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Background: The use of medications during pregnancy is a common event worldwide. Monitoring medicine prescriptions in clinical practice is a necessary step in assessing the impact of therapeutic choices in pregnant women as well as the adherence to clinical guidelines. The aim of this study was to provide prevalence data on medication use before, during and after pregnancy in the Italian population. Methods: A retrospective prevalence study using administrative healthcare databases was conducted. A cohort of 449,012 pregnant women (15–49 years) residing in eight Italian regions (59% of national population), who delivered in 2016–2018, were enrolled. The prevalence of medication use was estimated as the proportion (%) of pregnant women with any prescription. Results: About 73.1% of enrolled women received at least one drug prescription during pregnancy, 57.1% in pre-pregnancy and 59.3% in postpartum period. The prevalence of drug prescriptions increased with maternal age, especially during the 1st trimester of pregnancy. The most prescribed medicine was folic acid (34.6%), followed by progesterone (19%), both concentrated in 1st trimester of pregnancy (29.2% and 14.8%, respectively). Eight of the top 30 most prescribed medications were antibiotics, whose prevalence was higher during 2nd trimester of pregnancy in women ≥ 40 years (21.6%). An increase in prescriptions of anti-hypertensives, antidiabetics, thyroid hormone and heparin preparations was observed during pregnancy; on the contrary, a decrease was found for chronic therapies, such as anti-epileptics or lipid-modifying agents. Conclusions: This study represents the largest and most representative population-based study illustrating the medication prescription patterns before, during and after pregnancy in Italy. The observed prescriptive trends were comparable to those reported in other European countries. Given the limited information on medication use in Italian pregnant women, the performed analyses provide an updated overview of drug prescribing in this population, which can help to identify critical aspects in clinical practice and to improve the medical care of pregnant and childbearing women in Italy. [ABSTRACT FROM AUTHOR]

A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p21-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis., Author(s): Dietlinde Wolf [1]; Vanessa Witte [1]; Bernd Laffert [1]; Katja Blume [1]; Elisabeth Stromer [1]; Susanna Trapp [1]; Paola d'Aloja [1]; Annette Schurmann [2]; Andreas S. Baur (corresponding author) [...]

There is an acute need for research to acquire high-quality information on the use of medicines in pregnancy, both in terms of appropriateness and safety. For this purpose, the Italian Medicines Agency established a Network for Monitoring Medication use in pregnancy (MoM-Net) through the conduction of population-based studies using administrative data available at regional level. This paper aimed to describe the experiences and challenges within the network. MoM-Net currently involves eight regions and several experts from public and academic institutions. The first study conducted aimed to identify drug use before, during and after pregnancy investigating specific therapeutic categories, analysing regional variability and monitoring drug use in specific subpopulations (i.e. foreign women/multiple pregnancies). Aggregated demographic, clinical, and prescription data were analysed using a distributed network approach based on common data model. The study population included all women delivering during 2016–2018 in the participating regions (n = 449,012), and corresponding to 59% of deliveries in Italy. Seventy-three per cent of the cohort had at least one drug prescription during pregnancy, compared to 57% before and 59% after pregnancy. In general, a good adherence to guidelines for pregnant women was found although some drug categories at risk of inappropriateness, such as progestins and antibiotics, were prescribed. A strong variability in the use of drugs among regions and in specific subpopulations was observed. The MoM-Net represents a valuable surveillance system on the use of medicines in pregnancy, available to monitor drug categories at high risk of inappropriateness and to investigate health needs in specific regions or subpopulations. [ABSTRACT FROM AUTHOR]

