidence intervals (CI) were estimated using Cox model, adjusting for potential confounders., Results: Compared to women who scarcely adhere to the Mediterranean diet ( n = 332, 22.8%), those highly adherent ( n = 500, 34.4%) reported higher intakes of carbohydrates, mono-unsaturated and poly-unsaturated fatty acids, vitamins, folate, and carotenoids, and lower intakes of cholesterol and animal proteins. Adherence to the Mediterranean diet was associated with a better prognosis: 15-year overall survival of 63.1% for high and 53.6% for low adherence, respectively ( p = 0.013). HR for all-cause mortality was 0.72 (95% CI: 0.57-0.92) and HR for breast cancer mortality was 0.65 (95% CI: 0.43-0.98) for women 55 years and older. No significant association emerged for breast cancer mortality in the total cohort., Conclusions: Although dietary habits may have changed after breast cancer diagnosis, these findings indicate that women who ate according to the Mediterranean dietary pattern prior to their diagnosis may have greater chance of a favorable prognosis after breast cancer diagnosis compared to those who did not.