Publications by authors named "Simon White"

104 Publications

Modeling coronavirus spike protein dynamics: implications for immunogenicity and immune escape.

Biophys J 2021 Nov 10. Epub 2021 Nov 10.

Department of Mechanical Engineering, University of Connecticut, Storrs, Connecticut; Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut. Electronic address:

The ongoing COVID-19 pandemic is a global public health emergency requiring urgent development of efficacious vaccines. While concentrated research efforts have focused primarily on antibody-based vaccines that neutralize SARS-CoV-2, and several first-generation vaccines have either been approved or received emergency use authorization, it is forecasted that COVID-19 will become an endemic disease requiring updated second-generation vaccines. The SARS-CoV-2 surface spike (S) glycoprotein represents a prime target for vaccine development because antibodies that block viral attachment and entry, i.e., neutralizing antibodies, bind almost exclusively to the receptor-binding domain. Here, we develop computational models for a large subset of S proteins associated with SARS-CoV-2, implemented through coarse-grained elastic network models and normal mode analysis. We then analyze local protein domain dynamics of the S protein systems and their thermal stability to characterize structural and dynamical variability among them. These results are compared against existing experimental data and used to elucidate the impact and mechanisms of SARS-CoV-2 S protein mutations and their associated antibody binding behavior. We construct a SARS-CoV-2 antigenic map and offer predictions about the neutralization capabilities of antibody and S mutant combinations based on protein dynamic signatures. We then compare SARS-CoV-2 S protein dynamics to SARS-CoV and MERS-CoV S proteins to investigate differing antibody binding and cellular fusion mechanisms that may explain the high transmissibility of SARS-CoV-2. The outbreaks associated with SARS-CoV, MERS-CoV, and SARS-CoV-2 over the last two decades suggest that the threat presented by coronaviruses is ever-changing and long term. Our results provide insights into the dynamics-driven mechanisms of immunogenicity associated with coronavirus S proteins and present a new, to our knowledge, approach to characterize and screen potential mutant candidates for immunogen design, as well as to characterize emerging natural variants that may escape vaccine-induced antibody responses.
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http://dx.doi.org/10.1016/j.bpj.2021.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577870PMC
November 2021

Willingness of children and adolescents to have a COVID-19 vaccination: Results of a large whole schools survey in England.

EClinicalMedicine 2021 Oct 27;40:101144. Epub 2021 Sep 27.

Department of Psychiatry, University of Oxford, Warneford Lane, Oxford OX3 7JX, UK.

Background: Vaccine hesitancy has affected COVID-19 adult vaccination programs in many countries. Data on hesitancy amongst child and adolescent populations is largely confined to parent opinion. We investigated the characteristics of vaccine hesitant children and adolescents using results from a large, school-based self-report survey of the willingness to have a COVID-19 vaccination in students aged 9 -18 years in England.

Methods: Data from the OxWell Student Survey on mental health, life experiences and behaviours were used, collected from four counties across England. Local authority partners recruited schools. The vaccine hesitancy question gave six response options and were clustered to inform delivery: eager and willing were categorised as vaccination 'opt-in', don't know and not bothered categorised as 'undecided', and unwilling and anti-vaccination categorised as 'opt-out'. We conducted a multinomial regression to determine associations between vaccine hesitancy and sociodemographic, health behaviour and social connection variables.

Findings: 27,910 students from 180 schools answered the vaccine hesitancy question between 14th May and 21st July 2021, of whom 13984 (50.1%) would opt-in to take a vaccination, 10322 (37.0%) were undecided, and 3604 (12.9%) would opt-out. A lower percentage of younger students reported that they would opt-in to vaccination, for example, 35.7% of 9-year-olds and 51.3% of 13-year-olds compared to 77.8% of 17-year-olds would opt-in to take a vaccination. Students who were 'opt-out' or 'undecided' (a combined 'vaccine hesitant' group) were more likely to come from deprived socioeconomic contexts with higher rates of home rental versus home ownership and their school locations were more likely to be in areas of greater deprivation. They were more likely to smoke or vape, spend longer on social media, feel that they did not belong in their school community but had lower levels of anxiety and depression. The vaccine hesitant students- the undecided and opt-out groups- were similar in profile, although the opt-out students had higher reported confirmed or probable previous COVID-19 infection than the opt-in group, whereas those undecided, did not.

Interpretation: If government vaccination strategies move towards vaccinating younger school-aged students, efforts to increase vaccination uptake may be necessary. Compared with students who would opt-in, those who were vaccine hesitant had greater indicators of social deprivation and felt a lack of community cohesion by not feeling a sense of belonging at their school. There were indications that those students who would opt-out had higher levels of marginalisation and mistrust. If programmes are rolled out, focus on hesitant younger students will be important, targeting more marginalised and deprived young people with information from trusted sources utilising social media; improving access to vaccination centres with provision both in and outside school; and addressing fears and worries about the effects of the vaccine. The main limitation of this study is that the participant group may not be wholly representative of England or the UK, which may bias population-level estimates of willingness to be vaccinated.

Funding: The Westminster Foundation, the National Institute for Health Research (NIHR) Applied Research Collaboration Oxford and Thames Valley at Oxford Health NHS Foundation Trust and the NIHR Oxford Health Biomedical Research Centre.
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http://dx.doi.org/10.1016/j.eclinm.2021.101144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482530PMC
October 2021

Enhanced Emission from Interlayer Excitons Coupled to Plasmonic Gap Cavities.

Small 2021 Nov 3;17(45):e2103994. Epub 2021 Oct 3.

School of Mathematical and Physical Sciences, University of Technology Sydney, Ultimo, New South Wales, 2007, Australia.

