Long-term neuropsychological trajectories in children with epilepsy: does surgery halt decline?

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery might alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning [obtained from IQ tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory and processing speed) and tests of academic attainment (reading, spelling and numeracy)] and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery [median age at surgery = 11.9 years, interquartile range = (7.8, 15.0)] and neuropsychological assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all P-values ≤0.001; e.g. ßFSIQ = -1.9, SEFSIQ = 0.3, PFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27%-43% declined by ≥10 points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46%-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all P-values ≥0.128). However, children who became seizure free through surgery showed higher postoperative neuropsychological performance (e.g. rrb-FSIQ = 0.37, P < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g. ßFSIQ = 0.9, SEFSIQ = 0.3, PFSIQ = 0.004). Children who had discontinued antiseizure medication treatment at 1-year follow-up showed an 8- to 13-point advantage in postoperative working memory, processing speed and numeracy, and greater improvements in verbal IQ, working memory, reading and spelling (all P-values ≤0.034) over the postoperative period compared with children who were seizure free and still receiving antiseizure medication. In conclusion, by providing seizure freedom and the opportunity for antiseizure medication cessation, epilepsy surgery might not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible or, potentially, to prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Pediatric epilepsy surgery from 2000 to 2018: Changes in referral and surgical volumes, patient characteristics, genetic testing, and postsurgical outcomes.

OBJECTIVE: Neurosurgery is a safe and effective form of treatment for select children with drug-resistant epilepsy. Still, there is concern that it remains underutilized, and that seizure freedom rates have not improved over time. We investigated referral and surgical practices, patient characteristics, and postoperative outcomes over the past two decades. METHODS: We performed a retrospective cohort study of children referred for epilepsy surgery at a tertiary center between 2000 and 2018. We extracted information from medical records and analyzed temporal trends using regression analyses. RESULTS: A total of 1443 children were evaluated for surgery. Of these, 859 (402 females) underwent surgical resection or disconnection at a median age of 8.5 years (interquartile range [IQR] = 4.6-13.4). Excluding palliative procedures, 67% of patients were seizure-free and 15% were on no antiseizure medication (ASM) at 1-year follow-up. There was an annual increase in the number of referrals (7%, 95% confidence interval [CI] = 5.3-8.6; p < .001) and surgeries (4% [95% CI = 2.9-5.6], p < .001) over time. Duration of epilepsy and total number of different ASMs trialed from epilepsy onset to surgery were, however, unchanged, and continued to exceed guidelines. Seizure freedom rates were also unchanged overall but showed improvement (odds ratio [OR] 1.09, 95% CI = 1.01-1.18; p = .027) after adjustment for an observed increase in complex cases. Children who underwent surgery more recently were more likely to be off ASMs postoperatively (OR 1.04, 95% CI = 1.01-1.08; p = .013). There was a 17% annual increase (95% CI = 8.4-28.4, p < .001) in children identified to have a genetic cause of epilepsy, which was associated with poor outcome. SIGNIFICANCE: Children with drug-resistant epilepsy continue to be put forward for surgery late, despite national and international guidelines urging prompt referral. Seizure freedom rates have improved over the past decades, but only after adjustment for a concurrent increase in complex cases. Finally, genetic testing in epilepsy surgery patients has expanded considerably over time and shows promise in identifying patients in whom surgery is less likely to be successful.

Predicting seizure outcome after epilepsy surgery: Do we need more complex models, larger samples, or better data?

