Induced pluripotent stem cells in disease modelling and drug discovery.

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.

Understanding the relationship between family income and conduct problems: findings from the mental health of children and young people survey.

BACKGROUND: Children from low-socioeconomic backgrounds exhibit more behavioural difficulties than those from more affluent families. Influential theoretical models specify family stress and child characteristics as mediating this effect. These accounts, however, have often been based on cross-sectional data or longitudinal analyses that do not capture all potential pathways, and therefore may not provide good policy guidance. METHODS: In a UK representative sample of 2399 children aged 5-15, we tested mediation of the effect of household income on parent and teacher reports of conduct problems (CP) via unhealthy family functioning, poor parental mental health, stressful life events, child physical health and reading ability. We applied cross-lagged longitudinal mediation models which allowed for testing of reciprocal effects whereby the hypothesised mediators were modelled as outcomes as well as predictors of CP. RESULTS: We found the predicted significant longitudinal effect of income on CP, but no evidence that it was mediated by the child and family factors included in the study. Instead, we found significant indirect paths from income to parental mental health, child physical health and stressful life events that were transmitted via child CP. CONCLUSION: The results confirm that income is associated with change in CP but do not support models that suggest this effect is transmitted via unhealthy family functioning, parental mental health, child physical health, stressful life events or reading difficulties. Instead, the results highlight that child CP may be a mediator of social inequalities in family psychosocial functioning.

Haematopoietic stem and progenitor cells from human pluripotent stem cells.

A variety of tissue lineages can be differentiated from pluripotent stem cells by mimicking embryonic development through stepwise exposure to morphogens, or by conversion of one differentiated cell type into another by enforced expression of master transcription factors. Here, to yield functional human haematopoietic stem cells, we perform morphogen-directed differentiation of human pluripotent stem cells into haemogenic endothelium followed by screening of 26 candidate haematopoietic stem-cell-specifying transcription factors for their capacity to promote multi-lineage haematopoietic engraftment in mouse hosts. We recover seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1 and SPI1) that are sufficient to convert haemogenic endothelium into haematopoietic stem and progenitor cells that engraft myeloid, B and T cells in primary and secondary mouse recipients. Our combined approach of morphogen-driven differentiation and transcription-factor-mediated cell fate conversion produces haematopoietic stem and progenitor cells from pluripotent stem cells and holds promise for modelling haematopoietic disease in humanized mice and for therapeutic strategies in genetic blood disorders.

Navigating ECM barriers at the invasive front: the cancer cell-stroma interface.

A seminal event in cancer progression is the ability of the neoplastic cell to mobilize the necessary machinery to breach surrounding extracellular matrix barriers while orchestrating a host stromal response that ultimately supports tissue-invasive and metastatic processes. With over 500 proteolytic enzymes identified in the human genome, interconnecting webs of protease-dependent and protease-independent processes have been postulated to drive the cancer cell invasion program via schemes of daunting complexity. Increasingly, however, a body of evidence has begun to emerge that supports a unifying model wherein a small group of membrane-tethered enzymes, termed the membrane-type matrix metalloproteinases (MT-MMPs), plays a dominant role in regulating cancer cell, as well as stromal cell, traffic through the extracellular matrix barriers assembled by host tissues in vivo. Understanding the mechanisms that underlie the regulation and function of these metalloenzymes as host cell populations traverse the dynamic extracellular matrix assembled during neoplastic states should provide new and testable theories regarding cancer invasion and metastasis.

A nanobody targeting the LIN28:let-7 interaction fragment of TUT4 blocks uridylation of let-7.

The LIN28:pre-let-7:TUTase ternary complex regulates pluripotency and oncogenesis by controlling processing of the let-7 family of microRNAs. The complex oligouridylates the 3' ends of pre-let-7 molecules, leading to their degradation via the DIS3L2 exonuclease. Previous studies suggest that components of this complex are potential therapeutic targets in malignancies that aberrantly express LIN28. In this study we developed a functional epitope selection approach to identify nanobody inhibitors of the LIN28:pre-let-7:TUT4 complex. We demonstrate that one of the identified nanobodies, Nb-S2A4, targets the 106-residue LIN28:let-7 interaction (LLI) fragment of TUT4. Nb-S2A4 can effectively inhibit oligouridylation and monouridylation of pre-let-7g in vitro. Expressing Nb-S2A4 allows maturation of the let-7 species in cells expressing LIN28, highlighting the therapeutic potential of targeting the LLI fragment.