Abstract Background The availability of cell lines releasing fluorescent viral particles can significantly support a variety of investigations, including the study of virus-cell interaction and the screening of antiviral compounds. Regarding HIV-1, the recovery of such biologic reagents represents a very hard challenge due to the intrinsic cytotoxicity of many HIV-1 products. We sought to overcome such a limitation by using a cell line releasing HIV-1 particles in an inducible way, and by exploiting the ability of a HIV-1 Nef mutant to be incorporated in virions at quite high levels. Results Here, we report the isolation and characterization of a HIV-1 packaging cell line, termed 18-4s, able to release valuable amounts of fluorescent HIV-1 based Virus-Like Particles (VLPs) in an inducible way. 18-4s cells were recovered by constitutively expressing the HIV-1 NefG3C mutant fused with the enhanced-green fluorescent protein (NefG3C-GFP) in a previously isolated inducible HIV-1 packaging cell line. The G3C mutation creates a palmitoylation site which results in NefG3C-GFP incorporation into virions greatly exceeding that of the wild type counterpart. Upon induction of 18-4s cells with ponasterone A and sodium butyrate, up to 4 μg/ml of VLPs, which had incorporated about 150 molecules of NefG3C-GFP per viral particle, were released into the culture supernatant. Due to their intrinsic strong fluorescence, the 18-4s VLPs were easily detectable by a novel cytofluorometric-based assay developed here. The treatment of target cells with fluorescent 18-4 VLPs pseudotyped with different glycoprotein receptors resulted in these becoming fluorescent as early as two hours post-challenge. Conclusion We created a stable cell line releasing fluorescent HIV-1 based VLPs upon induction useful for several applications including the study of virus-cell interactions and the screening of antiviral compounds.

In this before and after cross-sectional analysis, the authors aim to assess the impact of the bundle of research and training initiatives implemented between 2013 and 2018, and coordinated by the Italian Obstetric Surveillance System (ItOSS) to reduce obstetric haemorrhagic emergencies in five selected Italian Regions. To this purpose, the haemorrhagic Maternal Mortality Ratios (MMR) per 100,000 live births were estimated before and after implementing the bundle, through the ItOSS's vital statistic linkage procedures and incident reporting and Confidential Enquiries. The research and training bundle was offered to all health professionals involved in pregnancy and birth care in the selected regions, representing 40% of national live births, and participating in the ItOSS audit cycle since its institution. The haemorrhagic MMR significantly decreased from 2.49/100,000 live births [95% CI 1.75 to 3.43] in the years 2007–2013 prior to the bundle implementation, to 0.77/100,000 live births [95% CI 0.31 to 1.58] in the years 2014–2018 after its implementation. According to the study results, the bundle of population-based initiatives might have contributed to reducing the haemorrhagic MMR in the participating regions, thus improving the quality of care of the major obstetric haemorrhage. [ABSTRACT FROM AUTHOR]

Introduction: Distance learning efficacy on physician performances and patient health outcomes has been demonstrated. This study explored the participation and evaluation of CME e-learning courses for Italian health care professionals addressing leading causes of maternal mortality identified by the Italian Obstetric Surveillance System (ItOSS) at the Italian National Health Institute, namely postpartum hemorrhage and pregnancy hypertensive disorders. Methods: A model for two online free 12-hour case-based training courses was used. Data on participants were collected, anonymized, and transferred to the Italian National Health Institute for later analysis. Participants were requested to sign an online informed consent form. Results: Twenty-one thousand five hundred thirty-two health care professionals enrolled to the courses from 2014 to 2017 as follows: midwives (14,187, 65.9%); obstetricians (3,716, 17.2%); anesthesiologists (1,896, 8.8%); and other medical specialists (1,733, 8.0%). Overall, 85% of participants acquired CME credits. Participants' satisfaction on quality, efficacy, and relevance was very high. Discussion: ItOSS courses were able to reach a substantial number of different professional profiles involved in perinatal care all over the country; ItOSS courses can be considered an effective way to spread evidence-based good clinical practices. Nevertheless, further studies are needed to verify the improvement in professional health care skills and patient outcomes. [ABSTRACT FROM AUTHOR]