OBJECTIVE: The accurate prediction of seizure freedom after epilepsy surgery remains challenging. We investigated if (1) training more complex models, (2) recruiting larger sample sizes, or (3) using data-driven selection of clinical predictors would improve our ability to predict postoperative seizure outcome using clinical features. We also conducted the first substantial external validation of a machine learning model trained to predict postoperative seizure outcome. METHODS: We performed a retrospective cohort study of 797 children who had undergone resective or disconnective epilepsy surgery at a tertiary center. We extracted patient information from medical records and trained three models-a logistic regression, a multilayer perceptron, and an XGBoost model-to predict 1-year postoperative seizure outcome on our data set. We evaluated the performance of a recently published XGBoost model on the same patients. We further investigated the impact of sample size on model performance, using learning curve analysis to estimate performance at samples up to N = 2000. Finally, we examined the impact of predictor selection on model performance. RESULTS: Our logistic regression achieved an accuracy of 72% (95% confidence interval [CI] = 68%-75%, area under the curve [AUC] = .72), whereas our multilayer perceptron and XGBoost both achieved accuracies of 71% (95% CIMLP = 67%-74%, AUCMLP = .70; 95% CIXGBoost own = 68%-75%, AUCXGBoost own = .70). There was no significant difference in performance between our three models (all p > .4) and they all performed better than the external XGBoost, which achieved an accuracy of 63% (95% CI = 59%-67%, AUC = .62; pLR = .005, pMLP = .01, pXGBoost own = .01) on our data. All models showed improved performance with increasing sample size, but limited improvements beyond our current sample. The best model performance was achieved with data-driven feature selection. SIGNIFICANCE: We show that neither the deployment of complex machine learning models nor the assembly of thousands of patients alone is likely to generate significant improvements in our ability to predict postoperative seizure freedom. We instead propose that improved feature selection alongside collaboration, data standardization, and model sharing is required to advance the field.

Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the REGARDS Study.

BACKGROUND: Social determinants of health (SDH) are individually associated with incident coronary heart disease (CHD) events. Indices reflecting social deprivation have been developed for population management, but are difficult to operationalize during clinical care. We examined whether a simple count of SDH is associated with fatal incident CHD and nonfatal myocardial infarction (MI). METHODS: We used data from the prospective longitudinal REGARDS cohort study (Reasons for Geographic and Racial Differences in Stroke), a national population-based sample of community-dwelling Black and White adults age ≥45 years recruited from 2003 to 2007. Seven SDH from the 5 Healthy People 2020 domains included social context (Black race, social isolation); education (educational attainment); economic stability (annual household income); neighborhood (living in a zip code with high poverty); and health care (lacking health insurance, living in 1 of the 9 US states with the least public health infrastructure). Outcomes were expert adjudicated fatal incident CHD and nonfatal MI. RESULTS: Of 22 152 participants free of CHD at baseline, 58.8% were women and 42.0% were Black; 20.6% had no SDH, 30.6% had 1, 23.0% had 2, and 25.8% had ≥3. There were 463 fatal incident CHD events and 932 nonfatal MIs over a median of 10.7 years (interquartile range, 6.6 to 12.7). Fewer SDHs were associated with nonfatal MI than with fatal incident CHD. The age-adjusted incidence per 1000 person-years increased with the number of SDH for both fatal incident CHD (0 SDH, 1.30; 1 SDH, 1.44; 2 SDH, 2.05; ≥3 SDH, 2.86) and nonfatal MI (0 SDH, 3.91; 1 SDH, 4.33; ≥2 SDH, 5.44). Compared with those without SDH, crude and fully adjusted hazard ratios for fatal incident CHD among those with ≥3 SDH were 3.00 (95% CI, 2.17 to 4.15) and 1.67 (95% CI, 1.18 to 2.37), respectively; hazard ratios for nonfatal MI among those with ≥2 SDH were 1.57 (95% CI, 1.30 to 1.90) and 1.14 (95% CI, 0.93 to 1.41), respectively. CONCLUSIONS: A greater burden of SDH was associated with a graded increase in risk of incident CHD, with greater magnitude and independent associations for fatal incident CHD. Counting the number of SDHs may be a promising approach that could be incorporated into clinical care to identify individuals at high risk of CHD.

The impact of the COVID-19 pandemic on antimicrobial prescribing at a specialist paediatric hospital: an observational study.

