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ObjectiveIt has been hypothesised that the use of ACE inhibitors and angiotensin receptor blockers (ARBs) might either increase or reduce the risk of severe or lethal COVID-19. The findings from the available observational studies varied, and summary estimates are urgently needed to elucidate whether these drugs should be suspended during the pandemic, or patients and physicians should be definitely reassured. This meta-analysis of adjusted observational data aimed to summarise the existing evidence on the association between these medications and severe/lethal COVID-19.MethodsWe searched MedLine, Scopus and preprint repositories up to 8 June 2020 to retrieve cohort or case–control studies comparing the risk of severe/fatal COVID-19 (either mechanical ventilation, intensive care unit admission or death), among hypertensive subjects treated with: (1) ACE inhibitors, (2) ARBs and (3) both, versus untreated subjects. Data were combined using a random-effect generic inverse variance approach.ResultsTen studies, enrolling 9890 hypertensive subjects were included in the analyses. Compared with untreated subjects, those using either ACE inhibitors or ARBs showed a similar risk of severe or lethal COVID-19 (summary OR: 0.90; 95% CI 0.65 to 1.26 for ACE inhibitors; 0.92; 95% CI 0.75 to 1.12 for ARBs). The results did not change when both drugs were considered together, when death was the outcome and excluding the studies with significant, divergent results.ConclusionThe present meta-analysis strongly supports the recommendation of several scientific societies to continue ARBs or ACE inhibitors for all patients, unless otherwise advised by their physicians who should thus be reassured.

Purpose: To describe the suprameatal–transzygomatic root endoscopic approach (STEA) to the geniculate ganglion (GG), the labyrinthine facial nerve (FN) and epitympanum. Methods: The feasibility and limits of the STEA, maintaining the integrity of the ossicular chain, were analysed. Ten human cadaveric ears were dissected. Step-by-step description of the technique and relevant measurements were taken during the approach. The visualization and surgical working field on the anterior and posterior medial epitympanum, GG, greater superficial petrosal nerve, the labyrinthine FN and suprageniculate area were evaluated. The range of motion through the approach and the rate of the decompression of the GG and the labyrinthine portion of the FN were assessed as well. CT-scan measurements were compared with those obtained during the dissection. Results: A complete exploration of the epitympanum was possible in every specimen. Decompression of the GG and first portion of the FN was achieved without any trauma to the ossicular chain in nine ears. The endoscope movements were mainly limited by the distance between bony buttress–short process of the incus–tegmen. The working space, during GG and labyrinthine FN decompression, was limited by the distance between malleus head–medial epitympanic wall and malleus head–GG. Radiologic measurements were consistent with those obtained during the dissections. Conclusion: The STEA is a promising minimally invasive approach for decompression of the GG and FN’s labyrinthine portion. The applications of this corridor include the exploration and surgery of the medial epitympanum, preserving the ossicular chain.

Background This study compared patients undergoing colorectal cancer surgery in 20 hospitals of northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes. Method This was a retrospective multicentre cohort analysis of patients undergoing colorectal cancer surgery in March to December 2019 versus March to December 2020. Independent predictors of disease stage (oncological stage, associated symptoms, clinical T4 stage, metastasis) and outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression. Results The sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean age 69.6 years). The proportion of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were respectively: 80.8 versus 84.5 per cent; 6.2 versus 8.7 per cent; 10.2 versus 10.3 per cent; and 3.0 versus 4.4 per cent. The proportions of surgical complications, palliative surgery and death in 2019 and 2020 were, respectively: 34.4 versus 31.9 per cent; 5.0 versus 7.5 per cent; and 1.7 versus 2.4 per cent. Cancers in 2020 (versus 2019) were more likely to be symptomatic (odds ratio 1.36 (95 per cent c.i. 1.09 to 1.69)), clinical T4 stage (odds ratio 1.38 (95 per cent c.i. 1.03 to 1.85)) and have multiple liver metastases (odds ratio 2.21 (95 per cent c.i. 1.24 to 3.94)), but were not more likely to be associated with surgical complications (odds ratio 0.79 (95 per cent c.i. 0.68 to 0.93)). Conclusion Colorectal cancer patients who had surgery between March and December 2020 had an increased risk of advanced disease in terms of associated symptoms, cancer location, clinical T4 stage and number of liver metastases.

Current data suggest that SARS-CoV-2 reinfections are rare, but uncertainties remain on the duration of the natural immunity, its protection against Omicron variant, finally the impact of vaccination to reduce reinfection rates. In this retrospective cohort analysis of the entire population of an Italian Region, we followed 1,293,941 subjects from the beginning of the pandemic to the current scenario of Omicron predominance (up to mid-January 2022). After an average of 334 days, we recorded 260 reinfections among 84,907 previously infected subjects (overall rate: 0.31%), two hospitalizations (2.4 x100,000), and one death. Importantly, the incidence of reinfection did not vary substantially over time: after 18-22 months from the primary infection, the reinfection rate was still 0.32%, suggesting that protection conferred by natural immunity may last beyond 12 months. The risk of reinfection was significantly higher among the unvaccinated subjects, and during the Omicron wave.

Objective: Specific comorbidities and old age create a greater vulnerability to severe Coronavirus Disease 19 (COVID-19). While obesity seems to aggravate the course of disease, the actual impact of the BMI and the cutoff which increases illness severity are still under investigation. The aim of the study was to analyze whether the BMI represented a risk factor for respiratory failure, admission to the intensive care unit (ICU) and death. Research design and methods: A retrospective cohort study of 482 consecutive COVID-19 patients hospitalised between March 1 and April 20, 2020. Logistic regression analysis and Cox proportion Hazard models including demographic characteristics and comorbidities were carried out to predict the endpoints within 30 days from the onset of symptoms. Results: Of 482 patients, 104 (21.6%) had a BMI ≥ 30 kg/m2. At logistic regression analysis, a BMI between 30 and 34.9 kg/m2 significantly increased the risk of respiratory failure (OR: 2.32; 95% CI: 1.31–4.09, P = 0.004) and admission to the ICU (OR: 4.96; 95% CI: 2.53–9.74, P 2 (OR: 12.1; 95% CI: 3.25–45.1, P Conclusions: Obesity is a strong, independent risk factor for respiratory failure, admission to the ICU and death among COVID-19 patients. A BMI ≥ 30 kg/m2 identifies a population of patients at high risk for severe illness, whereas a BMI ≥ 35 kg/m2 dramatically increases the risk of death.

Objectives: To explore whether early first-trimester ultrasound can predict the third-trimester sonographic stage of placenta accreta spectrum (PAS) disorder and to elucidate whether combining first-trimester ultrasound findings with the sonographic stage of PAS disorder can stratify the risk of adverse surgical outcome in women at risk for PAS disorder. Methods: This was a retrospective analysis of prospectively collected data from women with placenta previa, and at least one previous Cesarean delivery (CD) or uterine surgery, for whom early first-trimester (5-7 weeks' gestation) ultrasound images could be retrieved. The relationship between the position of the gestational sac and the prior CD scar was assessed using three sonographic markers for first-trimester assessment of Cesarean scar (CS) pregnancy, reported by Cali et al. (crossover sign (COS)), Kaelin Agten et al. (implantation of the gestational sac on the scar vs in the niche of the CS) and Timor-Tritsch et al. (position of the center of the gestational sac below vs above the midline of the uterus), by two different examiners blinded to the final diagnosis and clinical outcome. The primary aim of the study was to explore the association between first-trimester ultrasound findings and the stage of PAS disorder on third-trimester ultrasound. Our secondary aim was to elucidate whether the combination of first-trimester ultrasound findings and sonographic stage of PAS disorder can predict surgical outcome. Logistic regression analysis and area under the receiver-operating-characteristics curve (AUC) were used to analyze the data. Results: One hundred and eighty-seven women with vasa previa were included. In this cohort, 79.6% (95% CI, 67.1-88.2%) of women classified as COS-1, 94.4% (95% CI, 84.9-98.1%) of those with gestational-sac implantation in the niche of the prior CS and 100% (95% CI, 93.4-100%) of those with gestational sac located below the uterine midline, on first-trimester ultrasound, were affected by the severest form of PAS disorder (PAS3) on third-trimester ultrasound. On multivariate logistic regression analysis, COS-1 (odds ratio (OR), 7.9 (95% CI, 4.0-15.5); P < 0.001), implantation of the gestational sac in the niche (OR, 29.1 (95% CI, 8.1-104); P < 0.001) and location of the gestational sac below the midline of the uterus (OR, 38.1 (95% CI, 12.0-121); P < 0.001) were associated independently with PAS3, whereas parity (P = 0.4) and the number of prior CDs (P = 0.5) were not. When translating these figures into diagnostic models, first-trimester diagnosis of COS-1 (AUC, 0.94 (95% CI, 0.91-0.97)), pregnancy implantation in the niche (AUC, 0.92 (95% CI, 0.89-0.96)) and gestational sac below the uterine midline (AUC, 0.92 (95% CI, 0.88-0.96)) had a high predictive accuracy for PAS3. There was an adverse surgical outcome in 22/187 pregnancies and it was more common in women with, compared to those without, COS-1 (P < 0.001), gestational-sac implantation in the niche (P < 0.001) and gestational-sac position below the uterine midline (P < 0.001). On multivariate logistic regression analysis, third-trimester ultrasound diagnosis of PAS3 (OR, 4.3 (95% CI, 2.1-17.3)) and first-trimester diagnosis of COS-1 (OR, 7.9 (95% CI, 4.0-15.5); P < 0.001), pregnancy implantation in the niche (OR, 29.1 (95% CI, 8.1-79.0); P < 0.001) and position of the sac below the uterine midline (OR, 6.6 (95% CI, 3.9-16.2); P < 0.001) were associated independently with adverse surgical outcome. When combining the sonographic coordinates of the three first-trimester imaging markers, we identified an area we call high-risk-for-PAS triangle, which may enable an easy visual perception and application of the three methods to prognosticate the risk for CS pregnancy and PAS disorder, although it requires validation in large prospective studies. Conclusions: Early first-trimester sonographic assessment of pregnancies with previous CD can predict reliably ultrasound stage of PAS disorder. Combination of findings on first-trimester ultrasound with second- and third-trimester ultrasound examination can stratify the surgical risk in women affected by a PAS disorder. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stiffness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fluctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent findings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer. Graphical abstract

Aims: To evaluate the relationship between comorbidity and in-hospital mortality in elderly patients affected by dementia. Methods: Data were obtained from the Italian Ministry of Health and included all discharge records from Italian hospitals concerning subjects aged ≥ 65 years admitted to acute Internal Medicine or Geriatrics wards between January 2015 and December 2016 (3.695.278 admissions). The variables analyzed included age, sex, and in-hospital death. Twenty-five homogeneous clusters of diseases were identified in discharge codes according to the ICD-9-CM classification. Results: Patients with dementia represented 7.5% of the sample (n. 278.149); they were older, more often males (51.9%), and had a higher in-hospital mortality (24.3%) compared to patients without dementia (9.7%). Dementia per se doubled the odds of death (OR 1.98; 95% CI 1.95-2.00), independent of age, sex, and comorbidities. Seven clusters of disease (pneumonia, heart failure, kidneys disease, cancer, infectious diseases, diseases of fluids/electrolytes and general symptoms) were associated with increased in-hospital mortality, independent of the presence/absence of dementia. Among patients with dementia, heart failure, pneumonia and kidney disease on their own substantially doubled/tripled mortality risk. The risk increased from 10.1% (none of selected conditions), up to 28.9% when only one of selected comorbidities was present, rising to 52.3% (OR: 9.34; p < 0.001) when two or more comorbidities were simultaneously diagnosed, besides general symptoms. Conclusions: Our study confirmed an important increase of in-hospital mortality in older subjects with dementia. Despite a different comorbidity, the conditions associated with in-hospital mortality were substantially the same in patients with or without dementia. Heart failure, pneumonia, and kidney disease identified a high risk of in-hospital mortality among subjects with dementia.