Effects of perfluoroalkyl substances (PFAS) on antioxidant depletion from a high-density polyethylene geomembrane.

To safely contain Per-and Polyfluoroalkyl substances (PFAS) in municipal solid waste landfills and contaminated soil monofills, it is necessary to understand how these substances interact with components of engineered systems designed to contain them. This paper examines the interaction between one of the most critical components of the system: a high-density polyethylene (HDPE) geomembrane. The same geomembrane is immersed in PFAS solution and synthetic municipal solid waste leachate containing PFAS for 2.5 years, and the effects of PFAS on antioxidant depletion time is examined. The geomembrane is incubated in ovens at 85-40 °C to obtain data for Arrhenius predictions at typical landfill temperatures. When exposed to PFAS solution alone, the antioxidant depletion times are smaller than when the same geomembrane is immersed in synthetic municipal solid waste leachate alone. The combination of the two has a synergistic effect which leads to an even greater reduction in antioxidant depletion time for this geomembrane, with results showing a 68% decrease in predicted antioxidant depletion time at a typical landfill temperature of 35 °C when PFAS is present in leachate. This study highlights the need to consider the potential impact of PFAS on the service life of geomembranes used to contain them.

Intrapartum-related perinatal deaths in births planned in midwifery-led settings in Great Britain: findings and recommendations from the ESMiE confidential enquiry.

OBJECTIVE: To review quality of care in births planned in midwifery-led settings, resulting in an intrapartum-related perinatal death. DESIGN: Confidential enquiry. SETTING: England, Scotland and Wales. SAMPLE: Intrapartum stillbirths and intrapartum-related neonatal deaths in births planned in alongside midwifery units, freestanding midwifery units or at home, sampled from national perinatal surveillance data for 2015/16 (alongside midwifery units) and 2013-16 (freestanding midwifery units and home births). METHODS: Multidisciplinary panels reviewed medical notes for each death, assessing and grading quality of care by consensus, with reference to national standards and guidance. Data were analysed using thematic analysis and descriptive statistics. RESULTS: Sixty-four deaths were reviewed, 30 stillbirths and 34 neonatal deaths. At the start of labour care, 23 women were planning birth in an alongside midwifery unit, 26 in a freestanding midwifery unit and 15 at home. In 75% of deaths, improvements in care were identified that may have made a difference to the outcome for the baby. Improvements in care were identified that may have made a difference to the mother's physical and psychological health and wellbeing in 75% of deaths. Issues with care were identified around risk assessment and decisions about planning place of birth, intermittent auscultation, transfer during labour, resuscitation and neonatal transfer, follow up and local review. CONCLUSIONS: These confidential enquiry findings do not address the overall safety of midwifery-led settings for healthy women with straightforward pregnancies, but suggest areas where the safety of care can be improved. Maternity services should review their care with respect to our recommendations. TWEETABLE ABSTRACT: Confidential enquiry of intrapartum-related baby deaths highlights areas where care in midwifery-led settings can be made even safer.

Functional roles of MMP14 and MMP15 in early postnatal mammary gland development.

During late embryogenesis, mammary epithelial cells initiate migration programs that drive ductal invasion into the surrounding adipose-rich mesenchyme. Currently, branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases MMP14 (MT1-MMP) and MMP15 (MT2-MMP), which drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remain undefined. Here, we characterize the impact of global Mmp14 and Mmp15 targeting on early postnatal mammary gland development in mice. Unexpectedly, both Mmp14-/- and Mmp15-/- mammary glands retain the ability to generate intact ductal networks. Although neither proteinase is required for branching morphogenesis, transcriptome profiling reveals a key role for MMP14 and MMP15 in regulating mammary gland adipocyte differentiation. Whereas MMP14 promotes the generation of white fat depots crucial for energy storage, MMP15 differentially controls the formation of thermogenic brown fat. Taken together, these data not only indicate that current paradigms relevant to proteinase-dependent morphogenesis need be revisited, but also identify new roles for the enzymes in regulating adipocyte fate determination in the developing mammary gland.

