The "Preeclampsia and Hypertension Target Treatment" study: a multicenter prospective study to evaluate the effectiveness of the antihypertensive therapy based on maternal hemodynamic findings.

BACKGROUND: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values. OBJECTIVE: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings. STUDY DESIGN: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm2]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm2]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy. RESULTS: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02). CONCLUSION: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile.

Obliterated cavum septi pellucidi: Clinical significance and role of fetal magnetic resonance.

INTRODUCTION: The objective of this study was to describe a cohort of fetuses with an ultrasound prenatal diagnosis of obliterated cavum septi pellucidi (oCSP) with the aim to explore the rate of associated malformations, the progression during pregnancy and the role of fetal magnetic resonance imaging (MRI). MATERIAL AND METHODS: This was a retrospective multicenter international study of fetuses diagnosed with oCSP in the second trimester with available fetal MRI and subsequent ultrasound and/or fetal MRI follow-up in the third trimester. Where available, postnatal data were collected to obtain information on neurodevelopment. RESULTS: We identified 45 fetuses with oCSP at 20.5 weeks (interquartile range 20.1-21.1). oCSP was apparently isolated at ultrasound in 89% (40/45) and fetal MRI found additional findings in 5% (2/40) of cases, including polymicrogyria and microencephaly. In the remaining 38 fetuses, fetal MRI found a variable amount of fluid in CSP in 74% (28/38) and no fluid in 26% (10/38). Ultrasound follow-up at or after 30 weeks confirmed the diagnosis of oCSP in 32% (12/38) while fluid was visible in 68% (26/38). At follow-up MRI, performed in eight pregnancies, there were periventricular cysts and delayed sulcation with persistent oCSP in one case. Among the remaining cases with normal follow-up ultrasound and fetal MRI findings, the postnatal outcome was normal in 89% of cases (33/37) and abnormal in 11% (4/37): two with isolated speech delay, and two with neurodevelopmental delay secondary to postnatal diagnosis of Noonan syndrome at 5 years in one case and microcephaly with delayed cortical maturation at 5 months in the other. CONCLUSIONS: Apparently isolated oCSP at mid-pregnancy is a transient finding with the visualization of the fluid later in pregnancy in up to 70% of cases. At referral, associated defects can be found in around 11% of cases at ultrasound and 8% at fetal MRI indicating the need for a detailed evaluation by expert physicians when oCSP is suspected.

First trimester lower abdominal cysts as early predictor of anorectal malformations.

INTRODUCTION: Prenatal ultrasound diagnosis of anorectal malformations (ARMs) is challenging and often missed as direct visualization of the anal sphincter is not routinely performed, plus the technique is operator-dependent and inaccurate, also in expert hands. Other indirect signs, such as rectosigmoid overdistension or intraluminal calcifications, are occasionally present in late pregnancy. The detection of a cyst of the lower abdomen in the first trimester may be an early sign of ARM. Here we reported our experience and a review of the literature of such cases. MATERIAL AND METHODS: Isolated cases of lower abdomen cysts encountered in the first trimester at the Prenatal Diagnosis Unit during the last 5 years were retrieved and compared with those found in literature. Post-natal clinical data were analyzed to check the presence and type of malformations. RESULTS: A total of three cases of lower abdomen cysts were found in our center and 13 in literature. In our case series all the cysts spontaneously regressed and were no longer visible since the second trimester of pregnancy, while in literature this was reported in only 4 out of 13 cases. ARM was confirmed in all patients at birth or post-mortem. CONCLUSIONS: The finding of a lower abdomen cyst during the first trimester of pregnancy could be an early predictive sign of ARM, even if it disappears during pregnancy. In these cases, we suggest mentioning to the parents the possibility of an ARM during the counseling and to refer the couple to a Colorectal Center.

Effects of Lean Thinking and Emerging Technologies on Breast Cancer Patients' Therapeutic Process During COVID-19 Pandemic: A Case-Control Matched Study.