The University of Bologna School of Medicine in 2003 adopted a near-peer teaching (NPT) program with senior medical students teaching and assisting younger students in human anatomy laboratories. This study aimed to evaluate the effectiveness and outcomes of this program—unique on the Italian academic panorama—from the tutors’ perspective. An anonymous online survey was administered to all those who acted as peer tutors in the period from 2003 to 2021; it evaluated tutors’ perceptions regarding the influence of the tutoring experience on their skillset gains, academic performance, and professional career. Furthermore, tutors were asked to express their views on the value of cadaver dissection in medical education and professional development. The overall perception of the NPT program was overwhelmingly positive and the main reported benefits were improved long-term knowledge retention and academic performance, improved communication, team-working and time management skills, and enhanced self-confidence and motivation. Most tutors strongly believed that cadaver dissection was an invaluable learning tool in medical education, helped them to develop professionalism and human values, and positively influenced the caring of their future patients. Nearly all the participants highlighted the importance of voluntary body donation for medical education and research. The present results supported the thesis that tutors themselves benefited from the act of teaching peers; this impactful experience equipped them with a wide range of transferable skills that they could draw on as future educators and healthcare professionals.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8–0.9 per week increase; p Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

WOS:000613461600006 PubMed ID: 32926494 Objectives To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. Methods This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. Results In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251(27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. Conclusions SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. (C) 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Objective: To determine the role of progesterone, pessary and cervical cerclage in reducing the risk of (preterm birth) PTB in twin pregnancies and compare these interventions using pairwise and network meta-analysis. Study design: Medline, Embase, CINAHL and Cochrane databases were explored. The inclusion criteria were studies in which twin pregnancies were randomized to an intervention for the prevention of PTB (any type of progesterone, cervical cerclage, cervical pessary, or any combination of these) or to a control group (e.g. placebo or treatment as usual). Interventions of interest were either progesterone [vaginal or oral natural progesterone or intramuscular 17a-hydroxyprogesterone caproate (17-OHPC)], cerclage (McDonald or Shirodkar), or cervical pessary. The primary outcome was PTB < 34 weeks of gestation. Both primary and secondary outcomes were explored in an unselected population of twin pregnancies and in women at higher risk of PTB (defined as those with cervical length 0.05). When stratifying the analysis for spontaneous PTB, neither pessary, vaginal or intramuscular 17-OHPC were associated with a significant reduction in the risk of PTB compared to controls (all p > 0.05), while there was no study on cerclage which explored this outcome in an unselected population of twin pregnancies. When considering twin pregnancies with short cervical length (≤25 mm), there was no contribution of either pessary, vaginal progesterone, intra-muscular 17-OHPC or cerclage in reducing the risk of overall PTB < 34 weeks of gestation. Conclusions: Cervical pessary, progesterone and cerclage do not show a significant effect in reducing the rate of PTB or perinatal morbidity in twins, either when these interventions are applied to an unselected population of twins or in pregnancies with a short cervix.

Objective: The aim of this study was to report the rate of additional anomalies detected exclusively at prenatal magnetic resonance imaging (MRI) in fetuses with isolated severe ventriculomegaly undergoing neurosonography. Method: Multicenter, retrospective, cohort study involving 20 referral fetal medicine centers in Italy, United Kingdom, Spain and Denmark. Inclusion criteria were fetuses affected by isolated severe ventriculomegaly (≥15 mm), defined as ventriculomegaly with normal karyotype and no other additional central nervous system (CNS) and extra-CNS anomalies on ultrasound. In all cases, a multiplanar assessment of fetal brain as suggested by ISUOG guidelines on fetal neurosonography had been performed. The primary outcome was the rate of additional CNS anomalies detected exclusively at fetal MRI within two weeks from neurosonography. Subgroup analyses according to gestational age at MRI (

In Italy, recent legislation (Law No. 10/2020) has tuned regulations concerning the donation of one's postmortem body and tissues for study, training, and scientific research purposes. This study discusses several specific issues to optimise the applicability and effectiveness of such an important, novel regulatory setting. Some of these unsolved issues may involve the grantees of teaching and training activities, the role of academic anatomical institutes, the role of family members in the donation process, the universal time limit indicated for any donation, the handling of corpses, and the limited body donation and its subordination to the donation of organs and tissues. Critical issues arise concerning the learners, the type of training and teaching activities that can be planned, the position of academic anatomy institutes, the role of family members in the donation process, the time frame of the donation process, the eligibility of partial donation, or the simultaneous donation of organs and tissues to patients awaiting transplantation. In particular, a universal time limit for donations (i.e., one year) makes it impossible to plan the long-term use of specific body parts, which could be effectively preserved for the advanced teaching and training of medical students and surgeons. The abovementioned conditions lead to the limited use of corpses, thus resulting in the inefficiency of the whole system of body donation. Overall, the donors' scope for the donation of their body could be best honoured by a more flexible and tuneable approach that can be used on a case-by-case basis. Furthermore, it is deemed necessary to closely monitor the events scheduled for corpses in public nonacademic institutions or private enterprises. This paper presents useful insights from Italian anatomists with the hope of providing inspiration for drafting the regulations. In conclusion, this paper focuses on the critical issues derived from the recently introduced Italian law on the donation and use of the body after death and provides suggestions to lawmakers for future implementations.

Glioblastoma represents the most lethal brain tumor in adults. Several studies have shown the key role of phospholipase C β1 (PLCβ1) in the regulation of many mechanisms within the central nervous system suggesting PLCβ1 as a novel signature gene in the molecular classification of high-grade gliomas. This study aims to determine the pathological impact of PLCβ1 in glioblastoma, confirming that PLCβ1 gene expression correlates with glioma’s grade, and it is lower in 50 glioblastoma samples compared to 20 healthy individuals. PLCβ1 silencing in cell lines and primary astrocytes, leads to increased cell migration and invasion, with the increment of mesenchymal transcription factors and markers, as Slug and N-Cadherin and metalloproteinases. Cell proliferation, through increased Ki-67 expression, and the main survival pathways, as β-catenin, ERK1/2 and Stat3 pathways, are also affected by PLCβ1 silencing. These data suggest a potential role of PLCβ1 in maintaining a normal or less aggressive glioma phenotype.

Most medical and health science schools adopt innovative tools to implement the teaching of anatomy to their undergraduate students. The increase in technological resources for educational purposes allows the use of virtual systems in the field of medicine, which can be considered decisive for improving anatomical knowledge, a requisite for safe and competent medical practice. Among these virtual tools, the Anatomage Table 7.0 represents, to date, a pivotal anatomical device for student education and training medical professionals. This review focuses attention on the potential of the Anatomage Table in the anatomical learning process and clinical practice by discussing these topics based on recent publication findings and describing their trends during the COVID-19 pandemic period. The reports documented a great interest in and a positive impact of the use of this technological table by medical students for teaching gross anatomy. Anatomage allows to describe, with accuracy and at high resolution, organ structure, vascularization, and innervation, as well as enables to familiarize with radiological images of real patients by improving knowledge in the radiological and surgical fields. Furthermore, its use can be considered strategic in a pandemic period, since it ensures, through an online platform, the continuation of anatomical and surgical training on dissecting cadavers.

Renal failure is a worldwide disease with a continuously increasing prevalence and involving a rising need for long-term treatment, mainly by haemodialysis. Arteriovenous fistula (AVF) is the favourite type of vascular access for haemodialysis; however, the lasting success of this therapy depends on its maturation, which is directly influenced by many concomitant processes such as vein wall thickening or inflammation. Understanding the molecular mechanisms that drive AVF maturation and failure can highlight new or combinatorial drugs for more personalized therapy. In this review we analysed the relevance of critical enzymes such as PI3K, AKT and mTOR in processes such as wall thickening remodelling, immune system activation and inflammation reduction. We focused on these enzymes due to their involvement in the modulation of numerous cellular activities such as proliferation, differentiation and motility, and their impairment is related to many diseases such as cancer, metabolic syndrome and neurodegenerative disorders. In addition, these enzymes are highly druggable targets, with several inhibitors already being used in patient treatment for cancer and with encouraging results for AVF. Finally, we delineate how these enzymes may be targeted to control specific aspects of AVF in an effort to propose a more specialized therapy with fewer side effects.

Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular functions in an ADLD astrocytic in vitro model. Lamin B1 overexpression induces alterations in cell survival signaling pathways with GSK3β inactivation, but not the upregulation of β-catenin targets, therefore resulting in a reduction in astrocyte survival. Moreover, Lamin B1 build up affects proliferation and cell cycle progression with an increase of PPARγ and p27 and a decrease of Cyclin D1. These events are also associated to a reduction in cell viability and an induction of apoptosis. Interestingly, ADLD astrocytes trigger a tentative activation of survival pathways that are ineffective. Finally, astrocytes overexpressing Lamin B1 show increased immunoreactivity for both GFAP and vimentin together with NF-kB phosphorylation and c-Fos increase, suggesting astrocytes reactivity and substantial cellular activation. These data demonstrate that Lamin B1 accumulation is correlated to biochemical, metabolic, and morphologic remodeling, probably related to the induction of a reactive astrocytes phenotype that could be strictly associated to ADLD pathological mechanisms.

