Computed tomographic angiography measures of coronary plaque in clinical trials: opportunities and considerations to accelerate drug translation.

Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but new pharmacologic therapies require increasingly large and expensive cardiovascular outcome trials to assess their potential impact on MACE and to obtain regulatory approval. For many disease areas, nearly a half of drugs are approved by the U.S. Food & Drug Administration based on beneficial effects on surrogate endpoints. For cardiovascular disease, only low-density lipoprotein cholesterol and blood pressure are approved as surrogates for cardiovascular disease. Valid surrogates of CAD are urgently needed to facilitate robust evaluation of novel, beneficial treatments and inspire investment. Fortunately, advances in non-invasive imaging offer new opportunity for accelerating CAD drug development. Coronary computed tomography angiography (CCTA) is the most advanced candidate, with the ability to measure accurately and reproducibly characterize the underlying causal disease itself. Indeed, favourable changes in plaque burden have been shown to be associated with improved outcomes, and CCTA may have a unique role as an effective surrogate endpoint for therapies that are designed to improve CAD outcomes. CCTA also has the potential to de-risk clinical endpoint-based trials both financially and by enrichment of participants at higher likelihood of MACE. Furthermore, total non-calcified, and high-risk plaque volume, and their change over time, provide a causally linked measure of coronary artery disease which is inextricably linked to MACE, and represents a robust surrogate imaging biomarker with potential to be endorsed by regulatory authorities. Global consensus on specific imaging endpoints and protocols for optimal clinical trial design is essential as we work towards a rigorous, sustainable and staged pathway for new CAD therapies.

Relevance of CT for the detection of septic foci: diagnostic performance in a retrospective cohort of medical intensive care patients.

AIM: To analyse the diagnostic yield of computed tomography (CT) in septic patients from a medical intensive care unit (ICU). MATERIALS AND METHODS: A full-text search of the department's radiological information system (RIS) retrieved 227 body CT examinations undertaken to search for a septic focus in 2018 from medical ICU patients. CT reports were categorised according to the identified foci. Clinical and laboratory information was gathered. Data were analysed statistically using descriptive statistics, diagnostic test quality criteria, binomial tests and chi-square test. RESULTS: A total of 227 CT examinations from 165 septic patients detected 264 foci, which were distributed as follows: 58.3% (n=154/264) chest, 26.5% (n=70/264) abdomen, 5.3% (n=14/264) genitourinary system, and 9.8% (n=26/264) other body regions. In 15.9% (n=36/227) no focus was identified on CT. Based on CT reports, 37.5% (n=99/264) of foci were graded as certain, 18.9% (n=50/264) as likely, and 15.9% (n=42/264) as possible infectious sources. Septic foci were detected using CT with 75.8% sensitivity (95% confidence interval [CI] 69.6-81.9%) and 59.46% specificity (95% CI 42.9-76.1%). The positive predictive value was 90.6% (95% CI 86-95.2%), with a negative predictive value of 32.4% (95% CI 21-43.8%). CONCLUSION: The present results confirm that body CT is a suitable rule-in test for septic patients in medical intensive care, although it cannot reliably rule out a septic focus. Follow-up CT examinations may reveal a septic source in the further course of a patient's hospital stay.

A Historical Analysis of Racism Within the US Presidency: Implications for African Americans and the Political Process.

This article examines the history of racism in the American presidency and the implications that it has had for Black residents of this country. The paper begins with a discussion of President Trump's racist rhetoric towards Blacks but notes that a history of racism is woven into the US presidency. We employ critical race theory as a theoretical framework to demonstrate why institutional racism has always been pervasive in the American presidency. Using a case study analysis, the authors conduct a comparative study of the history of racism of American presidents with the presidency of former president Donald J. Trump. The authors conclude that for most of the nation's history, racism and indifference to African Americans permeated the US presidency. It has only been since the advent of the second half of the twentieth century, for the most part, that there have been meaningful efforts by US presidents to address the concerns of African Americans.

Causal effect of tooth loss on depression: evidence from a population-wide natural experiment in the USA.

