mRNA Display Identifies Potent, Paralog-Selective Peptidic Ligands for ARID1B.

The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant of SWI/SNF chromatin remodeling complexes. Loss of function mutations in ARID1A are frequently observed in various cancers, resulting in a dependency on the paralog ARID1B for cancer cell proliferation. However, ARID1B has never been targeted directly, and the high degree of sequence similarity to ARID1A poses a challenge for the development of selective binders. In this study, we used mRNA display to identify peptidic ligands that bind with nanomolar affinities to ARID1B and showed high selectivity over ARID1A. Using orthogonal biochemical, biophysical, and chemical biology tools, we demonstrate that the peptides engage two different binding pockets, one of which directly involves an ARID1B-exclusive cysteine that could allow covalent targeting by small molecules. Our findings impart the first evidence of the ligandability of ARID1B, provide valuable tools for drug discovery, and suggest opportunities for the development of selective molecules to exploit the synthetic lethal relationship between ARID1A and ARID1B in cancer.

The mitigating effect of masks on the spread of Covid-19.

We use US state-level data from early in the pandemic -March 15, 2020 to November 15, 2020- to estimate the effects of mask mandates and compliance with mandates on Covid-19 cases and deaths, conditional on mobility. A one-standard-deviation increase in mobility is associated with a 6 to 20 percent increase in the cases growth rate; a mask mandate can offset about one third of this increase with our most conservative estimates. Also, mask mandates are more effective in states with higher compliance. Given realized mobility, our estimates imply that total infections in the US on November 15, 2020 would have been 23.7 to 30.4 percent lower if a national mask mandate had been enacted on May 15, 2020. This reduction in cases translates to a 25 to 35 percent smaller decline in aggregate hours worked over the same period relative to a 2019 baseline.

The effectiveness of acupressure in the management of depressive symptoms and in improving quality of life in older people living in the community: a randomised sham-controlled trial.

Objective: The primary aim of the current trial was to assess the clinical effectiveness of acupressure in the management of depression in elderly people compared to patients receiving sham acupressure or standard care alone.Methods: Randomized sham-controlled trial of acupressure, sham acupressure and standard care alone in older patients with depression living in the community. Patients with a score>/=8 in the Geriatric Depression Scale were recruited for this study. Intervention/sham treatments were provided four times/week for three months. Assessments related to depressive symptoms (primary outcome), well-being, resilience, spirituality and quality of life domains were carried out at baseline, end of the intervention and three-months after the intervention.Results: 118 patients were randomized to intervention (n = 40), sham (n = 40) or control arm (n = 38), with 84 patients providing final analysis data. Significant reduction in mean score of depressive symptoms was found in the acupressure group (from 10.6 (sd = 0.03) to 7.7 (sd = 0.07), p < 0.001 at end of intervention and 8.7 (sd = 0.8), p = 0.002 at follow-up) and the sham acupressure group (from 10.5 (sd = 0.3) to 8.4 (sd = 0.8), p = 0.005) at end of intervention and 8.4 (sd = 0.8), p = 0.006 at follow-up but not in the control group (from 10.8 to 9.9, p = 0.20). Resilience (p = 0.02) and spirituality (p = 0.02) were also improved in the intervention group at the end of intervention assessment but this change was not sustained at follow-up. Mind-body-spirit well-being and social functioning were improved both at the end of intervention and follow-up in the experimental as well as sham group. The sham group showed additional improvements in daily functioning and environmental quality of life.Conclusions: Although acupressure improved outcomes, a placebo effect was evident. Acupressure may be an effective approach to manage depression in elderly patients, but more evidence is needed in the future before it can be recommended for practice as well as more clear elucidation of any placebo effects.

Adsorption of Phospholipids at the Air-Water Surface.