By the end of May 2020, SARS-CoV-2 pandemic caused more than 350,000 deaths worldwide. In the first months, there have been uncertainties on almost any area: infection transmission route, virus origin and persistence in the environment, diagnostic tests, therapeutic approach, high-risk subjects, lethality, and containment policies. We provide an updated summary of the current knowledge on the pandemic, discussing the available evidence on the effectiveness of the adopted mitigation strategies.

Objective: To investigate the outcome of pregnancies with small baby, including both small for gestational age (SGA) and late fetal growth restriction (FGR) fetuses, undergoing induction of labor (IOL) with Dinoprostone, Misoprostol or mechanical methods. Study design: Medline, Embase and Cochrane databases were searched. Inclusion criteria were non-anomalous singleton pregnancies complicated by the presence of a small fetus, defined as a fetus with estimated fetal weight (EFW) or abdominal circumference (AC) 3rd centile with normal cerebroplacental Dopplers). Quality assessment of each included study was performed using the Risk of Bias in Non-randomized Studies-of Interventions tool (ROBINS-I), while the GRADE methodology was used to assess the quality of the body of retrieved evidence. Meta-analyses of proportions and individual data random-effect logistic regression were used to analyze the data. Results: 12 studies (1711 pregnancies) were included. In the overall population of small fetuses, composite adverse intra-partum outcome occurred in 21.2 % (95 % CI 10.0−34.9) of pregnancies induced with Dinoprostone, 18.0 % (95 % CI 6.9−32.5) of those with Misoprostol and 11.6 % (95 % CI 5.5−19.3) of those undergoing IOL with mechanical methods. Cesarean section (CS) for non-reassuring fetal status (NRFS) was required in 18.1 % (95 % CI 9.9−28.3) of pregnancies induced with Dinoprostone, 9.4 % (95 % CI 1.4−22.0) of those with Misoprostol and 8.1 % (95 % CI 5.0−11.6) of those undergoing mechanical induction. Likewise, uterine tachysystole, was recorded on CTG in 13.8 % (95 % CI 6.9−22.3) of cases induced with Dinoprostone, 7.5 % (95 % CI 2.1−15.4) of those with Misoprostol and 3.8 % (95 % CI 0–4.4) of those induced with mechanical methods. Composite adverse perinatal outcome following delivery complicated 2.9 % (95 % CI 0.5−6.7) newborns after IOL with Dinoprostone, 0.6 % (95 % CI 0–2.5) with Misoprostol and 0.7 % (95 % CI 0–7.1) with mechanical methods. In pregnancies complicated by late FGR, adverse intrapartum outcome occurred in 25.3 % (95 % CI 18.8−32.5) of women undergoing IOL with Dinoprostone, compared to 7.4 % (95 % CI 3.9−11.7) of those with mechanical methods, while CS for NRFS was performed in 23.8 % (95 % CI 17.3−30.9) and 6.2 % (95 % CI 2.8−10.5) of the cases, respectively. Finally, in SGA fetuses, composite adverse intrapartum outcome complicated 8.4 % (95 % CI 4.6−13.0) of pregnancies induced with Dinoprostone, 18.6 % (95 % CI 13.1−25.2) of those with Misoprostol and 8.7 (95 % CI 2.5−17.5) of those undergoing mechanical IOL, while CS for NRF was performed in 8.4 % (95 % CI 4.6−13.0) of women induced with Dinoprostone, 18.6 % (95 % CI 13.1−25.2) of those with Misoprostol and 8.7 % (95 % CI 2.5−17.5) of those undergoing mechanical induction. Overall, the quality of the included studies was low and was downgraded due to considerable clinical and statistical heterogeneity. Conclusions: There is limited evidence on the optimal type of IOL in pregnancies with small fetuses. Mechanical methods seem to be associated with a lower occurrence of adverse intrapartum outcomes, but a direct comparison between different techniques could not be performed.

AimsThis retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs).Methods and resultsAll adults with SARS-CoV-2 infection in two Italian provinces were followed for a median of 24 days. ARBs and/or ACEi treatments, and hypertension, diabetes, cancer, COPD, renal and major cardiovascular diseases (CVD) were extracted from clinical charts and electronic health records, up to two years before infection. The sample consisted of 1603 subjects (mean age 58.0y; 47.3% males): 454 (28.3%) had severe symptoms, 192 (12.0%) very severe or lethal disease (154 deaths; mean age 79.3 years; 70.8% hypertensive, 42.2% with CVD). The youngest deceased person aged 44 years. Among hypertensive subjects (n = 543), the proportion of those treated with ARBs or ACEi were 88.4%, 78.7% and 80.6% among patients with mild, severe and very severe/lethal disease, respectively. At multivariate analysis, no association was observed between therapy and disease severity (Adjusted OR for very severe/lethal COVID-19: 0.87; 95% CI: 0.50-1.49). Significant predictors of severe disease were older age (with AORs largely increasing after 70 years of age), male gender (AOR: 1.76; 1.40-2.23), diabetes (AOR: 1.52; 1.05-2.18), CVD (AOR: 1.88; 1.32-2.70) and COPD (AOR: 1.88; 1.11-3.20). Only gender, age and diabetes also predicted very severe/lethal disease.ConclusionNo association was found between COVID-19 severity and treatment with ARBs and/or ACEi, supporting the recommendation to continue medication for all patients unless otherwise advised by their physicians.

Objectives: To assess the role of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses presenting with mild or moderate isolated ventriculomegaly (VM) undergoing multiplanar ultrasound evaluation of the fetal brain. Methods: This was a multicenter, retrospective, cohort study involving 15 referral fetal medicine centers in Italy, the UK and Spain. Inclusion criteria were fetuses affected by isolated mild (ventricular atrial diameter, 10.0–11.9 mm) or moderate (ventricular atrial diameter, 12.0–14.9 mm) VM on ultrasound, defined as VM with normal karyotype and no other additional central nervous system (CNS) or extra-CNS anomalies on ultrasound, undergoing detailed assessment of the fetal brain using a multiplanar approach as suggested by the International Society of Ultrasound in Obstetrics and Gynecology guidelines for the fetal neurosonogram, followed by fetal MRI. The primary outcome of the study was to report the incidence of additional CNS anomalies detected exclusively on prenatal MRI and missed on ultrasound, while the secondary aim was to estimate the incidence of additional anomalies detected exclusively after birth and missed on prenatal imaging (ultrasound and MRI). Subgroup analysis according to gestational age at MRI (< 24 vs ≥ 24 weeks), laterality of VM (unilateral vs bilateral) and severity of dilatation (mild vs moderate VM) were also performed. Results: Five hundred and fifty-six fetuses with a prenatal diagnosis of isolated mild or moderate VM on ultrasound were included in the analysis. Additional structural anomalies were detected on prenatal MRI and missed on ultrasound in 5.4% (95% CI, 3.8–7.6%) of cases. When considering the type of anomaly, supratentorial intracranial hemorrhage was detected on MRI in 26.7% of fetuses, while polymicrogyria and lissencephaly were detected in 20.0% and 13.3% of cases, respectively. Hypoplasia of the corpus callosum was detected on MRI in 6.7% of cases, while dysgenesis was detected in 3.3%. Fetuses with an associated anomaly detected only on MRI were more likely to have moderate than mild VM (60.0% vs 17.7%; P < 0.001), while there was no significant difference in the proportion of cases with bilateral VM between the two groups (P = 0.2). Logistic regression analysis showed that lower maternal body mass index (adjusted odds ratio (aOR), 0.85 (95% CI, 0.7–0.99); P = 0.030), the presence of moderate VM (aOR, 5.8 (95% CI, 2.6–13.4); P < 0.001) and gestational age at MRI ≥ 24 weeks (aOR, 4.1 (95% CI, 1.1–15.3); P = 0.038) were associated independently with the probability of detecting an associated anomaly on MRI. Associated anomalies were detected exclusively at birth and missed on prenatal imaging in 3.8% of cases. Conclusions: The incidence of an associated fetal anomaly missed on ultrasound and detected only on fetal MRI in fetuses with isolated mild or moderate VM undergoing neurosonography is lower than that reported previously. The large majority of these anomalies are difficult to detect on ultrasound. The findings from this study support the practice of MRI assessment in every fetus with a prenatal diagnosis of VM, although parents can be reassured of the low risk of an associated anomaly when VM is isolated on neurosonography. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

"This is the peer reviewed version of the following article:Zanardini, C.; D'Antonio, F.; Hvingel, B.; Vårtun, Å.; Prefumo, F.; Flacco, M.E.; Manzoli, L.; Acharya, G.(2019) Agreement between anatomical M-mode and tissue Doppler imaging in the assessment of fetal atrioventricular annular plane displacement in uncomplicated pregnancies: A prospective longitudinal study. Journal of obstetrics and gynaecology Research, 45 which has been published in final form at 10.1111/jog.14068. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions." Aim To evaluate the level of agreement between M‐mode and pulsed‐wave tissue Doppler imaging (PW‐TDI) techniques in assessing fetal mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE) and septal annular plane systolic excursion (SAPSE) in a low‐risk population. Methods This prospective longitudinal study included healthy fetuses assessed from 18 to 40 weeks of gestation. Tricuspid annular plane systolic excursion, MAPSE and SAPSE were measured using anatomical M‐mode and PW‐TDI. The agreement between the two diagnostic tests was assessed using Bland–Altman analysis. Results Fifty fetuses were included in the final analysis. Mean values of TASPE were higher than that of MAPSE. There was a progressive increase of TAPSE, MAPSE and SAPSE values with advancing gestation. For each parameter assessed, there was an overall good agreement between the measurements obtained with M‐mode and PW‐TDI techniques. However, the measurements made with M‐mode were slightly higher than those obtained with PW‐TDI (mean differences: 0.03, 0.05 and 0.03 cm for TAPSE, MAPSE and SAPSE, respectively). When stratifying the analyses by gestational age, the mean values of TAPSE, MAPSE and SAPSE measured with M‐Mode were higher compared to those obtained with PW‐TDI, although the mean differences between the two techniques tended to narrow with increasing gestation. Tricuspid annular plane systolic excursion, MAPSE and SAPSE measurements were all significantly, positively associated with gestational age (all P

