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1.
Rev Sci Instrum ; 95(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38573050

RESUMO

A study of the dead layer thickness and quenching factor of a plastic scintillator for use in ultracold neutron (UCN) experiments is described. Alpha spectroscopy was used to determine the thickness of a thin surface dead layer to be 630 ± 110 nm. The relative light outputs from the decay of 241Am and Compton scattering of electrons were used to extract Birks' law coefficient, yielding a kB value of 0.087 ± 0.003 mm/MeV, consistent with some previous reports for other polystyrene-based scintillators. The results from these measurements are incorporated into the simulation to show that an energy threshold of (∼9 keV) can be achieved for the UCNProBe experiment. This low threshold enables high beta particle detection efficiency and the indirect measurement of UCN. The ability to make the scintillator deuterated, accompanied by its relatively thin dead layer, gives rise to unique applications in a wide range of UCN experiments, where it can be used to trap UCN and detect charged particles in situ.

2.
Health Promot Int ; 39(1)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38243778

RESUMO

The sports clubs' role in promoting health has been acknowledged by policy makers and researchers, but there is little evidence on how sports clubs implement health-related interventions. The present article investigates the Gaelic Athletic Association Healthy Club Project (HCP) implementation process (mechanisms, barriers, leverages) over a 10-year timeframe. A case study design helped to produce and compare a data synthesis for five clubs involved since 2013. A qualitative iterative data collection, including document analysis was conducted through 20 focus groups with Healthy Club Officers, coaches, participants and members. The Consolidated Framework for Implementation Research was used in the deductive analysis process, conducted by the first author. Results have shown the success of the HCP in placing health promotion on the agenda of sports clubs leading to informal policy for health promotion, even if activities and recognition are directed toward and coming from the community. This study also underlines the virtuous cycle of the settings-based approach in enhancing membership and volunteer recognition through health promotion actions, and the importance of social good and corporate social activities for sports clubs. Nevertheless, the HCP still relies on limited human resources, is not recognized by competitive oriented adult playing members. and acknowledged as a resource by some coaches, limiting its rootedness in the core business of sports clubs. Future research should empower the HCP community to focus on organizational changes and develop outcomes for individuals, for the club as a whole as well as for the local community.


Assuntos
Esportes , Adulto , Humanos , Irlanda , Promoção da Saúde/métodos , Pesquisa Qualitativa , Grupos Focais
3.
J Med Genet ; 61(2): 163-170, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-37816627

RESUMO

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.


Assuntos
Síndromes da Dor Regional Complexa , Masculino , Feminino , Humanos , Síndromes da Dor Regional Complexa/genética , Síndromes da Dor Regional Complexa/epidemiologia , Frequência do Gene , Polimorfismo de Nucleotídeo Único/genética , Alelos , Patrimônio Genético
4.
Am J Hum Genet ; 110(8): 1343-1355, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37541188

RESUMO

Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.


Assuntos
Genoma Humano , Transtornos do Neurodesenvolvimento , Humanos , Genoma Humano/genética , Mapeamento Cromossômico , Sequência de Bases , Mutação INDEL , Transtornos do Neurodesenvolvimento/genética
5.
J Sports Sci ; 41(22): 1983-1993, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38305379

RESUMO

Identifying tools and processes to effectively and efficiently evaluate technologies is an area of need for many sport stakeholders. This study aimed to develop a standardised, evidence-based framework to guide the evaluation of sports technologies. In developing the framework, a review of standards, guidelines and research into sports technology was conducted. Following this, 55 experts across the sports industry were presented with a draft framework for feedback. Following a two-round Delphi survey, the final framework consisted of 25 measurable features grouped under five quality pillars. These were 1) Quality Assurance & Measurement (Accuracy, Repeatability, Reproducibility, Specifications), 2) Established Benefit (Construct Validity, Concurrent Validity, Predictive Validity, Functionality), 3) Ethics & Security (Compliance, Privacy, Ownership, Safety, Transparency, Environmental Sustainability), 4) User Experience (Usability, Robustness, Data Representation, Customer Support & Training, Accessibility) & 5) Data Management (Data Standardisation, Interoperability, Maintainability, Scalability). The framework can be used to help design and refine sports technology in order to optimise quality and maintain industry standards, as well as guide purchasing decisions by organisations. It may also serve to create a common language for organisations, manufacturers, investors, and consumers to improve the efficiency of their decision-making relating to sports technology.