AIMS: Depression severely affects people's health and well-being. Oral diseases have been suggested to be associated with depression, but so far, there is no causal evidence. This study aimed to identify the causal effect of tooth loss on depression among US adults in a natural experiment study. METHODS: Instrumental variable analysis was conducted using data from 169 061 respondents born in 1940-1978 who participated in the 2006, 2008 or 2010 waves of the Behavioral Risk Factor Surveillance System (BRFSS). Random variation in tooth loss due to differential childhood exposure to drinking water fluoride was exploited as an instrument. RESULTS: US adults who were exposed to drinking water fluoride in childhood had more remaining teeth, therefore providing a robust instrument (F = 73.4). For each additional tooth loss, depressive symptoms according to the eight-item Patient Health Questionnaire depression (PHQ-8) score increased by 0.146 (95% CI 0.008-0.284), and the probability of having clinical depression (PHQ ⩾10) increased by 0.81 percentage points (95% CI -0.12 to 1.73). CONCLUSIONS: Tooth loss causally increased depression among US adults. Losing ten or more teeth had an impact comparable to adults with major depressive disorder not receiving antidepressant drugs.

Mental health impact on the unmet need for family planning and fertility rate in rural Ethiopia: a population-based cohort study.

AIMS: Although much research has focused on socio-demographic determinants of uptake of contraception, few have studied the impact of poor mental health on women's reproductive behaviours. The aim of this study was to examine the impact of poor mental health on women's unmet need for contraception and fertility rate in a low-income country setting. METHODS: A population-based cohort of 1026 women recruited in their third trimester of pregnancy in the Butajira district in rural Ethiopia was assessed for symptoms of antenatal common mental disorders (CMDs; depression and anxiety) using Self-Reporting Questionnaire-20. Women were followed up regularly until 6.5 years postnatal (between 2005 and 2012). We calculated unmet need for contraception at 1 year (n = 999), 2.5 (n = 971) and 3.5 years (n = 951) post-delivery of index child and number of pregnancies during study period. We tested the association between CMD symptoms, unmet need for contraception and fertility rate. RESULTS: Less than one-third of women reported current use of contraception at each time point. Unmet need for birth spacing was higher at 1 year postnatal, with over half of women (53.8%) not using contraception wanting to wait 2 or more years before becoming pregnant. Higher CMD symptoms 1 year post-index pregnancy were associated with unmet need for contraception at 2.5 years postnatal in the unadjusted [odds ratio (OR) 1.09; 95% confidence interval (CI) 1.04-1.15] and fully adjusted model [OR 1.06; 95% CI 1.01-1.12]. During the 6.5 year cohort follow-up period, the mean number of pregnancies per woman was 2.4 (s.d. 0.98). There was no prospective association between maternal CMD and number of pregnancies in the follow-up period. CONCLUSIONS: CMD symptoms are associated with increased unmet need for family planning in this cohort of women with high fertility and low contraceptive use in rural Ethiopia. There is a lack of models of care promoting integration of mental and physical health in the family planning setting and further research is necessary to study the burden of preconception mental health conditions and how these can be best addressed.

Neural networks-based regularization for large-scale medical image reconstruction.

In this paper we present a generalized Deep Learning-based approach for solving ill-posed large-scale inverse problems occuring in medical image reconstruction. Recently, Deep Learning methods using iterative neural networks (NNs) and cascaded NNs have been reported to achieve state-of-the-art results with respect to various quantitative quality measures as PSNR, NRMSE and SSIM across different imaging modalities. However, the fact that these approaches employ the application of the forward and adjoint operators repeatedly in the network architecture requires the network to process the whole images or volumes at once, which for some applications is computationally infeasible. In this work, we follow a different reconstruction strategy by strictly separating the application of the NN, the regularization of the solution and the consistency with the measured data. The regularization is given in the form of an image prior obtained by the output of a previously trained NN which is used in a Tikhonov regularization framework. By doing so, more complex and sophisticated network architectures can be used for the removal of the artefacts or noise than it is usually the case in iterative NNs. Due to the large scale of the considered problems and the resulting computational complexity of the employed networks, the priors are obtained by processing the images or volumes as patches or slices. We evaluated the method for the cases of 3D cone-beam low dose CT and undersampled 2D radial cine MRI and compared it to a total variation-minimization-based reconstruction algorithm as well as to a method with regularization based on learned overcomplete dictionaries. The proposed method outperformed all the reported methods with respect to all chosen quantitative measures and further accelerates the regularization step in the reconstruction by several orders of magnitude.

