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Purpose This study was conducted to evaluate the prevalence of perineal trauma during childbirth and to assess the correlations of the pelvic floor dimensions and fetal head station with obstetric trauma in a prospectively recruited cohort of women. Methods The study included women with a gestational age of at least 37 weeks, who were carrying a single fetus in a cephalic presentation. Transperineal ultrasound (TPU) was performed prior to the onset of labor or labor induction. The purpose was to measure the anteroposterior diameter (APD) of the levator ani muscle (LAM) and the angle of progression, at both rest and maximum Valsalva maneuver. The head-perineum distance was assessed only at rest. Results A total of 296 women were included. Of the 253 women who delivered vaginally, 19% (48/253) experienced no perineal trauma, 18.2% (46/253) received an episiotomy during childbirth, 34.4% (87/253) sustained a first-degree laceration, 25.3% (64/253) had a second-degree laceration, and 3.2% had a third- or fourth-degree laceration (8/253). Women with episiotomy had a significantly shorter median APD under Valsalva than women without perineal trauma. Furthermore, women with LAM coactivation (identified by a negative difference between the APD at Valsalva and the APD at rest) were approximately three times more likely to undergo an operative vaginal delivery and over five times more likely to sustain a third- or fourth-degree tear during childbirth than women who exhibited normal relaxation of the LAM during the Valsalva maneuver. Conclusion TPU may predict the risk of perineal trauma in women with term pregnancy during childbirth.

Summary: In pancreatic ductal adenocarcinomas (PDAC), the KRASG12D-NRF2 axis controls cellular functions such as redox homeostasis and metabolism. Disruption of this axis through suppression of NRF2 leads to profound reprogramming of metabolism. Unbiased transcriptome and metabolome analyses showed that PDAC cells with disrupted KRASG12D-NRF2 signaling (NRF2−/− cells) shift from aerobic glycolysis to metabolic pathways fed by amino acids. Metabolome, RNA-seq and qRT-PCR analyses revealed a blockade of the urea cycle, making NRF2−/− cells dependent on exogenous arginine for survival. Arginine is channeled into anabolic pathways, including the synthesis of phosphocreatine, which generates an energy buffer essential for cell growth. A similar switch was observed in tumor clones that had survived FOLFIRINOX therapy or blockade of KRAS signaling. Inhibition of the creatine pathway with cyclocreatine reduced both ATP and invasion rate in 3D spheroids from NRF2-deficient PDAC cells. Our study provides basis for the rational development of combination therapies for pancreatic cancer.

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3–integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types.

Abstract Background Monochorionic dizygotic twins are a rare condition, mostly related to assisted reproductive technology. This type of twinning is burdened by the same risk of pregnancy complications found in monochorionic monozygotic pregnancies. Case presentation We report a case of spontaneous monochorionic dizygotic twins sharing situs inversus abdominalis and isolated levocardia, with only one twin affected by biliary atresia with splenic malformation syndrome. We also conducted a literature review of the 14 available documented monochorionic dizygotic twin gestations spontaneously conceived. Conclusions It is still unclear how this unusual type of twinning can occur in spontaneous conception. The evidence so far suggest the importance to timely diagnose the chorionicity, in order to adequately manage the typical complications associated with monochorionicity.