Assuntos
Esportes , Humanos , Reprodutibilidade dos Testes , Tecnologia , Previsões
6.
Eur Phys J A Hadron Nucl ; 58(12): 239, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36514540

RESUMO

Neutron capture reaction cross sections on 74 Ge are of importance to determine 74 Ge production during the astrophysical slow neutron capture process. We present new resonance data on 74 Ge( n , γ ) reactions below 70 keV neutron energy. We calculate Maxwellian averaged cross sections, combining our data below 70 keV with evaluated cross sections at higher neutron energies. Our stellar cross sections are in agreement with a previous activation measurement performed at Forschungszentrum Karlsruhe by Marganiec et al., once their data has been re-normalised to account for an update in the reference cross section used in that experiment.

7.
Public Health ; 209: 46-51, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35809350

RESUMO

OBJECTIVES: Healthcare worker (HCW) SARS-CoV-2 contacts in England have been required to quarantine, creating staff shortages. We piloted daily contact testing (DCT) to assess its feasibility as an alternative. STUDY DESIGN: Observational service evaluation. METHODS: We conducted an observational service evaluation of 7-day DCT using antigen lateral flow devices (LFDs) at four acute hospital trusts and one ambulance trust in England. Mixed methods were used, using aggregate and individual-level test monitoring data, semi-structured interviews, and a survey of eligible contacts. RESULTS: In total, 138 HCWs were identified as contacts of a confirmed SARS-CoV-2 case. Of these, 111 (80%) consented to daily LFD testing, of whom 82 (74%) completed the required programme without interruption and 12 (11%) completed with interruption. Fifty-eight participants (52%) and two non-participants (7.4%) completed the survey. In total, 28 interviews were conducted with participants, site and infection control leads, and union representatives. One participant tested positive on LFD and polymerase chain reaction (PCR) test. Three participants tested positive on PCR but not LFD. DCT was well-accepted by trusts and staff. Participants reported no relaxation of their infection prevention and control behaviours. No incidents of transmission were detected. An estimated 729 potential days of work absence were averted. CONCLUSIONS: DCT can be acceptably operated in a healthcare setting, averting quarantine-related work absences in HCW SARS-CoV-2 contacts.


Assuntos
COVID-19 , SARS-CoV-2 , Ambulâncias , COVID-19/diagnóstico , Inglaterra , Hospitais , Humanos
8.
Nat Rev Dis Primers ; 8(1): 41, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710757

RESUMO

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.


Assuntos
Canalopatias , Neuropatias Hereditárias Sensoriais e Autônomas , Insensibilidade Congênita à Dor , Neuropatias Hereditárias Sensoriais e Autônomas/complicações , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Humanos , Dor/genética , Insensibilidade Congênita à Dor/genética
10.
Ir Med J ; 115(3): 560, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35532732

RESUMO

Aim Physical Activity (PA) and Mindfulness-Based Stress Reduction (MBSR) both have positive effects on medical student well-being. The 'MED-WELL' programme is a curricular intervention that combines PA and education on exercise as medicine. This trial evaluates whether there is a mean difference in outcomes of participants of an exercise intervention, the 'MED-WELL' programme, versus a control group which engages in a MBSR programme. Methods All second-year medical students were voluntarily allocated into the intervention or control group. Data on overall health and well-being, sleep quality, loneliness, current level of PA, and confidence in prescribing exercise as medicine was analysed from both groups at baseline and after eight weeks. Results Within groups the intervention and control groups showed statistically significant improvements in overall well-being (p=0.010, p=0.005 respectively) and in sleep quality (p<0.001, p=0.007 respectively). The intervention group had statistically significant improvements in levels of PA (p=0.003) and confidence in prescribing exercise (p<0.001). However, there were no statistically significant differences in changes in outcome measures between groups. Conclusion This study has shown that participants in an exercise intervention, the 'MED-WELL' programme, had similar improvements in overall wellbeing and sleep quality to those in a control group who participated in a MBSR programme of the same duration.


