Publications by authors named "Andrew Wilson"

960 Publications

Paediatric headbox as aerosol and droplet barrier.

Arch Dis Child 2021 Jul 15. Epub 2021 Jul 15.

Department of General Paediatrics, Perth Children's Hospital, Perth, Western Australia, Australia.

Background: High-flow nasal oxygen (HFNO) is frequently used in hospitals, producing droplets and aerosols that could transmit SARS-CoV-2.

Aim: To determine if a headbox could reduce droplet and aerosol transmission from patients requiring HFNO.

Methods: The size and dispersion of propylene glycol (model for patient-derived infectious particles) was measured using a spectrometer and an infant mannequin receiving 10-50 L/min of HFNO using (1) no headbox, (2) open headbox, (3) headbox-blanket or (4) headbox with a high-efficiency particulate (HEP) filter covering the neck opening.

Results: All headbox set-ups reduced the dispersal of droplets and aerosols compared with no headbox. The headbox-blanket system increased aerosol dispersal compared with the open headbox. The fraction of aerosols retained in the headbox for HFNO of 10 and 50 L/min was, respectively, as follows: (1) open headbox: 82.4% and 42.2%; (2) headbox-blanket: 56.8% and 39.5%; (3) headbox-HEP filter: 99.9% and 99.9%.

Conclusion: A HEP-filter modified headbox may serve as an effective droplet and aerosol barrier adjunct for the protection of staff caring for children receiving HFNO.
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http://dx.doi.org/10.1136/archdischild-2020-321546DOI Listing
July 2021

Implementing spirometry and fractional exhaled nitric oxide testing in childhood asthma management in UK primary care: an observational study to examine training and implementation cost and impact on patient's health use and outcome.

Arch Dis Child 2021 Jul 9. Epub 2021 Jul 9.

Deaprtment of Respiratory Sciences, Leicester NIHR Biomedical Research Centre (Respiratory Theme), University of Leicester, Leicester, UK.

Objectives: Implementation of guidelines into clinical practice is challenging and complex. This study aims to (1) identify the training needs and capacity requirements, and (2) explore the impact on healthcare utilisation and asthma-related quality of life of implementing both spirometry and fraction of exhaled nitric oxide in diagnosis of asthma among children in the UK primary care.

Methods: Ten UK general practitioner practices and a total of 612 children (5-16 years) with diagnosed or suspected asthma were invited to participate in this prospective observational study. The total times that the trainer and trainee clinical staff spent on developing the training package, providing and receiving, and performing and interpreting the two tests as part of routine child asthma review were collected, and costs were calculated. We compared healthcare utilisation and asthma-related and general health-related quality of life data between the 6 months before and after the asthma review guided by objective tests.

Results: The average training cost for the 27 primary care clinical members was £1395. The average cost to implement and deliver the test-guided asthma review among the 612 included children was £22. In the 6 months following the tests-guided asthma review, both unplanned primary care attendance, and hospital admissions were reduced, and the asthma-related health status increased significantly.

Conclusion: This study provides robust cost estimates of the resources needed to implement the National Institute for Health and Care Excellence asthma guideline. It also demonstrates the potential to save healthcare costs and improve health status among asthmatic children by implementing this guideline.
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http://dx.doi.org/10.1136/archdischild-2020-319310DOI Listing
July 2021

Quantum Harmonic Oscillator Spectrum Analyzers.

Phys Rev Lett 2021 Jun;126(25):250507

National Institute of Standards and Technology, 325 Broadway, Boulder, Colorado 80305, USA.

Characterization and suppression of noise are essential for the control of harmonic oscillators in the quantum regime. We measure the noise spectrum of a quantum harmonic oscillator from low frequency to near the oscillator resonance by sensing its response to amplitude modulated periodic drives with a qubit. Using the motion of a trapped ion, we experimentally demonstrate two different implementations with combined sensitivity to noise from 500 Hz to 600 kHz. We apply our method to measure the intrinsic noise spectrum of an ion trap potential in a previously unaccessed frequency range.
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http://dx.doi.org/10.1103/PhysRevLett.126.250507DOI Listing
June 2021

Adenine Base Editing Reduces Misfolded Protein Accumulation and Toxicity in Alpha-1 Antitrypsin Deficient Patient iPSC-Hepatocytes.

Mol Ther 2021 Jul 1. Epub 2021 Jul 1.

Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address:

Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, a single base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient-induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole genome sequencing. These results reveal the feasibility and utility of base-editing to correct the Z mutation in AATD patient cells.
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http://dx.doi.org/10.1016/j.ymthe.2021.06.021DOI Listing
July 2021

Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder.

Brain Stimul 2021 Jun 23;14(4):1015-1021. Epub 2021 Jun 23.

TMS Clinical and Research Service, Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, And the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Los Angeles, CA, 90024, USA.

Background: Intermittent theta-burst stimulation priming (iTBS-P) can improve clinical outcome of patients with Major Depressive Disorder (MDD) who do not show early benefit from 10 Hz stimulation of left dorsolateral prefrontal cortex (DLPFC), also known as high-frequency left-sided (HFL) stimulation. The intensity and pulse number for iTBS-P needed to induce clinical benefit have not been systematically examined.

