Diffusion MRI Microstructural Abnormalities at Term-Equivalent Age Are Associated with Neurodevelopmental Outcomes at 3 Years of Age in Very Preterm Infants.

BACKGROUND AND PURPOSE: Microstructural white matter abnormalities on DTI using Tract-Based Spatial Statistics at term-equivalent age are associated with cognitive and motor outcomes at 2 years of age or younger. However, neurodevelopmental tests administered at such early time points are insufficiently predictive of mild-moderate motor and cognitive impairment at school age. Our objective was to evaluate the microstructural antecedents of cognitive and motor outcomes at 3 years' corrected age in a cohort of very preterm infants. MATERIALS AND METHODS: We prospectively recruited 101 very preterm infants (<32 weeks' gestational age) and performed DTI at term-equivalent age. The Differential Ability Scales, 2nd ed, Verbal and Nonverbal subtests, and the Bayley Scales of Infant and Toddler Development, 3rd ed, Motor subtest, were administered at 3 years of age. We correlated DTI metrics from Tract-Based Spatial Statistics with the Bayley Scales of Infant and Toddler Development, 3rd ed, and the Differential Ability Scales, 2nd ed, scores with correction for multiple comparisons. RESULTS: Of the 101 subjects, 84 had high-quality DTI data, and of these, 69 returned for developmental testing (82%). Their mean (SD) gestational age was 28.4 (2.5) weeks, and birth weight was 1121.4 (394.1) g. DTI metrics were significantly associated with Nonverbal Ability in the corpus callosum, posterior thalamic radiations, fornix, and inferior longitudinal fasciculus and with Motor scores in the corpus callosum, internal and external capsules, posterior thalamic radiations, superior and inferior longitudinal fasciculi, cerebral peduncles, and corticospinal tracts. CONCLUSIONS: We identified widespread microstructural white matter abnormalities in very preterm infants at term that were significantly associated with cognitive and motor development at 3 years' corrected age.

Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study

BACKGROUND: To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches. METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years. FINDINGS: This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs. INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care. (AU)

The household economic burden of non-communicable diseases in 18 countries

BACKGROUND: Non-communicable diseases (NCDs) are the leading cause of death globally. In 2014, the United Nations committed to reducing premature mortality from NCDs, including by reducing the burden of healthcare costs. Since 2014, the Prospective Urban and Rural Epidemiology (PURE) Study has been collecting health expenditure data from households with NCDs in 18 countries. METHODS: Using data from the PURE Study, we estimated risk of catastrophic health spending and impoverishment among households with at least one person with NCDs (cardiovascular disease, diabetes, kidney disease, cancer and respiratory diseases; n=17 435), with hypertension only (a leading risk factor for NCDs; n=11 831) or with neither (n=22 654) by country income group: high-income countries (Canada and Sweden), upper middle income countries (UMICs: Brazil, Chile, Malaysia, Poland, South Africa and Turkey), lower middle income countries (LMICs: the Philippines, Colombia, India, Iran and the Occupied Palestinian Territory) and low-income countries (LICs: Bangladesh, Pakistan, Zimbabwe and Tanzania) and China. RESULTS: The prevalence of catastrophic spending and impoverishment is highest among households with NCDs in LMICs and China. After adjusting for covariates that might drive health expenditure, the absolute risk of catastrophic spending is higher in households with NCDs compared with no NCDs in LMICs (risk difference=1.71%; 95% CI 0.75 to 2.67), UMICs (0.82%; 95% CI 0.37 to 1.27) and China (7.52%; 95% CI 5.88 to 9.16). A similar pattern is observed in UMICs and China for impoverishment. A high proportion of those with NCDs in LICs, especially women (38.7% compared with 12.6% in men), reported not taking medication due to costs. CONCLUSIONS: Our findings show that financial protection from healthcare costs for people with NCDs is inadequate, particularly in LMICs and China. While the burden of NCD care may appear greatest in LMICs and China, the burden in LICs may be masked by care foregone due to costs. The high proportion of women reporting foregone care due to cost may in part explain gender inequality in treatment of NCDs. (AU)

White matter microstructure predicts longitudinal social cognitive outcomes after paediatric traumatic brain injury: a diffusion tensor imaging study.