Modelling of vapour intrusion into a building impacted by a fuel spill in Antarctica.

A new vapour intrusion contaminant transport model was designed specifically to allow an assessment of the impact of a hydrocarbon fuel spill on air quality in cold region buildings. The model is applied to a recent situation in Antarctica, where a diesel spill impacted the construction of a new building. For the first time, this model allows consideration of the diffusive resistance of different vapour barrier to the transport of hydrocarbons into the building and an assessment of the effectiveness of different products. Site specific indoor air criteria are derived. Five scenarios are modelled at field temperatures: (1) build on current contaminated site; (2) excavate contaminated soil, backfill with clean soil and assess impact of residual contamination; (3) excavate and backfill with remediated (biopile) soil; (4) backfill with remediated soil and assess impact of residual contamination; (5) backfill with remediated soil and assess impact of a potential future fuel spill. Two different vapour barriers, a co-extruded ethylene vinyl alcohol (EVOH) geomembrane (VB1) and a linear low-density (LLDPE) geomembrane (VB2), are investigated for each scenario and compared to a base case with no vapour barrier, providing quantifiable evidence of the benefit of installing an engineered vapour barrier Contaminant concentrations were below regulatory limits for Scenarios (2-5) with VB1 and air exchange in the building. For all scenarios, the EVOH geomembrane (VB1) was consistently superior at reducing vapour transport into the building indoor air space over the LLDPE geomembrane (VB2) and no vapour barrier. The risk mitigation measures developed for this contaminated Antarctic site may be relevant for other buildings in cold regions.

Unique challenges of cystic fibrosis-related diabetes.

Individuals with cystic fibrosis and pancreatic insufficiency have a gradual decline in insulin secretion over time, which results in an increase in the prevalence of diabetes with age; up to 50% of adults with cystic fibrosis aged over 35 years have diabetes. Cystic fibrosis-related diabetes differs from Type 1 and Type 2 diabetes in several ways; there is a pattern of insulin deficiency with reduced and delayed insulin response to carbohydrates but a sparing of basal insulin that results in glucose abnormalities, which are frequently characterized by normal fasting glucose and postprandial hyperglycaemia. Insulin deficiency and hyperglycaemia, even at levels which do not reach the threshold for a diagnosis of diabetes, have an adverse impact on lung function and clinical status in people with cystic fibrosis. Although the risk of microvascular complications occurs as in other forms of diabetes, the main reason for treatment is to prevent deterioration in lung function and weight loss; treatment may therefore be required at an earlier stage than for other types of diabetes. Treatment is usually with insulin, but management needs to take into account all the other medical issues that arise in cystic fibrosis.

Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma.

BACKGROUND: In osteosarcoma, patient survival has not changed in over 30 years. Multiple phase II trials have been conducted in osteosarcoma using the Response Evaluation Criteria in Solid Tumors (RECIST) as a primary endpoint; however, none of these have revealed new treatment strategies. We investigated RECIST in newly diagnosed patients who received neoadjuvant chemotherapy proven to be beneficial. METHODS: Patients treated from 1986 to 2011 for newly diagnosed osteosarcoma with paired tumor imaging before and after adequate neoadjuvant chemotherapy were included in this retrospective study. Two radiologists performed independent, blinded (to image timing) RECIST measurements of primary tumor and lung metastases at diagnosis and post-neoadjuvant chemotherapy. Association between RECIST and histological necrosis and outcome were assessed. RESULTS: Seventy-four patients met inclusion criteria. Five-year overall survival and progression-free survival (PFS) were 77 ± 7% and 61 ± 8%, respectively. No patients had RECIST partial or complete response in the primary tumor. Sixty-four patients (86%) had stable disease, and 10 (14%) had progressive disease (PD). PD in the primary tumor was associated with significantly worse PFS in localized disease patients (P = 0.02). There was no association between RECIST in the primary tumor and necrosis. There were an insufficient number of patients with lung nodules ≥1 cm at diagnosis to evaluate RECIST in pulmonary metastases. CONCLUSIONS: PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed.

