Digital fetal scalp stimulation (dFSS) versus fetal blood sampling (FBS) to assess fetal wellbeing in labour-a multi-centre randomised controlled trial: Fetal Intrapartum Randomised Scalp Stimulation Trial (FIRSST NCT05306756).

BACKGROUND: Cardiotocography (CTG) is a screening test used to detect fetal hypoxia in labour. It has a high false positive rate resulting in many potentially unnecessary caesarean sections. Fetal blood sampling (FBS) is a second-line test of the acid-base status of the fetus. It is used to provide either reassurance that it is safe for labour to continue or objective evidence of compromise so that delivery can be expedited. Digital fetal scalp stimulation (dFSS) to elicit a fetal heart rate acceleration is an alternative less invasive second-line test of fetal wellbeing. This study aims to provide robust evidence on the role of these two second-line tests in assessing fetal wellbeing and potentially preventing operative delivery. METHODS: A multi-centre parallel group randomised controlled trial (RCT) is planned in four maternity centres in Ireland. The study aims to recruit 2500 nulliparous women with a term (≥37+0 weeks) singleton pregnancy who require a second-line test of fetal wellbeing in labour due to an abnormal CTG. Women will be allocated randomly to dFSS or FBS on a 1:1 ratio. The primary outcome is caesarean section. With 1250 women in each arm, the study will have 90% power to detect a difference of 5-6%, at a two-sided alpha significance level of 5%, assuming a caesarean section rate of at least 20% in the dFSS group. DISCUSSION: If the proposed study shows evidence that dFSS is a safe, reliable and effective alternative to FBS, this would have ground-breaking implications for labour management worldwide. It could potentially lead to a reduction in invasive procedures and emergency caesarean sections. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306756. Registered on 31 March 2022. The trial commenced enrolment on 10 May 2022. Ethical committee approval has been granted by the Research Ethics Committee (REC) of each hospital: Dublin/CWIUH REC: 12.06.2019; Cork/UCC REC: 29.11.2019; Galway/NUIG REC: 06.09.2019; Limerick/UL REC: 30.09.2019.

Comparing second-line tests to assess fetal wellbeing in Labor: a feasibility study and pilot randomized controlled trial.

OBJECTIVE: To explore the feasibility of conducting a randomized controlled trial (RCT) designed to compare the performance of digital fetal scalp stimulation (dFSS) and fetal blood sampling (FBS) as second-line tests of fetal wellbeing in Labor. DESIGN: A feasibility study included 66 women who consented to both dFSS and FBS performed contemporaneously. A pilot randomized controlled trial included 50 women who were randomized to either dFSS or FBS. SETTING: University-affiliated maternity hospital. POPULATION: Women in Labor who required second-line testing of fetal well-being following abnormal fetal heart rate monitoring. OUTCOME MEASURES: The primary outcome of interest was delivery by emergency cesarean section. Secondary outcomes included maternal and perinatal morbidity outcomes and procedural factors. RESULTS: Of the 66 women recruited to the feasibility study 50 (76%) received the two interventions as per protocol. The demographic data indicated that future RCT should be limited to nulliparous women. After initial training and reminders, the dFSS procedure appeared to be acceptable to patients and clinicians and was interpreted appropriately. Recruitment of eligible women to the pilot RCT was successful (88%) with 50 of 63 eligible women randomized (79%) and no drop-outs. The cesarean section rate was high in both arms as expected with a cohort of women requiring second-line tests for abnormal fetal heart rate monitoring in Labor (5/25; 20% dFSS versus 13/25; 52% FBS, p = .018). Conservative estimates suggest that a sample size of 2500 randomized women would be required for a definitive RCT. CONCLUSIONS: This study suggests that dFSS, which has the potential to be a reliable alternative to FBS, could be evaluated in a well-designed randomized controlled trial. TRIAL REGISTRATION: The definitive trial has been registered ISRCTN 13295826.

Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland).