Suicide has been identified as one of the most common causes of death among women within 1 year after the end of pregnancy in several high-income countries. The aim of this study was to provide the first estimate of the maternal suicide ratio and a description of the characteristics of women who died by suicide during pregnancy or within 1 year after giving birth, induced abortion or miscarriage (i.e., maternal suicide) in 10 Italian regions, covering 77% of total national births. Maternal suicides were identified through the linkage between regional death registries and hospital discharge databases. Background population data was collected from the national hospital discharge, abortion and mortality databases. The previous psychiatric history of the women who died by maternal suicide was retrieved from the regionally available data sources. A total of 67 cases of maternal suicide were identified, corresponding to a maternal suicide ratio of 2.30 per 100,000 live births in 2006–2012. The suicide rate was 1.18 per 100,000 after giving birth (n = 2,876,193), 2.77 after an induced abortion (n = 650,549) and 2.90 after a miscarriage (n = 379,583). The majority of the women who died by maternal suicide (34/57) had a previous psychiatric history; 15/18 previously diagnosed mental disorders were not registered along with the index pregnancy obstetric records. Suicide is a relevant cause of maternal death in Italy. The continuity of care between primary, mental health and maternity care were found to be critical. Clinicians should be aware of the issue, as they may play an important role in preventing suicide in their patients. [ABSTRACT FROM AUTHOR]

Introduction: Peripartum hysterectomy is usually undertaken in cases of life-threatening obstetric hemorrhage to prevent the death of the mother. Near-miss events are still under-researched and inappropriate care continues to be a critical issue, even in countries with advanced obstetric surveillance systems. The aim of the present study was to estimate the prevalence, associated factors, management and intraoperative and postoperative complications of peripartum hysterectomy due to obstetric hemorrhage.Material and Methods: A prospective population-based study has been conducted in six Italian regions covering 49% of births in Italy. The study population comprised all women aged 11-59 years undergoing peripartum hysterectomy, from September 2014 to August 2016, due to obstetric hemorrhage within 7 days of delivery. In each maternity unit a trained reference person reported incident cases using electronic data collection forms. The background population comprised all women who delivered in the participating regions during the study period.Results: The overall peripartum hysterectomy prevalence was 1.09 per 1000 maternities, with a large variability among regions, ranging from 0.52 to 1.60. Previous cesarean section (relative risk [RR] 4.97, 95% CI 4.13-5.96), assisted reproductive technology (RR 5.99, 95% CI 4.42-8.11) multiple pregnancy (RR 5.03, 95% CI 3.57-7.09) and maternal age ≥35 years (RR 2.69, 95% CI 2.25-3.21) were the main associated factors for hysterectomy. The most common causes of peripartum hysterectomy were uterine atony (45.1%) and abnormally invasive placentation (40.2%). Intensive care unit admission was reported in 49.9% of cases, 16.8% of women suffered severe morbidity and 5 women died.Conclusions: The rate of peripartum hysterectomy in Italy was three times higher compared with the UK, the Netherlands and the Nordic countries. The wide difference may be associated with women's characteristics, such as age at delivery and previous cesarean section, and with different management options leading to peripartum hysterectomy. [ABSTRACT FROM AUTHOR]

Introduction: Accurate estimates and reliable classification of maternal deaths are imperative steps in the chain of actions targeted at reducing avoidable maternal mortality. The aims of this study were to estimate the maternal mortality ratio (MMR) in 10 Italian regions covering 77% of total national births and to identify the most suitable approach to classify the causes of death.Material and Methods: Deaths during and within 1 year after pregnancy have been identified through linkage between death registry and hospital discharge database. Regional and national data sources from 2006 to 2012 were used. The MMR has been estimated and deaths were classified as direct or indirect and according to their primary causes.Results: A total of 277 maternal deaths within 42 days after pregnancy were identified: 149 direct, 102 indirect causes and 26 unclassified-resulting in a MMR of 9.18 per 100 000 live births. The under-reporting rate of official MMR figures in the participating regions is 60.3%. Hemorrhage (MMR 1.92), hypertensive disorders of pregnancy and cardiac diseases (MMR 1.06) were the leading causes of deaths occurring within 42 days after pregnancy, whereas malignancy (39%) and violent deaths (17%) were the most frequent of the 543 late maternal deaths.Conclusions: Record-linkage is an efficient and reliable method to estimate maternal mortality and to identify causes of maternal deaths. Both the indirect/direct and the classification by primary cause have a role in countries where direct deaths exceed indirect maternal mortality. Building upon linkage data, confidential enquiries further increase the likelihood of reducing maternal mortality. [ABSTRACT FROM AUTHOR]