The emergence of interlayer excitons (IEs) from atomic layered transition metal dichalcogenides (TMDCs) heterostructures has drawn tremendous attention due to their unique and exotic optoelectronic properties. Coupling the IEs into optical cavities provides distinctive electromagnetic environments which plays an important role in controlling multiple optical processes such as optical nonlinear generation or photoluminescence enhancement. Here, the integration of IEs in TMDCs into plasmonic nanocavities based on a nanocube on a metallic mirror is reported. Spectroscopic studies reveal an order of magnitude enhancement of the IE at room temperature and a 5-time enhancement in fluorescence at cryogenic temperatures. Cavity modeling reveals that the enhancement of the emission is attributed to both increased excitation efficiency and Purcell effect from the cavity. The results show a novel method to control the excitonic processes in TMDC heterostructures to build high performance photonics and optoelectronics devices.
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http://dx.doi.org/10.1002/smll.202103994DOI Listing
November 2021

Generation of High-Density Quantum Emitters in High-Quality, Exfoliated Hexagonal Boron Nitride.

ACS Appl Mater Interfaces 2021 Oct 22;13(39):47283-47292. Epub 2021 Sep 22.

School of Mathematical and Physical Sciences, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.

Single-photon emitters in hexagonal boron nitride (hBN) are promising constituents for integrated quantum photonics. Specifically, engineering these emitters in large-area, high-quality, exfoliated hBN is needed for their incorporation into photonic devices and two dimensional heterostructures. Here, we report on two different routes to generate high-density quantum emitters with excellent optical properties-including high brightness and photostability. We study in detail high-temperature annealing and plasma treatments as an efficient means to generate dense emitters. We show that both an optimal oxygen flow rate and annealing temperature are required for the formation of high-density quantum emitters. In parallel, we demonstrate that the plasma treatment in various environments, followed by standard annealing is also an effective route for emission engineering. Our work provides vital information for the fabrication of quantum emitters in high-quality, exfoliated hBN flakes and paves the way toward the integration of the quantum emitters with photonic devices.
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http://dx.doi.org/10.1021/acsami.1c14863DOI Listing
October 2021

Pungent and volatile constituents of dried Australian ginger.

Curr Res Food Sci 2021 4;4:612-618. Epub 2021 Sep 4.

School of Health, Medical & Applied Sciences, CQUniversity Australia, Bruce Hwy, North Rockhampton, Qld, 4701, Australia.

Ginger is well known for its pungent flavour and health-benefitting properties, both of which are imparted by various gingerol derivatives and other volatile constituents. Although there has been a considerable amount of research into the chemical constituents found in fresh ginger, there is little information available on the quality of Australian-grown dried ginger, particularly that intended for processing purposes. Here, we investigate differences in the chemical composition of three samples of processing-grade ginger, ranging from very poor to good quality. Gingerols and 6-shogaol were quantified using high performance liquid chromatograph (HPLC), while gas chromatography coupled with mass spectrometry (GC-MS) was used to identify and semi-quantify the volatile constituents and other gingerol derivatives. Significant differences were found between the samples in their content of gingerols and [6]-shogaol, as well as in their total phenolic content and antioxidant capacity. A total of 100 volatile compounds were identified in the dried ginger samples, including 54 terpenoid derivatives and 35 gingerol derivatives. Several compounds are reported from ginger for the first time, including limonene glycol and neryl laurate. In addition, we provide the second report of the presence of shyobunol, geranyl--cymene and geranyl-α-terpinene in ginger.
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http://dx.doi.org/10.1016/j.crfs.2021.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427268PMC
September 2021

Exploring Experiences of UK Pharmacy Graduates in Dealing With Professional Dilemmas in Transition to Practice.

Am J Pharm Educ 2021 Sep 10:8643. Epub 2021 Sep 10.

Keele University, School of Pharmacy and Bioengineering, Staffordshire, United Kingdom.

For many UK pharmacy students there are minimal opportunities to learn, or be exposed to, different ways of dealing with ethical and professional dilemmas in real life practice during undergraduate education. This study aimed to explore the experiences of graduates during their pre-registration year and early practice (up to two years post qualification) on their perceived preparedness to make professional decisions when faced with problems or dilemmas once in practice. Semi-structured interviews were undertaken with pre-registration trainees and early careers pharmacists (up to two years qualified). Interviews were transcribed verbatim and analysed thematically using the Framework Approach. Ethical approval was obtained to undertake the study. Eighteen interviews were conducted: nine pre-registration trainees and nine qualified pharmacists. Four key themes emerged: continued learning in practice; exposure to role-modelling; moral courage; and stress and moral distress. This study found that there is a perceived need for further support, challenge and positive role-modelling to help pre-registration trainees and early career pharmacists continue to develop their ethical and professional decision-making skills in the practice setting. The level and quality of support reported was variable, and there was a reliance on informal networks of peer support in many cases. This study suggests a need to raise awareness among pre-registration tutors and line managers to improve and increase support in this area.
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http://dx.doi.org/10.5688/ajpe8643DOI Listing
September 2021

Progression of Clinical Features in Lewy Body Dementia Can Be Detected Over 6 Months.

Neurology 2021 09 17;97(10):e1031-e1040. Epub 2021 Aug 17.

From the Department of Psychiatry (E.M., S.R.W., A.S., J.T.O.) and MRC Biostatistics Unit (S.R.W.), University of Cambridge, UK; Forefront Parkinson's Disease Research Clinic (E.M., G.M.H., S.J.G.L.) and Brain and Mind Centre (E.M., G.M.H., S.J.G.L.), Faculty of Medicine and Health, University of Sydney, Australia; Newcastle Translational and Clinical Research Institute (J.-P.T., A.T., I.G.M.), Campus for Ageing and Vitality, Newcastle University, Newcastle Upon Tyne; and Centre for Public Health (J.P.M.K.), Queen's University Belfast, UK.

Objective: This study aimed to quantify the trajectory and magnitude of change of the key clinical features and corresponding symptom domains of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), including global cognition, parkinsonism, recurrent visual hallucinations, cognitive fluctuations, and sleep disturbance.