BACKGROUND: The COVID-19 pandemic has severely impacted healthcare delivery and there are growing concerns that the pandemic will accelerate antimicrobial resistance. OBJECTIVES: To evaluate the impact of the COVID-19 pandemic on antibiotic prescribing in a tertiary paediatric hospital in London, UK. METHODS: Data on patient characteristics and antimicrobial administration for inpatients treated between 29 April 2019 and Sunday 28 March 2021 were extracted from the electronic health record (EHR). Interrupted time series analysis was used to evaluate antibiotic days of therapy (DOT) and the proportion of prescribed antibiotics from the WHO 'Access' class. RESULTS: A total of 23 292 inpatient admissions were included. Prior to the pandemic there were an average 262 admissions per week compared with 212 during the pandemic period. Patient demographics were similar in the two periods but there was a shift in the specialities that patients had been admitted to. During the pandemic, there was a crude increase in antibiotic DOTs, from 801 weekly DOT before the pandemic to 846. The proportion of Access antibiotics decreased from 44% to 42%. However, after controlling for changes in patient characteristics, there was no evidence for the pandemic having an impact on antibiotic prescribing. CONCLUSIONS: The patient population in a specialist children's hospital was affected by the COVID-19 pandemic, but after adjusting for these changes there was no evidence that antibiotic prescribing was significantly affected by the pandemic. This highlights both the value of routine, high-quality EHR data and importance of appropriate statistical methods that can adjust for underlying changes to populations when evaluating impacts of the pandemic on healthcare.

Experience of SARS-CoV-2 infection in two kidney transplant recipients living with HIV-1 infection.

There is still no consensus on the optimal management of COVID-19 within the general population due to the emerging evidence base. High-risk groups, including kidney transplant recipients living with HIV present unique additional challenges. Here we discuss two kidney transplant recipients living with HIV with SARS-CoV-2 infection and their clinical course, and review the existing literature for this subset of challenging patients.

Machine Learning Approaches to Determine Feature Importance for Predicting Infant Autopsy Outcome.

INTRODUCTION: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of postneonatal death. We explored whether machine learning could be used to derive data driven insights for prediction of infant autopsy outcome. METHODS: A paediatric autopsy database containing >7,000 cases, with >300 variables, was analysed by examination stage and autopsy outcome classified as 'explained (medical cause of death identified)' or 'unexplained'. Decision tree, random forest, and gradient boosting models were iteratively trained and evaluated. RESULTS: Data from 3,100 infant and young child (<2 years) autopsies were included. Naïve decision tree using external examination data had performance of 68% for predicting an explained death. Core data items were identified using model feature importance. The most effective model was XG Boost, with overall predictive performance of 80%, demonstrating age at death, and cardiovascular and respiratory histological findings as the most important variables associated with determining medical cause of death. CONCLUSION: This study demonstrates feasibility of using machine-learning to evaluate component importance of complex medical procedures (paediatric autopsy) and highlights value of collecting routine clinical data according to defined standards. This approach can be applied to a range of clinical and operational healthcare scenarios.

Potential Cardiovascular Disease Events Prevented with Adoption of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline.

BACKGROUND: Over 10 years, achieving and maintaining 2017 ACC/AHA guideline goals could prevent 3.0 million (UR, 1.1-5.1 million), 0.5 million (UR, 0.2-0.7 million), and 1.4 million (UR, 0.6-2.0 million) cardiovascular disease (CVD) events compared with maintaining current blood pressure (BP) levels, achieving 2003 Seventh Joint National Committee Report goals, and achieving 2014 Eighth Joint National Committee goals, respectively. We estimated the number of cardiovascular disease events prevented and treatment-related serious adverse events incurred over 10 years among US adults with hypertension by achieving 2017 ACC/AHA guideline-recommended BP goals compared with (1) current BP levels, (2) achieving 2003 Seventh Joint National Committee Report BP goals, and (3) achieving 2014 Eighth Joint National Committee panel member report BP goals. METHODS: US adults aged ≥45 years with an indication for BP treatment were grouped according to recommendations for antihypertensive drug therapy in the 2017 ACC/AHA guideline, 2003 Seventh Joint National Committee Report, and 2014 Eighth Joint National Committee. Population sizes were estimated from the 2011 to 2014 National Health and Nutrition Examination Surveys. Rates for fatal and nonfatal CVD events (stroke, coronary heart disease, or heart failure) were estimated from the REGARDS (REasons for Geographic And Racial Differences in Stroke) study, weighted to the US population. CVD risk reductions with treatment to BP goals and risk for serious adverse events were obtained from meta-analyses of BP-lowering trials. CVD events prevented and treatment-related nonfatal serious adverse events over 10 years were calculated. Uncertainty surrounding main data inputs was expressed in uncertainty ranges (UR). RESULTS: Over ten years, achieving and maintaining 2017 ACC/AHA guideline goals compared with current BP levels, achieving 2003 Seventh Joint National Committee Report goals, or achieving 2014 Eighth Joint National Committee goals could prevent 3.0 million (UR, 1.1-5.1 million), 0.5 million (UR, 0.2-0.7 million), or 1.4 million (UR, 0.6-2.0 million) CVD events, respectively. Compared with current BP levels, achieving and maintaining 2017 goals could prevent 71.9 (UR, 26.6-122.3) CVD events per 1000 treated. Achieving 2017 guideline BP goals compared with current BP levels could also lead to nearly 3.3 million more serious adverse events over 10 years (UR, 2.2-4.4 million). CONCLUSIONS: Achieving and maintaining 2017 ACC/AHA BP goals could prevent a greater number of CVD events than achieving 2003 Seventh Joint National Committee Report or 2014 Eighth Joint National Committee BP goals but could also lead to more serious adverse events.

