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Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.
COVID-19 vaccines are likely to be scarce for years to come. Many countries, from India to the U.K., have demonstrated vaccine nationalism. What are the ethical limits to this vaccine nationalism? Neither extreme nationalism nor extreme cosmopolitanism is ethically justifiable. Instead, we propose the fair priority for residents (FPR) framework, in which governments can retain COVID-19 vaccine doses for their residents only to the extent that they are needed to maintain a noncrisis level of mortality while they are implementing reasonable public health interventions. Practically, a noncrisis level of mortality is that experienced during a bad influenza season, which society considers an acceptable background risk. Governments take action to limit mortality from influenza, but there is no emergency that includes severe lockdowns. This “flu-risk standard” is a nonarbitrary and generally accepted heuristic. Mortality above the flu-risk standard justifies greater governmental interventions, including retaining vaccines for a country's own citizens over global need. The precise level of vaccination needed to meet the flu-risk standard will depend upon empirical factors related to the pandemic. This links the ethical principles to the scientific data emerging from the emergency. Thus, the FPR framework recognizes that governments should prioritize procuring vaccines for their country when doing so is necessary to reduce mortality to noncrisis flu-like levels. But after that, a government is obligated to do its part to share vaccines to reduce risks of mortality for people in other countries. We consider and reject objections to the FPR framework based on a country: (1) having developed a vaccine, (2) raising taxes to pay for vaccine research and purchase, (3) wanting to eliminate economic and social burdens, and (4) being ineffective in combating COVID-19 through public health interventions.
It is important to understand the temporal trend of the paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in schools and communities. We determined the differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. Serial cycle threshold values of SARS-CoV-2 from the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral loads (mean cycle threshold on day 7 of illness 28.6 vs. 36.7, P = 0.02). Peak SARS-CoV-2 viral loads occurred around day 2 of illness in infected children. Although we were unable to directly demonstrate infectivity, the detection of significant amount of virus in the upper airway of asymptomatic children suggest that they have the potential to shed and transmit SARS-CoV-2. Our study highlights the importance of contact tracing and screening for SARS-CoV-2 in children with epidemiological risk factors regardless of their symptom status, in order to improve containment of the virus in the community, including educational settings.
An acute gastroenteritis (AGE) outbreak caused by a norovirus occurred at a hospital in Shanghai, China, was studied for molecular epidemiology, host susceptibility and serological roles. Rectal and environmental swabs, paired serum samples and saliva specimens were collected. Pathogens were detected by real-time polymerase chain reaction and DNA sequencing. Histo-blood group antigens (HBGA) phenotypes of saliva samples and their binding to norovirus protruding proteins were determined by enzyme-linked immunosorbent assay. The HBGA-binding interfaces and the surrounding region were analysed by the MegAlign program of DNAstar 7.1. Twenty-seven individuals in two care units were attacked with AGE at attack rates of 9.02 and 11.68%. Eighteen (78.2%) symptomatic and five (38.4%) asymptomatic individuals were GII.6/b norovirus positive. Saliva-based HBGA phenotyping showed that all symptomatic and asymptomatic cases belonged to A, B, AB or O secretors. Only four (16.7%) out of the 24 tested serum samples showed low blockade activity against HBGA-norovirus binding at the acute phase, whereas 11 (45.8%) samples at the convalescence stage showed seroconversion of such blockade. Specific blockade antibody in the population played an essential role in this norovirus epidemic. A wide HBGA-binding spectrum of GII.6 supports a need for continuous health attention and surveillance in different settings.
Peri-orbital surgical emphysema is a rare complication that can occur after lacrimal surgery. It has only been described in isolated cases, following external dacryocystorhinostomy (n = 2) and Lester Jones tube insertion (n = 1).
A retrospective, non-comparative case series was conducted of patients who developed surgical emphysema following endoscopic dacryocystorhinostomy.
A total of 356 endoscopic dacryocystorhinostomy cases (primary, n = 316; revision, n = 40) were performed over a six-year period. Seven cases of post-operative surgical emphysema were identified, all of which were preceded by uncontrolled sneezing, nose-blowing or coughing within the first week of surgery. The occurrence of surgical emphysema post-endoscopic dacryocystorhinostomy in our centre was 7 in 356, or 2 per cent, over six years.
This is the first study to report the occurrence of surgical emphysema post-endoscopic dacryocystorhinostomy. Clinicians may wish to suggest patients stifle the aforementioned triggers within the first week to reduce the potential for surgical emphysema.