OBJECTIVE To evaluate the potential benefit of interventional radiology (IR) in improving the outcome of women undergoing surgery for a placenta accreta spectrum (PAS) disorder. METHODS MEDLINE, EMBASE and CINAHL databases were searched for studies comparing outcomes of women with a prenatal diagnosis of PAS who underwent an IR procedure before surgery vs those who did not, using a robust collection of terms relating to PAS. The primary outcome was intraoperative estimated blood loss (EBL). Secondary outcomes were the number of transfused units of packed red blood cells (PRBC), fresh frozen plasma (FFP), platelets and cryoprecipitate, operation time, length of hospital stay, EBL ≥ 2.5 L, PRBC transfused ≥ 5 units, surgical complications, bladder or ureteral injury, relaparotomy, infection, disseminated intravascular coagulation, and complications related to endovascular catheter placement. Only studies reporting on the incidence of, or the mean difference in, the observed outcomes in women affected by a PAS disorder who had vs those who did not have an IR procedure before surgery were considered for inclusion. All outcomes were explored in the overall population of women with a prenatally diagnosed PAS disorder and in those undergoing hysterectomy. Quality assessment of each included study was performed using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. The GRADE methodology was used to assess the quality of the body of retrieved evidence. RESULTS Fifteen studies (958 women with PAS) were included. In women who underwent IR before surgery, compared with those who did not, mean EBL (mean difference (MD), -1.02 L; 95% CI, -1.60 to -0.43 L; P

Microanatomical dissection; Mitochondrial disorders; MtDNA depletion Disección microanatómica; Trastornos mitocondriales; Agotamiento del ADNmt Dissecció microanatòmica; Trastorns mitocondrials; Esgotament de l'ADNmt Mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE. The work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca-Dipartimenti eccellenti on the Project Personalized medicine. LC and VC are supported by the Italian Ministry of Health (Ricerca Corrente 2021 funding). RDG is supported by funds from the University of Ferrara.

Summary The scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated that human SC islets reaggregated from cryopreserved cells display glucose-stimulated insulin secretion in vitro. Importantly, we showed that conformally coated SC islets displayed comparable in vitro function with unencapsulated SC islets, with conformal coating permitting physiological insulin secretion. Transplantation of SC islets into the gonadal fat pad of diabetic NOD-scid mice revealed that both unencapsulated and conformal-coated SC islets could reverse diabetes and maintain human-level euglycemia for more than 80 days. Overall, these results provide support for further evaluation of safety and efficacy of conformal-coated SC islets in larger species., Highlights • Reaggregated human SC islets display glucose-stimulated insulin secretion in vitro • Conformal-coated human SC islets displayed physiological insulin secretion • Conformal-coated human SC islets in mice reversed diabetes to human euglycemic levels, Scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Islet encapsulation may eliminate the need for chronic immunosuppression. Conformal coating seeks to overcome limitations of traditional microencapsulation. Transplantation of conformal-coated stem cell-derived islets might extend the applicability of islet transplantation to a larger cohort of patients.

Introduction: open tibial fractures are challenging due to the frequent severe bone injury associated with poor soft tissue conditions. This is relevant in low- and middle-income countries, mainly related to delayed definitive fixation and lack of adequate training in soft tissue coverage procedures. Due to these factors, open tibial fracture is an important source of disability for Latin American countries. Herein we sought to provide an epidemiological overview of isolated open tibial shaft fracture across seven hospitals in southern cone of Latin America. The secondary goal was to assess the impact on quality of life based on return-to-work rate (RWR). Methods: patients with an isolated open tibial shaft fracture treated in seven different hospitals from Brazil and Argentina from November 2017 to March 2020 were included in the study. Clinical and radiographic results were evaluated throughout the 120-day follow-up period. Final evaluation compared RWR with the SF-12 questionnaire, bone healing, and gait status. Results: Seventy-two patients were treated, 57 followed for 120 days and 48 completed the SF-12 questionnaire. After 120 days, 70.6% had returned to work, 61.4% had experienced bone healing. Age, antibiotic therapy, type of definitive treatment, and infection significantly influenced the RWR. Gait status exhibited strong correlations with RWR and SF-12 physical component score. Conclusions: Isolated open tibial shaft fractures are potentially harmful to the patient’s quality of life after 120 days of the initial management. RWR is significantly higher for younger patients, no history of infection, and those who could run in the gait status assessment.

Background: We assessed the effectiveness of an HPV (human papillomavirus) vaccination program in lowering cervical abnormality risk, and conferring herd protection. Methods: Retrospective cohort study using linked screening and vaccination administrative health data of the general population of Ancona Province, Italy. We included all female residents born in 1990–1993, eligible for catch-up HPV vaccination up to age 25 years, and adhering to organized screening in 2015–2020 (n = 4,665). Cervical abnormalities rates were compared between: Vaccinated and unvaccinated women, and cohorts with high and low vaccination uptake. Analyses were adjusted for age, country of birth, screening tests number, laboratory, and municipality average income. Main outcomes were ASC-US+ or LSIL+ Pap smears, and CIN1+ or CIN2+ histology. Results: Mean screening age was 26.6±1.5 years, and 1,118 screened women (24.0%) were vaccinated (mean vaccination age 19.2±1.5 years). The diagnosed cervical abnormalities were: 107 LSIL+ (2.3%), 70 CIN1+ (1.5%), and 35 CIN2+ (0.8%). The adjusted odds ratios of LSIL+, CIN1+, and CIN2+ among vaccinated versus unvaccinated women were, respectively: 0.55 [(95% confidence interval (CI), 0.33–0.91)], 0.43 (95% CI, 0.22–0.86), and 0.31 (95% CI, 0.11–0.91). Among the unvaccinated, those in the highest-uptake (45.3%) 1993 cohort, versus the last pre-vaccination 1990 cohort, showed AORs of LSIL+ and CIN1+ of 0.23 (95% CI, 0.10–0.50), and 0.22 (95% CI, 0.07–0.69), respectively. Conclusions: In the first evaluation from Central Italy, catch-up HPV vaccination considerably reduced the risk of all cervical abnormalities diagnosed within organized screening, and conferred an elevated degree of herd protection among unvaccinated women. Impact: The high protection conferred by HPV vaccination suggests the need to update cervical screening.

A precise estimate of the frequency and severity of SARS-CoV-2 reinfections would be critical to optimize restriction and vaccination policies for the hundreds of millions previously infected subjects. We performed a meta-analysis to evaluate the risk of reinfection and COVID-19 following primary infection.We searched MedLine, Scopus and preprint repositories for cohort studies evaluating the onset of new infections among baseline SARS-CoV-2-positive subjects. Random-effect meta-analyses of proportions were stratified by gender, exposure risk, vaccination status, viral strain, time between episodes, and reinfection definition.Ninety-one studies, enrolling 15,034,624 subjects, were included. Overall, 158,478 reinfections were recorded, corresponding to a pooled rate of 0.97% (95% CI: 0.71%-1.27%), with no substantial differences by definition criteria, exposure risk or gender. Reinfection rates were still 0.66% after ≥12 months from first infection, and the risk was substantially lower among vaccinated subjects (0.32% vs. 0.74% for unvaccinated individuals). During the first 3 months of Omicron wave, the reinfection rates reached 3.31%. Overall rates of severe/lethal COVID-19 were very low (2-7 per 10,000 subjects according to definition criteria) and were not affected by strain predominance.A strong natural immunity follows the primary infection and may last for more than one year, suggesting that the risk and health care needs of recovered subjects might be limited. Although the reinfection rates considerably increased during the Omicron wave, the risk of a secondary severe or lethal disease remained very low. The risk-benefit profile of multiple vaccine doses for this subset of population needs to be carefully evaluated.

The aim of the present study was to evaluate the contamination levels of some classes of persistent organic pollutants in free-range hen eggs and to estimate the related human dietary exposure in a site of national interest, characterized by a serious state of environmental pollution in the Bussi sul Tirino area in central Italy. For these purposes, 17 samples of free-range hen eggs collected in home-producing farms located in the site of national interest territory were analyzed for 17 polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), 12 dioxin-like polychlorinated biphenyls (dl-PCBs), and 6 non-dioxin-like PCBs (ndl-PCBs). Dietary exposure was assessed assuming a standard consumption of eggs per week. The concentration of ∑PCDD/Fs plus dl-PCBs ranged from 0.463 to 8.028 pg toxic equivalent g-1 fat, whereas the mean contamination level of the ∑ndl-PCBs ranged from 0.234 to 7.741 ng toxic equivalent g-1 fat. PCDD/Fs and PCBs contamination levels were lower than maximum values established by the Commission Regulation (European Union) 1259/2011, except for one sample. The estimated weekly intake, calculated to evaluate the contribution in terms of the monitored pollutants of the locally produced eggs to the diet, was lower than the tolerable weekly intake established by the European Food Safety Authority. HIGHLIGHTS

Bone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3′ untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function.

Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics. There are several types of PIs and enzymes implicated in brain activities and among these enzymes, PI-PLCs contribute to a specific and complex network in the developing nervous system. Moreover, considering the abundant presence of PI-PLCβ1, PI-PLCγ1 and PI-PLCβ4 in the brain, a specific role for each PLC subtype has been suggested in the control of neuronal activity, which is important for synapse function, development and other mechanisms. The focus of this review is to describe the latest research about the involvement of PI-PLC signaling in the nervous system, both physiologically and in pathological conditions. Indeed, PI-PLC signaling imbalance seems to be also linked to several brain disorders including epilepsy, movement and behavior disorders, neurodegenerative diseases and, in addition, some PI-PLC subtypes could become potential novel signature genes for high-grade gliomas.

Human body dissection is fundamental in medical education, as it allows future physicians to learn about the body's morphology in three dimensions, to recognize anatomical variations and to develop and increase the essential qualities of respect, compassion and empathy for patients. It is equally important in clinical training as it allows surgeons to improve their manual dexterity and practical skills and to test innovative surgical techniques and devices. In Italy prior to 2020, body acquisition and use for study and research purposes were regulated by a generic set of old directives and national decrees which dealt only marginally with these issues. However, in 2013, a whole body donation program was officially set up at the Institute of Human Anatomy of the University of Bologna. Completely free and voluntary informed consent has always been regarded as a core prerequisite and, since its inception, the program exclusively accepted bequeathed bodies. On February 10, 2020, a specific law governing the disposition of post mortem human body and tissues for study, training and scientific research purposes was definitively enacted. The present work traces the University of Bologna's experience leading to the whole body donation program and the brand new dissecting room. It describes the program of Bologna as an example of "good practice" in body donation, aimed at ensuring education and clinical training by means of both traditional gross anatomy and innovative technology. Moreover, it analyzes the results achieved in terms of increased donor enrollment and improved teaching/training quality and the strengths of this program in light of the provisions enshrined in the new law.

