Toxicity Investigations of (R)-3-Hydroxybutyrate Glycerides In Vitro and in Male and Female Rats.

TCN006, a formulation of (R)-3-Hydroxybutyrate glycerides, is a promising ingredient for enhancing ketone intake of humans. Ketones have been shown to have beneficial effects on human health. To be used by humans, TCN006 must be determined safe in appropriately designed safety studies. The results of a bacterial reverse mutation assay, an in vitro mammalian micronucleus study, and 14-and 90-day repeat dose toxicity studies in rats are reported herein. In the 14- and 90-day studies, male and female Wistar rats had free access to drinking water containing 0, 75,000, 125,000 or 200,000 ppm TCN006 for 92 and 93 days, respectively. TCN006 tested negative for genotoxicity and the no observed adverse effect level (NOAEL) for toxicity in the 14- and 90-day studies was 200,000 ppm, the highest dose administered. In the longer term study, the mean overall daily intake of TCN006 in the 200,000 ppm groups was 14,027.9 mg/kg bw/day for males and 20,507.0 mg/kg bw/day for females. At this concentration, palatability of water was likely affected, which led to a decrease in water consumption in both males and females compared to respective controls. This had no effect on the health of the animals. Although the rats were administered very high levels of (R)-3-Hydroxybutyrate glycerides, there were no signs of ketoacidosis.

Outcomes during delivery hospitalisations with inflammatory bowel disease.

OBJECTIVE: To characterise inflammatory bowel disease (IBD) trends and associated risk during delivery hospitalisations. DESIGN: Cross-sectional. SETTING: US delivery hospitalisations. POPULATION: Delivery hospitalisations in the 2000-2018 National Inpatient Sample. METHODS: This study analysed a nationally representative hospital discharge database based on the presence of IBD. Temporal trends in IBD were analysed using joinpoint regression to estimate the average annual percent change (AAPC). IBD severity was characterised by the presence of diagnoses such as penetrating and stricturing disease and history of bowel resection. Risks for adverse outcomes were analysed based on presence of IBD. Poisson regression models were performed with unadjusted and adjusted risk ratios (aRR) as measures of effect. MAIN OUTCOME MEASURE: Prevalence of IBD and associated adverse outcomes. RESULTS: Of 73 109 790 delivery hospitalisations, 89 965 had a diagnosis of IBD. IBD rose from 0.06% in 2000 to 0.21% in 2018 (AAPC 7.3%, 95% CI 6.7-7.9%). Among deliveries with IBD, IBD severity diagnoses increased from 4.1% to 8.1% from 2000 to 2018. In adjusted analysis, IBD was associated with increased risk for preterm delivery (aRR 1.50, 95% CI 1.47-1.53), severe maternal morbidity (aRR 1.93, 95% CI 1.83-2.04), venous thrombo-embolism (aRR 2.76, 95% CI 2.39-3.18) and surgical injury during caesarean delivery hospitalisation (aRR 5.03, 95% CI 4.76-5.31). In the presence of a severe IBD diagnosis, risk was further increased for all adverse outcomes. CONCLUSION: IBD is increasing in the obstetric population and is associated with adverse outcomes. Risk is increased in the presence of a severe IBD diagnosis. TWEETABLE ABSTRACT: Deliveries among women with inflammatory bowel disease are increasing. Disease severity is associated with adverse outcomes.

Population risk factors for nulliparous, term, singleton, vertex caesarean birth: a national cross-sectional study.

OBJECTIVE: To characterise medical, obstetric and demographic risk factors associated with nulliparous, term, singleton, vertex (NTSV) caesarean birth. STUDY DESIGN: Cross-sectional study. SETTING: United States delivery hospitalisations. POPULATION: NTSV births in 2016-18 US natality data. METHODS: This study analysed a national sample of natality data generated by the United States National Vital Statistics System. NTSV deliveries were identified. The primary outcome was caesarean birth. Risk factors including maternal age, body mass index (BMI) and pregestational diabetes were analysed. Multivariable log-linear regression models analysed factors associated with NTSV caesarean with adjusted risk ratios (aRR) as measures of effect. RESULTS: Of 11 622 400 deliveries, 3 764 707 met NTSV criteria, and their caesarean section rate was 25.9%. Maternal age 35-39 years (aRR 1.51, 95% CI 1.50-1.52) and 40-54 years (aRR 2.03, 95% 2.00-2.05) compared with age 19-34 years; BMI 25 to <30 kg/m2 (aRR 1.32, 95% CI 1.31-1.33), 30 to <35 kg/m2 (aRR 1.57 95% CI 1.56-1.58), 35 to <40 kg/m2 (aRR 1.82, 95% CI 1.80-1.83) and ≥40 kg/m2 (aRR 2.17, 95% CI 2.15-2.19) compared with BMI 18.5-24.9 kg/m2; and pregestational diabetes (aRR 1.54, 95% CI 1.51-1.57) were all associated with increased risk. Risk factors allowed stratification of patients into high-risk versus low-risk groups. The NTSV caesarean rate was 37.9% in women who had one or more of the following characteristics: age ≥35 years, BMI ≥30 kg/m2 or pregestational diabetes. In comparison, the NTSV caesarean rate was 20.8% among women without any of these three risk factors (P < 0.01). CONCLUSION: Among NTSV births, BMI, maternal age and medical conditions are important risk factors for caesarean delivery.