The species of Gagnepainia K.Schum. and Hemiorchis Kurz are revised throughout their ranges. These genera are shown with evidence from morphological and molecular studies to be distinct, although closely related to each other. Two species of Gagnepainia and three of Hemiorchis are recognised. A key to the genera of Globbeae and keys to the species of Gagnepainia and Hemiorchis are given, all names are typified and descriptions are provided. Conservation assessments of all taxa are proposed.
In this paper, the generation of relativistic electron mirrors (REM) and the reflection of an ultra-short laser off the mirrors are discussed, applying two-dimension particle-in-cell simulations. REMs with ultra-high acceleration and expanding velocity can be produced from a solid nanofoil illuminated normally by an ultra-intense femtosecond laser pulse with a sharp rising edge. Chirped attosecond pulse can be produced through the reflection of a counter-propagating probe laser off the accelerating REM. In the electron moving frame, the plasma frequency of the REM keeps decreasing due to its rapid expansion. The laser frequency, on the contrary, keeps increasing due to the acceleration of REM and the relativistic Doppler shift from the lab frame to the electron moving frame. Within an ultra-short time interval, the two frequencies will be equal in the electron moving frame, which leads to the resonance between laser and REM. The reflected radiation near this interval and corresponding spectra will be amplified due to the resonance. Through adjusting the arriving time of the probe laser, a certain part of the reflected field could be selectively amplified or depressed, leading to the selective adjustment of the corresponding spectra.
Introduction: Management of acute atrial fibrillation or flutter (AFF) in the emergency department (ED) can be performed with chemical or electrical cardioversion. Procainamide is the most common chemical agent used in Canada; however, there is substantial practice variation. The objective of this systematic review was to provide comparative evidence on return to normal sinus rhythm (NSR) and adverse events to better support clinical decisions. Methods: Systematic search of five electronic databases and grey literature. Randomized controlled trials (RCTs) and prospective controlled cohort studies including adults (≥17 years) with recent-onset of AFF comparing intravenous procainamide with other cardioversion strategies (e.g., electrical cardioversion, placebo or other antiarrhythmic drugs) were eligible. Two independent reviewers performed study selection and data extraction. Relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random-effects model. The protocol was registered with PROSPERO (CRD42019142080). Results: From 4060 potentially relevant citations, 7 studies were considered eligible and three RCTs and two cohort studies included in the analysis. Procainamide was less effective in promoting return to NSR at 1st attempt compared to other chemical (RR 0.76; 95% CI: 0.65 to 0.90) and electrical (RR 0.58; 95% CI: 0.53 to 0.64) options. Electrical cardioversion was more effective in restoring NSR compared to procainamide when used as 2nd attempt in one RCT (RR 0.46; 95% CI: 0.23 to 0.92). Pre-specified serious adverse events were assessed and reported by two studies showing that hypotension was more common in patients receiving procainamide in comparison with electrical cardioversion (RR 20.57; 95% CI: 1.59 to 265.63). Treatment discontinuation due to adverse events was infrequently reported with only two studies reporting that no patients withdrew from the study following treatment with procainamide. The remaining studies provided incomplete data reporting on adverse events. Conclusion: Shared decision-making for patients with acute AFF in the ED requires knowledge of the effectiveness and safety of comparative interventions. Overall, procainamide is less effective than other chemical options and electrical cardioversion strategies to restore NSR. Evidence shows that hypotension is a concern when procainamide is administered; however, the overall adverse events information provided from the studies is suboptimal.