Assuntos
Atenção Plena , Estudantes de Medicina , Exercício Físico , Humanos , Atenção Plena/métodos , Avaliação de Resultados em Cuidados de Saúde
11.
Int J Pediatr Otorhinolaryngol ; 158: 111157, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35504226

RESUMO

INTRODUCTION: Tracheomalacia is a common congenital condition causing stridor in young children. However, the evaluation of these children remains poorly standardised across institutions. METHODS: We conducted a retrospective review of all children undergoing an elective laryngotracheobronchoscopy at a single tertiary paediatric institution between March 2010 and December 2018. Emergency bronchoscopies and children with tracheostomies were excluded. 1163 children undergoing an elective bronchoscopy were included in this study, and 545 children also had an airway fluoroscopy. RESULTS: The median age at bronchoscopy was 17 months, and the majority of children were male. Tracheomalacia was diagnosed in 21.6% of children at bronchoscopy, of these 48.5% had tracheomalacia diagnosed on a previous airway fluoroscopy. Overall, airway fluoroscopy had a low sensitivity (62.3%) and a low specificity (67.5%) for diagnosis of tracheomalacia when compared with bronchoscopy. Increasing severity of tracheomalacia on airway screen significantly predicted a diagnosis of tracheomalacia on bronchoscopy. CONCLUSIONS: Airway fluoroscopy has a low sensitivity and specificity in diagnosis of tracheomalacia and should be used judiciously rather than as a screening tool for children with stridor. However, this imaging technique may be beneficial in investigating children with severe symptoms who have had other conditions such as laryngomalacia excluded.


Assuntos
Traqueomalácia , Broncoscopia/métodos , Criança , Pré-Escolar , Anormalidades Congênitas , Feminino , Fluoroscopia/métodos , Humanos , Lactente , Laringe/anormalidades , Masculino , Sons Respiratórios/etiologia , Estudos Retrospectivos , Traqueomalácia/complicações , Traqueomalácia/diagnóstico por imagem
12.
BMC Health Serv Res ; 22(1): 657, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35578247

RESUMO

BACKGROUND: The Southern Province of Sri Lanka is endemic with dengue, with frequent outbreaks and occurrence of severe disease. However, the economic burden of dengue is poorly quantified. Therefore, we conducted a cost analysis to assess the direct and indirect costs associated with hospitalized patients with dengue to households and to the public healthcare system. METHODS: From June 2017-December 2018, we prospectively enrolled children and adults with acute dengue hospitalized at the largest, public tertiary-care (1800 bed) hospital in the Southern Province, Sri Lanka. We administered a structured questionnaire to obtain information regarding direct costs spent by households on medical visits, medications, laboratory testing, and travel for seeking care for the illness. Indirect costs lost by households were estimated by identifying the days of work lost by patients and caregivers and school days lost by children. Direct hospital costs were estimated using gross costing approach and adjusted by multiplying by annual inflation rates in Sri Lankan rupees and converted to US dollars. RESULTS: A total of 1064 patients with laboratory-confirmed dengue were enrolled. The mean age (SD) was 35.9 years (15.6) with male predominance (66.2%). The mean durations of hospitalization for adults and paediatric patients were 3.86 (SD = 1.51) and 4 (SD = 1.32) days, respectively. The per-capita direct cost borne by the healthcare system was 233.76 USD, and was approximately 14 times greater than the per-capita direct cost borne by households (16.29 USD, SD = 14.02). The per-capita average number of loss of working days was 21.51 (SD = 41.71), with mean per-capita loss of income due to loss of work being 303.99 USD (SD = 569.77), accounting for over 70% of average monthly income. On average, 10.88 days (SD = 10.97) of school days were missed due to the dengue episode. School misses were expected to reduce future annual income of affected children by 0.44%. CONCLUSIONS: Dengue requiring hospitalization had a substantial economic burden on the public healthcare system in Sri Lanka and the affected households. These findings emphasize the importance of strengthening dengue control activities and improved use of hospital-based resources for care to reduce the economic impact of dengue in Sri Lanka.