Patterns of mortality in modern stroke care

Background Stroke is a leading cause of death. We looked at the causes (direct and indirect) of in-hospital mortality in a modern stroke unit over a two-year period. Methods We reviewed medical charts of stroke deaths in hospital from 2014-2015 inclusive. Data on stroke type, aetiology, age, length of stay, comorbidities, and documented cause of death were recorded. All patients were included. Results 518 patients were admitted acutely to the stroke service. Overall death rate was 7.5% (n=39). Of fatal strokes 29 (74%) were ischaemic. Average age 78.6 years. Mean survival was 26.4 days (range 1-154). 19 (49%) patients had atrial fibrillation. Forty-nine percent of deaths were due to pneumonia, and 33% were due to raised intracranial pressure. Discussion Mortality rate in our stroke service has decreased from 15% in 1997, and now appears dichotomised into early Secondary Stroke Related Cerebral Events (SSRCEs) and later infections.

Trends in operative vaginal delivery, 2005-2013: a population-based study.

OBJECTIVE: The objectives of this study were to determine temporal trends in forceps and vacuum delivery and factors associated with operative vaginal delivery. DESIGN: Retrospective cohort. SETTING: Population-based study of US birth records. POPULATION: US births from 2005 to 2013. METHODS: This study evaluated forceps and vacuum extraction during vaginal delivery in live-born, non-anomalous singleton gestations from ≥ 36 to < 42 weeks of gestation. The primary outcomes were vacuum, forceps and overall operative delivery. Obstetric, medical and demographic characteristics associated with operative vaginal delivery were analysed. Multivariable logistic regression models were developed to determine factors associated with forceps/vacuum use. RESULTS: A total of 22 598 971 vaginal deliveries between 2005 and 2013 were included in the analysis. In all, 1 083 318 (4.8%) were vacuum-assisted and 237 792 (1.1%) were by forceps. Both vacuum and forceps deliveries decreased over the study period; vacuum deliveries decreased from 5.8% in 2005 to 4.1% in 2013, and forceps deliveries decreased from 1.4% to 0.9% during the same period. The adjusted odds ratio for forceps delivery was 0.70 (95% CI 0.69-0.72) in 2013 with 2005 as a reference. For vacuum delivery the odds ratio was 0.68 (95% CI 0.67-0.69) comparing the same years. CONCLUSION: Forceps and vacuum deliveries decreased during the study period. Low rates of operative delivery pose a challenge for resident education and may limit the degree to which women have access to alternatives to caesarean delivery. Initiatives that allow future generations of obstetricians to develop expertise in performing operative deliveries in the setting of decreased volume are an urgent resident education priority. TWEETABLE ABSTRACT: Forceps and vacuum delivery decreased significantly in the USA from 2005 to 2013.

Infant mortality in the United States.

The infant mortality rate (IMR) of 6.0 per 1000 live births in the United States in 2013 is nearly the highest among developed countries. Moreover, the IMR among blacks is >twice that among whites-11.11 versus 5.06 deaths per 1000 live births.This higher IMR and racial disparity in IMR is due to a higher preterm birth rate (11.4% of live births in 2013) and higher IMR among term infants. The United States also ranks near the bottom for maternal mortality and life expectancy among the developed nations-despite ranking highest in the proportion of gross national product spent on health care. This suggests that factors other than health care contribute to the higher IMR and racial disparity in IMR. One factor is disadvantaged socioeconomic status. All of the actionable determinates that negatively impact health-personal behavior, social factors, heath-care access and quality and the environment-disproportionately affect the poor. Addressing disadvantaged socioeconomic status by improving access to quality health care and increasing social expenditures would have the greatest impact on the USA's IMR and racial disparity in IMR.