Key messages By the end of January 2021, almost 100 million people were infected with SARS-CoV-2 and over two million had died.1 Disruptions in healthcare delivery occurred in most countries as a direct consequence of the pressures posed by overwhelming numbers of COVID-19 cases, and as an indirect effect of strict infection containment measures such as social distancing and lockdowns.2 Italian regions halted cervical screening programmes in March 2020, for about 4 months, when only follow-up colposcopies were guaranteed.3 In the province of Ancona, primary conventional cervical cytology (Pap smear) screening was suspended from 9 March to 30 June 2020 as its organisation did not guarantee social distancing.4 Indeed, the programme was based on flexible-timing invitations: assuming an average 50% participation, more women than the available time slots were invited, without strict timings or having to confirm their appointment.5 This implied the possibility of overcrowding in waiting rooms. The pandemic posed a double challenge: while flexible-timing was eliminated to ensure social distancing, a greater number of tests was needed to clear the 16-week backlog. The adopted strategies differed greatly across Italian regions: several already used fixed appointments (with a precise date and time in the invitation letter, in accordance with national recommendations)6 and only had to allocate more time for each test in order to avoid overcrowding. Most of the other regions, which used flexible-timing, moved to fixed appointments, and some programmes required the women …

Background: This laboratory study was done to evaluate the efficacy of personal protective equipment (PPE) and high-volume evacuation (HVE) against the spread of human coronavirus type 229E (HCoV-229E) during a standard dental procedure. Methods: Patient and operator manikins were used to recreate a dental setting inside a custom-built class III cabinet–like chamber. The mouth of the patient manikin was inoculated with an HCoV-229E suspension, the viral load of which was similar to that of asymptomatic people infected with severe acute respiratory syndrome coronavirus 2. The dental procedure was performed with an air turbine handpiece and HVE for 10 seconds. The efficacy of surgical masks, N95 (filtering facepiece class 2) and filtering facepiece class 3 respirators, and face shields was tested via quantitative real-time polymerase chain reaction. Results: The wide surface on which the inoculum was spread caused low contamination. Over the external surfaces of masks and respirators, when a face shield was not worn, viral loads ranged from 1.2 through 1.4 log10 mean gene copies per cm2. When the shield was worn, viral loads dropped below the detection limit (< 0.317 log10 gene copies/cm2) for all PPE. On the operator's forehead, viral loads were 0.6 through 0.8 log10 gene copies/cm2. Inside the operator manikin's mouth, viral loads were under the detection limit when using any PPE, with or without the shield. HVE did not significantly change viral loads. Conclusions: All PPE combinations significantly reduced viral loads in the operator manikin's mouth to below the detection limit, but HVE did not decrease viral contamination. Practical Implications: Although caution is suggested when removing and disposing of PPE to avoid self-contamination, the combination of PPE and face shields drastically decreases the risk of transmitting human coronavirus during aerosol-generating dental procedures.

Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy, characterized by a heterogeneous genetic landscape and complex clonal evolution, with poor outcomes. Mutation at the internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic alterations in AML, associated with high relapse rates and poor survival due to the constitutive activation of the FLT3 receptor tyrosine kinase and its downstream effectors, such as PI3K signaling. Thus, aberrantly activated FLT3-kinase is regarded as an attractive target for therapy for this AML subtype, and a number of small molecule inhibitors of this kinase have been identified, some of which are approved for clinical practice. Nevertheless, acquired resistance to these molecules is often observed, leading to severe clinical outcomes. Therapeutic strategies to tackle resistance include combining FLT3 inhibitors with other antileukemic agents. Here, we report on the preclinical activity of the combination of the FLT3 inhibitor quizartinib with the dual PI3K/mTOR inhibitor PF-04691502 in FLT3-ITD cells. Briefly, we show that the association of these two molecules displays synergistic cytotoxicity in vitro in FLT3-ITD AML cells, triggering 90% cell death at nanomolar concentrations after 48 h.

Background: In Italy, a nationwide full lockdown was declared between March and May 2020 to hinder the novel coronavirus disease 2019 (COVID-19) pandemic. The potential individual health effects of long-term isolation are largely unknown. The current study investigated the arrhythmic consequences of the COVID-19 lockdown in patients with defibrillators (ICDs) living in the province of Ferrara, Italy. Methods: Both the arrhythmias and the delivered ICD therapies as notified by the devices were prospectively collected during the lockdown period (P1) and compared to those occurred during the 10weeks before the lockdown began (P2) and during the same period in 2019 (P3). Changes in outcome over the three study periods were evaluated for significance using McNemar's test. Results: A total of 413 patients were included in the analysis. No differences were found concerning either arrhythmias or shocks or anti-tachycardia pacing. Only the number of patients experiencing non-sustained ventricular tachycardias (NSVTs) during P1 significantly decreased as compared to P2 (p=0.026) and P3 (p=0.009). The subgroup analysis showed a significant decrease in NSVTs during P1 for men (vs. P2, p=0.014; vs. P3, p=0.040) and younger patients (vs. P2, p=0.002; vs. P3, p=0.040) and for ischemic etiology (vs. P2, p=0.003). No arrhythmic deaths occurred during P1. Conclusions: The complete nationwide lockdown, as declared by the Italian government during the first COVID-19 pandemic peak, did not impact on the incidence of arrhythmias in an urban cohort of patients with ICDs.

Background Current data suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections are rare, but no information are available on minors and after 12 months of follow-up. Methods This retrospective cohort study included all the population of an Italian Province, diagnosed with a SARS-CoV-2 infection from March 2020 to May 2021. The primary outcome was the incidence of a reinfection, defined as a new positive polymerase chain reaction (PCR) test occurring ≥90 days after complete resolution of the first infection, and data were retrieved from the official datasets (coronavirus disease 2019 [COVID-19], demographic, hospital and co-pay exemption) of the Local Health Unit (LHU) of Pescara. Results After an average of 201 days of follow-up (max. 414), we recorded 24 reinfections ≥90 days after the resolution of the first 7173 infections (0.33%). Four reinfections required hospitalization, one was lethal. Most of the reinfections (n = 13) occurred 6–9 months after the resolution of the first infection; no new infection was detected 12 or more months later and among the 832 minors. Conclusions This study confirms previous findings on a low risk of SARS-CoV-2 reinfection. If confirmed, these findings suggest that more targeted restriction policies can be applied to the subjects that recovered after a first infection.

Background Idiopathic Pulmonary Fibrosis (IPF) is an aggressive interstitial lung disease with an unpredictable course. Occupational dust exposure may contribute to IPF onset, but its impact on antifibrotic treatment and disease prognosis is still unknown. We evaluated clinical characteristics, respiratory function and prognostic predictors at diagnosis and at 12 month treatment of pirfenidone or nintedanib in IPF patients according to occupational dust exposure. Methods A total of 115 IPF patients were recruited. At diagnosis, we collected demographic, clinical characteristics, occupational history. Pulmonary function tests were performed and two prognostic indices [Gender, Age, Physiology (GAP) and Composite Physiologic Index (CPI)] calculated, both at diagnosis and after the 12 month treatment. The date of long-term oxygen therapy (LTOT) initiation was recorded during the entire follow-up (mean = 37.85, range 12–60 months). Results At baseline, patients exposed to occupational dust [≥ 10 years (n = 62)] showed a lower percentage of graduates (19.3% vs 54.7%; p = 0.04) and a higher percentage of asbestos exposure (46.8% vs 18.9%; p 0.002) than patients not exposed [

Objective To assess the effectiveness of an HPV vaccination programme in reducing the risk of cervical abnormalities identified at subsequent screening. Design Retrospective cohort study using administrative health data. Setting General population of Ferrara Province, Italy. Population Female residents born in 1986-1993 and participating in the organized cervical screening programme in 2011-2018, who were eligible for HPV vaccination in catch-up cohorts. Methods Logistic regression to evaluate the potential association between abnormal cervical cytology and one, two, three or at least one dose of HPV vaccine. Main outcome measures Cervical abnormalities, as predicted by low-grade or high-grade cytology, by number of vaccine doses, stratified by age. Results The sample consisted of 7785 women (mean age 27.5 years, SD 2.3). Overall, 391 (5.0%) were vaccinated with ≥1 dose and 893 (11.5%) had abnormal cytology. Women receiving at least one vaccine dose were significantly less likely to have an abnormal cytology (adjusted odds ratio 0.52; 95% confidence interval 0.34-0.79). Similar results were observed for women receiving a single dose, for both bivalent and quadrivalent vaccines, and applying buffer periods (excluding cytological outcomes within 1 month, 6 months and 1 year of the first dose). Conclusions In the context of an organised cervical screening programme in Italy, catch-up HPV vaccination almost halved the risk of cytological abnormalities. Tweetable abstract Among Ferrara women, vaccination against human papillomavirus halved the risk of screening cervical abnormalities.

An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA.

Introduction: The primary aim of this study was to ascertain the strength of association between cerebral blood flow assessed in anterior (ACA), middle (MCA), and posterior (PCA) cerebral arteries and the following clinical outcomes: small for gestational age (SGA), induction of labor (IOL) for oligohydramnios and caesarean section (CS) for nonreassuring fetal status (NRFS) during labor. Material and methods: Retrospective analysis of prospectively collected data on consecutive singleton pregnancies from 40 0/7 to 41 6/7 week of gestation. UA, ACA, MCA, PCA pulsatility index (PI) were measured from 40 weeks of gestations. Furthermore, the ratios between cerebral blood flow and UA (CPR, ACA/UA and PCA/UA) were calculated and correlated with the observed outcomes. Results: Two hundred twenty-four singleton pregnancies were included in the study. Mean PI of either ACA (p = .04), MCA (p = .008), and PCA (p = .003) were lower in the SGA compared to non-SGA group; furthermore, mean PCA PI was significantly lower than MCA PI (p = .04). Furthermore, CPR (p = .016), ACA/UA (p = .02), and PCA/UA (p = .003) were significantly lower in the SGA group compared to controls. UA, ACA, MCA, and PCA PI were higher in women undergoing IOL for oligohydramnios compared to controls. Logistic regression analysis showed that CPR and PCA/UA ratio were independently associated with SGA. SGA, ACA PI, and ACA/UA were independently associated with CS for NRFS. Finally, birthweight centile, were independently associated with IOL oligohydramnios. Despite this, the predictive accuracy of Doppler in detecting any of the explored outcome was only poor to moderate. Conclusion: Redistribution of cerebral blood flow at term is significantly associated with SGA, IOL for oligohydramnios and CS for NRFS in labor. However, the predictive accuracy of Doppler at term is only poor to moderate, thus advising against its use in clinical practice as a standalone screening test for adverse perinatal outcome in pregnancies at term. Key Message Redistribution of cerebral blood flow at term is significantly associated with SGA, IOL for oligohydramnios and CS for NRFS in labor.