Methods: One hundred sixteen patients with Lewy body dementia (DLB = 72, PDD = 44) underwent assessment at baseline and 3 and 6 months as part of a prospective multicenter randomized controlled trial. Linear mixed models were constructed for core outcome measures using the Mini-Mental State Examination (MMSE), motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III), Dementia Cognitive Fluctuations Scale (DCFS), and Neuropsychiatric Inventory (NPI).

Results: Within the time frame of our study (6 months), we were able to identify a significant cognitive decline of 1.3 points on the MMSE ( = 0.002) and significant worsening of motor parkinsonism with an increase in UPDRS-III score of 3.2 points ( = 0.018). Fluctuation severity also increased using the DCFS with a 6-month change in score of 1.3 points ( = 0.001). Uniquely, a signal for increased severity of sleep symptoms of 1.2 points (NPI-sleep) was also detectable ( = 0.04). Significant changes in neuropsychiatric symptoms were not detected. There was no difference in rates of change of scores between DLB and PDD.

Discussion: Clinically significant rates of change in core clinical features can be detected and quantified in Lewy body dementia over a relatively short period (6 months) using common clinical instruments and thus may be useful as clinical endpoints for therapeutic trials of disease-modifying and symptomatic agents.
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http://dx.doi.org/10.1212/WNL.0000000000012450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448556PMC
September 2021

Reducing risks associated with medicines and lifestyle in a residential care population with intellectual disabilities: evaluation of a pharmacy review initiative in England.

BMJ Open 2021 08 17;11(8):e046630. Epub 2021 Aug 17.

Cheshire and Wirral Partnership NHS Foundation Trust, Chester, Cheshire West and Chester, UK.

Objectives: A collaborative service initiative involving community pharmacists and a specialist mental health pharmacist was developed to provide pharmacist reviews for care home residents with intellectual disabilities (IDs). This study aimed to characterise the medicines and lifestyle risk outcomes of the service and determine how these align with national priority issues in ID.

Design: Descriptive statistical analysis of routinely collected service delivery data.

Setting: Residential care homes in the Wirral, England for people with ID.

Participants: 160 residents.

Interventions: Pharmacist review of residents' medicines and lifestyle risk factors between November 2019 and May 2020.

Primary And Secondary Outcome Measures: Numbers of medicines prescribed, the nature of pharmacists' interventions/recommendations and general practitioner (GP)/psychiatrist acceptance.

Results: The 160 residents were prescribed 1207 medicines, 74% were prescribed ≥5 medicines and 507 interventions/recommendations were made, averaging 3.3 per resident. The highest proportion (30.4%) were lifestyle risk related, while changing and stopping medicines accounted for 17.9% and 12.8%, respectively. Of the recommendations discussed with GPs/psychiatrists, 86% were accepted. Medicines with anticholinergic properties were prescribed for 115 (72%) residents, of whom 43 (37%) had a high anticholinergic burden score. Pharmacists recommended anticholinergic discontinuation or dose reduction for 28 (24%) residents. The pharmacists made interventions/recommendations about constipation management for 10% of residents and about respiratory medicines for 17 (81%) of the 21 residents with respiratory diagnoses.

Conclusions: The findings indicate considerable polypharmacy among the residents and a high level of pharmacists' interventions/recommendations about medicines and lifestyle risk, most of which were accepted by GPs/psychiatrists. This included anticholinergic burden reduction and improving respiratory disease and constipation management, which are national priority issues. Wider adoption of collaborative pharmacist review models could have similar benefits for residential populations with ID and potentially reduce pressure on other health services.
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http://dx.doi.org/10.1136/bmjopen-2020-046630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372807PMC
August 2021

Positive predictive value highlights four novel candidates for actionable genetic screening from analysis of 220,000 clinicogenomic records.

Genet Med 2021 Dec 13;23(12):2300-2308. Epub 2021 Aug 13.

Helix, San Mateo, CA, USA.

Purpose: To identify conditions that are candidates for population genetic screening based on population prevalence, penetrance of rare variants, and actionability.

Methods: We analyzed exome and medical record data from >220,000 participants across two large population health cohorts with different demographics. We performed a gene-based collapsing analysis of rare variants to identify genes significantly associated with disease status.

Results: We identify 74 statistically significant gene-disease associations across 27 genes. Seven of these conditions have a positive predictive value (PPV) of at least 30% in both cohorts. Three are already used in population screening programs (BRCA1, BRCA2, LDLR), and we also identify four new candidates for population screening: GCK with diabetes mellitus, HBB with β-thalassemia minor and intermedia, PKD1 with cystic kidney disease, and MIP with cataracts. Importantly, the associations are actionable in that early genetic screening of each of these conditions is expected to improve outcomes.

Conclusion: We identify seven genetic conditions where rare variation appears appropriate to assess in population screening, four of which are not yet used in screening programs. The addition of GCK, HBB, PKD1, and MIP rare variants into genetic screening programs would reach an additional 0.21% of participants with actionable disease risk, depending on the population.
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http://dx.doi.org/10.1038/s41436-021-01293-9DOI Listing
December 2021

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility.

PLoS One 2021 11;16(8):e0255402. Epub 2021 Aug 11.

Helix OpCo LLC, San Mateo, California, United States of America.

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357137PMC
August 2021

Pharmacy graduates' perceived impact of long-term undergraduate use of an ethical decision-support tool on their early practice.

Curr Pharm Teach Learn 2021 07 5;13(7):760-769. Epub 2021 Apr 5.

School of Pharmacy, Keele University, Keele, Staffordshire ST5 5BG, UK. Electronic address:

Introduction: Values-based practice is an important concept within healthcare decision-making that sits alongside evidence-based practice. Values Exchange (Vx) (http://www.vxcommunity.com) is an online tool that supports the development of ethical and professional decision-making skills through values transparency. The aim of this research was to explore the perceived impact of long-term use of the tool during undergraduate study on pharmacy graduates' early practice.