The Relationship Between Daily Physical Activity and Pain in Individuals with Knee Osteoarthritis.

OBJECTIVE: Investigate the association between physical activity and pain severity in individuals with knee osteoarthritis. DESIGN: Cross-sectional; systematic review with meta-analyses. METHODS: Thirty-one participants with knee osteoarthritis underwent assessment of symptoms via self-report questionnaires and quantitative sensory testing. Following testing, physical activity and symptoms were monitored for seven days using accelerometers and logbooks. Cross-correlation analyses were performed on fluctuations in symptoms and physical activity across the week to detect the relative timing of the strongest association between pain and activity. These data were complemented by meta-analyses of studies that examined correlations between pain from knee osteoarthritis and physical activity or fitness. RESULTS: Pain severity at baseline correlated with moderate to vigorous physical activity (r2 = 0.161-0.212, P < 0.05), whereby participants who were more physically active had less pain. Conversely, the peak of the cross-correlation analyses was most often positive and lagging, which indicated that pain was increased subsequent to periods of increased activity. These superficially discrepant findings were supported by the results of a meta-analysis of 13 studies and 9,363 participants, which identified significant heterogeneity for associations between physical activity and pain (I2 = 91%). Stronger inverse associations were found between fitness and pain. CONCLUSIONS: Associations between physical activity and pain in people with knee osteoarthritis are variable and dynamic. These results reflect the beneficial impact of an active lifestyle and accompanying higher fitness. Yet, the side effect of acute periods of physical activity to transiently exacerbate pain may influence the behavior of some people to avoid activity because of pain.

Revising Pediatric Vancomycin Dosing Accounting for Nephrotoxicity in a Pharmacokinetic-Pharmacodynamic Model.

This study aimed to suggest an initial pediatric vancomycin dose regimen through population pharmacokinetic-pharmacodynamic modeling. A population pharmacokinetic approach was used to analyze vancomycin concentration-time data from a large pediatric cohort. Pharmacokinetic target attainment for patients with bloodstream isolates was compared with clinical outcome using logistic regression and classification and regression trees. Change in serum creatinine during treatment was used as an indicator of acute nephrotoxicity. Probability of acute kidney injury (50% increase from baseline) or kidney failure (75% increase from baseline) was evaluated using logistic regression. An initial dosing regimen was derived, personalized by age, weight, and serum creatinine, using stochastic simulations. Data from 785 hospitalized pediatric patients (1 day to 21 years of age) with suspected Gram-positive infections were collected. Estimated (relative standard error) typical clearance, volume of distribution 1, intercompartmental clearance, and volume of distribution 2 were (standardized to 70 kg) 4.84 (2.38) liters/h, 39.9 (8.15) liters, 3.85 (17.3) liters/h, and 37.8 (10.2) liters, respectively. While cumulative vancomycin exposure correlated positively with the development of nephrotoxicity (713 patients), no clear relationship between vancomycin area under the plasma concentration-time curve and efficacy was found (102 patients). Predicted probability of acute kidney injury and kidney failure with the optimized dosing regimen at day 5 was 10 to 15% and 5 to 10%, increasing by approximately 50% on day 7 and roughly 100% on day 10 across all age groups. This study presents the first data-driven pediatric dose selection to date accounting for nephrotoxicity, and it indicates that cumulative vancomycin exposure best describes risk of acute kidney injury and acute kidney failure.