Objective To elucidate the role of Doppler ultrasound in predicting perinatal outcome in appropriate for gestational age (AGA) fetuses at term. Material and Methods Prospective study carried out in a dedicated research ultrasound clinic. The inclusion criterion was AGA fetuses, defined as those with an estimated fetal weight between the 10th and 90th percentile, at 36 + 0-37 + 6 weeks of gestation. The primary outcome was a composite score of adverse perinatal outcome including either adverse intrapartum events or abnormal acid-base status at birth. Secondary outcomes were the individual components of the primary outcome. The Doppler parameters explored were umbilical artery (UA) PI, middle cerebral artery (MCA) PI, uterine arteries (UtA) PI and cerebroplacental ratio (CPR). Attending clinicians were blinded to Doppler findings. Logistic regression and ROC curve analyses were used to analyze the data. Results 553 AGA fetuses were included. There was no difference in mean UA PI (p = 0.486), MCA PI (p = 0.621), CPR (p = 0.832) and UtA PI (p = 0.611) between pregnancies complicated by composite perinatal morbidity compared to those not complicated by composite perinatal morbidity. In pregnancies complicated by adverse intrapartum outcome, the mean MCA PI (1.47 ± 0.4 vs 1.61 ± 0.4, p = 0.0039) was lower compared to the control group, while there was no difference in UA PI (p = 0.758), CPR (p = 0.108), and UtA PI (p = 0.177). Finally, there was no difference in any of the Doppler parameters explored between AGA fetuses with abnormal acid-base status at birth compared to those without abnormal acid-base status at birth. In the logistic regression analysis, UA PI, MCA PI, CPR, UtA PI, EFW and AC percentiles were not independently associated with composite adverse outcome, adverse intrapartum outcome or abnormal acid-base status at birth in non-SGA fetuses. The diagnostic performance of all of these Doppler parameters for predicting composite adverse outcome, adverse intrapartum outcome and abnormal acid-base status was poor. Conclusion Cerebroplacental and maternal Doppler is not associated with or predictive of adverse pregnancy outcome in AGA fetuses close to term. Ziel Aufklärung der Rolle des Dopplerultraschalls bei der Vorhersage des perinatalen Outcomes von reifgeborenen Föten (AGA = appropriate for gestational age). Material und Methoden Prospektive Studie in einer speziellen Ultraschall- Forschungsklinik. Das Einschlusskriterium waren AGA-Föten, definiert durch ein geschätztes fetales Gewicht zwischen der 10. bis 90. Perzentile und der 36 + 0 bis 37 + 6 Schwangerschaftswoche. Der primäre Endpunkt war ein zusammengesetzter Score für das negative perinatale Outcome einschließlich unerwünschter intrapartaler Komplikationen oder einem abnormalen Säure-Basen-Status bei der Geburt. Den sekundären Endpunkt bildeten die Einzelparameter des primären Endpunkts. Die untersuchten Dopplerparameter waren der PI der A. umbilicalis (UA), der A. cerebri media (MCA) und der A. uterinae (UtA) und die zerebroplazentare Ratio (CPR). Die anwesenden Ärzte waren für die Dopplerbefunde blind. Zur Datenanalyse wurden logistische Regressions- und ROC-Kurvenanalysen verwendet. Ergebnisse 553 AGA-Föten wurden eingeschlossen. Es gab keinen Unterschied zwischen den mittleren Werten für UA-PI (p = 0,486), MCA-PI (p = 0,621), CPR (p = 0,832) und UtA-PI (p = 0,611) bei Schwangerschaften mit und ohne kombinierter perinataler Morbidität. In Schwangerschaften mit unerwünschten intrapartalen Komplikationen war der mittlere MCA-PI niedriger als in der Kontrollgruppe (1,47 ± 0,4 vs. 1,61 ± 0,4; p = 0,0039), während es keinen Unterschied zwischen UA-PI (p = 0,758), CPR (p = 0,108) und UtA-PI (p = 0,177) gab. Schließlich zeigten sich in keinem der untersuchten Dopplerparameter Unterschiede zwischen AGA-Föten mit abnormalem Säure-Basen-Status bei Geburt und solche ohne. In der logistischen Regressionsanalyse waren UA-PI, MCA-PI, CPR, UtA-PI, EFW und AC-Perzentilen nicht unabhängig voneinander mit einem kombinierten negativen Outcome, intrapartalen Komplikationen oder einem abnormalen Säure-Basen-Status bei der Geburt assoziiert. Die diagnostische Leistung all dieser Dopplerparameter zur Vorhersage von kombinierten intrapartalen Komplikationen und eines abnormalen Säure-Basen-Status war schlecht. Schlussfolgerung Bei AGA-Föten kurz vor Entbindung stehen zerebroplazentare und maternale Doppler nicht in Zusammenhang mit einem schlechten Schwangerschaftsoutcome bzw. sagen dieses voraus.