OBJECTIVE: To determine whether the addition of placental growth factor (PlGF) measurement to current clinical assessment of women with suspected pre-eclampsia before 37 weeks' gestation would reduce maternal morbidity without increasing neonatal morbidity. DESIGN: Stepped wedge cluster randomised control trial from 29 June 2017 to 26 April 2019. SETTING: National multisite trial in seven maternity hospitals throughout the island of Ireland PARTICIPANTS: Women with a singleton pregnancy between 20+0 to 36+6 weeks' gestation, with signs or symptoms suggestive of evolving pre-eclampsia. Of the 5718 women screened, 2583 were eligible and 2313 elected to participate. INTERVENTION: Participants were assigned randomly to either usual care or to usual care plus the addition of point-of-care PlGF testing based on the randomisation status of their maternity hospital at the time point of enrolment. MAIN OUTCOMES MEASURES: Co-primary outcomes of composite maternal morbidity and composite neonatal morbidity. Analysis was on an individual participant level using mixed-effects Poisson regression adjusted for time effects (with robust standard errors) by intention-to-treat. RESULTS: Of the 4000 anticipated recruitment target, 2313 eligible participants (57%) were enrolled, of whom 2219 (96%) were included in the primary analysis. Of these, 1202 (54%) participants were assigned to the usual care group, and 1017 (46%) were assigned the intervention of additional point-of-care PlGF testing. The results demonstrate that the integration of point-of-care PlGF testing resulted in no evidence of a difference in maternal morbidity-457/1202 (38%) of women in the control group versus 330/1017 (32%) of women in the intervention group (adjusted risk ratio (RR) 1.01 (95% CI 0.76 to 1.36), P=0.92)-or in neonatal morbidity-527/1202 (43%) of neonates in the control group versus 484/1017 (47%) in the intervention group (adjusted RR 1.03 (0.89 to 1.21), P=0.67). CONCLUSIONS: This was a pragmatic evaluation of an interventional diagnostic test, conducted nationally across multiple sites. These results do not support the incorporation of PlGF testing into routine clinical investigations for women presenting with suspected preterm pre-eclampsia, but nor do they exclude its potential benefit. TRIAL REGISTRATION: ClinicalTrials.gov NCT02881073.

The effect of a novel Bayesian penalised likelihood PET reconstruction algorithm on the assessment of malignancy risk in solitary pulmonary nodules according to the British Thoracic Society guidelines.

PURPOSE: British Thoracic Society (BTS) guidelines advocate using FDG PET-CT with the Herder model to estimate malignancy risk in solitary pulmonary nodules (SPNs). Qualitative and semi-quantitative assessment of SPN uptake is based upon analysis of Ordered Subset Expected Maximisation (OSEM) PET images. Our aim was to assess the effect of a Bayesian Penalised Likelihood (BPL) PET reconstruction on the assessment of SPN FDG uptake and estimation of malignancy risk (Herder score). METHODS: Subjects with SPNs who underwent FDG PET-CT between 2014-2017, with histological confirmation of malignancy or histological/imaging follow-up confirmation of benignity were included. Two blinded readers independently classified SPN uptake on both OSEM and BPL (BTS score; 1 = none; 2 = ≤ mediastinal blood pool (MBP); 3 = >MBP but ≤ 2x liver; 4 = >2x liver), with resultant calculation of the Herder score (%) for both reconstructions. RESULTS: 97 subjects with 75 (77%) malignant SPNs were included. BPL increased the BTS score in 25 (26%) SPNs; 9 SPNs (7 malignant) increased from BTS score 2 to 3, 16 (13 malignant) from BTS score 3 to 4, with a mean Herder score increase of 18 ±â€¯22%. The mean Herder score for all SPNs with BPL was higher than OSEM (73 ±â€¯29 vs 68 ±â€¯32%, p = 0.001). There was no difference in Herder model diagnostic performance between BPL and OSEM, with similar areas under the curve (0.84 vs 0.83, p = 0.39). CONCLUSION: BPL increases the Herder score in 26% of SPNs compared to OSEM but does not alter the diagnostic performance of the Herder model.

Loco-regional staging of malignant pleural mesothelioma by integrated 18F-FDG PET/MRI.

AIM: To examine the performance of 18F-FDG PET/MRI in the loco-regional staging of malignant pleural mesothelioma (MPM). METHODS: Consecutive subjects with MPM undergoing pre-operative staging with 18F-FDG PET/CT who underwent a same day integrated 18F-FDG PET/MRI were prospectively studied. Clinical TNM staging (AJCC 7th edition) was performed separately and in consensus by two readers on the 18F-FDG PET/MRI studies, and compared with staging by 18F-FDG PET/CT, and with final pathological stage, determined by a combination of intra-operative and histological findings. RESULTS: 10 subjects (9 male, mean age 68 years) with biopsy-proven MPM (9 epithelioid tumours, 1 biphasic) were included. One subject underwent neo-adjuvant chemotherapy between imaging and surgery and was excluded from the clinical versus pathological stage analysis. Pathological staging was concordant with staging by 18F-FDG PET/MRI in 67% (n = 6) of subjects, and with 18F-FDG PET/CT staging in 33% (n = 3). Pathological T stage was concordant with 18F-FDG PET/MRI in 78% (n = 7), and with 18F-FDG PET/CT in 33% (n = 3) of subjects. Pathological N stage was concordant with both 18F-FDG PET/MRI and 18F-FDG PET/CT in 78% (n = 7) of cases. No subject had metastatic disease. There was good inter-observer agreement for overall PET/MRI staging (weighted kappa 0.63) with moderate inter-reader agreement for T staging (weighted kappa 0.59). All 6 subjects with prior talc pleurodesis demonstrated mismatch between elevated FDG uptake and restricted diffusion in areas of visible talc deposition. CONCLUSION: Clinical MPM staging by 18F-FDG PET/MRI is feasible, and potentially provides more accurate loco-regional staging than PET/CT, particularly in T staging.