Introduction: The advent of the COVID-19 pandemic has led to the sudden disruption of routine medical care, and the subsequent reorganization of hospital structures and therapeutic algorithms, aiming at protecting patients and health professionals. This was inevitably bound to affect our Breast Unit, dilating both pre- and post-operative times. The aim of this study was to evaluate the effect on patients' flow of organizational and logistic changes (key interventions) based on lean thinking implemented after the COVID-19 outbreak. Materials and Methods: Clinical and demographic data were retrospectively collected from patients undergoing sentinel lymph node biopsy for breast cancer at the Verona University Hospital from January 2018 to June 2020. Patients enrolled (n = 341) were divided into two groups according to date of admission: before (Group A; n = 294) and after (Group B; n = 47) the implementation of key interventions. Each case in Group B was subsequently matched 1:1 by means of case-control matching with cases from Group A for age, comorbidities, and type of surgery (Subgroup A1; N = 47). Pre-admission time (T0) and length of stay (T1) were compared between the three groups. Results: Median T0 was 312 h, whereas median T1 was 24 h. Patients in Group B had a higher frequency of comorbidities (57.4 vs. 25.2%, p = 0.001) and underwent mastectomy more often than patients in Group A (61.7 vs. 36.7%, p = 0.001). Both median T0 and T1 were higher in group B than in group A (384 vs. 300 h, p = 0.001, 48 vs. 24 h, p = 0.001, respectively). Median T0 and T1 did not significantly differ between Group B and Subgroup A1 (all p > 0.05). Conclusions: Lean thinking and new technologies could prove useful to the optimization of preoperative and postoperative times during the current pandemic, minimizing healthcare personnel and patients' exposure to SARS-CoV-2, and promoting a rational use of limited resources, while complying with oncological principles.

Seasonal epiphytic microbial dynamics on grapevine leaves under biocontrol and copper fungicide treatments.

Winemakers have long used copper as a conventional fungicide treatment on grapevine and only recently, the use of biocontrol agents depicted a promising alternative. Most of the studies that investigate the impact of fungicide treatments, focus on specific pathogenic microbes. In the present work instead, a field experiment conducted in South Africa shows the seasonal microbial change occurring on grapevine leaves, periodically treated with two different fungicide treatments: copper sulphate and Lactobacillus plantarum MW-1. In this work, NGS data were combined with strain-specific and community qPCRs to reveal the shift of the microbial communities throughout the growing season and highlight the impact of fungicides on the microbiota. Only the family of Lactobacillaceae systematically changed between treatments, while the bacterial community remained relatively stable over time. MW-1 was exclusively detected on biocontrol-sprayed leaves. Conversely, the fungal community was largely shaped by sampling time, underlining the succession of different dominant taxa over the months. Between treatments, only a few fungal taxa appeared to change significantly and the fungal load was also comparable. Monitoring the dynamics of the microbial community under different fungicide treatments may advise the best timing to apply treatments to the plants, toward the realization of more sustainable agricultural practices.

Outcomes in pregnancies with a confined placental mosaicism and implications for prenatal screening using cell-free DNA.

PURPOSE: To assess the association between confined placental mosaicism (CPM) and adverse pregnancy outcome. METHODS: A retrospective cohort study was carried out evaluating the outcome of pregnancies with and without CPM involving a rare autosomal trisomy (RAT) or tetraploidy. Birthweight, gestational age at delivery, fetal growth restriction (FGR), Apgar score, neonatal intensive care admission, preterm delivery, and hypertensive disorders of pregnancy were considered. RESULTS: Overall 181 pregnancies with CPM and 757 controls were recruited. Outcome information was available for 69% of cases (n = 124) and 62% of controls (n = 468). CPM involving trisomy 16 (T16) was associated with increased incidence of birthweight <3rd centile (P = 0.007, odds ratio [OR] = 11.2, 95% confidence interval [CI] = 2.7-47.1) and preterm delivery (P = 0.029, OR = 10.2, 95% CI = 1.9-54.7). For the other RATs, an association with prenatally diagnosed FGR was not supported by birthweight data and there were no other strong associations with adverse outcomes. CONCLUSION: Excluding T16, the incidence of adverse pregnancy outcomes for pregnancies carrying a CPM is low. RATs can also be identified through genome-wide cell-free DNA screening. Because most of these will be attributable to CPMs, we conclude that this screening is of minimal benefit.