Phospholipids are ubiquitous components of biomembranes and common biomaterials used in many bioengineering applications. Understanding adsorption of phospholipids at the air-water surface plays an important role in the study of pulmonary surfactants and cell membranes. To date, however, the biophysical mechanisms of phospholipid adsorption are still unknown. It is challenging to reveal the molecular structure of adsorbed phospholipid films. Using combined experiments with constrained drop surfactometry and molecular dynamics simulations, here, we studied the biophysical mechanisms of dipalmitoylphosphatidylcholine (DPPC) adsorption at the air-water surface. It was found that the DPPC film adsorbed from vesicles showed distinct equilibrium surface tensions from the DPPC monolayer spread via organic solvents. Our simulations revealed that only the outer leaflet of the DPPC vesicle is capable of unzipping and spreading at the air-water surface, whereas the inner leaflet remains intact and forms an inverted micelle to the interfacial monolayer. This inverted micelle increases the local curvature of the monolayer, thus leading to a loosely packed monolayer at the air-water surface and hence a higher equilibrium surface tension. These findings provide novel insights, to our knowledge, into the mechanism of the phospholipid and pulmonary surfactant adsorption and may help understand the structure-function correlation in biomembranes.

Effect of CYP2D6 and CYP3A4 Genotypes on the Efficacy of Cholinesterase Inhibitors in Southern Chinese Patients With Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of dementia, and age is strongly associated with the incidence of AD. This study aimed to investigate the association between the genotypes of CYP2D6, CYP3A4, and CYP2C9 genes to the clinical efficacy and tolerability of cholinesterase inhibitors (ChEIs) in Chinese patients with AD. One hundred seventy-nine patients with AD with newly prescribed with ChEIs were recruited. The clinical response and tolerability were evaluated at baseline, 3rd-, 6th-, and 12th-month follow-ups and were compared according to their genotypes of CYP2D6, CYP3A4, and CYP2C9. Among patients prescribed with donepezil/galantamine, CYP2D6*10 carriers showed significantly less side effects (P = .009). CYP2D6*10 carriers responded better to ChEIs and resulted in better improvement in Alzheimer's Disease Assessment Scale-Cognitive subscale (P = .027) and Mini-Mental State Examination (P = .012). Further study is required to replicate the finding, and it might be useful for clinicians to decide the medication based on the patients' CYP genotypes.

Diverse NADase effector families mediate interbacterial antagonism via the type VI secretion system.

The bacterial type VI secretion system (T6SS) mediates antagonistic cell-cell interactions between competing Gram-negative bacteria. In plant-beneficial bacteria, this pathway has been shown to suppress the growth of bacterial pathogens; however, the identification and mode of action of T6SS effector proteins that mediate this protective effect remain poorly defined. Here, we identify two previously uncharacterized effectors required for interbacterial antagonism by the plant commensal bacterium Pseudomonas protegens Consistent with the established effector-immunity paradigm for antibacterial T6SS substrates, the toxic activities of these effectors are neutralized by adjacently encoded cognate immunity determinants. Although one of these effectors, RhsA, belongs to the family of DNase enzymes, the activity of the other was not apparent from its sequence. To determine the mechanism of toxicity of this latter effector, we determined its 1.3 Å crystal structure in complex with its immunity protein and found that it resembles NAD(P)+-degrading enzymes. In line with this structural similarity, biochemical characterization of this effector, termed Tne2 (Type VI secretion NADase effector family 2), demonstrates that it possesses potent NAD(P)+ hydrolase activity. Tne2 is the founding member of a widespread family of interbacterial NADases predicted to transit not only the Gram-negative T6SS but also the Gram-positive type VII secretion system, a pathway recently implicated in interbacterial competition among Firmicutes. Together, this work identifies new T6SS effectors employed by a plant commensal bacterium to antagonize its competitors and broadly implicates NAD(P)+-hydrolyzing enzymes as substrates of interbacterial conflict pathways found in diverse bacterial phyla.

Compliance with noninvasive home ventilation in children with obstructive sleep apnoea.