Methods: Alumni in their pre-registration year or up to two years qualified were invited to participate via a question at the end of a survey, with additional students invited prospectively during an undergraduate lecture. All had completed three cases per year on Vx during the four-year master of pharmacy course. Semi-structured interviews were audio-recorded and transcribed verbatim, and framework analysis was applied. Ethical approval was obtained.

Results: A total of 18 interviews (nine pharmacists and nine pre-registration tutees) were conducted between May 2015 and March 2016. Thirteen participants were female, 13 were based in community pharmacy, and 10 were Caucasian. Interviews ranged from 50 min to 2 hours. Three themes emerged from the data: (1) the Vx learning environment, (2) learning and reflection, and (3) potential enhancements for learning. Participants perceived Vx to be an effective teaching tool supporting the development of skills necessary to exercise professional judgement in pharmacy practice.

Conclusions: Vx appears to be a worthy addition to the armoury of teaching methods necessary to support future pharmacists in their preparedness to deal with ethical and professional dilemmas in practice.
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http://dx.doi.org/10.1016/j.cptl.2021.03.001DOI Listing
July 2021

Emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

Cell 2021 05 30;184(10):2587-2594.e7. Epub 2021 Mar 30.

Illumina, San Diego, CA 92122, USA.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.
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http://dx.doi.org/10.1016/j.cell.2021.03.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009040PMC
May 2021

Simulating a Community Mental Health Service During the COVID-19 Pandemic: Effects of Clinician-Clinician Encounters, Clinician-Patient-Family Encounters, Symptom-Triggered Protective Behaviour, and Household Clustering.

Front Psychiatry 2021 25;12:620842. Epub 2021 Feb 25.

Cambridgeshire & Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, United Kingdom.

Face-to-face healthcare, including psychiatric provision, must continue despite reduced interpersonal contact during the COVID-19 (SARS-CoV-2 coronavirus) pandemic. Community-based services might use domiciliary visits, consultations in healthcare settings, or remote consultations. Services might also alter direct contact between clinicians. We examined the effects of appointment types and clinician-clinician encounters upon infection rates. Computer simulation. We modelled a COVID-19-like disease in a hypothetical community healthcare team, their patients, and patients' household contacts (family). In one condition, clinicians met patients and briefly met family (e.g., home visit or collateral history). In another, patients attended alone (e.g., clinic visit), segregated from each other. In another, face-to-face contact was eliminated (e.g., videoconferencing). We also varied clinician-clinician contact; baseline and ongoing "external" infection rates; whether overt symptoms reduced transmission risk behaviourally (e.g., personal protective equipment, PPE); and household clustering. Service organisation had minimal effects on whole-population infection under our assumptions but materially affected clinician infection. Appointment type and inter-clinician contact had greater effects at low external infection rates and without a behavioural symptom response. Clustering magnified the effect of appointment type. We discuss infection control and other factors affecting appointment choice and team organisation. Distancing between clinicians can have significant effects on team infection. Loss of clinicians to infection likely has an adverse impact on care, not modelled here. Appointments must account for clinical necessity as well as infection control. Interventions to reduce transmission risk can synergize, arguing for maximal distancing and behavioural measures (e.g., PPE) consistent with safe care.
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http://dx.doi.org/10.3389/fpsyt.2021.620842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947690PMC
February 2021

Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

medRxiv 2021 Feb 7. Epub 2021 Feb 7.

As of January of 2021, the highly transmissible B.1.1.7 variant of SARS-CoV-2, which was first identified in the United Kingdom (U.K.), has gained a strong foothold across the world. Because of the sudden and rapid rise of B.1.1.7, we investigated the prevalence and growth dynamics of this variant in the United States (U.S.), tracking it back to its early emergence and onward local transmission. We found that the RT-qPCR testing anomaly of S gene target failure (SGTF), first observed in the U.K., was a reliable proxy for B.1.1.7 detection. We sequenced 212 B.1.1.7 SARS-CoV-2 genomes collected from testing facilities in the U.S. from December 2020 to January 2021. We found that while the fraction of B.1.1.7 among SGTF samples varied by state, detection of the variant increased at a logistic rate similar to those observed elsewhere, with a doubling rate of a little over a week and an increased transmission rate of 35-45%. By performing time-aware Bayesian phylodynamic analyses, we revealed several independent introductions of B.1.1.7 into the U.S. as early as late November 2020, with onward community transmission enabling the variant to spread to at least 30 states as of January 2021. Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.
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http://dx.doi.org/10.1101/2021.02.06.21251159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872373PMC
February 2021

Large few-layer hexagonal boron nitride flakes for nonlinear optics.

Opt Lett 2021 Feb;46(3):564-567

Hexagonal boron nitride (hBN) is a layered dielectric material with a wide range of applications in optics and photonics. In this work, we demonstrate a fabrication method for few-layer hBN flakes with areas up to 5000µ. We show that hBN in this form can be integrated with photonic microstructures: as an example, we use a circular Bragg grating (CBG). The layer quality of the exfoliated hBN flake on and off a CBG is confirmed by Raman spectroscopy and second-harmonic generation (SHG) microscopy. We show that the SHG signal is uniform across the hBN sample outside the CBG and is amplified in the center of the CBG.
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http://dx.doi.org/10.1364/OL.416564DOI Listing
February 2021

A novel equivalence probability weighted power prior for using historical control data in an adaptive clinical trial design: A comparison to standard methods.

Pharm Stat 2021 05 20;20(3):462-484. Epub 2021 Jan 20.

MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.