Incident Cardiovascular Disease Among Adults With Blood Pressure <140/90 mm Hg.

BACKGROUND: Data from before the 2000s indicate that the majority of incident cardiovascular disease (CVD) events occur among US adults with systolic and diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg. Over the past several decades, BP has declined and hypertension control has improved. METHODS: We estimated the percentage of incident CVD events that occur at SBP/DBP <140/90 mm Hg in a pooled analysis of 3 contemporary US cohorts: the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), the MESA (Multi-Ethnic Study of Atherosclerosis), and the JHS (Jackson Heart Study) (n=31 856; REGARDS=21 208; MESA=6779; JHS=3869). Baseline study visits were conducted in 2003 to 2007 for REGARDS, 2000 to 2002 for MESA, and 2000 to 2004 for JHS. BP was measured by trained staff using standardized methods. Antihypertensive medication use was self-reported. The primary outcome was incident CVD, defined by the first occurrence of fatal or nonfatal stroke, nonfatal myocardial infarction, fatal coronary heart disease, or heart failure. Events were adjudicated in each study. RESULTS: Over a mean follow-up of 7.7 years, 2584 participants had incident CVD events. Overall, 63.0% (95% confidence interval [CI], 54.9-71.1) of events occurred in participants with SBP/DBP <140/90 mm Hg; 58.4% (95% CI, 47.7-69.2) and 68.1% (95% CI, 60.1-76.0) among those taking and not taking antihypertensive medication, respectively. The majority of events occurred in participants with SBP/DBP <140/90 mm Hg among those <65 years of age (66.7%; 95% CI, 60.5-73.0) and ≥65 years of age (60.3%; 95% CI, 51.0-69.5), women (61.4%; 95% CI, 49.9-72.9) and men (63.8%; 95% CI, 58.4-69.1), and for whites (68.7%; 95% CI, 66.1-71.3), blacks (59.0%; 95% CI, 49.5-68.6), Hispanics (52.7%; 95% CI, 45.1-60.4), and Chinese-Americans (58.5%; 95% CI, 45.2-71.8). Among participants taking antihypertensive medication with SBP/DBP <140/90 mm Hg, 76.6% (95% CI, 75.8-77.5) were eligible for statin treatment, but only 33.2% (95% CI, 32.1-34.3) were taking one, and 19.5% (95% CI, 18.5-20.5) met the SPRINT (Systolic Blood Pressure Intervention Trial) eligibility criteria and may benefit from a SBP target goal of 120 mm Hg. CONCLUSIONS: Although higher BP levels are associated with increased CVD risk, in the modern era, the majority of incident CVD events occur in US adults with SBP/DBP <140/90 mm Hg. While absolute risk and cost-effectiveness should be considered, additional CVD risk-reduction measures for adults with SBP/DBP <140/90 mm Hg at high risk for CVD may be warranted.

Thresholds for Ambulatory Blood Pressure Among African Americans in the Jackson Heart Study.

