External validation of prognostic models to predict stillbirth using International Prediction of Pregnancy Complications (IPPIC) Network database: individual participant data meta-analysis.

OBJECTIVE: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. METHODS: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. RESULTS: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. CONCLUSIONS: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: case-control study.

Chronic fatigue syndrome (CFS) is characterized by fatigue after exertion. A systematic review suggested that transforming growth factor (TGF)-ß concentrations are often elevated in cases of CFS when compared to healthy controls. This study attempted to replicate this finding and investigate whether post-exertional symptoms were associated with altered cytokine protein concentrations and their RNA in CFS patients. Twenty-four patients fulfilling Centers for Disease Control criteria for CFS, but with no comorbid psychiatric disorders, were recruited from two CFS clinics in London, UK. Twenty-one healthy, sedentary controls were matched by gender, age and other variables. Circulating proteins and RNA were measured for TGF-ß, tumour necrosis factor (TNF), interleukin (IL)-8, IL-6 and IL-1ß. We measured six further cytokine protein concentrations (IL-2, IL-4, IL-5, IL-10, IL-12p70, and interferon (IFN)-γ). Measures were taken at rest, and before and after both commuting and aerobic exercise. CFS cases had higher TGF-ß protein levels compared to controls at rest (median (quartiles) = 43·9 (19·2, 61·8) versus 18·9 (16·1, 30·0) ng/ml) (P = 0·003), and consistently so over a 9-day period. However, this was a spurious finding due to variation between different assay batches. There were no differences between groups in changes to TGF-ß protein concentrations after either commuting or exercise. All other cytokine protein and RNA levels were similar between cases and controls. Post-exertional symptoms and perceived effort were not associated with any increased cytokines. We were unable to replicate previously found elevations in circulating cytokine concentrations, suggesting that elevated circulating cytokines are not important in the pathophysiology of CFS.

Childhood adversity and midlife suicidal ideation.

BACKGROUND: Childhood adversity predicts adolescent suicidal ideation but there are few studies examining whether the risk of childhood adversity extends to suicidal ideation in midlife. We hypothesized that childhood adversity predicts midlife suicidal ideation and this is partially mediated by adolescent internalizing disorders, externalizing disorders and adult exposure to life events and interpersonal difficulties. METHOD: At 45 years, 9377 women and men from the UK 1958 British Birth Cohort Study participated in a clinical survey. Childhood adversity was prospectively assessed at the ages of 7, 11 and 16 years. Suicidal ideation at midlife was assessed by the depressive ideas subscale of the Revised Clinical Interview Schedule. Internalizing and externalizing disorders were measured by the Rutter scales at 16 years. Life events, periods of unemployment, partnership separations and alcohol dependence were measured through adulthood. RESULTS: Illness in the household, paternal absence, institutional care, parental divorce and retrospective reports of parental physical and sexual abuse predicted suicidal ideation at 45 years. Three or more childhood adversities were associated with suicidal ideation at 45 years [odds ratio (OR) 4.31, 95% confidence interval (CI) 2.67-6.94]. Psychological distress at 16 years partially mediated the associations of physical abuse (OR 3.41, 95% CI 2.29-5.75), sexual abuse (OR 4.99, 95% CI 2.90-11.16) with suicidal ideation. Adult life events partially mediated the association of parental divorce (OR 6.34, 95% CI -7.16 to 36.75) and physical (OR 9.59, 95% CI 4.97-27.88) and sexual abuse (OR 6.59, 95% CI 2.40-38.36) with suicidal ideation at 45 years. CONCLUSIONS: Adversity in childhood predicts suicidal ideation in midlife, partially mediated by adolescent internalizing and externalizing disorders, adult life events and interpersonal difficulties. Understanding the pathways from adversity to suicidal ideation can inform suicide prevention and the targeting of preventive interventions.

Impact of childhood and adulthood psychological health on labour force participation and exit in later life.

BACKGROUND: Adulthood psychological health predicts labour force activity but few studies have examined childhood psychological health. We hypothesized that childhood psychological ill-health would be associated with labour force exit at 55 years. METHOD: Data were from the 55-year follow-up of the National Child Development Study (n = 9137). Labour force participation and exit (unemployment, retirement, permanent sickness, homemaking/other) were self-reported at 55 years. Internalizing and externalizing problems in childhood (7, 11 and 16 years) and malaise in adulthood (23, 33, 42, 50 years) were assessed. Education, social class, periods of unemployment, partnership separations, number of children, and homemaking activity were measured throughout adulthood. RESULTS: Childhood internalizing and externalizing problems were associated with unemployment, permanent sickness and homemaking/other at 55 years, after adjustment for adulthood psychological health and education: one or two reports of internalizing was associated with increased risk for unemployment [relative risk (RR) 1.59, 95% confidence interval (CI) 1.12-2.25; RR 2.37, 95% CI 1.48-3.79] and permanent sickness (RR 1.32, 95% CI 1.00-1.74; RR, 1.48, 95% CI 1.00-2.17); three reports of externalizing was associated with increased risk for unemployment (RR 2.26, 95% CI 1.01-5.04), permanent sickness (RR 2.63, 95% CI 1.46-4.73) and homemaking/other (RR 1.95, 95% CI 1.00-3.78). CONCLUSIONS: Psychological ill-health across the lifecourse, including during childhood, reduces the likelihood of working in older age. Support for those with mental health problems at different life stages and for those with limited connections to the labour market, including homemakers, is an essential dimension of attempts to extend working lives.