Impact of integrated district level mental health care on clinical and social outcomes of people with severe mental illness in rural Ethiopia: an intervention cohort study.

AIM: There is limited evidence of the safety and impact of task-shared care for people with severe mental illnesses (SMI; psychotic disorders and bipolar disorder) in low-income countries. The aim of this study was to evaluate the safety and impact of a district-level plan for task-shared mental health care on 6 and 12-month clinical and social outcomes of people with SMI in rural southern Ethiopia. METHODS: In the Programme for Improving Mental health carE, we conducted an intervention cohort study. Trained primary healthcare (PHC) workers assessed community referrals, diagnosed SMI and initiated treatment, with independent research diagnostic assessments by psychiatric nurses. Primary outcomes were symptom severity and disability. Secondary outcomes included discrimination and restraint. RESULTS: Almost all (94.5%) PHC worker diagnoses of SMI were verified by psychiatric nurses. All prescribing was within recommended dose limits. A total of 245 (81.7%) people with SMI were re-assessed at 12 months. Minimally adequate treatment was received by 29.8%. All clinical and social outcomes improved significantly. The impact on disability (standardised mean difference 0.50; 95% confidence interval (CI) 0.35-0.65) was greater than impact on symptom severity (standardised mean difference 0.28; 95% CI 0.13-0.44). Being restrained in the previous 12 months reduced from 25.3 to 10.6%, and discrimination scores reduced significantly. CONCLUSIONS: An integrated district level mental health care plan employing task-sharing safely addressed the large treatment gap for people with SMI in a rural, low-income country setting. Randomised controlled trials of differing models of task-shared care for people with SMI are warranted.

Precision determination of absolute neutron flux.

A technique for establishing the total neutron rate of a highly-collimated monochromatic cold neutron beam was demonstrated using an alpha-gamma counter. The method involves only the counting of measured rates and is independent of neutron cross sections, decay chain branching ratios, and neutron beam energy. For the measurement, a target of 10B-enriched boron carbide totally absorbed the neutrons in a monochromatic beam, and the rate of absorbed neutrons was determined by counting 478 keV gamma rays from neutron capture on 10B with calibrated high-purity germanium detectors. A second measurement based on Bragg diffraction from a perfect silicon crystal was performed to determine the mean de Broglie wavelength of the beam to a precision of 0.024%. With these measurements, the detection efficiency of a neutron monitor based on neutron absorption on 6Li was determined to an overall uncertainty of 0.058%. We discuss the principle of the alpha-gamma method and present details of how the measurement was performed including the systematic effects. We also describe how this method may be used for applications in neutron dosimetry and metrology, fundamental neutron physics, and neutron cross section measurements.

aCORN: An experiment to measure the electron-antineutrino correlation coefficient in free neutron decay.

We describe an apparatus used to measure the electron-antineutrino angular correlation coefficient in free neutron decay. The apparatus employs a novel measurement technique in which the angular correlation is converted into a proton time-of-flight asymmetry that is counted directly, avoiding the need for proton spectroscopy. Details of the method, apparatus, detectors, data acquisition, and data reduction scheme are presented, along with a discussion of the important systematic effects.

The aCORN Backscatter-Suppressed Beta Spectrometer.

Backscatter of electrons from a beta spectrometer, with incomplete energy deposition, can lead to undesirable effects in many types of experiments. We present and discuss the design and operation of a backscatter-suppressed beta spectrometer that was developed as part of a program to measure the electronantineutrino correlation coefficient in neutron beta decay (aCORN). An array of backscatter veto detectors surrounds a plastic scintillator beta energy detector. The spectrometer contains an axial magnetic field gradient, so electrons are efficiently admitted but have a low probability for escaping back through the entrance after backscattering. The design, construction, calibration, and performance of the spectrometer are discussed.

Measurement of the Electron-Antineutrino Angular Correlation in Neutron ß Decay.