A comparison of recommendations for pharmacologic thromboembolism prophylaxis after caesarean delivery from three major guidelines.

OBJECTIVE: Guidelines for pharmacologic obstetric venous thromboembolism (VTE) prophylaxis from the American Congress of Obstetricians (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), and the American College of Chest Physicians (Chest) vary significantly. The objective of this study was to determine the practical implications of these recommendations in terms of prophylaxis rates for a tertiary obstetric population. STUDY DESIGN: Cross-sectional. SETTING: Tertiary referral hospital. POPULATION: Patients post-operative day 1 after caesarean delivery. METHODS: This cross-sectional study evaluated rates of pharmacologic prophylaxis for women based on RCOG, ACOG, and Chest recommendations. Medical, obstetric, and demographic risk factors for thromboembolism were reviewed for individual patients. Rates of prophylaxis based on each of the guidelines with 95% confidence intervals were calculated. OUTCOME MEASURE: Recommended pharmacologic prophylaxis. RESULTS: About 293 patients were included in the analysis. Under RCOG guidelines, 85.0% of patients would receive post-caesarean pharmacologic prophylaxis [95% confidence interval (CI) 80.5-88.6%] compared with 1.0% of patients under ACOG guidelines (95% CI 0.3-3.0%) and 34.8% of patients under Chest guidelines (95% CI 29.6-40.4%). Caesarean during labour, obesity, advanced maternal age, pre-eclampsia, and multiple gestation were among the most commonrisk factors. CONCLUSION: Recommended prophylaxis differed significantly. Under ACOG recommendations a small minority of patients would receive prophylaxis, whereas under RCOG recommendations a large majority of patients would receive low-molecular-weight heparin. Given the large differences in prophylaxis rates for post-caesarean thromboprophylaxis based on different guidelines, further research is urgently needed to compare the risks and benefits of recommendations. TWEETABLE ABSTRACT: Recommendations from major society guidelines for post-caesarean thromboprophylaxis differ greatly.

Nuchal Translucency Quality Review (NTQR) program: first one and half million results.

OBJECTIVE: To evaluate the performance of first-trimester nuchal translucency (NT) measurement by providers (physician-sonologists and sonographers) within the Nuchal Translucency Quality Review (NTQR) program. METHODS: After training and credentialing providers, the NTQR monitored performance of NT measurement by the extent to which an individual's median multiple of the normal median (MoM) for crown-rump length (CRL) was within the range 0.9-1.1 MoM of a published normal median curve. The SD of log10 MoM and regression slope of NT on CRL were also evaluated. We report the distribution between providers of these performance indicators and evaluate potential sources of variation. RESULTS: Among the first 1.5 million scans in the NTQR program, performed between 2005 and 2011, there were 1 485 944 with CRL in the range 41-84 mm, from 4710 providers at 2150 ultrasound units. Among the 3463 providers with at least 30 scans in total, the median of the providers' median NT-MoMs was 0.913. Only 1901 (55%) had a median NT-MoM within the expected range; there were 89 above 1.1 MoM, 1046 at 0.8-0.9 MoM, 344 at 0.7-0.8 MoM and 83 below 0.7 MoM. There was a small increase in the median NT-MoM according to providers' length of time in the NTQR program and number of scans entered annually. On average, physician-sonologists had a higher median NT-MoM than did sonographers, as did those already credentialed before joining the program. The median provider SD was 0.093 and the median slope was 13.5%. SD correlated negatively with the median NT-MoM (r = -0.34) and positively with the slope (r = 0.22). CONCLUSION: Even with extensive training, credentialing and monitoring, there remains considerable variability between NT providers. There was a general tendency towards under-measurement of NT compared with expected values, although more experienced providers had performance closer to that expected.

Disabling disease codes predict worse outcomes for acute medical admissions.

BACKGROUND: Concurrent with an extension in longevity, a prodrome of ill-health ('disability' identifiable by certain International Classification of Disease (ICD) 9/ICD10 codes) predates the acute emergency presentation. To date, no study has assessed the effect of such 'disability' on outcomes of emergency medical admissions. AIM: To devise a new method of scoring the burden of 'disability' and assess its relevance to outcomes of acute hospital admissions. METHODS: All emergency admissions (67 971 episodes in n = 37 828 patients) to St James' Hospital, Dublin, Ireland over an 11-year period (2002-2012) were studied, and 30-day in-hospital mortality and length of stay were assessed as objective end-points. Patients were classified according to a validated 'disability' classification method and scored from 0 to 4+ (5 classes), dependent on number of ICD9/ICD10 'hits' in hospital episode codes. RESULTS: A disabling score of zero was present in 10.6% of patients. Scores of 1, 2, 3 and 4+ (classified by the number of organ systems involved) occurred with frequencies of 23.3%, 28.7%, 21.9% and 15.5% respectively. The 'disability' score was strongly driven by age. The 30-day mortality rates were 0.9% (no score), 2.6%, 4.1%, 6.3% and 10.9%. Surviving patients remained in hospital for medians of 1.8 (no score), 3.9, 6.1, 8.1 and 9.7 days respectively. High 'disability' and illness severity predicted a particularly bad outcome. CONCLUSION: Disability burden, irrespective of organ system at emergency medical admission, independently predicts worse outcomes and a longer in-hospital stay.

