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Maternal inflammation in early pregnancy has been identified epidemiologically as a prenatal pathogenic factor for the offspring's later mental illness. Early newborn manifestations of the effects of maternal inflammation on human fetal brain development are largely unknown.
Maternal infection, depression, obesity, and other factors associated with inflammation were assessed at 16 weeks gestation, along with maternal C-reactive protein (CRP), cytokines, and serum choline. Cerebral inhibition was assessed by inhibitory P50 sensory gating at 1 month of age, and infant behavior was assessed by maternal ratings at 3 months of age.
Maternal CRP diminished the development of cerebral inhibition in newborn males but paradoxically increased inhibition in females. Similar sex-dependent effects were seen in mothers' assessment of their infant's self-regulatory behaviors at 3 months of age. Higher maternal choline levels partly mitigated the effect of CRP in male offspring.
The male fetal-placental unit appears to be more sensitive to maternal inflammation than females. Effects are particularly marked on cerebral inhibition. Deficits in cerebral inhibition 1 month after birth, similar to those observed in several mental illnesses, including schizophrenia, indicate fetal developmental pathways that may lead to later mental illness. Deficits in early infant behavior follow. Early intervention before birth, including prenatal vitamins, folate, and choline supplements, may help prevent fetal development of pathophysiological deficits that can have life-long consequences for mental health.
This study investigated whether higher maternal choline levels mitigate effects of marijuana on fetal brain development. Choline transported into the amniotic fluid from the mother activates α7-nicotinic acetylcholine receptors on fetal cerebro-cortical inhibitory neurons, whose development is impeded by cannabis blockade of their cannabinoid-1(CB1) receptors.
Marijuana use was assessed during pregnancy from women who later brought their newborns for study. Mothers were informed about choline and other nutrients, but not specifically for marijuana use. Maternal serum choline was measured at 16 weeks gestation.
Marijuana use for the first 10 weeks gestation or more by 15% of mothers decreased newborns' inhibition of evoked potentials to repeated sounds (d’ = 0.55, p < 0.05). This effect was ameliorated if women had higher gestational choline (rs = −0.50, p = 0.011). At 3 months of age, children whose mothers continued marijuana use through their 10th gestational week or more had poorer self-regulation (d’ = −0.79, p < 0.05). This effect was also ameliorated if mothers had higher gestational choline (rs = 0.54, p = 0.013). Maternal choline levels correlated with the children's improved duration of attention, cuddliness, and bonding with parents.
Prenatal marijuana use adversely affects fetal brain development and subsequent behavioral self-regulation, a precursor to later, more serious problems in childhood. Stopping marijuana use before 10 weeks gestational age prevented these effects. Many mothers refuse to cease use because of familiarity with marijuana and belief in its safety. Higher maternal choline mitigates some of marijuana's adverse effects on the fetus.
Background: There is an unmet need for blood-based biomarkers that can reliably detect MS disease activity. Serum Biomarkers of interest includ Neurofilament-light-chain (NfL), Glial-fibrillary-strocyte-protein(GFAP) and Tau. Bone Marrow Transplantation (BMT) is reserved for aggressive forms of MS and has been shown to halt detectable CNS inflammatory activity for prolonged periods. Significant pre-treatment tissue damage at followed by inflammatory disease abeyance should be reflected longitudinal sera collected from these patients. Methods: Sera were collected from 23 MS patients pre-treatment, and following BMT at 3, 6, 9 and 12-months in addition from 33 non-inflammatory neurological controls. Biomarker quantification was performed with SiMoA. Results: Pre-AHSCT levels of serum NfL and GFAP but not Tau were elevated compared to controls (p=0.0001), and NfL correlated with lesion-based disease activity (6-month-relapse, MRI-T2 and Gadolinium-enhancement). 3-months post-treatment, while NfL levels remained elevated, Tau/GFAP paradoxically increased (p=0.0023/0.0017). These increases at 3m correlated with MRI ‘pseudoatrophy’ at 6-months. NfL/Tau levels dropped to that of controls by 6-months (p=0.0036/0.0159). GFAP levels dropped progressively after 6-months although even at 12-months remained higher than controls (p=0.004). Conclusions: NfL was the closest correlate of MS disease activity and treatment response. Chemotherapy-related toxicity may account for transient increases in NfL, Tau and MRI brain atrophy post-BMT.