Admission cardiotocography versus intermittent auscultation of the fetal heart in low-risk pregnancy during evaluation for possible labour admission - a multicentre randomised trial: the ADCAR trial.

OBJECTIVE: To assess the effect of admission cardiotocography (ACTG) versus intermittent auscultation (IA) of the fetal heart (FH) in low-risk pregnancy during assessment for possible labour on caesarean section rates. DESIGN: A parallel multicentre randomised trial. SETTING: Three maternity units in the Republic of Ireland. POPULATION: Healthy, low-risk pregnant women, at term and ≥ 18 years old, who provided written informed consent. METHODS: Women were randomised to receive IA of the FH or 20 minutes ACTG on admission for possible labour onset, using remote telephone randomisation. Both groups received IA during labour, with conversion to continuous CTG as clinically indicated. MAIN OUTCOME MEASURES: Caesarean section (primary outcome), obstetric interventions (e.g. continuous CTG during labour, fetal blood sampling, augmentation of labour) and neonatal morbidity (e.g. metabolic acidosis, admission to the neonatal intensive care unit, neonatal death). RESULTS: Based on 3034 women (1513 and 1521 randomised to IA and ACTG, respectively), there was no statistical difference between the groups in caesarean section [130 (8.6%) and 105 (6.9%) for IA and ACTG groups, respectively; relative risk (RR) 1.24; 95% CI 0.97-1.58], or in any other outcome except for use of continuous CTG during labour, which was lower in the IA group (RR 0.90, 95% CI 0.86-0.93). CONCLUSION: Our study demonstrates no differences in obstetric or neonatal outcomes between IA and ACTG for women with possible labour onset, other than an increased risk for continuous CTG in women receiving ACTG. TWEETABLE ABSTRACT: No differences in outcomes between intermittent auscultation and admission cardiotocography for women with possible labour onset.

Vascular CT and MRI: a practical guide to imaging protocols.

Non-invasive cross-sectional imaging techniques play a crucial role in the assessment of the varied manifestations of vascular disease. Vascular imaging encompasses a wide variety of pathology. Designing vascular imaging protocols can be challenging owing to the non-uniform velocity of blood in the aorta, differences in cardiac output between patients, and the effect of different disease states on blood flow. In this review, we provide the rationale behind-and a practical guide to-designing and implementing straightforward vascular computed tomography (CT) and magnetic resonance imaging (MRI) protocols.Teaching Points • There is a wide range of vascular pathologies requiring bespoke imaging protocols. • Variations in cardiac output and non-uniform blood velocity complicate vascular imaging. • Contrast media dose, injection rate and duration affect arterial enhancement in CTA. • Iterative CT reconstruction can improve image quality and reduce radiation dose. • MRA is of particular value when imaging small arteries and venous studies.

Calcium signalling links MYC to NUAK1.

NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1. Here we show that, in tumour cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway involving calcium-dependent activation of PKCα. Calcium/PKCα-dependent activation of NUAK1 supports engagement of the AMPK-TORC1 metabolic checkpoint, thereby protecting tumour cells from MYC-driven cell death, and indeed, MYC selects for this pathway in part via transcriptional regulation of PKCα and ITPR. Our data point to a novel role for calcium in supporting tumour cell viability and clarify the synthetic lethal interaction between NUAK1 and MYC.

Interarterial Left Circumflex: The Forgotten Coronary Artery Anomaly.

Anomalous coronary artery origin is a rare, but important cause of cardiac ischemia, particularly in younger patients. These anomalies of origin can be divided into two groups, benign or malignant, based on their propensity to cause ischemia or sudden death. Symptomatic, or malignant coronary artery anomalies are usually described with respect to anomalous origins of the right coronary artery or left main coronary artery. We present a unique case of a previously unreported entity, an anomalous left circumflex coronary artery causing ischemia.

An important role for Myb-MuvB and its target gene KIF23 in a mouse model of lung adenocarcinoma.