Objective: To study the effect of intensity and pulse number on the clinical efficacy of iTBS-P.

Methods: We conducted a retrospective review of 71 participants who received at least five sessions of HFL with limited clinical benefit and received iTBS-P augmentation for between 5 and 25 sessions. Intensity of iTBS-P priming stimuli ranged from 75 to 120% of motor threshold (MT) and pulse number ranged from 600 to 1800. Associations among intensity, pulse number, and clinical outcome were analyzed using a mixed methods linear model with change in IDS-SR as the primary outcome variable, priming stimulation intensity (subthreshold or suprathreshold), pulse number (<1200 or >1200 pulses), and gender as fixed factors, and number of iTBS-P treatments and age as continuous covariates.

Results: Subjects who received subthreshold intensity iTBS-P experienced greater reduction in depressive symptoms than those who received suprathreshold iTBS-P (p = 0.011) with no effect of pulse number after controlling for stimulus intensity.

Conclusions: Subthreshold intensity iTBS-P was associated with greater clinical improvement than suprathreshold stimulation. This finding is consistent with iTBS-P acting through homeostatic plasticity mechanisms.
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http://dx.doi.org/10.1016/j.brs.2021.06.008DOI Listing
June 2021

The Virtual Care Experience of Patients Diagnosed With COVID-19.

J Patient Exp 2021 18;8:23743735211008310. Epub 2021 Apr 18.

Research and Development Unit, Centre for Health Equity, University of New South Wales, Sydney, New South Wales, Australia.

Virtual models of care are seen as a sustainable solution to the growing demand for health care. This paper analyses the experience of virtual care among patients diagnosed with COVID-19 in home isolation or health hotel quarantine using a patient-reported experience questionnaire. Results found that patients respond well to virtual models of care during a pandemic. Lessons learned can inform future developments of virtual care models.
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http://dx.doi.org/10.1177/23743735211008310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205417PMC
April 2021

Identification of β-strand mediated protein-protein interaction inhibitors using ligand-directed fragment ligation.

Chem Sci 2021 Jan 6;12(6):2286-2293. Epub 2021 Jan 6.

School of Chemistry, University of Leeds Woodhouse Lane Leeds LS2 9JT UK

β-Strand mediated protein-protein interactions (PPIs) represent underexploited targets for chemical probe development despite representing a significant proportion of known and therapeutically relevant PPI targets. β-Strand mimicry is challenging given that both amino acid side-chains and backbone hydrogen-bonds are typically required for molecular recognition, yet these are oriented along perpendicular vectors. This paper describes an alternative approach, using GKAP/SHANK1 PDZ as a model and dynamic ligation screening to identify small-molecule replacements for tranches of peptide sequence. A peptide truncation of GKAP functionalized at the N- and C-termini with acylhydrazone groups was used as an anchor. Reversible acylhydrazone bond exchange with a library of aldehyde fragments in the presence of the protein as template and screening using a fluorescence anisotropy (FA) assay identified peptide hybrid hits with comparable affinity to the GKAP peptide binding sequence. Identified hits were validated using FA, ITC, NMR and X-ray crystallography to confirm selective inhibition of the target PDZ-mediated PPI and mode of binding. These analyses together with molecular dynamics simulations demonstrated the ligands make transient interactions with an unoccupied basic patch through electrostatic interactions, establishing proof-of-concept that this unbiased approach to ligand discovery represents a powerful addition to the armory of tools that can be used to identify PPI modulators.
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http://dx.doi.org/10.1039/d0sc05694dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179271PMC
January 2021

Query-guided protein-protein interaction inhibitor discovery.

Chem Sci 2021 Mar 2;12(13):4753-4762. Epub 2021 Mar 2.

Astbury Centre for Structural Molecular Biology, University of Leeds Woodhouse Lane Leeds LS2 9JT UK

Protein-protein interactions (PPIs) are central to biological mechanisms, and can serve as compelling targets for drug discovery. Yet, the discovery of small molecule inhibitors of PPIs remains challenging given the large and typically shallow topography of the interacting protein surfaces. Here, we describe a general approach to the discovery of orthosteric PPI inhibitors that mimic specific secondary protein structures. Initially, hot residues at protein-protein interfaces are identified or from experimental data, and incorporated into secondary structure-based queries. Virtual libraries of small molecules are then shape-matched against the queries, and promising ligands docked to target proteins. The approach is exemplified experimentally using two unrelated PPIs that are mediated by an α-helix (p53/DM2) and a β-strand (GKAP/SHANK1-PDZ). In each case, selective PPI inhibitors are discovered with low μM activity as determined by a combination of fluorescence anisotropy and H-N HSQC experiments. In addition, hit expansion yields a series of PPI inhibitors with defined structure-activity relationships. It is envisaged that the generality of the approach will enable discovery of inhibitors of a wide range of unrelated secondary structure-mediated PPIs.
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http://dx.doi.org/10.1039/d1sc00023cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179539PMC
March 2021

Repetitive transcranial magnetic stimulation treatment of major depressive disorder and comorbid chronic pain: response rates and neurophysiologic biomarkers.