A standard two-arm randomised controlled trial usually compares an intervention to a control treatment with equal numbers of patients randomised to each treatment arm and only data from within the current trial are used to assess the treatment effect. Historical data are used when designing new trials and have recently been considered for use in the analysis when the required number of patients under a standard trial design cannot be achieved. Incorporating historical control data could lead to more efficient trials, reducing the number of controls required in the current study when the historical and current control data agree. However, when the data are inconsistent, there is potential for biased treatment effect estimates, inflated type I error and reduced power. We introduce two novel approaches for binary data which discount historical data based on the agreement with the current trial controls, an equivalence approach and an approach based on tail area probabilities. An adaptive design is used where the allocation ratio is adapted at the interim analysis, randomising fewer patients to control when there is agreement. The historical data are down-weighted in the analysis using the power prior approach with a fixed power. We compare operating characteristics of the proposed design to historical data methods in the literature: the modified power prior; commensurate prior; and robust mixture prior. The equivalence probability weight approach is intuitive and the operating characteristics can be calculated exactly. Furthermore, the equivalence bounds can be chosen to control the maximum possible inflation in type I error.
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http://dx.doi.org/10.1002/pst.2088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611797PMC
May 2021

Validation of a hospital clinical pharmacy workforce calculator: A methodology for pharmacy?

Int J Clin Pract 2021 May 16;75(5):e13932. Epub 2021 Mar 16.

Royal Stoke University Hospital, United Hospitals of North Midlands, Newcastle-under-Lyme, UK.

Background: The benefits of clinical pharmacy services are established within hospital practice but staff numbers required for service delivery are not well described and staffing levels vary. The need for a consistent, objective method of determining staffing levels was recognised at a UK University Hospital and a Clinical Pharmacy Workforce Calculator (CPWC) was developed.

Objective: To develop the Activity Standard (AS) for pharmaceutical care and establish the reliability of the CPWC across acute hospital settings in UK.

Setting: Acute hospital in-patient clinical pharmacy services on medical and surgical wards.

Method: Using the World Health Organisation's Workload Indicators of Staffing Need (WISN) methodology, a two-round Delphi study was undertaken. This developed the Activity Standard for pharmaceutical care and identified the staff-time unavailable for clinical work. Consenting panel members then tested the CPWC, calculating the staff required for three scenarios to determine whether it could be reliably used by different operators.

Results: Thirty-six participants consented to participate. Data were returned from 22 (61%) of whom 20 (56%) supplied analysable data. Consensus was achieved on the tasks required for pharmaceutical care delivery, the mean time each takes, how frequently they should be completed and the time unavailable for clinical work for each grade of staff. The CPWC calculates staffing requirements using these data. Eleven participants (55%) tested the CPWC and analysis of responses demonstrated that 30 of 33 (91%) calculations were accurately completed.

Discussion: This study defined the WISN Activity Standard for UK pharmaceutical care delivery to hospital inpatients and showed content validity for the CPWC in acute medical and surgical hospital settings. Different operators used the CPWC reliably and applied it to local sites.

Conclusion: The CPWC offers hospital pharmacy managers a useful tool to negotiate adequate staffing to deliver pharmaceutical care. Its development methodology could be applied widely in pharmacy practice.
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http://dx.doi.org/10.1111/ijcp.13932DOI Listing
May 2021

The Missing Tailed Phages: Prediction of Small Capsid Candidates.

Microorganisms 2020 Dec 8;8(12). Epub 2020 Dec 8.

Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.

Tailed phages are the most abundant and diverse group of viruses on the planet. Yet, the smallest tailed phages display relatively complex capsids and large genomes compared to other viruses. The lack of tailed phages forming the common icosahedral capsid architectures T = 1 and T = 3 is puzzling. Here, we extracted geometrical features from high-resolution tailed phage capsid reconstructions and built a statistical model based on physical principles to predict the capsid diameter and genome length of the missing small-tailed phage capsids. We applied the model to 3348 isolated tailed phage genomes and 1496 gut metagenome-assembled tailed phage genomes. Four isolated tailed phages were predicted to form T = 3 icosahedral capsids, and twenty-one metagenome-assembled tailed phages were predicted to form T < 3 capsids. The smallest capsid predicted was a T = 4/3 ≈ 1.33 architecture. No tailed phages were predicted to form the smallest icosahedral architecture, T = 1. We discuss the feasibility of the missing T = 1 tailed phage capsids and the implications of isolating and characterizing small-tailed phages for viral evolution and phage therapy.
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http://dx.doi.org/10.3390/microorganisms8121944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762592PMC
December 2020

Interactive Clinical Avatar Use in Pharmacist Preregistration Training: Design and Review.

J Med Internet Res 2020 11 6;22(11):e17146. Epub 2020 Nov 6.

School of Pharmacy and Bioengineering, Keele University, Keele, United Kingdom.

Background: Virtual patients are interactive computer-based simulations that are being increasingly used in modern health care education. They have been identified as tools that can provide experiential learning and assessment in a standardized and safe environment. However, the study of high-fidelity virtual patients such as interactive clinical avatars within pharmacy is limited.

Objective: The aim of this paper is to describe the design and review of three interactive clinical avatar simulations as part of pharmacist preregistration training.

Methods: A multistep design approach was taken to create interactive clinical avatar simulations on the topics of emergency hormonal contraception (EHC), calculation of renal function, and childhood illnesses. All case studies were reviewed by registered pharmacists to establish content and face validity. The EHC case study and data collection questionnaire were also reviewed by a purposive sample of preregistration trainees and newly qualified pharmacists. The questionnaire used Likert ranking statements and open-ended questions to obtain users' feedback on the design, usability, and usefulness of the interactive clinical avatars as learning tools. Descriptive statistics and content analysis were undertaken on the data.

Results: Ten preregistration trainees and newly qualified pharmacists reviewed the EHC interactive clinical avatars and data collection questionnaire. The data collection questionnaire was associated with a Cronbach alpha=.95, demonstrating good reliability. All three interactive clinical avatar simulations were reported as usable and appropriately designed for preregistration training. Users perceived they were developing skills and knowledge from the simulations. The high-fidelity nature of the avatars and relevance of the simulations to real-life practice were reported as aspects that encouraged the application of theory to practice. Improvements were suggested to ensure the simulations were more user-friendly.