Background: The availability of cell lines releasing fluorescent viral particles can significantly support a variety of investigations, including the study of virus-cell interaction and the screening of antiviral compounds. Regarding HIV-1, the recovery of such biologic reagents represents a very hard challenge due to the intrinsic cytotoxicity of many HIV-1 products. We sought to overcome such a limitation by using a cell line releasing HIV-1 particles in an inducible way, and by exploiting the ability of a HIV-1 Nef mutant to be incorporated in virions at quite high levels. Results: Here, we report the isolation and characterization of a HIV-1 packaging cell line, termed 18-4s, able to release valuable amounts of fluorescent HIV-1 based Virus-Like Particles (VLPs) in an inducible way. 18-4s cells were recovered by constitutively expressing the HIV-1 NefG3C mutant fused with the enhanced-green fluorescent protein (NefG3C-GFP) in a previously isolated inducible HIV-1 packaging cell line. The G3C mutation creates a palmitoylation site which results in NefG3CGFP incorporation into virions greatly exceeding that of the wild type counterpart. Upon induction of 18-4s cells with ponasterone A and sodium butyrate, up to 4 μg/ml of VLPs, which had incorporated about 150 molecules of NefG3C-GFP per viral particle, were released into the culture supernatant. Due to their intrinsic strong fluorescence, the 18-4s VLPs were easily detectable by a novel cytofluorometric-based assay developed here. The treatment of target cells with fluorescent 18-4 VLPs pseudotyped with different glycoprotein receptors resulted in these becoming fluorescent as early as two hours post-challenge. Conclusion: We created a stable cell line releasing fluorescent HIV-1 based VLPs upon induction useful for several applications including the study of virus-cell interactions and the screening of antiviral compounds. [ABSTRACT FROM AUTHOR]

Abstract: For the first time in Europe hair and urine testing have been applied to assess drugs of abuse consumption in couples undergoing assisted reproductive technology and the eventual association of toxic habits with other lifestyle, health status and sociodemographic factors was also investigated. Couples attending five assisted reproduction centers in Rome were invited to join the study. When they presented at the Centre for the visit, they were asked to answer a structured questionnaire concerning sociodemographic characteristics and lifestyle habits, and at the same time to provide hair and urine samples. Hair and urine testing for drugs of abuse, urinary profile of principal endogenous steroids involved in fertility process (testosterone, epitestosterone, androsterone, etiocholanolone and dehydroepiandrosterone) and of alcohol and tobacco smoke biomarkers were performed with validated methodologies. Of the 594 enrolled individuals (297 couples), 352 (164 couples and 24 single individuals from the couple) completed the questionnaire and gave both hair and urine samples, apart from 3 bald men, who only gave urine samples. Urine testing showed an overall 4.8% (17 individuals) positivity to drugs of abuse: 4.2% to cannabinoids, 1.4% to cocaine and 0.85% to both drugs. Results of 4cm segment hair samples testing matched those from urine samples. Thus, taking together, results of urine and hair testing confirmed repeated use of cannabis, cocaine and both drugs in 3.7, 0.85 and 0.57% examined individuals, respectively. Drug consumers were in a statistically higher percentage active smokers and alcohol drinkers, less prone to physical activity and with a trend towards higher weight than non consumers. Finally, repeated drug consumption was associated with significant lower concentration of urinary testosterone in males and of urinary dehydroepiandrosterone in females. The findings of the present study confirm the suitability of urine testing to disclose recent drugs of abuse consumption and of hair analysis to verify repeated consumption. Association between different toxic habits and sedentary lifestyle is also substantiated by the obtained results in our cohort of couples attending assisted reproduction centers. [Copyright &y& Elsevier]