Objective: Standard carotid endarterectomy (CEA) is usually performed with patch closure or eversion. However, sometimes a 'modified' carotid artery revascularization (MCAR) technique is required if the lesion is complex, extended and anatomically or technically challenging. MCAR is defined as carotid artery bypass; otherwise, it is the combination of common carotid artery (CCA) primary suture or patch angioplasty, associated with internal carotid artery (ICA) patch closure or eversion. The aim of this study was to evaluate the outcomes of MCAR during complex carotid procedures, comparing them with standard CEA. Methods: A retrospective analysis of asymptomatic patients who underwent CEA during a 16-year period (June 2005 to June 2021) was performed. Patients were divided into three different groups: ECEA (eversion CEA), PCEA (CEA with patch angioplasty) and MCAR. Primary endpoints were relevant neurological complication rate (RNCR), death within 30 days, freedom from ipsilateral stroke, reintervention rates and freedom from carotid artery restenosis. Results: A total of 1,752 patients were included (ECEA: 699; PCEA: 948; MCAR: 105) in the study. Patients treated with MCAR were significantly older and had a higher SVS score for arterial hypertension compared with ECEA and PCEA groups. A long plaque in the CCA was the most common indication for MCAR (40.1%); inadequate distal plaque-end or distal dissection (25.7%) was the second most prevalent indication. Overall perioperative RNCR, defined as minor and major stroke, was 0.7% (ECEA: 0.4%; PCEA: 0.7%; MCAR: 1.9%; p = 0.22), without any significant difference among the three groups. However, patients treated with MCAR had a significantly higher rate of global central neurological complications (defined as transient ischaemic attack, minor stroke and major stroke) than the other cohorts (ECEA: 0.7%; PCEA: 1.2%; MCAR: 3.8%; p = 0.02). One patient (0.05%) died perioperatively of a major cerebral infarction. Long-term follow-up (66.7 ± 43.9) showed a significantly lower rate of freedom from ipsilateral stroke for the MCAR group (96.8%) compared with ECEA and PCEA groups (99.8% and 98.9%, respectively, p = 0.03). Similar reintervention rates (ECEA: 2.7%; PCEA: 3.3%; MCAR: 3.8%; p = 0.74) and freedom from carotid restenosis rates (ECEA: 1.3%; PCEA: 2.6%; MCAR: 1.9%; p = 0.16) were observed. Conclusions: Patients who underwent ICA revascularization with MCAR showed risks of perioperative death, major or minor stroke (<2%), reintervention rates and carotid restenosis rates that are comparable with PCEA or ECEA groups. Nevertheless, the MCAR group showed a significantly higher rate of global central neurological complications (considering together TIA, minor stroke and major stroke) than patients treated with standard CEA. MCAR techniques appear to be effective alternatives to standard CEAs, with an acceptable surgical risk. However, these should be performed mainly in selected cases, for example, in complex anatomy (detected in a non-negligible percentage of patients by preoperative imaging), or in the case of unexpected intraoperative technical issues. [ABSTRACT FROM AUTHOR]

Severe maternal and newborn morbidity and mortality associated with pre-eclampsia, which are caused partly by premature delivery, affect a factual proportion of pregnancies. Despite its prevalence, the underlying causes of pre-eclampsia remain elusive, with emerging evidence implicating the aryl hydrocarbon receptor (AhR) in its pathogenesis. This study sought to elucidate the involvement of the AhR and its associated pathway in pre-eclampsia by comparing placental components of the AhR pathway in pregnant individuals with and without pre-eclampsia. This case–control investigation was conducted at the University Hospital of Udine from May 2021 to February 2023. The AhR was assessed using immunohistochemistry and immunofluorescence, and its mRNA was evaluated using a Real-Time Quantitative Reverse Transcription PCR. Levels of mRNA expression were also estimated for other components of the AhR pathway (CYP1B1, IDO1, ARNT, TIPARP, S100A4, and AHRR). Our findings show decreased levels of expression of AhR, IDO1, ARNT, TiPARP, and S100A4 in the placental tissues of individuals with pre-eclampsia compared to controls (p < 0.05). The AhR exhibited a distinct localization within the syncytiotrophoblast (nuclei and cytoplasm) and CD45-positive cells (nuclei and cytoplasm). Furthermore, a significant positive correlation between the AhR and S100A4 (rho = 0.81) was observed in normal placentas, while CYP1B1 displayed a significant negative correlation with the AhR (rho = −0.72), within addition to its negative correlation with TiPARP (rho = −0.83). This study illuminates pre-eclampsia’s molecular aberrations, suggesting new diagnostic, therapeutic, and mechanistic approaches. This study emphasizes the need for more research to validate and broaden these findings to improve the management of this complex pregnancy condition.