To report the outcome of pregnancies complicated by twin-twin transfusion syndrome (TTTS) according to Quintero stage.MEDLINE, EMBASE and CINAHL databases were searched for studies reporting the outcome of pregnancies complicated by TTTS stratified according to Quintero stage (I-V). The primary outcome was fetal survival rate according to Quintero stage. Secondary outcomes were gestational age at birth, preterm birth (PTB) before 34, 32 and 28 weeks' gestation and neonatal morbidity. Outcomes are reported according to the different management options (expectant management, laser therapy or amnioreduction) for pregnancies with Stage-I TTTS. Only cases treated with laser therapy were considered for those with Stages-II-IV TTTS and only cases managed expectantly were considered for those with Stage-V TTTS. Random-effects head-to-head meta-analysis was used to analyze the extracted data.Twenty-six studies (2699 twin pregnancies) were included. Overall, 610 (22.6%) pregnancies were diagnosed with Quintero stage-I TTTS, 692 (25.6%) were Stage II, 1146 (42.5%) were Stage III, 247 (9.2%) were Stage IV and four (0.1%) were Stage V. Survival of at least one twin occurred in 86.9% (95% CI, 84.0-89.7%) (456/552) of pregnancies with Stage-I, in 85% (95% CI, 79.1-90.1%) (514/590) of those with Stage-II, in 81.5% (95% CI, 76.6-86.0%) (875/1040) of those with Stage-III, in 82.8% (95% CI, 73.6-90.4%) (172/205) of those with Stage-IV and in 54.6% (95% CI, 24.8-82.6%) (5/9) of those with Stage-V TTTS. The rate of a pregnancy with no survivor was 11.8% (95% CI, 8.4-15.8%) (69/564) in those with Stage-I, 15.0% (95% CI, 9.9-20.9%) (76/590) in those with Stage-II, 18.6% (95% CI, 14.2-23.4%) (165/1040) in those with Stage-III, 17.2% (95% CI, 9.6-26.4%) (33/205) in those with Stage-IV and in 45.4% (95% CI, 17.4-75.2%) (4/9) in those with Stage-V TTTS. Gestational age at birth was similar in pregnancies with Stages-I-III TTTS, and gradually decreased in those with Stages-IV and -V TTTS. Overall, the incidence of PTB and neonatal morbidity increased as the severity of TTTS increased, but data on these two outcomes were limited by the small sample size of the included studies. When stratifying the analysis of pregnancies with Stage-I TTTS according to the type of intervention, the rate of fetal survival of at least one twin was 84.9% (95% CI, 70.4-95.1%) (94/112) in cases managed expectantly, 86.7% (95% CI, 82.6-90.4%) (249/285) in those undergoing laser therapy and 92.2% (95% CI, 84.2-97.6%) (56/60) in those after amnioreduction, while the rate of double survival was 67.9% (95% CI, 57.0-77.9%) (73/108), 69.7% (95% CI, 61.6-77.1%) (203/285) and 80.8% (95% CI, 62.0-94.2%) (49/60), respectively.Overall survival in monochorionic diamniotic pregnancies affected by TTTS is higher for earlier Quintero stages (I and II), but fetal survival rates are moderately high even in those with Stage-III or -IV TTTS when treated with laser therapy. Gestational age at birth was similar in pregnancies with Stages-I-III TTTS, and gradually decreased in those with Stages-IV and -V TTTS treated with laser and expectant management, respectively. In pregnancies affected by Stage-I TTTS, amnioreduction was associated with slightly higher survival compared with laser therapy and expectant management, although these findings may be confirmed only by future head-to-head randomized trials. Copyright © 2020 ISUOG. Published by John WileySons Ltd.Resultado del síndrome de transfusión feto-fetal según el estadio de Quintero de la enfermedad: revisión sistemática y metaanálisis OBJETIVOS: Informar sobre el resultado de los embarazos complicados por el síndrome de transfusión feto-fetal (TTTS, por sus siglas en inglés) según el estadio de Quintero. MÉTODOS: Se hicieron búsquedas en las bases de datos de MEDLINE, EMBASE y CINAHL de estudios que hubieran informado sobre el resultado de embarazos complicados por TTTS, estratificados según el estadio de Quintero (I-V). El resultado primario fue la tasa de supervivencia fetal según el estadio de Quintero. Los resultados secundarios fueron la edad gestacional al nacer, el parto pretérmino (PPT) antes de las 34, 32 y 28 semanas de gestación y la morbilidad neonatal. Los resultados se reportan de acuerdo con las diferentes opciones de tratamiento (expectante, terapia de láser o amniorreducción) para los embarazos con TTTS en Estadio I. Sólo se consideraron los casos tratados con terapia de láser para aquellos con TTTS de las Etapas II-IV y sólo se consideraron los casos tratados de manera expectante para aquellos con TTTS de la Etapa V. Para analizar los datos extraídos se utilizó un metaanálisis directo de efectos aleatorios. RESULTADOS: Se incluyeron veintiséis estudios (2699 embarazos de gemelos). En total, 610 (22,6%) embarazos fueron diagnosticados con TTTS de Estadio I de Quintero, 692 (25,6%) de Estadio II, 1146 (42,5%) de Estadio III, 247 (9,2%) de Estadio IV y cuatro (0,1%) de Estadio V. La supervivencia de al menos un gemelo se produjo en el 86,9% (IC 95%, 84,0-89,7%) (456/552) de los embarazos en Estadio I, en el 85% (IC 95%, 79,1-90,1%) (514/590) de aquellos en Estadio II, en el 81,5% (IC 95%, 76,6-86,0%) (875/1040) de aquellos en Estadio-III, en el 82,8% (IC 95%, 73,6-90,4%) (172/205) de aquellos en Estadio-IV y en el 54,6% (IC 95%, 24,8-82,6%) (5/9) de aquellos en Estadio-V de TTTS. La tasa de embarazos sin supervivientes fue del 11,8% (IC 95%, 8,4-15,8%) (69/564) de aquellos en Estadio-I, 15,0% (IC 95%, 9,9-20,9%) (76/590) de aquellos en Estadio-II, 18,6% (IC 95%, 14,2-23,4%) (165/1040) de aquellos en Estadio-III, 17,2% (IC 95%, 9,6-26,4%) (33/205) de aquellos en Estadio-IV y en el 45,4% (IC 95%, 17,4-75,2%) (4/9) de aquellos en Estadio-V de TTTS. La edad gestacional al nacer fue similar en los embarazos con TTTS en los Estadios I-III, y disminuyó gradualmente en aquellos con TTTS en los Estadios IV y V. En general, la incidencia de PPT y la morbilidad neonatal aumentaron a medida que se incrementó la gravedad del TTTS, pero los datos sobre estos dos resultados se vieron limitados por el pequeño tamaño de la muestra de los estudios incluidos. Al estratificar el análisis de los embarazos con TTTS en Estadio I según el tipo de tratamiento, la tasa de supervivencia fetal de al menos un gemelo fue del 84,9% (IC 95%, 70,4-95,1%) (94/112) en los casos tratados de forma expectante, del 86,7% (IC 95%, 82,6-90.4%) (249/285) en los sometidos a terapia láser y del 92,2% (IC 95%, 84,2-97,6%) (56/60) en los sometidos a amniorreducción, mientras que la tasa de supervivencia doble fue del 67,9% (IC 95%, 57,0-77,9%) (73/108), del 69,7% (IC 95%, 61,6-77,1%) (203/285) y del 80,8% (IC 95%, 62,0-94,2%) (49/60), respectivamente. CONCLUSIONES: La supervivencia en general en los embarazos biamnióticos monocoriónicos afectados por TTTS es mayor en los estadios tempranos de Quintero (I y II), pero las tasas de supervivencia fetal son moderadamente altas incluso en aquellos con TTTS en estadios III o IV cuando se tratan con terapia láser. La edad gestacional al nacer fue similar en los embarazos con TTTS en los Estadios I-III, y disminuyó gradualmente en aquellos con TTTS en los Estadios IV y V tratados con láser y tratamiento expectante, respectivamente. En los embarazos afectados por TTTS en Estadio I, la amniorreducción estuvo asociada con una supervivencia ligeramente mayor en comparación con la terapia de láser y el tratamiento expectante, aunque estos hallazgos solo pueden confirmarse mediante futuros estudios aleatorizados directos. Copyright © 2020 ISUOG. Published by John WileySons Ltd.根据Quintero分级的双胎输血综合征预后:系统评价与meta分析 目的: 根据Quintero分级，报告双胎输血综合征(TTTS)患者的预后。 方法: 根据Quintero分级(1-5级)，在MEDLINE(美国医学文献联机数据库)、EMBASE(荷兰医学文摘数据库)和CINAHL(护理学数据库)中进行检索，找出报告双胎输血综合征(TTTS)患者预后的研究。根据Quintero分级，主要预后指标是胎儿的存活率。其次是出生时胎龄、孕期在34周、32周和28周之前的早产(PTB)，以及新生儿发病率。针对1级TTTS患者，根据不同的治疗方案(期待治疗、激光治疗或羊水减量术)来报告预后。对2-4级TTTS患者仅考虑使用激光治疗，而对5级TTTS患者则仅考虑期待治疗。对提取数据进行了随机效应头对头meta分析。 结果: 包含26项研究(2699个双胎妊娠)。总的说来，610个妊娠(占22.6%)被诊断为Quintero分级1级TTTS，692个妊娠(占25.6%)被诊断为Quintero分级2级TTTS，1146个妊娠(占42.5%)被诊断为Quintero分级3级TTTS，247个妊娠(占9.2%)被诊断为Quintero分级4级TTTS，以及四个妊娠(占0.1%)被诊断为Quintero分级5级TTTS。1级患者双胎中至少有一胎存活的占86.9%(95% CI，84.0-89.7%)(456/552)，2级患者双胎中至少有一胎存活的占 85%(95% Ci，79.1-90.1%)(514/590)，3级患者双胎中至少有一胎存活的占81.5% (95% CI，76.6-86.0%)(875/1040)，4级患者双胎中至少有一胎存活的占82.8% (95% CI, 73.6-90.4%)(172/205)，以及5级患者双胎中至少有一胎存活的占54.6% (95% CI, 24.8-82.6%)(5/9)。无胎儿存活的概率在1级患者中占11.8%(95% CI，8.4-15.8%)(69/564)，在2级患者中占15.0%(95% CI，9.9-20.9%)(76/590)，在3级患者中占18.6%(95% CI，14.2-23.4%)(165/1040)，在4级患者中占17.2%(95% CI，9.6-26.4%)(33/205)，以及在5级患者中占45.4%(95% CI，17.4-75.2%)(4/9)。出生时胎龄在1-3级患者中均类似，而在4-5级TTTS患者中逐渐降低。总体来看，PTB发生率和新生儿发病率随着TTTS严重程度的增加而增加，但这两种结果的相关数据受到所包含研究的小样本限制。当根据医疗干预类型来分层分析1级TTTS患者时，在采取期待治疗的病例中，双胎中至少有一胎存活的占84.9%(95% CI，70.4-95.1%)(94/112)；在采取激光治疗的病例中， 双胎中至少有一胎存活的占86.7%(95% CI，82.6-90.4%)(249/285)，而在进行了羊水减量术的病例中，双胎中至少有一胎存活的占92.2%(95% CI，84.2-97.6%)(56/60)。对于这三种医疗干预类型，双胎存活率分别为67.9%(95% CI，57.0-77.9%)(73/108)，69.7%(95% CI，61.6-77.1%)(203/285)和80.8%(95% CI，62.0-94.2%)(49/60)。 结论: 在患有TTTS的单绒毛膜囊双羊膜囊妊娠中，Quintero分级越早期(1级和2级)，总体存活率越高，但在采取了激光治疗的3级或4级患者中均有较高的胎儿存活率。出生时胎龄在1-3级患者中均类似，而在4级和5级(分别采取激光和期待治疗的)TTTS患者中逐渐降低。在1级TTTS患者中，与激光治疗和期待治疗相比，羊水减量术有略高的存活率，然而，这些研究结果也许只有通过将来的头对头随机试验来进行确认。版权 © 2020 ISUOG。由威利父子公司(John WileySons Ltd)出版。.

OBJECTIVE: Information on the long-term safety of electronic cigarettes (e-cig) is still limited. We report the results after six years of follow-up of the first observational study assessing e-cig long-term effectiveness and safety. PATIENTS AND METHODS: Participants were adults who smoked ≥1 tobacco cigarette/day (tobacco smokers); or used any type of e-cig inhaling ≥50 puffs weekly (e-cig users); or used both (dual users). Participants were contacted directly or by phone and/or internet interviews. Hospital discharge abstract data and carbon monoxide level tests were also used. RESULTS: Data were available for 228 e-cig users (all ex-smokers), 469 tobacco smokers, 215 dual users. A possibly smoking-related disease (PSRD) was recorded in 90 subjects (9.9%); 11 deceased (1.2%). No differences were observed across groups in PSRD rates, with minor changes in self-reported health. Among e-cig users, 64.0% remained tobacco abstinent. Dual users and tobacco smokers did not significantly differ in the rate of cessation of tobacco (38.6% vs. 33.9%, respectively) and all products (23.7% vs. 26.4%). A comparable decrease in daily cigarettes was also observed. 39.5% of the sample switched at least once (tobacco smokers: 15.1%; dual users: 83.3%). CONCLUSIONS: After six years, no evidence of harm reduction was found among e-cig or dual users. The complete switch to e-cig might support tobacco quitters remain abstinent, but the use of e-cig in addition to tobacco did not improve smoking cessation or reduction.

Background Emergency Department (ED) crowding reduces staff satisfaction and healthcare quality and safety, which in turn increase costs. Despite a number of proposed solutions, ED length of stay (LOS) - a main cause of overcrowding - remains a major issue worldwide. This retrospective cohort study was aimed at evaluating the effectiveness on ED LOS of a procedure called “Diagnostic Anticipation” (DA), which consisted in anticipating the ordering of blood tests by nurses, at triage, following a diagnostic algorithm approved by physicians. Methods In the second half of 2019, the ED of the University Hospital of Ferrara, Italy, adopted the DA protocol on alternate weeks for all patients with chest pain, abdominal pain, and non-traumatic bleeding. A retrospective cohort study on DA impact was conducted. Using ED electronic data, LOS independent predictors (age, sex, NEDOCS and Priority Color Code, imaging tests, specialistic consultations, hospital admission) were evaluated through multiple regression. Results During the weeks when DA was adopted, as compared to control weeks, the mean LOS was shorter by 18.2 min for chest pain, but longer by 15.7 min for abdominal pain, and 33.3 for non-traumatic bleeding. At multivariate analysis, adjusting for age, gender, triage priority, specialist consultations, imaging test, hospitalization and ED crowding, the difference in visit time was significant for chest pain only (p Conclusions The impact of DA varied by patients’ condition, being significant for chest pain only. Further research is needed before the implementation, estimating the potential proportion of inappropriate blood tests and ED crowding status.