Objectives: to describe the results of a pilot population-based perinatal mortality surveillance system, with regards to stillbirths; to study maternal, obstetric, and foetal characteristics, evaluating risk factors and understanding causes., Design: a cross-sectional study was conducted on incident cases of stillbirths collected by the surveillance system from July 2017 to June 2019 in three Italian Regions (Lombardy, Tuscany, and Sicily)., Setting and Participants: data on stillbirths, resulting from the in-hospital multidisciplinary audits, organised using the Significant Event Audit methodology, were analysed. According to the World Health Organization (WHO) definitions, the project identified stillbirths as foetuses born dead >=28 weeks of gestation. The WHO International Classification of Diseases-Perinatal Mortality was used to categorise the causes of foetal death., Main Outcomes Measures: maternal characteristics, obstetric and foetal findings were investigated. Unadjusted relative risks and 95% confidence intervals were computed with respect to the background population. Finally, causes of death and contributing maternal conditions have been considered., Results: the maternity and neonatal units of the three participating Regions notified 520 stillbirths, of which 435 cases underwent to the multidisciplinary audit (83.7%); 40.0% of cases occurred in the gestational age range between 36 and 39 weeks. The risk of stillbirth was significantly increased in mothers with foreign citizenship (RR: 1.39; 95%CI: 1.13-1.71), multiple pregnancies (RR: 1.59; 95%CI 1.05-2.42), and pregnancies conceived with assisted reproductive technologies (RR: 2.15; 95%CI 1.45-3.19). The rate of congenital malformations was 6.0%. A diagnosis of foetal growth restriction was reported in 10.3% of cases, although the percentage of dead foetuses weighting <10° centile was at least twice in almost all gestational age periods. Post-mortem and placental histological examinations were carried out in more than 70% and more than 90% of cases, respectively., Conclusions: the implementation of a population-based surveillance system with high participation rate of maternity units and the use of universally accepted definitions could improve the identification of stillbirth avoidable risk factors and potentially modifiable predisposing maternal conditions, highlighting issues of perinatal assistance in need of improvement.

The new coronavirus emergency spread to Italy when little was known about the infection's impact on mothers and newborns. This study aims to describe the extent to which clinical practice has protected childbirth physiology and preserved the mother-child bond during the first wave of the pandemic in Italy. A national population-based prospective cohort study was performed enrolling women with confirmed SARS-CoV-2 infection admitted for childbirth to any Italian hospital from 25 February to 31 July 2020. All cases were prospectively notified, and information on peripartum care (mother-newborn separation, skin-to-skin contact, breastfeeding, and rooming-in) and maternal and perinatal outcomes were collected in a structured form and entered in a web-based secure system. The paper describes a cohort of 525 SARS-CoV-2 positive women who gave birth. At hospital admission, 44.8% of the cohort was asymptomatic. At delivery, 51.9% of the mothers had a birth support person in the delivery room; the average caesarean section rate of 33.7% remained stable compared to the national figure. On average, 39.0% of mothers were separated from their newborns at birth, 26.6% practised skin-to-skin, 72.1% roomed in with their babies, and 79.6% of the infants received their mother's milk. The infants separated and not separated from their SARS-CoV-2 positive mothers both had good outcomes. At the beginning of the pandemic, childbirth raised awareness and concern due to limited available evidence and led to "better safe than sorry" care choices. An improvement of the peripartum care indicators was observed over time.