What impact do assumptions about missing data have on conclusions? A practical sensitivity analysis for a cancer survival registry.

BACKGROUND: Within epidemiological and clinical research, missing data are a common issue and often over looked in publications. When the issue of missing observations is addressed it is usually assumed that the missing data are 'missing at random' (MAR). This assumption should be checked for plausibility, however it is untestable, thus inferences should be assessed for robustness to departures from missing at random. METHODS: We highlight the method of pattern mixture sensitivity analysis after multiple imputation using colorectal cancer data as an example. We focus on the Dukes' stage variable which has the highest proportion of missing observations. First, we find the probability of being in each Dukes' stage given the MAR imputed dataset. We use these probabilities in a questionnaire to elicit prior beliefs from experts on what they believe the probability would be in the missing data. The questionnaire responses are then used in a Dirichlet draw to create a Bayesian 'missing not at random' (MNAR) prior to impute the missing observations. The model of interest is applied and inferences are compared to those from the MAR imputed data. RESULTS: The inferences were largely insensitive to departure from MAR. Inferences under MNAR suggested a smaller association between Dukes' stage and death, though the association remained positive and with similarly low p values. CONCLUSIONS: We conclude by discussing the positives and negatives of our method and highlight the importance of making people aware of the need to test the MAR assumption.

Longitudinal associations of experiences of adversity and socioeconomic disadvantage during childhood with labour force participation and exit in later adulthood.

The Extending Working Lives (EWL) agenda seeks to sustain employment up to and beyond traditional retirement ages. This study examined the potential role of childhood factors in shaping labour force participation and exit among older adults, with a view to informing proactive interventions early in the life-course to enhance individuals' future capacity for extending their working lives. Childhood adversity and socioeconomic disadvantage have previously been linked to ill-health across the life-span and sickness benefit in early adulthood. This study builds upon previous research by examining associations between childhood adversity and self-reported labour force participation among older adults (aged 55). Data was from the National Child Development Study - a prospective cohort of all English, Scottish, & Welsh births in one week in 1958. There was evidence for associations between childhood adversity and increased risk of permanent sickness at 55 years - which were largely sustained after adjustment for educational disengagement and adulthood factors (mental/physical health, qualifications, socioeconomic disadvantage). Specifically, children who were abused or neglected were more likely to be permanently sick at 55 years. In addition, among males, those in care, those experiencing illness in the home, and those experiencing two or more childhood adversities were more likely to be permanently sick at 55 years. Childhood factors were also associated with part-time employment and retirement at 55 years. Severe childhood adversities may represent important distal predictors of labour force exit at 55 years, particularly via permanent sickness. Notably, some adversities show associations among males only, which may inform interventions designed to extend working lives.

Renal clearance of estriol and its conjugates in normal and abnormal pregnancies.

Renal clearance of estriol (E3), E3-3-sulfate (E3S), E3-16-glucuronide (E316G), E3-3-glucuronide (E33G), and E3-3-sulfate-16-glucuronide (E3SG) has been measured in 13 normal and 17 abnormal pregnancies between the 33rd and 40th weeks of gestation. The methodology involved a chromatographic separation on a celite column in the presence of tritiated tracers, enzymic hydrolysis of the conjugates, and measurement of the E3 moiety by a specific RIA. Preeclampsia (eight patients) was characterized by a significant decrease of renal clearance for all conjugates except E33G. In contrast to that pattern, a patient with cholestatic icterus had normal clearances except for E33G, which was reduced to less than 15% of its normal mean value. Administration of ampicillin to a pregnant woman induced an important decrease of all E3 clearances, especially for E33G which decreased to nearly 1% of its initial value; normal clearances were resumed within a week after the end of the treatment. In a small number of complicated pregnancies, E3 clearances were normal. A significant correlation between the renal clearance of E316G and that of urea and creatinine has been demonstrated.

16-Dehydrogenase in human placenta.

Human placenta subfractions were incubated with radioactive oestriol and 16-oxo-oestradiol. 16-oxo-oestradiol was identified from the oestriol incubation. Oestriol and 16-epi-oestriol were characterized from the incubation while 16-epi-oestriol were characterized from the incubation with 16-oxo-oestradiol. The 16alpha-dehydrogenase has been located in the soluble fraction (105 000 g supernatant) of the human placenta.

Serum progesterone in nonpregnant women. I. Comparative study of serum progesterone concentration and urinary pregnanediol excretion.

PIP: The normal range of serum progesterone (measured by radioimmunoassay) and urinary pregnanediol during the menstrual cycle was determined in 86 patients (33 control and 53 with menstrual disorders or sterility) and the values were found to show a logarithmic distribution. The overall correlation between serum progesterone and urinary pregnanediol concentration was .82. Clinical diagnostic applications of these measurements include: 1) anovulatory demonstration, 2) determination of secondary amenorrhea, 3) investigation of prolonged cycles, 4) investigation of probable luteal insufficiency, and 5) response to clomiphene citrate.^ieng