We report the first result for the electron-antineutrino angular correlation (a coefficient) in free neutron ß decay from the aCORN experiment. aCORN uses a novel method in which the a coefficient is proportional to an asymmetry in proton time of flight for events where the ß electron and recoil proton are detected in delayed coincidence. Data are presented from a 15 month run at the NIST Center for Neutron Research. We obtained a=-0.1090±0.0030(stat)±0.0028(sys), the most precise measurement of the neutron a coefficient reported to date.

Type 2 diabetes mellitus in people with severe mental illness: inequalities by ethnicity and age. Cross-sectional analysis of 588 408 records from the UK.

AIMS: To investigate whether the association of severe mental illness with Type 2 diabetes varies by ethnicity and age. METHODS: We conducted a cross-sectional analysis of data from an ethnically diverse sample of 588 408 individuals aged ≥18 years, registered to 98% of general practices (primary care) in London, UK. The outcome of interest was prevalent Type 2 diabetes. RESULTS: Relative to people without severe mental illness, the relative risk of Type 2 diabetes in people with severe mental illness was greatest in the youngest age groups. In the white British group the relative risks were 9.99 (95% CI 5.34, 18.69) in those aged 18-34 years, 2.89 (95% CI 2.43, 3.45) in those aged 35-54 years and 1.16 (95% CI 1.04, 1.30) in those aged ≥55 years, with similar trends across all ethnic minority groups. Additional adjustment for anti-psychotic prescriptions only marginally attenuated the associations. Assessment of estimated prevalence of Type 2 diabetes in severe mental illness by ethnicity (absolute measures of effect) indicated that the association between severe mental illness and Type 2 diabetes was more marked in ethnic minorities than in the white British group with severe mental illness, especially for Indian, Pakistani and Bangladeshi individuals with severe mental illness. CONCLUSIONS: The relative risk of Type 2 diabetes is elevated in younger populations. Most associations persisted despite adjustment for anti-psychotic prescriptions. Ethnic minority groups had a higher prevalence of Type 2 diabetes in the presence of severe mental illness. Future research and policy, particularly with respect to screening and clinical care for Type 2 diabetes in populations with severe mental illness, should take these findings into account.

Antenatal depressive symptoms as a predictor of deterioration in perceived social support across the perinatal period: a four-wave cohort study in Turkey.

BACKGROUND: In a perinatal cohort of women in urban and rural Turkey, we investigated associations between antenatal depressive symptoms and subsequent changes in perceived quality of key family relationships. METHOD: Of 730 women recruited in their third trimester (94.6% participation), 578 (79.2%) were reassessed at a mean of 4.1 (s.d. = 3.3) months after childbirth, 488 (66.8%) were reassessed at 13.7 (s.d. = 2.9) months, and 448 (61.4%) at 20.8 (s.d. = 2.7) months. At all four examinations, self-reported quality of relationship with the husband, mother and mother-in-law was ascertained using the Close Persons Questionnaire with respect to emotional support, practical support and negative aspects of the relationship. Antenatal depressive symptoms were defined using the Edinburgh Postnatal Depression Scale. A range of covariates in mixed models was considered including age, education, number of children, family structure, physical health, past emotional problems and stressful life events. RESULTS: Key findings were as follows: (i) reported emotional and practical support from all three relationships declined over time in the cohort overall; (ii) reported emotional support from the husband, and emotional and practical support from the mother-in-law, declined more strongly in women with antenatal depressive symptoms; (iii) associations between depressive symptoms and worsening spouse relationship were more pronounced in traditional compared with nuclear families. CONCLUSIONS: Antenatal depressive symptoms predicted marked decline in the quality of key relationships over the postnatal period. This may account for some of the contemporaneous associations between depression and worse social support, and may compound the risk of perinatal depression in subsequent pregnancies.

Temporal averaging for analysis of four-dimensional whole-heart computed tomography perfusion of the myocardium: proof-of-concept study.