Conclusions: The design and creation of the interactive clinical avatar simulations was successful. The multistep review process ensured validity and reliability of the simulations and data collection questionnaire. The in-depth explanation of the design process and provision of a questionnaire may help widen the use and evaluation of interactive clinical avatars or other simulation tools in pharmacy education. The interactive clinical avatars were reported as novel learning tools that promoted experiential learning and allowed users to feel like they were engaging in real-life scenarios, thus developing transferable knowledge and skills. This may be potentially beneficial for many health care training courses as a way to provide standardized experiences promoting active learning and reflection.
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http://dx.doi.org/10.2196/17146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679212PMC
November 2020

The use and misuse of ratio and proportion exposure measures in food environment research.

Int J Behav Nutr Phys Act 2020 09 21;17(1):118. Epub 2020 Sep 21.

Medical Research Council (MRC) Biostatistics Unit, University of Cambridge, Cambridge, UK.

Background: The food stores within residential environments are increasingly investigated as a possible mechanism driving food behaviours and health outcomes. Whilst increased emphasis is being placed on the type of study designs used and how we measure the outcomes, surprisingly little attention gets diverted to the measures of the food environment beyond calls for standardised approaches for food store coding and geographic scales of exposure. Food environments are a challenging concept to measure and model and the use of ratio and proportion measures are becoming more common in food environment research. Whilst these are seemingly an advance on single store type indicators, such as simply counting the number of supermarkets or fast food restaurants present, they have several limitations that do not appear to have been fully considered.

Main Body: In this article we report on five issues related to the use of ratio and proportion food environment measures: 1) binary categorisation of food stores; 2) whether they truly reflect a more or less healthy food environment; 3) issues with these measures not reflecting the quantity of food stores; 4) difficulties when no stores are present; and 5) complications in statistical treatment and interpretation of ratio and proportion measures. Each of these issues are underappreciated in the literature to date and highlight that ratio and proportion measures need to be treated with caution.

Conclusion: Calls for the broader adoption of relative food environment measures may be misguided. Whilst we should continue to search for better ways to represent the complexity of food environments, ratio and proportion measures are unlikely to be the answer.
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http://dx.doi.org/10.1186/s12966-020-01019-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507725PMC
September 2020

Central nervous system (CNS) medications and polypharmacy in later life: cross-sectional analysis of the English Longitudinal Study of Ageing (ELSA).

BMJ Open 2020 09 14;10(9):e034346. Epub 2020 Sep 14.

School of Pharmacy, Keele University, Keele, UK.

Objectives: Many central nervous system (CNS) medications are considered potentially inappropriate for prescribing in older people; however, these medications are common in polypharmacy (≥5 medicines) regimens. This paper aims to determine the prevalence of CNS drug classes commonly taken by older people. Furthermore, this paper aims to determine whether polypharmacy and other factors, previously found to be associated with overall polypharmacy, are associated with the most common CNS drug classes.

Design: Cross-sectional study.

Setting: English Longitudinal Study of Ageing (wave 6).

Participants: 7730 participants (≥50 years).

Main Outcome Measures: Adjusted Odds Ratios (OR) and 95% confidence intervals (CI) for CNS drug classes.

Results: 31% of the sample were currently taking ≥5 medications (polypharmacy), of whom 58% (n=1362/2356) were taking CNS medicines as part of their regimen. The most common CNS drug classes in polypharmacy regimens were non-opioid analgesics, opioid analgesics, tricyclic and related antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) (34.6%, 13.2%, 10.9% and 10.4%, respectively). Compared with people currently taking 1-4 prescribed medicines, polypharmacy was associated with adjusted ORs of 5.71 (95% CI: 4.29 to 7.61, p<0.01) for opioid analgesics, 3.80 (95% CI: 3.25 to 4.44, p<0.01) for non-opioid analgesics, 3.11 (95% CI: 2.43 to 3.98, p<0.01) for TCAs and 2.30 (95% CI: 1.83 to 2.89, p<0.01) for SSRIs. Lower wealth was also associated with the aforementioned CNS drug classes.

Conclusion: Opioid and non-opioid analgesics were the most prevalent classes of CNS medicines in this study. Polypharmacy is strongly associated with the aforementioned classes of analgesics. Polypharmacy is also associated with TCAs and SSRIs, although to a lesser extent than for analgesics. For all CNS medicine classes, polypharmacy may need to be considered in relation to reducing the risk of potential adverse events. After adjustment, lower wealth is associated particularly with analgesics, highlighting that socioeconomic factors may play a role in the prescribing of CNS medicines. These findings provide a baseline for future research into this area.
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http://dx.doi.org/10.1136/bmjopen-2019-034346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490946PMC
September 2020

Virtual patients as a tool for training pre-registration pharmacists and increasing their preparedness to practice: A qualitative study.

PLoS One 2020 31;15(8):e0238226. Epub 2020 Aug 31.

School of Pharmacy and Bioengineering, Keele University, Keele, Staffordshire, United Kingdom.

Virtual patients are an active learning pedagogical tool which simulate clinical scenarios in a three-dimensional environment. Their use in pharmacy education is under-researched in comparison to other healthcare professions. In the United Kingdom, pre-registration training refers to a year of workplace based training which pharmacy graduates must complete prior to professional registration as pharmacists. This study aimed to evaluate pre-registration pharmacists' perceptions on the integration, usefulness and enjoyment of completing virtual patient simulations or non-interactive case studies as part of their training. Pre-registration trainees completed three virtual patient simulations or three non-interactive case studies on the topics of: emergency hormonal contraception, renal function and childhood illnesses. Telephone interviews were conducted with twenty pre-registration pharmacists, exploring their perspectives on the use of the virtual patient or non-interactive case studies. Data was analysed using the five-stage framework approach. Four main themes emerged from the data: case study design; usefulness of the case studies as a training tool; support in pre-registration training; utility of the learning tools. Trainees also identified technical issues they had experienced while completing the virtual patient simulations, specifically with keyword recognition. Pre-registration trainees who used the virtual patients provided comments relating to the novelty, realism and enjoyment in completing them. Trainees in both groups reported developing knowledge and skills from completing the case studies; those who used the virtual patient commented on the development of communication skills and an increase in confidence for practice and those who used the non-interactive cases focused on knowledge acquisition and numeracy. Participants were enthusiastic about virtual patients as a novel training tool which provided an opportunity for learners to practice realistic scenarios in a safe environment. Virtual patients offer the potential to 'bridge the gap' in pharmacist pre-registration sector-related training variation, promote learning through reflection on doing and increase overall preparedness for practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458319PMC
October 2020

Actual vs. Perceived Competency Development-How Can Virtual Patients Impact Pharmacist Pre-Registration Training?

