Cardiac maladaptation in term pregnancies with preeclampsia.

OBJECTIVES: To study biventricular cardiac changes with conventional echocardiography and new echocardiographic speckle tracking technologies such strain, twist and torsion in pregnant women with preeclampsia at term and normotensive control term pregnant women. STUDY DESIGN: For this prospective single centre case-control study, we consecutively recruited 30 women with preeclampsia at term as cases and 40 healthy control term pregnant women. All women underwent transthoracic echocardiographic examination at the time point of inclusion into the study. MAIN OUTCOME MEASURES: Signs of systolic and/or diastolic cardiac maladaptation to the increased volume load associated with pregnancy. RESULTS: Conventional echocardiography revealed mild left sided diastolic impairment in the form of significantly increased E/E' in preeclampsia (7.58 ± 1.72 vs. 6.18 ± 1.57, p = 0.001) compared to normotensive controls, but no evidence of systolic impairment. With speckle tracking analysis, significant decreases in left ventricular global (-13.32 ± 2.37% vs. -17.61 ± 1.89%, p < 0.001), endocardial (-15.64 ± 2.79% vs. -19.84 ± 2.35%, p < 0.001) and epicardial strain (-11.48 ± 2.15% vs. -15.73 ± 1.66%, p < 0.001) as well as left ventricular longitudinal strain rate (-0.84 ± 0.14 s-1 vs. -0.98 ± 0.12 s-1, p < 0.001) and left ventricular early diastolic strain rate (0.86 ± 0.30 s-1 vs. 1.24 ± 0.26 s-1, p < 0.001) could be observed in women with term preeclampsia. CONCLUSIONS: The findings of this study demonstrate that pregnant women with term preeclampsia with minimal functional changes on conventional echocardiography, demonstrated significant subclinical myocardial changes on speckle tracking analysis

Profiles and trajectories of mental health service utilisation during early intervention in psychosis

Background: Early intervention in psychosis services (EIS) support individuals experiencing a first episode of psychosis. Support required will vary in response to the remittance and reoccurrence of symptoms, including relapses. Characterising individuals who will need more intensive support can inform care planning. This study explores service utilisation profiles and their trajectories of service use in a sample of individuals referred to EIS. Method: We analysed service utilisation during the 3 years following referral to EIS (n = 2363) in West London between 2011 and 2020. Mental health service utilisation data were submitted to model-based clustering. Latent growth models were then estimated for identified profiles. Profiles were compared regarding clinical and demographic characteristics and onward pathways of care. Results: Analyses revealed 5 profiles of individuals attending EIS based on their service utilisation over 3 years. 55.5% of the sample were members of a low utilisation and less clinically severe profile. The distinct service use patterns of these profiles were associated with Health of the Nations Outcome Scale scores at treatment initiation (at total, subscale, and individual item level), along with age and gender. These patterns of use were also associated with onward care and ethnicity. Conclusions: Profiles and trajectories of service utilisation call for development of integrated care pathways and use of more personalised interventions. Services should consider patient symptoms and characteristics when making clinical decisions informing the provision of care. The profiles represent typical patterns of service use, and identifying factors associated with these subgroups might help optimise EIS support

Peripartum echocardiographic changes in women with hypertensive disorders of pregnancy

Women with hypertensive disorders of pregnancy (HDP) present with evidence of significant myocardial dysfunction on echocardiographic assessment at the time of diagnosis. Birth not only cures the syndrome of HDP, but is also associated with a reduction in cardiovascular (CV) volume and resistance load in the mother due to the delivery of the fetoplacental unit. The impact of this physiological change on maternal myocardial function in women with HDP has not been systematically evaluated. The aim of this study is to compare echocardiographic findings immediately before and after childbirth in women with HDP. In this prospective longitudinal study, 30 women with a diagnosis of HDP underwent two consecutive transthoracic echocardiography (TTE) examinations: the first prepartum and the second in the early postpartum period. Paired comparisons of these assessments were performed. Left ventricular (LV) concentric remodelling or hypertrophy were found in 21 (70%) patients and there were no significant differences in cardiac morphology indices: LV mass index (78.9±16.3 g/m vs 77.9 ±15.4 g/m , p=0.611) and relative wall thickness (0.45±0.1 vs 0.44±0.1, p=0.453). LV diastolic function did not demonstrate any peripartum variation: left atrial volume (52.40±15.3 vs 50.97±15.6, p=0.433); lateral E' (0.12±0.03 vs 0.12±0.03, p=0.307) and E/E' ratio (7.88±2.19 vs 7.91±1.74, p=0.934). Systolic function indices such as LV ejection fraction (57.5±4.4% vs 56.4±2.1%, p=0.295) and global longitudinal strain (-15.3±2.6% vs -15.1±3.1%, p=0.715) also remained unchanged. Maternal hemodynamic changes associated with birth did not significantly influence peripartum TTE indices in women with HDP. Suboptimal maternal echocardiographic findings in HDP are likely to be the consequence of chronic pregnancy CV load changes or pre-existing maternal CV impairment. Severity and persistence of myocardial dysfunction into the postpartum period may be related to the long-term maternal CV disease legacy of HDP. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.