Diffusion of multiwall carbon nanotubes (MWCNTs) through a high density polyethylene (HDPE) geomembrane.

The new applications for carbon nanotubes (CNTs) in various fields and consequently their greater production volume have increased their potential release to the environment. Landfills are one of the major locations where carbon nanotubes are expected to be disposed and it is important to ensure that they can limit the release of CNTs. Diffusion of multiwall carbon nanotubes (MWCNTs) dispersed in an aqueous media through a high-density polyethylene (HDPE) geomembrane (as a part of the landfill barrier system) was examined. Based on the laboratory tests, the permeation coefficient was estimated to be less than 5.1×10-15 m2/s. The potential performance of a HDPE geomembrane and geosynthetic clay liner (GCL) as parts of a composite liner in containing MWCNTs was modelled for six different scenarios. The results suggest that the low value of permeation coefficient of an HDPE geomembrane makes it an effective diffusive barrier for MWCNTs and by keeping the geomembrane defects to minimum during the construction (e.g., number of holes and length of wrinkles) a composite liner commonly used in municipal solid waste landfills will effectively contain MWCNTs.

Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Risk Factors for Primary Infection and Cases of Recurrent and Late Infection at a Single Center.

Cytomegalovirus (CMV) infection is a significant source of morbidity and mortality in allogeneic stem cell transplantation (SCT). We identified a cohort of 91 pediatric SCT patients at risk (defined as either donor and/or recipient seropositivity) for CMV infection at our institution. We retrospectively categorized at-risk SCT recipients as those who (1) were at risk of CMV infection in the post-SCT period, (2) had documented CMV infection before SCT, (3) experienced recurrence of post-SCT CMV viremia, or (4) experienced late post-SCT CMV viremia; categories were not mutually exclusive. We analyzed the impact of SCT-related factors on incidence of CMV infection and outcome, and we described the outcome of each of these cohorts. In univariate analysis, recipient CMV seropositivity, use of umbilical cord blood graft, and acute graft-versus-host disease (GVHD) predicted post-SCT CMV viremia, and the effects of acute GVHD (odds ratio, 4.018; 95% confidence interval, 1.032 to 15.643) and CMV seropositivity (odds ratio, 16.525; 95% confidence interval, 2.041 to 133.803) were confirmed in multivariate analysis. Patients with recurrence of post-SCT CMV viremia had a 50% all-cause mortality rate, compared with 12% in all 91 patients. Patients with pre-SCT CMV infection had a high incidence of post-SCT CMV infection but could successfully undergo SCT with antiviral prophylaxis and pre-emptive CMV treatment. All patients with late CMV infection had prior GVHD. Theses findings identify risk factors for post-SCT CMV infection and provide novel descriptions of childhood SCT recipients with pre-SCT, recurrent, and late CMV infection, which may contribute to risk stratification strategies for CMV at-risk patients in pediatric allogeneic SCT.

Severe Tumor Lysis Syndrome and Acute Pulmonary Edema Requiring Extracorporeal Membrane Oxygenation Following Initiation of Chemotherapy for Metastatic Alveolar Rhabdomyosarcoma.

We present an 8-year-old male with metastatic alveolar rhabdomyosarcoma (ARMS) who developed precipitous cardiopulmonary collapse with severe tumor lysis syndrome (TLS) 48 hr after initiation of chemotherapy. Despite no detectable pulmonary metastases, acute hypoxemic respiratory failure developed, requiring extracorporeal membrane oxygenation (ECMO). Although TLS has been reported in disseminated ARMS, this singular case of life-threatening respiratory deterioration developing after initiation of chemotherapy presented unique therapeutic dilemmas. We review the clinical aspects of this case, including possible mechanisms of respiratory failure, and discuss the role of ECMO utilization in pediatric oncology.

Maternal and perinatal outcomes in women planning vaginal birth after caesarean (VBAC) at home in England: secondary analysis of the Birthplace national prospective cohort study.