Assuntos
Dengue , Hospitalização , Adulto , Criança , Dengue/epidemiologia , Dengue/terapia , Características da Família , Feminino , Custos Hospitalares , Humanos , Masculino , Sri Lanka/epidemiologia
13.
Phys Rev Lett ; 127(20): 202501, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34860042

RESUMO

Two long-standing puzzles in the decay of ^{185}Bi, the heaviest known proton-emitting nucleus are revisited. These are the nonobservation of the 9/2^{-} state, which is the ground state of all heavier odd-A Bi isotopes, and the hindered nature of proton and α decays of its presumed 60-µs 1/2^{+} ground state. The ^{185}Bi nucleus has now been studied with the ^{95}Mo(^{93}Nb,3n) reaction in complementary experiments using the Fragment Mass Analyzer and Argonne Gas-Filled Analyzer at Argonne National Laboratory's ATLAS facility. The experiments have established the existence of two states in ^{185}Bi; the short-lived T_{1/2}=2.8_{-1.0}^{+2.3} µs, proton- and α-decaying ground state, and a 58(2)-µs γ-decaying isomer, the half-life of which was previously attributed to the ground state. The reassignment of the ground-state lifetime results in a proton-decay spectroscopic factor close to unity and represents the only known example of a ground-state proton decay to a daughter nucleus (^{184}Pb) with a major shell closure. The data also demonstrate that the ordering of low- and high-spin states in ^{185}Bi is reversed relative to the heavier odd-A Bi isotopes, with the intruder-based 1/2^{+} configuration becoming the ground, similar to the lightest At nuclides.

14.
Phys Rev Lett ; 127(16): 162501, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34723594

RESUMO

We report an improved measurement of the free neutron lifetime τ_{n} using the UCNτ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10^{6} surviving ultracold neutrons (UCNs) after storing in UCNτ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τ_{n} from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τ_{n} measurements and by performing a global likelihood fit to all data while self-consistently incorporating the ß-decay lifetime. Both techniques achieve consistent results and find a value τ_{n}=877.75±0.28_{stat}+0.22/-0.16_{syst} s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

15.
Rev Sci Instrum ; 92(2): 023305, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648127

RESUMO

In this paper, we report studies of the Fermi potential and loss per bounce of ultracold neutrons (UCNs) on a deuterated scintillator (Eljen-299-02D). These UCN properties of the scintillator enable its use in a wide variety of applications in fundamental neutron research.

16.
Nat Commun ; 12(1): 347, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436620

RESUMO

When two-dimensional crystals are brought into close proximity, their interaction results in reconstruction of electronic spectrum and crystal structure. Such reconstruction strongly depends on the twist angle between the crystals, which has received growing attention due to interesting electronic and optical properties that arise in graphene and transitional metal dichalcogenides. Here we study two insulating crystals of hexagonal boron nitride stacked at small twist angle. Using electrostatic force microscopy, we observe ferroelectric-like domains arranged in triangular superlattices with a large surface potential. The observation is attributed to interfacial elastic deformations that result in out-of-plane dipoles formed by pairs of boron and nitrogen atoms belonging to opposite interfacial surfaces. This creates a bilayer-thick ferroelectric with oppositely polarized (BN and NB) dipoles in neighbouring domains, in agreement with our modeling. These findings open up possibilities for designing van der Waals heterostructures and offer an alternative probe to study moiré-superlattice electrostatic potentials.

17.
J Sci Med Sport ; 24(2): 206-210, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32951975

RESUMO

OBJECTIVES: This study aimed to identify styles of play in the National Rugby League (NRL) relative to season and end of season rank (position on the NRL ladder) across the 2015-2019 seasons. DESIGN: Retrospective, longitudinal analysis of performance indicators. METHODS: Forty-eight performance indicators (e.g. runs, tackles) from all NRL teams and matches during the 2015-2019 seasons (n=2010) were quantified. Principal component analysis (PCA) was then used to identify styles of play based on dimensions (Factors) of performance indicators. Multivariate analysis of covariance (MANCOVA) was then used to explain these emergent styles of play relative to 'season' and 'end of season rank'. RESULTS: The PCA revealed nine Factors (six attacking, two defensive and one contested style) accounting for ∼51% of seasonal team performance variance. These nine Factors differed across 'seasons', with four showing an effect against 'end of season rank'. From these four, two Factors (ball possession and player efforts) impacted upon the combined effects of 'season' and 'end of season rank'. CONCLUSIONS: The PCA identified nine Factors reflecting a spread of attacking, defensive and contested styles of play within the NRL. These styles differed relative to season and a team's end of season ranking. These results may assist practitioners with the recognition of more contemporary styles of play in the NRL, enabling the development of strategies to exploit competition trends.