Speckle tracking echocardiography: new ways of translational approaches in preeclampsia to detect cardiovascular dysfunction

Several studies have shown that women with a preeclamptic pregnancy exhibit an increased risk of cardiovascular disease. However, the underlying molecular mechanisms are unknown. Animal models are essential to investigate the causes of this increased risk and have the ability to assess possible preventive and therapeutic interventions. Using the latest technologies such as speckle tracking echocardiography (STE), it is feasible to map subclinical changes in cardiac diastolic and systolic function as well as structural changes of the maternal heart. The aim of this work is to compare cardiovascular changes in an established transgenic rat model with preeclampsia-like pregnancies with findings from human preeclamptic pregnancies by STE. The same algorithms were used to evaluate and compare the changes in echos of human and rodents. Parameters of functionality like global longitudinal strain (animal -23.54 ± 1.82 % vs. -13.79 ± 0.57 %, human -20.60 ± 0.47 % vs. -15.45 ± 1.55 %) as well as indications of morphological changes like relative wall thickness (animal 0.20 ± 0.01 vs. 0.25 ± 0.01, human 0.34 ± 0.01 vs. 0.40 ± 0.02) are significantly altered in both species after preeclamptic pregnancies. Thus, the described rat model simulates the human situation quite well and is a valuable tool for future investigations regarding cardiovascular changes. STE is a unique technique which can be applied in animal models and human with a high potential to uncover cardiovascular maladaptation and subtle pathologies

Intersecting brane world models from D8-branes on (T^2 x T^4/Z_3)/Omega R_1 type IIA orientifolds

We present orientifold models of type IIA string theory with D8-branes compactified on a two torus times a four dimensional orbifold. The orientifold group is chosen such that one coordinate of the two torus is reversed when applying worldsheet parity. RR tadpole cancellation requires D8-branes which wrap 1-cycles on the two torus and transform non-trivially under the orbifold group. These models are T-dual to orientifolds with D4-branes only which admit large volume compactifications. The intersections of the D8-branes are chosen in such a way that supersymmetry is broken in the open string sector and chiral fermions arise. Stability of the models is discussed in the context of NSNS tadpoles. Two examples with the SM gauge group and two left-right symmetric models are given.Comment: 30 pages, 7 figure

How useful are post consultation letters to patients?

BACKGROUND: As part of the NHS plan it was suggested that all patients receive copies of letters sent to their General Practitioner following outpatient consultations. The former Secretary of State for Health extended this proposal, suggesting that patients have a specific letter to themselves after a hospital consultation. METHODS: The aim of this study was to send cardiorespiratory patients attending Charing Cross Hospital, a copy of the letter sent to their G.P. plus a specific letter to themselves and to assess the usefulness and comprehensibility of each. The letters were analysed for dictation time, Flesch Reading Ease Score, Flesch-Kincaid Grade Level and word count. Eighty-four out of 105 sequential patients (80%) consented and were sent both types of letter after their attendance. Patients returned both letters circling any items they did not understand and stated a preference for the GP letter, patient letter, or both. The patients' GPs were subsequently also asked for their views on each letter. RESULTS: GP letters took significantly longer to dictate than patient letters. The Flesch Reading Ease Score was significantly higher in the patient letters, indicating that the patient letters were easier to read. The GP letters were significantly longer than the patient letters and patients were significantly more likely to circle more items in the GP letters (p < 0.001). The content of letters is sometimes inaccurate. Thirty-six out of 62 patients (58%) would like to receive both letters, 13/62 (21.6%) would prefer the GP letter and 13/62 (20%) wanted only the patient letter. 45 GPs replied (62.5%), 28/45 (62.5%) wanted the GP letter, 14 GPs (31.1%) wanted both letters and 3/45 (6.7%) wanted the patient letter only. General themes concerned insufficient clinical details and the GPs preferred the structure of the letters written to them. CONCLUSION: Patients appreciate copies of the letter being sent to their GP but comprehension is less good than with a shorter letter written especially to the patient. More attention needs to be paid to making letters to GPs simpler to read without losing the structure and detail liked by GPs. A compromise might be to dictate the letter in front of the patient and to provide a speciality-specific glossary to accompany each letter