Psychol Med 2021 Jun 22:1-10. Epub 2021 Jun 22.

TMS Clinical and Research Service, Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, and the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Los Angeles, CA90024, USA.

Background: Major depressive disorder (MDD) and chronic pain are highly comorbid, and pain symptoms are associated with a poorer response to antidepressant medication treatment. It is unclear whether comorbid pain also is associated with a poorer response to treatment with repetitive transcranial magnetic stimulation (rTMS).

Methods: 162 MDD subjects received 30 sessions of 10 Hz rTMS treatment administered to the left dorsolateral prefrontal cortex (DLPFC) with depression and pain symptoms measured before and after treatment. For a subset of 96 patients, a resting-state electroencephalogram (EEG) was recorded at baseline. Clinical outcome was compared between subjects with and without comorbid pain, and the relationships among outcome, pain severity, individual peak alpha frequency (PAF), and PAF phase-coherence in the EEG were examined.

Results: 64.8% of all subjects reported pain, and both depressive and pain symptoms were significantly reduced after rTMS treatment, irrespective of age or gender. Patients with severe pain were 27% less likely to respond to MDD treatment than pain-free individuals. PAF was positively associated with pain severity. PAF phase-coherence in the somatosensory and default mode networks was significantly lower for MDD subjects with pain who failed to respond to MDD treatment.

Conclusions: Pain symptoms improved after rTMS to left DLPFC in MDD irrespective of age or gender, although the presence of chronic pain symptoms reduced the likelihood of treatment response. Individual PAF and baseline phase-coherence in the sensorimotor and midline regions may represent predictors of rTMS treatment outcome in comorbid pain and MDD.
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http://dx.doi.org/10.1017/S0033291721002178DOI Listing
June 2021

Quality of Neurologic Care in the United States: Initial Report From the Axon Registry.

Neurology 2021 Jun 18. Epub 2021 Jun 18.

Department of Neurology, Mayo Clinic, Rochester, MN.

Objective: To provide the initial description of quality of outpatient US neurologic care as collected and reported in the Axon Registry.

Methods: We describe characteristics of registry participants and the performance of neurology providers on 20 of the 2019 Axon Registry quality measures. From the distribution of providers' scores on a quality measure, we calculate the median performance for each quality measure. We test for associations between quality measure performance, provider characteristics, and intrinsic measure parameters.

Results: There were 948 neurology providers who contributed a total of 6,480 provider-metric observations. Overall, the average quality measure performance score at the provider level was 66 (median 77). At the measure level (n=20), the average quality measure performance score was 53 (median 55) with a range of 2-100 (interquartile range of 20-91). Measures with a lower complexity category (e.g., discrete orders, singular concepts) or developed through the specialty's qualified clinical data registry (QCDR) pathway had higher performance distributions. There was no difference in performance between Merit-based Incentive Payment System (MIPS) and non-MIPS providers. There was no association between quality measure performance and practice size, measure clinical topic/neurological condition, or measure year of entry.

Conclusions: This cross-sectional assessment of quality measure performance in 2019 Axon Registry data demonstrates modest performance scores and considerable variability across measures and providers. More complex measures were associated with lower performance. These findings serve as a baseline assessment of quality of ambulatory neurologic care in the US and provide insights into future measure design.
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http://dx.doi.org/10.1212/WNL.0000000000012378DOI Listing
June 2021

Antenatal care providers' attitudes and beliefs towards maternal vaccination in Kenya.

Gates Open Res 2020 22;4:19. Epub 2021 Apr 22.

Department of Global Health, Emory University, Atlanta, GA, 30322, USA.

Maternal immunization is known to be one of the best strategies to protect both mothers and their infants from infectious diseases. Studies have shown that healthcare providers play a critical role in implementation of maternal immunization. However, little is known about providers' attitudes and beliefs towards vaccination that can influence their vaccine recommendations, specifically in low to middle income countries (LMIC). A self-administrated knowledge, attitude and behavior (KAB) survey was provided to 150 antenatal care providers across four different regions (Nairobi, Mombasa, Marsabit, and Siaya counties) of Kenya. The research staff visited the 150 clinics and hospitals and distributed a quantitative KAB survey. Nearly all of the antenatal care providers (99%) recommended tetanus maternal vaccination. Similarly, 99% of the providers agreed that they would agree to provide additional vaccinations for pregnant women and reported that they always advise their patients to get vaccinated. Between 80 and 90% of the providers reported that religious beliefs, ethnicity, cultural background and political leaders do not affect their attitude or beliefs towards recommending vaccines. Considering the positive responses of healthcare providers towards vaccine acceptance and recommendation, these results highlight an opportunity to work in partnership with these providers to improve coverage of maternal vaccination and to introduce additional vaccines (such as influenza). In order to achieve this, logistical barriers that have affected the coverage of the currently recommended vaccines, should be addressed as part of this partnership.
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http://dx.doi.org/10.12688/gatesopenres.13091.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181780PMC
April 2021

Predicting asthma-related crisis events using routine electronic healthcare data.