BACKGROUND: Ambulatory blood pressure (BP) monitoring is the reference standard for out-of-clinic BP measurement. Thresholds for identifying ambulatory hypertension (daytime systolic BP [SBP]/diastolic BP [DBP] ≥135/85 mm Hg, 24-hour SBP/DBP ≥130/80 mm Hg, and nighttime SBP/DBP ≥120/70 mm Hg) have been derived from European, Asian, and South American populations. We determined BP thresholds for ambulatory hypertension in a US population-based sample of African American adults. METHODS: We analyzed data from the Jackson Heart Study, a population-based cohort study comprised exclusively of African American adults (n=5306). Analyses were restricted to 1016 participants who completed ambulatory BP monitoring at baseline in 2000 to 2004. Mean SBP and DBP levels were calculated for daytime (10:00 am-8:00 pm), 24-hour (all available readings), and nighttime (midnight-6:00 am) periods, separately. Daytime, 24-hour, and nighttime BP thresholds for ambulatory hypertension were identified using regression- and outcome-derived approaches. The composite of a cardiovascular disease or an all-cause mortality event was used in the outcome-derived approach. For this latter approach, BP thresholds were identified only for SBP because clinic DBP was not associated with the outcome. Analyses were stratified by antihypertensive medication use. RESULTS: Among participants not taking antihypertensive medication, the regression-derived thresholds for daytime, 24-hour, and nighttime SBP/DBP corresponding to clinic SBP/DBP of 140/90 mm Hg were 134/85 mm Hg, 130/81 mm Hg, and 123/73 mm Hg, respectively. The outcome-derived thresholds for daytime, 24-hour, and nighttime SBP corresponding to a clinic SBP ≥140 mm Hg were 138 mm Hg, 134 mm Hg, and 129 mm Hg, respectively. Among participants taking antihypertensive medication, the regression-derived thresholds for daytime, 24-hour, and nighttime SBP/DBP corresponding to clinic SBP/DBP of 140/90 mm Hg were 135/85 mm Hg, 133/82 mm Hg, and 128/76 mm Hg, respectively. The corresponding outcome-derived thresholds for daytime, 24-hour, and nighttime SBP were 140 mm Hg, 137 mm Hg, and 133 mm Hg, respectively, among those taking antihypertensive medication. CONCLUSIONS: On the basis of the outcome-derived approach for SBP and regression-derived approach for DBP, the following definitions for daytime, 24-hour, and nighttime hypertension corresponding to clinic SBP/DBP ≥140/90 mm Hg are proposed for African American adults: daytime SBP/DBP ≥140/85 mm Hg, 24-hour SBP/DBP ≥135/80 mm Hg, and nighttime SBP/DBP ≥130/75 mm Hg, respectively.

Nephrotic syndrome in adults.

Nephrotic syndrome is an important presentation of glomerular disease characterised by heavy proteinuria, hypoalbuminaemia and oedema. The differential diagnosis of the underlying condition is wide including primary renal disorders and secondary diseases such as malignancy, infection, diabetes and amyloid. Presentations to acute medicine may be with hypervolaemia, complications of the nephrotic state (such as venous thromboembolism), or complications of therapy (such as infection). Early recognition of nephrotic syndrome is possible through simple urinalysis for protein and testing serum albumin, although a high index of suspicion is sometimes required in patients with comorbidities including potentially distracting cardiac or hepatic diseases.

An Improved Variant of Soybean Type 1 Diacylglycerol Acyltransferase Increases the Oil Content and Decreases the Soluble Carbohydrate Content of Soybeans.

Kinetically improved diacylglycerol acyltransferase (DGAT) variants were created to favorably alter carbon partitioning in soybean (Glycine max) seeds. Initially, variants of a type 1 DGAT from a high-oil, high-oleic acid plant seed, Corylus americana, were screened for high oil content in Saccharomyces cerevisiae Nearly all DGAT variants examined from high-oil strains had increased affinity for oleoyl-CoA, with S0.5 values decreased as much as 4.7-fold compared with the wild-type value of 0.94 µm Improved soybean DGAT variants were then designed to include amino acid substitutions observed in promising C. americana DGAT variants. The expression of soybean and C. americana DGAT variants in soybean somatic embryos resulted in oil contents as high as 10% and 12%, respectively, compared with only 5% and 7.6% oil achieved by overexpressing the corresponding wild-type DGATs. The affinity for oleoyl-CoA correlated strongly with oil content. The soybean DGAT variant that gave the greatest oil increase contained 14 amino acid substitutions out of a total of 504 (97% sequence identity with native). Seed-preferred expression of this soybean DGAT1 variant increased oil content of soybean seeds by an average of 3% (16% relative increase) in highly replicated, single-location field trials. The DGAT transgenes significantly reduced the soluble carbohydrate content of mature seeds and increased the seed protein content of some events. This study demonstrated that engineering of the native DGAT enzyme is an effective strategy to improve the oil content and value of soybeans.