BACKGROUND: Deficits in social cognition may be among the most profound and disabling sequelae of paediatric traumatic brain injury (TBI); however, the neuroanatomical correlates of longitudinal outcomes in this domain remain unexplored. This study aimed to characterize social cognitive outcomes longitudinally after paediatric TBI, and to evaluate the use of sub-acute diffusion tensor imaging (DTI) to predict these outcomes. METHODS: The sample included 52 children with mild complex-severe TBI who were assessed on cognitive theory of mind (ToM), pragmatic language and affective ToM at 6- and 24-months post-injury. For comparison, 43 typically developing controls (TDCs) of similar age and sex were recruited. DTI data were acquired sub-acutely (mean = 5.5 weeks post-injury) in a subset of 65 children (TBI = 35; TDC = 30) to evaluate longitudinal prospective relationships between white matter microstructure assessed using Tract-Based Spatial Statistics and social cognitive outcomes. RESULTS: Whole brain voxel-wise analysis revealed significantly higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in the sub-acute TBI group compared with TDC, with differences observed predominantly in the splenium of the corpus callosum (sCC), sagittal stratum (SS), dorsal cingulum (DC), uncinate fasciculus (UF) and middle and superior cerebellar peduncles (MCP & SCP, respectively). Relative to TDCs, children with TBI showed poorer cognitive ToM, affective ToM and pragmatic language at 6-months post-insult, and those deficits were related to abnormal diffusivity of the sCC, SS, DC, UF, MCP and SCP. Moreover, children with TBI showed poorer affective ToM and pragmatic language at 24-months post-injury, and those outcomes were predicted by sub-acute alterations in diffusivity of the DC and MCP. CONCLUSIONS: Abnormal microstructure within frontal-temporal, limbic and cerebro-cerebellar white matter may be a risk factor for long-term social difficulties observed in children with TBI. DTI may have potential to unlock early prognostic markers of long-term social outcomes.

Chronic kidney disease among Aboriginal people living in Canada.

AIMS: Chronic kidney disease (CKD) poses a significant health burden on Aboriginal communities around the world. High rates of diabetes among Aboriginal Canadians are an important contributing factor to the rising rates of CKD in this population, and diabetes has been the leading cause of kidney failure among Aboriginal patients initiating dialysis in Canada for the last decade. This paper will describe access to, quality of, and outcomes associated with the renal care of Aboriginal people living in Canada. RESULTS: Research shows that rates of CKD are higher among Aboriginal people residing in Canada, and that despite remote residence location, use of peritoneal dialysis is substantially lower than in white patients. Similarly, although mortality rates among Canadian hemodialysis patients are similar for Aboriginals and for whites, Aboriginal patients have substantially reduced access to kidney transplantation. CONCLUSIONS: A concerted effort to lower rates of CKD in this population is needed. Changes in healthcare policy that successfully translate into healthcare provider and patient level improvements in access to and the quality of care will be needed to significantly reduce the risk of CKD and progression to kidney failure.

Aboriginal patients on the road to kidney transplantation: is residence location a barrier?

Aboriginal dialysis patients have reduced access to kidney transplantation. The reasons for this disparity are unknown. Tonelli et al. show that in Canada, residence location does not significantly impact on an Aboriginal dialysis patient's likelihood of receiving kidney transplantation. This Commentary explores the issue of decreased access and examines issues surrounding the findings of Tonelli et al.

Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor.

Hypoxia-inducible factor (HIF) mediates a widespread transcriptional response to hypoxia through binding to cis-acting DNA sequences termed hypoxia response elements (HREs). Activity of the transcriptional complex is suppressed in the presence of oxygen by processes that include the targeting of HIF-alpha subunits for ubiquitin-mediated proteolysis. To provide further insights into these processes we constructed Chinese hamster ovary (CHO) cells bearing stably integrated plasmids that expressed HRE-linked surface antigens and used these cells in genetic screens for mutants that demonstrated constitutive up-regulation of HRE activity. From mutagenized cultures, clones were isolated that demonstrated up-regulation of HRE activity and increased HIF-1alpha protein levels in normoxic culture. Transfection and cell fusion studies suggested that these cells possess recessive defects that affect one or more pathways involved in HIF-alpha proteolysis. Two lines were demonstrated to harbor truncating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. In these cells, defects in ubiquitylation of exogenous human HIF-1alpha in vitro could be complemented by wild type pVHL, and re-expression of a wild type VHL gene restored a normal pattern of HIF/HRE activity, demonstrating the critical dependence of HIF regulation on pVHL in CHO cells. In contrast, other mutant cells had no demonstrable mutation in the VHL gene, and ubiquitylated exogenous HIF-1alpha normally, suggesting that they contain defects at other points in the oxygen-regulated processing of HIF-alpha subunits.