Pharmacy (Basel) 2020 Aug 5;8(3). Epub 2020 Aug 5.

School of Pharmacy and Bioengineering, Keele University, Keele, Newcastle ST5 5BG, UK.

Virtual patients are an active learning pedagogical tool that simulate clinical scenarios. There is an established disparity in pre-registration examination pass rates depending on whether individuals complete their training in a community or hospital pharmacy. This study aimed to evaluate virtual patient (VP) and non-interactive (NI) case studies, concerning knowledge, skill and confidence development of pre-registration pharmacist trainees. A quasi-experimental evaluation was conducted. Pre-registration pharmacists completed three VP or NI case studies. Each case study was associated with a pre-and post-knowledge quiz. Pre-registration trainees were invited to complete a questionnaire consisting of Likert ranking statements and open-ended questions on the case study features, usability and individual development. Both learning tools significantly improved trainees' knowledge on the topic areas (except for the NI group in case study 3). Although no significant differences in knowledge improvement were identified between the learning tools, trainees who used the VP reported the development of a wider knowledge base and skill set, an increase in confidence for practice and an opportunity to apply their learning. The sector in which pre-registration pharmacists were completing their training (community or hospital) had a significant impact on knowledge improvement in the three case studies. Future research evaluating VPs with pre-registration and qualified pharmacists should be conducted to explore their benefits and establish their effectiveness as learning tools.
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http://dx.doi.org/10.3390/pharmacy8030138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558302PMC
August 2020

Long-term cognitive outcome in adult survivors of an early childhood posterior fossa brain tumour.

Int J Clin Oncol 2020 Oct 8;25(10):1763-1773. Epub 2020 Jul 8.

Cambridgeshire and Peterborough NHS Foundation Trust, South Team, Comberton Road, Toft, Cambridgeshire, CB23 2RY, UK.

Purpose: Posterior fossa brain tumours (PFT) and their treatment in young children are often associated with subsequent cognitive impairment. However, reported follow-up periods rarely exceed 10 years. This study reports very long-term cognitive consequences of surviving an early childhood PFT.

Methods: 62 adult survivors of a PFT, ascertained from a national register, diagnosed before 5 years of age, and a sibling control, received a single IQ assessment an average of 32 years (range 18-53) after initial diagnosis, using the Weschler Abbreviated Scale of Intelligence. Regression models were fitted to survivor-sibling pair differences on verbal and performance IQ (VIQ and PIQ) scores to investigate whether increasing time between PFT diagnosis and follow-up IQ assessment contributed to survivor-sibling IQ differences.

Results: At follow-up, survivors had, on average, VIQ 15 points and PIQ 19 points lower than their siblings. There was no significant effect of time since diagnosis on survivor-sibling VIQ difference. Survivors who received radiotherapy showed no significant effect of time since diagnosis on survivor-sibling PIQ difference. Survivors who did not receive radiotherapy demonstrated a trend for it to reduce.

Conclusions: VIQ and PIQ deficits persist in adulthood, suggesting the effect of a fixed injury imposing on cognitive development, rather than an ongoing pathological process.

Implications For Cancer Survivors: The findings will help parents and others supporting survivors of an early life PFT to identify and plan for possible cognitive outcomes, and highlight the importance of early interventions to optimize cognitive function during the developmental period.
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http://dx.doi.org/10.1007/s10147-020-01725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498491PMC
October 2020

A possible mechanism underlying mood disorders associated with LUTS: Chronic bladder outlet obstruction causes NLRP3-dependent inflammation in the hippocampus and depressive behavior in rats.

Neurourol Urodyn 2020 08 29;39(6):1700-1707. Epub 2020 Jun 29.

Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina.

Aims: Reports link urinary dysfunction and mood disorders, such as depression, but a causative mechanism has never been postulated. Contemporary discoveries demonstrate a local inflammatory response in peripheral organs can trigger inflammation in the brain, particularly the hippocampus, mediated through the NLRP3 inflammasome. Critically, central inflammation causes depressive behavior. Since bladder outlet obstruction (BOO) evokes a local inflammatory response in the bladder, we hypothesize it will induce NLRP3-dependent inflammation in the hippocampus and depressive behavior.

Methods: There were four groups of rats: control, sham, BOO, or BOO + glyburide (an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm catheter. Sham was tied loosely. Glyburide was provided by slow-release pellet (subcutaneous 50 mg, 21 day, replaced as needed). Rats were analyzed 12 weeks post-op for: hippocampal inflammation, microglial density, neurogenesis, and depression symptoms (open field and sucrose preference).

Results: BOO elicited hippocampal inflammation, accompanied by an increase in activated microglia (22%) and a decrease in neurogenesis (35%), which was blocked by glyburide. In addition, BOO rats displayed anxiety (57% decrease in exploratory behavior in the open field assay) and anhedonia (21% decrease in sucrose preference), two symptoms of depression. Like inflammation, these symptoms were diminished by glyburide to levels not statistically significantly different from controls.

Conclusions: BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the rat hippocampus after 12 weeks and this inflammation causes depressive behavior. This is the first mechanistic explanation of the link between BOO and depression and provides evidence for a distinct bladder-brain axis.
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http://dx.doi.org/10.1002/nau.24448DOI Listing
August 2020

Quasi-BIC Resonant Enhancement of Second-Harmonic Generation in WS Monolayers.