Sr isotopes indicate millennial-scale formation of metal-rich layers by reactive melt percolation in an open-system layered intrusion

&amp;lt;p&amp;gt;In order to test whether the crystal mushes that form layered mafic intrusions can behave as open systems, we investigated mineral-scale textural, chemical and Sr isotopic heterogeneity in the c. 60 Ma Rum intrusion, Scotland. Within Unit 10 of the Rum intrusion, intercumulus plagioclase and clinopyroxene crystals in peridotite 1-2 cm above and below millimetric Cr-spinel seams exhibit complex optical and chemical zoning (Hepworth et al. 2017). These Cr-spinel seams are closely associated with sulphide and platinum-group element (PGE) mineralization. High precision Sr isotopic analyses (undertaken by thermal ionisation mass spectrometry) of individual intracrystal zones (sampled by micromilling) in intercumulus plagioclase and clinopyroxene from within the PGE-enriched Cr-spinel seams have revealed significant intra-crystalline heterogeneity. &amp;lt;sup&amp;gt;87&amp;lt;/sup&amp;gt;Sr/&amp;lt;sup&amp;gt;86&amp;lt;/sup&amp;gt;Sr heterogeneity is present between plagioclase crystals, between clinopyroxene and plagioclase, and within plagioclase crystals, throughout the studied section. The preservation of Sr isotope heterogeneities at 10-100 &amp;amp;#181;m length-scales implies cooling of the melts that formed the precious metal-rich layers at rates &amp;gt;1 &amp;amp;#176;C per year, and cooling to diffusive closure within 10s-100s of years. The combined textural observations and intra-crystal plagioclase &amp;lt;sup&amp;gt;87&amp;lt;/sup&amp;gt;Sr/&amp;lt;sup&amp;gt;86&amp;lt;/sup&amp;gt;Sr data also highlight the importance of repeated cycles of dissolution and recrystallization within the crystal mush, and together with recent documentation of &amp;amp;#8216;out-of-sequence&amp;amp;#8217; layers in other layered intrusions (Mungall et al. 2016; Wall et al. 2018), raise the prospect that basaltic magmatic systems may undergo repeated self-intrusion during solidification.&amp;lt;/p&amp;gt;&amp;lt;p&amp;gt;Hepworth, L.N., O&amp;amp;#8217;Driscoll, B., Gertisser, R., Daly, J.S. and Emeleus, H.C. 2017. Journal of Petrology 58, 137-166; Mungall, J. E., Kamo, S. L. &amp;amp; McQuade, S. 2016. Nature Communications 7, 13385; Wall, C. J., Scoates, J. S., Weis, D., Friedman, R. M., Amini, M. &amp;amp; Meurer, W. P. 2018. Journal of Petrology 59, 153&amp;amp;#8211;190.&amp;lt;/p&amp;gt; </jats:p

Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome

A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression

Real-world performance and accuracy of stress echocardiography: The EVAREST observational multi-centre study

Aims - Stress echocardiography is widely used to identify obstructive coronary artery disease. High accuracy is reported in expert hands but is dependent on operator training and image quality. The EVAREST study provides UK-wide data to evaluate real-world performance and accuracy of stress echocardiography. Methods and Results - Participants undergoing stress echocardiography for coronary artery disease were recruited from 31 hospitals. Participants were followed up through health records which underwent expert adjudication. Cardiac outcome was defined as anatomically or functionally-significant stenosis on angiography, revascularisation, medical management of ischaemia, acute coronary syndrome or cardiac-related death within six months. 5131 patients (55% male) participated with a median age of 65 years (IQR 57 – 74). 72.9% of studies used dobutamine and 68.5% were contrast studies. Inducible ischaemia was present in 19.3% of scans. Sensitivity and specificity for prediction of a cardiac outcome were 95.4% and 96.0%, respectively, with an accuracy of 95.9%. Sub-group analysis revealed high levels of predictive accuracy across a wide range of patient and protocol sub-groups, with the presence of a resting regional wall motion abnormalitiy significantly reducing the performance of both dobutamine (p<0.01) and exercise (p<0.05) stress echocardiography (p<0.05). Overall accuracy remained consistently high across all participating hospitals. Conclusion – Stress echocardiography has high accuracy across UK-based hospitals and thus indicates stress echocardiography is being delivered effectively in real-world practice, reinforcing its role as a first-line investigation in the assessment of patients with stable chest pain