Introduction: Although acute gastroenteritis is an extremely common childhood illness, there is a paucity of literature characterizing the associated pain and its management. Our primary objective was to quantify the pain experienced by children with acute gastroenteritis in the 24-hours prior to emergency department (ED) presentation. Secondary objectives included describing maximum pain, analgesic use, discharge recommendations, and factors that influenced analgesic use in the ED. Methods: Study participants were recruited into this prospective cohort study by the Alberta Provincial Pediatric EnTeric Infection TEam between January 2014 and September 2017. This study was conducted at two Canadian pediatric EDs; the Alberta Children's Hospital (Calgary) and the Stollery Children's Hospital (Edmonton). Eligibility criteria included < 18 years of age, acute gastroenteritis (□ 3 episodes of diarrhea or vomiting in the previous 24 hours), and symptom duration □ 7 days. The primary study outcome, caregiver-reported maximum pain in the 24-hours prior to presentation, was assessed using the 11-point Verbal Numerical Rating Scale. Results: We recruited 2136 patients, median age 20.8 months (IQR 10.4, 47.4); 45.8% (979/2136) female. In the 24-hours prior to enrolment, 28.6% (610/2136) of caregivers reported that their child experienced moderate (4-6) and 46.2% (986/2136) severe (7-10) pain in the preceding 24-hours. During the emergency visit, 31.1% (664/2136) described pain as moderate and 26.7% (571/2136) as severe. In the ED, analgesia was provided to 21.2% (452/2131) of children. The most commonly administered analgesics in the ED were ibuprofen (68.1%, 308/452) and acetaminophen (43.4%, 196/452); at home, acetaminophen was most commonly administered (77.7%, 700/901), followed by ibuprofen (37.5%, 338/901). Factors associated with analgesia use in the ED were greater pain scores during the visit, having a primary-care physician, shorter illness duration, fewer diarrheal episodes, presence of fever and hospitalization. Conclusion: Although children presenting to the ED with acute gastroenteritis experience moderate to severe pain, both prior to and during their emergency visit, analgesic use is limited. Future research should focus on appropriate pain management through the development of effective and safe pain treatment plans.
To describe trends of childhood stunting among under-5s in Uganda and to assess the impact of maternal education, wealth and residence on stunting.
Serial and pooled cross-sectional analyses of data from Uganda Demographic and Health Surveys (UDHS) of 1995, 2001, 2006 and 2011. Prevalence of stunting and mean height-for-age Z-score were computed by maternal education, wealth index, region and other sociodemographic characteristics. Multivariable logistic and linear regression models were fitted to survey-specific and pooled data to estimate independent associations between covariates and stunting or Z-score. Sampling weights were applied in all analyses.
Children aged <5 years.
Weighted sample size was 14 747 children. Stunting prevalence decreased from 44·8% in 1995 to 33·2% in 2011. UDHS reported stunting as 38% in 1995, underestimating the decline because of transitioning from National Center for Health Statistics/Centers for Disease Control and Prevention standards to WHO standards. Nevertheless, one in three Ugandan children was still stunted by 2011. South Western, Mid Western, Kampala and East Central regions had highest odds of stunting. Being born in a poor or middle-income household, of a teen mother, without secondary education were associated with stunting. Other persistent stunting predictors included small birth size, male gender and age 2–3 years.
Sustained decrease in stunting suggests that child nutrition interventions have been successful; however, current prevalence does not meet Millennium Development Goals. Stunting remains a public health concern and must be addressed. Customizing established measures such as female education and wealth creation while targeting the most vulnerable groups may further reduce childhood stunting.
Introduction: Gastroenteritis accounts for 1.7 million emergency department visits by children annually in the United States. We conducted a double-blind trial to determine whether twice daily probiotic administration for 5 days, improves outcomes. Methods: 886 children aged 348 months with gastroenteritis were enrolled in six Canadian pediatric emergency departments. Participants were randomly assigned to twice daily Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052, 4.0 x 109 CFU, in a 95:5 ratio or placebo. Primary outcome was development of moderate-severe disease within 14 days of randomization defined by a Modified Vesikari Scale score 9. Secondary outcomes included duration of diarrhea and vomiting, subsequent physician visits and adverse events. Results: Moderate-severe disease occurred in 108 (26.1%) participants administered probiotics and 102 (24.7%) participants allocated to placebo (OR 1.06; 95%CI: 0.77, 1.46; P=0.72). After adjustment for site, age, and frequency of vomiting and diarrhea, treatment assignment did not predict moderate-severe disease (OR, 1.11, 95%CI, 0.80 to 1.56; P=0.53). In the probiotic versus placebo groups, there were no differences in the median duration of diarrhea [52.5 (18.3, 95.8) vs. 55.5 (20.2, 102.3) hours; P=0.31], vomiting [17.7 (0, 58.6) vs. 18.7 (0, 51.6) hours; P=0.18], physician visits (30.2% vs. 26.6%; OR 1.19; 95% CI0.87. 1.62; P=0.27), or adverse events (32.9% vs. 36.8%; OR 0.83; 95%CI 0.62. 1.11; P=0.21). Conclusion: In children presenting to an emergency department with gastroenteritis, twice daily administration of 4.0 x 109 CFU of a Lactobacillus rhamnosus/helveticus probiotic does not prevent development of moderate-severe disease or improvements in other outcomes measured.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