Quantitative and qualitative evaluation of the impact of the G2 enhancer, bead sizes and lysing tubes on the bacterial community composition during DNA extraction from recalcitrant soil core samples based on community sequencing and qPCR.

Soil DNA extraction encounters numerous challenges that can affect both yield and purity of the recovered DNA. Clay particles lead to reduced DNA extraction efficiency, and PCR inhibitors from the soil matrix can negatively affect downstream analyses when applying DNA sequencing. Further, these effects impede molecular analysis of bacterial community compositions in lower biomass samples, as often observed in deeper soil layers. Many studies avoid these complications by using indirect DNA extraction with prior separation of the cells from the matrix, but such methods introduce other biases that influence the resulting microbial community composition. To address these issues, a direct DNA extraction method was applied in combination with the use of a commercial product, the G2 DNA/RNA Enhancer, marketed as being capable of improving the amount of DNA recovered after the lysis step. The results showed that application of G2 increased DNA yields from the studied clayey soils from layers from 1.00 to 2.20 m. Importantly, the use of G2 did not introduce bias, as it did not result in any significant differences in the biodiversity of the bacterial community measured in terms of alpha and beta diversity and taxonomical composition. Finally, this study considered a set of customised lysing tubes for evaluating possible influences on the DNA yield. Tubes customization included different bead sizes and amounts, along with lysing tubes coming from two suppliers. Results showed that the lysing tubes with mixed beads allowed greater DNA recovery compared to the use of either 0.1 or 1.4 mm beads, irrespective of the tube supplier. These outcomes may help to improve commercial products in DNA/RNA extraction kits, besides raising awareness about the optimal choice of additives, offering opportunities for acquiring a better understanding of topics such as vertical microbial characterisation and environmental DNA recovery in low biomass samples.

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.

BACKGROUND: The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. METHODS: Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67. RESULTS: At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 < 6%, between 6 and 21%, and >21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology. CONCLUSIONS: Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.

Local over-expression of VEGF-DΔNΔC in the uterine arteries of pregnant sheep results in long-term changes in uterine artery contractility and angiogenesis.

BACKGROUND: The normal development of the uteroplacental circulation in pregnancy depends on angiogenic and vasodilatory factors such as vascular endothelial growth factor (VEGF). Reduced uterine artery blood flow (UABF) is a common cause of fetal growth restriction; abnormalities in angiogenic factors are implicated. Previously we showed that adenovirus (Ad)-mediated VEGF-A165 expression in the pregnant sheep uterine artery (UtA) increased nitric oxide synthase (NOS) expression, altered vascular reactivity and increased UABF. VEGF-D is a VEGF family member that promotes angiogenesis and vasodilatation but, in contrast to VEGF-A, does not increase vascular permeability. Here we examined the effect of Ad.VEGF-DΔNΔC vector encoding a fully processed form of VEGF-D, on the uteroplacental circulation. METHODS: UtA transit-time flow probes and carotid artery catheters were implanted in mid-gestation pregnant sheep (n = 5) to measure baseline UABF and maternal haemodynamics respectively. 7-14 days later, after injection of Ad.VEGF-DΔNΔC vector (5×10(11) particles) into one UtA and an Ad vector encoding ß-galactosidase (Ad.LacZ) contralaterally, UABF was measured daily until scheduled post-mortem examination at term. UtAs were assessed for vascular reactivity, NOS expression and endothelial cell proliferation; NOS expression was studied in ex vivo transduced UtA endothelial cells (UAECs). RESULTS: At 4 weeks post-injection, Ad.VEGF-DΔNΔC treated UtAs showed significantly lesser vasoconstriction (Emax144.0 v/s 184.2, p = 0.002). There was a tendency to higher UABF in Ad.VEGF-DΔNΔC compared to Ad.LacZ transduced UtAs (50.58% v/s 26.94%, p = 0.152). There was no significant effect on maternal haemodynamics. An increased number of proliferating endothelial cells and adventitial blood vessels were observed in immunohistochemistry. Ad.VEGF-DΔNΔC expression in cultured UAECs upregulated eNOS and iNOS expression. CONCLUSIONS: Local over-expression of VEGF-DΔNΔC in the UtAs of pregnant mid-gestation sheep reduced vasoconstriction, promoted endothelial cell proliferation and showed a trend towards increased UABF. Studies in cultured UAECs indicate that VEGF-DΔNΔC may act in part through upregulation of eNOS and iNOS.

