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Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma.
ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure.
ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
We aimed to provide comprehensive estimates of laboratory-confirmed respiratory syncytial virus (RSV)-associated hospitalisations. Between 2012 and 2015, active surveillance of acute respiratory infection (ARI) hospitalisations during winter seasons was used to estimate the seasonal incidence of laboratory-confirmed RSV hospitalisations in children aged <5 years in Auckland, New Zealand (NZ). Incidence rates were estimated by fine age group, ethnicity and socio-economic status (SES) strata. Additionally, RSV disease estimates determined through active surveillance were compared to rates estimated from hospital discharge codes. There were 5309 ARI hospitalisations among children during the study period, of which 3923 (73.9%) were tested for RSV and 1597 (40.7%) were RSV-positive. The seasonal incidence of RSV-associated ARI hospitalisations, once corrected for non-testing, was 6.1 (95% confidence intervals 5.8–6.4) per 1000 children <5 years old. The highest incidence was among children aged <3 months. Being of indigenous Māori or Pacific ethnicity or living in a neighbourhood with low SES independently increased the risk of an RSV-associated hospitalisation. RSV hospital discharge codes had a sensitivity of 71% for identifying laboratory-confirmed RSV cases. RSV infection is a leading cause of hospitalisation among children in NZ, with significant disparities by ethnicity and SES. Our findings highlight the need for effective RSV vaccines and therapies.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
We investigated risk factors for severe acute lower respiratory infections (ALRI) among hospitalised children <2 years, with a focus on the interactions between virus and age. Statistical interactions between age and respiratory syncytial virus (RSV), influenza, adenovirus (ADV) and rhinovirus on the risk of ALRI outcomes were investigated. Of 1780 hospitalisations, 228 (12.8%) were admitted to the intensive care unit (ICU). The median (range) length of stay (LOS) in hospital was 3 (1–27) days. An increase of 1 month of age was associated with a decreased risk of ICU admission (rate ratio (RR) 0.94; 95% confidence intervals (CI) 0.91–0.98) and with a decrease in LOS (RR 0.96; 95% CI 0.95–0.97). Associations between RSV, influenza, ADV positivity and ICU admission and LOS were significantly modified by age. Children <5 months old were at the highest risk from RSV-associated severe outcomes, while children >8 months were at greater risk from influenza-associated ICU admissions and long hospital stay. Children with ADV had increased LOS across all ages. In the first 2 years of life, the effects of different viruses on ALRI severity varies with age. Our findings help to identify specific ages that would most benefit from virus-specific interventions such as vaccines and antivirals.
Electron and proton microprobes, along with electron backscatter diffraction (EBSD) analysis were used to study the microstructure of the contemporary Al–Cu–Li alloy AA2099-T8. In electron probe microanalysis, wavelength and energy dispersive X-ray spectrometry were used in parallel with soft X-ray emission spectroscopy (SXES) to characterize the microstructure of AA2099-T8. The electron microprobe was able to identify five unique compositions for constituent intermetallic (IM) particles containing combinations of Al, Cu, Fe, Mn, and Zn. A sixth IM type was found to be rich in Ti and B (suggesting TiB2), and a seventh IM type contained Si. EBSD patterns for the five constituent IM particles containing Al, Cu, Fe, Mn, and Zn indicated that they were isomorphous with four phases in the 2xxx series aluminium alloys including Al6(Fe, Mn), Al13(Fe, Mn)4 (two slightly different compositions), Al37Cu2Fe12 and Al7Cu2Fe. SXES revealed that Li was present in some constituent IM particles. Al SXES mapping revealed an Al-enriched (i.e., Cu, Li-depleted) zone in the grain boundary network. From the EBSD analysis, the kernel average misorientation map showed higher levels of localized misorientation in this region, suggesting greater deformation or stored energy. Proton-induced X-ray emission revealed banding of the TiB2 IM particles and Cu inter-band enrichment.
Background:ATP8A2 mutations have only recently been associated with human disease. We present the clinical features from the largest cohort of patients with this disorder reported to date. Methods: An observational study of 9 unreported and 2 previously reported patients with biallelic ATP8A2 mutations was carried out at multiple centres. Results: The mean age of the cohort was 9.4 years old (range: 2.5-28 yrs). All patients demonstrated developmental delay, severe hypotonia and movement disorders: chorea/choreoathetosis (100%), dystonia (27%) or facial dyskinesia (18%). Hypotonia was apparent at birth (70%) or before 6 months old (100%). Optic atrophy was observed in 75% of patients who had a funduscopic examination. MRI of the brain was normal for most patients with a small proportion showing mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Epilepsy was seen in two older patients. Conclusions:ATP8A2 gene mutations have emerged as a cause of a novel phenotype characterized by developmental delay, severe hypotonia and hyperkinetic movement disorders. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation. Early recognition of the cardinal features of this condition will facilitate diagnosis of this disorder.