Consumption of sugar-sweetened beverages (SSB) by infants and young children are less explored in Asian populations. The Growing Up in Singapore Towards healthy Outcomes cohort study examined associations between SSB intake at 18 months and 5 years of age, with adiposity measures at 6 years of age. We studied Singaporean infants/children with SSB intake assessed by FFQ at 18 months of age (n 555) and 5 years of age (n 767). The median for SSB intakes is 28 (interquartile range 5·5–98) ml at 18 months of age and 111 (interquartile range 57–198) ml at 5 years of age. Association between SSB intake (100 ml/d increments and tertile categories) and adiposity measures (BMI standard deviation scores (sd units), sum of skinfolds (SSF)) and overweight/obesity status were examined using multivariable linear and Poisson regression models, respectively. After adjusting for confounders and additionally for energy intake, SSB intake at age 18 months were not significantly associated with later adiposity measures and overweight/obesity outcomes. In contrast, at age 5 years, SSB intake when modelled as 100 ml/d increments were associated with higher BMI by 0·09 (95 % CI 0·02, 0·16) sd units, higher SSF thickness by 0·68 (95 % CI 0·06, 1·44) mm and increased risk of overweight/obesity by 1·2 (95 % CI 1·07, 1·23) times at age 6 years. Trends were consistent with SSB intake modelled as categorical tertiles. In summary, SSB intake in young childhood is associated with higher risks of adiposity and overweight/obesity. Public health policies working to reduce SSB consumption need to focus on prevention programmes targeted at young children.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Evidence on long-term influences of maternal vitamin B12 deficiency or concentrations on infant cognition is limited. We examined associations between maternal plasma vitamin B12 and cognitive development in 24-month-old infants. Maternal plasma vitamin B12 concentrations were measured at 26–28 weeks’ gestation; infant cognitive development was assessed with the Bayley Scales of Infant and Toddler Development-III at 24 months, for 443 mother–infant pairs from the Growing Up in Singapore Towards Healthy Outcomes cohort. Linear regressions adjusted for key confounders examined associations of maternal vitamin B12 with cognitive, receptive and expressive language, fine and gross motor subscales. Co-occurrence of maternal vitamin B12 with folate or vitamin B6 insufficiencies on child’s cognition was explored. Average maternal plasma vitamin B12 concentrations was 220·5 ± 80·5 pmol/l; 15 % and 41 % of mothers were vitamin B12 deficient (<148 pmol/l) and insufficient (148–220·9 pmol/l), respectively. Infants of mothers with vitamin B12 deficiency had 0·42 (95 % CI −0·70, −0·14) sd lower cognitive scores, compared with infants of mothers with sufficient vitamin B12. Co-occurrence of maternal vitamins B12 and B6 insufficiencies was associated with 0·37 (95 % CI −0·69, −0·06) sd lower cognitive scores in infants compared with infants of mothers sufficient in both vitamins. No significant associations were observed with other subscales. Study findings suggest the possible need to ensure adequate vitamin B12 during pregnancy. The impact of co-occurrence of maternal B-vitamins insufficiencies on early cognitive development warrants further investigation.
Whether there are distinct subtypes of schizophrenia is an important issue to advance understanding and treatment of schizophrenia.
To understand and treat individuals with schizophrenia, the aim was to advance understanding of differences between individuals, whether there are discrete subtypes, and how fist-episode patients (FEP) may differ from multiple episode patients (MEP).
These issues were analysed in 687 FEP and 1880 MEP with schizophrenia using the Positive and Negative Syndrome Scale for (PANSS) schizophrenia before and after antipsychotic medication for 6 weeks.
The seven Negative Symptoms were correlated with each other and with P2 (conceptual disorganisation), G13 (disturbance of volition), and G7 (motor retardation). The main difference between individuals was in the cluster of seven negative symptoms, which had a continuous unimodal distribution. Medication decreased the PANSS scores for all the symptoms, which were similar in the FEP and MEP groups.
The negative symptoms are a major source of individual differences, and there are potential implications for treatment.
Food group guideline adherence is vital to prevent obesity and diabetes. Various studies have demonstrated that environmental variables influence food intake behaviour. In the present study we examined the effect of a portion design plate with food group portion guidelines demarcated by coloured lines (ETE Plate™). A two-group quasi-experimental design was used to measure proportions of carbohydrate, vegetable and protein portions and user experience in a hospital staff lounge setting in Singapore. Lunch was served on the portion design plate before 12.15 hours. For comparison, a normal plate (without markings) was used after 12.15 hours. Changes in proportions of food groups from 2 months before the introduction of the design plate were analysed in a stratified sample at baseline (859 subjects, all on normal plates) to 1, 3 and 6 months after (in all 1016 subjects on the design plate, 968 subjects on the control plate). A total of 151 participants were asked about their experiences and opinions. Between-group comparisons were performed using t tests. Among those served on the portion design plate at 6 months after its introduction, the proportion of vegetables was 4·71 % (P < 0·001) higher and that of carbohydrates 2·83 % (P < 0·001) lower relative to the baseline. No significant change was found for proteins (−1·85 %). Over 6 months, we observed different change patterns between the different food group proportions. While participants were positive about the portion design plate, they did not think it would influence their personal behaviour. A portion design plate might stimulate food group guideline adherence among hospital staff and beyond.