Br J Gen Pract 2021 Jun 15. Epub 2021 Jun 15.

University of East Anglia Norwich Medical School, Norwich, United Kingdom.

Background: There is no published algorithm predicting asthma crisis events (Accident and Emergency (A&E) attendance, hospitalisation or death) using routinely available electronic health record (EHR) data.

Aim: To develop an algorithm to identify individuals at high risk of an asthma crisis event.

Design And Setting: Database analysis from primary care EHRs.

Method: Multivariable logistic regression was applied to a dataset of 61,861 people with asthma from England and Scotland using the Clinical Practice Research Datalink. External validation was performed using the Secure Anonymised Information Linkage databank of 174,240 patients from Wales. Outcomes were one or more hospitalisation (development dataset) and asthma-related hospitalisation, A&E attendance or death (validation dataset) within a 12-month period.

Results: Risk factors for asthma-related crisis events included previous hospitalisation, older age, underweight, smoking and blood eosinophilia. The prediction algorithm had acceptable predictive ability with a Receiver Operating Characteristic (ROC) of 0.71 (0.70, 0.72) in the validation dataset. Using a cut-point based on the 7% of the population at greatest risk results in a positive predictive value of 5.7% (95% CI 5.3 - 6.1) and a negative predictive value of 98.9% (98.9 - 99.0), with sensitivity of 28.5% (26.7 - 30.3) and specificity of 93.3% (93.2 - 93.4); they had an event risk of 6.0% compared 1.1% for the remaining population. Eighteen people would be "needed to follow" to identify one admission.

Conclusions: This externally validated algorithm has acceptable predictive ability for identifying patients at high risk of asthma-related crisis events and excluding individuals not at high risk.
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http://dx.doi.org/10.3399/BJGP.2020.1042DOI Listing
June 2021

Leveraging electronic health records to improve management of noncommunicable diseases at primary healthcare centres in Saudi Arabia: a qualitative study.

BMC Fam Pract 2021 May 27;22(1):106. Epub 2021 May 27.

Menzies Centre for Health Policy and Economics, Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.

Background: Electronic Health Records (EHRs) can contribute to the earlier detection and better treatment of chronic diseases by improving accuracy and accessibility of patient data. The Saudi Ministry of Health (MOH) implemented an EHR system in all primary health care clinics (PHCs) as part of measures to improve their performance in managing chronic disease. This study examined the perspective of physicians on the current scope and content of NCDs management at PHCs including the contribution of the EHR system.

Methods: Semi-structured interviews were conducted with 22 physicians working in chronic disease clinics at PHCs covering a range of locations and clinic sizes. The participants were selected based on their expertise using a combination of purposive and convenience sampling. The interviews were transcribed, analyzed and coded into the key themes.

Results: Physicians indicated that the availability of the EHR helped organise their work and positively influenced NCDs patient encounters in their PHCs. They emphasised the multiple benefits of EHR in terms of efficiency, including the accuracy of patient documentation and the availability of patient information. Shortcomings identified included the lack of a patient portal to allow patients to access information about their health and lack of capacity to facilitate multi-disciplinary care for example through referral to allied health services. Access to the EHR was limited to MOH primary healthcare centres and clinicians noted that patients also received care in private clinics and hospitals.

Conclusion: While well regarded by clinicians, the EHR system impact on patient care at chronic disease clinics is not being fully realised. Enabling patient access to their EHR would be help promote self-management, a core attribute of effective NCD management. Co-ordination of care is another core attribute and in the Saudi health system with multiple public and private providers, this may be substantially improved if the patients EHR was accessible wherever care was provided. There is also a need for enhanced capacity to support improving patient's nutrition and physical activity.
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http://dx.doi.org/10.1186/s12875-021-01456-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157615PMC
May 2021

Determinants of sleep problems in children with intellectual disability.

J Sleep Res 2021 May 24:e13361. Epub 2021 May 24.

Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.

Children with intellectual disabilities are more likely to experience sleep disorders of insomnia, excessive daytime sleepiness and sleep breathing disorders than typically developing children. The present study examined risk factors for these sleep disorders in 447 children (aged 5-18 years), diagnosed with an intellectual disability and comorbid autism spectrum disorder, cerebral palsy, Down syndrome or Rett syndrome. Primary caregivers reported on their child's sleep using the Sleep Disturbance Scale for Children (SDSC), as well as medical comorbidities and functional abilities. Multivariate linear and logistic regressions were used to examine the effects of these factors on SDSC t scores and a binary indicator, respectively for the relevant subscales. Receiving operating characteristic curves were generated for each logistic regression model to determine their ability to discriminate between poor and good sleep. Comorbidities rather than functional abilities were associated with poorer sleep. In particular, recurrent pain, frequent seizures, frequent coughing, constipation and prescription of sleep medications were associated with abnormal sleep across the entire sample, but predictors differed between diagnostic groups. The present study suggests that comorbidities are more strongly associated with quality of sleep than functional impairments. The present study provides new information on potential associations between frequent coughing, prescription sleep medications and sleep quality that should be further investigated.
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http://dx.doi.org/10.1111/jsr.13361DOI Listing
May 2021

Feasibility of investigating methylphenidate for the treatment of sarcoidosis-associated fatigue (the FaST-MP study): a double-blind, parallel-arm randomised feasibility trial.