To assess the feasibility of four-dimensional (4D) whole-heart computed tomography perfusion (CTP) of the myocardium and the added value of temporal averaging of consecutive 3D datasets from different heartbeats for analysis. We included 30 patients with suspected or known coronary artery disease (CAD) who underwent 320-row coronary CT angiography (CTA) and myocardial CTP. Out of these, 15 patients underwent magnetic resonance myocardial perfusion imaging (MR MPI). All CTP examinations were initiated after 3 min of intravenous infusion of adenosine (140 µg/kg/min) and were performed dynamically covering the entire heart every heart beat over a period of 20 ± 3 heart beats. Temporal averaging for dynamic CTP visualisation was analysed for the combination of two, three, four, six, and eight consecutive 3D datasets. Input time attenuation curves (TAC) were delivered from measurement points in the centre of the left ventricle. In all 30 patients, myocardial 4D CTP was feasible and temporal averaging was successfully implemented for all planned combinations of 3D datasets. Temporal averaging of three consecutive 3D datasets showed best performance in the analysis of all CTP image quality parameters: noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), subjective image quality, and diagnostic accuracy with an improvement of SNR and CNR by a factor of 2.2 ± 1.3 and 1.3 ± 0.9. With increasing level of temporal averaging, the input TACs became smoother, but also shorter. Out of the 11 perfusion defects detected with MR MPI, 9 defects were also visible on the 4D CTP images. Whole-heart CTP of the myocardium is feasible and temporal averaging of dynamic datasets improves quantitative image quality parameters and visualization of perfusion defects while further studies are needed to assess its added value for quantification of perfusion parameters.

Precision Measurement of the Radiative ß Decay of the Free Neutron.

The standard model predicts that, in addition to a proton, an electron, and an antineutrino, a continuous spectrum of photons is emitted in the ß decay of the free neutron. We report on the RDK II experiment which measured the photon spectrum using two different detector arrays. An annular array of bismuth germanium oxide scintillators detected photons from 14 to 782 keV. The spectral shape was consistent with theory, and we determined a branching ratio of 0.00335±0.00005[stat]±0.00015[syst]. A second detector array of large area avalanche photodiodes directly detected photons from 0.4 to 14 keV. For this array, the spectral shape was consistent with theory, and the branching ratio was determined to be 0.00582±0.00023[stat]±0.00062[syst]. We report the first precision test of the shape of the photon energy spectrum from neutron radiative decay and a substantially improved determination of the branching ratio over a broad range of photon energies.

Adapting the Bayley Scales of infant and toddler development in Ethiopia: evaluation of reliability and validity.

BACKGROUND: There is a need for valid and reliable observational measures of early child development in low-income and middle-income country settings. METHODS: The aims of the study were to adapt the Bayley Scales of Infant Development (Bayley III) for a rural Ethiopian setting and evaluate reliability and validity. The study was carried out between January 2008 and January 2009 in the Butajira demographic surveillance site, south central Ethiopia. The Bayley III was adapted to be socioculturally appropriate for a rural Ethiopian context. Nurses and high school graduates were trained in administration of the measure for 10 days. Inter-rater reliability was evaluated (n = 60). Content, construct and convergent validity was then examined on a population-based cohort of children at the ages of 30 (n = 440) and 42 months (n = 456). Mokken scale analysis was used to determine the scalability of items in unidimensional, hierarchical sub-scales. The mean score was compared by age of child and by stunting status (less than -2 z scores below the standard height-for-age). RESULTS: The intra-class correlations between raters were above 0.90 for all sub-scales of the child development measure. Some scale items were not contextually relevant and showed poor scalability. However, the majority of items scaled onto the existing sub-scales of the international measure to form adequate-to-strong hierarchical scales with good internal consistency (Cronbach's α above 0.70 except for gross motor and expressive language sub-scales). Item-scale coefficients were good. The mean score of all sub-scales was significantly higher in the older group of children (33.02 higher total score; P < 0.001) and in the children who were stunted (total Bayley score 2.58 (95% confidence interval 0.07 to 5.10) points lower at 30 months and 3.87 (1.94 to 5.81) points lower at 42 months. CONCLUSIONS: An adapted version of an international, observational measure of child development was found to be reliable, valid and feasible in a rural Ethiopian setting.