To assess the rate of fetal loss following amniocentesis or chorionic villus sampling (CVS) in twin pregnancy.MEDLINE, EMBASE and Cochrane databases were searched for studies reporting procedure-related complications following amniocentesis or CVS in twin pregnancy. The primary outcome was the rate of procedure-related fetal loss. The secondary outcomes were fetal loss occurring before 24 weeks of gestation and fetal loss occurring within 4 weeks after the procedure. Head-to-head meta-analyses were used to compare directly each outcome, between women undergoing amniocentesis and those not undergoing amniocentesis and between women undergoing CVS and those not undergoing CVS, and to compute pooled risk differences (RD) between women exposed and those not exposed to each invasive procedure. Additionally, meta-analyses of proportions were used to estimate the pooled rates of each of the three outcomes in women undergoing amniocentesis or CVS and in controls.Sixteen studies (3419 twin pregnancies undergoing and 2517 not undergoing an invasive procedure) were included. Head-to-head meta-analyses comparing directly twin pregnancies undergoing and those not undergoing amniocentesis showed a higher risk for overall fetal loss in those undergoing amniocentesis (odds ratio (OR), 1.46 (P = 0.04); RD, 0.013 (P = 0.04)), while there was no difference in the risk of either fetal loss before 24 weeks of gestation (OR, 1.59 (P = 0.06); RD, 0.010 (P = 0.11)) or fetal loss within 4 weeks after the procedure (OR, 1.38 (P = 0.3); RD, 0.003 (P = 0.8)). Overall, the pooled rate of fetal loss was 2.4% (95% CI, 1.4-3.6%) in twin pregnancies undergoing amniocentesis compared with 2.4% (95% CI, 0.9-4.6%) in those not undergoing amniocentesis. Head-to-head meta-analyses directly comparing twin pregnancies undergoing and those not undergoing CVS showed no significant difference in either overall fetal loss (OR, 1.61 (P = 0.5); RD, 0.003 (P = 0.8)) or fetal loss before 24 weeks of gestation (OR, 1.61 (P = 0.5); RD, 0.003 (P = 0.8)). Overall, the pooled rate of fetal loss was 2.0% (95% CI, 0.0-6.5%) in twin pregnancies undergoing CVS compared with 1.8% (95% CI, 0.3-4.2%) in those not undergoing CVS.The risk of fetal loss following amniocentesis and CVS in twins is lower than reported previously and the rate of fetal loss before 24 weeks of gestation, or within 4 weeks after the procedure, did not differ from the background risk in twin pregnancy not undergoing invasive prenatal testing. These data can guide prenatal counseling for twin pregnancies undergoing invasive procedures. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.Riesgo de pérdida del feto tras una amniocentesis o una biopsia de vellosidades coriónicas en un embarazo de gemelos: revisión sistemática y metaanálisis OBJETIVO: Evaluar la tasa de pérdida del feto tras una amniocentesis o una biopsia de vellosidades coriónicas (BVC) en un embarazo de gemelos. MÉTODOS: Se hizo una búsqueda en las bases de datos MEDLINE, EMBASE y Cochrane de estudios que habían reportado complicaciones relacionadas con el procedimiento después de una amniocentesis o una BVC en un embarazo de gemelos. El resultado primario fue la tasa de pérdida del feto relacionada con el procedimiento. Los resultados secundarios fueron la pérdida del feto producida antes de las 24 semanas de gestación y la pérdida del feto producida dentro de las 4 semanas posteriores al procedimiento. Se utilizaron metaanálisis cara a cara para comparar cada resultado directamente, entre las mujeres que se sometieron a una amniocentesis y las que no se sometieron a ella, y entre las mujeres que se sometieron a una BVC y las que no se sometieron a ella, así como para calcular las diferencias de riesgo (DR) combinadas entre las mujeres expuestas y las no expuestas a cada procedimiento agresivo. Además, se utilizaron los metaanálisis de proporciones para estimar las tasas combinadas de cada uno de los tres resultados en las mujeres que se sometieron a amniocentesis o a BVC y en los controles. RESULTADOS: Se incluyeron 16 estudios (3.419 embarazos de gemelos sometidos a un procedimiento agresivo y 2.517 no sometidos). Los metaanálisis cara a cara que compararon directamente los embarazos de gemelos sometidos y no sometidos a amniocentesis mostraron un mayor riesgo de pérdida general del feto en total en los sometidos a amniocentesis (Razón de Momios (RM), 1,46 (P=0,04); DR, 0,013 (P=0,04)), mientras que no hubo diferencias en el riesgo de pérdida del feto antes de las 24 semanas de gestación (RM, 1,59 (P=0,06); DR, 0,010 (P=0,11)) ni en el de las 4 semanas posteriores al procedimiento (RM, 1,38 (P=0,3); DR, 0,003 (P=0,8)). En general, la tasa conjunta de pérdida del feto fue del 2,4% (IC 95%, 1,4-3,6%) en los embarazos de gemelos sometidos a amniocentesis, en comparación con el 2,4% (IC 95%, 0,9-4,6%) en los que no se sometieron a amniocentesis. Los metaanálisis cara a cara que compararon directamente los embarazos de gemelos que se sometieron y que no se sometieron a una BVC no mostraron diferencias significativas ni en la pérdida del feto en total (RM, 1,61 (P=0,5); DR, 0,003 (P=0,8)) ni en la pérdida del feto antes de las 24 semanas de gestación (RM, 1,61 (P=0,5); DR, 0,003 (P=0,8)). En general, la tasa combinada de pérdida del feto fue del 2,0% (IC 95%, 0,0-6,5%) de los embarazos de gemelos sometidos a BVC, comparada con el 1,8% (IC 95%, 0,3-4,2%) de los que no se sometieron a BVC. CONCLUSIÓN: El riesgo de pérdida del feto tras la amniocentesis y la BVC en gemelos es menor que lo reportado en el pasado y la tasa de pérdida del feto antes de las 24 semanas de gestación, o dentro de las 4 semanas posteriores al procedimiento, no difiere de la del riesgo de contexto en los embarazos de gemelos que no se someten a pruebas prenatales agresivas. Estos datos pueden servir de guía para el asesoramiento prenatal de los embarazos de gemelos que se someten a procedimientos agresivos.双胎妊娠中继羊膜穿刺术或绒膜绒毛取样后发生流产的风险:系统评价和荟萃分析 目的: 评估双胎妊娠中继羊膜穿刺术或绒膜绒毛取样(CVS)后发生的流产率。 方法: 在MEDLINE(美国医学文献联机数据库)、EMBASE(荷兰医学文摘数据库)和实证医学资料库中针对报告双胎妊娠中继羊膜穿刺术或CVS后发生与医疗程序相关的并发症进行了搜索。主要结果是与医疗程序相关的流产率。次要结果是发生在孕期24周前的流产和疗程后4周内发生的流产。采用头对头荟萃分析来直接对比每个结果，在已进行过羊膜穿刺术的孕妇与未进行羊膜穿刺术的孕妇之间，并在已经历CVS的孕妇和未经历CVS的孕妇之间进行对比，以计算出暴露于每种侵入性疗程和未暴露于每种侵入性疗程的孕妇之间的汇总风险差异。此外，采用按比例的荟萃分析来评估经历羊膜穿刺术或CVS的孕妇及对照组中三种预后的 每个汇总比率。 结果: 包含了16项研究(经历过侵入性医疗程序的3419个双胎妊娠和未经历侵入性医疗程序的2517个 双胎妊娠)。直接对比经历和未经历羊膜穿刺术的双胎妊娠的头对头荟萃分析，表明经历了羊膜穿刺术的双胎孕妇发生流产的总体风险更高(比值比(OR)，1.46 (P=0.04)；RD, 0.013 (P=0.04))，在孕期24周前(OR, 1.59 (P=0.06); RD, 0.010 (P=0.11))或疗程后四周内(OR, 1.38(P=0.3); RD, 0.003 (P=0.8))，这两种情况的流产风险没有差别。总体来看，经历羊膜穿刺术的双胎妊娠的流产汇总比率为2.4%(95% CI, 1.4-3.6%)，相比之下，未经历羊膜穿刺术的双胎妊娠的流产汇总比率为2.4%(95% CI, 0.9-4.6%)。直接对比经历过和未经历CVS的双胎妊娠的头对头荟萃分析，表明总体流产情况(OR, 1.61 (P=0.5); RD, 0.003 (P=0.8))和孕期24周前的流产情况(OR, 1.61 (P=0.5); RD, 0.003 (P=0.8))无显著差异。总体来看，经历过CVS的双胎妊娠的流产汇总比率为2.0%(95% CI, 0.0-6.5%)，相比之下，未经历CVS的双胎妊娠的流产汇总比率为1.8%(95% CI, 0.3-4.2%)。 结论: 双胎妊娠中继羊膜穿刺术或绒膜绒毛取样(CVS)后发生流产的风险低于以前的报告，而且孕期24周前或疗程后四周内的流产率与未经历侵入性产前检查的双胎妊娠中的背景风险没有差异。这些数据能够为双胎妊娠进行侵入性检查提供产前咨询指导。© 2020 国际妇产科超声学会.

Introduction: To explore the strength of association and the diagnostic accuracy of umbilical (UA), middle cerebral (MCA), uterine arteries pulsatility index (PI) and the cerebroplacental ratio in predicting an adverse outcome when applied to singleton pregnancies at term. Material and methods: Prospective study carried out in a dedicated research ultrasound clinic. Attended clinicians were blinded to Doppler findings. Inclusion criteria were consecutive singleton pregnancies between 36+0 and 37+6weeks of gestation. The primary outcome was a composite score of adverse perinatal outcome. Logistic regression and ROC curve analyses were used to analyze the data. Results: In all, 600 consecutive singleton pregnancies from 36weeks of gestation were included in the study. Mean MCA PI (1.1± 0.2 vs 1.5± 0.4, P&nbsp

The epidermal growth factor receptor (EGFR) interacts with various downstream molecules including phospholipase C (PLC)/protein kinase C (PKC), Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/GSK-3, Jak/STAT and others. Often these pathways are deregulated in human malignancies such as breast cancer. Various therapeutic approaches to inhibit the activity of EGFR family members including small molecule inhibitors and monoclonal antibodies (MoAb) have been developed. A common problem with cancer treatments is the development of drug-resistance. We examined the effects of a conditionally-activated EGFR (v-Erb-B:ER) on the resistance of breast cancer cells to commonly used chemotherapeutic drugs such as doxorubicin, daunorubicin, paclitaxel, cisplatin and 5-flurouracil as well as ionizing radiation (IR). v-Erb-B is similar to the EGFR-variant EGFRvIII, which is expressed in various cancers including breast, brain, prostate. Both v-Erb-B and EGFRvIII encode the EGFR kinase domain but lack key components present in the extracellular domain of EGFR which normally regulate its activity and ligand-dependence. The v-Erb-B oncogene was ligated to the hormone binding domain of the estrogen receptor (ER) which results in regulation of the activity of the v-Erb-ER construct by addition of either estrogen (E2) or 4-hydroxytamoxifen (4HT) to the culture media. Introduction of the v-Erb-B:ER construct into the MCF-7 breast cancer cell line increased the resistance to the cells to various chemotherapeutic drugs, hormonal-based therapeutics and IR. These results point to the important effects that aberrant expression of EGFR kinase domain can have on therapeutic resistance.