BMJ Open Respir Res 2021 05;8(1)

Department of Respiratory Medicine, Norfolk and Norwich University Hospital NHS Trust, Norwich, UK.

Introduction: Sarcoidosis-associated fatigue (SAF) is a common clinical problem with limited treatment options. This study was undertaken to determine the feasibility of performing a definitive trial to determine the clinical efficacy methylphenidate in SAF.

Methods: This was a parallel-arm, double-blind, placebo-controlled randomised controlled feasibility trial enrolling sarcoidosis patients reporting significant fatigue. Patients with a Fatigue Assessment Scale score of more than 21 were randomised to receive up to either 10 mg two times per day methylphenidate or identical placebo capsules two times per day, in a dose escalation fashion, for up to 24 weeks. Outcomes included number of participants eligible and willing to participate, withdrawal rates, adherence rates and ability to maintain blinding.

Results: Of 385 patients screened, 56 (14.5%) were eligible and 23 (41% of eligible patients) were randomised. No withdrawals occurred. One participant in the methylphenidate arm discontinued study medications due to chest pain. The side effect profile was not different between the groups. Median medication adherence rates were 98% and 99% in the methylphenidate and placebo arms, respectively. A greater proportion of participants receiving methylphenidate predicted their allocated treatment while blinded compared with those receiving placebo (93.3% vs 57.1%). The investigator could not predict the treatment allocation. Both groups showed clinically meaningful improvements in fatigue from baseline, although no between-group difference was seen.

Conclusions: The data support the feasibility of performing a double-blind parallel trial powered to determine the clinical efficacy of methylphenidate for SAF, however, a multicentre study will be required.

Trial Registration Number: NCT02643732.
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http://dx.doi.org/10.1136/bmjresp-2020-000814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144057PMC
May 2021

Risk factors for asthma attacks and poor control in children: a prospective observational study in UK primary care.

Arch Dis Child 2021 May 20. Epub 2021 May 20.

Department of Respiratory Sciences, University of Leicester, Leicester, UK

Objective: To identify risk factors for asthma attacks and poor asthma control in children aged 5-16 years.

Methods: Prospective observational cohort study of 460 children with asthma or suspected asthma from 10 UK general practices.Gender, age, ethnicity, body mass index, practice deprivation decile, spirometry and fraction of exhaled nitric oxide (FeNO) were recorded at baseline. Asthma control scores, asthma medication ratio (AMR) and the number of asthma attacks were recorded at baseline and at 6 months.The above independent variables were included in binary multiple logistic regression analyses for the dependent variables of: (1) poor symptom control and (2) asthma attacks during follow-up.

Results: Poor symptom control at baseline predicted poor symptom control at 6 months (OR 4.4, p=0.001), while an increase in deprivation decile (less deprived) was negatively associated with poor symptom control at 6 months (OR 0.79, p=0.003). Higher FeNO levels (OR 1.02, p<0.001) and a recent history of asthma attacks (OR 2.03, p=0.02) predicted asthma attacks during follow-up. Asian ethnicity was associated with a lower OR for a future attack (OR 0.32, p=0.02).A decrease in AMR was also associated with an increased OR for future asthma attacks (OR 2.99, p=0.003) when included as an independent variable.

Conclusions: We identified risk factors for poor symptom control and asthma attacks in children. Routine assessment of these factors should form part of the asthma review to identify children at an increased risk of adverse asthma-related events.
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http://dx.doi.org/10.1136/archdischild-2020-320110DOI Listing
May 2021

Peptide-based inhibitors of protein-protein interactions: biophysical, structural and cellular consequences of introducing a constraint.

Chem Sci 2021 Mar 25;12(17):5977-5993. Epub 2021 Mar 25.

Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences 5625 Renmin St. Changchun 130022 Jilin China

Protein-protein interactions (PPIs) are implicated in the majority of cellular processes by enabling and regulating the function of individual proteins. Thus, PPIs represent high-value, but challenging targets for therapeutic intervention. The development of constrained peptides represents an emerging strategy to generate peptide-based PPI inhibitors, typically mediated by α-helices. The approach can confer significant benefits including enhanced affinity, stability and cellular penetration and is ingrained in the premise that pre-organization simultaneously pays the entropic cost of binding, prevents a peptide from adopting a protease compliant β-strand conformation and shields the hydrophilic amides from the hydrophobic membrane. This conceptual blueprint for the empirical design of peptide-based PPI inhibitors is an exciting and potentially lucrative way to effect successful PPI inhibitor drug-discovery. However, a plethora of more subtle effects may arise from the introduction of a constraint that include changes to binding dynamics, the mode of recognition and molecular properties. In this review, we summarise the influence of inserting constraints on biophysical, conformational, structural and cellular behaviour across a range of constraining chemistries and targets, to highlight the tremendous success that has been achieved with constrained peptides alongside emerging design opportunities and challenges.
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http://dx.doi.org/10.1039/d1sc00165eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098664PMC
March 2021

FERONIA restricts Pseudomonas in the rhizosphere microbiome via regulation of reactive oxygen species.