IntroductionThis study aimed to compare the outcomes of preterm infants given 12 vs. 24mg of betamethasone prophylaxis to understand whether a partial course of antenatal corticosteroids (CCS) could prevent or mitigate the major preterm birth complications.MethodsThis is a retrospective single-center cohort study including neonates born between 24 and 34 weeks of gestation from 2001 to 2019 at the University Hospital of Udine. The study population was divided into two groups: one group received 12mg, and another received a 24mg dose of betamethasone before the delivery. A separate analysis was performed for single and multiple pregnancies. The two groups were evaluated for various neonatal outcomes.ResultsThe study population included a total of 1,258 pregnancies and 1,543 neonates delivered between 24 and 34 weeks of gestation, of which 1,022 (803 single and 219 multiple pregnancies) were exposed to the complete CCS prophylaxis, whereas 236 (192 single and 44 multiple pregnancies) received the incomplete CCS prophylaxis. In single pregnancies, as for maternal characteristics, the most significant differences observed between the two groups are the following: a higher prevalence of spontaneous vaginal deliveries in the incomplete CCS prophylaxis (36.46 vs. 23.91%) and, by contrast, a higher prevalence of cesarean deliveries in the complete CCS prophylaxis group (75.72 vs. 63.02%). As for neonatal outcomes, the low Apgar score in the first and fifth min was significantly more prevalent in the incomplete CCS prophylaxis group compared with the complete CCS prophylaxis group. The group of incomplete CCS prophylaxis reported a higher occurrence of the following outcomes: IVH grade 3-4 (7.81 vs. 3.74%, p < 0.05), PVL (7.29 vs. 1.99% p < 0.05), ROP (23.96 vs. 18.06% p = 0.062), and RDS (84.38 vs. 78.83% p = 0.085). After adjusting for covariates, the complete CCS prophylaxis group in single pregnancies was significantly protective for IVH grade 3-4, PVL, and low Apgar's scores. Similar results were found in multiple pregnancies except for RDS.DiscussionThis retrospective single-center cohort study found that, compared with preterm infants treated with 24mg betamethasone in utero, those given half course of betamethasone had a significantly higher prevalence of IVH grade 3-4, PVL, RDS, and lower Apgar scores at 1 and 5 min. In conclusion, the evidence from this single-center retrospective study supports the preference for the complete CCS prophylaxis in women at risk of preterm birth because of its beneficial effect on the main adverse outcomes.

In contemporary societies merit, one of the cornerstones of our Constitution, is losing its original moral connotation. The economy of the global market, which now tends to disregard politics, actually supports a kind of meritocratic ideology whose perspective, extensively discussed in these pages, fades over time to obtain the opposite effect. This article highlights the contradictions of meritocracy, without endorsing the incompatibility between democracy and merit that it raises as an opportunity for each and everyone through education.

Bi-directional transcription of Human Endogenous Retroviruses (hERVs) is a common feature of autoimmunity, neurodegeneration and cancer. Higher rates of cancer incidence, neurodegeneration and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties. An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of dsRNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS–STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

Background/objective: Target vessels related complications are one of the most important 'Achille's heel' of complex thoracoabdominal endovascular procedures. The aim of this report is to describe a case of spontaneous bridging stent-graft (BSG) delayed expansion in a patient treated for type III mega-aortic syndrome, associated with aberrant right subclavian artery and independent origin of the two common carotid arteries. Methods: The patient underwent different surgical procedures (ascending aorta replacement with carotid arteries debranching, bilateral carotid-subclavian bypass with subclavian origins embolization and TEVAR in zone 0, associated with a multibranched thoracoabdominal endograft deployment). Visceral vessels stenting was performed using balloon-expandable BSGs for celiac trunk, superior mesenteric artery and right renal artery, while for the left renal artery a 6 × 60 mm self-expandable BSG was deployed. The first follow-up (FU) by computed tomography angiography (CTA) showed a severe compression of the left renal artery BSG. Considering the challenging access to the directional branches (SAT's debranching and a tightly curve of the steerable sheath inside the branched main body), a conservative treatment was considered, performing a control CTA after 6-months. Results: Six months later, the CTA demonstrated a spontaneous expansion of the BSG, with a two-fold increase in the minimum stent diameter, excluding the need for new reinterventions such as angioplasty or BSG relining. Conclusions: Directional branch compression is a frequent complication during BEVAR; however, in this case, it spontaneously resolved after 6 months, without the need for secondary adjunctive procedures. Further studies on predictor factors for BSG related adverse events and regarding spontaneous delayed BSGs' expansion mechanisms are needed. [ABSTRACT FROM AUTHOR]