Bidirectional child-family influences on outcomes of traumatic brain injury in children.

Child behavior problems, injury-related family burden, and parent psychological distress were assessed longitudinally over the first year post injury in 40 children with severe traumatic brain injury (TBI), 52 with moderate TBI, and 55 with orthopedic injuries not involving brain insult. Parents rated children's preinjury behavior soon after injury. Postinjury child behavior and family outcomes were assessed at 6- and 12-month follow-ups. Findings from path analysis revealed both direct and indirect effects of TBI on child behavior and family outcomes, as well as cross-lagged child-family associations. Higher parent distress at 6 months predicted more child behavior problems at 12 months, controlling for earlier behavior problems; and more behavior problems at 6 months predicted poorer family outcomes at 12 months, controlling for earlier family outcomes. Support for bidirectional influences is tentative given that limited sample size precluded use of structural equation modeling. The findings nevertheless provide impetus for considering the influences of person-environment interactions on outcomes of TBI.

The relationship of caregiver coping to family outcomes during the initial year following pediatric traumatic injury.

This study identified coping strategies associated with caregiver outcomes following pediatric injury and examined injury type as a moderator of coping efficacy. Families of 103 children with traumatic brain injury (TBI) and 71 children with orthopedic injuries were followed prospectively during the initial year postinjury. The groups had comparable preinjury characteristics and hospitalization experiences but differed on neurological insult. In hierarchical regression analyses, acceptance was associated with lower burden and denial was associated with greater distress in both groups. Active coping resulted in higher distress following TBI but not orthopedic injuries. Conversely, the use of humor was related to diminishing distress following TBI but unrelated to distress following orthopedic injuries. Results are discussed in terms of the implications for intervention following TBI.

Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain.

Hypoxia-inducible factor (HIF) mediates a large number of transcriptional responses to hypoxia and has an important role in processes that include angiogenesis and erythropoiesis. The HIF DNA binding complex consists of 2 basic-helix-loop-helix PAS proteins designated alpha and beta subunits. Regulation occurs principally through the alpha subunits, which are stabilized and activated in hypoxia. Although substantial evidence implicates reactive oxygen species (ROS) in the regulatory process, the precise mechanisms remain unclear. Mitochondria are an important source of ROS, and in one model it has been proposed that hypoxia increases the generation of ROS at complex III in the mitochondrion and that this signal acts through a transduction pathway to stabilize HIF-1alpha and to activate HIF. To test this model the induction of the HIF-1alpha subunit and the HIF target gene, glucose-transporter-1, was examined in a variety of mutant cells that lacked mitochondrial DNA (rho0) or had other genetic defects in mitochondrial respiration. HIF induction by hypoxia was essentially normal in all cells tested. Hydrogen peroxide production was measured by the luminol/peroxidase method and found to be reduced in rho0 versus wild-type cells and reduced by hypoxia in both rho0 and wild-type cells. Furthermore, concentrations of rotenone that maximally inhibited respiration did not affect HIF activation by hypoxia. These data do not support the model outlined above and indicate that a functional respiratory chain is not necessary for the regulation of HIF by oxygen.

Child and family functioning 6 and 12 months after a serious pediatric fracture.