Telemetric monitoring of fetal blood pressure and heart rate in the freely moving pregnant sheep: a feasibility study.

Remote telemetric monitoring of fetal haemodynamics in pregnant sheep would allow unrestricted animal movement, minimize suffering and distress, and improve animal welfare, while enhancing the quality of data collected. This may also be useful in clinical practice following fetal surgery. Using an open fetal surgical technique at approximately two-thirds of gestation, we implanted the catheter of a D70-PCTP haemodynamic telemetric device (Data Sciences International, Tilburg, The Netherlands) into the carotid artery of the fetal sheep (n = 4). The attached transmitter was secured to the posterior aspect of the maternal anterior abdominal wall. Two receivers, with a range of 1 m each, were sited in an 11 m² sheep enclosure to maximize animal freedom while allowing continuous monitoring of the ewe. The receivers were connected by cable to a nearby computer. In the first two procedures, both fetuses died eight and 12 days after surgery, and the catheter tip was observed to be lying in the bicarotid trunk. In the next two procedures the catheter tip was threaded further upstream from the insertion point, in an attempt to reach the fetal aorta, and both fetuses survived until the scheduled postmortem examination at the end of pregnancy. After catheter implantation, fetal blood pressure (BP) and heart rate (HR) were successfully recorded continuously for seven days and then hourly per day for a further three weeks. The fetal BP and HR values were in the normal range for healthy sheep fetuses.

Doppler ultrasonography for the noninvasive measurement of uterine artery volume blood flow through gestation in the pregnant sheep.

Accurate noninvasive quantification of volume blood flow in the uterine arteries (UtAs) would have clinical and research benefits. We evaluated the correlation and agreement between uterine artery volume blood flow (UtABF) as calculated (cUtABF) from color/pulsed-wave Doppler acquisitions and that measured (mUtABF) by bilateral perivascular transit-time flow probes in 6 pregnant sheep at 2 gestational ages. Out of 22 Doppler acquisitions, 19 were successful. The overall correlation between cUtABF and mUtABF was 0.55 (n = 19, P = .01). Calculated UtABF and mUtABF were significantly correlated in late gestation (n = 11, r = 0.71, P = .01) but not at mid-gestation (n = 8, r = .02, P = .96). By Bland-Altman analysis, the mean cUtABF/mUtABF was 1.15 with 95% limit of agreement (-0.26 to 2.56), similar to results previously achieved using power/pulsed-wave Doppler. Despite the acceptable correlation, the limits of agreement between Doppler and transit-time flow probe measurements remain wide. This makes Doppler ultrasonography less than a desirable method to quantify UtABF in studies where accurate quantification is required.

Dichorionic triamniotic triplet pregnancy complicated by acardius acormus.

This report describes an acardiac fetus of the acormus phenotype in a triplet pregnancy. The diagnosis was confirmed at 15 weeks. In the absence of signs of heart failure in the co-fetus the pregnancy was managed conservatively. The pregnancy was complicated by preterm labour and the fetuses were delivered at 26+5 weeks. The prenatal diagnosis of the acormus phenotype with a well-developed cephalic pole is extremely rare and has never been described antenatally in a higher order multiple pregnancy. We suggest that this rare acardiac fetus phenotype may have a different pathophysiology than those of other phenotypes. The report also summarizes the perinatal outcomes of triplet pregnancies complicated by an acardiac fetus, where the median gestational age at delivery is 26-27 weeks, and discusses the possible therapeutic interventions.

Bilateral neck cysts as an isolated sonographic finding in the antenatal detection of fetal aneuploidy: a case report.

Isolated fetal lateral neck cysts can represent a cystic hygroma or a developmental remnant cyst. In the absence of an increased nuchal translucency or associated malformations the risk of aneuploidy has been considered negligible. Still, dysmorphology in aneuploid fetuses might not be evident except at a later stage. We report on a case of isolated fetal bilateral neck cysts where aneuploidy was suspected and confirmed despite the lack of associated morphologic abnormalities.