Indications for caesarean sections at ≥34 weeks among nulliparous women and differential composite maternal and neonatal morbidity.

OBJECTIVE: To compare composite maternal and neonatal morbidities (CMM, CNM) among nulliparous women with primary indications for caesarean section (CS) as acute clinical emergency (group I; ACE), non-reassuring fetal heart rate (group II) and arrest disorder (group III). DESIGN: A multicentre prospective study. SETTING: Nineteen academic centres in the USA, with deliveries in 1999-2002. POPULATION: Nulliparous women (n = 9829) that had CS. METHODS: Nulliparous women undergoing CS for three categories of indications were compared using logistic regression model, adjusted for five variables. MAIN OUTCOME MEASURES: CMM was defined as the presence of any of the following: intrapartum or postpartum transfusion, uterine rupture, hysterectomy, cystotomy, ureteral or bowel injury or death; CNM was defined as the presence of any of the following: umbilical arterial pH <7.00, neonatal seizure, cardiac, hepatic, renal dysfunction, hypoxic ischaemic encephalopathy or neonatal death. RESULTS: The primary reasons for CS were ACE in 1% (group I, n = 114) non-reassuring FHR in 29% (group II; n = 2822) and failed induction/dystocia in the remaining 70% (group III; n = 6893). The overall risks of CMM and CNM were 2.5% (95% confidence intervals, CI, 2.2-2.8%) and 1.9% (95% CI 1.7-2.2), respectively. The risk of CMM was higher in group I than in group II (RR 4.1, 95% CI 3.1, 5.3), and group III (RR 3.2, 95% CI 2.7, 3.7). The risk of CNM was also higher in group I than in group II (RR 2.8, 95% CI 2.3, 3.4) and group III (RR 14.1, 95% CI 10.7, 18.7). CONCLUSIONS: Nulliparous women who have acute clinically emergent caesarean sections are at the highest risks of both composite maternal and neonatal morbidity and mortality.

Street drug use during pregnancy: potential programming effects on preschool wheeze.

Street drug use during pregnancy is detrimental to fetal development. Although the prevalence of wheeze is high in offspring of substance-abusing mothers, nothing is known about the role of street drug use during pregnancy in its development. We investigated the impact of maternal street drug use and distress during pregnancy on the development of wheeze and allergy in preschool children. Questionnaire data were accessed from the Community Perinatal Care trial of 791 mother-child pairs in Calgary, Alberta. Using logistic regression, the association between maternal substance use and distress during pregnancy, and wheeze and allergy at age 3 years was determined in boys and girls. After adjusting for alcohol use during pregnancy, pre- and postnatal tobacco use, preterm birth, duration of exclusive breastfeeding, daycare attendance and maternal socioeconomic status, maternal street drug use during pregnancy [odds ratio (OR): 5.02, 95% confidence interval (CI): 1.30-19.4] and severe maternal distress during pregnancy (OR: 5.79, 95% CI: 1.25-26.8) were associated with wheeze in girls. In boys, an independent association was found between severe distress during pregnancy (OR: 3.85, 95% CI: 1.11-13.3) and allergies, but there was no association with maternal street drug use. In conclusion, we found an association between maternal street drug use and wheeze in preschool girls that could not be accounted for by maternal distress, smoking or alcohol use during pregnancy. Prenatal programming effects of street drugs may explain this association.

Cross-trimester repeated measures testing for Down's syndrome screening: an assessment.

OBJECTIVES: To provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein A (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution.

Maintaining quality assurance for sonographic nuchal translucency measurement: lessons from the FASTER Trial.