BACKGROUND: Previous findings indicate that pediatric fractures can have adverse consequences for child adjustment and family functioning immediately after injury. However, longer term effects of the fractures are unknown. The purposes of the present prospective study were to examine the child and family outcomes of pediatric traumatic fractures at 6 months and 1 year after injury, and to identify injury and treatment factors associated with these outcomes. METHODS: We evaluated 57 children 6 to 12 years of age with traumatic fractures requiring hospitalization. Using standardized measures and parent interview, we obtained measures of pre- and postinjury child and family functioning. RESULTS: Although outcomes were primarily positive at 1 year after injury, child functional limitations and family stress were observed up to 6 months after injury. Lower extremity fractures had a more negative impact on families across all three assessment points. Children with fracture interventions that involved prolonged immobilization had more functional limitations at 6 months than children who were ambulatory. Family burden was higher at 1 month for the immobilized children, but not at later follow-up. CONCLUSION: Some children and families experience adverse effects during the year after a serious pediatric fracture, especially if sustained in a lower extremity. Fracture stabilization that allows for greater ambulation may offer some benefits related to functional outcomes and family impact.

Neurobehavioral symptoms in childhood closed-head injuries: changes in prevalence and correlates during the first year postinjury.

OBJECTIVE: To examine changes in the prevalence and correlates of neurobehavioral symptoms during the first year following childhood closed-head injuries (CHIs). METHODS: Participants included 31 children with severe CHIs, 38 with moderate CHIs, and 53 with orthopedic injuries (OIs). Children and their families were assessed shortly after injury and at 6- and 12-month follow-ups. Parents rated 15 symptoms classified as either cognitive/somatic (C/S) or emotional/behavioral (E/B). RESULTS: Both kinds of symptoms were more common in the CHI groups than in the OI group. C/S symptoms declined in the CHI groups over time, whereas E/B symptoms became relatively more common. Measures of injury severity, children's premorbid behavioral adjustment, and concurrent cognitive functioning predicted C/S symptoms. E/B symptoms were predicted by injury severity, concurrent cognitive functioning soon after the injury, and concurrent parent and family functioning later in time. Both types of symptoms contributed to the prediction of perceived family burden, with the relationships strengthening over time. CONCLUSIONS: The findings indicate that the prevalence and correlates of neurobehavioral symptoms in childhood CHIs vary as a function of symptom type and time since injury.

Prevalence and correlates of depressive symptoms following traumatic brain injuries in children.

The prevalence and correlates of depressive symptoms following childhood traumatic brain injuries (TBI) were examined using data drawn from a prospective longitudinal study. Participants included 38 children with severe TBI, 51 with moderate TBI, and 55 with orthopedic injuries (OI). Assessments occurred shortly after injury (baseline) and at 6- and 12-month follow-ups. Children completed the Child Depression Inventory (CDI). Parents rated depressive symptoms using the Child Behavior Checklist (CBC), with baseline ratings reflecting premorbid status. Assessments also included measures of children's neurocognitive functioning and the family environment. The three groups did not differ overall in self-reported symptoms on the CDI, but did display different trends over time. The three groups did not differ on parent ratings of premorbid depressive symptoms on the CBC, but parents reported more depressive symptoms in the TBI groups than in the OI group at 6- and 12-month follow-ups. Child and parent reports were correlated for children in the TBI groups, but not for those in the OI group. Depressive symptoms were related to socioeconomic status in all groups. Socioeconomic status also was a significant moderator of group differences, such that the effects of TBI were exacerbated in children from more disadvantaged homes. Although self-reports of depressive symptoms were related inconsistently to children's verbal memory, parent reports of depressive symptoms were unrelated to IQ or verbal memory. The findings suggest that TBI increases the risk of depressive symptoms, especially among more socially disadvantaged children, and that depressive symptoms are not strongly related to post-injury neurocognitive deficits.

Postconcussive symptoms in children with mild closed head injuries.

OBJECTIVE: To examine the incidence and neuropsychological, behavioral, and neuroimaging correlates of postconcussive symptoms (PCS) in children with mild closed head injuries (CHI). DESIGN: 26 Children with mild CHI and 8 of their uninjured siblings, from 8 to 15 years old, were recruited prospectively and assessed at baseline (ie, within 7 days of injury) and at 3 months postinjury. Parents rated PCS, motivation and affective lability, and behavioral adjustment. Baseline ratings assessed premorbid functioning retrospectively, and follow-up ratings assessed postinjury status. On both occasions, children completed neuropsychological testing, and those with mild CHI also underwent magnetic resonance imaging (MRI). RESULTS: Children with mild CHI did not differ from siblings in baseline ratings of premorbid PCS but displayed higher ratings on several PCS at 3 months postinjury. Thirty-five percent of children with mild CHI showed increases in PCS, compared with baseline premorbid ratings, but none of the siblings did so. Children with mild CHI whose PCS increased from premorbid levels showed poorer neuropsychological functioning at baseline than did children whose PCS did not increase, although the differences had partially resolved by 3 months. They also displayed decreased motivation over time. Their behavioral adjustment was poorer and they had smaller white matter volumes on MRI, but the latter differences were present at baseline and did not change over time, suggesting that they existed prior to the injury. CONCLUSION: Postinjury increases in PCS occur in a sizable minority of children with mild CHI and more often than among uninjured siblings. Increases in PCS following mild CHI are associated with premorbid neurological and psychosocial vulnerability, but also with postinjury decrements in neuropsychological and neurobehavioral functioning.