Abstract Since sexual health education (SHE) is not mandatory in Italian schools, we conducted a survey on freshmen of four Italian university campuses in 2012 to investigate the respective level of sexual health knowledge (SHK) in relation to birth control, with the aim to inform public health policy makers. A convenience strategy was employed to sample 4,552 freshmen registered with various undergraduate courses at four Italian universities: Padua university (Veneto Region); university of Milan (Lombardy Region); university of Bergamo (Lombardy Region); university of Palermo (Sicily Region). We investigated the level of SHK on birth control using 6 proxy indicators: (1) the average length of a woman’s period [outcome with 3 levels: wrong (base) vs. acceptable vs. correct]; (2) the most fertile interval within a woman’s period (binary outcome: correct vs. wrong answer); (3) the event between the end of a period and the beginning of the next cycle (binary outcome: correct vs. wrong answer); (4) the average survival of spermatozoa in the womb (binary outcome: correct vs. wrong answer); (5) the concept of contraception (binary outcome: correct vs. wrong answer); (6) the efficacy of various contraceptives to prevent unintended pregnancies (linear score: 0–17). We fitted 6 separate models of multiple regression: multinomial for outcome 1; logistic for outcomes 2, 3, 4, 6; linear for outcome 6. Statistical estimates were adjusted for a number of socio-demographic factors. Results were expressed as odds ratios (OR) for the 4 multiple logistic regression models, linear coefficients (RC) for the linear regression model and relative risk ratio (RRR) for the multinomial logistic regression model. The level of significance of each risk estimate was set at 0.05. The level of SHK of freshmen sampled was rather low, as 60% interviewees did not know the average length of a woman’s period, the average survival of spermatozoa in the womb and the concept of contraception, whilst the most fertile interval within a woman’s period was known only to 55% of interviewees. The mean score of SHK on the efficacy of various contraceptive methods was only 5 (scale 0–17). Some categories of students were consistently and significantly less knowledgeable on birth control at multivariable analysis: males; students from the university of Palermo; those with vocational secondary school education and those not in a romantic relationship at the time the survey was conducted. The results of this survey clearly call for the introduction of SHE programs in Italian schools, as already done in several European countries. School SHE should start as early as possible, ideally even before secondary school. SHE should be holistic and delivered with a multiple agency coordinated approach involving the Ministry of Health, the Ministry of Education, University and Scientific Research (MIUR), families, schools, public health departments, primary health care providers, pharmacists, media, other.

Background: Recently, the literature suggested that placental transfusion facilitated by delayed cord clamping (DCC), besides having benefits on hematological parameters, might improve the infants' brain development.Objective: The present review primarily evaluates the Ages and Stages Questionnaire (ASQ) total score mean difference (MD) at long-term follow-up (≥4 months) comparing DCC (>90 or >180 s) to early cord clamping (ECC). Secondary aims consisted of evaluating the ASQ domains' MD and the results obtained from other methods adopted to evaluate the infants' neurodevelopment.Methods: MEDLINE, Scopus, Cochrane, and ClinicalTrials.gov databases were searched (up to 2nd November 2020) for systematic review and meta-analysis. All randomized controlled trials (RCTs) of term singleton gestations received DCC or ECC. Multiple pregnancies, pre-term delivery, non-randomized studies, and articles in languages other than English were excluded. The included studies were assessed for bias and quality. ASQ data were pooled stratified by time to follow up.Results: This meta-analysis of 4 articles from 3 RCTs includes 765 infants with four-month follow-up and 672 with 12 months follow-up. Primary aim (ASQ total score) pooled analysis was possible only for 12 months follow-up, and no differences were found between DCC and ECC (MD 1.1; CI 95: −5.1; 7.3). DCC approach significantly improves infants' communication domains (MD 0.6; CI 95: 0.1; 1.1) and personal-social assessed (MD 1.0; CI 95: 0.3; 1.6) through ASQ at 12 months follow-up. Surprisingly, the four-month ASQ personal social domain (MD −1.6; CI 95: −2.8; −0.4) seems to be significantly lower in the DCC group than in the ECC group.Conclusions: DCC, a simple, non-interventional, and cost-effective approach, might improve the long-term infants' neurological outcome. Single-blinding and limited studies number were the main limitations. Further research should be performed to confirm these observations, ideally with RCTs adopting standard methods to assess infants' neurodevelopment.Trial registration: NCT01245296, NCT01581489, NCT02222805, NCT01620008, IRCT201702066807N19, and NCT02727517