OBJECTIVES/SPECIFIC AIMS: Background: Delirium is a well described form of acute brain organ dysfunction characterized by decreased or increased movement, changes in attention and concentration as well as perceptual disturbances (i.e., hallucinations) and delusions. Catatonia, a neuropsychiatric syndrome traditionally described in patients with severe psychiatric illness, can present as phenotypically similar to delirium and is characterized by increased, decreased and/or abnormal movements, staring, rigidity, and mutism. Delirium and catatonia can co-occur in the setting of medical illness, but no studies have explored this relationship by age. Our objective was to assess whether advancing age and the presence of catatonia are associated with delirium. METHODS/STUDY POPULATION: Methods: We prospectively enrolled critically ill patients at a single institution who were on a ventilator or in shock and evaluated them daily for delirium using the Confusion Assessment for the ICU and for catatonia using the Bush Francis Catatonia Rating Scale. Measures of association (OR) were assessed with a simple logistic regression model with catatonia as the independent variable and delirium as the dependent variable. Effect measure modification by age was assessed using a Likelihood ratio test. RESULTS/ANTICIPATED RESULTS: Results: We enrolled 136 medical and surgical critically ill patients with 452 matched (concomitant) delirium and catatonia assessments. Median age was 59 years (IQR: 52–68). In our cohort of 136 patients, 58 patients (43%) had delirium only, 4 (3%) had catatonia only, 42 (31%) had both delirium and catatonia, and 32 (24%) had neither. Age was significantly associated with prevalent delirium (i.e., increasing age associated with decreased risk for delirium) (p=0.04) after adjusting for catatonia severity. Catatonia was significantly associated with prevalent delirium (p<0.0001) after adjusting for age. Peak delirium risk was for patients aged 55 years with 3 or more catatonic signs, who had 53.4 times the odds of delirium (95% CI: 16.06, 176.75) than those with no catatonic signs. Patients 70 years and older with 3 or more catatonia features had half this risk. DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusions: Catatonia is significantly associated with prevalent delirium even after controlling for age. These data support an inverted U-shape risk of delirium after adjusting for catatonia. This relationship and its clinical ramifications need to be examined in a larger sample, including patients with dementia. Additionally, we need to assess which acute brain syndrome (delirium or catatonia) develops first.
Objectives: Preterm children demonstrate deficits in executive functions including inhibition, working memory, and cognitive flexibility; however, their goal setting abilities (planning, organization, strategic reasoning) remain unclear. This study compared goal setting abilities between very preterm (VP: <30 weeks/<1250 grams) and term born controls during late childhood. Additionally, early risk factors (neonatal brain abnormalities, medical complications, and sex) were examined in relationship to goal setting outcomes within the VP group. Methods: Participants included 177 VP and 61 full-term born control children aged 13 years. Goal setting was assessed using several measures of planning, organization, and strategic reasoning. Parents also completed the Behavior Rating Inventory of Executive Function. Regression models were performed to compare groups, with secondary analyses adjusting for potential confounders (sex and social risk), and excluding children with major neurosensory impairment and/or IQ<70. Within the VP group, regression models were performed to examine the relationship between brain abnormalities, medical complications, and sex, on goal setting scores. Results: The VP group demonstrated a clear pattern of impairment and inefficiency across goal setting measures, consistent with parental report, compared with their full-term born peers. Within the VP group, moderate/severe brain abnormalities on neonatal MRI predicted adverse goal setting outcomes at 13. Conclusions: Goal setting difficulties are a significant area of concern in VP children during late childhood. These difficulties are associated with neonatal brain abnormalities, and are likely to have functional consequences academically, socially and vocationally. (JINS, 2018, 24, 372–381)
Central nervous system infections (CNSI) are a leading cause of death and long-term disability in children. Using ICD-10 data from 2005 to 2015 from three central hospitals in Ho Chi Minh City (HCMC), Vietnam, we exploited generalized additive mixed models (GAMM) to examine the spatial-temporal distribution and spatial and climatic risk factors of paediatric CNSI, excluding tuberculous meningitis, in this setting. From 2005 to 2015, there were 9469 cases of paediatric CNSI; 33% were ⩽1 year old at admission and were mainly diagnosed with presumed bacterial CNSI (BI) (79%), the remainder were >1 year old and mainly diagnosed with presumed non-bacterial CNSI (non-BI) (59%). The urban districts of HCMC in proximity to the hospitals as well as some outer districts had the highest incidences of BI and non-BI; BI incidence was higher in the dry season. Monthly BI incidence exhibited a significant decreasing trend over the study. Both BI and non-BI were significantly associated with lags in monthly average temperature, rainfall, and river water level. Our findings add new insights into this important group of infections in Vietnam, and highlight where resources for the prevention and control of paediatric CNSI should be allocated.