Childhood neoplasms presenting at autopsy: A 20-year experience.

OBJECTIVE: The aims of the review are to establish the number of undiagnosed neoplasms presenting at autopsy in a single centre and to determine the incidence and most common causes of sudden unexpected death due to neoplasia in infancy and childhood (SUDNIC). DESIGN: Retrospective observational study of paediatric autopsies performed on behalf of Her Majesty's Coroner over a 20-year period (1996-2015; n = 2,432). Neoplasms first diagnosed at autopsy were identified from an established database and cases meeting the criteria for sudden unexpected death were further categorised. RESULTS: Thirteen previously undiagnosed neoplasms were identified, including five haematological malignancies, two medulloblastomas, two neuroblastomas, two cardiac tumours and two malignancies of renal origin. Eight cases met the criteria for SUDNIC (0.33% of autopsies), the commonest group of which were haematological malignancies (n = 3). CONCLUSIONS: Neoplasms presenting as unexpected death in infancy and childhood and diagnosed at autopsy are rare. The findings suggest that haematological malignancies are the commonest cause of SUDNIC and highlight the importance of specialist autopsy in cases of sudden unexpected death.

Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults.

BACKGROUND AND PURPOSE: In previous observational studies, hemoglobin concentrations have been associated with an increased risk of stroke. However, these studies were limited by a relatively low number of stroke events, making it difficult to determine whether the association of hemoglobin and stroke differed by demographic or clinical factors. METHODS: Using Cox proportional hazards analysis and Kaplan-Meier plots, we examined the association of baseline hemoglobin concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years. RESULTS: A total of 518 participants developed stroke over a mean 7±2 years of follow-up. There was a statistically significant interaction between hemoglobin and sex (P=0.05) on the risk of incident stroke. In Cox regression models adjusted for demographic and clinical variables, there was no association of baseline hemoglobin concentration with incident stroke in men, whereas in women, the lowest (<12.4 g/dL) and highest (>14.0 g/dL) quartiles of hemoglobin were associated with higher risk of stroke when compared with the second quartile (12.4-13.2 g/dL; quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.09-2.31; quartile 2: referent; quartile 3: hazard ratio, 0.91; 95% confidence interval, 0.59-1.38; quartile 4: hazard ratio, 1.59; 95% confidence interval, 1.08-2.35). Similar results were observed in models stratified by hemoglobin and sex and when hemoglobin was modeled as a continuous variable using restricted quadratic spline regression. CONCLUSIONS: Lower and higher hemoglobin concentrations were associated with a higher risk of incident stroke in women. No such associations were found in men.

Clinical characteristics and outcomes of HIV-associated immune complex kidney disease.

BACKGROUND: The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. METHODS: In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. RESULTS: Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. CONCLUSIONS: These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.

Sedentary behavior and subclinical atherosclerosis in African Americans: cross-sectional analysis of the Jackson heart study.

BACKGROUND: Previous studies have reported conflicting results as to whether an association exists between sedentary time and cardiovascular disease (CVD) risk among African Americans. These studies, however, were limited by lack of consideration of sedentary behavior in leisure versus non-leisure settings. To elucidate this relation, we investigated the associations of television (TV) viewing time and occupational sitting with carotid intima-media thickness (CIMT), a subclinical atherosclerosis measure, in a community-based sample of African Americans. METHODS: We studied 3410 participants from the Jackson Heart Study, a single-site, community-based study of African Americans residing in Jackson, MS. CIMT was assessed by ultrasonography and represented mean far-wall thickness across right and left sides of the common carotid artery. TV viewing time, a measure of leisure sedentary behavior, and occupational sitting, a measure of non-leisure sedentary behavior, were assessed by questionnaire. RESULTS: In a multivariable regression model that included physical activity and CVD risk factors, longer TV viewing time (2-4 h/day and >4 h/day) was associated with greater CIMT (adjusted mean ± SE difference from referent [<2 h/day] of 0.009 ± 0.008 mm for 2-4 h/day, and 0.028 ± 0.009 mm for >4 h/day; P-trend =0.001). In contrast, more frequent occupational sitting ('sometimes' and 'often/always') was associated with lower CIMT (adjusted mean ± SE difference from referent ['never/seldom']:-0.021 ± 0.009 mm for 'sometimes', and-0.018 ± 0.008 mm for 'often/always'; P-trend = 0.042). CONCLUSIONS: Longer TV viewing time was associated with greater CIMT, while occupational sitting was associated with lower CIMT. These findings suggest the role of sedentary behaviors in the pathogenesis of CVD among African Americans may vary by whether individuals engage in leisure versus non-leisure sedentary behaviors.