Nat Plants 2021 05 10;7(5):644-654. Epub 2021 May 10.

Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada.

Maintaining microbiome structure is critical for the health of both plants and animals. By re-screening a collection of Arabidopsis mutants affecting root immunity and hormone crosstalk, we identified a FERONIA (FER) receptor kinase mutant (fer-8) with a rhizosphere microbiome enriched in Pseudomonas fluorescens without phylum-level dysbiosis. Using microbiome transplant experiments, we found that the fer-8 microbiome was beneficial. The effect of FER on rhizosphere pseudomonads was largely independent of its immune scaffold function, role in development and jasmonic acid autoimmunity. We found that the fer-8 mutant has reduced basal levels of reactive oxygen species (ROS) in roots and that mutants deficient in NADPH oxidase showed elevated rhizosphere pseudomonads. The addition of RALF23 peptides, a FER ligand, was sufficient to enrich P. fluorescens. This work shows that FER-mediated ROS production regulates levels of beneficial pseudomonads in the rhizosphere microbiome.
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http://dx.doi.org/10.1038/s41477-021-00914-0DOI Listing
May 2021

A rich catalog of C-C bonded species formed in CO reduction on a plasmonic photocatalyst.

Nat Commun 2021 May 10;12(1):2612. Epub 2021 May 10.

Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

The understanding and rational design of heterogeneous catalysts for complex reactions, such as CO reduction, requires knowledge of elementary steps and chemical species prevalent on the catalyst surface under operating conditions. Using in situ nanoscale surface-enhanced Raman scattering, we probe the surface of a Ag nanoparticle during plasmon-excitation-driven CO reduction in water. Enabled by the high spatiotemporal resolution and surface sensitivity of our method, we detect a rich array of C-C species formed on the photocatalytically active surface. The abundance of multi-carbon compounds, such as butanol, suggests the favorability of kinetically challenging C-C coupling on the photoexcited Ag surface. Another advance of this work is the use of isotope labeling in nanoscale probing, which allows confirmation that detected species are the intermediates and products of the catalytic reaction rather than spurious contaminants. The surface chemical knowledge made accessible by our approach will inform the modeling and engineering of catalysts.
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http://dx.doi.org/10.1038/s41467-021-22868-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110802PMC
May 2021

Natural History of Epstein-Barr Virus Replication and Viral Load Dynamics after Alemtuzumab-Based Allogeneic Stem Cell Transplantation.

Transplant Cell Ther 2021 May 4. Epub 2021 May 4.

Department of Haematology, UCL Cancer Institute, University College London, London, Uinted Kingdom; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.

Epstein-Barr virus (EBV) load monitoring after allogeneic hematopoietic stem cell transplantation (HSCT) enables earlier detection of EBV replication and often serves as a trigger for preemptive therapies aimed at reducing EBV-related diseases. Our institutional strategy is to treat patients with clinical signs of EBV-related disease accompanied by a rising viral load, rather than to intervene based solely on viral load. This affords an opportunity to study the natural history of EBV replication and to assess whether our strategy reduces overtreatment without compromising outcomes. The objectives of the present study were to assess the natural history of untreated EBV replication in patients who underwent an alemtuzumab-based allogeneic HSCT and to examine whether our clinical strategy reduced overtreatment without compromising patient outcomes. In this retrospective single-center observational study of 515 consecutive patients (age ≥18 years) undergoing T cell-depleted allogeneic HSCT incorporating alemtuzumab, patients underwent surveillance monitoring for EBV by quantitative PCR in the peripheral blood at least weekly up to 100 days post-transplantation and longer if they remained on immunosuppressive therapy. The cumulative incidence of EBV detection and EBV-related disease were assessed. Among the 515 patients, 192 had EBV DNA detectable on ≥1 occasion, with a cumulative incidence of 35.8% (31.8% to 40.4%), although this remained below the limit of quantification in 93 patients. The median time to first detection was 89.5 days (range, 0 to 2254 days). The incidence was higher in recipients of sibling donor transplants (45.4% versus 30%; P = .00021) compared with recipients of unrelated donor transplants. Twenty patients developed EBV-related disease (cumulative incidence, 3.9%). Two patients had immunosuppression reduction alone, 18 received rituximab, and 5 required additional therapies. Five patients died from post-transplantation lymphoproliferative disorder, all of whom had received rituximab. The positive predictive value of EBV load for disease was higher in the unrelated donor cohort but remained <75% regardless of EBV threshold (57.1% to 72.7%). The cumulative incidence of EBV-related disease in our study (3.9%) is comparable to that reported in other studies incorporating alemtuzumab, and our clinical strategy reduced overtreatment in this patient population. PCR-based surveillance strategies have limitations, as reflected in the relatively low sensitivity of the assay coupled with the low positive predictive value, which may influence the potential choice of a threshold for preemptive intervention. We conclude that it remains unclear whether treatment based on a rising EBV viral load alone provides superior overall results to treatment based on the development of clinical signs of EBV-related disease in the context of a rising viral load.
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http://dx.doi.org/10.1016/j.jtct.2021.04.020DOI Listing
May 2021

The effects of social distancing and self-isolation during the COVID-19 pandemic on adults diagnosed with asthma: A qualitative study.