INTRODUCTION: This study aimed to determine compliance with noninvasive home ventilation in children with obstructive sleep apnoea and the factors affecting this compliance. METHODS: We retrospectively reviewed 51 children who were prescribed noninvasive home ventilation for the management of obstructive sleep apnoea from 1 January 2000 until 31 May 2008. Noninvasive ventilation was started based on positive polysomnogram, i.e. obstructive apnoea hypopnea index ≥ 1/hr. Compliance was defined as the use of noninvasive ventilation ≥ 4 days/week. RESULTS: Noninvasive home ventilation was started at a median age of 11.5 years. In all, 21 (41.2 %) children were reported to be compliant with treatment. Univariate analysis revealed that the female gender (p = 0.017), presence of asthma (p = 0.023), presence of genetic syndromes (p = 0.023), use of bi-level ventilation versus continuous positive airway pressure (p = 0.027), and funding from the social work department (p = 0.049) were associated with compliance with noninvasive home ventilation. Logistic regression revealed the presence of asthma (p = 0.008) and female gender (p = 0.047) to be significantly associated with compliance with treatment. However, factors such as counselling prior to initiation of treatment, severity of obstructive sleep apnoea before initiation of treatment, obesity, use of humidification, and polysomnogram indices were not found to be associated with treatment compliance. CONCLUSION: Only 41.2% of the children in this study were reported to be compliant with noninvasive home ventilation. The female gender and the presence of asthma were associated with treatment compliance. Future research focusing on effective methods to improve compliance with noninvasive home ventilation in children should be undertaken.

Efficacy of metered-dose inhalers for children with acute asthma exacerbations.

OBJECTIVE: To compare the effectiveness of the administration of inhaled beta-agonists delivered via a metered-dose inhaler (MDI) with spacers--as part of an evidence-based asthma pathway developed to manage acute asthma exacerbations in children at the emergency room level and in inpatient management--against administration via nebulization. DESIGN: Case with historical control. SETTING: KK Women's and Children's Hospital (Singapore). PARTICIPANTS: A total of 19,951 children (infants to older children) aged 18 years and younger who attended the emergency room for asthma exacerbations. MAIN OUTCOME MEASURES: Average length of stay, proportion admitted to high dependency or intensive care, proportion readmitted for unresolved symptoms within 72 hr, cost per patient and overall. RESULTS: There was no increase in the mean proportion of emergency room attendances admitted to inpatient care with use of an MDI (mean difference 0.97%, 95% CI: -1.6-3.5%, P = 0.447), nor of children admitted to intensive care (0.21 vs. 0.20 pre- and post-pathway, P = 0.827) or to high dependency units (2.21 vs. 1.37 pre- and post-pathway, P = 0.200) but a significant reduction in the within 72 hr re-attendance rate (mean difference 1.4%, 95% CI: 0.78-2.0%, P < 0.001) with use of an MDI. The average length and cost per patient for an inpatient stay for acute asthma exacerbations was reduced with use of an MDI. CONCLUSIONS: The use of an MDI with spacer as part of an evidence-based asthma pathway was effective in the management of acute asthma exacerbations in the emergency room setting and for inpatient management.

Obesity and obstructive sleep apnoea hypopnoea syndrome in Singapore children.

INTRODUCTION: Obesity affects about 10% to 15% of our school-going population in Singapore and is a risk factor for development of obstructive sleep apnoea hypopnoea syndrome (OSAHS). This article reviews the prevalence, aetiology, pathophysiology, diagnosis, complications and treatment of obese children with OSAHS with particular reference to children in Singapore. METHODS: Review of articles or conference papers reporting data with regards to OSAHS in Singapore children. RESULTS: Prevalence of OSAHS was high in obese children in Singapore and was more common in males with no racial predisposition. Hypersomnolence as a presenting symptom was uncommon. Cognitive function, behaviour, attention and processing speed was affected and improved after intervention. Abnormalities of glucose metabolism were also found with the respiratory disturbance index (RDI) as an independent predictor of insulin resistance. Tonsillectomy and or adenoidectomy was efficacious as treatment and risk of complications was low. No significant increase in weight occurred post intervention in those enrolled in concurrent weight management programmes. CONCLUSIONS: Prevalence of OSAHS is high in obese Singapore children and many are 'asymptomatic'. A low threshold for evaluation is necessary for early diagnosis and intervention for prevention of morbidity. Tonsillectomy and/or adenoidectomy is safe and efficacious and remains the first-line treatment in most obese patients.

Hypersensitivity to paracetamol in Asian children with early onset of nonsteroidal anti-inflammatory drug allergy.