The association of reduced lung function with blood pressure variability in African Americans: data from the Jackson Heart Study.

BACKGROUND: African Americans (AAs) have lower lung function, higher blood pressure variability (BPV) and increased risk for hypertension and cardiovascular disease (CVD) compared with whites. The mechanism through which reduced lung-function is associated with increased CVD risk is unclear. METHODS: We evaluated the association between percent predicted lung-function and 24-hour BPV in 1008 AAs enrolled in the Jackson Heart Study who underwent ambulatory blood pressure (BP) monitoring. Lung-function was assessed as forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1-to-FVC during a pulmonary function test using a dry rolling sealed spirometer and grouped into gender-specific quartiles. The pairwise associations of these three lung-function measures with two measures of 24-hour BPV, (1) day-night standard deviation (SDdn) and (2) average real variability (ARV) were examined for systolic BP (SBP) and, separately, diastolic BP (DBP). RESULTS: SDdn of SBP was not associated with FEV1 (mean ± standard deviation from lowest-to-highest quartile: 9.5 ± 2.5, 9.4 ± 2.4, 9.1 ± 2.3, 9.3 ± 2.6; p-trend = 0.111). After age and sex adjustment, the difference in SDdn of SBP was 0.0 (95% CI -0.4,0.4), -0.4 (95% CI -0.8,0.1) and -0.3 (95% CI -0.7,0.1) in the three progressively higher versus lowest quartiles of FEV1 (p-trend = 0.041). Differences in SDdn of SBP across FEV1 quartiles were not statistically significant after further multivariable adjustment. After multivariable adjustment, no association was present between FEV1 and ARV of SBP or SDdn and ARV of DBP or when evaluating the association of FVC and FEV1-to-FVC with 24-hour BPV. CONCLUSION: Lung-function was not associated with increased 24-hour BPV.

Limited Association Between Aerobic Fitness and Pain in Healthy Individuals: A Cross-Sectional Study.

OBJECTIVE: In healthy individuals and people with chronic pain, an inverse association between physical activity level and pain has been reported. Associations between objectively measured fitness and pain have also been found in people with chronic pain, but it is not clear whether the same relations are apparent in healthy individuals. The purpose of the present study was to examine the relation between aerobic capacity and pain in healthy individuals. METHODS: Pressure pain threshold, ischemic pain tolerance, and pain ratings during ischemia were assessed and analyzed in relation to aerobic capacity in 35 healthy individuals. Correlation and multiple linear regression were used to analyze the data. Data from previous similar studies in healthy individuals and people with fibromyalgia were extracted and collated by literature review to support interpretation of the experimental data. RESULTS: No relation was found between aerobic capacity and any measure of pain, with the exception of a moderate inverse association between aerobic capacity and lower body pressure pain threshold in males (r = -0.58, P = 0.03) when data from male and female participants were analyzed separately. The limited association between aerobic capacity and quantitative sensory testing of pain was consistent with the data synthesis from previous studies of healthy individuals but differed from studies of people with fibromyalgia. CONCLUSIONS: Aerobic capacity is unrelated to pain in healthy young adults. For people with chronic pain, the negative relation between aerobic capacity and pain presumably arises from the underlying pathophysiology and/or associated behaviors of the disease process.