Objectives: to describe the methodology of a pilot perinatal mortality surveillance system (SPItOSS) aimed to improve quality of care and prevent avoidable perinatal severe morbidity and mortality in three Italian regions., Design: population-based surveillance project monitoring incident cases of stillbirths, born dead ≥ 28 weeks of gestation and live births dying within 7 days. Local multidisciplinary audits in obstetric and neonatal units were conducted to assess causes of each death. A selection of deaths was also discussed by experts in regional and national Confidential Enquiries to assess causes and avoidability. The WHO perinatal mortality definition and the ICD-PM classification were adopted to codify perinatal deaths., Setting and Participants: health professionals working in any obstetric and neonatal unit in Lombardy (Northern Italy), Tuscany (Central Italy), and Sicily (Southern Italy), accounting for 32.3% of births in Italy. Data collection started on 01.07.2017 and ended on 30.06.2019., Main Outcome Measures: obstetric and neonatal units' participation rate in the participating regions, facility structural organisation description, health professionals' training course participation, estimate of perinatal death rates, clinical audits and Confidential Enquiries rates., Results: health professionals from all obstetric and/or neonatal units (N. 138) joined the pilot project. Overall, 830 incident perinatal deaths were reported; 699 underwent a facility-based clinical audit, and 94 selected cases were analysed in detail through regional and national Confidential Enquiries. Among the latter, 16.0% were assessed as avoidable deaths. Interregional differences related to the facility structural organisation were identified., Conclusions: SPItOSS was efficient in identifying and analysing incident cases of perinatal deaths and detecting improvable aspects of care and avoidable perinatal deaths. The next objective is to extend the surveillance at the national level, considering that stable funding and a higher number of participating healthcare professionals and experts will be needed.

The primary human immunodeficiency virus type 1 (HIV-1) Nef mutant F12-HIVNef is characterized by three rare amino acid substitutions, G(140)E, V(153)L and E(177)G. It was reported previously that the expression of F12-HIVNef in the context of the highly productive NL4-3 HIV-1 strain blocks virus replication at the level of virus assembly and/or release by a mechanism depending on the presence of the CD4 intracytoplasmic tail. Here, it is reported that NL4-3 HIV-1 strains expressing F12-HIVnef alleles that were back-mutated in each amino acid substitution readily replicated in CD4(+) cells. Attempting to correlate possible functional alterations with antiviral effects, both F12-HIVNef and its back mutants were tested in terms of well-characterized markers of Nef expression. Both F12-HIVNef and its G(177)E back mutant did not down-regulate CD4 as the consequence of a greatly reduced rate of CD4 internalization. On the other hand, F12-HIVNef as well as the E(140)G and L(153)V back mutants failed to activate the p62 Nef-associated kinase (p62NAK). Thus, only F12-HIVNef was defective in both accelerated rates of CD4 internalization and p62NAK activation, whereas at least one Nef function was restored in all of the back mutants. Infection of cells expressing Nef-resistant CD4 molecules with HIV-1 strains encoding F12-HIVNef back mutants showed that both the lack of accelerated CD4 endocytosis and an, as yet, still unidentified function are required for the F12-HIVNef inhibitory phenotype. These results provide a detailed functional analysis of the F12-HIVnef allele and support the idea that both CD4 accelerated internalization and p62NAK activation are part of the essential steps in the virus replication cycle.

Increasing interest has been devoted to the role that monocyte-macrophages play in the pathogenesis of AIDS. The hypothesis of an involvement in AIDS pathogenesis of human/simian immunodeficiency virus (HIV/SIV) Nef also is currently under evaluation by many investigators. The original basis of this hypothesis came from evidence that monkeys infected with a nef-deleted SIV strain failed to develop simian AIDS. Here, we show that treatment of human monocyte-derived macrophages (MDM) with recombinant HIV-1 Nef protein (rNef) induces a strong inhibition of the replication of either macrophage (M-) or dual-tropic HIV-1 strains. Through cytofluorimetric analyses, we detected internalization of FITC-conjugated rNef in MDM as early as 6 h after treatment. Confocal microscope observations demonstrated that the intracellular distribution of internalized rNef was identical to that of endogenously produced Nef. Down-regulation of the CD4 HIV receptor detected upon rNef treatment of MDM suggested that the rNef-induced HIV inhibition occurred at the virus entry step. This deduction was strengthened by the observation that CD4-independent infection was totally insensitive to rNef treatment. The specificity of all observed effects was demonstrated by immunodepletion of rNef. Finally, we showed that the resistance to HIV replication induced by rNef treatment in MDM favours the spread of T-tropic over M-tropic HIV strains in doubly infected CD4(+) lymphocyte-MDM co-cultures. We propose that extracellular Nef contributes to AIDS pathogenesis by inducing resistance to M-tropic HIV replication in MDM, thereby facilitating the switching from M- to T-tropic HIV prevalence that correlates frequently with AIDS progression.