Little is known about the combined use of benzodiazepines and antidepressants in older psychiatric patients. This study examined the prescription pattern of concurrent benzodiazepines in older adults treated with antidepressants in Asia, and explored its demographic and clinical correlates.
The data of 955 older adults with any type of psychiatric disorders were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Demographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. Both univariate and multiple logistic regression analyses were performed.
The proportion of benzodiazepine and antidepressant combination in this cohort was 44.3%. Multiple logistic regression analysis revealed that higher doses of antidepressants, younger age (<65 years), inpatients, public hospital, major comorbid medical conditions, antidepressant types, and country/territory were significantly associated with more frequent co-prescription of benzodiazepines and antidepressants.
Nearly, half of the older adults treated with antidepressants in Asia are prescribed concurrent benzodiazepines. Given the potentially adverse effects of benzodiazepines, the rationale of benzodiazepines and antidepressants co-prescription needs to be revisited.
The bird cherry-oat aphid Rhopalosiphum padi (L.) is one of the most important wheat pests with polyphagia and autumn migrants. And, chemosensory genes were thought to play a key role in insect searching their hosts, food and mate. However, a systematic identification of the chemosensory genes in this pest has not been reported. Thus, in this study, we identified 14 odorant-binding proteins, nine chemosensory proteins, one sensory neuron membrane protein, 15 odorant receptors, 19 gustatory receptors and 16 ionotropic receptors from R. padi transcriptomes with a significantly similarity (E-value < 10−5) to known chemosensory genes in Acyrthosiphon pisum and Aphis gossypii. In addition, real-time quantitative polymerase chain reaction (RT-qPCR) was employed to determine the expression profiles of obtained genes. Among these obtained genes, we selected 23 chemosensory genes to analyze their expression patterns in different tissues, wing morphs and host plants. We found that except RpOBP1, RpOBP3, RpOBP4 and RpOBP5, the rest of the selected genes were highly expressed in the head with antennae compared with body without head and antennae. Besides that, the stimulation and depression of chemosensory genes by plant switch indicated that chemosensory genes might be involved in the plant suitability assessment. These results not only provide insights for the potential roles of chemosensory genes in plant search and perception of R. padi but also provide initial background information for the further research on the molecular mechanism of the polyphagia and autumn migrants of it. Furthermore, these chemosensory genes are also the candidate targets for pest management control in future.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Aphelinus mali (Haldeman) is an effective natural enemy of woolly apple aphid (WAA), Eriosoma lanigerum (Hausmann). Previous studies have found that, with WAA from Shandong Province (Qingdao) as the host, there are significant differences in various biological characteristics between a Shandong clade and Liaoning clade of A. mali. The ability of the Shandong clade to control this aphid was significantly higher than that of the Liaoning clade in Shandong Province. In order to determine whether differences were caused by better adaptation of the Shandong parasitoid clade to the population of the host in that province or if it represents a more general fitness of this clade to control the host regardless of location, we compared the same parasitoid clades with hosts from Hebei Province. We found no significant differences in the developmental threshold temperature, effective accumulated temperature, fecundity, longevity, and oviposition period of the two clades, but the duration of host searching of the Shandong clade was significantly longer than that of the Liaoning clade. The instantaneous attack rate, the control ability (a/Th), the search parameter (Q) of the Shandong clade (0.0946, 0.543, 0.0725) of A. mali were higher than that of the Liaoning clade (0.0713, 0.382, 0.0381), and therefore, with WAA from Hebei Province as the host, the host adaptability of the Shandong clade of A. mali was not worse than that of the Liaoning clade, while the pest control ability of the Shandong clade was still greater than that of the Liaoning clade.
A new method, called Cloud of Points (COP) Reconstruction, is proposed in the present work to extend the meshfree method to simulate viscous flows. With the characters of viscous flows, the anisotropic COP structure is distributed in boundary layer. The proposed method can improve the anisotropic COP structure to isotropic COP structure and reduce the condition number of the least square coefficient matrix for conventional meshfree method. The values of the new reconstructed points are calculated by the Lagrange interpolation. The accuracy and the robustness of the presented meshfree solver are demonstrated on a number of standard test cases, including the functions with analytical gradients and the viscous flows past NACA0012 airfoil. The comparison of the simulation results with the experimental data and other numerical simulation data are also investigated.