Introduction: Multiples barriers to appropriate analgesia are reported in the paediatric emergency department (PED), including limited accessibility to effective strategies. Our objective: was to evaluate the improvement in the accessibility of pain and anxiety management strategies in Canadian PEDs, after the creation of a national pediatric pain Quality Improvement Collaborative (QIC), through Pediatric Emergency Research Canada (PERC). Methods: In 2013, the TRAPPED 1 survey was administered to Canadian PEDs, in order to evaluate what resources were in place for pain and anxiety management. A pain QIC was then created to stimulate the implementation of new strategies, through information sharing between PEDs. In 2015, the TRAPPED 2 cross sectional survey was administered. Its focus was to evaluate the improvement in the accessibility of specific strategies reported by each centre, after participating in this QIC, and working to implement change within their own PEDs. Results: All 15/15 Canadian PEDs responded to the TRAPPED 1 survey in 2013 and 11 agreed to participate in the national pain QIC. In-person, phone meetings, follow up surveys and email communications were employed for information sharing. Strategies identified by the QIC to be newly introduced in individual centres were educational initiatives, distraction options, nurse-initiated protocols and intranasal (IN) medications. All 15 PEDs completed the TRAPPED 2 survey. Compared to 2013, an increased number of PEDs used face-based pain scales (14/15 vs 6/15) and behavioural scales (5/15 vs 1/15) for pain assessment in 2015. Use of reminder posters on pain management at triage increased from 4/15 to 6/15 PEDs. Availability of tablets for distraction increased from 4/15 to 10/15 PEDs. Nurse-initiated protocols for topical anesthetic and oral sucrose (for needle procedures) increased from 10/15 to 12/15 sites and from 12/15 to 14/15 sites respectively. Availability of IN medications increased; fentanyl from 9/15 to 14/15 sites and midazolam from 8/15 to 10/15 sites. Ten of the 11 PEDs involved in the QIC strategy reported the implementation of at least one of their own identified strategies. Conclusion: This study suggests that the use of a QIC may improve the introduction of new strategies to reduce pain and anxiety in EDs. QICs may also be helpful to other centres when introducing new strategies.
Background: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal. Methods: To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists. Results: This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system. Conclusions: The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.
The Relative Consequence Model proposes multiple sclerosis (MS) patients have a fundamental deficit in processing speed that compromises other cognitive functions. The present study examined the mediating role of processing speed, as well as working memory, in the MS-related effects on other cognitive functions for early relapsing-remitting patients. Seventy relapsing-remitting MS patients with disease duration not greater than 10 years and 72 controls completed tasks assessing processing speed, working memory, learning, and executive functioning. The possible mediating roles of speed and working memory in the MS-related effects on other cognitive functions were evaluated using structural equation modeling. Processing speed was not significantly related to group membership and could not have a mediating role. Working memory was related to group membership and functioned as a mediating/intervening factor. The results do not support the Relative Consequence Model in this sample and they challenge the notion that working memory impairment only emerges at later disease stages. The results do support a mediating/intervening role of working memory. These results were obtained for early relapsing-remitting MS patients and should not be generalized to the broader MS population. Instead, future research should examine the relations that exist at other disease stages. (JINS, 2013, 19, 1–12)
The Carnegie Hubble Program (CHP) is a Warm Spitzer program with the aim of reducing the uncertainty in the Hubble constant to below 3%. The program is calibrated using Galactic Cepheids with precise parallax distances from the Hubble Space Telescope (HST), combined with a large sample of Cepheids in the Large Magellanic Cloud. We extend the Cepheid distance scale to the Local Group and beyond, into the regime probed by the Tully–Fisher relation. The entire program—from Galactic Cepheids to the most distant galaxies—uses the Spitzer/IRAC instrument. Completing the entire program with a single instrument on a single telescope virtually eliminates instrumental effects, whilst moving to the mid-infrared drastically reduces the reddening and metallicity effects that trouble the optical Cepheid distance scale. Our first measurement of the Hubble constant, using only two CHP galaxies tied into the HST Key Project results has produced a measurement of H0 = 74.3 ± 2.1 (systematic) km s−1 Mpc−1, which corresponds to a systematic uncertainty of 2.8%.