Nano Lett 2020 Jul 22;20(7):5309-5314. Epub 2020 Jun 22.

School of Mathematical and Physical Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia.

Atomically thin monolayers of transition metal dichalcogenides (TMDs) have emerged as a promising class of novel materials for optoelectronics and nonlinear optics. However, the intrinsic nonlinearity of TMD monolayers is weak, limiting their functionalities for nonlinear optical processes such as frequency conversion. Here we boost the effective nonlinear susceptibility of a TMD monolayer by integrating it with a resonant dielectric metasurface that supports pronounced optical resonances with high quality factors: bound states in the continuum (BICs). We demonstrate that a WS monolayer combined with a silicon metasurface hosting BICs exhibits enhanced second-harmonic intensity by more than 3 orders of magnitude relative to a WS monolayer on top of a flat silicon film of the same thickness. Our work suggests a pathway to employ high-index dielectric metasurfaces as hybrid structures for enhancement of TMD nonlinearities with applications in nonlinear microscopy, optoelectronics, and signal processing.
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http://dx.doi.org/10.1021/acs.nanolett.0c01603DOI Listing
July 2020

Methods for accounting for neighbourhood self-selection in physical activity and dietary behaviour research: a systematic review.

Int J Behav Nutr Phys Act 2020 04 1;17(1):45. Epub 2020 Apr 1.

Health Research Institute, University of Canberra, Canberra, Australia.

Background: Self-selection into residential neighbourhoods is a widely acknowledged, but under-studied problem in research investigating neighbourhood influences on physical activity and diet. Failure to handle neighbourhood self-selection can lead to biased estimates of the association between the neighbourhood environment and behaviour. This means that effects could be over- or under-estimated, both of which have implications for public health policies related to neighbourhood (re)design. Therefore, it is important that methods to deal with neighbourhood self-selection are identified and reviewed. The aim of this review was to assess how neighbourhood self-selection is conceived and accounted for in the literature.

Methods: Articles from a systematic search undertaken in 2017 were included if they examined associations between neighbourhood environment exposures and adult physical activity or dietary behaviour. Exposures could include any objective measurement of the built (e.g., supermarkets), natural (e.g., parks) or social (e.g., crime) environment. Articles had to explicitly state that a given method was used to account for neighbourhood self-selection. The systematic review was registered with the PROSPERO International Prospective Register of Systematic Reviews (number CRD42018083593) and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Results: Of 31 eligible articles, almost all considered physical activity (30/31); few examined diet (2/31). Methods used to address neighbourhood self-selection varied. Most studies (23/31) accounted for items relating to participants' neighbourhood preferences or reasons for moving to the neighbourhood using multi-variable adjustment in regression models (20/23) or propensity scores (3/23). Of 11 longitudinal studies, three controlled for neighbourhood self-selection as an unmeasured confounder using fixed effects regression.

Conclusions: Most studies accounted for neighbourhood self-selection by adjusting for measured attributes of neighbourhood preference. However, commonly the impact of adjustment could not be assessed. Future studies using adjustment should provide estimates of associations with and without adjustment for self-selection; consider temporality in the measurement of self-selection variables relative to the timing of the environmental exposure and outcome behaviours; and consider the theoretical plausibility of presumed pathways in cross-sectional research where causal direction is impossible to establish.
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http://dx.doi.org/10.1186/s12966-020-00947-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115077PMC
April 2020

Structures of Three Actinobacteriophage Capsids: Roles of Symmetry and Accessory Proteins.

Viruses 2020 03 8;12(3). Epub 2020 Mar 8.

Biology/Physics Building, Department of Molecular and Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit-3125. Storrs, CT 06269-3125, USA.

Here, we describe the structure of three actinobacteriophage capsids that infect . The capsid structures were resolved to approximately six angstroms, which allowed confirmation that each bacteriophage uses the HK97-fold to form their capsid. One bacteriophage, Rosebush, may have a novel variation of the HK97-fold. Four novel accessory proteins that form the capsid head along with the major capsid protein were identified. Two of the accessory proteins were minor capsid proteins and showed some homology, based on bioinformatic analysis, to the TW1 bacteriophage. The remaining two accessory proteins are decoration proteins that are located on the outside of the capsid and do not resemble any previously described bacteriophage decoration protein. SDS-PAGE and mass spectrometry was used to identify the accessory proteins and bioinformatic analysis of the accessory proteins suggest they are used in many actinobacteriophage capsids.
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http://dx.doi.org/10.3390/v12030294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150772PMC
March 2020

Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts.

Nat Commun 2020 Jan 28;11(1):542. Epub 2020 Jan 28.

Helix, 101S Ellsworth Ave Suite 350, San Mateo, CA, 94401, USA.

Understanding the impact of rare variants is essential to understanding human health. We analyze rare (MAF < 0.1%) variants against 4264 phenotypes in 49,960 exome-sequenced individuals from the UK Biobank and 1934 phenotypes (1821 overlapping with UK Biobank) in 21,866 members of the Healthy Nevada Project (HNP) cohort who underwent Exome + sequencing at Helix. After using our rare-variant-tailored methodology to reduce test statistic inflation, we identify 64 statistically significant gene-based associations in our meta-analysis of the two cohorts and 37 for phenotypes available in only one cohort. Singletons make significant contributions to our results, and the vast majority of the associations could not have been identified with a genotyping chip. Our results are available for interactive browsing in a webapp (https://ukb.research.helix.com). This comprehensive analysis illustrates the biological value of large, deeply phenotyped cohorts of unselected populations coupled with NGS data.
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http://dx.doi.org/10.1038/s41467-020-14288-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987107PMC
January 2020

Cyclophosphamide-induced cystitis results in NLRP3-mediated inflammation in the hippocampus and symptoms of depression in rats.

Am J Physiol Renal Physiol 2020 02 23;318(2):F354-F362. Epub 2019 Dec 23.

Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina.

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1β. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.
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http://dx.doi.org/10.1152/ajprenal.00408.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052649PMC
February 2020
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