The family burden of injury interview: reliability and validity studies.

OBJECTIVE: To assess the reliability and validity of a new instrument, the Family Burden of Injury Interview (FBII) was designed to assess the impact of childhood traumatic head injuries (THI) on the family. PARTICIPANTS: 99 Mothers of school-age children who experienced THI. RESULTS: The FBII Total Score revealed group differences between families of children with severe THI and families of children with moderate THI. The measure also showed concurrent and predictive relationships to measures of the general impact of injury on families and maternal and child functioning. CONCLUSION: The FBII is a promising tool for measuring the impact of injury-related stressors on the family.

Posttraumatic stress symptoms in children following orthopedic or traumatic brain injury.

Examined posttraumatic stress (PTS) symptoms in children following pediatric traumatic brain injury (TBI). Children (ages 6-12) with TBI (n = 81) and orthopedic injury (OI; n = 59) were assessed 6 and 12 months postinjury. Parents of children with severe TBI reported higher levels of child PTS symptoms than did parents of children with moderate TBI or OI at the 6- and 12-month follow-ups. Group differences in child-reported PTS symptoms emerged at the 12-month follow-up with higher symptom levels reported by children with severe TBI than by those with moderate TBI or OI. At both follow-ups, rates of clinically significant symptom levels were higher in the severe TBI group than in the moderate TBI or OI groups. The group differences in parent and child reports were significant even after taking ethnicity, social disadvantage, and age at injury into account. Parent and child reports of child PTS symptoms were related to family socioeconomic status. Implications for clinical intervention with children and families following pediatric TBI are discussed.

Influences on first-year recovery from traumatic brain injury in children.

This study examined recovery over the first year following traumatic brain injury (TBI) in children 6-12 years of age. Forty-two children with severe TBI and 52 with moderate TBI were compared to 58 children with orthopedic injuries. The children and their families were evaluated at a baseline assessment and at 6- and 12-month follow-ups. Findings documented cognitive, achievement, and behavioral sequelae of TBI, with only limited evidence for recovery over the first year postinjury. Outcomes were predicted by preinjury factors, TBI severity, and measures of the postinjury family environment. Some of the sequelae of severe TBI were more marked in the context of higher compared with lower levels of family burden or dysfunction. The findings confirm the need to consider environmental contributions to outcomes of TBI in children.

Acute psychosocial impact of pediatric orthopedic trauma with and without accompanying brain injuries.

BACKGROUND: The acute psychosocial effects of orthopedic injuries on children and their families are poorly understood. Previous studies have relied on retrospective reports or failed to take into account accompanying brain injuries. The purpose of the present study was to examine prospectively the psychosocial impact of pediatric orthopedic traumatic fractures with and without accompanying brain injuries. METHODS: Participants were 108 children 6 to 12 years old with orthopedic injuries requiring hospitalization: group 1 (n=80) had fractures only, group 2 (n=28) also had moderate or severe brain injuries. Using standardized measures and parent interviews, we obtained preinjury estimates of family functioning and child behavior problems and postinjury measures of parental distress, family stresses, and child behavior. RESULTS: Parents reported significant clinical distress (35% in group 1, 57% in group 2), family burdens (group 2 > group 1), and child behavioral changes (41% in group 1, 89% in group 2). Multiple regression analyses indicated that preinjury family status and brain injuries predicted postinjury parental and family distress. CONCLUSION: Pediatric orthopedic injuries have greater social effects on children with accompanying brain injuries and poorer preinjury family functioning.