OBJECTIVE: To compare vaginal birth rates in women planning vaginal birth after caesarean (VBAC) at home versus in an obstetric unit (OU) and explore transfer rates in women planning home VBAC. DESIGN: Prospective cohort study. SETTING: OUs and planned home births in England. POPULATION: 1436 women planning VBAC in the Birthplace cohort, including 209 planning home VBAC. METHODS: We used Poisson regression to calculate relative risks adjusted for maternal characteristics. MAIN OUTCOMES: (i) vaginal birth and (ii) transfer from planned home birth to OU during labour or immediately after birth. SECONDARY OUTCOMES: (i) composite of maternal blood transfusion or admission to higher level care, (ii) stillbirth or Apgar score <7 at 5 minutes, (iii) neonatal unit admission. RESULTS: Planned VBAC at home was associated with a statistically significant increase in the chances of having a vaginal birth compared with planned VBAC in an OU (adjusted relative risk 1.15, 95% confidence interval 1.06-1.24). The risk of an adverse maternal outcome was around 2-3% in both settings, with a similar risk of an adverse neonatal outcome. Transfer rates were high (37%) and varied markedly by parity (para 1, 56.7% versus para 2+, 24.6%). CONCLUSION: Women in the cohort who planned VBAC at home had an increased chance of a vaginal birth compared with those planning VBAC in an OU, but transfer rates were high, particularly for women with only one previous birth, and the risk of an adverse maternal or perinatal outcome was around 2-3%. No change in guidance can be recommended. TWEETABLE ABSTRACT: Higher vaginal birth rates in planned VBAC at home versus in OU but 2-3% adverse outcomes and high transfer rate.

Geomembrane applications for controlling diffusive migration of petroleum hydrocarbons in cold region environments.

Laboratory permeation tests examine the migration of aromatic hydrocarbons (benzene, toluene, ethylbenzene and xylenes (BTEX)) at 2, 7 and 14 °C through three different types of geomembrane (high density polyethylene (HDPE), linear low density polyethylene (LLDPE) and polyvinyl chloride (PVC)). Tests on both virgin and exhumed field samples provide permeation parameters (partitioning (Sgf), diffusion (Dg), and permeation (Pg) coefficients) for the three geomembranes. These results are combined with published values for the same geomembranes at 23 °C to establish an Arrhenius relationship that can be used to estimate diffusion parameters at temperatures other than those for which tests were conducted. Tests on an HDPE geomembrane sample exhumed after 3 years from a landfill site in the Canadian Arctic showed no significant difference in diffusion characteristics compared to an otherwise similar unaged and unexposed HDPE geomembrane. Contaminant transport modeling for benzene through HDPE, LLPDE and PVC in a simulated landfill cover show that for the conditions examined the presence of any of the three geomembranes below the 2 m thick soil cover substantially reduced the contaminant flux compared to the soils alone for realistic degrees of saturation in the cover soil. For these same realistic cold climate cases, of the three geomembranes examined, the HDPE geomembrane was the most effective at controlling the contaminant flux out of the landfill. An increase in soil cover and liner temperature by 2 °C (from potential climate change effects) above those currently measured at an Arctic landfill showed an increase in contaminant transport through the cover system for all geomembranes due to the increase surface temperature (especially in the summer months). Modeling of the addition of an extra 0.5 m of soil cover, as a mitigation measure for the effects of climate change, indicates that the main benefit of adding this unsaturated soil was to reduce the geomembrane temperature and that this did reduce the magnitude of the increase in contaminant transport.

Perinatal and maternal outcomes in planned home and obstetric unit births in women at 'higher risk' of complications: secondary analysis of the Birthplace national prospective cohort study.