J Health Psychol 2021 May 4:13591053211012766. Epub 2021 May 4.

University of East Anglia, UK.

This study aimed to explore how social distancing and self-isolation measures, aimed at protecting vulnerable groups from COVID-19, affected the wellbeing and physical activity levels among adults diagnosed with asthma. Twenty-seven participants took part across four online focus groups. Transcripts were analysed using thematic analysis. Participants reported becoming more health conscious due to being labelled as vulnerable. Their relationship with the severity of their asthma was altered and they reported making positive changes to increase their physical activity levels. Findings suggest there is a window of opportunity to engage with people diagnosed with asthma to promote beneficial lifestyle changes and self-management.
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http://dx.doi.org/10.1177/13591053211012766DOI Listing
May 2021

Parent Carer Quality of Life and Night-Time Attendance in Non-Ambulant Youth with Neuromuscular Disorders.

Dev Neurorehabil 2021 May 4:1-10. Epub 2021 May 4.

Telethon Kids Institute, Hospital Avenue, Nedlands, Western Australia, Australia.

: To describe and explore carer quality of life (QoL) and night-time attendance to their child in parents of non-ambulant youth with Neuromuscular Disorders. A cross-sectional population-based, comprehensive survey including the Adult Carer QoL (AC-QoL) questionnaire, measures of social context and youths' physical status. Associations between carer-QoL or frequency of parents' night-time attendance with independent variables were explored using linear and logistic regression models, respectively. Parents' perceived lower carer-QoL (mean 76.5/120, SD 18.5) when they attended to their child twice a night or more (n = 17/35) and with shorter time since their child was prescribed noninvasive ventilation (NIV). Parental night-time attendance was not associated with youth's actual use of NIV, but was more likely when youth required assistance to turn in bed, reported frequent sleep discomfort and had more severe joint contractures. To optimize parent carer-QoL, interventions must address parents' frequency of night-time attendance and youths' sleep comfort.
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http://dx.doi.org/10.1080/17518423.2021.1908440DOI Listing
May 2021

Aberrant epithelial polarity cues drive the development of precancerous airway lesions.

Proc Natl Acad Sci U S A 2021 May;118(18)

Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118;

Molecular events that drive the development of precancerous lesions in the bronchial epithelium, which are precursors of lung squamous cell carcinoma (LUSC), are poorly understood. We demonstrate that disruption of epithelial cellular polarity, via the conditional deletion of the apical determinant Crumbs3 (Crb3), initiates and sustains precancerous airway pathology. The loss of Crb3 in adult luminal airway epithelium promotes the uncontrolled activation of the transcriptional regulators YAP and TAZ, which stimulate intrinsic signals that promote epithelial cell plasticity and paracrine signals that induce basal-like cell growth. We show that aberrant polarity and YAP/TAZ-regulated gene expression associates with human bronchial precancer pathology and disease progression. Analyses of YAP/TAZ-regulated genes further identified the ERBB receptor ligand Neuregulin-1 (NRG1) as a key transcriptional target and therapeutic targeting of ERBB receptors as a means of preventing and treating precancerous cell growth. Our observations offer important molecular insight into the etiology of LUSC and provides directions for potential interception strategies of lung cancer.
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http://dx.doi.org/10.1073/pnas.2019282118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106308PMC
May 2021

Entinostat, a selective HDAC1/2 inhibitor, potentiates the effects of olaparib in homologous recombination proficient ovarian cancer.

Gynecol Oncol 2021 Jul 16;162(1):163-172. Epub 2021 Apr 16.

Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Objective: Poly ADP ribose polymerase inhibitors (PARPi) are most effective in BRCA1/2 mutated ovarian tumors. Better treatments are needed for homologous recombination HR-proficient cancer, including CCNE1 amplified subtypes. We have shown that histone deacetylase inhibitors (HDACi) sensitize HR-proficient ovarian cancer to PARPi. In this study, we provide complementary preclinical data for an investigator-initiated phase 1/2 clinical trial of the combination of olaparib and entinostat in recurrent, HR-proficient ovarian cancer.

Methods: We assessed the in vitro effects of the combination of olaparib and entinostat in SKOV-3, OVCAR-3 and primary cells derived from CCNE1 amplified high grade serous ovarian cancer (HGSOC) patients. We then tested the combination in a SKOV-3 xenograft model and in a patient-derived xenograft (PDX) model.

Results: Entinostat potentiates the effect of olaparib in reducing cell viability and clonogenicity of HR-proficient ovarian cancer cells. The combination reduces peritoneal metastases in a SKOV-3 xenograft model and prolongs survival in a CCNE1 amplified HR-proficient PDX model. Entinostat also enhances olaparib-induced DNA damage. Further, entinostat decreases BRCA1, a key HR repair protein, associated with decreased Ki-67, a proliferation marker, and increased cleaved PARP, a marker of apoptosis. Finally, entinostat perturbs replication fork progression, which increases genome instability.