BACKGROUND: The published incidence of paracetamol cross-reactivity in adults and adolescents with nonsteroidal anti-inflammatory drug (NSAID) reactions is low and all data on such reactions in young children is sparse. The study aim was to characterize the clinical presentation and cross-reactivity with paracetamol in patients with a reported onset of NSAID hypersensitivity before 6 years of age. METHODS: A retrospective case review was done of patients with cross-reactive hypersensitivity reactions to antipyretic/analgesic medications from the pediatric allergy clinic of the Kendang Kerbau Hospital, Singapore. Included patients reported the onset of such reactions before 6 years of age. Hypersensitivity was established through a detailed history of recurrent reactions to NSAIDs or an oral provocation test. RESULTS: Eighteen patients fulfilled the diagnostic criteria within the study period. Eighty-three percent had cross-reactive reactions with paracetamol. When compared to the group of children with later onset of NSAID hypersensitivity, children with onset before 6 years of age had a significantly increased likelihood of reacting to paracetamol (odds ratio 9.6, 95% confidence interval 1.6-58.0, p < 0.05). CONCLUSION: Paracetamol seems to be a major eliciting drug in this group of children.

Epidemiology, clinical characteristics and antimicrobial resistance patterns of community-acquired pneumonia in 1702 hospitalized children in Singapore.

OBJECTIVE AND BACKGROUND: Childhood community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality worldwide. The features of childhood CAP vary between countries. The aim of this study was to delineate the clinical characteristics, complications, spectrum of pathogens and patterns of antimicrobial resistance associated with hospitalized cases of childhood CAP in Singapore. METHODS: A retrospective study was conducted of patients discharged from Singapore's only children's hospital over a 3-year period with a principal diagnosis of CAP. RESULTS: A total of 1702 children, with a median age of 4.2 years (range: 1 month-16.3 years) were enrolled. A pathogen was identifiable in 38.4% of cases, including Mycoplasma pneumoniae in 20.3%, typical respiratory bacteria in 10.3% (64.6%Streptococcus pneumoniae; 21.7% non-typeable Haemophilus influenzae), viruses in 5.5% and mixed bacterial/viral infections in 2%. The majority of M. pneumoniae infections were in school-aged children (>5 years). Severity of infection was greater in CAP caused by typical bacteria, as reflected by length of hospital stay, CRP level, white cell and absolute neutrophil counts. Mortality from typical bacterial infections (8.9%) exceeded that from M. pneumoniae (0.3%) and viral pneumonias (0%) (P < 0.001). Aminopenicillins were often prescribed empirically for suspected S. pneumoniae and H. influenzae infections; however, resistance to these agents was frequently documented among S. pneumoniae (58.5%) and H. influenzae isolates (51%). CONCLUSION: In Singaporean children hospitalized with CAP, M. pneumoniae is the most commonly identified causative organism, followed by common respiratory viruses, S. pneumoniae and H. influenzae. Streptococcus pneumoniae and H. influenzae are associated with greater severity of infection than other organisms, and have high levels of resistance to commonly prescribed antibiotics.

Identification of sleep-disordered breathing in children: variation with event definition.

STUDY OBJECTIVES: To determine the effect of varying approaches to the measurement of the respiratory disturbance index (RDI) on identification of sleep disordered breathing (SDB) in children. DESIGN: Cross-sectional study of SDB in a well-characterized birth cohort (stratified for term and preterm birth) participating in longitudinal studies of cognition and behavior. SETTING: Community-based; overnight studies conducted in participant's homes. PARTICIPANTS: 433 children, ages 8-11 years, un-referred for clinical assessment of SDB. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants underwent unattended overnight in-home recording of respiratory inductance plethysmography, pulse oximetry, body position, and heart rate. The relationships among RDIs derived from various definitions of apnea and hypopneas and thresholds for frequency of events were assessed. Median RDI varied by more than 20-fold for definitions using the more liberal criteria for event definition (all respiratory events; i.e., central or obstructive events and hypopneas with no requirement for associated desaturation) to the most conservative definition (using obstructive apneas only or obstructive apnea and hypopneas requiring a 5% associated desaturation). Prevalence estimates for SDB based on RDIs that included central apneas were 40% to 140% higher than those that excluded central apneas. CONCLUSIONS: Different approaches for quantifying RDI contribute to substantial variability in identification and classification of SDB in children and will lead to discrepant estimates of its presence and severity.