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
During May 2015, an increase in Salmonella Agona cases was reported from western Sydney, Australia. We examine the public health actions used to investigate and control this increase. A descriptive case-series investigation was conducted. Six outbreak cases were identified; all had consumed cooked tuna sushi rolls purchased within a western Sydney shopping complex. Onset of illness for outbreak cases occurred between 7 April and 24 May 2015. Salmonella was isolated from food samples collected from the implicated premise and a prohibition order issued. No further cases were identified following this action. Whole genome sequence (WGS) analysis was performed on isolates recovered during this investigation, with additional S. Agona isolates from sporadic-clinical cases and routine food sampling in New South Wales, January to July 2015. Clinical isolates of outbreak cases were indistinguishable from food isolates collected from the implicated sushi outlet. Five additional clinical isolates not originally considered to be linked to the outbreak were genomically similar to outbreak isolates, indicating the point-source contamination may have started before routine surveillance identified an increase. This investigation demonstrated the value of genomics-guided public health action, where near real-time WGS enhanced the resolution of the epidemiological investigation.
Non-right handedness (NRH) is reportedly more common in very preterm (VPT; <32 weeks’ gestation) children compared with term-born peers, but it is unclear whether neonatal brain injury or altered brain morphology and microstructure underpins NRH in this population. Given that NRH has been inconsistently reported to be associated with cognitive and motor difficulties, this study aimed to examine associations between handedness and neurodevelopmental outcomes in VPT 7-year-olds. Furthermore, the relationship between neonatal brain injury and integrity of motor tracts (corpus callosum and corticospinal tract) with handedness at age 7 years in VPT children was explored. One hundred seventy-five VPT and 69 term-born children completed neuropsychological and motor assessments and a measure of handedness at 7 years’ corrected age. At term-equivalent age, brain injury on MRI was assessed and diffusion tensor measures were obtained for the corpus callosum and posterior limb of the internal capsule. There was little evidence of stronger NRH in the VPT group compared with term controls (regression coefficient [b] −1.95, 95% confidence interval [−5.67, 1.77]). Poorer academic and working memory outcomes were associated with stronger NRH in the VPT group. While there was little evidence that neonatal unilateral brain injury was associated with stronger NRH, increased area and fractional anisotropy of the corpus callosum splenium were predictive of stronger NRH in the VPT group. VPT birth may alter the relationship between handedness and academic outcomes, and neonatal corpus callosum integrity predicts hand preference in VPT children at school age. (JINS, 2015, 21, 610–621)
We investigated the prevalence, diversity, and antimicrobial resistance (AMR) profiles of non-typhoidal Salmonella (NTS) and associated risk factors on 341 pig, chicken, and duck farms in Dong Thap province (Mekong Delta, Vietnam). Sampling was stratified by species, district (four categories), and farm size (three categories). Pooled faeces, collected using boot swabs, were tested using ISO 6575: 2002 (Annex D). Isolates were serogrouped; group B isolates were tested by polymerase chain reaction to detect S. Typhimurium and (monophasic) serovar 4,,12:i:- variants. The farm-level adjusted NTS prevalence was 64·7%, 94·3% and 91·3% for chicken, duck and pig farms, respectively. Factors independently associated with NTS were duck farms [odds ratio (OR) 21·2], farm with >50 pigs (OR 11·9), pig farm with 5–50 pigs (OR 4·88) (vs. chickens), and frequent rodent sightings (OR 2·3). Both S. Typhimurium and monophasic S. Typhimurium were more common in duck farms. Isolates had a high prevalence of resistance (77·6%) against tetracycline, moderate resistance (20–30%) against chloramphenicol, sulfamethoxazole-trimethoprim, ampicillin and nalidixic acid, and low resistance (<5%) against ciprofloxacin and third-generation cephalosporins. Multidrug resistance (resistance against ⩾3 classes of antimicrobial) was independently associated with monophasic S. Typhimurium and other group B isolates (excluding S. Typhimurium) and pig farms. The unusually high prevalence of NTS on Mekong Delta farms poses formidable challenges for control.
In North America, terrestrial records of biodiversity and climate change that span Marine Oxygen Isotope Stage (MIS) 5 are rare. Where found, they provide insight into how the coupling of the ocean–atmosphere system is manifested in biotic and environmental records and how the biosphere responds to climate change. In 2010–2011, construction at Ziegler Reservoir near Snowmass Village, Colorado (USA) revealed a nearly continuous, lacustrine/wetland sedimentary sequence that preserved evidence of past plant communities between ~140 and 55 ka, including all of MIS 5. At an elevation of 2705 m, the Ziegler Reservoir fossil site also contained thousands of well-preserved bones of late Pleistocene megafauna, including mastodons, mammoths, ground sloths, horses, camels, deer, bison, black bear, coyotes, and bighorn sheep. In addition, the site contained more than 26,000 bones from at least 30 species of small animals including salamanders, otters, muskrats, minks, rabbits, beavers, frogs, lizards, snakes, fish, and birds. The combination of macro- and micro-vertebrates, invertebrates, terrestrial and aquatic plant macrofossils, a detailed pollen record, and a robust, directly dated stratigraphic framework shows that high-elevation ecosystems in the Rocky Mountains of Colorado are climatically sensitive and varied dramatically throughout MIS 5.