The conserved Myb-MuvB (MMB) multiprotein complex has an important role in transcriptional activation of mitotic genes. MMB target genes are overexpressed in several different cancer types and their elevated expression is associated with an advanced tumor state and a poor prognosis. This suggests that MMB could contribute to tumorigenesis by mediating overexpression of mitotic genes. However, although MMB has been extensively characterized biochemically, the requirement for MMB in tumorigenesis in vivo has not been investigated. Here we demonstrate that MMB is required for tumor formation in a mouse model of lung cancer driven by oncogenic K-RAS. We also identify a requirement for the mitotic kinesin KIF23, a key target gene of MMB, in tumorigenesis. RNA interference-mediated depletion of KIF23 inhibited lung tumor formation in vivo and induced apoptosis in lung cancer cell lines. Our results suggest that inhibition of KIF23 could be a strategy for treatment of lung cancer.

Cross-sectional imaging of aortic infections.

Aortic infections are uncommon clinical entities, but are associated with high rates of morbidity and mortality. In this review, we focus on the cross-sectional imaging appearance of aortic infections, including aortic valve endocarditis, pyogenic aortitis, mycotic aneurysm and aortic graft infections, with an emphasis on CT, MRI and PET/CT appearance. Teaching Points • Aortic infections are associated with high morbidity and mortality. • CT, MRI and FDG PET/CT play complementary roles in aortic infection imaging. • Radiologists should be vigilant for aortic infection manifestations to ensure timely diagnosis.

Water Use and Management in the Bakken Shale Oil Play in North Dakota.

Oil and natural gas development in the Bakken shale play of North Dakota has grown substantially since 2008. This study provides a comprehensive overview and analysis of water quantity and management impacts from this development by (1) estimating water demand for hydraulic fracturing in the Bakken from 2008 to 2012; (2) compiling volume estimates for maintenance water, or brine dilution water; (3) calculating water intensities normalized by the amount of oil produced, or estimated ultimate recovery (EUR); (4) estimating domestic water demand associated with the large oil services population; (5) analyzing the change in wastewater volumes from 2005 to 2012; and (6) examining existing water sources used to meet demand. Water use for hydraulic fracturing in the North Dakota Bakken grew 5-fold from 770 million gallons in 2008 to 4.3 billion gallons in 2012. First-year wastewater volumes grew in parallel, from an annual average of 1,135,000 gallons per well in 2008 to 2,905,000 gallons in 2012, exceeding the mean volume of water used in hydraulic fracturing and surpassing typical 4-year wastewater totals for the Barnett, Denver, and Marcellus basins. Surprisingly, domestic water demand from the temporary oilfield services population in the region may be comparable to the regional water demand from hydraulic fracturing activities. Existing groundwater resources are inadequate to meet the demand for hydraulic fracturing, but there appear to be adequate surface water resources, provided that access is available.

A Multi-Year Analysis of Fatal Farm and Agricultural Injuries in Pennsylvania.

Agriculture, forestry, fishing, and hunting comprise the most hazardous industry in the U.S., and production agriculture accounts for the majority of fatalities in the industry. Using Penn State's farm and agricultural injury database, data were coded according to ASABE's Farm and Agricultural Injury Classification (FAIC) code and the U.S. Bureau of Labor Statistics' Occupational Injury and Illness Classification System (OIICS) for source and event or exposure types. Occupational and non-occupational incidents were compared based on age groups, religious sect, source of injury, and the injury event or exposure. There were 355 farm and agricultural fatalities in Pennsylvania from 2000 through 2012, and 56% of these fatalities were occupational. The fatality rate was 33.4 per 100,000 farm household residents per year. Youth under 15 years old, seniors age 65 and older, Anabaptist youth, and young females were at high risk of fatal farm injury. Vehicles and transportation incidents were the most common injury source and event/exposure type, respectively. This research illustrates how state-level or national-level data can be collected, coded, and analyzed based on the FAIC and OIICS classification systems to better understand fatal injury causes and connections among important variables. This process can also help to target intervention programs and efforts.

Subclassification of small bowel Crohn's disease using magnetic resonance enterography: a review using evidence-based medicine methodology.

Magnetic resonance enterography (MRE) has a growing role in imaging small bowel Crohn's disease (SBCD), both in diagnosis and assessment of treatment response. Certain SBCD phenotypes respond well to biologic therapy and others require surgery; MRE has an expanding role in triaging these patients. In this review, we evaluate the MRE signs that subclassify SBCD using evidence-based medicine (EBM) methodology and provide a structured approach to MRE interpretation.

In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells.

Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS(61K) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.