Generating evidence to narrow the treatment gap for mental disorders in sub-Saharan Africa: rationale, overview and methods of AFFIRM.

There is limited evidence on the acceptability, feasibility and cost-effectiveness of task-sharing interventions to narrow the treatment gap for mental disorders in sub-Saharan Africa. The purpose of this article is to describe the rationale, aims and methods of the Africa Focus on Intervention Research for Mental health (AFFIRM) collaborative research hub. AFFIRM is investigating strategies for narrowing the treatment gap for mental disorders in sub-Saharan Africa in four areas. First, it is assessing the feasibility, acceptability and cost-effectiveness of task-sharing interventions by conducting randomised controlled trials in Ethiopia and South Africa. The AFFIRM Task-sharing for the Care of Severe mental disorders (TaSCS) trial in Ethiopia aims to determine the acceptability, affordability, effectiveness and sustainability of mental health care for people with severe mental disorder delivered by trained and supervised non-specialist, primary health care workers compared with an existing psychiatric nurse-led service. The AFFIRM trial in South Africa aims to determine the cost-effectiveness of a task-sharing counselling intervention for maternal depression, delivered by non-specialist community health workers, and to examine factors influencing the implementation of the intervention and future scale up. Second, AFFIRM is building individual and institutional capacity for intervention research in sub-Saharan Africa by providing fellowship and mentorship programmes for candidates in Ethiopia, Ghana, Malawi, Uganda and Zimbabwe. Each year five Fellowships are awarded (one to each country) to attend the MPhil in Public Mental Health, a joint postgraduate programme at the University of Cape Town and Stellenbosch University. AFFIRM also offers short courses in intervention research, and supports PhD students attached to the trials in Ethiopia and South Africa. Third, AFFIRM is collaborating with other regional National Institute of Mental Health funded hubs in Latin America, sub-Saharan Africa and south Asia, by designing and executing shared research projects related to task-sharing and narrowing the treatment gap. Finally, it is establishing a network of collaboration between researchers, non-governmental organisations and government agencies that facilitates the translation of research knowledge into policy and practice. This article describes the developmental process of this multi-site approach, and provides a narrative of challenges and opportunities that have arisen during the early phases. Crucial to the long-term sustainability of this work is the nurturing and sustaining of partnerships between African mental health researchers, policy makers, practitioners and international collaborators.

Patient satisfaction with coronary CT angiography, myocardial CT perfusion, myocardial perfusion MRI, SPECT myocardial perfusion imaging and conventional coronary angiography.

OBJECTIVES: To evaluate patient acceptance of noninvasive imaging tests for detection of coronary artery disease (CAD), including single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI), stress perfusion magnetic resonance imaging (MRI), coronary CT angiography (CTA) in combination with CT myocardial stress perfusion (CTP), and conventional coronary angiography (CCA). METHODS: Intraindividual comparison of perception of 48 patients from the CORE320 multicentre multinational study who underwent rest and stress SPECT-MPI with a technetium-based tracer, combined CTA and CTP (both with contrast agent, CTP with adenosine), MRI, and CCA. The analysis was performed by using a validated questionnaire. RESULTS: Patients had significantly more concern prior to CCA than before CTA/CTP (p < 0.001). CTA/CTP was also rated as more comfortable than SPECT-MPI (p = 0.001). Overall satisfaction with CT was superior to that of MRI (p = 0.007). More patients preferred CT (46%; p < 0.001) as a future diagnostic test. Regarding combined CTA/CTP, CTP was characterised by higher pain levels and an increased frequency of angina pectoris during the examination (p < 0.001). Subgroup analysis showed a higher degree of pain during SPECT-MPI with adenosine stress compared to physical exercise (p = 0.016). CONCLUSIONS: All noninvasive cardiac imaging tests are well accepted by patients, with CT being the preferred examination. KEY POINTS: • A variety of cardiac imaging tests is available without known patient preference • CTA/CTP shows a lower degree of concern than conventional coronary angiography • CTA/CTP shows higher overall satisfaction compared to stress perfusion magnetic resonance imaging • CTA/CTP is rated as more comfortable than SPECT-MPI • CTA/CTP is the preferred cardiac imaging test.