OBJECTIVE: To evaluate nuchal translucency measurement quality assurance techniques in a large-scale study. METHODS: From 1999 to 2001, unselected patients with singleton gestations between 10 + 3 weeks and 13 + 6 weeks were recruited from 15 centers. Sonographic nuchal translucency measurement was performed by trained technicians. Four levels of quality assurance were employed: (1) a standardized protocol utilized by each sonographer; (2) local-image review by a second sonographer; (3) central-image scoring by a single physician; and (4) epidemiological monitoring of all accepted nuchal translucency measurements cross-sectionally and over time. RESULTS: Detailed quality assessment was available for 37 018 patients. Nuchal translucency measurement was successful in 96.3% of women. Local reviewers rejected 0.8% of images, and the single central physician reviewer rejected a further 2.9%. Multivariate analysis indicated that higher body mass index, earlier gestational age and transvaginal probe use were predictors of failure of nuchal translucency measurement and central image rejection (P = 0.001). Epidemiological monitoring identified a drift in measurements over time. CONCLUSION: Despite initial training and continuous image review, changes in nuchal translucency measurements occur over time. To maintain screening accuracy, ongoing quality assessment is needed.

CPAP treatment in obstructive sleep apnoea: a randomised, controlled trial of follow-up with a focus on patient satisfaction.

AIM OF THE STUDY: To assess a simplified model for follow-up in patients undergoing CPAP-treatment for obstructive sleep apnoea syndrome. PATIENTS AND METHODS: A total of 200 patients in stable condition were randomised to annual follow-up visits either by a specialist nurse (intervention) or physician-led visits including oximetry (control). Patients were followed for two years and assessed for the following outcomes: global satisfaction, quality of life, medical events, and resource utilisation. RESULTS: The overall experience of CPAP treatment was rated as excellent or good by 99% in each group. Global satisfaction was high in both groups, and there were no clinically significant differences between the groups. Quality of life did not differ between the groups. No serious medical events related to OSAS occurred during the study period. Extra physician consultations occurred rarely, and were managed within the limits of the follow-up visits. CONCLUSION: For stable patients undergoing CPAP treatment for obstructive sleep apnoea, regular follow-up visits by a specialist nurse can optimise the use of health care resources while retaining high patient satisfaction, without increasing medical risks.

An islet-stabilizing implant constructed using a preformed vasculature.

Islet transplantation for the purpose of treating insulin-sensitive diabetes is currently limited by several factors, including islet survival posttransplantation. In the current study, a tissue-engineered prevascularized pancreatic encapsulating device (PPED) was developed. Isolated islets were placed in collagen gels, and they exhibited fourfold more insulin release than islets not in collagen. The insulin released by beta-cells in islets encapsulated in collagen exhibited unobstructed diffusion within the collagen gels. Subsequent studies evaluated the ability to create a sandwich comprised of two layers of prevascularized collagen gels around a central collagen gel containing islets. In vitro characterization of the islets showed that islets are functional and responded to glucose stimulation. The PPEDs were implanted subcutaneously into severe combined immunodeficient mice. Islet survival was assessed after 7, 14, and 28 days. Immunohistochemical analysis was performed on the implants to detect insulin and the presence of intraislet endothelial cells. At all time points, insulin was localized in association with intact and partially dissociated islets. Moreover, cells that exhibited insulin staining were colocalized with intraislet endothelial cells. These data indicate that the PPED enhances islet survival by supporting islet viability and maintaining intraislet endothelial cell structures.

First- and second-trimester Down syndrome screening markers in pregnancies achieved through assisted reproductive technologies (ART): a FASTER trial study.

OBJECTIVE: To determine whether first- and second-trimester Down syndrome screening markers and screen-positive rates are altered in pregnancies conceived using assisted reproductive technologies (ARTs). METHODS: ART pregnancies in the multicenter FASTER trial were identified. Marker levels were evaluated for five types of ART: in vitro fertilization with ovulation induction (IVF-OI), IVF with OI and egg donation (IVF-OI-ED), IVF with ED (IVF-ED), and intrauterine insemination with OI (IUI-OI) or without OI (IUI). Each group was compared to non-ART controls using Mann-Whitney U analysis. RESULTS: First-trimester marker levels were not significantly different between ART and control pregnancies, with the exception of reduced PAPP-A levels in the IUI-OI group. In contrast, second-trimester inhibin A levels were increased in all ART pregnancies, estriol was reduced and human chorionic gonadotropin (hCG) was increased in IVF and IUI pregnancies without ED, and alpha-fetoprotein (AFP) was increased in ED pregnancies. Second-trimester screen-positive rates were significantly higher than expected for ART pregnancies, except when ED was used. CONCLUSIONS: These data show that ART significantly impacts second-, but not first-, trimester markers and screen-positive rates. The type of adjustment needed in second-trimester screening depends on the particular type of ART used.