OBJECTIVE: To explore and compare perinatal and maternal outcomes in women at 'higher risk' of complications planning home versus obstetric unit (OU) birth. DESIGN: Prospective cohort study. SETTING: OUs and planned home births in England. POPULATION: 8180 'higher risk' women in the Birthplace cohort. METHODS: We used Poisson regression to calculate relative risks adjusted for maternal characteristics. Sensitivity analyses explored possible effects of differences in risk between groups and alternative outcome measures. MAIN OUTCOME MEASURES: Composite perinatal outcome measure encompassing 'intrapartum related mortality and morbidity' (intrapartum stillbirth, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, fractured humerus or clavicle) and neonatal admission within 48 hours for more than 48 hours. Two composite maternal outcome measures capturing intrapartum interventions/adverse maternal outcomes and straightforward birth. RESULTS: The risk of 'intrapartum related mortality and morbidity' or neonatal admission for more than 48 hours was lower in planned home births than planned OU births [adjusted relative risks (RR) 0.50, 95% CI 0.31-0.81]. Adjustment for clinical risk factors did not materially affect this finding. The direction of effect was reversed for the more restricted outcome measure 'intrapartum related mortality and morbidity' (RR adjusted for parity 1.92, 95% CI 0.97-3.80). Maternal interventions were lower in planned home births. CONCLUSIONS: The babies of 'higher risk' women who plan birth in an OU appear more likely to be admitted to neonatal care than those whose mothers plan birth at home, but it is unclear if this reflects a real difference in morbidity. Rates of intrapartum related morbidity and mortality did not differ statistically significantly between settings at the 5% level but a larger study would be required to rule out a clinically important difference between the groups.

The impact of maternal obesity on intrapartum outcomes in otherwise low risk women: secondary analysis of the Birthplace national prospective cohort study.

OBJECTIVES: To evaluate the impact of maternal BMI on intrapartum interventions and adverse outcomes that may influence choice of planned birth setting in healthy women without additional risk factors. DESIGN: Prospective cohort study. SETTING: Stratified random sample of English obstetric units. SAMPLE: 17,230 women without medical or obstetric risk factors other than obesity. METHODS: Multivariable log Poisson regression was used to evaluate the effect of BMI on risk of intrapartum interventions and adverse maternal and perinatal outcomes adjusted for maternal characteristics. MAIN OUTCOME MEASURES: Maternal intervention or adverse outcomes requiring obstetric care (composite of: augmentation, instrumental delivery, intrapartum caesarean section, general anaesthesia, blood transfusion, 3rd/4th degree perineal tear); neonatal unit admission or perinatal death. RESULTS: In otherwise healthy women, obesity was associated with an increased risk of augmentation, intrapartum caesarean section and some adverse maternal outcomes but when interventions and outcomes requiring obstetric care were considered together, the magnitude of the increased risk was modest (adjusted RR 1.12, 95% CI 1.02-1.23, for BMI > 35 kg/m(2) relative to low risk women of normal weight). Nulliparous low risk women of normal weight had higher absolute risks and were more likely to require obstetric intervention or care than otherwise healthy multiparous women with BMI > 35 kg/m(2) (maternal composite outcome: 53% versus 21%). The perinatal composite outcome exhibited a similar pattern. CONCLUSIONS: Otherwise healthy multiparous obese women may have lower intrapartum risks than previously appreciated. BMI should be considered in conjunction with parity when assessing the potential risks associated with birth in non-obstetric unit settings.

Infant temperament and childhood psychiatric disorder: longitudinal study.

BACKGROUND: Temperamental characteristics emerge early in life and can shape children's development, adjustment and behaviour. We aimed to investigate the association between early infant temperament and later childhood psychiatric disorder in a community sample. METHODS: This prospective, population-based study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). In a sample of 7318 children, we investigated whether temperamental characteristics assessed at the ages of 6 months and 24 months are associated with an independent diagnosis of psychiatric disorder ascertained at age 7 years. RESULTS: After adjusting for confounders, temperamental characteristics assessed at 6 and 24 months of age were associated with psychiatric disorder at age 7 years. In particular, intensity of emotional reaction at age 6 months was associated with later disorder (adjusted odds ratio = 1.56; 95% confidence interval 1.19, 2.04; P = 0.002). These associations were stronger in girls and in those children with high levels of intensity at both 6 and 24 months of age. CONCLUSIONS: Temperamental characteristics involving high levels of emotional intensity within the first year of life are longitudinally associated with psychiatric disorder in mid-childhood, suggesting that the roots of psychiatric disorder may, in some cases, lie very early in life.