Assuntos
Desempenho Atlético/fisiologia , Comportamento Competitivo/fisiologia , Futebol Americano/fisiologia , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , Condicionamento Físico Humano , Análise de Componente Principal , Estudos Retrospectivos , Estações do Ano
18.
Diabet Med ; 38(6): e14412, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32997841

RESUMO

AIMS: To establish the impact of uncomplicated type 2 diabetes on cognitive and neuropsychological performance in midlife. METHODS: We performed a cross-sectional study of middle-aged adults with uncomplicated type 2 diabetes and a cohort of healthy control participants. General cognition was assessed using the Montreal Cognitive Assessment test and neuropsychological assessment was undertaken using a detailed neuropsychological assessment battery. RESULTS: A total of 152 participants (102 with type 2 diabetes and 50 controls) were recruited (mean age 52 ± 8 years, 51% women). Participants with midlife type 2 diabetes were more than twice as likely to make an error on the Montreal Cognitive Assessment test [incidence rate ratio 2.44 (95% CI 1.54 to 3.87); P < 0.001]. Further, type 2 diabetes was also associated with significantly lower memory composite score [ß: -0.20 (95% CI -0.39 to -0.01); P = 0.04] and paired associates learning score [ß: = -1.97 (95% CI -3.51, -0.43); P = 0.01] on the neuropsychological assessment battery following adjustment for age, sex, BMI, educational attainment and hypercholesterolaemia. CONCLUSIONS: Even in midlife, type 2 diabetes was associated with small but statistically significant cognitive decrements. These statistically significant decrements, whilst not clinically significant in terms of objective cognitive impairment, may have important implications in selecting out individuals most at risk of later cognitive decline for potential preventative interventions in midlife.


Assuntos
Cognição/fisiologia , Disfunção Cognitiva/etiologia , Diabetes Mellitus Tipo 2/complicações , Memória/fisiologia , Adulto , Idoso , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/psicologia , Escolaridade , Feminino , Seguimentos , Humanos , Incidência , Irlanda/epidemiologia , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco
20.
J Transl Med ; 18(1): 280, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650803

RESUMO

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is often diagnosed at an advanced stage because the disease often causes minimal symptoms other than metastasis to neck lymph nodes. Better tools are required to assist with the early detection of OPSCC. MicroRNAs (miRNAs, miRs) are potential biomarkers for early head and neck squamous cell cancer diagnosis, prognosis, recurrence, and presence of metastatic disease. However, there is no widespread agreement on a panel of miRNAs with clinically meaningful utility for head and neck squamous cell cancers. This could be due to variations in the collection, storage, pre-processing, and isolation of RNA, but several reports have indicated that the selection and reproducibility of biomarkers has been widely affected by the methods used for data analysis. The primary analysis issues appear to be model overfitting and the incorrect application of statistical techniques. The purpose of this study was to develop a robust statistical approach to identify a miRNA signature that can distinguish controls and patients with inflammatory disease from patients with human papilloma virus positive (HPV +) OPSCC. METHODS: Small extracellular vesicles were harvested from the serum of 20 control patients, 20 patients with gastroesophageal reflux disease (GORD), and 40 patients with locally advanced HPV + OPSCC. MicroRNAs were purified, and expression profiled on OpenArray™. A novel cross validation method, using lasso regression, was developed to stabilise selection of miRNAs for inclusion in a prediction model. The method, named StaVarSel (for Stable Variable Selection), was used to derive a diagnostic biomarker signature. RESULTS: A standard cross validation approach was unable to produce a biomarker signature with good cross validated predictive capacity. In contrast, StaVarSel produced a regression model containing 11 miRNA ratios with potential clinical utility. Sample permutations indicated that the estimated cross validated prediction accuracy of the 11-miR-ratio model was not due to chance alone. CONCLUSIONS: We developed a novel method, StaVarSel, that was able to identify a panel of miRNAs, present in small extracellular vesicles derived from blood serum, that robustly cross validated as a biomarker for the detection of HPV + OPSCC. This approach could be used to derive diagnostic biomarkers of other head and neck cancers.


Assuntos
Carcinoma de Células Escamosas , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Humanos , MicroRNAs/genética , Recidiva Local de Neoplasia , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/genética , Papillomaviridae , Reprodutibilidade dos Testes , Soro , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
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