Conclusion: Entinostat inhibits HR repair by reducing BRCA1 expression and stalling replication fork progression, leading to irreparable DNA damage and ultimate cell death. This work provides preclinical support for the clinical trial of the combination of olaparib and entinostat in HR-proficient ovarian cancer and suggests potential benefit even for CCNE1 amplified subtypes.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.015DOI Listing
July 2021

Decision-making process for introduction of maternal vaccines in Kenya, 2017-2018.

Implement Sci 2021 Apr 12;16(1):39. Epub 2021 Apr 12.

Department of Medicine, Division of Pediatrics, Emory University School of Medicine, 1518 Clifton Rd NE, Atlanta, GA, 30322, USA.

Background: Maternal immunization is a key strategy for reducing morbidity and mortality associated with infectious diseases in mothers and their newborns. Recent developments in the science and safety of maternal vaccinations have made possible development of new maternal vaccines ready for introduction in low- and middle-income countries. Decisions at the policy level remain the entry point for maternal immunization programs. We describe the policy and decision-making process in Kenya for the introduction of new vaccines, with particular emphasis on maternal vaccines, and identify opportunities to improve vaccine policy formulation and implementation process.

Methods: We conducted 29 formal interviews with government officials and policy makers, including high-level officials at the Kenya National Immunization Technical Advisory Group, and Ministry of Health officials at national and county levels. All interviews were recorded and transcribed. We analyzed the qualitative data using NVivo 11.0 software.

Results: All key informants understood the vaccine policy formulation and implementation processes, although national officials appeared more informed compared to county officials. County officials reported feeling left out of policy development. The recent health system decentralization had both positive and negative impacts on the policy process; however, the negative impacts outweighed the positive impacts. Other factors outside vaccine policy environment such as rumours, sociocultural practices, and anti-vaccine campaigns influenced the policy development and implementation process.

Conclusions: Public policy development process is complex and multifaceted by its nature. As Kenya prepares for introduction of other maternal vaccines, it is important that the identified policy gaps and challenges are addressed.
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http://dx.doi.org/10.1186/s13012-021-01101-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042952PMC
April 2021

Structural insights into peptide self-assembly using photo-induced crosslinking experiments and discontinuous molecular dynamics.

AIChE J 2021 Mar 7;67(3):e17101. Epub 2020 Nov 7.

Department of Chemical and Biomolecular Engineering North Carolina State University Raleigh North Carolina USA.

Determining the structure of the (oligomeric) intermediates that form during the self-assembly of amyloidogenic peptides is challenging because of their heterogeneous and dynamic nature. Thus, there is need for methodology to analyze the underlying molecular structure of these transient species. In this work, a combination of fluorescence quenching, photo-induced crosslinking (PIC) and molecular dynamics simulation was used to study the assembly of a synthetic amyloid-forming peptide, Aβ. A PIC amino acid containing a trifluormethyldiazirine (TFMD) group-Fmoc(TFMD)Phe-was incorporated into the sequence (Aβ*). Electrospray ionization ion-mobility spectrometry mass-spectrometry (ESI-IMS-MS) analysis of the PIC products confirmed that Aβ* forms assemblies with the monomers arranged as anti-parallel, in-register β-strands at all time points during the aggregation assay. The assembly process was also monitored separately using fluorescence quenching to profile the fibril assembly reaction. The molecular picture resulting from discontinuous molecule dynamics simulations showed that Aβ assembles through a single-step nucleation into a β-sheet fibril in agreement with these experimental observations. This study provides detailed structural insights into the Aβ self-assembly processes, paving the way to explore the self-assembly mechanism of larger, more complex peptides, including those whose aggregation is responsible for human disease.
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http://dx.doi.org/10.1002/aic.17101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988534PMC
March 2021

Enhanced Suppression of a Protein-Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an -Acyl--alkyl Sulfonamide Warhead.

J Am Chem Soc 2021 Mar 18;143(12):4766-4774. Epub 2021 Mar 18.

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.

Protein-protein interactions (PPIs) intimately govern various biological processes and disease states and therefore have been identified as attractive therapeutic targets for small-molecule drug discovery. However, the development of highly potent inhibitors for PPIs has proven to be extremely challenging with limited clinical success stories. Herein, we report irreversible inhibitors of the human double minute 2 (HDM2)/p53 PPI, which employ a reactive -acyl--alkyl sulfonamide (NASA) group as a warhead. Mass-based analysis successfully revealed the kinetics of covalent inhibition and the modification sites on HDM2 to be the N-terminal α-amine and Tyr67, both rarely seen in traditional covalent inhibitors. Finally, we demonstrated prolonged p53-pathway activation and more effective induction of the p53-mediated cell death in comparison to a noncovalent inhibitor. This study highlights the potential of the NASA warhead as a versatile electrophile for the covalent inhibition of PPIs and opens new avenues for the rational design of potent covalent PPI inhibitors.
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http://dx.doi.org/10.1021/jacs.1c00703DOI Listing
March 2021