Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls, with 95% of RTT cases resulting from mutations in the methyl-CpG-binding protein 2 (
MECP2
) gene. ...Choline, a dietary micronutrient found in most foods, has been shown to be important for brain development and function. However, the exact effects and mechanisms are still unknown. We found that 13 mg/day (1.7 × required daily intake) of postnatal choline treatment to
Mecp2
-conditional knockout mice rescued not only deficits in motor coordination, but also their anxiety-like behaviour and reduced social preference. Cortical neurons in the brains of
Mecp2
-conditional knockout mice supplemented with choline showed enhanced neuronal morphology and increased density of dendritic spines. Modelling RTT in vitro by knocking down the expression of the MeCP2 protein with shRNA, we found that choline supplementation to MeCP2-knockdown neurons increased their soma sizes and the complexity of their dendritic arbors. Rescue of the morphological defects could lead to enhanced neurotransmission, as suggested by an observed trend of increased expression of synaptic proteins and restored miniature excitatory postsynaptic current frequency in choline-supplemented MeCP2-knockdown neurons. Through the use of specific inhibitors targeting each of the known physiological pathways of choline, synthesis of phosphatidylcholine from choline was found to be essential in bringing about the changes seen in the choline-supplemented MeCP2-knockdown neurons. Taken together, these data reveal a role of choline in modulating neuronal plasticity, possibly leading to behavioural changes, and hence, a potential for using choline to treat RTT.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
In Western countries, Asian children have higher food allergy risk than Caucasian children. The early‐life environmental exposures for this discrepancy are unclear. We aimed to compare ...prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia.
Methods
We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE‐mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14‐18 months (HealthNuts). Eczema was defined as parent‐reported doctor diagnosis.
Results
Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia (P<0.001). Egg introduction was more often delayed (>10 months) in Singapore (63.5%) than Australia (16.3%; P<0.001). Prevalence of early‐onset eczema (<6 months) was lower in Singapore (8.4%) than Australia (30.5%) (P<0.001). Children with early‐onset eczema were more likely to have food allergy than those without eczema in Australia aOR 5.11 (2.34‐11.14); P<0.001 and Singapore aOR4.00 (0.62‐25.8); P = 0.145.
Conclusions
Among Asian children, prevalence of early‐onset eczema and food allergy was higher in Australia than Singapore. Further research with larger sample sizes and harmonized definitions of food allergy between cohorts is required to confirm and extend these findings. Research on environmental factors influencing eczema onset in Australia and Singapore may aid understanding of food allergy pathogenesis in different parts of the world.
Prevalence of food allergy and early‐onset eczema is lower in Singaporean Asian children than Australian Asian children.
Only 5.7% of Singaporean children with early‐onset eczema also have food allergy compared to 32.6% of Australian children of Asian descent.
More Australian Asian children have delayed peanut consumption and higher maternal consumption of egg and peanut during pregnancy while more Singaporean Asians had siblings, exposure to tobacco smoking and delayed egg consumption.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A hemodynamic Lab-on-a-chip system was developed in this study. This system has two unique features: (1) it consists of a microfluidic network with an array of endothelial cell seeding sites for ...testing them under multiple conditions, and (2) the flow rate and the frequency of the culture medium in the microchannel are controlled by a pulsation free pump to mimic the flow profile of the blood in the blood vessel under different physiological conditions. The investigated physiological conditions were: (1) the resting condition in a normal shear stress of 15 dyne cm(-2) with a normal heart rate of 70 bpm, (2) an exhaustive exercise condition with a high shear stress of 30 dyne cm(-2) and a fast heart rate of 140 bpm, and (3) a constant high shear stress of 30 dyne cm(-2). Two chemical conditions were investigated (10 mM and 20 mM glucose) to mimic hyperglycemic conditions in diabetes patients. The effects of various shear stresses either alone or in combination with different glucose concentrations on endothelial cells were examined using the developed hemodynamic Lab-on-a-chip system by assessing two parameters. One is the intracellular level of reactive oxygen species (ROS) determined by a fluorescent probe, H(2)DCFDA. Another is the mitochondrial morphology revealed with a fluorescent dye, MitoTracker Green FM. The results showed that ROS level was elevated nearly 4-fold after 60 min of exhaustive exercise. We found that the pulsatile nature of the fluid was the determination factor for causing ROS generation in the cells as almost no increase of ROS was detected in the constant shear stress condition. Similarly, much higher level of ROS was detected when 10 mM glucose was applied to the cells under normal or high pulsatile shear stresses compared with under a static condition. These results suggest that it is necessary to use pulsatile shear stress to represent the physiological conditions of the blood flow, and demonstrate the advantage of utilizing this newly developed hemodynamic Lab-on-a-chip system over the conventional non-pulsatile system in the future shear stress related studies.
Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we ...performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death by restraining BAK activating conformation change and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The timetabling problem of local Elderly Day Care Centers (EDCCs) is formulated into a weighted maximum constraint satisfaction problem (Max-CSP) in this study. The EDCC timetabling problem is a ...multi-dimensional assignment problem, where users (elderly) are required to perform activities that require different venues and timeslots, depending on operational constraints. These constraints are categorized into two: hard constraints, which must be fulfilled strictly, and soft constraints, which may be violated but with a penalty. Numerous methods have been successfully applied to the weighted Max-CSP; these methods include exact algorithms based on branch and bound techniques, and approximation methods based on repair heuristics, such as the min-conflict heuristic. This study aims to explore the potential of evolutionary algorithms by proposing a genetic-based discrete particle swarm optimization (GDPSO) to solve the EDCC timetabling problem. The proposed method is compared with the min-conflict random-walk algorithm (MCRW), Tabu search (TS), standard particle swarm optimization (SPSO), and a guided genetic algorithm (GGA). Computational evidence shows that GDPSO significantly outperforms the other algorithms in terms of solution quality and efficiency.
•Proposed GDPSO combines min-conflict strategy, random walk and genetic operators.•Proposed GDPSO outperforms in stability and efficiency than MCRW, TS, GGA, and SPSO.•Proposed GDPSO has a faster and consistent rate of convergence.•Proposed GDPSO results in superior performance to solve complex timetabling problem.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Let G be an abelian group and
be nonempty subsets of G. The sets
are said to form a complete decomposition of G of order k if
and
are pairwise disjoint. The size of a complete decomposition
of G is ...defined to be
In this paper, we determine the minimum and maximum size of a complete decomposition of a finite cyclic group.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Abstract
Purpose:
Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective ...was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.
Patients and Methods:
This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.
Results:
The per-protocol population consisted of 70 patients cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33. Median patient age and prostate-specific antigen levels were 63.5 years interquartile range (IQR), 58.0–68.0 and 21.9 ng/mL (IQR, 14.6–42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).
Conclusions:
Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.
This clinical practice guideline is based on a systematic review to assess the use of multiparametric magnetic resonance imaging (mpMRI) in the diagnosis of clinically significant prostate cancer ...(csPCa) for biopsy-naive men and men with a prior negative transrectal ultrasound-guided systematic biopsy (TRUS-SB) at elevated risk.
The methods of the clinical practice guideline included searches to September of 2020 of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Internal and external reviews were conducted.
The recommendations are:Recommendation 1: For biopsy-naive patients at elevated risk of csPCa, mpMRI is recommended prior to biopsy in patients who are candidates for curative management with suspected clinically localized prostate cancer.- If the mpMRI is positive, mpMRI-targeted biopsy (TB) and TRUS-SB should be performed together to maximize detection of csPCa.- If the mpMRI is negative, consider forgoing any biopsy after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup.Recommendation 2: In patients who had a prior negative TRUS-SB and demonstrate a high risk of having csPCa in whom curative management is being considered:- mpMRI should be performed.- If the mpMRI is positive, targeted biopsy should be performed. Concomitant TRUS-SB can be considered depending on the patient's risk profile and time since prior TRUS-SB biopsy.- If the mpMRI is negative, consider forgoing a TRUS-SB only after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup.Recommendation 3: mpMRI should be performed and interpreted in compliance with the current Prostate Imaging Reporting & Data System (PI-RADS) guidelines.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
New Zealand went into lockdown March 2020 successfully eliminating the circulation of the coronavirus disease 2019 (COVID‐19) virus. During lockdown there were reduced rates of respiratory ...infections and hospital admission numbers were low. At the time, rumours of benefit and harm of medicines for COVID‐19 were widespread in the lay and medical media.
Aim
To describe changes in inpatient prescribing in an acute general medicine service during the New Zealand COVID‐19 lockdown in 2020.
Methods
Rates of prescribing of medicines during the 33 days of lockdown were compared with a 33‐day control period before lockdown. Prescriptions, patients and bed days were calculated from the hospital patient administration and electronic prescribing and administration systems.
Results
In the general medicine service, acute admissions were 20% lower during lockdown (from 1216 pre‐lockdown to 974). There was a small decrease in the rate of prescriptions per patient (10.1 vs 10.4, P = 0.01) during lockdown, and the average length of stay was shorter (3.2 vs 3.6 days). Nebulised administration decreased by 75% (1.3% vs 5.3% of admissions) but unexpectedly there was no change in the prescribing rates of antibacterial medicines, e.g. amoxicillin (26% vs 26%). There were no changes in rates of prescribing of medicines being rumoured to potentially improve (e.g. hydroxychloroquine) or worsen (e.g. angiotensin‐converting enzyme inhibitors) COVID‐19 outcomes.
Conclusions
Acute medical admissions decreased 20% during lockdown for COVID‐19, with a proportional decrease in prescriptions. Reduced rates of respiratory tract infections did not lead to decreased prescribing of antibacterial medicines. Rumour‐based prescribing did not eventuate.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and ...acceptability of the ANZ PSA for final-year medical students.
This study used a mixed-method approach involving student data (n=6440) for 2017-2019 (PSA overall score and eight domain sub-scores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted.
The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain sub-scores. There was low intercorrelation between sub-scores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training.
The ANZ PSA was associated with high pass rates and acceptability although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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