Because of its strong association (r 0·85) with percentage of body fat determined by dual-energy X-ray absorptiometry, hip circumference divided by height1·5 (the body adiposity index) has recently been proposed as an index of body fatness among adults. We examined whether this proposed index was more strongly associated with skinfold thicknesses and levels of CVD risk factors (lipids, fasting insulin and glucose, and blood pressure) than was BMI among 2369 18- to 49-year-olds in the Bogalusa Heart Study. All analyses indicated that the body adiposity index was less strongly associated with skinfold thicknesses and CVD risk factors than was either waist circumference or BMI. Correlations with the skinfold sum, for example, were r 0·81 (BMI) v.r 0·75 (body adiposity index) among men, and r 0·87 (BMI) v.r 0·80 among women; P< 0·001 for both differences. An overall index of seven CVD risk factors was also more strongly associated with BMI (r 0·58) and waist circumference (r 0·61) than with the body adiposity index (r 0·49). The weaker associations with the body adiposity index were observed in analyses stratified by sex, race, age and year of examination. Multivariable analyses indicated that if either BMI or waist circumference were known, the body adiposity index provided no additional information on skinfold thicknesses or risk factor levels. These findings indicate that the body adiposity index is likely to be an inferior index of adiposity than is either BMI or waist circumference.
To determine if different methods of evaluating cognitive change over time yield measurably different outcomes.
Twelve cognitively impaired patients with clinically definite Multiple sclerosis (10 relapsing-remitting, 2 secondary progressive) underwent neuropsychological testing (baseline, 6, 12 months). Data was analysed using: t-tests evaluating group differences on individual tests, group differences in composite scores, reliable change analyses at the level of the individual, and comparisons regarding number of tests failed at each time point.
Group t-tests on individual tests yielded no change. When tests were grouped according to theoretical constructs, analyses revealed change in processing speed. Reliable change estimates revealed that 16% of the sample deteriorated. When change was measured with respect to the number of domains affected at each time point, 58% of the sample deteriorated on at least one subtest.
Methodology has a significant impact on interpretation of longitudinal data. In the same group of subjects, traditional group analyses documented no change in individual test scores or change on a single composite score. Analyses of individual results documented change from 16 to 58% of the sample. Advantages and disadvantages of each method were discussed. Findings have implications for interpretation of longitudinal studies.
Normal-pressure hydrocephalus (NPH) is characterized by gait disturbance, cognitive impairment, with or without urinary incontinence, enlarged ventricles with or without cerebral atrophy and normal cerebrospinal fluid pressure.
We report two sisters with NPH who lived together their entire lives and whose natural history might provide insights into genetic and environmental mechanisms underlying this disorder. Both patients were in their early seventies, single, had similar daily habits and hypertension. No other family members had NPH.
They both underwent shunt placement and showed improvement documented by history and neuropsychological assessment. Both showed a delayed deterioration due to vasculopathy. Both patients were homozygous for the apolipoprotein E (ApoE) e3 allele on chromosome 19. No environmental factors that might have influenced the development of NPH were identified.
Our report of two sisters with NPH may indicate the presence of genetic predisposition and further studies involving genetics and environmental factors are necessary to elucidate their role in the pathogenesis of NPH.
In order to characterize the nature and extent of neuropsychological dysfunction in primary lateral sclerosis (PLS), we studied prospectively cognitive, emotional, and behavioral functioning in PLS, and compared performances to functioning in amyotrophic lateral sclerosis (ALS).
Eighteen patients with PLS and 13 patients with ALS completed a neuropsychological test battery assessing both cognitive skills and emotional/behavioral functioning.
Both PLS and ALS groups scored broadly within normal limits (mean T-scores greater than 40) on all cognitive measures and no significant between-group differences were found with the exception of one variable. However, when examined on a case by case basis, the data revealed considerable heterogeneity amongst patients in both groups. Overall, 39% of PLS patients and 31% of ALS patients were considered cognitively impaired. A higher than expected frequency of abnormal scores was noted for several tests of executive function in both groups, and a majority of PLS patients also exhibited abnormal behavioural symptoms. There was no relationship in PLS or ALS groups between cognitive functioning and disease duration, current site of disease, site of onset, functional status, and respiratory variables. Comparison between the PLS and ALS groups indicated virtually no differences in cognitive test scores and overall emotional/behavioural symptoms.
We observed deficits in cognition and behaviour in a significant proportion of PLS patients which were comparable to those observed in ALS cases. Although deficits were not in the range of frontotemporal dementia, both ALS and PLS cases demonstrated deficits most prominently on tests of executive functioning.
We present the deepest optical CMD to date of M 32, obtained from HST ACS/HRC images. The dominant feature is the RC, whose CMD location suggests a mean age between 8 and 10 Gyr for [Fe/H] = −0.2 in M 32. We detect for the first time the RGB and AGB bumps in M 32 which constrain its mean age to be 5–10 Gyr old at 2′ from the center. Bright AGB stars indicate the presence of intermediate-age populations. A detected blue component of stars may indicate for the first time the presence of a young stellar population of ~0.5 Gyr in our M 32 field. However, it is likely that the younger stars of this blue plume belong to M 31 rather than to M 32. The fainter stars populating the blue plume indicate the presence of stars not younger than 1 Gyr and/or blue straggler stars in M 32.